Ganglioneuroma - dismech

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Classifications

Harrison's Part

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Mappings

MONDO

MONDO:0005033 ganglioneuroma

Primary MONDO identifier for this entry. MONDO defines ganglioneuroma as a benign neuroblastic tumor of the sympathetic nervous system, records NCIT:C3049 and Orphanet 251992 as exact matches, and carries the ICD-O cross-reference 9490/0.

NCIT

NCIT:C3049 Ganglioneuroma

NCIT concept that MONDO records as an exact match of MONDO:0005033. NCIT files ganglioneuromatosis (NCIT:C66804) and skin, choroidal and colorectal ganglioneuroma beneath it, which this entry does not cover; Maturing Ganglioneuroma (NCIT:C42064) and Mature Ganglioneuroma (NCIT:C42065) are this entry's subtypes.

NCIT

NCIT:C3049 Ganglioneuroma

NCIT concept that MONDO records as an exact match of MONDO:0005033. NCIT files ganglioneuromatosis (NCIT:C66804) and skin, choroidal and colorectal ganglioneuroma beneath it, which this entry does not cover; Maturing Ganglioneuroma (NCIT:C42064) and Mature Ganglioneuroma (NCIT:C42065) are this entry's subtypes.

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Subtypes

2

Ganglioneuroma, maturing (Schwannian stroma-dominant) NCIT:C42064

VERY_FREQUENT

In the INPC, maturing ganglioneuroma (Schwannian stroma-dominant) is composed predominantly of ganglioneuromatous stroma with a minor component of individually scattered differentiating neuroblasts and/or maturing ganglion cells, in addition to fully mature ganglion cells; the fully mature ganglion cells are always covered with satellite cells. The INPC assigns tumors in this category to its favorable histology group. The subtype corresponds to the tumor group that the earlier Shimada classification called ganglioneuroblastoma, well differentiated. In German trials of localized tumors in patients aged 21 years or younger, 144 of 162 ganglioneuromas (88.9%) were maturing, with a median age at diagnosis of 71 months; the very-frequent band describes that cohort. In CCG/COG studies, all 36 patients with maturing ganglioneuroma and a known stage had INSS stage 1-3 disease.

Show evidence (7 references)

PMID:19530234 SUPPORT DIRECT BACKGROUND Other

"Ganglioneuroma-Maturing (Schwannian stroma-dominant): Composed predominantly of ganglioneuromatous stroma with a minor component of individually scattered, evenly or unevenly distributed differentiating neuroblasts and/or maturing ganglion cells, in addition to fully mature ganglion cells. Fully..."

Table I of this CCG/COG clinicopathological series of 552 ganglioneuroma and ganglioneuroblastoma cases restates the International Neuroblastoma Pathology Classification definition of the ganglioneuroma-maturing subtype (Schwannian stroma-dominant). The tumor is mostly ganglioneuromatous stroma, with a minor component of individually scattered differentiating neuroblasts and/or maturing ganglion cells beside fully mature ganglion cells. The fully mature ganglion cells are always covered with satellite cells, and tumors in this category are classified as favorable histology. It is a classification rule restated from the INPC papers, not a result of this cohort.

PMID:19530234 SUPPORT DIRECT BACKGROUND Other

"According to the INPC, tumors in the GN category are further classified into GN-Maturing subtype (the same tumor group described as “Ganglioneuroblastoma, well differentiated” in the Shimada classification system3) and GN-Mature subtype (completely mature form of neuroblastic tumor)."

In the introduction of a Children's Cancer Group and Children's Oncology Group (CCG/COG) clinicopathological series, Okamatsu et al. restate the INPC subdivision of the ganglioneuroma category: GN-Maturing, which they equate with the tumor group that the earlier Shimada classification (the system the INPC adapted) called ganglioneuroblastoma, well differentiated, and GN-Mature, the completely mature form of neuroblastic tumor. This is the split the Maturing and Mature subtypes encode. The sentence restates a published classification; it is not a result from the paper's own cohort.

PMID:10421272 SUPPORT DIRECT PRIMARY RESULT Human clinical

"Based on morphologic criteria defined in this article, NTs were classified into four categories and their subtypes: 1) neuroblastoma (Schwannian stroma-poor), undifferentiated, poorly differentiated, and differentiating; 2) ganglioneuroblastoma, intermixed (Schwannian stroma-rich); 3)..."

The 1999 terminology paper of the International Neuroblastoma Pathology Committee, whose six member pathologists defined the morphologic criteria from a review of 227 cases, classifies neuroblastic tumors into four categories. Ganglioneuroma is the third, the Schwannian stroma-dominant category, with maturing and mature subtypes. The abstract prints the composite label of nodular ganglioneuroblastoma as 'stroma-richlstroma-dominant', and the quote keeps that spelling. The abstract does not assign ganglioneuroma to a prognostic group; the classification itself is reported in the companion article (PMID:10421273).

+ 4 more references

Ganglioneuroma, mature (Schwannian stroma-dominant) NCIT:C42065

OCCASIONAL

The completely mature form of neuroblastic tumor: ganglioneuroma whose ganglion cells are all completely mature, in Schwannian stroma. Completely mature ganglion cells are covered with satellite cells, in either subtype. In German trials of localized tumors in patients aged 21 years or younger, 18 of 162 ganglioneuromas (11.1%) were mature, with a median age at diagnosis of 125 months; the occasional band describes that cohort, which left out older patients. Mature ganglioneuroma was not eligible for the CCG/COG studies and was excluded from the CCG/COG series of ganglioneuroma and ganglioneuroblastoma, whose ganglioneuroma data therefore cover the maturing subtype only.

Show evidence (7 references)

PMID:41612478 SUPPORT DIRECT REVIEW SYNTHESIS Other

"They are either completely mature (mature GN) or a mixture of mature and maturing ganglion cells (maturing GN). Completely mature ganglion cells are covered with satellite cells."

In the 2026 review's paragraph on the ganglioneuroma category these sentences separate the two INPC subtypes: in mature GN the ganglion cells are completely mature, while maturing GN mixes mature and maturing ganglion cells. The review adds that completely mature ganglion cells are covered with satellite cells, which holds for such cells in either subtype. This restates the INPC subtype criteria rather than reporting case data.

PMID:19530234 SUPPORT DIRECT BACKGROUND Other

"According to the INPC, tumors in the GN category are further classified into GN-Maturing subtype (the same tumor group described as “Ganglioneuroblastoma, well differentiated” in the Shimada classification system3) and GN-Mature subtype (completely mature form of neuroblastic tumor)."

In the introduction of a Children's Cancer Group and Children's Oncology Group (CCG/COG) clinicopathological series, Okamatsu et al. restate the INPC subdivision of the ganglioneuroma category into GN-Maturing and GN-Mature, the completely mature form of neuroblastic tumor. The sentence restates a published classification; it is not a result from the paper's own cohort.

PMID:19530234 SUPPORT DIRECT Human clinical

"Cases with the diagnosis of GN-Mature subtype were excluded from the analysis, since they were not eligible for the CCG/COG studies."

Okamatsu et al. state that cases diagnosed as the mature subtype of ganglioneuroma (GN-Mature) were not eligible for the Children's Cancer Group and Children's Oncology Group (CCG/COG) studies and were excluded from their analysis. This CCG/COG series therefore holds no mature ganglioneuroma, and its ganglioneuroma cases are the maturing subtype only. The sentence states ineligibility; it gives no reason for it and does not say that no case with this diagnosis was ever registered on a CCG/COG study.

+ 4 more references

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Discussions and Knowledge Gaps

1

Does every ganglioneuroma arise by maturation of a neuroblastoma or ganglioneuroblastoma, or can some arise without passing through a neuroblastoma or ganglioneuroblastoma stage?

CONTROVERSY OPEN gn_origin

Attached to

pathophysiology#Neuroblast-to-Ganglion Cell Maturation pathophysiology#AKT-mTOR-S6 Pathway Activation

Evidence items use this convention: SUPPORT means ganglioneuroma arises by maturation of a neuroblastic tumor; REFUTE means at least some ganglioneuromas arise without passing through a neuroblastoma or ganglioneuroblastoma stage, against the proposal that all do. Both readings start from sympathetic neuroblasts, which the authors of the zebrafish study name as the common origin of ganglioneuroma and neuroblastoma; the question is whether a neuroblastic tumor comes first. The authors of the German NB97/NB2004 series note that a good part of ganglioneuroma has been hypothesized to originate from neuroblastoma, but that whether this holds for all ganglioneuromas, as Shimada proposed, remains unproven, and they read the rise of median age with the grade of differentiation as indirect support. A 2026 pathology review recounts that Cushing and Wolbach, comparing one patient's specimen at diagnosis with one resected 10 years later, reported that a malignant neuroblastoma could differentiate into a benign ganglioneuroma. In a 2022 case report, ganglioneuroblastoma and ganglioneuroma at different sites of one patient shared the same molecular signatures, which the authors read as probable spontaneous differentiation from neuroblastoma to ganglioneuroma. In zebrafish, constitutively activated Akt2 in the sympathetic nervous system produced low-grade ganglioneuroma, and the fish did not develop neuroblastoma; this is a model of ganglioneuroma forming without a neuroblastoma stage, and its tumors had poor Schwannian stroma. The authors regard the model as faithful to human ganglioneuroma, which also shows AKT activation, but whether human ganglioneuromas form without a neuroblastoma stage has not been shown. The answer decides whether ganglioneuroma biology can be read as the end state of favorable neuroblastoma.

Posed 2026-10-28T00:00:00Z

Show evidence (6 references)

PMID:27465021 SUPPORT INDIRECT BACKGROUND Human clinical

"It has been hypothesized that a good part of GN originates from neuroblastoma. ... However, whether this is true for all GN, as proposed by Shimada ... still remains unproven."

In the discussion of this retrospective study of localized neuroblastic tumors registered in the German neuroblastoma trials, the authors restate the hypothesis, which they trace to Cushing and to later reports in stage 4S and localized neuroblastoma, that a good part of ganglioneuroma arises from neuroblastoma, and add that whether this is true for all ganglioneuromas, as Shimada proposed, remains unproven. The quoted sentences summarize earlier reports rather than the study's own data. The first sentence reports a hypothesis rather than asserting it, so it supports maturation from a neuroblastic tumor only at one remove, through the earlier reports the authors summarize (Cushing; stage 4S and localized neuroblastoma); the second records that the claim for all ganglioneuromas is unproven.

PMID:27465021 SUPPORT INDIRECT PRIMARY RESULT Human clinical

"An indirect support for this hypothesis can be seen by our observation that patients with GN and GNBI are older at diagnosis than those with immature NT. As Fig. 1 shows, the grade of neuroblastic differentiation increases with the median age at diagnosis. This is in line with the theory that..."

The same authors take their own age gradient as indirect support for maturation: patients with ganglioneuroma or intermixed ganglioneuroblastoma, taken together, were older at diagnosis than those with immature tumors, which fits mature tumors having had time to mature in situ. The gradient compares different patients at diagnosis, and the paper reports no tumor seen to mature during follow-up; the authors add in the next paragraph that ultrasound check-ups of infants and young toddlers could find small immature neuroblastomas early, which bears on the same age difference without involving maturation.

PMID:41612478 SUPPORT DIRECT REVIEW SYNTHESIS Human clinical

"By comparing the same patient's specimen at diagnosis and a resected specimen 10 years later, Cushing and Wolbach reported that malignant NB could differentiate into benign GN [9]."

In its history of neuroblastic-tumor pathology, this 2026 review recounts that Cushing and Wolbach compared one patient's tumor at diagnosis with the specimen resected 10 years later and reported that a malignant neuroblastoma could differentiate into a benign ganglioneuroma. It is the review's account of a single human case it did not study, hence HUMAN_CLINICAL with REVIEW_SYNTHESIS; this review's classification-rule sentences, which report no patient data, are graded OTHER elsewhere in the KB. On the review's account a neuroblastoma matured into a ganglioneuroma in at least one patient. The sentence does not say whether this was spontaneous or followed treatment, and it says nothing about where ganglioneuromas come from in general.

+ 3 more references

⚙

Pathophysiology

5

Neuroblast-to-Ganglion Cell Maturation

Differentiation of neuroblastic cells into ganglion cells. Biologically favorable peripheral neuroblastic tumors are considered to mature by age-dependent steps from neuroblastoma through intermixed ganglioneuroblastoma to ganglioneuroma. In German trials of localized tumors, median age at diagnosis rose with the grade of differentiation, which the authors read as indirect support for tumors maturing in situ. Whether every ganglioneuroma arises this way is unproven (discussion gn_origin).

differentiating neuroblast CL:0002676 ganglion cell CL:0011103

maturation of neuroblasts into ganglion cells GO:0030182

Animal models

Zebrafish dbh:myr-Akt2 transgenic ganglioneuroma model Zebrafish partially recapitulates The fish tumours are made of differentiated, mature ganglion cells that carry neural markers and derive from sympathetic neuroblasts rather than chromaffin cells, and the authors find that they resemble human ganglioneuroma histologically and by gene expression. The model shows this mature end state, not the maturation itself.

Show evidence (2 references)

PMID:41612478 SUPPORT DIRECT REVIEW SYNTHESIS Other

"To note, tumors in the biologically favorable pNTs are considered to proceed by age-dependent differentiation/maturational steps from NB to GNB-i, and finally to GN."

This 2026 pathology review states that biologically favorable peripheral neuroblastic tumors are considered to proceed by age-dependent differentiation and maturation steps from neuroblastoma to GNB-intermixed and finally to ganglioneuroma, the maturation this node describes. The sentence sits in the review's account of the INPC categories and gives a consensus view ('are considered to') without supporting data, and it does not say that every ganglioneuroma arises this way.

PMID:27465021 SUPPORT INDIRECT PRIMARY RESULT Human clinical

"An indirect support for this hypothesis can be seen by our observation that patients with GN and GNBI are older at diagnosis than those with immature NT. As Fig. 1 shows, the grade of neuroblastic differentiation increases with the median age at diagnosis. This is in line with the theory that..."

In the Discussion of their German NB97/NB2004 series of localized neuroblastic tumors, the authors take their own age gradient as indirect support for the hypothesis that a good part of ganglioneuroma originates from neuroblastoma: patients with ganglioneuroma or intermixed ganglioneuroblastoma, taken together, were older at diagnosis than those with immature tumors, and the grade of differentiation rose with median age, which fits mature tumors having had time to mature in situ before they were found. The support is indirect: the gradient compares different patients at diagnosis, and although residual tumors were followed over time, the paper reports no tumor seen to mature during follow-up. It bears on whether ganglioneuroma arises from an earlier neuroblastic tumor more than on how neuroblasts differentiate into ganglion cells. In the next paragraph the authors add that widespread ultrasound check-ups of infants and young toddlers in Germany could find more small, asymptomatic localized immature neuroblastomas in infancy, a point that bears on the same age difference without involving maturation.

Schwannian Stromal Development

The Schwann-cell stroma that dominates ganglioneuroma tissue; the INPC names ganglioneuroma for this feature (Schwannian stroma-dominant). Stromal Schwann cells in ganglioneuroma share the expression of nerve repair-associated genes with the repair Schwann cells of human nerve injured ex vivo, and repair-type Schwann cells and their secretome induce neuronal differentiation of neuroblastoma cells in culture. It has been suggested that a minor increase in the volume of mature tumors may also be caused by proliferation of the Schwannian stroma rather than of tumor cells. Whether the stromal cells derive from the neoplastic clone is discussed in the Ganglioneuroblastoma entry.

Schwannian stromal cell CL:0002573

Schwann cell proliferation GO:0014010

Animal models

Zebrafish dbh:myr-Akt2 transgenic ganglioneuroma model Zebrafish fails to recapitulate The fish ganglioneuromas have poor Schwannian stroma, whereas human ganglioneuroma is defined as the Schwannian stroma-dominant neuroblastic tumour.

Downstream

Neuroblast-to-Ganglion Cell Maturation Repair-type Schwann cells and their secreted products induce neuronal differentiation of neuroblastoma cells in culture; the evidence is in vitro.

Retroperitoneal Mass The tumor, composed largely of Schwannian stroma, forms a mass at its primary site; the retroperitoneum was the commonest site in a single-institution series.

Posterior Mediastinal Mass The tumor, composed largely of Schwannian stroma, forms a mass at its primary site; most thoracic ganglioneuromas lie in the posterior mediastinum.

Pelvic Mass The tumor, composed largely of Schwannian stroma, forms a mass at its primary site, which in some series is the presacral space.

Pain Symptoms come from the effects of the tumor mass; how the tumor produces pain is not described.

Show evidence (3 references)

PMID:10421272 SUPPORT INDIRECT PRIMARY RESULT Human clinical

"Based on morphologic criteria defined in this article, NTs were classified into four categories and their subtypes: 1) neuroblastoma (Schwannian stroma-poor), undifferentiated, poorly differentiated, and differentiating; 2) ganglioneuroblastoma, intermixed (Schwannian stroma-rich); 3)..."

The 1999 terminology paper of the International Neuroblastoma Pathology Committee names ganglioneuroma the Schwannian stroma-dominant category of neuroblastic tumors, so the tumor is defined by its dominant Schwannian stroma. This is a classification label: it says nothing about how the stroma develops or where its cells come from, so its support for this node is indirect. The quote keeps the abstract's spelling 'stroma-richlstroma-dominant'.

PMID:33712610 SUPPORT DIRECT PRIMARY RESULT Human clinical

"Indeed, stromal SCs in ganglioneuromas and repair SCs share the expression of nerve repair-associated genes."

The authors ran RNA-seq on fresh-frozen, Schwann cell stroma-rich areas of six diagnostic human ganglioneuroma specimens, collected at surgery or biopsy, in which S100B staining showed Schwann cells to be the prevalent cell population. They compared them with neuroblastoma tissue, which almost entirely lacks Schwann cells, and with human peripheral nerve fascicles, collected at reconstructive surgery, amputation or organ donation and left to degenerate ex vivo, a model in which Schwann cells take on the repair phenotype. After genes also expressed in neuroblastoma were excluded, the signature shared by ganglioneuroma and injured nerve contained nerve repair-associated genes, and the authors read this as stromal Schwann cells in ganglioneuroma taking on a repair-like state. This supports Schwann cells as the cell type of this node; it says nothing about Schwann cell proliferation. The profiles are of bulk tissue, so assigning the shared signature to the Schwann cells rests on sampling Schwann cell-rich areas and on subtracting the genes expressed in neuroblastoma. The grade reflects the ganglioneuroma side, which is patient tumor tissue; the injured-nerve comparator was a cultured nerve explant.

PMID:27465021 SUPPORT INDIRECT BACKGROUND Human clinical

"An interesting question is why mature tumors can show progression at all. Nishihira et al suggested that a minor increase of tumor volume may also be caused by proliferation of Schwannian stroma rather than that of tumor cells [34]."

In the discussion of this retrospective study of localized ganglioneuroma and intermixed ganglioneuroblastoma in patients aged 21 years or younger at diagnosis, registered in the German NB97 and NB2004 neuroblastoma trials, the authors ask why mature tumors can progress at all. They restate a suggestion by Nishihira and colleagues that a minor increase in tumor volume may also be caused by proliferation of the Schwannian stroma rather than of tumor cells, and add that this could explain volume changes too small to count as progression under the International Neuroblastoma Response Criteria. This is the evidence from patients for Schwann cell proliferation (GO:0014010) in this node, and it is weak: it is a hedged suggestion restated from another group, not a result of this study, and the sentence does not say what the original observation was. No measurement of Schwann cell division in ganglioneuroma is cited, so an increase in Schwann cells by recruitment into the tumor is not ruled out.

Tumoral Vasoactive Intestinal Peptide Secretion

Secretion of vasoactive intestinal peptide (VIP) by the tumor, described in case reports of young children with ganglioneuroma and diarrhea. In one child with a retroperitoneal tumor, the tumor contained large amounts of VIP, plasma VIP was raised before surgery and the VIP concentration was normal after it; in a child with a thoracic tumor, the authors attributed the diarrhea to an excess of VIP secreted by the tumor; and in a 3-year-old girl with a thoracic paraspinal tumor, serum VIP was 314 pmol/l before surgery (normal less than 30) and 14 pmol/l 6 months after it.

vasoactive intestinal peptide (VIP) secretion by the tumor GO:0030072 ↑ INCREASED

Downstream

Watery Diarrhea In the case reports the authors attributed the watery diarrhea to VIP secreted by the tumor, and in two children it stopped once the VIP excess was removed with the tumor.

Hypokalemia Hypokalemia was attributed to a VIP-secreting ganglioneuroma in a case report; the route from VIP to low potassium is not described.

Show evidence (3 references)

PMID:7376870 SUPPORT DIRECT PRIMARY RESULT Human clinical

"The tumour contained large amounts of vasoactive intestinal polypeptide (VIP) and preoperative plasma concentration of this peptide was increased. Postoperatively the VIP concentration was normalized, and the diarrhea ceased. Analysis of catecholamine metabolites in urine was normal. The..."

Single case report of a 2 1/2-year-old girl with persistent watery diarrhea and a retroperitoneal ganglioneuroma. The tumor contained large amounts of VIP and plasma VIP was raised before surgery. After the operation the VIP concentration returned to normal and the diarrhea stopped, while urinary catecholamine metabolites were normal; the authors suggest the watery diarrhea was due to the VIP-producing tumor. This supports the tumor as the source of a circulating VIP excess. It is one case, the abstract does not say how much of the tumor was removed, and the tumor and an involved lymph node were made of benign ganglioneuroma cells, which the authors judged compatible with an originally metastasizing neuroblastoma that had matured late.

PMID:1211964 SUPPORT DIRECT PRIMARY RESULT Human clinical

"The findings suggest that the diarrhoea in the syndrome of ganglioneuroma and bowel dysfunction is due to an excess of VIP secreted by the tumour."

Case report of a young girl presenting with diarrhea and stridor who had a thoracic ganglioneuroma, partially resected, whose tissue held an abnormally high VIP content by radioimmunoassay. From this case the authors suggest that the diarrhea of the syndrome of ganglioneuroma and bowel dysfunction is due to an excess of VIP secreted by the tumor, which supports tumoral VIP secretion. It is a single case, generalized by the authors to the syndrome. The abstract reports no plasma VIP and records abnormal urinary catecholamines and catechol metabolites in the same child.

PMID:2833214 SUPPORT DIRECT PRIMARY RESULT Human clinical

"The pre-operative serum VIP was 314 pmol/l (normal less than 30). Her diarrhoea stopped after the removal of the tumour. The VIP was 14 pmol/l 6 months post-operatively."

The authors' own case of a 3-year-old girl with a VIP-secreting thoracic paraspinal ganglioneuroma: serum VIP was 314 pmol/l before surgery, where normal is less than 30 pmol/l, her diarrhea stopped after the tumor was removed, and VIP was 14 pmol/l 6 months after the operation. The fall to a normal value after resection points to the tumor as the source of the excess VIP. It is a single case, and the abstract does not say whether the tumor tissue was assayed for VIP.

Tumoral Catecholamine Secretion

Secretion of catecholamines by the tumor, which some ganglioneuromas show. In a series of primary ganglioneuromas, plasma and/or urinary catecholamines were increased in 39%, and the authors concluded that ganglioneuroma may present with increased catecholamine secretion; in an adrenal ganglioneuroma, raised urinary catecholamines normalized after resection, which the authors took as confirming the tumor as their source. Secretion is not universal: the authors of an adrenal series concluded that isolated adrenal ganglioneuromas do not produce catecholamines. In a chart review, raised urinary vanillylmandelic and homovanillic acid appeared to become more common with larger ganglioneuromas, and the authors advised a search for occult neuroblastoma when the values are extremely high.

catecholamine secretion by the tumor GO:0050432 ↑ INCREASED

Downstream

Elevated Urinary Homovanillic Acid Homovanillic acid is a catecholamine metabolite excreted in urine. In a chart review of ganglioneuromas, raised values appeared to become more common with larger tumors, which points to the tumor as their source, though the authors report this only as a trend; they advise a search for occult neuroblastoma, which can be the source instead, when values are extremely high.

Elevated Urinary Vanillylmandelic Acid Vanillylmandelic acid is a catecholamine metabolite excreted in urine. In a chart review of ganglioneuromas, raised values appeared to become more common with larger tumors, which points to the tumor as their source, though the authors report this only as a trend; they advise a search for occult neuroblastoma, which can be the source instead, when values are extremely high.

Show evidence (3 references)

PMID:11346873 SUPPORT DIRECT PRIMARY RESULT Human clinical

"Levels of catecholamines in plasma and/or urine were increased in 39%. ... Ganglioneuroma may present with metabolic activity such as increased secretion of catecholamines and/or mIBG uptake."

Retrospective series of primary ganglioneuromas, meaning tumors that were ganglioneuroma at diagnosis rather than ones evolving from a differentiating neuroblastoma, in patients registered with but not enrolled in national neuroblastoma trials. Plasma and/or urinary catecholamines were increased in 39%, and the authors conclude that ganglioneuroma may present with metabolic activity such as increased catecholamine secretion, which is the claim of this node. The abstract does not say how many patients were tested, which catecholamines were raised or in which fluid, and it reports no values after resection, so the tumor is the source by the authors' reading rather than by a demonstration such as normalization after surgery.

PMID:35800596 SUPPORT DIRECT PRIMARY RESULT Human clinical

"Following resection, catecholamine levels normalized, confirming the resected right adrenal ganglioneuroma as the source of the catecholamine excess."

Case report of an elderly man with an incidental adrenal ganglioneuroma of maturing type and mildly raised urinary catecholamines. The levels normalized after open adrenalectomy, which the authors take as confirming the tumor as the source of the excess. It is a single case, and an adrenal tumor that secretes catecholamines may carry an unsampled pheochromocytoma component, so the case does not show which cells secreted them.

PMID:24033606 REFUTE DIRECT PRIMARY RESULT Human clinical

"Isolated AGNs do not produce catecholamines and have CT imaging characteristics that can help in distinguishing them from other adrenal and para-adrenal neoplasms."

Conclusion of a retrospective series of adrenal ganglioneuromas (AGNs) at a tertiary referral cancer center, in which catecholamine levels were normal in every patient with results. The authors conclude that isolated adrenal ganglioneuromas do not produce catecholamines, which contradicts this node for tumors at that site. 'Isolated' most likely means without a pheochromocytoma component, the adrenal case above shows that the conclusion is not absolute, and the second half of the sentence, on CT features, is not used here.

AKT-mTOR-S6 Pathway Activation

Activation of the kinase AKT and of its downstream effectors mTOR and ribosomal protein S6 in ganglioneuroma tissue. In archival tumors from one hospital, immunohistochemistry detected phosphorylated AKT (Ser473) in 10 of 11 ganglioneuromas, a panel that included two ganglioneuroblastomas, against 1 of 15 poorly differentiated neuroblastomas, and phosphorylated mTOR and S6 in 9 and 10 of the 11, against 5 and 7 of the 15. In zebrafish, constitutively activated myr-Akt2 expressed in the sympathetic nervous system produced ganglioneuroma without progression to neuroblastoma, inducing sympathoadrenal lineage hyperplasia through increased cell proliferation, with activation of mTOR. The authors note that AKT activation in a tumor may be a consequence rather than a cause of its growth, and that the upstream signals activating AKT in human ganglioneuroma are not yet identified.

AKT signaling, read as phosphorylated AKT (Ser473) GO:0043491 ↑ INCREASED mTOR signaling, read as phosphorylated mTOR (Ser2448) and S6 (Ser235/236) GO:0031929 ↑ INCREASED

Animal models

Zebrafish dbh:myr-Akt2 transgenic ganglioneuroma model Zebrafish perturbs The transgene switches AKT signalling on in sympathoadrenal cells, and the resulting tumours carry the downstream state seen in human ganglioneuromas: high phosphorylated mTOR, S6 ribosomal protein and EIF4EBP1. Phosphorylated mTOR and S6 were undetectable in the MYCN-driven fish neuroblastomas.

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PMID:32728700 SUPPORT DIRECT PRIMARY RESULT Human clinical

"Here, we found that phosphorylated, activated AKT and the downstream effectors mTOR and ribosomal protein S6 were more frequently detected in human primary ganglioneuromas than in poorly differentiated human neuroblastomas."

The authors summarize their immunohistochemistry of archival human tumors from Boston Children's Hospital: phosphorylated, activated AKT and its downstream effectors mTOR and ribosomal protein S6 were detected more often in primary ganglioneuromas than in poorly differentiated neuroblastomas. This is the human evidence for the node. The comparison group is poorly differentiated neuroblastoma only, and the samples were those available with sufficient quality for immunohistochemistry.

PMID:32728700 SUPPORT DIRECT PRIMARY RESULT Human clinical

"To understand the contribution of AKT to human primary neuroblastic tumors, we performed immunohistochemistry (IHC) for phosphorylated AKT on a panel of human primary ganglioneuromas (including two ganglioneuroblastoma samples) and compared these results with those from human primary..."

Phosphorylated AKT (Ser473) was moderate to high in 10 of 11 tumors of the ganglioneuroma panel, against detectable staining in 1 of 15 poorly differentiated neuroblastomas (P < 0.0001); the ellipses skip the bracketed confidence intervals. The authors state that the panel included two ganglioneuroblastoma samples, so the 11 are not all ganglioneuromas. Total AKT was present in every tumor of the panel, so the difference lies in its phosphorylation. A section counted as positive when more than 25% of viable tumor cells stained.

PMID:32728700 SUPPORT DIRECT PRIMARY RESULT Human clinical

"We found that phosphorylated mTOR (Ser2448) was expressed in 9 of 11 ganglioneuromas (81.82%; 95% CI ... but only in 5 of 15 poorly differentiated neuroblastomas (33.33%; 95% CI ... P = 0.0214; Fig. 1 B and Fig. S1 A). Similarly, phosphorylated S6 ribosomal protein (Ser235/236) was expressed in..."

In the same panel, phosphorylated mTOR (Ser2448) was found in 9 of 11 ganglioneuromas against 5 of 15 poorly differentiated neuroblastomas (P = 0.0214), and phosphorylated S6 ribosomal protein (Ser235/236) in 10 of 11 against 7 of 15 (P = 0.0362); the ellipses skip the bracketed confidence intervals. This supports activation downstream of AKT, though both markers were also found in some neuroblastomas (5 and 7 of 15), and the 11 tumors include two ganglioneuroblastomas.

+ 1 more reference

✶

Histopathology

3

Ganglion Cells in a Schwannian Stroma-Dominant Background

Ganglion cells distributed singly or in small clusters in Schwannian stroma; in mature ganglioneuroma they are all completely mature, and in maturing ganglioneuroma mature and maturing ganglion cells are mixed. Completely mature ganglion cells are covered with satellite cells. Neurites produced by the ganglion cells are incorporated into the cytoplasm of Schwannian stromal cells, so naked neurites are not identified around the ganglion cells. Grossly the tumors are elastic, yellowish white, well circumscribed and encapsulated, although deeply seated tumors may grow into the surrounding fat, without prognostic significance. The INPC classifies ganglioneuroma as its Schwannian stroma-dominant category and always places it in the favorable histology group.

Show evidence (4 references)

PMID:41612478 SUPPORT DIRECT REVIEW SYNTHESIS Other

"Tumors in this category represent the most mature form of pNTs. They are elastic and yellowish white, and free surfaces are well-circumscribed and encapsulated. However, infiltrative growth into the surrounding fatty tissue, without prognostic significance, may be observed in deeply seated GN...."

In this 2026 pathology review these sentences open the paragraph headed 'Ganglioneuroma (Schwannian stroma-dominant)', a heading the cached text drops; the quote itself refers to deeply seated GN, mature GN and maturing GN, and cites Fig. 2C, the ganglioneuroma panel. The review calls these tumors the most mature form of peripheral neuroblastic tumor and describes them as elastic, yellowish white, well circumscribed and encapsulated, with infiltration of the surrounding fat in deeply seated tumors that has no prognostic significance. It places the ganglion cells singly or in small clusters in Schwannian stroma, defines mature GN by completely mature ganglion cells and maturing GN by a mixture of mature and maturing ganglion cells, and states that completely mature ganglion cells are covered with satellite cells. This restates the INPC morphologic criteria rather than reporting case data.

PMID:41612478 SUPPORT DIRECT REVIEW SYNTHESIS Other

"Neurites produced by the ganglion cells are immediately incorporated in the cytoplasm of Schwannian stromal cells, so that naked neurites are not identified around the ganglion cells."

This sentence comes from the 2026 review's paragraph headed 'Ganglioneuroma (Schwannian stroma-dominant)' (the cached text drops the heading), directly after the definitions of mature and maturing GN, and the review's Fig. 2C ganglioneuroma legend says the same. Neurites produced by the ganglion cells are immediately incorporated in the cytoplasm of Schwannian stromal cells, so naked neurites are not identified around the ganglion cells. This restates an INPC morphologic criterion and reports no case data.

PMID:10421272 SUPPORT DIRECT PRIMARY RESULT Human clinical

"Based on morphologic criteria defined in this article, NTs were classified into four categories and their subtypes: 1) neuroblastoma (Schwannian stroma-poor), undifferentiated, poorly differentiated, and differentiating; 2) ganglioneuroblastoma, intermixed (Schwannian stroma-rich); 3)..."

The 1999 terminology paper of the International Neuroblastoma Pathology Committee, whose six member pathologists defined the morphologic criteria from a review of 227 cases, classifies neuroblastic tumors into four categories. Ganglioneuroma is the third, the Schwannian stroma-dominant category, with maturing and mature subtypes; neuroblastoma is the stroma-poor category and intermixed ganglioneuroblastoma the stroma-rich one. Nodular ganglioneuroblastoma is a composite of stroma-rich or stroma-dominant tissue with stroma-poor tissue, so ganglioneuroma is the only category whose label is stroma-dominant alone. The abstract prints the composite label as 'stroma-richlstroma-dominant', and the quote keeps that spelling. The abstract does not assign ganglioneuroma to a prognostic group; the classification itself is reported in the companion article (PMID:10421273).

+ 1 more reference

PHOX2B Immunoreactivity

PHOX2B was expressed in every ganglioneuroma examined in two immunohistochemistry series: diffusely in all 65 peripheral neuroblastic tumors of a pediatric series, which included 10 ganglioneuromas, with less intensity in differentiating neuroblastoma, ganglioneuroblastoma and ganglioneuroma than in undifferentiated and poorly differentiated neuroblastoma, and in all 8 ganglioneuromas of a series of 77 autonomic nervous system tumors. A third series, which did not report ganglioneuromas separately, found PHOX2B in 92% of 76 peripheral neuroblastic tumors, including two of four adult cases, so the marker is not positive in every tumor of the family.

Show evidence (3 references)

PMID:28986989 SUPPORT DIRECT PRIMARY RESULT Human clinical

"Phox2b was expressed diffusely in pNT (n = 65 of 65), strongly in NB-UD and NB-PD and with less intensity in NB-D, GNB and GN."

In this pediatric immunohistochemistry series, the 65 peripheral neuroblastic tumors (pNT) included 10 ganglioneuromas (GN), alongside undifferentiated (NB-UD), poorly differentiated (NB-PD) and differentiating (NB-D) neuroblastomas and ganglioneuroblastomas (GNB). Phox2b was expressed diffusely in all 65 pNT: strongly in NB-UD and NB-PD, and with less intensity in NB-D, GNB and GN. The sentence directly supports PHOX2B expression in ganglioneuroma, as in every pNT tested in this series, at lower intensity than in undifferentiated and poorly differentiated neuroblastoma. The abstract does not say whether the staining was nuclear or which ganglioneuroma cells stained, and the ganglioneuroma group is 10 tumors.

PMID:23715162 SUPPORT DIRECT PRIMARY RESULT Human clinical

"Phox2b expression was seen in all neuroblastomas, ganglioneuroblastomas, and ganglioneuromas and in 40% of paragangliomas, but pheochromocytomas and all other tumors were negative."

Immunohistochemistry on 77 autonomic nervous system tumors, including 8 ganglioneuromas, found Phox2b expression in every neuroblastoma, ganglioneuroblastoma and ganglioneuroma tested. This second series, by a different author group from PMID:28986989, supports PHOX2B expression in ganglioneuroma and in every neuroblastic tumor it examined. It reports no staining intensity, does not describe the staining as nuclear and gives no patient ages, and the ganglioneuroma group is 8 tumors. The sentence's paraganglioma and pheochromocytoma results are outside this finding.

PMID:28640941 SUPPORT INDIRECT PRIMARY RESULT Human clinical

"PHOX2B was positive in 70 (92%) peripheral neuroblastic tumours, including 68 of 72 (94%) paediatric and two of four (50%) adult cases."

In a series of 76 peripheral neuroblastic tumors (median age 2 years, four adults) stained with a rabbit monoclonal antibody, positivity was defined as nuclear immunoreactivity in at least 5% of cells, and PHOX2B was positive in 70 (92%), including 68 of 72 pediatric and two of four adult cases. The abstract does not report ganglioneuromas separately, so it bears on this finding only through the tumor family as a whole; it shows that PHOX2B is not positive in every peripheral neuroblastic tumor.

Tyrosine Hydroxylase Immunoreactivity

In a pediatric immunohistochemistry series, tyrosine hydroxylase staining was diffuse in every ganglioneuroma, as in all poorly differentiated and differentiating neuroblastomas and ganglioneuroblastomas, whereas nine of 15 undifferentiated neuroblastomas and a nodule in a nodular ganglioneuroblastoma did not express it.

Show evidence (1 reference)

PMID:28986989 SUPPORT DIRECT PRIMARY RESULT Human clinical

"Diffuse TH was seen in all NB-PD, NB-D, GNB and GN, but nine of 15 NB-UD and a nodule in GNBn did not express TH (n = 55 of 65)."

In the same pediatric series, which included 10 ganglioneuromas (GN), diffuse tyrosine hydroxylase (TH) staining was seen in all poorly differentiated and differentiating neuroblastomas, ganglioneuroblastomas and ganglioneuromas, while nine of 15 undifferentiated neuroblastomas and a nodule in a nodular ganglioneuroblastoma did not express TH. The sentence directly supports diffuse TH staining in ganglioneuroma. The ganglioneuroma group is 10 tumors, and the abstract does not say which ganglioneuroma cells stained.

⬡

Pathograph

Use Group by to collapse related nodes into one box. Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.

●

Phenotypes

8

Digestive 3

Retroperitoneal Mass HP:6000285

Show evidence (2 references)

PMID:42537227 SUPPORT DIRECT PRIMARY RESULT Human clinical

"Tumors most commonly arose in the retroperitoneum (n = 46, 45.5%), thoracic paraspinal/mediastinal region (n = 33, 32.7%), presacral space (n = 18, 17.8%), and cervical region (n = 4, 4%)."

In this single-institution series of 101 patients the retroperitoneum was the commonest site, with 46 tumors (45.5%); a tumor arising there is a retroperitoneal mass. The abstract gives no separate adrenal category, and one institution's series is not a population estimate.

PMID:27465021 SUPPORT INDIRECT PRIMARY RESULT Human clinical

"| | GN (n = 162) | p1 | GNBI (n = 55) | GN / GNBI (n=217) | p 2 | NB / GNBN (n = 591) | | Localization | | | | | | | | Adrenal ... | 51/161 | 0.613* ... | 15/55 | 66/216 | 0.001 * ... | 256/591 | | 31.7 % | 27.3 % | 30.6 % | 43.3 % | | Abdomino-pelvic ... | 67/161 | | 21/55 | 88/216 | | 211/591..."

Table 1 of a retrospective study of localized neuroblastic tumors in patients aged 21 years or younger, registered in the German NB97 and NB2004 trials: in the ganglioneuroma (GN) column, 51 of 161 tumors (31.7%) were adrenal, 67 (41.6%) abdomino-pelvic and 43 (26.7%) thoraco-cervical. The table has no retroperitoneal category. Reading the adrenal and abdomino-pelvic rows as retroperitoneal masses assumes that those tumors lie behind the peritoneum, which the paper does not state, and the abdomino-pelvic row is not split into sites; the two rows are not added together here because the paper reports no combined figure. The 43 thoraco-cervical tumors were not retroperitoneal.

Pelvic Mass HP:0031501

Show evidence (1 reference)

PMID:42537227 SUPPORT INDIRECT PRIMARY RESULT Human clinical

"Tumors most commonly arose in the retroperitoneum (n = 46, 45.5%), thoracic paraspinal/mediastinal region (n = 33, 32.7%), presacral space (n = 18, 17.8%), and cervical region (n = 4, 4%)."

In this single-institution series of 101 patients, 18 tumors (17.8%) arose in the presacral space. Reading a presacral tumor as a pelvic mass is the inference step.

Watery Diarrhea HP:0002014

Bound to Diarrhea rather than Secretory diarrhea (HP:0005208): the cited reports describe watery diarrhea and attribute it to VIP but do not describe the secretory mechanism.

Show evidence (4 references)

PMID:7376870 SUPPORT DIRECT PRIMARY RESULT Human clinical

"In a 2 1/2-year-old girl with persistent watery diarrhea a retroperitoneal tumour and lymph node composed of benign ganglioneuroma cells were found."

Case report of a 2 1/2-year-old girl with persistent watery diarrhea in whom a retroperitoneal tumor and a lymph node made of benign ganglioneuroma cells were found; it records watery diarrhea in a child with ganglioneuroma. It is a single case, and the authors judged the histology compatible with an originally metastasizing neuroblastoma that had matured late.

PMID:7376870 SUPPORT INDIRECT PRIMARY RESULT Human clinical

"Postoperatively the VIP concentration was normalized, and the diarrhea ceased."

In the same case report, the VIP concentration returned to normal after the operation and the girl's diarrhea stopped. Resolution after the operation supports the authors' attribution of the watery diarrhea to the tumor; the support comes through the response to surgery, so it is indirect, and the abstract does not say how much of the tumor was removed. It is a single case.

PMID:2833214 SUPPORT DIRECT PRIMARY RESULT Human clinical

"A 3 year old Chinese girl with watery diarrhoea, abdominal distension and hypokalaemia due to a thoracic paraspinal vasoactive intestinal peptide (VIP) secreting ganglioneuroma is reported."

The authors' own case: a 3-year-old girl had watery diarrhea, abdominal distension and hypokalemia, which they state were due to a VIP-secreting thoracic paraspinal ganglioneuroma. This records watery diarrhea in a VIP-secreting ganglioneuroma. It is a single case, so it shows that the phenotype occurs in the VIP-secreting form of the tumor but gives no frequency.

+ 1 more reference

Genitourinary 2

Elevated Urinary Homovanillic Acid FREQUENT HP:0011977

Show evidence (1 reference)

PMID:27465021 SUPPORT DIRECT PRIMARY RESULT Human clinical

"| | GN (n = 162) | p1 | GNBI (n = 55) | GN / GNBI (n=217) | p 2 | NB / GNBN (n = 591) | ... | HVA elevated ... | 45/142 | 0.001 ... | 27/44 | 72/186 | <0.001 ... | 327/531 | | 31.7 % | 61.4 % | 38.7 % | 61.6 % |"

Table 1 of this retrospective study of localized neuroblastic tumors registered in the German NB97 and NB2004 trials; the excerpt gives the column headings and the HVA row. Urinary homovanillic acid was elevated in 45 of 142 tested patients with ganglioneuroma (31.7%), which places the finding in the frequent band for this cohort, against 27 of 44 with intermixed ganglioneuroblastoma (61.4%) and 327 of 531 with neuroblastoma or nodular ganglioneuroblastoma (61.6%). The p-values compare ganglioneuroma with intermixed tumors (p1) and the pooled mature tumors with the immature ones (p2). Metastatic tumors and patients over 21 were excluded.

Elevated Urinary Vanillylmandelic Acid OCCASIONAL HP:0011978

Show evidence (1 reference)

PMID:27465021 SUPPORT DIRECT PRIMARY RESULT Human clinical

"| | GN (n = 162) | p1 | GNBI (n = 55) | GN / GNBI (n=217) | p 2 | NB / GNBN (n = 591) | ... | VMA elevated ... | 28/145 | <0.001 ... | 23/47 | 51/192 | <0.001 ... | 345/538 | | 19.3 % | 48.9 % | 26.6% | 64.1 % |"

Table 1 of the same German NB97/NB2004 study of localized neuroblastic tumors; the excerpt gives the column headings and the VMA row. Urinary vanillylmandelic acid was elevated in 28 of 145 tested patients with ganglioneuroma (19.3%), which places the finding in the occasional band for this cohort, against 23 of 47 with intermixed ganglioneuroblastoma (48.9%) and 345 of 538 with neuroblastoma or nodular ganglioneuroblastoma (64.1%). Metastatic tumors and patients over 21 were excluded.

Metabolism 1

Hypokalemia HP:0002900

Show evidence (1 reference)

PMID:2833214 SUPPORT DIRECT PRIMARY RESULT Human clinical

"A 3 year old Chinese girl with watery diarrhoea, abdominal distension and hypokalaemia due to a thoracic paraspinal vasoactive intestinal peptide (VIP) secreting ganglioneuroma is reported."

The authors' own case: a 3-year-old girl had watery diarrhea, abdominal distension and hypokalemia, which they state were due to a VIP-secreting thoracic paraspinal ganglioneuroma. This records hypokalemia in a VIP-secreting ganglioneuroma. It is a single case, so it gives no frequency, and the abstract does not say by what route the tumor lowered the potassium.

Respiratory 1

Posterior Mediastinal Mass HP:0033829

Show evidence (1 reference)

PMID:22573298 SUPPORT DIRECT PRIMARY RESULT Human clinical

"Of 22 lesions, 19 occurred in the posterior mediastinum, 2 in the lateral pleura and 1 in the right chest."

Retrospective series of 22 thoracic ganglioneuromas confirmed by surgery and pathology, collected from July 2002 to December 2010, in patients aged 4 to 57 years (median 21). Of the 22 lesions, 19 lay in the posterior mediastinum, 2 in the lateral pleura and 1 in the right chest. All 22 were resected tumors, so the sentence places a posterior mediastinal mass directly. The 19 of 22 is a share of resected thoracic tumors in this series, not of all ganglioneuromas.

Constitutional 1

Pain FREQUENT HP:0012531

Show evidence (1 reference)

PMID:27465021 SUPPORT DIRECT PRIMARY RESULT Human clinical

"As reported by local clinics, most frequent symptoms leading to diagnosis were pain (GN 34.2 %, GNBI 14.5 %, NB/GNBN 13.6 %, p < 0.001), palpable tumor mass (GN 9.3 %, GNBI 12.7 %, NB/GNBN 18.0 %, p = 0.022) and reduced general condition (GN 6.2 %, GNBI 7.3 %, NB/GNBN 15.8 %, p = 0.003)."

In localized ganglioneuromas registered in the German neuroblastoma trials NB97 and NB2004, pain was the most frequent symptom leading to diagnosis (GN 34.2%), ahead of palpable tumor mass (9.3%) and reduced general condition (6.2%), as reported by local clinics. The figure is the share of GN patients whose diagnosis was prompted by pain, so it is a floor for pain at presentation rather than a full prevalence; at 34.2% it places Pain in the frequent band for this registry cohort of children and young people, and it does not say what causes the pain.

🧬

Genetic Associations

1

MYCN Amplification (Rare Somatic Amplification)

Gene: MYCN hgnc:7559 gene page relationship_type: BIOMARKER variant_origin: SOMATIC

Show evidence (3 references)

PMID:19530234 SUPPORT DIRECT PRIMARY RESULT Human clinical

"| GN-maturing N (%) | GNB-intermixed N (%) | GNB-nodular FS N (%) | GNB-nodular US N (%) | ... MYCN status ... | Not Amp** | 32 (94%) | 174 (99%) | 53 (100%) | 231 (97%) | | Amp** | 2 (6%) | 2 (1%) | 0 (0%) | 6 (3%) | | Unknown | 9 | 22 | 6 | 15 |"

Table III of this CCG/COG series of patients registered on neuroblastoma studies in 1991-2006, tabulating MYCN status by centrally reviewed histology; the excerpt gives the column headings and the MYCN rows. In the GN-maturing column, 2 of the 34 tumors with a result (6%) had amplified MYCN, 32 were not amplified and 9 were untested. The series is not population-based, MYCN was determined by Southern blot, PCR and/or FISH in the reference laboratories, and mature ganglioneuroma was not eligible for these studies.

PMID:19530234 SUPPORT DIRECT PRIMARY RESULT Human clinical

"As expected, there were only 4 FH tumors (4/210, 1.9%) that had amplified MYCN in our series of GN-M (2 cases) and GNB-I (2 cases), and all 4 patients were alive and well at the time of last follow-up. It is suggested that amplified MYCN may not have an adverse prognostic effect in these rare FH cases."

In the Discussion of the same CCG/COG series, the authors note that only 4 favorable-histology tumors had amplified MYCN, 2 maturing ganglioneuromas and 2 intermixed ganglioneuroblastomas, and that all 4 patients were alive and well at last follow-up, and they suggest that amplified MYCN may not have an adverse prognostic effect in these rare cases. The suggestion rests on 4 patients, of whom the Results say 3 had more than one year of follow-up.

PMID:11745206 SUPPORT DIRECT PRIMARY RESULT Human clinical

"MYCN amplification was seen almost exclusively in tumors of the NB category, and no patients with tumors in either the GNBi category or in the GN category and only two patients with tumors in the GNBn category had amplified MYCN."

This Children's Cancer Group series classified 628 neuroblastic tumors under the INPC, 9 of them ganglioneuromas, and tested each for MYCN status. Amplification was seen almost exclusively in the neuroblastoma category, and none of the ganglioneuromas was amplified. This supports amplification being rare in ganglioneuroma and largely confined to neuroblastoma; it does not show that amplification never occurs, and the ganglioneuroma group is 9 tumors.

💊

Medical Actions

2

Surgical Resection

Category: Therapeutic Action: surgical resection Ontology label: Tumor Resection NCIT:C164212

Platform: Surgery

In German trials of localized tumors in patients aged 21 years or younger, no ganglioneuroma or intermixed ganglioneuroblastoma progressed after complete resection or with residuals under 2 cm, and incomplete resection leaving minor residuals appeared to be sufficient treatment; the 11 patients given chemotherapy, 2 of them with ganglioneuroma, showed no substantial effect, and the authors' conclusion that chemotherapy is not effective pools the two tumor types. Postoperative complications are common: short-term complications followed 43.1% of operations, most often neurological deficits (22.2%), in a 101-patient single-institution series; complications followed surgery in 11 of 51 patients (21.6%) with a resected retroperitoneal ganglioneuroma at a sarcoma center, one of whom died on postoperative day 8 of bowel ischemia; post-operative complications occurred in 15 of 50 surgical patients (30%) in a pediatric series, and a UK nationwide series reported a 19% complication rate, both pooling ganglioneuroma with intermixed ganglioneuroblastoma. In two children with a VIP-secreting ganglioneuroma, VIP returned to normal after the operation and the diarrhea stopped.

Mechanism Target:

INHIBITS Schwannian Stromal Development — Resection removes the stroma-dominant tumor tissue. In German trials of localized tumors, no tumor progressed after complete resection or with residuals under 2 cm; that this reflects removal of the stromal tissue is an inference, and the authors could not rule out that progression in large residuals came from immature components.

Show evidence (1 reference)

PMID:27465021 SUPPORT INDIRECT PRIMARY RESULT Human clinical

"No progression was seen after complete resection or in patients with minor tumor residuals (<2 cm), neither in patients with GN nor in patients with GNBI."

In this retrospective study of localized ganglioneuroma (GN) and intermixed ganglioneuroblastoma (GNBI) in children and young people registered in the German neuroblastoma trials NB97 and NB2004, no tumor was seen to progress after complete resection or when the residual left behind was under 2 cm on MRI. This held for GN and GNBI taken separately, and every progression in the series arose in a larger residual. The sentence reports a clinical outcome and does not mention the stroma. Reading it as support for this link rests on resection removing the stroma-dominant tumor tissue, so it is indirect. The authors could not rule out that progression in large residuals came from immature components, and they cite a suggestion that minor increases in tumor volume may come from Schwannian stroma proliferation, so the quote does not show that stromal growth is what resection controls.

INHIBITS Tumoral Vasoactive Intestinal Peptide Secretion — Removing a VIP-secreting tumor ended the VIP excess in two children: after the operation VIP was normal, falling in one child from 314 pmol/l before surgery to 14 pmol/l 6 months after it, and the diarrhea stopped.

Show evidence (2 references)

PMID:7376870 SUPPORT DIRECT PRIMARY RESULT Human clinical

"The tumour contained large amounts of vasoactive intestinal polypeptide (VIP) and preoperative plasma concentration of this peptide was increased. Postoperatively the VIP concentration was normalized, and the diarrhea ceased. Analysis of catecholamine metabolites in urine was normal. The..."

In a 2 1/2-year-old girl with a retroperitoneal ganglioneuroma, plasma VIP was raised before surgery, and after the operation the VIP concentration returned to normal and the diarrhea stopped, which links the operation to the end of the VIP excess. It is one case, and the abstract does not say how much of the tumor was removed.

PMID:2833214 SUPPORT DIRECT PRIMARY RESULT Human clinical

"The pre-operative serum VIP was 314 pmol/l (normal less than 30). Her diarrhoea stopped after the removal of the tumour. The VIP was 14 pmol/l 6 months post-operatively."

In a 3-year-old girl with a VIP-secreting thoracic paraspinal ganglioneuroma, serum VIP was 314 pmol/l before surgery (normal less than 30) and 14 pmol/l 6 months after the tumor was removed, and her diarrhea stopped after the removal, which links the operation to the end of the VIP excess. It is a single case, and the abstract does not say whether the resection was complete.

Show evidence (7 references)

PMID:27465021 SUPPORT DIRECT PRIMARY RESULT Human clinical

"Outcome was excellent and chemotherapy seems not effective while incomplete resection with minor residuals (<2 cm) appears to be sufficient for treatment."

This summarizes a retrospective study of localized tumors registered in the German neuroblastoma trials NB97 and NB2004, including 162 ganglioneuroma and 55 intermixed ganglioneuroblastoma patients aged 21 years or younger. The authors conclude that outcome was excellent, that chemotherapy seems not to be effective and that incomplete resection leaving minor residuals under 2 cm appears to be sufficient treatment. Few patients received chemotherapy, most of them with intermixed ganglioneuroblastoma, and the conclusion pools the two tumor types.

PMID:27465021 SUPPORT INDIRECT PRIMARY RESULT Human clinical

"Eleven patients received chemotherapy without substantial effect. ... Cytotoxic treatment was given to two patients with GN and 9 patients with GNBI. One patient with GN presented with a large stage 3 tumor and received chemotherapy because diagnosis of GN was made only from biopsy and immature..."

In the same German series, 11 patients received chemotherapy without substantial effect, and the Results show that only 2 of them had ganglioneuroma: one with a large stage 3 tumor diagnosed only on biopsy, in whom local physicians suspected immature components, and one with an intraspinal tumor mass. Neither responded significantly, and residual tumor was still being observed. The ganglioneuroma evidence against chemotherapy therefore rests on two patients; the other 9 had intermixed ganglioneuroblastoma. It bears on resection as the treatment only indirectly, by showing that chemotherapy was not an effective alternative in these patients.

PMID:27465021 SUPPORT DIRECT PRIMARY RESULT Human clinical

"No progression was seen after complete resection or in patients with minor tumor residuals (<2 cm), neither in patients with GN nor in patients with GNBI."

In the same German series of localized tumors in patients aged 21 years or younger, no tumor progressed after complete resection or with minor residuals under 2 cm, in ganglioneuroma and in intermixed ganglioneuroblastoma taken separately; all five progressions in the series had residuals over 2 cm. The finding holds for this series and its follow-up, in which time to progression ranged from 3 to 80 months.

+ 4 more references

Watchful Observation

Category: Monitoring Action: watchful active observation Ontology label: Observation Activity NCIT:C25598

Observation of selected asymptomatic tumors. In a single-institution series of 101 patients, 31 (mean age 32.3 years) were managed by observation, chosen mainly because the tumor lay close to major vascular or neural structures (74.2%); none developed new symptoms over a mean follow-up of 90.9 months, reported as 90.9 ± 151 months, and two tumors grew minimally (0.08-0.17 cm/year). The authors concluded that observation is safe for asymptomatic tumors, particularly when adjacent to critical structures; the observed group was selected rather than randomized. A UK nationwide series of ganglioneuroma and intermixed ganglioneuroblastoma concluded that watchful active observation can be a safe approach, with resection reserved for symptomatic patients, although a small proportion of observed patients had their diagnosis revised to malignant at surgery, and a Hospital for Sick Children series concluded that, because these tumors grow slowly and resection can carry significant morbidity, watch-and-wait approaches should be considered for some patients. Both series pool ganglioneuroma with intermixed ganglioneuroblastoma, and in both a part of the observed group grew or went to surgery: in the UK series 21 of 58 observed patients (36%) required subsequent surgery, with progressive tumor growth given as a reason, and in the Hospital for Sick Children series 6 of 21 observed patients had progressive disease and 4 later underwent resection. The authors of a series of 51 retroperitoneal ganglioneuromas, all of them resected, regard active surveillance as a reasonable option for selected patients with small, asymptomatic tumors, particularly those with elevated surgical risk.

Show evidence (7 references)

PMID:42537227 SUPPORT DIRECT PRIMARY RESULT Human clinical

"Thirty-one patients were managed with observation (mean age 32.3 ± 17.7 years; mean follow-up duration 90.9 ± 151 months). Observation was chosen primarily due to proximity to major vascular or neural structures (74.2%). No patient in the observation group developed new symptoms, and 2 tumors..."

In this single-institution retrospective series, 31 patients (mean age 32.3 years) were managed with observation and followed for a mean of 90.9 months. The abstract reports this follow-up as 90.9 ± 151 months without saying what the ± value is; a spread larger than the mean suggests that follow-up length varied widely between patients. Proximity to major vascular or neural structures was the main reason for choosing observation (74.2%), which is a reason for the choice, not a comparison between tumors in different locations. No observed patient developed new symptoms, and two tumors grew minimally, at 0.08-0.17 cm/year. The abstract gives no imaging schedule, does not state whether the observed patients had symptoms when observation began, and does not say how their diagnosis was established.

PMID:42537227 SUPPORT DIRECT PRIMARY RESULT Human clinical

"Observation is safe for asymptomatic tumors, particularly when adjacent to critical structures, with no growth observed on long-term follow-up, except for minimal growth in few cases."

This single-institution retrospective review covers 101 patients diagnosed with ganglioneuroma between 1995 and 2025. The authors conclude that observation is safe for asymptomatic tumors, particularly when they lie next to critical structures, with no growth observed on long-term follow-up apart from minimal growth in a few cases. This is their judgement about the 31 patients they observed, a group selected rather than randomized. The series did not compare observed tumors next to critical structures with others, so 'particularly' is the authors' recommendation, not a finding that observation is safer there. The abstract does not define safety; the outcomes it reports for the observed group are no new symptoms and at most minimal tumor growth.

PMID:39582110 SUPPORT DIRECT PRIMARY RESULT Human clinical

"Watchful active observation can be a safe approach, with surgical resection reserved for symptomatic patients. However, a small proportion of patients in the observation group had their diagnosis revised to malignant at surgery."

This UK CCLG nationwide retrospective review covers 259 patients with histologically confirmed non-metastatic ganglioneuroma or intermixed ganglioneuroblastoma (median age 62 months), 163 of them with ganglioneuroma. It concludes that observation can be safe, with resection reserved for symptomatic patients, though a small proportion of observed patients had their diagnosis revised to malignant at surgery. The two diagnoses are pooled and survival is not reported by management arm, so the safety statement is the authors' judgement. Twenty-one of the 58 observed patients (36%) later needed surgery, with progressive tumor growth cited as a reason.

+ 4 more references

🔬

Diagnosis

2

Histopathologic Classification

Ganglioneuroma is diagnosed and subtyped by histopathologic examination of tumor tissue under the INPC. A biopsy diagnosis is not always upheld at surgery: in a UK nationwide series of ganglioneuroma and intermixed ganglioneuroblastoma, 14 (12%) biopsy diagnoses of ganglioneuroma or intermixed ganglioneuroblastoma changed to neuroblastoma or nodular ganglioneuroblastoma on surgical pathology, whereas in a Hospital for Sick Children series of the two tumors classification changed at resection in three cases and no ganglioneuroma was reclassified as neuroblastoma. A 2026 pathology review advises noting in the report that a favorable classification made on a core needle biopsy showing only intermixed ganglioneuroblastoma or ganglioneuroma was determined on review of limited material.

histopathologic examination under the International Neuroblastoma Pathology Classification NCIT:C18190

Show evidence (3 references)

PMID:39582110 SUPPORT DIRECT PRIMARY RESULT Human clinical

"In 45 cases (39%), surgical pathology was different from pathology at biopsy, and in 14 (12%) the pathology changed from GN/GNBi to neuroblastoma/GNB nodular."

In this UK CCLG retrospective series of 259 patients with non-metastatic ganglioneuroma or intermixed ganglioneuroblastoma, surgical pathology differed from the biopsy diagnosis in 45 cases, and in 14 (12%) a biopsy diagnosis of ganglioneuroma or intermixed ganglioneuroblastoma became neuroblastoma or nodular ganglioneuroblastoma at surgery. The abstract gives no denominator for the percentages, does not split the changes by biopsy diagnosis or management arm, and does not say whether they reflect limited sampling, reinterpretation or change in the tumor before surgery.

PMID:29369484 SUPPORT DIRECT PRIMARY RESULT Human clinical

"Pathology classification changed at resection for three cases, but no GN was reclassified to NB."

In this Hospital for Sick Children retrospective series (1990-2014) of 67 children and adolescents with ganglioneuroma (50) or intermixed ganglioneuroblastoma (17), the pathology classification changed at resection in three cases, which shows that a pre-resection diagnosis is not always upheld, but no ganglioneuroma was reclassified as neuroblastoma. It is a counterweight to the UK figure: in this series the changes did not turn a ganglioneuroma into neuroblastoma. The abstract does not say what the three changes were, whether the earlier diagnoses were made on biopsy, or how many patients had a biopsy before resection.

PMID:41612478 SUPPORT DIRECT REVIEW SYNTHESIS Other

"especially when the samples obtained by PCNB show only GNB-i or GN histology, it is advisable to include a note of "Favorable Histology of this case according to the International Neuroblastoma Pathology Classification is determined based on review of limited material" in the surgical pathology report."

This 2026 pathology review advises, as the authors' routine practice, that when percutaneous core needle biopsy (PCNB) samples show only GNB-intermixed or ganglioneuroma histology, the report should note that the favorable INPC classification was determined on review of limited material. The preceding sentence gives the reason: a core needle biopsy can miss the neuroblastoma nodule of a nodular ganglioneuroblastoma. It is an expert recommendation about core needle biopsy, without case data.

Urinary Catecholamine Metabolites

In localized tumors registered in the German NB97 and NB2004 trials (patients aged 21 years or younger), urinary homovanillic acid was raised in 31.7% and vanillylmandelic acid in 19.3% of tested patients with ganglioneuroma, less often than in intermixed ganglioneuroblastoma or in neuroblastoma and nodular ganglioneuroblastoma, so a normal result does not exclude the tumor. In a series of 27 adrenal ganglioneuromas at a referral cancer center, catecholamine levels were normal in all 21 patients with results. Among 45 histologically confirmed adrenal ganglioneuromas at one center, every tumor with an adrenergic or noradrenergic catecholamine profile was a composite ganglioneuroma-pheochromocytoma, and the authors, finding that pure and composite tumors overlap on imaging, judged testing for catecholamine excess essential in any indeterminate adrenal mass.

urinary catecholamine metabolite measurement NCIT:C61044

urinary vanillylmandelic acid (VMA) LOINC:LP15947-2 urinary homovanillic acid (HVA) LOINC:LP15096-8

VMA and HVA are bound at the LOINC Part level (Vanillylmandelate, Homovanillate), which names the analyte rather than one specimen or method code. The procedure is bound to Urine Chemistry Measurement because diagnosis_term takes one term and this row covers both analytes, as in the Neuroblastoma entry. The adrenal series cited here measured plasma or urine catecholamines or metanephrines, or did not say which.

Show evidence (5 references)

PMID:27465021 SUPPORT DIRECT PRIMARY RESULT Human clinical

"| | GN (n = 162) | p1 | GNBI (n = 55) | GN / GNBI (n=217) | p 2 | NB / GNBN (n = 591) | ... | HVA elevated ... | 45/142 | 0.001 ... | 27/44 | 72/186 | <0.001 ... | 327/531 | | 31.7 % | 61.4 % | 38.7 % | 61.6 % |"

Table 1 of the German NB97/NB2004 study of localized neuroblastic tumors: urinary homovanillic acid was elevated in 45 of 142 tested patients with ganglioneuroma (31.7%), against 61.4% with intermixed ganglioneuroblastoma and 61.6% with neuroblastoma or nodular ganglioneuroblastoma, so most patients with ganglioneuroma had a normal result.

PMID:27465021 SUPPORT DIRECT PRIMARY RESULT Human clinical

"| | GN (n = 162) | p1 | GNBI (n = 55) | GN / GNBI (n=217) | p 2 | NB / GNBN (n = 591) | ... | VMA elevated ... | 28/145 | <0.001 ... | 23/47 | 51/192 | <0.001 ... | 345/538 | | 19.3 % | 48.9 % | 26.6% | 64.1 % |"

Table 1 of the same study: urinary vanillylmandelic acid was elevated in 28 of 145 tested patients with ganglioneuroma (19.3%), against 48.9% with intermixed ganglioneuroblastoma and 64.1% with neuroblastoma or nodular ganglioneuroblastoma, so most patients with ganglioneuroma had a normal result.

PMID:24033606 SUPPORT INDIRECT PRIMARY RESULT Human clinical

"Catecholamine levels, available for 21 patients, were normal."

Results sentence from a retrospective series of 27 adrenal ganglioneuromas at a tertiary referral cancer center (median age 31 years, range 1.7-64): catecholamine levels were normal in all 21 patients with results. The abstract does not say whether urine or plasma was measured or which analytes, so using it for urinary catecholamine metabolites rests on an inference, and it does not say whether the 21 included the series' composite tumors.

+ 2 more references

🩻

Imaging Findings

1

MIBG Uptake OCCASIONAL

In localized tumors registered in the German NB97 and NB2004 trials (patients aged 21 years or younger), MIBG uptake was positive in 27 of 110 tested patients with ganglioneuroma (24.5%), against 22 of 36 with intermixed ganglioneuroblastoma (61.1%) and 398 of 444 with neuroblastoma or nodular ganglioneuroblastoma, reported together (89.6%).

Modality: Other

Finding: MIBG uptake on scintigraphy NCIT:C79553

The German series does not state the MIBG isotope, and NCIT:C79553 is specific to 123I-MIBG; OLS NCIT searches on 2026-10-28 for MIBG uptake and MIBG scintigraphy returned NCIT:C79553 as the only uptake finding, so NCIT has no isotope-neutral term (see also the Neuroblastoma entry's MIBG rows). Modality is OTHER because planar scintigraphy is not in ImagingModalityEnum. The frequency band rests on the ganglioneuroma column of the German series; the pooled mature-tumor figure in the same row (33.6%) would fall in a higher band. An adrenal series of adolescents and adults in which 131I-MIBG was negative in all 4 ganglioneuromas scanned (PMID:19781327) is cited under the Adrenal Gland Pheochromocytoma differential diagnosis rather than here, because a negative scan does not support uptake.

Show evidence (2 references)

PMID:27465021 SUPPORT DIRECT PRIMARY RESULT Human clinical

"| | GN (n = 162) | p1 | GNBI (n = 55) | GN / GNBI (n=217) | p 2 | NB / GNBN (n = 591) | ... | Positive mIBG-uptake ... | 27/110 | <0.001 ... | 22/36 | 49/146 | <0.001 ... | 398/444 | | 24.5 % | 61.1 % | 33.6 % | 89.6 % |"

Table 1 of this retrospective study of localized neuroblastic tumors registered in the German NB97 and NB2004 trials (diagnosed 2000-2009, age 21 or younger at diagnosis); the excerpt gives the column headings and the positive mIBG-uptake row. MIBG uptake was positive in 27 of 110 tested patients with ganglioneuroma (24.5%), 22 of 36 with intermixed ganglioneuroblastoma (61.1%), 49 of 146 for the two mature types pooled (33.6%), and 398 of 444 with neuroblastoma or nodular ganglioneuroblastoma (89.6%). 24.5% falls in the occasional band (5-29%), while the pooled mature figure in the same row would fall in the frequent band, so the band rests on the ganglioneuroma column alone. Per the table footnote, p1 (<0.001) compares ganglioneuroma with intermixed ganglioneuroblastoma, and p2 (<0.001) compares the pooled mature tumors with the immature ones; no p-value compares ganglioneuroma alone with neuroblastoma. The percentages use the table's denominators, so 110 of the 162 ganglioneuromas contribute; the paper does not say why the others have no result. The paper does not name the MIBG isotope.

PMID:27465021 SUPPORT DIRECT PRIMARY RESULT Human clinical

"Moreover, GN showed less often positive mIBG-uptake and elevated urine catecholamine metabolites than GNBI."

This Results sentence from the same German NB97/NB2004 series of localized neuroblastic tumors (patients aged 21 or younger at diagnosis) states the comparison directly: patients with ganglioneuroma less often showed positive MIBG uptake, and less often had elevated urinary catecholamine metabolites, than patients with intermixed ganglioneuroblastoma. The sentence gives no rates and says nothing about neuroblastoma.

🌍

Epidemiology

3

Age at diagnosis

Ganglioneuroma is usually diagnosed in older children and adults. In German trials of localized neuroblastic tumors in patients aged 21 years or younger, median age at diagnosis was 71 months for maturing and 125 months for mature ganglioneuroma, against 61 months for intermixed ganglioneuroblastoma and 9 months for neuroblastoma and nodular ganglioneuroblastoma taken together. Hospital series that set no age limit report a mean age of 26.9 years for 101 patients at one institution and a median age at diagnosis of 28 years (range 12-73) for 51 patients with a resected retroperitoneal tumor, and a single-center adrenal cohort pooled with a systematic review of published adrenal series gives a mean age at diagnosis of 39 years.

Show evidence (5 references)

PMID:19530234 SUPPORT DIRECT BACKGROUND Human clinical

"GN is recognized as a benign tumor usually diagnosed in older children and in adults (11) (12)."

The introduction states, citing earlier literature (references 11 and 12), that ganglioneuroma is a benign tumor usually diagnosed in older children and in adults. It restates prior work rather than a result of this study's CCG/COG cohort, which was pediatric and excluded mature ganglioneuroma.

PMID:27465021 SUPPORT DIRECT PRIMARY RESULT Human clinical

"Median age at diagnosis increased with grade of differentiation (NB/GNBN: 9; GNBI: 61; GN-maturing: 71; GN-mature: 125 months, p < 0.001)."

In this retrospective study of 808 consecutive localized neuroblastic tumors registered in the German neuroblastoma trials NB97 and NB2004, in patients aged 21 years or younger with central histology review by INPC criteria, median age at diagnosis rose in order across the groups: 9 months for neuroblastoma and nodular ganglioneuroblastoma, which the paper reports only as one pooled group of 591, 61 months for the 55 intermixed ganglioneuroblastomas, 71 months for the 144 maturing and 125 months for the 18 mature ganglioneuromas. The abstract gives one p-value (p < 0.001) for the comparison, and no pairwise comparisons are reported in the text. Metastatic tumors and patients over 21 were excluded, so the 9-month figure is not the median age of neuroblastoma as a whole, and the ganglioneuroma medians leave out older patients.

PMID:42537227 SUPPORT DIRECT PRIMARY RESULT Human clinical

"A total of 101 patients (62.3% female, mean age 26.9 ± 15.9 years) were identified."

In this retrospective review of all patients diagnosed with ganglioneuroma at one institution between 1995 and 2025, the 101 patients had a mean age of 26.9 ± 15.9 years. The abstract gives no age range and does not say whether age was taken at diagnosis or at presentation. No age limit is stated and PubMed indexes the record for child and adolescent age groups, so this is not an adult-only series. It is one institution's case mix, not a population sample.

+ 2 more references

Sex distribution

The share of women differs between series: 62.3% of 101 patients at one institution and 33 of 51 patients with a resected retroperitoneal tumor, against 47% in a single-center adrenal cohort pooled with a systematic review of published adrenal series. These are hospital case mixes, not population sex ratios, and they do not establish a sex predilection.

Show evidence (3 references)

PMID:42537227 SUPPORT DIRECT PRIMARY RESULT Human clinical

"A total of 101 patients (62.3% female, mean age 26.9 ± 15.9 years) were identified."

This single-institution retrospective series of 101 patients diagnosed with ganglioneuroma between 1995 and 2025 was 62.3% female. That is one institution's case mix and does not establish a sex predilection.

PMID:41306794 SUPPORT DIRECT PRIMARY RESULT Human clinical

"Fifty-one consecutive patients (18 males, 33 females; median age 28 years, range 12-73) with newly diagnosed RGN were enrolled."

The cohort of 51 patients with a resected primary retroperitoneal ganglioneuroma comprised 18 males and 33 females. This is one center's surgical series, not a population-level sex ratio.

PMID:33721367 SUPPORT DIRECT REVIEW SYNTHESIS Human clinical

"Overall, in the cohort study and systematic review, the mean age at diagnosis of AGN was 39 years, and 47% were women, Table 2."

In the pooled adrenal data of a single-center cohort and a systematic review of 14 published series, 47% were women, with demographics reported in only 10 of the 14 included studies. This pooled figure is a case mix of hospital series, not a population sex ratio, and it does not establish a sex predilection.

Primary tumor site

In a single-institution series of 101 patients, tumors arose in the retroperitoneum (45.5%), the thoracic paraspinal or mediastinal region (32.7%), the presacral space (17.8%) and the cervical region (4%); that series does not report the adrenal gland as a separate site. In German trials of localized neuroblastic tumors in patients aged 21 years or younger, 51 of 161 ganglioneuromas (31.7%) were adrenal, 67 (41.6%) abdomino-pelvic and 43 (26.7%) thoraco-cervical. In a separate surgical series of 22 thoracic ganglioneuromas, 19 lay in the posterior mediastinum.

Show evidence (3 references)

PMID:42537227 SUPPORT DIRECT PRIMARY RESULT Human clinical

"Tumors most commonly arose in the retroperitoneum (n = 46, 45.5%), thoracic paraspinal/mediastinal region (n = 33, 32.7%), presacral space (n = 18, 17.8%), and cervical region (n = 4, 4%)."

Retrospective review of all 101 patients diagnosed with ganglioneuroma at a single institution between 1995 and 2025 (mean age 26.9 years). Tumors arose in the retroperitoneum in 46 (45.5%), the thoracic paraspinal or mediastinal region in 33 (32.7%), the presacral space in 18 (17.8%) and the cervical region in 4 (4%). The abstract gives no separate adrenal category, so it does not show how adrenal tumors were counted, and a single institution's series is not a population estimate of where ganglioneuromas arise.

PMID:27465021 SUPPORT DIRECT PRIMARY RESULT Human clinical

"| | GN (n = 162) | p1 | GNBI (n = 55) | GN / GNBI (n=217) | p 2 | NB / GNBN (n = 591) | | Localization | | | | | | | | Adrenal ... | 51/161 | 0.613* ... | 15/55 | 66/216 | 0.001 * ... | 256/591 | | 31.7 % | 27.3 % | 30.6 % | 43.3 % | | Abdomino-pelvic ... | 67/161 | | 21/55 | 88/216 | | 211/591..."

Table 1 of this retrospective analysis of localized neuroblastic tumors registered in the German neuroblastoma trials NB97 and NB2004 and diagnosed between 2000 and 2009 in patients aged 21 years or younger, with central histological review; the excerpt gives the column headings and the three Localization rows, each count row followed by its percentage row, whose first value belongs to the ganglioneuroma (GN) column. In that column the site rows use a denominator of 161 of the 162 ganglioneuromas (the table does not say why one is missing): 51 were adrenal (31.7%), 67 abdomino-pelvic (41.6%) and 43 thoraco-cervical (26.7%). The other columns are intermixed ganglioneuroblastoma, the pooled mature tumors, and neuroblastoma with nodular ganglioneuroblastoma. The abdomino-pelvic row is not split into abdominal, pelvic or retroperitoneal sites, and the thoraco-cervical row counts thoracic and neck tumors together. The distribution describes this pediatric registry cohort, not ganglioneuroma at all ages.

PMID:22573298 SUPPORT DIRECT PRIMARY RESULT Human clinical

"Of 22 lesions, 19 occurred in the posterior mediastinum, 2 in the lateral pleura and 1 in the right chest."

Retrospective series of 22 thoracic ganglioneuromas confirmed by surgery and pathology, collected from July 2002 to December 2010, in patients aged 4 to 57 years (median 21). Of the 22 lesions, 19 lay in the posterior mediastinum, 2 in the lateral pleura and 1 in the right chest; the authors could not tell whether the right-chest tumor came from the posterior mediastinum or the lateral pleura. The 19 of 22 is a share of resected thoracic tumors in this series, not of all ganglioneuromas.

⚖️

Clinical Burden

Low

Ganglioneuroma is benign and many tumors are found incidentally: 72% of lesions in a single-institution series of 101 patients were incidental findings, 70 of 161 patients aged 21 years or younger with localized ganglioneuroma in German trials (43.5%) were diagnosed by chance, and 72% of adrenal ganglioneuromas pooled from a single-center cohort and a systematic review were discovered incidentally. In the German trials no patient died of tumor progression; the one patient with ganglioneuroma who died had complications of surgery after complete resection. Treatment carries its own morbidity: a UK nationwide series reported a 19% complication rate and a Hospital for Sick Children series post-operative complications in 30% of surgical patients, both pooling ganglioneuroma with intermixed ganglioneuroblastoma; complications followed surgery in 21.6% of 51 patients with a resected retroperitoneal ganglioneuroma, one of whom died of intestinal ischemia and necrosis, and short-term complications followed 43.1% of operations in the 101-patient series. Malignant transformation is rare: a 2000 literature review counted ten reported cases of malignant peripheral nerve sheath tumor arising in a ganglioneuroma, either de novo or at a site of previous irradiation, and the 101-patient series observed no malignant transformation during its follow-up.

Show evidence (10 references)

PMID:42537227 SUPPORT DIRECT PRIMARY RESULT Human clinical

"A total of 101 patients (62.3% female, mean age 26.9 ± 15.9 years) were identified. ... Most lesions (72%) were incidental findings."

Retrospective single-institution series of patients diagnosed with ganglioneuroma between 1995 and 2025, published in a neurosurgical journal. Among 101 patients (mean age 26.9 years), 72% of lesions were incidental findings. The abstract counts patients rather than lesions and does not say what the 72% is a share of. Tumors arose in the retroperitoneum, the thoracic paraspinal or mediastinal region, the presacral space and the cervical region; no adrenal site is listed, so the case mix may differ from adrenal or childhood series.

PMID:27465021 SUPPORT DIRECT PRIMARY RESULT Human clinical

"Diagnosis of localized NT was made by routine check-ups or visits to the doctor for other reasons in 50 % of all cases with no significant difference between mature and immature tumors. ... | | GN (n = 162) | p1 | GNBI (n = 55) | GN / GNBI (n=217) | p 2 | NB / GNBN (n = 591) | ... | Diagnosis by..."

Retrospective study of localized neuroblastic tumors registered in the German NB97 and NB2004 trials (diagnosed 2000-2009 at age 21 or younger, with central histology review). The text says diagnosis was made at routine check-ups or visits to the doctor for other reasons in 50% of all cases, with no significant difference between mature and immature tumors. Table 1 (the column headings and the Diagnosis by chance row) gives 70 of 161 patients with ganglioneuroma (43.5%), against 30 of 55 with intermixed ganglioneuroblastoma (54.5%) and 306 of 591 with neuroblastoma or nodular ganglioneuroblastoma (51.8%); p1 compares ganglioneuroma with intermixed tumors (0.163) and p2 the pooled mature tumors with the immature ones (0.177). Chance discovery is therefore common in ganglioneuroma but not distinctive of it. Metastatic tumors were excluded.

PMID:33721367 SUPPORT DIRECT REVIEW SYNTHESIS Human clinical

"Overall, in the cohort study and systematic review, the mean age at diagnosis of AGN was 39 years, and 47% were women, Table 2. AGN were discovered incidentally in 72% of patients, due to symptoms of mass effect in 20%, and due to other symptoms in 8%."

Pooled descriptive total from a single-center retrospective cohort of 45 patients with adrenal ganglioneuroma (Mayo Clinic, 1995-2019) and a PRISMA systematic review of 14 published series, 421 patients in the pooled analysis. Across the cohort and the review, 72% of patients were discovered incidentally, 20% through symptoms of mass effect and 8% through other symptoms. The authors judged the data insufficient for meta-analysis, and mode of discovery was reported in only 10 of the 14 reviewed studies, so the 72% is a share of the patients in those series and the cohort, not of all 421; one of those series, a 50-patient cross-sectional multicenter study, recorded every case as incidental (Table 2). It covers adrenal tumors only. In the single-center cohort alone 76% were incidental, and its 20 composite ganglioneuroma-pheochromocytoma tumors were found incidentally less often than pure ganglioneuromas (65% vs 84%).

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🔀

Differential Diagnoses

4

Conditions with similar clinical presentations that must be differentiated from Ganglioneuroma:

Ganglioneuroblastoma MONDO:0005035

Overlapping Features The next INPC category toward immaturity. Intermixed ganglioneuroblastoma is characterized by well-defined microscopic nests of neuroblastic cells whose neurites are segmentally naked within the nests, and nodular ganglioneuroblastoma is a composite of stroma-rich or stroma-dominant tissue with stroma-poor neuroblastoma. A biopsy diagnosis of ganglioneuroma or intermixed ganglioneuroblastoma is not always upheld at surgery: in a UK nationwide series that pooled the two tumors, 14 (12%) such biopsy diagnoses became neuroblastoma or nodular ganglioneuroblastoma on surgical pathology, whereas in a Hospital for Sick Children series, also pooled, classification changed at resection in three cases and no ganglioneuroma was reclassified as neuroblastoma. In German trials of localized tumors, ganglioneuroma less often took up MIBG and less often raised urinary catecholamine metabolites than intermixed ganglioneuroblastoma.

Distinguishing Features

Ganglioneuroma: neurites incorporated into the cytoplasm of Schwannian stromal cells, with no naked neurites identified around the ganglion cells; intermixed ganglioneuroblastoma: well-defined microscopic nests of neuroblastic cells whose neurites are segmentally naked within the nests
Ganglioneuroma has no stroma-poor neuroblastomatous component, which nodular ganglioneuroblastoma contains
In German trials of localized tumors in patients aged 21 years or younger, MIBG uptake was positive in 24.5% of ganglioneuromas against 61.1% of intermixed ganglioneuroblastomas, and ganglioneuroma less often raised urinary catecholamine metabolites

Show evidence (7 references)

PMID:41612478 SUPPORT DIRECT REVIEW SYNTHESIS Other

"Neurites produced by the ganglion cells are immediately incorporated in the cytoplasm of Schwannian stromal cells, so that naked neurites are not identified around the ganglion cells."

This sentence comes from the 2026 review's paragraph headed 'Ganglioneuroma (Schwannian stroma-dominant)' (the cached text drops the heading), directly after the definitions of mature and maturing GN, and the review's Fig. 2C ganglioneuroma legend says the same. It states that neurites produced by the ganglion cells are immediately incorporated in the cytoplasm of Schwannian stromal cells, so naked neurites are not identified around the ganglion cells. Under this differential it is the ganglioneuroma side of the contrast with the review's paragraph on intermixed ganglioneuroblastoma, where neurites are segmentally naked within microscopic neuroblastic nests; the review describes the two categories in separate paragraphs and does not compare them directly. It restates INPC morphologic criteria and reports no case data.

PMID:41612478 SUPPORT DIRECT REVIEW SYNTHESIS Other

"The tumors are characterized by the presence of well-defined microscopic nests of neuroblastic cells in various stages of differentiation with actively producing and easily recognizable neurites around their cytoplasm (Fig. 2B). Their neurites are segmentally naked in those microscopic nests and..."

These sentences close the paragraph headed 'Ganglioneuroblastoma, intermixed (Schwannian stroma-rich)' in this 2026 pathology review; the cached text drops the heading, and the quote itself says only 'The tumors'. The Fig. 2B legend they cite labels the image as ganglioneuroblastoma, intermixed, with microscopic nests of neuroblastic cells and their naked neurites. They state that intermixed tumors are characterized by well-defined microscopic nests of neuroblastic cells at various stages of differentiation, whose neurites are segmentally naked within the nests and are eventually incorporated into Schwannian cell cytoplasm in the stromal areas. The review's ganglioneuroma paragraph describes ganglion cells lying singly or in small clusters, with no naked neurites around them, and does not describe neuroblastic nests; the review describes the two categories in separate paragraphs and does not compare them directly. The quote concerns the intermixed category only, not nodular ganglioneuroblastoma, and restates INPC morphologic criteria rather than reporting case data.

PMID:10421272 SUPPORT DIRECT PRIMARY RESULT Human clinical

"Based on morphologic criteria defined in this article, NTs were classified into four categories and their subtypes: 1) neuroblastoma (Schwannian stroma-poor), undifferentiated, poorly differentiated, and differentiating; 2) ganglioneuroblastoma, intermixed (Schwannian stroma-rich); 3)..."

The 1999 terminology paper of the International Neuroblastoma Pathology Committee classifies neuroblastic tumors into four categories: ganglioneuroma is Schwannian stroma-dominant, intermixed ganglioneuroblastoma stroma-rich, and nodular ganglioneuroblastoma a composite of stroma-rich or stroma-dominant tissue with stroma-poor tissue. The stroma-poor component therefore separates nodular ganglioneuroblastoma from ganglioneuroma. The quote keeps the abstract's spelling 'stroma-richlstroma-dominant'.

+ 4 more references

Neuroblastoma MONDO:0005072

Overlapping Features The Schwannian stroma-poor end of the same INPC spectrum. Neuroblastoma is classified as favorable or unfavorable histology by an age-linked evaluation of its grade of differentiation and mitosis-karyorrhexis index, whereas ganglioneuroma is always of favorable histology. In German trials of localized tumors, neuroblastoma and nodular ganglioneuroblastoma, reported together, were diagnosed younger and more often took up MIBG and raised urinary catecholamine metabolites than ganglioneuroma.

Distinguishing Features

Schwannian stroma-poor histology in neuroblastoma, against stroma-dominant histology in ganglioneuroma
Median age at diagnosis 9 months for localized neuroblastoma and nodular ganglioneuroblastoma taken together, against 71 months for maturing and 125 months for mature ganglioneuroma, in German trials of patients aged 21 years or younger; these are group medians, not a cut-off
MIBG uptake positive in 89.6% of localized neuroblastoma or nodular ganglioneuroblastoma against 24.5% of ganglioneuroma in the same series, a descriptive comparison with no test of ganglioneuroma alone against neuroblastoma
Urinary homovanillic acid raised in 61.6% and vanillylmandelic acid in 64.1% of localized neuroblastoma or nodular ganglioneuroblastoma, against 31.7% and 19.3% of ganglioneuroma

Show evidence (6 references)

PMID:10421272 SUPPORT DIRECT PRIMARY RESULT Human clinical

"Based on morphologic criteria defined in this article, NTs were classified into four categories and their subtypes: 1) neuroblastoma (Schwannian stroma-poor), undifferentiated, poorly differentiated, and differentiating; 2) ganglioneuroblastoma, intermixed (Schwannian stroma-rich); 3)..."

The 1999 terminology paper of the International Neuroblastoma Pathology Committee places neuroblastoma in the Schwannian stroma-poor category and ganglioneuroma in the Schwannian stroma-dominant one, the two ends of the four-category classification; its six member pathologists defined the criteria from a review of 227 cases. The quote keeps the abstract's spelling 'stroma-richlstroma-dominant'.

PMID:19530234 SUPPORT DIRECT BACKGROUND Other

"NB (Schwannian stroma-poor tumor) is classified into FH or UH depending on age-linked evaluation of grade of neuroblastic differentiation and mitosis-karyorrhexis index (MKI). GNB-Intermixed (Schwannian stroma-rich) and GN (Schwannian stroma-dominant) tumors are always classified into the FH group."

In the introduction of a Children's Cancer Group and Children's Oncology Group study of 552 ganglioneuroma and ganglioneuroblastoma cases, Okamatsu et al. restate the INPC rules for the two ends of the spectrum: neuroblastoma (Schwannian stroma-poor) is classified as favorable or unfavorable histology by an age-linked evaluation of its grade of neuroblastic differentiation and mitosis-karyorrhexis index, whereas ganglioneuroma (Schwannian stroma-dominant), like intermixed ganglioneuroblastoma, is always of favorable histology. The sentences restate the INPC papers rather than reporting a result of the cohort.

PMID:27465021 SUPPORT DIRECT PRIMARY RESULT Human clinical

"Median age at diagnosis increased with grade of differentiation (NB/GNBN: 9; GNBI: 61; GN-maturing: 71; GN-mature: 125 months, p < 0.001)."

In German trials of localized neuroblastic tumors in patients aged 21 years or younger, neuroblastoma and nodular ganglioneuroblastoma, reported as one group, were diagnosed at a median of 9 months, against 71 months for maturing and 125 months for mature ganglioneuroma. These are group medians and the age ranges overlap: the paper's table of delayed surgeries includes a maturing ganglioneuroma diagnosed at 0-18 months. Metastatic tumors were excluded, so the 9-month figure is not the median age of neuroblastoma as a whole.

+ 3 more references

Adrenal Gland Pheochromocytoma Not Yet Curated MONDO:0004974

Overlapping Features An adrenal ganglioneuroma must be told from pheochromocytoma (see the Pheochromocytoma and Paraganglioma entry), with which it can occur as a composite tumor. Pure and composite adrenal ganglioneuromas overlap on imaging, and an unrecognized pheochromocytoma carries perioperative morbidity, so the distinction matters before adrenalectomy. Catecholamine excess and MIBG uptake favored pheochromocytoma in an adolescent and adult adrenal series, but a minority of ganglioneuromas in German trials of younger patients took up MIBG or raised urinary homovanillic acid, so neither finding excludes ganglioneuroma.

Distinguishing Features

In an adolescent and adult adrenal series, catecholamine excess and MIBG uptake pointed to pheochromocytoma: 24-hour urinary catecholamines were raised in all 36 pheochromocytomas and normal in the 4 ganglioneuroma patients reported, and 131I-MIBG was positive in 25 (96.2%) pheochromocytomas and negative in all 4 ganglioneuromas scanned
Neither finding excludes ganglioneuroma: in German trials of localized tumors at any site in patients aged 21 years or younger, 24.5% of tested ganglioneuromas took up MIBG and 31.7% raised urinary homovanillic acid, a catecholamine metabolite
In another adrenal series catecholamine levels were normal in all 21 ganglioneuroma patients with results, and the authors concluded that isolated adrenal ganglioneuromas do not produce catecholamines; a catecholamine-secreting adrenal ganglioneuroma has been reported
Among 45 histologically confirmed adrenal ganglioneuromas at one center, every tumor with an adrenergic or noradrenergic catecholamine profile was a composite ganglioneuroma-pheochromocytoma

Show evidence (8 references)

PMID:19781327 SUPPORT DIRECT PRIMARY RESULT Human clinical

"Catecholamine levels in a 24-hour urine sample were normal in 4 patients with adrenal ganglioneuroma and increased in 36 (100%) cases with adrenal pheochromocytoma. (131)I-MIBG nuclear scan showed negative results in 4 patients (100%) with adrenal ganglioneuroma and positive results in 25..."

Retrospective series of 18 adrenal ganglioneuromas and 36 adrenal pheochromocytomas (1999-2007; ganglioneuroma mean age 41.2 years, range 16-67). 24-hour urinary catecholamines were raised in all 36 pheochromocytomas and normal in the 4 ganglioneuroma patients reported, and 131I-MIBG was positive in 25 (96.2%) pheochromocytomas and negative in all 4 ganglioneuromas scanned. The ganglioneuroma numbers are small: 9 asymptomatic ganglioneuromas under 4 cm had neither test, and the abstract does not say how many had urinary catecholamines measured. The result concerns adolescent and adult adrenal tumors. 'pheochromocytom' is PubMed's own spelling.

PMID:27465021 SUPPORT DIRECT PRIMARY RESULT Human clinical

"| | GN (n = 162) | p1 | GNBI (n = 55) | GN / GNBI (n=217) | p 2 | NB / GNBN (n = 591) | ... | Positive mIBG-uptake ... | 27/110 | <0.001 ... | 22/36 | 49/146 | <0.001 ... | 398/444 | | 24.5 % | 61.1 % | 33.6 % | 89.6 % |"

Table 1 of the German NB97/NB2004 study of localized neuroblastic tumors (patients aged 21 or younger at diagnosis, all primary sites): MIBG uptake was positive in 27 of 110 tested patients with ganglioneuroma (24.5%). This qualifies the adult adrenal series above, in which all 4 scanned ganglioneuromas were MIBG-negative: uptake is uncommon in ganglioneuroma but does occur, so a positive scan does not by itself point to pheochromocytoma. The German cohort was not restricted to adrenal tumors, included no pheochromocytomas, and does not name the MIBG isotope.

PMID:27465021 SUPPORT DIRECT PRIMARY RESULT Human clinical

"| | GN (n = 162) | p1 | GNBI (n = 55) | GN / GNBI (n=217) | p 2 | NB / GNBN (n = 591) | ... | HVA elevated ... | 45/142 | 0.001 ... | 27/44 | 72/186 | <0.001 ... | 327/531 | | 31.7 % | 61.4 % | 38.7 % | 61.6 % |"

Table 1 of the same German study: urinary homovanillic acid was elevated in 45 of 142 tested patients with ganglioneuroma (31.7%), so a raised catecholamine metabolite does not by itself exclude ganglioneuroma. The German series measured the metabolite homovanillic acid in children and young people at all primary sites, while the adult adrenal series measured 24-hour urinary catecholamines, so the two results are not directly comparable.

+ 5 more references

Schwannoma MONDO:0002546

Overlapping Features In a pooled series of adrenal cases, most of them drawn from published reports, adrenal schwannoma and adrenal ganglioneuroma were similar except that ganglioneuroma patients were younger; all of the schwannomas and 92.5% of the ganglioneuromas were nonsecretory, so hormone testing does not separate them.

Distinguishing Features

Patients with adrenal ganglioneuroma were younger than those with adrenal schwannoma (28 vs 49.5 years) in a pooled adrenal series

Show evidence (2 references)

PMID:41563553 SUPPORT DIRECT REVIEW SYNTHESIS Human clinical

"AS and AG were similar, except AG patients were younger (28 vs. 49.5 years, p = 0.003)."

This pooled series combines the authors' own adrenal schwannomas (AS) and adrenal ganglioneuromas (AG) with histopathologically confirmed cases from a systematic literature review; most of the cases come from published reports (25 of the 30 schwannomas and 25 of the 27 ganglioneuromas), so the comparison is graded as a review synthesis. The authors report the two tumors as similar except for age: patients with ganglioneuroma were younger (28 vs 49.5 years). The abstract does not list which features entered this comparison, or say whether the ages are medians or means, and it reports separately that progressive delayed enhancement occurred in all AS but not in all AG, so 'similar' should not be read as covering CT enhancement. The finding covers the adrenal site only.

PMID:41563553 SUPPORT DIRECT REVIEW SYNTHESIS Human clinical

"All AS and 92.5% of AG were nonsecretory."

In the same pooled adrenal series, all adrenal schwannomas (AS) and 92.5% of adrenal ganglioneuromas (AG) were nonsecretory, so a nonsecretory mass does not separate the two tumors. The figures describe this selected, mostly published-case adrenal series only, and the abstract does not describe what the secretory minority of ganglioneuromas secreted.

📊

Related Datasets

2

Schwann cell plasticity regulates neuroblastic tumor cell differentiation geo:GSE147635

Bulk RNA-seq of 24 human samples: six ganglioneuromas, 15 primary neuroblastomas at diagnosis and three neuroblastoma cell lines. The series reuses part of the RNA-seq data of GSE94035 and GSE90711. The paper compares the stromal Schwann cells of ganglioneuroma with the repair Schwann cells of injured human nerve; the injured-nerve samples are not among these 24.

human BULK RNA SEQ

PMID:33712610

The sample counts are from the GEO sample titles and source names.

Aberrant AKT Activation Drives Ganglioneuroma and Can Be Therapeutically Targeted by mTOR Inhibitors geo:GSE135682

Bulk RNA-seq of FACS-sorted tumour cells from the zebrafish dβh:myr-Akt2 ganglioneuroma model (four samples) and the dβh:EGFP-MYCN neuroblastoma model (four samples): the zebrafish side of the paper's cross-species comparison of ganglioneuroma and neuroblastoma gene expression.

zebrafish BULK RNA SEQ

PMID:32728700

The sample counts are from the GEO sample titles and source names.

🐁

Animal Models

1

Zebrafish dbh:myr-Akt2 transgenic ganglioneuroma model

Stable transgenic zebrafish lines that co-express mCherry and a constitutively active, membrane-targeted (myristoylated) mouse Akt2 in the peripheral sympathetic nervous system under the zebrafish dβh promoter. Tumours arise in the interrenal gland, the fish counterpart of the adrenal gland, from 13 weeks post-fertilization and reach a penetrance of 40-50% by 29 weeks. They are ganglioneuromas of differentiated, mature ganglion cells with poor Schwannian stroma, and they do not progress to neuroblastoma. A MYCN-transgenic line, Tg(dβh:EGFP-MYCN), which develops neuroblastoma in the same gland, is the paper's comparator.

Species

Zebrafish

Genotype

Tg(dβh:mCherry;dβh:myr-Akt2), two independent lines

Background

Lines maintained by crossing heterozygous transgenic fish with wild-type AB fish

Publication

PMID:32728700

Pathograph links

AKT-mTOR-S6 Pathway Activation perturbs fidelity: moderate observes: organism The transgene switches AKT signalling on in sympathoadrenal cells, and the resulting tumours carry the downstream state seen in human ganglioneuromas: high phosphorylated mTOR, S6 ribosomal protein and EIF4EBP1. Phosphorylated mTOR and S6 were undetectable in the MYCN-driven fish neuroblastomas.

Limitations: The activating event is a forced, membrane-targeted mouse Akt2, not a lesion found in patients; the cause of AKT activation in human ganglioneuroma is unknown. Because the construct bypasses upstream regulation, an allosteric AKT inhibitor that needs that regulation (MK-2206) cannot be tested in this model.

Divergences from the human mechanism

cause unrepresented qualifying

Pathway activation is imposed by a constitutively active transgene rather than arising from a patient lesion, so the model shows that active AKT is sufficient for a ganglioneuroma-like tumour, not how AKT becomes active in human tumours.

species mismatch qualifying

The readouts are from zebrafish interrenal tumours; the human side of the comparison rests on immunohistochemistry of archival tumours in the same paper.

Readouts

Phosphorylated mTOR, S6 ribosomal protein and EIF4EBP1 in tumour sections

Direction: INCREASED

Interpretation: The pathway downstream of the transgene is active in the fish ganglioneuromas, as phosphorylated mTOR and S6 are in most human ganglioneuromas.

Show evidence (1 reference)

PMID:32728700 SUPPORT PRIMARY RESULT Model organism

"Immunohistochemical analysis of tumor sections revealed high level expression of phosphorylated mTOR (Ser2448) and the mTOR targets S6 ribosomal protein (Ser235/236) and EIF4EBP1 (Thr37/46) in myr-Akt2 tumors, whereas levels of phosphorylated mTOR (Ser2448) and S6 ribosomal protein (Ser235/236)..."

Immunohistochemistry of the myr-Akt2 tumours found high phosphorylated mTOR (Ser2448), S6 ribosomal protein (Ser235/236) and EIF4EBP1 (Thr37/46), while phosphorylated mTOR and S6 were undetectable in MYCN-induced neuroblastomas.

Show evidence (1 reference)

PMID:32728700 SUPPORT PRIMARY RESULT Model organism

"Zebrafish transgenic for constitutively activated myr-Akt2 in the sympathetic nervous system were found to develop ganglioneuroma without progression to neuroblastoma. ... Mechanistically, myr-Akt2 overexpression induced sympathoadrenal lineage hyperplasia through increased cell proliferation,..."

The abstract's summary of the model: activated Akt2 in the sympathetic nervous system produces ganglioneuroma, through sympathoadrenal hyperplasia with mTOR activation.

Neuroblast-to-Ganglion Cell Maturation partially recapitulates fidelity: moderate observes: organism The fish tumours are made of differentiated, mature ganglion cells that carry neural markers and derive from sympathetic neuroblasts rather than chromaffin cells, and the authors find that they resemble human ganglioneuroma histologically and by gene expression. The model shows this mature end state, not the maturation itself.

Limitations: The model forms ganglion cells under a forced AKT signal; whether human ganglioneuromas mature from neuroblastic tumours in situ is not tested by it.

Divergences from the human mechanism

boundary omission qualifying

The node describes a neuroblastic tumour maturing step by step through intermixed ganglioneuroblastoma to ganglioneuroma. The model shows only the end of that sequence, ganglion cells of neuroblast origin, and does not show the tumour passing through the earlier stages.

species mismatch qualifying

The tumours arise in the zebrafish interrenal gland, and their expression differences from fish neuroblastoma track the human differences only moderately (Pearson r = 0.39 across 407 orthologous genes).

Show evidence (4 references)

PMID:32728700 SUPPORT PRIMARY RESULT Model organism

"Histopathological analyses revealed that these tumors were ganglioneuromas and composed of differentiated, mature ganglion cells with poor Schwannian stroma"

Histology of the myr-Akt2 tumours shows ganglioneuromas of differentiated, mature ganglion cells.

+ 3 more references

Schwannian Stromal Development fails to recapitulate fidelity: low observes: organism The fish ganglioneuromas have poor Schwannian stroma, whereas human ganglioneuroma is defined as the Schwannian stroma-dominant neuroblastic tumour.

Limitations: The model cannot be used to study how the Schwannian stroma of ganglioneuroma develops or what it does to the neuroblastic cells; the paper does not say whether the poor stroma reflects the species or the construct.

Divergences from the human mechanism

boundary omission invalidating

Schwann stromal cells, the dominant component of human ganglioneuroma, are largely absent from the fish tumours, which consist of ganglion cells.

Show evidence (1 reference)

PMID:32728700 SUPPORT PRIMARY RESULT Model organism

"Histopathological analyses revealed that these tumors were ganglioneuromas and composed of differentiated, mature ganglion cells with poor Schwannian stroma"

The same histology sentence records the poor Schwannian stroma of the fish tumours.

Show evidence (1 reference)

PMID:32728700 SUPPORT PRIMARY RESULT Model organism

"Fish transgenic for myr-Akt2 developed mCherry-positive ganglioneuromas in the IRG starting at 13 wk postfertilization (wpf) with a penetrance of 40–50% by 29 wpf"

Both myr-Akt2 lines developed ganglioneuromas in the interrenal gland from 13 weeks post-fertilization, at 40-50% penetrance by 29 weeks.

{ }

Source YAML

click to show

name: Ganglioneuroma
creation_date: '2026-10-28T16:12:00Z'
description: >-
  Ganglioneuroma is a benign peripheral neuroblastic tumor of the sympathetic
  nervous system and the most mature form in the family that also includes
  neuroblastoma and ganglioneuroblastoma. Its ganglion cells lie singly or in
  small clusters in Schwannian stroma, whose cells incorporate the neurites of
  the ganglion cells, so that no naked neurites are identified around them. The
  International Neuroblastoma Pathology Classification (INPC) makes
  ganglioneuroma its Schwannian stroma-dominant category, with a maturing
  subtype, which besides fully mature ganglion cells contains a minor component
  of scattered differentiating neuroblasts and/or maturing ganglion cells, and a
  mature subtype, whose ganglion cells are all completely mature; the INPC
  always classifies ganglioneuroma as favorable histology. Ganglioneuroma is
  usually diagnosed in older children and adults. In German trials of localized
  neuroblastic tumors in patients aged 21 years or younger, 144 of 162
  ganglioneuromas (88.9%) were of the maturing subtype, and median age at
  diagnosis was 71 months for maturing and 125 months for mature
  ganglioneuroma, against 9 months for neuroblastoma and nodular
  ganglioneuroblastoma taken together. In the cited hospital series the tumors
  arose most often in the retroperitoneum or elsewhere in the abdomen,
  including the adrenal gland, and next in the thorax, mainly in the posterior
  mediastinum; fewer arose in the presacral space or the neck, and many were
  found incidentally. Pain was the commonest symptom leading to diagnosis in
  the German trials, and watery diarrhea that the authors attributed to tumor
  secretion of vasoactive intestinal peptide has been described in case
  reports. In two immunohistochemistry series every ganglioneuroma tested
  expressed PHOX2B, and in one hospital's tumors phosphorylated AKT, mTOR and
  S6 were detected more often in ganglioneuroma than in poorly differentiated
  neuroblastoma. No initiating lesion has been described; MYCN amplification
  has been found in a few maturing ganglioneuromas. In the German trials urinary
  catecholamine metabolites were raised, and MIBG was taken up, less often in
  ganglioneuroma than in intermixed ganglioneuroblastoma or in neuroblastoma.
  Treatment is surgical resection or, for selected asymptomatic tumors,
  observation. In the German trials no tumor progressed after complete
  resection or with residuals under 2 cm, chemotherapy had no substantial
  effect in the 11 patients who received it, 2 of them with ganglioneuroma, no
  patient died of tumor progression, and the one patient with ganglioneuroma
  who died had complications of surgery. The cited surgical series report postoperative
  complication rates of 19% to 43.1%, counted per patient or per operation and
  in two series pooled with intermixed ganglioneuroblastoma, and one patient
  in a 51-patient series of resected retroperitoneal tumors died after
  surgery. Whether every ganglioneuroma arises by maturation of a
  neuroblastoma is unproven (discussion gn_origin).
categories:
- Benign Neoplasm
- Neural Tumor
- Solid Tumor
parents:
- neuroblastic tumor
synonyms:
- ganglioneuroma (Schwannian stroma-dominant)
- GN
notes: >-
  This entry covers ganglioneuroma of the peripheral sympathetic nervous system
  in both INPC subtypes, maturing and mature. MONDO:0005033 also has two central
  nervous system parents, central nervous system primitive neuroectodermal
  neoplasm (MONDO:0000640) and mixed neuronal-glial tumor (MONDO:0016729), and
  one child, cutaneous ganglioneuroma (MONDO:0002293); NCIT files
  ganglioneuromatosis (NCIT:C66804) and skin (NCIT:C4481), choroidal
  (NCIT:C188956) and colorectal (NCIT:C96514) ganglioneuroma beneath
  NCIT:C3049. None of these is covered. MONDO defines ganglioneuroma as a tumor
  that occurs in childhood, but the cited series that include adults
  (PMID:42537227, PMID:41306794, PMID:33721367) show that it also presents in
  adults. Intestinal ganglioneuromatosis is a different lesion and is not
  modelled as a subtype: its generalized form is usually associated with NF1 or
  MEN (PMID:23512313), and in a literature review of 55 patients with MEN2B and
  gastrointestinal symptoms the histological finding of intestinal
  ganglioneuromatosis led to the diagnosis of MEN2B in 15 (PMID:27899172).
  Composite pheochromocytoma-ganglioneuroma is recorded under the adrenal gland
  pheochromocytoma differential diagnosis, not as a subtype. Several cited
  series pool ganglioneuroma with intermixed ganglioneuroblastoma
  (PMID:39582110, PMID:29369484) or restrict it by age and stage: the German
  series covers localized tumors diagnosed in 2000-2009 in patients aged 21
  years or younger (PMID:27465021), and mature ganglioneuroma was not eligible
  for the CCG/COG studies and was excluded from the CCG/COG series
  (PMID:19530234). No node is marked as the origin node (genetic_context),
  because no initiating lesion has been described for ganglioneuroma: the
  authors of the AKT study write that little is known about the genetics of
  mature ganglioneuroma and that the etiology and molecular basis of childhood
  ganglioneuroma remain elusive, and they only propose that somatically
  acquired mutations or epigenetic alterations in the PI3K-AKT-mTOR pathway
  may initiate it in individual patients (PMID:32728700). MYCN amplification,
  found in 2 maturing ganglioneuromas of the CCG/COG series, is recorded as a
  biomarker, not as an initiating lesion. icdo_morphology is not asserted:
  MONDO records the ICD-O cross-reference 9490/0, a benign code, while
  Embryonal Neoplasm, the value the Neuroblastoma and Ganglioneuroblastoma
  entries use, is defined as cancer arising from embryonic tissue, and its
  meaning NCIT:C3264 is not an ancestor of NCIT:C3049, whose NCIT parents are
  Benign Peripheral Nervous System Neoplasm (NCIT:C213862) and Autonomic
  Nervous System Neoplasm (NCIT:C5112).
epidemiology:
- name: Age at diagnosis
  description: >-
    Ganglioneuroma is usually diagnosed in older children and adults. In German
    trials of localized neuroblastic tumors in patients aged 21 years or
    younger, median age at diagnosis was 71 months for maturing and 125 months
    for mature ganglioneuroma, against 61 months for intermixed
    ganglioneuroblastoma and 9 months for neuroblastoma and nodular
    ganglioneuroblastoma taken together. Hospital series that set no age limit
    report a mean age of 26.9 years for 101 patients at one institution and a
    median age at diagnosis of 28 years (range 12-73) for 51 patients with a
    resected retroperitoneal tumor, and a single-center adrenal cohort pooled
    with a systematic review of published adrenal series gives a mean age at
    diagnosis of 39 years.
  evidence:
  - reference: PMID:19530234
    reference_title: "Clinicopathological characteristics of ganglioneuroma and ganglioneuroblastoma: a report from the CCG and COG."
    supports: SUPPORT
    directness: DIRECT
    quote_role: BACKGROUND
    evidence_source: HUMAN_CLINICAL
    snippet: "GN is recognized as a benign tumor usually diagnosed in older children and in adults (11) (12)."
    explanation: >-
      The introduction states, citing earlier literature (references 11 and
      12), that ganglioneuroma is a benign tumor usually diagnosed in older
      children and in adults. It restates prior work rather than a result of
      this study's CCG/COG cohort, which was pediatric and excluded mature
      ganglioneuroma.
  - reference: PMID:27465021
    reference_title: "Treatment and outcome of Ganglioneuroma and Ganglioneuroblastoma intermixed."
    supports: SUPPORT
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    evidence_source: HUMAN_CLINICAL
    snippet: "Median age at diagnosis increased with grade of differentiation (NB/GNBN: 9; GNBI: 61; GN-maturing: 71; GN-mature: 125 months, p < 0.001)."
    explanation: >-
      In this retrospective study of 808 consecutive localized neuroblastic
      tumors registered in the German neuroblastoma trials NB97 and NB2004, in
      patients aged 21 years or younger with central histology review by INPC
      criteria, median age at diagnosis rose in order across the groups: 9
      months for neuroblastoma and nodular ganglioneuroblastoma, which the paper
      reports only as one pooled group of 591, 61 months for the 55 intermixed
      ganglioneuroblastomas, 71 months for the 144 maturing and 125 months for
      the 18 mature ganglioneuromas. The abstract gives one p-value (p < 0.001)
      for the comparison, and no pairwise comparisons are reported in the text.
      Metastatic tumors and patients over 21 were excluded, so the 9-month
      figure is not the median age of neuroblastoma as a whole, and the
      ganglioneuroma medians leave out older patients.
  - reference: PMID:42537227
    reference_title: "A comprehensive analysis of ganglioneuromas: a 30-year experience of 101 patients."
    supports: SUPPORT
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    evidence_source: HUMAN_CLINICAL
    snippet: "A total of 101 patients (62.3% female, mean age 26.9 ± 15.9 years) were identified."
    explanation: >-
      In this retrospective review of all patients diagnosed with ganglioneuroma
      at one institution between 1995 and 2025, the 101 patients had a mean age
      of 26.9 ± 15.9 years. The abstract gives no age range and does not say
      whether age was taken at diagnosis or at presentation. No age limit is
      stated and PubMed indexes the record for child and adolescent age groups,
      so this is not an adult-only series. It is one institution's case mix, not
      a population sample.
  - reference: PMID:41306794
    reference_title: "Clinical features and oncologic outcomes of primary retroperitoneal ganglioneuroma: a retrospective cohort study of 51 patients from a high-volume sarcoma center."
    supports: SUPPORT
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    evidence_source: HUMAN_CLINICAL
    snippet: "Fifty-one consecutive patients (18 males, 33 females; median age 28 years, range 12-73) with newly diagnosed RGN were enrolled."
    explanation: >-
      This retrospective cohort of 51 consecutive patients whose primary
      retroperitoneal ganglioneuroma (RGN) was resected at one high-volume
      sarcoma center (Peking University International Hospital) reports a median
      age at diagnosis of 28 years (range 12-73). The range starts at 12 years,
      so the series is not restricted to adults. It covers resected
      retroperitoneal tumors at one specialist center, not all ganglioneuromas.
  - reference: PMID:33721367
    reference_title: "Presentation and outcomes of adrenal ganglioneuromas: A cohort study and a systematic review of literature."
    supports: SUPPORT
    directness: DIRECT
    quote_role: REVIEW_SYNTHESIS
    evidence_source: HUMAN_CLINICAL
    snippet: "Overall, in the cohort study and systematic review, the mean age at diagnosis of AGN was 39 years, and 47% were women, Table 2."
    explanation: >-
      Pooling the authors' single-center cohort of adrenal ganglioneuroma (AGN)
      at Mayo Clinic with the 14 published series in their systematic review
      (the pooled-analysis row of Table 2), the mean age at diagnosis was 39
      years. It applies to adrenal tumors only, and it is not an adult-only
      figure: the pooled series include a pediatric one (mean age 7.3 years in
      Table 2). The pooled patients include composite
      ganglioneuroma-pheochromocytoma tumors, 20 of the authors' 45 patients,
      who were older than patients with pure AGN. The authors state that the
      data were insufficient for meta-analysis, so this is a descriptive pooled
      figure, and demographics were reported in only 10 of the 14 included
      studies.
- name: Sex distribution
  description: >-
    The share of women differs between series: 62.3% of 101 patients at one
    institution and 33 of 51 patients with a resected retroperitoneal tumor,
    against 47% in a single-center adrenal cohort pooled with a systematic
    review of published adrenal series. These are hospital case mixes, not
    population sex ratios, and they do not establish a sex predilection.
  evidence:
  - reference: PMID:42537227
    reference_title: "A comprehensive analysis of ganglioneuromas: a 30-year experience of 101 patients."
    supports: SUPPORT
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    evidence_source: HUMAN_CLINICAL
    snippet: "A total of 101 patients (62.3% female, mean age 26.9 ± 15.9 years) were identified."
    explanation: >-
      This single-institution retrospective series of 101 patients diagnosed
      with ganglioneuroma between 1995 and 2025 was 62.3% female. That is one
      institution's case mix and does not establish a sex predilection.
  - reference: PMID:41306794
    reference_title: "Clinical features and oncologic outcomes of primary retroperitoneal ganglioneuroma: a retrospective cohort study of 51 patients from a high-volume sarcoma center."
    supports: SUPPORT
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    evidence_source: HUMAN_CLINICAL
    snippet: "Fifty-one consecutive patients (18 males, 33 females; median age 28 years, range 12-73) with newly diagnosed RGN were enrolled."
    explanation: >-
      The cohort of 51 patients with a resected primary retroperitoneal
      ganglioneuroma comprised 18 males and 33 females. This is one center's
      surgical series, not a population-level sex ratio.
  - reference: PMID:33721367
    reference_title: "Presentation and outcomes of adrenal ganglioneuromas: A cohort study and a systematic review of literature."
    supports: SUPPORT
    directness: DIRECT
    quote_role: REVIEW_SYNTHESIS
    evidence_source: HUMAN_CLINICAL
    snippet: "Overall, in the cohort study and systematic review, the mean age at diagnosis of AGN was 39 years, and 47% were women, Table 2."
    explanation: >-
      In the pooled adrenal data of a single-center cohort and a systematic
      review of 14 published series, 47% were women, with demographics reported
      in only 10 of the 14 included studies. This pooled figure is a case mix of
      hospital series, not a population sex ratio, and it does not establish a
      sex predilection.
- name: Primary tumor site
  description: >-
    In a single-institution series of 101 patients, tumors arose in the
    retroperitoneum (45.5%), the thoracic paraspinal or mediastinal region
    (32.7%), the presacral space (17.8%) and the cervical region (4%); that
    series does not report the adrenal gland as a separate site. In German
    trials of localized neuroblastic tumors in patients aged 21 years or
    younger, 51 of 161 ganglioneuromas (31.7%) were adrenal, 67 (41.6%)
    abdomino-pelvic and 43 (26.7%) thoraco-cervical. In a separate surgical
    series of 22 thoracic ganglioneuromas, 19 lay in the posterior mediastinum.
  evidence:
  - reference: PMID:42537227
    reference_title: "A comprehensive analysis of ganglioneuromas: a 30-year experience of 101 patients."
    supports: SUPPORT
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    evidence_source: HUMAN_CLINICAL
    snippet: "Tumors most commonly arose in the retroperitoneum (n = 46, 45.5%), thoracic paraspinal/mediastinal region (n = 33, 32.7%), presacral space (n = 18, 17.8%), and cervical region (n = 4, 4%)."
    explanation: >-
      Retrospective review of all 101 patients diagnosed with ganglioneuroma at
      a single institution between 1995 and 2025 (mean age 26.9 years). Tumors
      arose in the retroperitoneum in 46 (45.5%), the thoracic paraspinal or
      mediastinal region in 33 (32.7%), the presacral space in 18 (17.8%) and
      the cervical region in 4 (4%). The abstract gives no separate adrenal
      category, so it does not show how adrenal tumors were counted, and a
      single institution's series is not a population estimate of where
      ganglioneuromas arise.
  - reference: PMID:27465021
    reference_title: "Treatment and outcome of Ganglioneuroma and Ganglioneuroblastoma intermixed."
    supports: SUPPORT
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    evidence_source: HUMAN_CLINICAL
    snippet: "| | GN (n = 162) | p1 | GNBI (n = 55) | GN / GNBI (n=217) | p 2 | NB / GNBN (n = 591) | | Localization | | | | | | | | Adrenal ... | 51/161 | 0.613* ... | 15/55 | 66/216 | 0.001 * ... | 256/591 | | 31.7 % | 27.3 % | 30.6 % | 43.3 % | | Abdomino-pelvic ... | 67/161 | | 21/55 | 88/216 | | 211/591 | | 41.6 % | | 38.2 % | 40.7% | | 35.7 % | | Thoraco-cervical ... | 43/161 | | 19/55 | 62/216 | | 123/591 | | 26.7 % | | 34.5 % | 28.7 % | | 20.8 % |"
    explanation: >-
      Table 1 of this retrospective analysis of localized neuroblastic tumors
      registered in the German neuroblastoma trials NB97 and NB2004 and
      diagnosed between 2000 and 2009 in patients aged 21 years or younger, with
      central histological review; the excerpt gives the column headings and the
      three Localization rows, each count row followed by its percentage row,
      whose first value belongs to the ganglioneuroma (GN) column. In that
      column the site rows use a denominator of 161 of the 162 ganglioneuromas
      (the table does not say why one is missing): 51 were adrenal (31.7%), 67
      abdomino-pelvic (41.6%) and 43 thoraco-cervical (26.7%). The other columns
      are intermixed ganglioneuroblastoma, the pooled mature tumors, and
      neuroblastoma with nodular ganglioneuroblastoma. The abdomino-pelvic row
      is not split into abdominal, pelvic or retroperitoneal sites, and the
      thoraco-cervical row counts thoracic and neck tumors together. The
      distribution describes this pediatric registry cohort, not ganglioneuroma
      at all ages.
  - reference: PMID:22573298
    reference_title: "CT and MRI findings of thoracic ganglioneuroma."
    supports: SUPPORT
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    evidence_source: HUMAN_CLINICAL
    snippet: "Of 22 lesions, 19 occurred in the posterior mediastinum, 2 in the lateral pleura and 1 in the right chest."
    explanation: >-
      Retrospective series of 22 thoracic ganglioneuromas confirmed by surgery
      and pathology, collected from July 2002 to December 2010, in patients aged
      4 to 57 years (median 21). Of the 22 lesions, 19 lay in the posterior
      mediastinum, 2 in the lateral pleura and 1 in the right chest; the authors
      could not tell whether the right-chest tumor came from the posterior
      mediastinum or the lateral pleura. The 19 of 22 is a share of resected
      thoracic tumors in this series, not of all ganglioneuromas.
clinical_burden:
  burden_level: LOW
  rationale: >-
    Ganglioneuroma is benign and many tumors are found incidentally: 72% of
    lesions in a single-institution series of 101 patients were incidental
    findings, 70 of 161 patients aged 21 years or younger with localized
    ganglioneuroma in German trials (43.5%) were diagnosed by chance, and 72% of
    adrenal ganglioneuromas pooled from a single-center cohort and a systematic
    review were discovered incidentally. In the German trials no patient died of
    tumor progression; the one patient with ganglioneuroma who died had
    complications of surgery after complete resection. Treatment carries its
    own morbidity: a UK nationwide series reported a 19% complication rate and
    a Hospital for Sick Children series post-operative complications in 30% of
    surgical patients, both pooling ganglioneuroma with intermixed
    ganglioneuroblastoma; complications followed surgery in 21.6% of 51 patients
    with a resected retroperitoneal ganglioneuroma, one of whom died of
    intestinal ischemia and necrosis, and short-term complications followed
    43.1% of operations in the 101-patient series. Malignant transformation is
    rare: a 2000 literature review counted ten reported cases of malignant
    peripheral nerve sheath tumor arising in a ganglioneuroma, either de novo
    or at a site of previous irradiation, and the 101-patient series observed
    no malignant transformation during its follow-up.
  evidence:
  - reference: PMID:42537227
    reference_title: "A comprehensive analysis of ganglioneuromas: a 30-year experience of 101 patients."
    supports: SUPPORT
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    evidence_source: HUMAN_CLINICAL
    snippet: "A total of 101 patients (62.3% female, mean age 26.9 ± 15.9 years) were identified. ... Most lesions (72%) were incidental findings."
    explanation: >-
      Retrospective single-institution series of patients diagnosed with
      ganglioneuroma between 1995 and 2025, published in a neurosurgical
      journal. Among 101 patients (mean age 26.9 years), 72% of lesions were
      incidental findings. The abstract counts patients rather than lesions and
      does not say what the 72% is a share of. Tumors arose in the
      retroperitoneum, the thoracic paraspinal or mediastinal region, the
      presacral space and the cervical region; no adrenal site is listed, so the
      case mix may differ from adrenal or childhood series.
  - reference: PMID:27465021
    reference_title: "Treatment and outcome of Ganglioneuroma and Ganglioneuroblastoma intermixed."
    supports: SUPPORT
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    evidence_source: HUMAN_CLINICAL
    snippet: "Diagnosis of localized NT was made by routine check-ups or visits to the doctor for other reasons in 50 % of all cases with no significant difference between mature and immature tumors. ... | | GN (n = 162) | p1 | GNBI (n = 55) | GN / GNBI (n=217) | p 2 | NB / GNBN (n = 591) | ... | Diagnosis by chance ... | 70/161 | 0.163 ... | 30/55 | 100/216 | 0.177 ... | 306/591 | | 43.5 % | 54,5 % | 46.3 % | 51.8 % |"
    explanation: >-
      Retrospective study of localized neuroblastic tumors registered in the
      German NB97 and NB2004 trials (diagnosed 2000-2009 at age 21 or younger,
      with central histology review). The text says diagnosis was made at
      routine check-ups or visits to the doctor for other reasons in 50% of all
      cases, with no significant difference between mature and immature tumors.
      Table 1 (the column headings and the Diagnosis by chance row) gives 70 of
      161 patients with ganglioneuroma (43.5%), against 30 of 55 with intermixed
      ganglioneuroblastoma (54.5%) and 306 of 591 with neuroblastoma or nodular
      ganglioneuroblastoma (51.8%); p1 compares ganglioneuroma with intermixed
      tumors (0.163) and p2 the pooled mature tumors with the immature ones
      (0.177). Chance discovery is therefore common in ganglioneuroma but not
      distinctive of it. Metastatic tumors were excluded.
  - reference: PMID:33721367
    reference_title: "Presentation and outcomes of adrenal ganglioneuromas: A cohort study and a systematic review of literature."
    supports: SUPPORT
    directness: DIRECT
    quote_role: REVIEW_SYNTHESIS
    evidence_source: HUMAN_CLINICAL
    snippet: "Overall, in the cohort study and systematic review, the mean age at diagnosis of AGN was 39 years, and 47% were women, Table 2. AGN were discovered incidentally in 72% of patients, due to symptoms of mass effect in 20%, and due to other symptoms in 8%."
    explanation: >-
      Pooled descriptive total from a single-center retrospective cohort of 45
      patients with adrenal ganglioneuroma (Mayo Clinic, 1995-2019) and a PRISMA
      systematic review of 14 published series, 421 patients in the pooled
      analysis. Across the cohort and the review, 72% of patients were
      discovered incidentally, 20% through symptoms of mass effect and 8%
      through other symptoms. The authors judged the data insufficient for
      meta-analysis, and mode of discovery was reported in only 10 of the 14
      reviewed studies, so the 72% is a share of the patients in those series
      and the cohort, not of all 421; one of those series, a 50-patient
      cross-sectional multicenter study, recorded every case as incidental
      (Table 2). It covers adrenal tumors only. In the single-center cohort
      alone 76% were incidental, and its 20 composite
      ganglioneuroma-pheochromocytoma tumors were found incidentally less often
      than pure ganglioneuromas (65% vs 84%).
  - reference: PMID:27465021
    reference_title: "Treatment and outcome of Ganglioneuroma and Ganglioneuroblastoma intermixed."
    supports: SUPPORT
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    evidence_source: HUMAN_CLINICAL
    snippet: "Two patients died of treatment related complications. One patient with GN died of surgery related complications after complete tumor resection in initial surgery. One patient with GNBI died of heart failure due to chemotherapy related pulmonary edema. However, no patient died of tumor progression."
    explanation: >-
      This retrospective analysis of the German neuroblastoma trials NB97 and
      NB2004 covers patients aged 21 or younger with a localized neuroblastic
      tumor diagnosed between 1 January 2000 and 31 December 2009; 162 of the 808
      tumors were ganglioneuroma (GN) and 55 were intermixed
      ganglioneuroblastoma (GNBI). Two deaths are reported, both from
      treatment-related complications: one GN patient died of surgery-related
      complications after complete resection at initial surgery, and one GNBI
      patient died of chemotherapy-related pulmonary edema. No patient in the
      pooled GN/GNBI cohort died of tumor progression, which includes every GN
      patient. The finding is limited to localized disease and to the study's
      follow-up: residual GN tumors had a median observation time of 42 months.
      Local progression did occur in three GN patients, all with residuals over
      2 cm, so the quote supports the absence of tumor deaths rather than the
      absence of progression.
  - reference: PMID:42537227
    reference_title: "A comprehensive analysis of ganglioneuromas: a 30-year experience of 101 patients."
    supports: SUPPORT
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    evidence_source: HUMAN_CLINICAL
    snippet: "Short-term postoperative complications occurred in 43.1% of cases, most commonly neurological deficits (22.2%)."
    explanation: >-
      This 30-year single-institution retrospective review of 101 patients with
      ganglioneuroma reports that seventy patients underwent 72 surgeries, all
      of them gross-total (53/72) or subtotal (19/72) resections, and the
      abstract uses 'cases' for those operations. Short-term postoperative
      complications followed 43.1% of these operations, most commonly
      neurological deficits (22.2%). The abstract does not say what the 22.2% is
      a share of, and it does not grade the complications by severity. The
      figure measures short-term surgical morbidity in this series, not lasting
      harm: the same abstract reports most patients stable or improved from
      baseline at final follow-up.
  - reference: PMID:41306794
    reference_title: "Clinical features and oncologic outcomes of primary retroperitoneal ganglioneuroma: a retrospective cohort study of 51 patients from a high-volume sarcoma center."
    supports: SUPPORT
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    evidence_source: HUMAN_CLINICAL
    snippet: "Postoperative complications occurred in 11 patients (21.6%), including gastroparesis (n = 3), pancreatic fistula (n = 3), liver function impairment (n = 2), wound infection (n = 2), and one mortality due to intestinal ischemia and necrosis."
    explanation: >-
      In this retrospective cohort of 51 consecutive patients whose primary
      retroperitoneal ganglioneuroma was resected at one high-volume sarcoma
      center, postoperative complications occurred in 11 patients (21.6%), and
      one patient died of intestinal ischemia and necrosis; the Results place
      the death on postoperative day 8, from bowel ischemia with septic shock.
      The tumors were large (maximum diameter 4.1-30.2 cm) and 14 patients had
      multivisceral resection, and the authors warn that their referral cohort
      may be biased towards complex cases, so the rates may not generalize. The
      figure counts patients, not operations, and covers retroperitoneal tumors
      only.
  - reference: PMID:39582110
    reference_title: "Management of Ganglioneuroma and Ganglioneuroblastoma Intermixed: A United Kingdom Children's Cancer and Leukaemia Group (UK CCLG) Nationwide Study Report."
    supports: SUPPORT
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    evidence_source: HUMAN_CLINICAL
    snippet: "Gross total resection (GTR) was achieved in 79% of patients with a 19% complication rate."
    explanation: >-
      In this UK CCLG retrospective series of 259 patients with non-metastatic
      ganglioneuroma or intermixed ganglioneuroblastoma (163 with
      ganglioneuroma), gross total resection was achieved in 79% of patients
      with a 19% complication rate. The abstract does not say whether the 19% is
      a share of all operated patients, of operations or of the gross total
      resections, does not grade the complications, and does not report them
      for ganglioneuroma separately.
  - reference: PMID:29369484
    reference_title: "Characteristics and management of ganglioneuroma and ganglioneuroblastoma-intermixed in children and adolescents."
    supports: SUPPORT
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    evidence_source: HUMAN_CLINICAL
    snippet: "There were post-operative complications in 15 of the 50 (30%) surgical patients."
    explanation: >-
      In this Hospital for Sick Children retrospective series (1990-2014) of 67
      children and adolescents with ganglioneuroma (50) or intermixed
      ganglioneuroblastoma (17), 15 of the 50 surgical patients (30%) had
      post-operative complications. The abstract does not split the
      complications by histology, and it reports that the presence of
      imaging-defined risk factors correlated with complications.
  - reference: PMID:42537227
    reference_title: "A comprehensive analysis of ganglioneuromas: a 30-year experience of 101 patients."
    supports: SUPPORT
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    evidence_source: HUMAN_CLINICAL
    snippet: "GNs demonstrate indolent behavior, low recurrence rates, and no observed malignant transformation in this large cohort."
    explanation: >-
      A retrospective review of 101 patients diagnosed with ganglioneuroma at a
      single institution between 1995 and 2025 concludes that the tumors behave
      indolently, recur rarely and showed no malignant transformation. The
      abstract's results give the figures: 'Two patients experienced recurrence
      (2.9%, 2/70). No malignant transformations were observed.' The recurrence
      denominator is the 70 operated patients, not all 101. The absence of
      transformation was observed over a mean final follow-up of 33.8 months
      (90.9 months for the 31 patients managed by observation), so it cannot
      exclude a rare late event.
  - reference: PMID:10755757
    reference_title: "Malignant peripheral nerve-sheath tumor arising in a previously irradiated neuroblastoma: report of 2 cases and a review of the literature."
    supports: SUPPORT
    directness: DIRECT
    quote_role: BACKGROUND
    evidence_source: HUMAN_CLINICAL
    snippet: "Only ten cases of the rare occurrence of a malignant peripheral nerve-sheath tumor (MPNST) arising in a ganglioneuroma either de novo or at a site of previous irradiation have been reported."
    explanation: >-
      This case report and literature review, published in 2000, states in its
      background that only ten cases of malignant peripheral nerve sheath tumor
      (MPNST) arising in a ganglioneuroma had been reported, either de novo or at
      a site of previous irradiation. A count of reported cases is not an
      incidence rate; it supports malignant transformation being rare while
      showing that it does occur. The sentence restates earlier literature
      rather than the paper's own finding. The abstract does not say how many of
      the ten arose de novo. The paper's own two cases, additional to the ten,
      arose inside a benign ganglioneuroma 12 years after radiotherapy for a
      ganglioneuroblastoma and a neuroblastoma, so some reported
      transformations occur at previously irradiated sites rather than in an
      untreated primary ganglioneuroma. Ten is the count as of this review, not
      a current total.
has_subtypes:
- name: Maturing
  display_name: "Ganglioneuroma, maturing (Schwannian stroma-dominant)"
  classification: histological
  subtype_term:
    preferred_term: maturing ganglioneuroma
    term:
      id: NCIT:C42064
      label: Maturing Ganglioneuroma
  subtype_frequency: VERY_FREQUENT
  description: >-
    In the INPC, maturing ganglioneuroma (Schwannian stroma-dominant) is
    composed predominantly of ganglioneuromatous stroma with a minor component
    of individually scattered differentiating neuroblasts and/or maturing
    ganglion cells, in addition to fully mature ganglion cells; the fully mature
    ganglion cells are always covered with satellite cells. The INPC assigns
    tumors in this category to its favorable histology group. The subtype
    corresponds to the tumor group that the earlier Shimada classification
    called ganglioneuroblastoma, well differentiated. In German trials of
    localized tumors in patients aged 21 years or younger, 144 of 162
    ganglioneuromas (88.9%) were maturing, with a median age at diagnosis of 71
    months; the very-frequent band describes that cohort. In CCG/COG studies,
    all 36 patients with maturing ganglioneuroma and a known stage had INSS
    stage 1-3 disease.
  evidence:
  - reference: PMID:19530234
    reference_title: "Clinicopathological characteristics of ganglioneuroma and ganglioneuroblastoma: a report from the CCG and COG."
    supports: SUPPORT
    directness: DIRECT
    quote_role: BACKGROUND
    evidence_source: OTHER
    snippet: "Ganglioneuroma-Maturing (Schwannian stroma-dominant): Composed predominantly of ganglioneuromatous stroma with a minor component of individually scattered, evenly or unevenly distributed differentiating neuroblasts and/or maturing ganglion cells, in addition to fully mature ganglion cells. Fully mature ganglion cells are always covered with satellite cells. Tumors in this category are classified into a Favorable Histology Group."
    explanation: >-
      Table I of this CCG/COG clinicopathological series of 552 ganglioneuroma
      and ganglioneuroblastoma cases restates the International Neuroblastoma
      Pathology Classification definition of the ganglioneuroma-maturing
      subtype (Schwannian stroma-dominant). The tumor is mostly
      ganglioneuromatous stroma, with a minor component of individually
      scattered differentiating neuroblasts and/or maturing ganglion cells
      beside fully mature ganglion cells. The fully mature ganglion cells are
      always covered with satellite cells, and tumors in this category are
      classified as favorable histology. It is a classification rule restated
      from the INPC papers, not a result of this cohort.
  - reference: PMID:19530234
    reference_title: "Clinicopathological characteristics of ganglioneuroma and ganglioneuroblastoma: a report from the CCG and COG."
    supports: SUPPORT
    directness: DIRECT
    quote_role: BACKGROUND
    evidence_source: OTHER
    snippet: "According to the INPC, tumors in the GN category are further classified into GN-Maturing subtype (the same tumor group described as “Ganglioneuroblastoma, well differentiated” in the Shimada classification system3) and GN-Mature subtype (completely mature form of neuroblastic tumor)."
    explanation: >-
      In the introduction of a Children's Cancer Group and Children's Oncology
      Group (CCG/COG) clinicopathological series, Okamatsu et al. restate the
      INPC subdivision of the ganglioneuroma category: GN-Maturing, which they
      equate with the tumor group that the earlier Shimada classification (the
      system the INPC adapted) called ganglioneuroblastoma, well
      differentiated, and GN-Mature, the completely mature form of neuroblastic
      tumor. This is the split the Maturing and Mature subtypes encode. The
      sentence restates a published classification; it is not a result from the
      paper's own cohort.
  - reference: PMID:10421272
    reference_title: "Terminology and morphologic criteria of neuroblastic tumors: recommendations by the International Neuroblastoma Pathology Committee."
    supports: SUPPORT
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    evidence_source: HUMAN_CLINICAL
    snippet: "Based on morphologic criteria defined in this article, NTs were classified into four categories and their subtypes: 1) neuroblastoma (Schwannian stroma-poor), undifferentiated, poorly differentiated, and differentiating; 2) ganglioneuroblastoma, intermixed (Schwannian stroma-rich); 3) ganglioneuroma (Schwannian stroma-dominant), maturing and mature; and 4) ganglioneuroblastoma, nodular (composite Schwannian stroma-richlstroma-dominant and stroma-poor)."
    explanation: >-
      The 1999 terminology paper of the International Neuroblastoma Pathology
      Committee, whose six member pathologists defined the morphologic criteria
      from a review of 227 cases, classifies neuroblastic tumors into four
      categories. Ganglioneuroma is the third, the Schwannian stroma-dominant
      category, with maturing and mature subtypes. The abstract prints the
      composite label of nodular ganglioneuroblastoma as
      'stroma-richlstroma-dominant', and the quote keeps that spelling. The
      abstract does not assign ganglioneuroma to a prognostic group; the
      classification itself is reported in the companion article
      (PMID:10421273).
  - reference: PMID:19530234
    reference_title: "Clinicopathological characteristics of ganglioneuroma and ganglioneuroblastoma: a report from the CCG and COG."
    supports: SUPPORT
    directness: DIRECT
    quote_role: BACKGROUND
    evidence_source: OTHER
    snippet: "GNB-Intermixed (Schwannian stroma-rich) and GN (Schwannian stroma-dominant) tumors are always classified into the FH group."
    explanation: >-
      In the introduction of a Children's Cancer Group and Children's Oncology
      Group study of 552 ganglioneuroma and ganglioneuroblastoma cases, Okamatsu
      et al. restate the International Neuroblastoma Pathology Classification
      (INPC) rule: ganglioneuroma (Schwannian stroma-dominant) tumors, like
      intermixed ganglioneuroblastoma, are always classified into the Favorable
      Histology (FH) group. The sentence restates the INPC papers rather than
      reporting a result of this cohort, and it states the rule for the
      ganglioneuroma category as a whole, which includes this subtype.
  - reference: PMID:27465021
    reference_title: "Treatment and outcome of Ganglioneuroma and Ganglioneuroblastoma intermixed."
    supports: SUPPORT
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    evidence_source: HUMAN_CLINICAL
    snippet: "In detail, 162 of 808 tumors (20.0 %) were classified as GN. The vast majority (n = 144, 88.9 %) of GN were subclassified as maturing subtype, only 18 GN (11.1 %) as mature subtype."
    explanation: >-
      Results of a retrospective analysis of localized neuroblastic tumors
      registered in the German neuroblastoma trials NB97 and NB2004, restricted
      to patients diagnosed between 1 January 2000 and 31 December 2009, aged 21
      years or younger, with central histological review and INPC
      classification and a diagnosis made histologically before any cytotoxic
      treatment. Of the 162 tumors classified as ganglioneuroma, 144 (88.9%)
      were the maturing subtype and 18 (11.1%) the mature subtype, which places
      maturing ganglioneuroma in the very-frequent band and mature
      ganglioneuroma in the occasional band in this cohort. Patients over 21
      were not included, and the same study reported a higher median age at
      diagnosis for the mature than for the maturing subtype (125 vs 71
      months), so a series that includes adults may give a different split. The
      authors also note that individual pathologists might set the border
      between intermixed ganglioneuroblastoma and maturing ganglioneuroma
      slightly differently, so that central review by one pathologist could
      shift tumors systematically towards ganglioneuroma or intermixed
      ganglioneuroblastoma.
  - reference: PMID:27465021
    reference_title: "Treatment and outcome of Ganglioneuroma and Ganglioneuroblastoma intermixed."
    supports: SUPPORT
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    evidence_source: HUMAN_CLINICAL
    snippet: "Median age at diagnosis increased with grade of differentiation (NB/GNBN: 9; GNBI: 61; GN-maturing: 71; GN-mature: 125 months, p < 0.001)."
    explanation: >-
      In German trials of localized neuroblastic tumors in patients aged 21
      years or younger, the median age at diagnosis of the 144 maturing
      ganglioneuromas was 71 months, against 125 months for the 18 mature ones
      and 61 months for intermixed ganglioneuroblastoma. The abstract gives a
      single p-value for the gradient as a whole rather than a test of maturing
      against mature, and patients over 21 were excluded.
  - reference: PMID:19530234
    reference_title: "Clinicopathological characteristics of ganglioneuroma and ganglioneuroblastoma: a report from the CCG and COG."
    supports: SUPPORT
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    evidence_source: HUMAN_CLINICAL
    snippet: "| GN-maturing N (%) | GNB-intermixed N (%) | GNB-nodular FS N (%) | GNB-nodular US N (%) | ... INSS stage ... | 1, 2, 3 | 36 (100%) | 187 (99%) | 56 (95%) | 116 (47%) | | 4 | 0 (0%) | 2 (1%) | 3 (5%) | 132 (53%) | | Unknown | 7 | 9 | 0 | 4 |"
    explanation: >-
      Table III of this CCG/COG series tabulates INSS stage by centrally
      reviewed histology; the excerpt quotes its column headings and its three
      stage rows. In the GN-maturing column, all 36 patients with known stage had
      stage 1-3 disease and none had stage 4 disease; stage was unknown in 7. The
      series covers patients registered on CCG/COG neuroblastoma studies in
      1991-2006, not a population-based sample, and mature ganglioneuroma was not
      eligible for those studies.
- name: Mature
  display_name: "Ganglioneuroma, mature (Schwannian stroma-dominant)"
  classification: histological
  subtype_term:
    preferred_term: mature ganglioneuroma
    term:
      id: NCIT:C42065
      label: Mature Ganglioneuroma
  subtype_frequency: OCCASIONAL
  description: >-
    The completely mature form of neuroblastic tumor: ganglioneuroma whose
    ganglion cells are all completely mature, in Schwannian stroma. Completely
    mature ganglion cells are covered with satellite cells, in either subtype.
    In German trials of localized tumors in patients aged 21 years or younger,
    18 of 162 ganglioneuromas (11.1%) were mature, with a median age at
    diagnosis of 125 months; the occasional band describes that cohort, which
    left out older patients. Mature ganglioneuroma was not eligible for the
    CCG/COG studies and was excluded from the CCG/COG series of ganglioneuroma
    and ganglioneuroblastoma, whose ganglioneuroma data therefore cover the
    maturing subtype only.
  evidence:
  - reference: PMID:41612478
    reference_title: "Pathology of peripheral neuroblastic tumors."
    supports: SUPPORT
    directness: DIRECT
    quote_role: REVIEW_SYNTHESIS
    evidence_source: OTHER
    snippet: "They are either completely mature (mature GN) or a mixture of mature and maturing ganglion cells (maturing GN). Completely mature ganglion cells are covered with satellite cells."
    explanation: >-
      In the 2026 review's paragraph on the ganglioneuroma category these
      sentences separate the two INPC subtypes: in mature GN the ganglion cells
      are completely mature, while maturing GN mixes mature and maturing
      ganglion cells. The review adds that completely mature ganglion cells are
      covered with satellite cells, which holds for such cells in either
      subtype. This restates the INPC subtype criteria rather than reporting
      case data.
  - reference: PMID:19530234
    reference_title: "Clinicopathological characteristics of ganglioneuroma and ganglioneuroblastoma: a report from the CCG and COG."
    supports: SUPPORT
    directness: DIRECT
    quote_role: BACKGROUND
    evidence_source: OTHER
    snippet: "According to the INPC, tumors in the GN category are further classified into GN-Maturing subtype (the same tumor group described as “Ganglioneuroblastoma, well differentiated” in the Shimada classification system3) and GN-Mature subtype (completely mature form of neuroblastic tumor)."
    explanation: >-
      In the introduction of a Children's Cancer Group and Children's Oncology
      Group (CCG/COG) clinicopathological series, Okamatsu et al. restate the
      INPC subdivision of the ganglioneuroma category into GN-Maturing and
      GN-Mature, the completely mature form of neuroblastic tumor. The sentence
      restates a published classification; it is not a result from the paper's
      own cohort.
  - reference: PMID:19530234
    reference_title: "Clinicopathological characteristics of ganglioneuroma and ganglioneuroblastoma: a report from the CCG and COG."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "Cases with the diagnosis of GN-Mature subtype were excluded from the analysis, since they were not eligible for the CCG/COG studies."
    explanation: >-
      Okamatsu et al. state that cases diagnosed as the mature subtype of
      ganglioneuroma (GN-Mature) were not eligible for the Children's Cancer
      Group and Children's Oncology Group (CCG/COG) studies and were excluded
      from their analysis. This CCG/COG series therefore holds no mature
      ganglioneuroma, and its ganglioneuroma cases are the maturing subtype
      only. The sentence states ineligibility; it gives no reason for it and
      does not say that no case with this diagnosis was ever registered on a
      CCG/COG study.
  - reference: PMID:10421272
    reference_title: "Terminology and morphologic criteria of neuroblastic tumors: recommendations by the International Neuroblastoma Pathology Committee."
    supports: SUPPORT
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    evidence_source: HUMAN_CLINICAL
    snippet: "Based on morphologic criteria defined in this article, NTs were classified into four categories and their subtypes: 1) neuroblastoma (Schwannian stroma-poor), undifferentiated, poorly differentiated, and differentiating; 2) ganglioneuroblastoma, intermixed (Schwannian stroma-rich); 3) ganglioneuroma (Schwannian stroma-dominant), maturing and mature; and 4) ganglioneuroblastoma, nodular (composite Schwannian stroma-richlstroma-dominant and stroma-poor)."
    explanation: >-
      The 1999 terminology paper of the International Neuroblastoma Pathology
      Committee, whose six member pathologists defined the morphologic criteria
      from a review of 227 cases, classifies neuroblastic tumors into four
      categories, the third being ganglioneuroma (Schwannian stroma-dominant)
      with maturing and mature subtypes. The quote keeps the abstract's
      spelling 'stroma-richlstroma-dominant'. The abstract does not assign
      ganglioneuroma to a prognostic group; the classification itself is
      reported in the companion article (PMID:10421273).
  - reference: PMID:19530234
    reference_title: "Clinicopathological characteristics of ganglioneuroma and ganglioneuroblastoma: a report from the CCG and COG."
    supports: SUPPORT
    directness: DIRECT
    quote_role: BACKGROUND
    evidence_source: OTHER
    snippet: "GNB-Intermixed (Schwannian stroma-rich) and GN (Schwannian stroma-dominant) tumors are always classified into the FH group."
    explanation: >-
      Okamatsu et al. restate the INPC rule that ganglioneuroma (Schwannian
      stroma-dominant) tumors, like intermixed ganglioneuroblastoma, are always
      classified into the Favorable Histology (FH) group. The rule is stated for
      the ganglioneuroma category as a whole and reaches the mature subtype
      through category membership; the CCG/COG cohort itself excluded the
      GN-mature subtype, because those cases were not eligible for the CCG/COG
      studies.
  - reference: PMID:27465021
    reference_title: "Treatment and outcome of Ganglioneuroma and Ganglioneuroblastoma intermixed."
    supports: SUPPORT
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    evidence_source: HUMAN_CLINICAL
    snippet: "In detail, 162 of 808 tumors (20.0 %) were classified as GN. The vast majority (n = 144, 88.9 %) of GN were subclassified as maturing subtype, only 18 GN (11.1 %) as mature subtype."
    explanation: >-
      Results of a retrospective analysis of localized neuroblastic tumors
      registered in the German neuroblastoma trials NB97 and NB2004 (diagnosed
      between 1 January 2000 and 31 December 2009, aged 21 years or younger,
      centrally reviewed and classified under INPC, and diagnosed
      histologically before any cytotoxic treatment). Of the 162
      ganglioneuromas, 18 (11.1%) were the mature subtype, which places it in
      the occasional band in this cohort. Patients older than 21 were not
      included, and the mature subtype was diagnosed later than the maturing
      one (median 125 vs 71 months), so a series that includes adults may give
      a larger mature share. The authors note that the border between
      intermixed ganglioneuroblastoma and maturing ganglioneuroma might be set
      slightly differently by individual pathologists.
  - reference: PMID:27465021
    reference_title: "Treatment and outcome of Ganglioneuroma and Ganglioneuroblastoma intermixed."
    supports: SUPPORT
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    evidence_source: HUMAN_CLINICAL
    snippet: "Median age at diagnosis increased with grade of differentiation (NB/GNBN: 9; GNBI: 61; GN-maturing: 71; GN-mature: 125 months, p < 0.001)."
    explanation: >-
      In German trials of localized neuroblastic tumors in patients aged 21
      years or younger, the 18 mature ganglioneuromas had the highest median age
      at diagnosis, 125 months, against 71 months for the 144 maturing ones.
      The mature-subtype median rests on 18 patients, and the abstract gives a
      single p-value for the gradient as a whole rather than a test of maturing
      against mature.
pathophysiology:
- name: Neuroblast-to-Ganglion Cell Maturation
  description: >-
    Differentiation of neuroblastic cells into ganglion cells. Biologically
    favorable peripheral neuroblastic tumors are considered to mature by
    age-dependent steps from neuroblastoma through intermixed
    ganglioneuroblastoma to ganglioneuroma. In German trials of localized
    tumors, median age at diagnosis rose with the grade of differentiation,
    which the authors read as indirect support for tumors maturing in situ.
    Whether every ganglioneuroma arises this way is unproven (discussion
    gn_origin).
  biological_scale: CELLULAR
  cell_types:
  - preferred_term: differentiating neuroblast
    term:
      id: CL:0002676
      label: neural crest derived neuroblast
  - preferred_term: ganglion cell
    term:
      id: CL:0011103
      label: sympathetic neuron
  biological_processes:
  - preferred_term: maturation of neuroblasts into ganglion cells
    term:
      id: GO:0030182
      label: neuron differentiation
  notes: >-
    No node is marked as the origin node (genetic_context), because no
    initiating lesion has been described for ganglioneuroma: the authors of the
    AKT study write that little is known about the genetics of mature
    ganglioneuroma, and they only propose that somatically acquired mutations
    or epigenetic alterations in the PI3K-AKT-mTOR pathway may initiate it in
    individual patients (PMID:32728700). The MYCN amplification found in 2
    maturing ganglioneuromas is recorded as a biomarker in the genetic section.
  evidence:
  - reference: PMID:41612478
    reference_title: "Pathology of peripheral neuroblastic tumors."
    supports: SUPPORT
    directness: DIRECT
    quote_role: REVIEW_SYNTHESIS
    evidence_source: OTHER
    snippet: "To note, tumors in the biologically favorable pNTs are considered to proceed by age-dependent differentiation/maturational steps from NB to GNB-i, and finally to GN."
    explanation: >-
      This 2026 pathology review states that biologically favorable peripheral
      neuroblastic tumors are considered to proceed by age-dependent
      differentiation and maturation steps from neuroblastoma to
      GNB-intermixed and finally to ganglioneuroma, the maturation this node
      describes. The sentence sits in the review's account of the INPC
      categories and gives a consensus view ('are considered to') without
      supporting data, and it does not say that every ganglioneuroma arises
      this way.
  - reference: PMID:27465021
    reference_title: "Treatment and outcome of Ganglioneuroma and Ganglioneuroblastoma intermixed."
    supports: SUPPORT
    directness: INDIRECT
    quote_role: PRIMARY_RESULT
    evidence_source: HUMAN_CLINICAL
    snippet: "An indirect support for this hypothesis can be seen by our observation that patients with GN and GNBI are older at diagnosis than those with immature NT. As Fig. 1 shows, the grade of neuroblastic differentiation increases with the median age at diagnosis. This is in line with the theory that mature NT might just have had enough time to mature in situ before they were discovered."
    explanation: >-
      In the Discussion of their German NB97/NB2004 series of localized
      neuroblastic tumors, the authors take their own age gradient as indirect
      support for the hypothesis that a good part of ganglioneuroma originates
      from neuroblastoma: patients with ganglioneuroma or intermixed
      ganglioneuroblastoma, taken together, were older at diagnosis than those
      with immature tumors, and the grade of differentiation rose with median
      age, which fits mature tumors having had time to mature in situ before
      they were found. The support is indirect: the gradient compares different
      patients at diagnosis, and although residual tumors were followed over
      time, the paper reports no tumor seen to mature during follow-up. It bears
      on whether ganglioneuroma arises from an earlier neuroblastic tumor more
      than on how neuroblasts differentiate into ganglion cells. In the next
      paragraph the authors add that widespread ultrasound check-ups of infants
      and young toddlers in Germany could find more small, asymptomatic
      localized immature neuroblastomas in infancy, a point that bears on the
      same age difference without involving maturation.
- name: Schwannian Stromal Development
  description: >-
    The Schwann-cell stroma that dominates ganglioneuroma tissue; the INPC names
    ganglioneuroma for this feature (Schwannian stroma-dominant). Stromal
    Schwann cells in ganglioneuroma share the expression of nerve
    repair-associated genes with the repair Schwann cells of human nerve
    injured ex vivo, and repair-type Schwann cells and their secretome induce
    neuronal differentiation of neuroblastoma cells in culture. It has been
    suggested that a minor increase in the volume of mature tumors may also be
    caused by proliferation of the Schwannian stroma rather than of tumor
    cells. Whether the stromal cells derive from the neoplastic clone is
    discussed in the Ganglioneuroblastoma entry.
  biological_scale: TISSUE
  cell_types:
  - preferred_term: Schwannian stromal cell
    term:
      id: CL:0002573
      label: Schwann cell
  biological_processes:
  - preferred_term: Schwann cell proliferation
    term:
      id: GO:0014010
      label: Schwann cell proliferation
  notes: >-
    The node is named for the INPC term Schwannian stromal development rather
    than for stroma recruitment, because recruitment presumes a non-neoplastic
    origin that is disputed (discussion gnb_schwannian_stroma_origin in the
    Ganglioneuroblastoma entry).
  evidence:
  - reference: PMID:10421272
    reference_title: "Terminology and morphologic criteria of neuroblastic tumors: recommendations by the International Neuroblastoma Pathology Committee."
    supports: SUPPORT
    directness: INDIRECT
    quote_role: PRIMARY_RESULT
    evidence_source: HUMAN_CLINICAL
    snippet: "Based on morphologic criteria defined in this article, NTs were classified into four categories and their subtypes: 1) neuroblastoma (Schwannian stroma-poor), undifferentiated, poorly differentiated, and differentiating; 2) ganglioneuroblastoma, intermixed (Schwannian stroma-rich); 3) ganglioneuroma (Schwannian stroma-dominant), maturing and mature; and 4) ganglioneuroblastoma, nodular (composite Schwannian stroma-richlstroma-dominant and stroma-poor)."
    explanation: >-
      The 1999 terminology paper of the International Neuroblastoma Pathology
      Committee names ganglioneuroma the Schwannian stroma-dominant category of
      neuroblastic tumors, so the tumor is defined by its dominant Schwannian
      stroma. This is a classification label: it says nothing about how the
      stroma develops or where its cells come from, so its support for this node
      is indirect. The quote keeps the abstract's spelling
      'stroma-richlstroma-dominant'.
  - reference: PMID:33712610
    reference_title: "Schwann cell plasticity regulates neuroblastic tumor cell differentiation via epidermal growth factor-like protein 8."
    supports: SUPPORT
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    evidence_source: HUMAN_CLINICAL
    snippet: "Indeed, stromal SCs in ganglioneuromas and repair SCs share the expression of nerve repair-associated genes."
    explanation: >-
      The authors ran RNA-seq on fresh-frozen, Schwann cell stroma-rich areas of
      six diagnostic human ganglioneuroma specimens, collected at surgery or
      biopsy, in which S100B staining showed Schwann cells to be the prevalent
      cell population. They compared them with neuroblastoma tissue, which
      almost entirely lacks Schwann cells, and with human peripheral nerve
      fascicles, collected at reconstructive surgery, amputation or organ
      donation and left to degenerate ex vivo, a model in which Schwann cells
      take on the repair phenotype. After genes also expressed in neuroblastoma
      were excluded, the signature shared by ganglioneuroma and injured nerve
      contained nerve repair-associated genes, and the authors read this as
      stromal Schwann cells in ganglioneuroma taking on a repair-like state.
      This supports Schwann cells as the cell type of this node; it says nothing
      about Schwann cell proliferation. The profiles are of bulk tissue, so
      assigning the shared signature to the Schwann cells rests on sampling
      Schwann cell-rich areas and on subtracting the genes expressed in
      neuroblastoma. The grade reflects the ganglioneuroma side, which is
      patient tumor tissue; the injured-nerve comparator was a cultured nerve
      explant.
  - reference: PMID:27465021
    reference_title: "Treatment and outcome of Ganglioneuroma and Ganglioneuroblastoma intermixed."
    supports: SUPPORT
    directness: INDIRECT
    quote_role: BACKGROUND
    evidence_source: HUMAN_CLINICAL
    snippet: "An interesting question is why mature tumors can show progression at all. Nishihira et al suggested that a minor increase of tumor volume may also be caused by proliferation of Schwannian stroma rather than that of tumor cells [34]."
    explanation: >-
      In the discussion of this retrospective study of localized ganglioneuroma
      and intermixed ganglioneuroblastoma in patients aged 21 years or younger
      at diagnosis, registered in the German NB97 and NB2004 neuroblastoma
      trials, the authors ask why mature tumors can progress at all. They
      restate a suggestion by Nishihira and colleagues that a minor increase in
      tumor volume may also be caused by proliferation of the Schwannian stroma
      rather than of tumor cells, and add that this could explain volume
      changes too small to count as progression under the International
      Neuroblastoma Response Criteria. This is the evidence from patients for
      Schwann cell proliferation (GO:0014010) in this node, and it is weak: it
      is a hedged suggestion restated from another group, not a result of this
      study, and the sentence does not say what the original observation was.
      No measurement of Schwann cell division in ganglioneuroma is cited, so an
      increase in Schwann cells by recruitment into the tumor is not ruled out.
  downstream:
  - target: Neuroblast-to-Ganglion Cell Maturation
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Repair-type Schwann cells and their secreted products induce neuronal
      differentiation of neuroblastoma cells in culture; the evidence is in
      vitro.
    evidence:
    - reference: PMID:33712610
      reference_title: "Schwann cell plasticity regulates neuroblastic tumor cell differentiation via epidermal growth factor-like protein 8."
      supports: SUPPORT
      directness: INDIRECT
      quote_role: PRIMARY_RESULT
      evidence_source: IN_VITRO
      snippet: "Neuroblastoma cells, derived from aggressive tumors, respond to primary repair-related SCs and their secretome with increased neuronal differentiation and reduced proliferation."
      explanation: >-
        Neuroblastoma cell lines and patient-derived short-term cultures grown
        with primary human repair-related Schwann cells, or with their secreted
        products, showed increased neuronal differentiation and reduced
        proliferation. This supports Schwann cells driving neuroblast
        differentiation, the step this edge names, but the experiments are in
        vitro, the tumor cells came from aggressive neuroblastomas, and no
        ganglioneuroma tissue was studied, so the support is indirect.
  - target: Retroperitoneal Mass
    causal_link_type: DIRECT
    description: >-
      The tumor, composed largely of Schwannian stroma, forms a mass at its
      primary site; the retroperitoneum was the commonest site in a
      single-institution series.
    evidence:
    - reference: PMID:41612478
      reference_title: "Pathology of peripheral neuroblastic tumors."
      supports: SUPPORT
      directness: INDIRECT
      quote_role: REVIEW_SYNTHESIS
      evidence_source: OTHER
      snippet: "Tumors in this category represent the most mature form of pNTs. They are elastic and yellowish white, and free surfaces are well-circumscribed and encapsulated. However, infiltrative growth into the surrounding fatty tissue, without prognostic significance, may be observed in deeply seated GN. Tumor cells (ganglion cells) are distributed individually or making small clusters in Schwannian stroma (Fig. 2C). They are either completely mature (mature GN) or a mixture of mature and maturing ganglion cells (maturing GN). Completely mature ganglion cells are covered with satellite cells."
      explanation: >-
        In this 2026 pathology review's account of the INPC ganglioneuroma
        category, the tumors are elastic, yellowish white, well circumscribed
        and encapsulated, and their ganglion cells lie singly or in small
        clusters in Schwannian stroma, so the mass is made largely of
        stroma-dominant tissue. Reading the Schwannian stroma as forming the
        mass is an inference, and the sentences name no site; where the mass
        lies is recorded on the phenotype. The passage restates INPC
        morphologic criteria and reports no case data.
  - target: Posterior Mediastinal Mass
    causal_link_type: DIRECT
    description: >-
      The tumor, composed largely of Schwannian stroma, forms a mass at its
      primary site; most thoracic ganglioneuromas lie in the posterior
      mediastinum.
    evidence:
    - reference: PMID:41612478
      reference_title: "Pathology of peripheral neuroblastic tumors."
      supports: SUPPORT
      directness: INDIRECT
      quote_role: REVIEW_SYNTHESIS
      evidence_source: OTHER
      snippet: "Tumors in this category represent the most mature form of pNTs. They are elastic and yellowish white, and free surfaces are well-circumscribed and encapsulated. However, infiltrative growth into the surrounding fatty tissue, without prognostic significance, may be observed in deeply seated GN. Tumor cells (ganglion cells) are distributed individually or making small clusters in Schwannian stroma (Fig. 2C). They are either completely mature (mature GN) or a mixture of mature and maturing ganglion cells (maturing GN). Completely mature ganglion cells are covered with satellite cells."
      explanation: >-
        In this 2026 pathology review's account of the INPC ganglioneuroma
        category, the tumors are well circumscribed and encapsulated, and their
        ganglion cells lie singly or in small clusters in Schwannian stroma, so
        the mass is made largely of stroma-dominant tissue. Reading the
        Schwannian stroma as forming the mass is an inference, and the
        sentences name no site; where the mass lies is recorded on the
        phenotype. The passage restates INPC morphologic criteria and reports
        no case data.
  - target: Pelvic Mass
    causal_link_type: DIRECT
    description: >-
      The tumor, composed largely of Schwannian stroma, forms a mass at its
      primary site, which in some series is the presacral space.
    evidence:
    - reference: PMID:41612478
      reference_title: "Pathology of peripheral neuroblastic tumors."
      supports: SUPPORT
      directness: INDIRECT
      quote_role: REVIEW_SYNTHESIS
      evidence_source: OTHER
      snippet: "Tumors in this category represent the most mature form of pNTs. They are elastic and yellowish white, and free surfaces are well-circumscribed and encapsulated. However, infiltrative growth into the surrounding fatty tissue, without prognostic significance, may be observed in deeply seated GN. Tumor cells (ganglion cells) are distributed individually or making small clusters in Schwannian stroma (Fig. 2C). They are either completely mature (mature GN) or a mixture of mature and maturing ganglion cells (maturing GN). Completely mature ganglion cells are covered with satellite cells."
      explanation: >-
        In this 2026 pathology review's account of the INPC ganglioneuroma
        category, the tumors are well circumscribed and encapsulated, and their
        ganglion cells lie singly or in small clusters in Schwannian stroma, so
        the mass is made largely of stroma-dominant tissue. Reading the
        Schwannian stroma as forming the mass is an inference, and the
        sentences name no site; where the mass lies is recorded on the
        phenotype. The passage restates INPC morphologic criteria and reports
        no case data.
  - target: Pain
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Symptoms come from the effects of the tumor mass; how the tumor produces
      pain is not described.
    evidence:
    - reference: PMID:33721367
      reference_title: "Presentation and outcomes of adrenal ganglioneuromas: A cohort study and a systematic review of literature."
      supports: SUPPORT
      directness: INDIRECT
      quote_role: REVIEW_SYNTHESIS
      evidence_source: HUMAN_CLINICAL
      snippet: "AGN were discovered incidentally in 72% of patients, due to symptoms of mass effect in 20%, and due to other symptoms in 8%."
      explanation: >-
        Pooling the authors' single-center cohort with the 14 published series
        in their systematic review, adrenal ganglioneuromas were discovered
        incidentally in 72% of patients, because of mass-effect symptoms in 20%
        and because of other symptoms in 8%. The authors attribute the symptoms
        in that fifth to the tumor mass, which their introduction describes as a
        stroma of mature Schwann cells, ganglion cells and nerve fibers. Support
        for an edge to Pain is indirect: the paper does not say which mass-effect
        symptoms occurred, never names pain, and does not discuss stromal growth.
        The pooled patients had adrenal tumors only, were mostly adults (mean age
        at diagnosis 39 years), and include composite
        ganglioneuroma-pheochromocytoma tumors.
- name: Tumoral Vasoactive Intestinal Peptide Secretion
  description: >-
    Secretion of vasoactive intestinal peptide (VIP) by the tumor, described in
    case reports of young children with ganglioneuroma and diarrhea. In one
    child with a retroperitoneal tumor, the tumor contained large amounts of
    VIP, plasma VIP was raised before surgery and the VIP concentration was
    normal after it; in a child with a thoracic tumor, the authors attributed
    the diarrhea to an excess of VIP secreted by the tumor; and in a 3-year-old
    girl with a thoracic paraspinal tumor, serum VIP was 314 pmol/l before
    surgery (normal less than 30) and 14 pmol/l 6 months after it.
  biological_scale: CELLULAR
  biological_processes:
  - preferred_term: vasoactive intestinal peptide (VIP) secretion by the tumor
    term:
      id: GO:0030072
      label: peptide hormone secretion
    modifier: INCREASED
  notes: >-
    No cell type is bound, because the cited reports do not say which tumor
    cells secrete VIP. OLS GO searches on 2026-10-28 for "vasoactive intestinal
    peptide secretion", "vasoactive intestinal" and "VIP secretion" returned VIP
    receptor binding and receptor activity terms (GO:0031890, GO:0004999) but no
    VIP secretion process, so the parent process peptide hormone secretion is
    bound.
  evidence:
  - reference: PMID:7376870
    reference_title: "Vasocative intestinal polypeptide (VIP)-producing ganglioneuroma in a child with chronic diarrhea."
    supports: SUPPORT
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    evidence_source: HUMAN_CLINICAL
    snippet: "The tumour contained large amounts of vasoactive intestinal polypeptide (VIP) and preoperative plasma concentration of this peptide was increased. Postoperatively the VIP concentration was normalized, and the diarrhea ceased. Analysis of catecholamine metabolites in urine was normal. The findings suggest that the watery diarrhea was due to the benign VIP-producing neural crest tumour."
    explanation: >-
      Single case report of a 2 1/2-year-old girl with persistent watery
      diarrhea and a retroperitoneal ganglioneuroma. The tumor contained large
      amounts of VIP and plasma VIP was raised before surgery. After the
      operation the VIP concentration returned to normal and the diarrhea
      stopped, while urinary catecholamine metabolites were normal; the authors
      suggest the watery diarrhea was due to the VIP-producing tumor. This
      supports the tumor as the source of a circulating VIP excess. It is one
      case, the abstract does not say how much of the tumor was removed, and
      the tumor and an involved lymph node were made of benign ganglioneuroma
      cells, which the authors judged compatible with an originally
      metastasizing neuroblastoma that had matured late.
  - reference: PMID:1211964
    reference_title: "Watery diarrhoea and ganglioneuroma with secretion of vasoactive intestinal peptide."
    supports: SUPPORT
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    evidence_source: HUMAN_CLINICAL
    snippet: "The findings suggest that the diarrhoea in the syndrome of ganglioneuroma and bowel dysfunction is due to an excess of VIP secreted by the tumour."
    explanation: >-
      Case report of a young girl presenting with diarrhea and stridor who had
      a thoracic ganglioneuroma, partially resected, whose tissue held an
      abnormally high VIP content by radioimmunoassay. From this case the
      authors suggest that the diarrhea of the syndrome of ganglioneuroma and
      bowel dysfunction is due to an excess of VIP secreted by the tumor, which
      supports tumoral VIP secretion. It is a single case, generalized by the
      authors to the syndrome. The abstract reports no plasma VIP and records
      abnormal urinary catecholamines and catechol metabolites in the same
      child.
  - reference: PMID:2833214
    reference_title: "Vasoactive intestinal peptide secreting tumours in children: a case report with literature review."
    supports: SUPPORT
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    evidence_source: HUMAN_CLINICAL
    snippet: "The pre-operative serum VIP was 314 pmol/l (normal less than 30). Her diarrhoea stopped after the removal of the tumour. The VIP was 14 pmol/l 6 months post-operatively."
    explanation: >-
      The authors' own case of a 3-year-old girl with a VIP-secreting thoracic
      paraspinal ganglioneuroma: serum VIP was 314 pmol/l before surgery, where
      normal is less than 30 pmol/l, her diarrhea stopped after the tumor was
      removed, and VIP was 14 pmol/l 6 months after the operation.
      The fall to a normal value after resection points to the tumor as the
      source of the excess VIP. It is a single case, and the abstract does not
      say whether the tumor tissue was assayed for VIP.
  downstream:
  - target: Watery Diarrhea
    causal_link_type: DIRECT
    description: >-
      In the case reports the authors attributed the watery diarrhea to VIP
      secreted by the tumor, and in two children it stopped once the VIP excess
      was removed with the tumor.
    evidence:
    - reference: PMID:1211964
      reference_title: "Watery diarrhoea and ganglioneuroma with secretion of vasoactive intestinal peptide."
      supports: SUPPORT
      directness: DIRECT
      quote_role: PRIMARY_RESULT
      evidence_source: HUMAN_CLINICAL
      snippet: "The findings suggest that the diarrhoea in the syndrome of ganglioneuroma and bowel dysfunction is due to an excess of VIP secreted by the tumour."
      explanation: >-
        Case report of a young girl presenting with diarrhea and stridor and a
        thoracic ganglioneuroma whose tissue held an abnormally high VIP
        content. The authors suggest that the diarrhea of the syndrome of
        ganglioneuroma and bowel dysfunction is due to an excess of VIP secreted
        by the tumor, which is the causal step this edge names; the paper's
        title calls the diarrhea watery. It is a single case. The abstract
        reports no plasma VIP, says only that VIP decreased after the partial
        resection, and gives no postoperative course for the diarrhea.
    - reference: PMID:7376870
      reference_title: "Vasocative intestinal polypeptide (VIP)-producing ganglioneuroma in a child with chronic diarrhea."
      supports: SUPPORT
      directness: DIRECT
      quote_role: PRIMARY_RESULT
      evidence_source: HUMAN_CLINICAL
      snippet: "The tumour contained large amounts of vasoactive intestinal polypeptide (VIP) and preoperative plasma concentration of this peptide was increased. Postoperatively the VIP concentration was normalized, and the diarrhea ceased. Analysis of catecholamine metabolites in urine was normal. The findings suggest that the watery diarrhea was due to the benign VIP-producing neural crest tumour."
      explanation: >-
        In a 2 1/2-year-old girl with a retroperitoneal ganglioneuroma, plasma
        VIP was raised before surgery, the VIP concentration was normal after
        the operation and the watery diarrhea stopped, while urinary
        catecholamine metabolites were normal; the authors suggest the watery
        diarrhea was due to the VIP-producing tumor. This supports the edge from
        tumoral VIP secretion to watery diarrhea in one case.
    - reference: PMID:2833214
      reference_title: "Vasoactive intestinal peptide secreting tumours in children: a case report with literature review."
      supports: SUPPORT
      directness: INDIRECT
      quote_role: PRIMARY_RESULT
      evidence_source: HUMAN_CLINICAL
      snippet: "The pre-operative serum VIP was 314 pmol/l (normal less than 30). Her diarrhoea stopped after the removal of the tumour. The VIP was 14 pmol/l 6 months post-operatively."
      explanation: >-
        In the authors' 3-year-old patient with a VIP-secreting thoracic
        paraspinal ganglioneuroma, serum VIP was 314 pmol/l before surgery
        (normal less than 30), the diarrhea stopped after the tumor was removed,
        and VIP was 14 pmol/l 6 months later. The diarrhea and the VIP excess
        ended together with the tumor's removal, which supports the edge; the
        support is indirect, because the quote does not itself say that VIP
        caused the diarrhea, and removing the tumor also removed anything else
        it secreted. The abstract's opening sentence, cited on the Hypokalemia
        edge, attributes the watery diarrhea to the VIP-secreting tumor. It is a
        single case.
  - target: Hypokalemia
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Hypokalemia was attributed to a VIP-secreting ganglioneuroma in a case
      report; the route from VIP to low potassium is not described.
    evidence:
    - reference: PMID:2833214
      reference_title: "Vasoactive intestinal peptide secreting tumours in children: a case report with literature review."
      supports: SUPPORT
      directness: INDIRECT
      quote_role: PRIMARY_RESULT
      evidence_source: HUMAN_CLINICAL
      snippet: "A 3 year old Chinese girl with watery diarrhoea, abdominal distension and hypokalaemia due to a thoracic paraspinal vasoactive intestinal peptide (VIP) secreting ganglioneuroma is reported."
      explanation: >-
        The authors' own case: a 3-year-old girl with watery diarrhea, abdominal
        distension and hypokalemia, which they attribute to a thoracic
        paraspinal ganglioneuroma that secreted VIP. This supports the edge from
        tumor VIP secretion to hypokalemia indirectly: the sentence attributes
        the hypokalemia to the tumor, which it describes as VIP-secreting, but
        does not say that VIP itself produced the hypokalemia or by what route.
        It is a single case.
- name: Tumoral Catecholamine Secretion
  description: >-
    Secretion of catecholamines by the tumor, which some ganglioneuromas show.
    In a series of primary ganglioneuromas, plasma and/or urinary
    catecholamines were increased in 39%, and the authors concluded that
    ganglioneuroma may present with increased catecholamine secretion; in an
    adrenal ganglioneuroma, raised urinary catecholamines normalized after
    resection, which the authors took as confirming the tumor as their source.
    Secretion is not universal: the authors of an adrenal series concluded
    that isolated adrenal ganglioneuromas do not produce catecholamines. In a
    chart review, raised urinary vanillylmandelic and homovanillic acid
    appeared to become more common with larger ganglioneuromas, and the
    authors advised a search for occult neuroblastoma when the values are
    extremely high.
  biological_scale: CELLULAR
  biological_processes:
  - preferred_term: catecholamine secretion by the tumor
    term:
      id: GO:0050432
      label: catecholamine secretion
    modifier: INCREASED
  notes: >-
    No cell type is bound, because the cited reports do not say which tumor
    cells secrete catecholamines.
  evidence:
  - reference: PMID:11346873
    reference_title: "Metabolic activity and clinical features of primary ganglioneuromas."
    supports: SUPPORT
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    evidence_source: HUMAN_CLINICAL
    snippet: "Levels of catecholamines in plasma and/or urine were increased in 39%. ... Ganglioneuroma may present with metabolic activity such as increased secretion of catecholamines and/or mIBG uptake."
    explanation: >-
      Retrospective series of primary ganglioneuromas, meaning tumors that were
      ganglioneuroma at diagnosis rather than ones evolving from a
      differentiating neuroblastoma, in patients registered with but not
      enrolled in national neuroblastoma trials. Plasma and/or urinary
      catecholamines were increased in 39%, and the authors conclude that
      ganglioneuroma may present with metabolic activity such as increased
      catecholamine secretion, which is the claim of this node. The abstract
      does not say how many patients were tested, which catecholamines were
      raised or in which fluid, and it reports no values after resection, so
      the tumor is the source by the authors' reading rather than by a
      demonstration such as normalization after surgery.
  - reference: PMID:35800596
    reference_title: "Rare Case of Large Catecholamine Secreting Ganglioneuroma in an Asymptomatic Elderly Male."
    supports: SUPPORT
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    evidence_source: HUMAN_CLINICAL
    snippet: "Following resection, catecholamine levels normalized, confirming the resected right adrenal ganglioneuroma as the source of the catecholamine excess."
    explanation: >-
      Case report of an elderly man with an incidental adrenal ganglioneuroma
      of maturing type and mildly raised urinary catecholamines. The levels
      normalized after open adrenalectomy, which the authors take as
      confirming the tumor as the source of the excess. It is a single case,
      and an adrenal tumor that secretes catecholamines may carry an unsampled
      pheochromocytoma component, so the case does not show which cells
      secreted them.
  - reference: PMID:24033606
    reference_title: "Adrenal ganglioneuroma: features and outcomes of 27 cases at a referral cancer centre."
    supports: REFUTE
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    evidence_source: HUMAN_CLINICAL
    snippet: "Isolated AGNs do not produce catecholamines and have CT imaging characteristics that can help in distinguishing them from other adrenal and para-adrenal neoplasms."
    explanation: >-
      Conclusion of a retrospective series of adrenal ganglioneuromas (AGNs) at
      a tertiary referral cancer center, in which catecholamine levels were
      normal in every patient with results. The authors conclude that isolated
      adrenal ganglioneuromas do not produce catecholamines, which contradicts
      this node for tumors at that site. 'Isolated' most likely means without
      a pheochromocytoma component, the adrenal case above shows that the
      conclusion is not absolute, and the second half of the sentence, on CT
      features, is not used here.
  downstream:
  - target: Elevated Urinary Homovanillic Acid
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - Metabolism of the secreted catecholamines to homovanillic acid and its excretion in urine
    description: >-
      Homovanillic acid is a catecholamine metabolite excreted in urine. In a
      chart review of ganglioneuromas, raised values appeared to become more
      common with larger tumors, which points to the tumor as their source,
      though the authors report this only as a trend; they advise a search for
      occult neuroblastoma, which can be the source instead, when values are
      extremely high.
    evidence:
    - reference: PMID:8107654
      reference_title: "Catecholamine metabolites in ganglioneuroma."
      supports: SUPPORT
      directness: INDIRECT
      quote_role: PRIMARY_RESULT
      evidence_source: HUMAN_CLINICAL
      snippet: "Even excluding this patient, there was a trend for elevated values in GN patients to correlate with tumor size (P = .07 and .14 for VMA and HVA, respectively). The incidence of elevated values appears to increase as a function of tumor size, and small tumors are not likely to result in positive urinary measurements. We conclude that while elevations of VMA and HVA are consistent with a well-documented diagnosis of GN, extreme elevations (> 3 x nl) should prompt careful serial evaluation for occult NB."
      explanation: >-
        In a chart review of patients with ganglioneuroma (GN), raised urinary
        vanillylmandelic acid (VMA) and homovanillic acid (HVA) tended to go
        with larger tumors, even after excluding the patient whose later
        resection disclosed foci of neuroblastoma (NB), and the authors
        conclude that small tumors are unlikely to give positive urinary
        results. Raised values becoming more common with tumor size points to
        the tumor as the source of the urinary HVA, which is the inference
        this edge rests on, and the authors report the HVA association only as
        a trend (P = .14). They also conclude that raised VMA and HVA are
        consistent with a well-documented ganglioneuroma, but that extreme
        elevations should prompt a search for occult neuroblastoma, which may
        then be their source.
  - target: Elevated Urinary Vanillylmandelic Acid
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - Metabolism of the secreted catecholamines to vanillylmandelic acid and its excretion in urine
    description: >-
      Vanillylmandelic acid is a catecholamine metabolite excreted in urine. In
      a chart review of ganglioneuromas, raised values appeared to become more
      common with larger tumors, which points to the tumor as their source,
      though the authors report this only as a trend; they advise a search for
      occult neuroblastoma, which can be the source instead, when values are
      extremely high.
    evidence:
    - reference: PMID:8107654
      reference_title: "Catecholamine metabolites in ganglioneuroma."
      supports: SUPPORT
      directness: INDIRECT
      quote_role: PRIMARY_RESULT
      evidence_source: HUMAN_CLINICAL
      snippet: "Even excluding this patient, there was a trend for elevated values in GN patients to correlate with tumor size (P = .07 and .14 for VMA and HVA, respectively). The incidence of elevated values appears to increase as a function of tumor size, and small tumors are not likely to result in positive urinary measurements. We conclude that while elevations of VMA and HVA are consistent with a well-documented diagnosis of GN, extreme elevations (> 3 x nl) should prompt careful serial evaluation for occult NB."
      explanation: >-
        In a chart review of patients with ganglioneuroma (GN), raised urinary
        vanillylmandelic acid (VMA) and homovanillic acid (HVA) tended to go
        with larger tumors, even after excluding the patient whose later
        resection disclosed foci of neuroblastoma (NB), and the authors
        conclude that small tumors are unlikely to give positive urinary
        results. Raised values becoming more common with tumor size points to
        the tumor as the source of the urinary VMA, which is the inference
        this edge rests on, and the authors report the VMA association only as
        a trend (P = .07). They also conclude that raised VMA and HVA are
        consistent with a well-documented ganglioneuroma, but that extreme
        elevations should prompt a search for occult neuroblastoma, which may
        then be their source.
- name: AKT-mTOR-S6 Pathway Activation
  description: >-
    Activation of the kinase AKT and of its downstream effectors mTOR and
    ribosomal protein S6 in ganglioneuroma tissue. In archival tumors from one
    hospital, immunohistochemistry detected phosphorylated AKT (Ser473) in 10 of
    11 ganglioneuromas, a panel that included two ganglioneuroblastomas, against
    1 of 15 poorly differentiated neuroblastomas, and phosphorylated mTOR and S6
    in 9 and 10 of the 11, against 5 and 7 of the 15. In zebrafish,
    constitutively activated myr-Akt2 expressed in the sympathetic nervous
    system produced ganglioneuroma without progression to neuroblastoma,
    inducing sympathoadrenal lineage hyperplasia through increased cell
    proliferation, with activation of mTOR. The authors note that AKT activation
    in a tumor may be a consequence rather than a cause of its growth, and that
    the upstream signals activating AKT in human ganglioneuroma are not yet
    identified.
  biological_scale: MOLECULAR
  biological_processes:
  - preferred_term: AKT signaling, read as phosphorylated AKT (Ser473)
    term:
      id: GO:0043491
      label: phosphatidylinositol 3-kinase/protein kinase B signal transduction
    modifier: INCREASED
  - preferred_term: mTOR signaling, read as phosphorylated mTOR (Ser2448) and S6 (Ser235/236)
    term:
      id: GO:0031929
      label: TOR signaling
    modifier: INCREASED
  notes: >-
    No genetic_context is recorded and the node is not an origin node: the study
    names no lesion that activates AKT in human ganglioneuroma, and its authors
    only propose that somatically acquired mutations or epigenetic alterations
    in the PI3K-AKT-mTOR pathway may initiate the tumor in individual patients.
    No cell type is bound, because the immunohistochemistry was scored in
    viable tumor cells without saying which cells stained. No downstream edge
    is drawn: the entry has no node for tumor cell proliferation, and only the
    zebrafish experiment tests whether the pathway drives tumor growth. Modifier
    INCREASED rather than GAIN_OF_FUNCTION, because the human data show the
    pathway more often phosphorylated, not escaped from its normal regulation.
    The mTOR inhibitors the authors tested in zebrafish are not entered as a
    treatment: no human ganglioneuroma has been treated in the cited work.
  evidence:
  - reference: PMID:32728700
    reference_title: "Ganglioneuromas are driven by activated AKT and can be therapeutically targeted with mTOR inhibitors."
    supports: SUPPORT
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    evidence_source: HUMAN_CLINICAL
    snippet: "Here, we found that phosphorylated, activated AKT and the downstream effectors mTOR and ribosomal protein S6 were more frequently detected in human primary ganglioneuromas than in poorly differentiated human neuroblastomas."
    explanation: >-
      The authors summarize their immunohistochemistry of archival human tumors
      from Boston Children's Hospital: phosphorylated, activated AKT and its
      downstream effectors mTOR and ribosomal protein S6 were detected more
      often in primary ganglioneuromas than in poorly differentiated
      neuroblastomas. This is the human evidence for the node. The comparison
      group is poorly differentiated neuroblastoma only, and the samples were
      those available with sufficient quality for immunohistochemistry.
  - reference: PMID:32728700
    reference_title: "Ganglioneuromas are driven by activated AKT and can be therapeutically targeted with mTOR inhibitors."
    supports: SUPPORT
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    evidence_source: HUMAN_CLINICAL
    snippet: "To understand the contribution of AKT to human primary neuroblastic tumors, we performed immunohistochemistry (IHC) for phosphorylated AKT on a panel of human primary ganglioneuromas (including two ganglioneuroblastoma samples) and compared these results with those from human primary neuroblastomas using two-sided Fisher's exact tests. These data revealed that 10 of 11 ganglioneuromas (90.91%; 95% confidence interval ... expressed moderate to high levels of activated, phosphorylated AKT (Ser473), while only 1 of 15 poorly differentiated neuroblastomas (6.67%; 95% CI ... expressed detectable phosphorylated AKT (Ser473; P < 0.0001; Fig. 1)."
    explanation: >-
      Phosphorylated AKT (Ser473) was moderate to high in 10 of 11 tumors of the
      ganglioneuroma panel, against detectable staining in 1 of 15 poorly
      differentiated neuroblastomas (P < 0.0001); the ellipses skip the
      bracketed confidence intervals. The authors state that the panel included
      two ganglioneuroblastoma samples, so the 11 are not all ganglioneuromas.
      Total AKT was present in every tumor of the panel, so the difference lies
      in its phosphorylation. A section counted as positive
      when more than 25% of viable tumor cells stained.
  - reference: PMID:32728700
    reference_title: "Ganglioneuromas are driven by activated AKT and can be therapeutically targeted with mTOR inhibitors."
    supports: SUPPORT
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    evidence_source: HUMAN_CLINICAL
    snippet: "We found that phosphorylated mTOR (Ser2448) was expressed in 9 of 11 ganglioneuromas (81.82%; 95% CI ... but only in 5 of 15 poorly differentiated neuroblastomas (33.33%; 95% CI ... P = 0.0214; Fig. 1 B and Fig. S1 A). Similarly, phosphorylated S6 ribosomal protein (Ser235/236) was expressed in 10 of 11 ganglioneuromas (90.91%; 95% CI ... but only in 7 of 15 poorly differentiated neuroblastomas (46.67%; 95% CI ... P = 0.0362; Fig. 1 B and Fig. S1 B)."
    explanation: >-
      In the same panel, phosphorylated mTOR (Ser2448) was found in 9 of 11
      ganglioneuromas against 5 of 15 poorly differentiated neuroblastomas
      (P = 0.0214), and phosphorylated S6 ribosomal protein (Ser235/236) in 10
      of 11 against 7 of 15 (P = 0.0362); the ellipses skip the bracketed
      confidence intervals. This supports activation downstream of AKT, though
      both markers were also found in some neuroblastomas (5 and 7 of 15), and
      the 11 tumors include two ganglioneuroblastomas.
  - reference: PMID:32728700
    reference_title: "Ganglioneuromas are driven by activated AKT and can be therapeutically targeted with mTOR inhibitors."
    supports: SUPPORT
    directness: INDIRECT
    quote_role: PRIMARY_RESULT
    evidence_source: MODEL_ORGANISM
    snippet: "Zebrafish transgenic for constitutively activated myr-Akt2 in the sympathetic nervous system were found to develop ganglioneuroma without progression to neuroblastoma. ... Mechanistically, myr-Akt2 overexpression induced sympathoadrenal lineage hyperplasia through increased cell proliferation, concurrent with activation of the AKT target mTOR."
    explanation: >-
      Transgenic zebrafish expressing a constitutively active, myristoylated
      murine Akt2 in the sympathetic nervous system developed ganglioneuroma in
      the interrenal gland, the fish counterpart of the adrenal gland, without
      progression to neuroblastoma; the transgene induced sympathoadrenal
      lineage hyperplasia through increased proliferation, with activation of
      mTOR. This shows that activated AKT is sufficient to produce a
      ganglioneuroma-like tumor in fish, which supports the pathway's
      relevance, not its activation in human tumors, so the support is
      indirect. The transgene is a forced, constitutively active kinase rather
      than a lesion found in patients, and the fish tumors had poor Schwannian
      stroma.
histopathology:
- name: Ganglion Cells in a Schwannian Stroma-Dominant Background
  finding_term:
    preferred_term: Schwannian stroma-dominant ganglioneuromatous tissue with mature or maturing ganglion cells
    term:
      id: NCIT:C42063
      label: Schwannian Stroma Predominant Component of the Tumor Volume
  description: >-
    Ganglion cells distributed singly or in small clusters in Schwannian stroma;
    in mature ganglioneuroma they are all completely mature, and in maturing
    ganglioneuroma mature and maturing ganglion cells are mixed. Completely
    mature ganglion cells are covered with satellite cells. Neurites produced by
    the ganglion cells are incorporated into the cytoplasm of Schwannian stromal
    cells, so naked neurites are not identified around the ganglion cells.
    Grossly the tumors are elastic, yellowish white, well circumscribed and
    encapsulated, although deeply seated tumors may grow into the surrounding
    fat, without prognostic significance. The INPC classifies ganglioneuroma as
    its Schwannian stroma-dominant category and always places it in the
    favorable histology group.
  diagnostic: true
  context: Tumor tissue classified by the INPC
  notes: >-
    NCIT:C3049 Ganglioneuroma names the neoplasm rather than a microscopic
    finding, so the finding is bound to the morphologic-finding term
    NCIT:C42063, a child of NCIT:C42062 Schwannian Stroma More than 50 Percent
    of the Tumor Volume, which the Ganglioneuroblastoma entry binds.
  evidence:
  - reference: PMID:41612478
    reference_title: "Pathology of peripheral neuroblastic tumors."
    supports: SUPPORT
    directness: DIRECT
    quote_role: REVIEW_SYNTHESIS
    evidence_source: OTHER
    snippet: "Tumors in this category represent the most mature form of pNTs. They are elastic and yellowish white, and free surfaces are well-circumscribed and encapsulated. However, infiltrative growth into the surrounding fatty tissue, without prognostic significance, may be observed in deeply seated GN. Tumor cells (ganglion cells) are distributed individually or making small clusters in Schwannian stroma (Fig. 2C). They are either completely mature (mature GN) or a mixture of mature and maturing ganglion cells (maturing GN). Completely mature ganglion cells are covered with satellite cells."
    explanation: >-
      In this 2026 pathology review these sentences open the paragraph headed
      'Ganglioneuroma (Schwannian stroma-dominant)', a heading the cached text
      drops; the quote itself refers to deeply seated GN, mature GN and maturing
      GN, and cites Fig. 2C, the ganglioneuroma panel. The review calls these
      tumors the most mature form of peripheral neuroblastic tumor and describes
      them as elastic, yellowish white, well circumscribed and encapsulated,
      with infiltration of the surrounding fat in deeply seated tumors that has
      no prognostic significance. It places the ganglion cells singly or in
      small clusters in Schwannian stroma, defines mature GN by completely
      mature ganglion cells and maturing GN by a mixture of mature and maturing
      ganglion cells, and states that completely mature ganglion cells are
      covered with satellite cells. This restates the INPC morphologic criteria
      rather than reporting case data.
  - reference: PMID:41612478
    reference_title: "Pathology of peripheral neuroblastic tumors."
    supports: SUPPORT
    directness: DIRECT
    quote_role: REVIEW_SYNTHESIS
    evidence_source: OTHER
    snippet: "Neurites produced by the ganglion cells are immediately incorporated in the cytoplasm of Schwannian stromal cells, so that naked neurites are not identified around the ganglion cells."
    explanation: >-
      This sentence comes from the 2026 review's paragraph headed
      'Ganglioneuroma (Schwannian stroma-dominant)' (the cached text drops the
      heading), directly after the definitions of mature and maturing GN, and
      the review's Fig. 2C ganglioneuroma legend says the same. Neurites
      produced by the ganglion cells are immediately incorporated in the
      cytoplasm of Schwannian stromal cells, so naked neurites are not
      identified around the ganglion cells. This restates an INPC morphologic
      criterion and reports no case data.
  - reference: PMID:10421272
    reference_title: "Terminology and morphologic criteria of neuroblastic tumors: recommendations by the International Neuroblastoma Pathology Committee."
    supports: SUPPORT
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    evidence_source: HUMAN_CLINICAL
    snippet: "Based on morphologic criteria defined in this article, NTs were classified into four categories and their subtypes: 1) neuroblastoma (Schwannian stroma-poor), undifferentiated, poorly differentiated, and differentiating; 2) ganglioneuroblastoma, intermixed (Schwannian stroma-rich); 3) ganglioneuroma (Schwannian stroma-dominant), maturing and mature; and 4) ganglioneuroblastoma, nodular (composite Schwannian stroma-richlstroma-dominant and stroma-poor)."
    explanation: >-
      The 1999 terminology paper of the International Neuroblastoma Pathology
      Committee, whose six member pathologists defined the morphologic criteria
      from a review of 227 cases, classifies neuroblastic tumors into four
      categories. Ganglioneuroma is the third, the Schwannian stroma-dominant
      category, with maturing and mature subtypes; neuroblastoma is the
      stroma-poor category and intermixed ganglioneuroblastoma the stroma-rich
      one. Nodular ganglioneuroblastoma is a composite of stroma-rich or
      stroma-dominant tissue with stroma-poor tissue, so ganglioneuroma is the
      only category whose label is stroma-dominant alone. The abstract prints the
      composite label as 'stroma-richlstroma-dominant', and the quote keeps that
      spelling. The abstract does not assign ganglioneuroma to a prognostic
      group; the classification itself is reported in the companion article
      (PMID:10421273).
  - reference: PMID:19530234
    reference_title: "Clinicopathological characteristics of ganglioneuroma and ganglioneuroblastoma: a report from the CCG and COG."
    supports: SUPPORT
    directness: DIRECT
    quote_role: BACKGROUND
    evidence_source: OTHER
    snippet: "GNB-Intermixed (Schwannian stroma-rich) and GN (Schwannian stroma-dominant) tumors are always classified into the FH group."
    explanation: >-
      In the introduction of a Children's Cancer Group and Children's Oncology
      Group study of 552 ganglioneuroma and ganglioneuroblastoma cases, Okamatsu
      et al. restate the International Neuroblastoma Pathology Classification
      (INPC) rule: ganglioneuroma (Schwannian stroma-dominant) tumors, like
      intermixed ganglioneuroblastoma, are always classified into the Favorable
      Histology (FH) group. The sentence restates the INPC papers rather than
      reporting a result of this cohort.
- name: PHOX2B Immunoreactivity
  description: >-
    PHOX2B was expressed in every ganglioneuroma examined in two
    immunohistochemistry series: diffusely in all 65 peripheral neuroblastic
    tumors of a pediatric series, which included 10 ganglioneuromas, with less
    intensity in differentiating neuroblastoma, ganglioneuroblastoma and
    ganglioneuroma than in undifferentiated and poorly differentiated
    neuroblastoma, and in all 8 ganglioneuromas of a series of 77 autonomic
    nervous system tumors. A third series, which did not report ganglioneuromas
    separately, found PHOX2B in 92% of 76 peripheral neuroblastic tumors,
    including two of four adult cases, so the marker is not positive in every
    tumor of the family.
  notes: >-
    No finding term is bound: an OLS NCIT search for PHOX2B on 2026-10-28
    returned the gene (NCIT:C97724), its wild-type allele (NCIT:C97725), gene
    mutation (NCIT:C135016), the protein (NCIT:C97726 Paired Mesoderm Homeobox
    Protein 2B), an anti-PHOX2B CAR T-cell product (NCIT:C220615) and two
    predisposition terms (NCIT:C115225 Hereditary Neuroblastoma, NCIT:C179469
    Genetic Predisposition to Neuroblastoma), and no immunoreactivity finding.
    The two ganglioneuroma series do not say whether staining was nuclear or
    which ganglioneuroma cells stained. They disagree on pheochromocytoma and
    paraganglioma (all 23 positive in PMID:28986989; pheochromocytomas negative
    and 40% of paragangliomas positive in PMID:23715162), so PHOX2B is not used
    to separate ganglioneuroma from them.
  evidence:
  - reference: PMID:28986989
    reference_title: "Utility of Phox2b immunohistochemical stain in neural crest tumours and non-neural crest tumours in paediatric patients."
    supports: SUPPORT
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    evidence_source: HUMAN_CLINICAL
    snippet: "Phox2b was expressed diffusely in pNT (n = 65 of 65), strongly in NB-UD and NB-PD and with less intensity in NB-D, GNB and GN."
    explanation: >-
      In this pediatric immunohistochemistry series, the 65 peripheral
      neuroblastic tumors (pNT) included 10 ganglioneuromas (GN), alongside
      undifferentiated (NB-UD), poorly differentiated (NB-PD) and
      differentiating (NB-D) neuroblastomas and ganglioneuroblastomas (GNB).
      Phox2b was expressed diffusely in all 65 pNT: strongly in NB-UD and NB-PD,
      and with less intensity in NB-D, GNB and GN. The sentence directly supports
      PHOX2B expression in ganglioneuroma, as in every pNT tested in this series,
      at lower intensity than in undifferentiated and poorly differentiated
      neuroblastoma. The abstract does not say whether the staining was nuclear
      or which ganglioneuroma cells stained, and the ganglioneuroma group is 10
      tumors.
  - reference: PMID:23715162
    reference_title: "A study of gata3 and phox2b expression in tumors of the autonomic nervous system."
    supports: SUPPORT
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    evidence_source: HUMAN_CLINICAL
    snippet: "Phox2b expression was seen in all neuroblastomas, ganglioneuroblastomas, and ganglioneuromas and in 40% of paragangliomas, but pheochromocytomas and all other tumors were negative."
    explanation: >-
      Immunohistochemistry on 77 autonomic nervous system tumors, including 8
      ganglioneuromas, found Phox2b expression in every neuroblastoma,
      ganglioneuroblastoma and ganglioneuroma tested. This second series, by a
      different author group from PMID:28986989, supports PHOX2B expression in
      ganglioneuroma and in every neuroblastic tumor it examined. It reports no
      staining intensity, does not describe the staining as nuclear and gives no
      patient ages, and the ganglioneuroma group is 8 tumors. The sentence's
      paraganglioma and pheochromocytoma results are outside this finding.
  - reference: PMID:28640941
    reference_title: "PHOX2B reliably distinguishes neuroblastoma among small round blue cell tumours."
    supports: SUPPORT
    directness: INDIRECT
    quote_role: PRIMARY_RESULT
    evidence_source: HUMAN_CLINICAL
    snippet: "PHOX2B was positive in 70 (92%) peripheral neuroblastic tumours, including 68 of 72 (94%) paediatric and two of four (50%) adult cases."
    explanation: >-
      In a series of 76 peripheral neuroblastic tumors (median age 2 years, four
      adults) stained with a rabbit monoclonal antibody, positivity was defined
      as nuclear immunoreactivity in at least 5% of cells, and PHOX2B was
      positive in 70 (92%), including 68 of 72 pediatric and two of four adult
      cases. The abstract does not report ganglioneuromas separately, so it
      bears on this finding only through the tumor family as a whole; it shows
      that PHOX2B is not positive in every peripheral neuroblastic tumor.
- name: Tyrosine Hydroxylase Immunoreactivity
  description: >-
    In a pediatric immunohistochemistry series, tyrosine hydroxylase staining
    was diffuse in every ganglioneuroma, as in all poorly differentiated and
    differentiating neuroblastomas and ganglioneuroblastomas, whereas nine of
    15 undifferentiated neuroblastomas and a nodule in a nodular
    ganglioneuroblastoma did not express it.
  notes: >-
    No finding term is bound: an OLS NCIT search for tyrosine hydroxylase on
    2026-10-28 returned the enzyme (NCIT:C127896 Tyrosine 3-Monooxygenase), the
    gene (NCIT:C127894) and its wild-type allele (NCIT:C127895), an inhibitor
    class (NCIT:C2155), a deficiency disorder (NCIT:C157158) and unrelated
    substances, and no immunoreactivity finding.
  evidence:
  - reference: PMID:28986989
    reference_title: "Utility of Phox2b immunohistochemical stain in neural crest tumours and non-neural crest tumours in paediatric patients."
    supports: SUPPORT
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    evidence_source: HUMAN_CLINICAL
    snippet: "Diffuse TH was seen in all NB-PD, NB-D, GNB and GN, but nine of 15 NB-UD and a nodule in GNBn did not express TH (n = 55 of 65)."
    explanation: >-
      In the same pediatric series, which included 10 ganglioneuromas (GN),
      diffuse tyrosine hydroxylase (TH) staining was seen in all poorly
      differentiated and differentiating neuroblastomas, ganglioneuroblastomas
      and ganglioneuromas, while nine of 15 undifferentiated neuroblastomas and
      a nodule in a nodular ganglioneuroblastoma did not express TH. The
      sentence directly supports diffuse TH staining in ganglioneuroma. The
      ganglioneuroma group is 10 tumors, and the abstract does not say which
      ganglioneuroma cells stained.
phenotypes:
- category: Abdominal
  name: Retroperitoneal Mass
  description: >-
    The retroperitoneum was the commonest site in a single-institution series,
    with 46 of 101 tumors (45.5%). In German trials of localized tumors in
    patients aged 21 years or younger, 51 of 161 ganglioneuromas (31.7%) were
    adrenal and 67 (41.6%) abdomino-pelvic; that series does not report a
    retroperitoneal category.
  phenotype_term:
    preferred_term: retroperitoneal mass
    term:
      id: HP:6000285
      label: Retroperitoneal mass
  evidence:
  - reference: PMID:42537227
    reference_title: "A comprehensive analysis of ganglioneuromas: a 30-year experience of 101 patients."
    supports: SUPPORT
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    evidence_source: HUMAN_CLINICAL
    snippet: "Tumors most commonly arose in the retroperitoneum (n = 46, 45.5%), thoracic paraspinal/mediastinal region (n = 33, 32.7%), presacral space (n = 18, 17.8%), and cervical region (n = 4, 4%)."
    explanation: >-
      In this single-institution series of 101 patients the retroperitoneum
      was the commonest site, with 46 tumors (45.5%); a tumor arising there is
      a retroperitoneal mass. The abstract gives no separate adrenal category,
      and one institution's series is not a population estimate.
  - reference: PMID:27465021
    reference_title: "Treatment and outcome of Ganglioneuroma and Ganglioneuroblastoma intermixed."
    supports: SUPPORT
    directness: INDIRECT
    quote_role: PRIMARY_RESULT
    evidence_source: HUMAN_CLINICAL
    snippet: "| | GN (n = 162) | p1 | GNBI (n = 55) | GN / GNBI (n=217) | p 2 | NB / GNBN (n = 591) | | Localization | | | | | | | | Adrenal ... | 51/161 | 0.613* ... | 15/55 | 66/216 | 0.001 * ... | 256/591 | | 31.7 % | 27.3 % | 30.6 % | 43.3 % | | Abdomino-pelvic ... | 67/161 | | 21/55 | 88/216 | | 211/591 | | 41.6 % | | 38.2 % | 40.7% | | 35.7 % | | Thoraco-cervical ... | 43/161 | | 19/55 | 62/216 | | 123/591 | | 26.7 % | | 34.5 % | 28.7 % | | 20.8 % |"
    explanation: >-
      Table 1 of a retrospective study of localized neuroblastic tumors in
      patients aged 21 years or younger, registered in the German NB97 and
      NB2004 trials: in the ganglioneuroma (GN) column, 51 of 161 tumors (31.7%)
      were adrenal, 67 (41.6%) abdomino-pelvic and 43 (26.7%) thoraco-cervical.
      The table has no retroperitoneal category. Reading the adrenal and
      abdomino-pelvic rows as retroperitoneal masses assumes that those tumors
      lie behind the peritoneum, which the paper does not state, and the
      abdomino-pelvic row is not split into sites; the two rows are not added
      together here because the paper reports no combined figure. The 43
      thoraco-cervical tumors were not retroperitoneal.
- category: Thoracic
  name: Posterior Mediastinal Mass
  description: >-
    In a surgical series of 22 thoracic ganglioneuromas, 19 lay in the
    posterior mediastinum.
  phenotype_term:
    preferred_term: posterior mediastinal mass
    term:
      id: HP:0033829
      label: Posterior mediastinal mass
  evidence:
  - reference: PMID:22573298
    reference_title: "CT and MRI findings of thoracic ganglioneuroma."
    supports: SUPPORT
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    evidence_source: HUMAN_CLINICAL
    snippet: "Of 22 lesions, 19 occurred in the posterior mediastinum, 2 in the lateral pleura and 1 in the right chest."
    explanation: >-
      Retrospective series of 22 thoracic ganglioneuromas confirmed by surgery
      and pathology, collected from July 2002 to December 2010, in patients aged
      4 to 57 years (median 21). Of the 22 lesions, 19 lay in the posterior
      mediastinum, 2 in the lateral pleura and 1 in the right chest. All 22
      were resected tumors, so the sentence places a posterior mediastinal mass
      directly. The 19 of 22 is a share of resected thoracic tumors in this
      series, not of all ganglioneuromas.
- category: Abdominal
  name: Pelvic Mass
  description: >-
    In a single-institution series of 101 patients, 18 tumors (17.8%) arose in
    the presacral space.
  phenotype_term:
    preferred_term: pelvic mass
    term:
      id: HP:0031501
      label: Pelvic mass
  evidence:
  - reference: PMID:42537227
    reference_title: "A comprehensive analysis of ganglioneuromas: a 30-year experience of 101 patients."
    supports: SUPPORT
    directness: INDIRECT
    quote_role: PRIMARY_RESULT
    evidence_source: HUMAN_CLINICAL
    snippet: "Tumors most commonly arose in the retroperitoneum (n = 46, 45.5%), thoracic paraspinal/mediastinal region (n = 33, 32.7%), presacral space (n = 18, 17.8%), and cervical region (n = 4, 4%)."
    explanation: >-
      In this single-institution series of 101 patients, 18 tumors (17.8%)
      arose in the presacral space. Reading a presacral tumor as a pelvic mass
      is the inference step.
- category: Constitutional
  name: Pain
  frequency: FREQUENT
  description: >-
    In localized ganglioneuromas of patients aged 21 years or younger registered
    in the German neuroblastoma trials NB97 and NB2004, local clinics reported
    pain as the most frequent symptom leading to diagnosis (34.2%), ahead of a
    palpable tumor mass (9.3%) and reduced general condition (6.2%); pain led to
    diagnosis in 14.5% of intermixed ganglioneuroblastomas and 13.6% of
    neuroblastomas and nodular ganglioneuroblastomas. The figure is the share
    of patients whose diagnosis was prompted by pain, and the frequent band
    rests on this one cohort of young patients.
  phenotype_term:
    preferred_term: pain
    term:
      id: HP:0012531
      label: Pain
  evidence:
  - reference: PMID:27465021
    reference_title: "Treatment and outcome of Ganglioneuroma and Ganglioneuroblastoma intermixed."
    supports: SUPPORT
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    evidence_source: HUMAN_CLINICAL
    snippet: "As reported by local clinics, most frequent symptoms leading to diagnosis were pain (GN 34.2 %, GNBI 14.5 %, NB/GNBN 13.6 %, p < 0.001), palpable tumor mass (GN 9.3 %, GNBI 12.7 %, NB/GNBN 18.0 %, p = 0.022) and reduced general condition (GN 6.2 %, GNBI 7.3 %, NB/GNBN 15.8 %, p = 0.003)."
    explanation: >-
      In localized ganglioneuromas registered in the German neuroblastoma
      trials NB97 and NB2004, pain was the most frequent symptom leading to
      diagnosis (GN 34.2%), ahead of palpable tumor mass (9.3%) and reduced
      general condition (6.2%), as reported by local clinics. The figure is the
      share of GN patients whose diagnosis was prompted by pain, so it is a
      floor for pain at presentation rather than a full prevalence; at 34.2% it
      places Pain in the frequent band for this registry cohort of children and
      young people, and it does not say what causes the pain.
- category: Gastrointestinal
  name: Watery Diarrhea
  description: >-
    Watery diarrhea is described in case reports of young children with
    ganglioneuroma, attributed by the authors to vasoactive intestinal peptide
    secreted by the tumor; in two children it stopped after the tumor was
    removed. No frequency is known.
  phenotype_term:
    preferred_term: watery diarrhea
    term:
      id: HP:0002014
      label: Diarrhea
  notes: >-
    Bound to Diarrhea rather than Secretory diarrhea (HP:0005208): the cited
    reports describe watery diarrhea and attribute it to VIP but do not
    describe the secretory mechanism.
  evidence:
  - reference: PMID:7376870
    reference_title: "Vasocative intestinal polypeptide (VIP)-producing ganglioneuroma in a child with chronic diarrhea."
    supports: SUPPORT
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    evidence_source: HUMAN_CLINICAL
    snippet: "In a 2 1/2-year-old girl with persistent watery diarrhea a retroperitoneal tumour and lymph node composed of benign ganglioneuroma cells were found."
    explanation: >-
      Case report of a 2 1/2-year-old girl with persistent watery diarrhea in
      whom a retroperitoneal tumor and a lymph node made of benign
      ganglioneuroma cells were found; it records watery diarrhea in a child
      with ganglioneuroma. It is a single case, and the authors judged the
      histology compatible with an originally metastasizing neuroblastoma that
      had matured late.
  - reference: PMID:7376870
    reference_title: "Vasocative intestinal polypeptide (VIP)-producing ganglioneuroma in a child with chronic diarrhea."
    supports: SUPPORT
    directness: INDIRECT
    quote_role: PRIMARY_RESULT
    evidence_source: HUMAN_CLINICAL
    snippet: "Postoperatively the VIP concentration was normalized, and the diarrhea ceased."
    explanation: >-
      In the same case report, the VIP concentration returned to normal after
      the operation and the girl's diarrhea stopped. Resolution after the
      operation supports the authors' attribution of the watery diarrhea to the
      tumor; the support comes through the response to surgery, so it is
      indirect, and the abstract does not say how much of the tumor was removed.
      It is a single case.
  - reference: PMID:2833214
    reference_title: "Vasoactive intestinal peptide secreting tumours in children: a case report with literature review."
    supports: SUPPORT
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    evidence_source: HUMAN_CLINICAL
    snippet: "A 3 year old Chinese girl with watery diarrhoea, abdominal distension and hypokalaemia due to a thoracic paraspinal vasoactive intestinal peptide (VIP) secreting ganglioneuroma is reported."
    explanation: >-
      The authors' own case: a 3-year-old girl had watery diarrhea, abdominal
      distension and hypokalemia, which they state were due to a VIP-secreting
      thoracic paraspinal ganglioneuroma. This records watery diarrhea in a
      VIP-secreting ganglioneuroma. It is a single case, so it shows that the
      phenotype occurs in the VIP-secreting form of the tumor but gives no
      frequency.
  - reference: PMID:2833214
    reference_title: "Vasoactive intestinal peptide secreting tumours in children: a case report with literature review."
    supports: SUPPORT
    directness: INDIRECT
    quote_role: PRIMARY_RESULT
    evidence_source: HUMAN_CLINICAL
    snippet: "Her diarrhoea stopped after the removal of the tumour."
    explanation: >-
      In the same case report, the girl's diarrhea stopped after the
      VIP-secreting ganglioneuroma was removed. Resolution after resection
      supports the authors' attribution of the watery diarrhea to the tumor;
      the support comes through the response to tumor removal, so it is
      indirect. The abstract gives no timing for the resolution and does not
      report potassium after surgery. It is a single case.
- category: Laboratory
  name: Hypokalemia
  description: >-
    Reported with watery diarrhea and abdominal distension in a 3-year-old girl
    with a VIP-secreting thoracic paraspinal ganglioneuroma. No frequency is
    known.
  phenotype_term:
    preferred_term: hypokalemia
    term:
      id: HP:0002900
      label: Hypokalemia
  evidence:
  - reference: PMID:2833214
    reference_title: "Vasoactive intestinal peptide secreting tumours in children: a case report with literature review."
    supports: SUPPORT
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    evidence_source: HUMAN_CLINICAL
    snippet: "A 3 year old Chinese girl with watery diarrhoea, abdominal distension and hypokalaemia due to a thoracic paraspinal vasoactive intestinal peptide (VIP) secreting ganglioneuroma is reported."
    explanation: >-
      The authors' own case: a 3-year-old girl had watery diarrhea, abdominal
      distension and hypokalemia, which they state were due to a VIP-secreting
      thoracic paraspinal ganglioneuroma. This records hypokalemia in a
      VIP-secreting ganglioneuroma. It is a single case, so it gives no
      frequency, and the abstract does not say by what route the tumor lowered
      the potassium.
- category: Laboratory
  name: Elevated Urinary Homovanillic Acid
  frequency: FREQUENT
  description: >-
    In localized tumors registered in the German NB97 and NB2004 trials
    (patients aged 21 years or younger), urinary homovanillic acid was elevated
    in 45 of 142 tested patients with ganglioneuroma (31.7%), against 61.4% of
    patients with intermixed ganglioneuroblastoma and 61.6% with neuroblastoma
    or nodular ganglioneuroblastoma.
  phenotype_term:
    preferred_term: elevated urinary homovanillic acid
    term:
      id: HP:0011977
      label: Elevated urinary homovanillic acid
  evidence:
  - reference: PMID:27465021
    reference_title: "Treatment and outcome of Ganglioneuroma and Ganglioneuroblastoma intermixed."
    supports: SUPPORT
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    evidence_source: HUMAN_CLINICAL
    snippet: "| | GN (n = 162) | p1 | GNBI (n = 55) | GN / GNBI (n=217) | p 2 | NB / GNBN (n = 591) | ... | HVA elevated ... | 45/142 | 0.001 ... | 27/44 | 72/186 | <0.001 ... | 327/531 | | 31.7 % | 61.4 % | 38.7 % | 61.6 % |"
    explanation: >-
      Table 1 of this retrospective study of localized neuroblastic tumors
      registered in the German NB97 and NB2004 trials; the excerpt gives the
      column headings and the HVA row. Urinary homovanillic acid was elevated
      in 45 of 142 tested patients with ganglioneuroma (31.7%), which places
      the finding in the frequent band for this cohort, against 27 of 44 with
      intermixed ganglioneuroblastoma (61.4%) and 327 of 531 with neuroblastoma
      or nodular ganglioneuroblastoma (61.6%). The p-values compare
      ganglioneuroma with intermixed tumors (p1) and the pooled mature tumors
      with the immature ones (p2). Metastatic tumors and patients over 21 were
      excluded.
- category: Laboratory
  name: Elevated Urinary Vanillylmandelic Acid
  frequency: OCCASIONAL
  description: >-
    In the same series, urinary vanillylmandelic acid was elevated in 28 of 145
    tested patients with ganglioneuroma (19.3%), against 48.9% of patients with
    intermixed ganglioneuroblastoma and 64.1% with neuroblastoma or nodular
    ganglioneuroblastoma.
  phenotype_term:
    preferred_term: elevated urinary vanillylmandelic acid
    term:
      id: HP:0011978
      label: Elevated urinary vanillylmandelic acid
  evidence:
  - reference: PMID:27465021
    reference_title: "Treatment and outcome of Ganglioneuroma and Ganglioneuroblastoma intermixed."
    supports: SUPPORT
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    evidence_source: HUMAN_CLINICAL
    snippet: "| | GN (n = 162) | p1 | GNBI (n = 55) | GN / GNBI (n=217) | p 2 | NB / GNBN (n = 591) | ... | VMA elevated ... | 28/145 | <0.001 ... | 23/47 | 51/192 | <0.001 ... | 345/538 | | 19.3 % | 48.9 % | 26.6% | 64.1 % |"
    explanation: >-
      Table 1 of the same German NB97/NB2004 study of localized neuroblastic
      tumors; the excerpt gives the column headings and the VMA row. Urinary
      vanillylmandelic acid was elevated in 28 of 145 tested patients with
      ganglioneuroma (19.3%), which places the finding in the occasional band
      for this cohort, against 23 of 47 with intermixed ganglioneuroblastoma
      (48.9%) and 345 of 538 with neuroblastoma or nodular
      ganglioneuroblastoma (64.1%). Metastatic tumors and patients over 21 were
      excluded.
genetic:
- name: MYCN Amplification
  association: Rare Somatic Amplification
  gene_term:
    preferred_term: MYCN
    term:
      id: hgnc:7559
      label: MYCN
  relationship_type: BIOMARKER
  variant_origin: SOMATIC
  notes: >-
    MYCN amplification is rare in ganglioneuroma. In a CCG/COG series it was
    found in 2 of the 34 maturing ganglioneuromas with a MYCN result, and both
    patients were alive and well at last follow-up; the authors suggest that
    amplified MYCN may not have an adverse prognostic effect in these rare
    favorable-histology tumors. An earlier Children's Cancer Group series found
    no amplification in its 9 ganglioneuromas. The two cooperative-group
    series may share patients, and mature ganglioneuroma was not eligible for
    the CCG/COG studies. No frequency band is set, because the two small series
    disagree (2 of 34 against 0 of 9). No cited source treats MYCN
    amplification as the initiating lesion of ganglioneuroma, so no
    pathophysiology node carries it and no node is marked as the origin node.
  evidence:
  - reference: PMID:19530234
    reference_title: "Clinicopathological characteristics of ganglioneuroma and ganglioneuroblastoma: a report from the CCG and COG."
    supports: SUPPORT
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    evidence_source: HUMAN_CLINICAL
    snippet: "| GN-maturing N (%) | GNB-intermixed N (%) | GNB-nodular FS N (%) | GNB-nodular US N (%) | ... MYCN status ... | Not Amp** | 32 (94%) | 174 (99%) | 53 (100%) | 231 (97%) | | Amp** | 2 (6%) | 2 (1%) | 0 (0%) | 6 (3%) | | Unknown | 9 | 22 | 6 | 15 |"
    explanation: >-
      Table III of this CCG/COG series of patients registered on neuroblastoma
      studies in 1991-2006, tabulating MYCN status by centrally reviewed
      histology; the excerpt gives the column headings and the MYCN rows. In
      the GN-maturing column, 2 of the 34 tumors with a result (6%) had
      amplified MYCN, 32 were not amplified and 9 were untested. The series is
      not population-based, MYCN was determined by Southern blot, PCR and/or
      FISH in the reference laboratories, and mature ganglioneuroma was not
      eligible for these studies.
  - reference: PMID:19530234
    reference_title: "Clinicopathological characteristics of ganglioneuroma and ganglioneuroblastoma: a report from the CCG and COG."
    supports: SUPPORT
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    evidence_source: HUMAN_CLINICAL
    snippet: "As expected, there were only 4 FH tumors (4/210, 1.9%) that had amplified MYCN in our series of GN-M (2 cases) and GNB-I (2 cases), and all 4 patients were alive and well at the time of last follow-up. It is suggested that amplified MYCN may not have an adverse prognostic effect in these rare FH cases."
    explanation: >-
      In the Discussion of the same CCG/COG series, the authors note that only
      4 favorable-histology tumors had amplified MYCN, 2 maturing
      ganglioneuromas and 2 intermixed ganglioneuroblastomas, and that all 4
      patients were alive and well at last follow-up, and they suggest that
      amplified MYCN may not have an adverse prognostic effect in these rare
      cases. The suggestion rests on 4 patients, of whom the Results say 3 had
      more than one year of follow-up.
  - reference: PMID:11745206
    reference_title: "Histopathology (International Neuroblastoma Pathology Classification) and MYCN status in patients with peripheral neuroblastic tumors: a report from the Children's Cancer Group."
    supports: SUPPORT
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    evidence_source: HUMAN_CLINICAL
    snippet: "MYCN amplification was seen almost exclusively in tumors of the NB category, and no patients with tumors in either the GNBi category or in the GN category and only two patients with tumors in the GNBn category had amplified MYCN."
    explanation: >-
      This Children's Cancer Group series classified 628 neuroblastic tumors
      under the INPC, 9 of them ganglioneuromas, and tested each for MYCN
      status. Amplification was seen almost exclusively in the neuroblastoma
      category, and none of the ganglioneuromas was amplified. This supports
      amplification being rare in ganglioneuroma and largely confined to
      neuroblastoma; it does not show that amplification never occurs, and
      the ganglioneuroma group is 9 tumors.
diagnosis:
- name: Histopathologic Classification
  description: >-
    Ganglioneuroma is diagnosed and subtyped by histopathologic examination of
    tumor tissue under the INPC. A biopsy diagnosis is not always upheld at
    surgery: in a UK nationwide series of ganglioneuroma and intermixed
    ganglioneuroblastoma, 14 (12%) biopsy diagnoses of ganglioneuroma or
    intermixed ganglioneuroblastoma changed to neuroblastoma or nodular
    ganglioneuroblastoma on surgical pathology, whereas in a Hospital for Sick
    Children series of the two tumors classification changed at resection in
    three cases and no ganglioneuroma was reclassified as neuroblastoma. A 2026
    pathology review advises noting in the report that a favorable
    classification made on a core needle biopsy showing only intermixed
    ganglioneuroblastoma or ganglioneuroma was determined on review of limited
    material.
  diagnosis_term:
    preferred_term: histopathologic examination under the International Neuroblastoma Pathology Classification
    term:
      id: NCIT:C18190
      label: Histopathologic Examination
  evidence:
  - reference: PMID:39582110
    reference_title: "Management of Ganglioneuroma and Ganglioneuroblastoma Intermixed: A United Kingdom Children's Cancer and Leukaemia Group (UK CCLG) Nationwide Study Report."
    supports: SUPPORT
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    evidence_source: HUMAN_CLINICAL
    snippet: "In 45 cases (39%), surgical pathology was different from pathology at biopsy, and in 14 (12%) the pathology changed from GN/GNBi to neuroblastoma/GNB nodular."
    explanation: >-
      In this UK CCLG retrospective series of 259 patients with non-metastatic
      ganglioneuroma or intermixed ganglioneuroblastoma, surgical pathology
      differed from the biopsy diagnosis in 45 cases, and in 14 (12%) a biopsy
      diagnosis of ganglioneuroma or intermixed ganglioneuroblastoma became
      neuroblastoma or nodular ganglioneuroblastoma at surgery. The abstract
      gives no denominator for the percentages, does not split the changes by
      biopsy diagnosis or management arm, and does not say whether they reflect
      limited sampling, reinterpretation or change in the tumor before surgery.
  - reference: PMID:29369484
    reference_title: "Characteristics and management of ganglioneuroma and ganglioneuroblastoma-intermixed in children and adolescents."
    supports: SUPPORT
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    evidence_source: HUMAN_CLINICAL
    snippet: "Pathology classification changed at resection for three cases, but no GN was reclassified to NB."
    explanation: >-
      In this Hospital for Sick Children retrospective series (1990-2014) of 67
      children and adolescents with ganglioneuroma (50) or intermixed
      ganglioneuroblastoma (17), the pathology classification changed at
      resection in three cases, which shows that a pre-resection diagnosis is
      not always upheld, but no ganglioneuroma was reclassified as
      neuroblastoma. It is a counterweight to the UK figure: in this series the
      changes did not turn a ganglioneuroma into neuroblastoma. The abstract
      does not say what the three changes were, whether the earlier diagnoses
      were made on biopsy, or how many patients had a biopsy before resection.
  - reference: PMID:41612478
    reference_title: "Pathology of peripheral neuroblastic tumors."
    supports: SUPPORT
    directness: DIRECT
    quote_role: REVIEW_SYNTHESIS
    evidence_source: OTHER
    snippet: "especially when the samples obtained by PCNB show only GNB-i or GN histology, it is advisable to include a note of \"Favorable Histology of this case according to the International Neuroblastoma Pathology Classification is determined based on review of limited material\" in the surgical pathology report."
    explanation: >-
      This 2026 pathology review advises, as the authors' routine practice, that
      when percutaneous core needle biopsy (PCNB) samples show only
      GNB-intermixed or ganglioneuroma histology, the report should note that
      the favorable INPC classification was determined on review of limited
      material. The preceding sentence gives the reason: a core needle biopsy
      can miss the neuroblastoma nodule of a nodular ganglioneuroblastoma. It is
      an expert recommendation about core needle biopsy, without case data.
- name: Urinary Catecholamine Metabolites
  description: >-
    In localized tumors registered in the German NB97 and NB2004 trials
    (patients aged 21 years or younger), urinary homovanillic acid was raised in
    31.7% and vanillylmandelic acid in 19.3% of tested patients with
    ganglioneuroma, less often than in intermixed ganglioneuroblastoma or in
    neuroblastoma and nodular ganglioneuroblastoma, so a normal result does not
    exclude the tumor. In a series of 27 adrenal ganglioneuromas at a referral
    cancer center, catecholamine levels were normal in all 21 patients with
    results. Among 45 histologically confirmed adrenal ganglioneuromas at one
    center, every tumor with an adrenergic or noradrenergic catecholamine
    profile was a composite ganglioneuroma-pheochromocytoma, and the authors,
    finding that pure and composite tumors overlap on imaging, judged testing
    for catecholamine excess essential in any indeterminate adrenal mass.
  diagnosis_term:
    preferred_term: urinary catecholamine metabolite measurement
    term:
      id: NCIT:C61044
      label: Urine Chemistry Measurement
  measurements:
  - preferred_term: urinary vanillylmandelic acid (VMA)
    term:
      id: LOINC:LP15947-2
      label: Vanillylmandelate
  - preferred_term: urinary homovanillic acid (HVA)
    term:
      id: LOINC:LP15096-8
      label: Homovanillate
  notes: >-
    VMA and HVA are bound at the LOINC Part level (Vanillylmandelate,
    Homovanillate), which names the analyte rather than one specimen or method
    code. The procedure is bound to Urine Chemistry Measurement because
    diagnosis_term takes one term and this row covers both analytes, as in the
    Neuroblastoma entry. The adrenal series cited here measured plasma or
    urine catecholamines or metanephrines, or did not say which.
  evidence:
  - reference: PMID:27465021
    reference_title: "Treatment and outcome of Ganglioneuroma and Ganglioneuroblastoma intermixed."
    supports: SUPPORT
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    evidence_source: HUMAN_CLINICAL
    snippet: "| | GN (n = 162) | p1 | GNBI (n = 55) | GN / GNBI (n=217) | p 2 | NB / GNBN (n = 591) | ... | HVA elevated ... | 45/142 | 0.001 ... | 27/44 | 72/186 | <0.001 ... | 327/531 | | 31.7 % | 61.4 % | 38.7 % | 61.6 % |"
    explanation: >-
      Table 1 of the German NB97/NB2004 study of localized neuroblastic tumors:
      urinary homovanillic acid was elevated in 45 of 142 tested patients with
      ganglioneuroma (31.7%), against 61.4% with intermixed
      ganglioneuroblastoma and 61.6% with neuroblastoma or nodular
      ganglioneuroblastoma, so most patients with ganglioneuroma had a normal
      result.
  - reference: PMID:27465021
    reference_title: "Treatment and outcome of Ganglioneuroma and Ganglioneuroblastoma intermixed."
    supports: SUPPORT
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    evidence_source: HUMAN_CLINICAL
    snippet: "| | GN (n = 162) | p1 | GNBI (n = 55) | GN / GNBI (n=217) | p 2 | NB / GNBN (n = 591) | ... | VMA elevated ... | 28/145 | <0.001 ... | 23/47 | 51/192 | <0.001 ... | 345/538 | | 19.3 % | 48.9 % | 26.6% | 64.1 % |"
    explanation: >-
      Table 1 of the same study: urinary vanillylmandelic acid was elevated in
      28 of 145 tested patients with ganglioneuroma (19.3%), against 48.9% with
      intermixed ganglioneuroblastoma and 64.1% with neuroblastoma or nodular
      ganglioneuroblastoma, so most patients with ganglioneuroma had a normal
      result.
  - reference: PMID:24033606
    reference_title: "Adrenal ganglioneuroma: features and outcomes of 27 cases at a referral cancer centre."
    supports: SUPPORT
    directness: INDIRECT
    quote_role: PRIMARY_RESULT
    evidence_source: HUMAN_CLINICAL
    snippet: "Catecholamine levels, available for 21 patients, were normal."
    explanation: >-
      Results sentence from a retrospective series of 27 adrenal
      ganglioneuromas at a tertiary referral cancer center (median age 31 years,
      range 1.7-64): catecholamine levels were normal in all 21 patients with
      results. The abstract does not say whether urine or plasma was measured or
      which analytes, so using it for urinary catecholamine metabolites rests on
      an inference, and it does not say whether the 21 included the series'
      composite tumors.
  - reference: PMID:33721367
    reference_title: "Presentation and outcomes of adrenal ganglioneuromas: A cohort study and a systematic review of literature."
    supports: SUPPORT
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    evidence_source: HUMAN_CLINICAL
    snippet: "All tumors with either adrenergic or noradrenergic catecholamine profiles were found to be composite AGN-PHEO."
    explanation: >-
      Mayo Clinic single-center cohort of 45 histologically confirmed adrenal
      ganglioneuromas (1995-2019; median age 44, range 6-87), 20 of them
      composite ganglioneuroma-pheochromocytomas. Every tumor with an
      adrenergic or noradrenergic catecholamine profile was composite (Table 1:
      15 adrenergic and 3 noradrenergic, all in the composite group), and all
      17 tested pure ganglioneuromas were non-functional. The finding holds only
      for tumors with ganglioneuroma histology; it does not mean that
      adrenergic adrenal tumors in general are composite. One composite tumor
      was non-functioning, so a normal catecholamine result does not completely
      exclude a pheochromocytoma component.
  - reference: PMID:33721367
    reference_title: "Presentation and outcomes of adrenal ganglioneuromas: A cohort study and a systematic review of literature."
    supports: SUPPORT
    directness: INDIRECT
    quote_role: PRIMARY_RESULT
    evidence_source: HUMAN_CLINICAL
    snippet: "Since imaging characteristics of AGN and composite AGN-PHEO overlap, evaluation for catecholamine excess is essential in any indeterminate adrenal mass."
    explanation: >-
      In this cohort, pure and composite adrenal ganglioneuromas did not differ
      in laterality, calcification, homogeneity, shape or appearance, although
      composite tumors were smaller (median 39 vs 57 mm). From this the authors
      recommend testing for catecholamine excess in any indeterminate adrenal
      mass, which makes catecholamine status, not imaging, the way to detect a
      pheochromocytoma component. The support is indirect, because the sentence
      is a testing recommendation rather than a measured difference, and the
      cohort classified tumors by plasma or urine metanephrines or
      catecholamines, so it is not specific to urine testing.
imaging_findings:
- name: MIBG Uptake
  modality: OTHER
  frequency: OCCASIONAL
  imaging_finding_term:
    preferred_term: MIBG uptake on scintigraphy
    term:
      id: NCIT:C79553
      label: Increased Uptake by 123-Iodine-Meta-Iodobenzylguanidine Scintigraphy
  description: >-
    In localized tumors registered in the German NB97 and NB2004 trials
    (patients aged 21 years or younger), MIBG uptake was positive in 27 of 110
    tested patients with ganglioneuroma (24.5%), against 22 of 36 with
    intermixed ganglioneuroblastoma (61.1%) and 398 of 444 with neuroblastoma or
    nodular ganglioneuroblastoma, reported together (89.6%).
  notes: >-
    The German series does not state the MIBG isotope, and NCIT:C79553 is
    specific to 123I-MIBG; OLS NCIT searches on 2026-10-28 for MIBG uptake and
    MIBG scintigraphy returned NCIT:C79553 as the only uptake finding, so NCIT
    has no isotope-neutral term (see also the Neuroblastoma entry's MIBG rows).
    Modality is OTHER because planar scintigraphy is not in
    ImagingModalityEnum. The frequency band rests on the ganglioneuroma column
    of the German series; the pooled mature-tumor figure in the same row
    (33.6%) would fall in a higher band. An adrenal series of adolescents and
    adults in which 131I-MIBG was negative in all 4 ganglioneuromas scanned
    (PMID:19781327) is cited under the Adrenal Gland Pheochromocytoma
    differential diagnosis rather than here, because a negative scan does not
    support uptake.
  evidence:
  - reference: PMID:27465021
    reference_title: "Treatment and outcome of Ganglioneuroma and Ganglioneuroblastoma intermixed."
    supports: SUPPORT
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    evidence_source: HUMAN_CLINICAL
    snippet: "| | GN (n = 162) | p1 | GNBI (n = 55) | GN / GNBI (n=217) | p 2 | NB / GNBN (n = 591) | ... | Positive mIBG-uptake ... | 27/110 | <0.001 ... | 22/36 | 49/146 | <0.001 ... | 398/444 | | 24.5 % | 61.1 % | 33.6 % | 89.6 % |"
    explanation: >-
      Table 1 of this retrospective study of localized neuroblastic tumors
      registered in the German NB97 and NB2004 trials (diagnosed 2000-2009, age
      21 or younger at diagnosis); the excerpt gives the column headings and the
      positive mIBG-uptake row. MIBG uptake was positive in 27 of 110 tested
      patients with ganglioneuroma (24.5%), 22 of 36 with intermixed
      ganglioneuroblastoma (61.1%), 49 of 146 for the two mature types pooled
      (33.6%), and 398 of 444 with neuroblastoma or nodular
      ganglioneuroblastoma (89.6%). 24.5% falls in the occasional band (5-29%),
      while the pooled mature figure in the same row would fall in the frequent
      band, so the band rests on the ganglioneuroma column alone. Per the table
      footnote, p1 (<0.001) compares ganglioneuroma with intermixed
      ganglioneuroblastoma, and p2 (<0.001) compares the pooled mature tumors
      with the immature ones; no p-value compares ganglioneuroma alone with
      neuroblastoma. The percentages use the table's denominators, so 110 of the
      162 ganglioneuromas contribute; the paper does not say why the others have
      no result. The paper does not name the MIBG isotope.
  - reference: PMID:27465021
    reference_title: "Treatment and outcome of Ganglioneuroma and Ganglioneuroblastoma intermixed."
    supports: SUPPORT
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    evidence_source: HUMAN_CLINICAL
    snippet: "Moreover, GN showed less often positive mIBG-uptake and elevated urine catecholamine metabolites than GNBI."
    explanation: >-
      This Results sentence from the same German NB97/NB2004 series of
      localized neuroblastic tumors (patients aged 21 or younger at diagnosis)
      states the comparison directly: patients with ganglioneuroma less often
      showed positive MIBG uptake, and less often had elevated urinary
      catecholamine metabolites, than patients with intermixed
      ganglioneuroblastoma. The sentence gives no rates and says nothing about
      neuroblastoma.
differential_diagnoses:
- name: Ganglioneuroblastoma
  disease_term:
    preferred_term: ganglioneuroblastoma
    term:
      id: MONDO:0005035
      label: ganglioneuroblastoma
  description: >-
    The next INPC category toward immaturity. Intermixed ganglioneuroblastoma
    is characterized by well-defined microscopic nests of neuroblastic cells
    whose neurites are segmentally naked within the nests, and nodular
    ganglioneuroblastoma is a composite of stroma-rich or stroma-dominant tissue
    with stroma-poor neuroblastoma. A biopsy diagnosis of ganglioneuroma or
    intermixed ganglioneuroblastoma is not always upheld at surgery: in a UK
    nationwide series that pooled the two tumors, 14 (12%) such biopsy
    diagnoses became neuroblastoma or nodular ganglioneuroblastoma on surgical
    pathology, whereas in a Hospital for Sick Children series, also pooled,
    classification changed at resection in three cases and no ganglioneuroma
    was reclassified as neuroblastoma. In German trials of localized tumors,
    ganglioneuroma less often took up MIBG and less often raised urinary
    catecholamine metabolites than intermixed ganglioneuroblastoma.
  distinguishing_features:
  - "Ganglioneuroma: neurites incorporated into the cytoplasm of Schwannian stromal cells, with no naked neurites identified around the ganglion cells; intermixed ganglioneuroblastoma: well-defined microscopic nests of neuroblastic cells whose neurites are segmentally naked within the nests"
  - "Ganglioneuroma has no stroma-poor neuroblastomatous component, which nodular ganglioneuroblastoma contains"
  - "In German trials of localized tumors in patients aged 21 years or younger, MIBG uptake was positive in 24.5% of ganglioneuromas against 61.1% of intermixed ganglioneuroblastomas, and ganglioneuroma less often raised urinary catecholamine metabolites"
  evidence:
  - reference: PMID:41612478
    reference_title: "Pathology of peripheral neuroblastic tumors."
    supports: SUPPORT
    directness: DIRECT
    quote_role: REVIEW_SYNTHESIS
    evidence_source: OTHER
    snippet: "Neurites produced by the ganglion cells are immediately incorporated in the cytoplasm of Schwannian stromal cells, so that naked neurites are not identified around the ganglion cells."
    explanation: >-
      This sentence comes from the 2026 review's paragraph headed
      'Ganglioneuroma (Schwannian stroma-dominant)' (the cached text drops the
      heading), directly after the definitions of mature and maturing GN, and
      the review's Fig. 2C ganglioneuroma legend says the same. It states that
      neurites produced by the ganglion cells are immediately incorporated in
      the cytoplasm of Schwannian stromal cells, so naked neurites are not
      identified around the ganglion cells. Under this differential it is the
      ganglioneuroma side of the contrast with the review's paragraph on
      intermixed ganglioneuroblastoma, where neurites are segmentally naked
      within microscopic neuroblastic nests; the review describes the two
      categories in separate paragraphs and does not compare them directly. It
      restates INPC morphologic criteria and reports no case data.
  - reference: PMID:41612478
    reference_title: "Pathology of peripheral neuroblastic tumors."
    supports: SUPPORT
    directness: DIRECT
    quote_role: REVIEW_SYNTHESIS
    evidence_source: OTHER
    snippet: "The tumors are characterized by the presence of well-defined microscopic nests of neuroblastic cells in various stages of differentiation with actively producing and easily recognizable neurites around their cytoplasm (Fig. 2B). Their neurites are segmentally naked in those microscopic nests and eventually incorporated in the cytoplasm of Schwannian cells in the stromal areas."
    explanation: >-
      These sentences close the paragraph headed 'Ganglioneuroblastoma,
      intermixed (Schwannian stroma-rich)' in this 2026 pathology review; the
      cached text drops the heading, and the quote itself says only 'The
      tumors'. The Fig. 2B legend they cite labels the image as
      ganglioneuroblastoma, intermixed, with microscopic nests of neuroblastic
      cells and their naked neurites. They state that intermixed tumors are
      characterized by well-defined microscopic nests of neuroblastic cells at
      various stages of differentiation, whose neurites are segmentally naked
      within the nests and are eventually incorporated into Schwannian cell
      cytoplasm in the stromal areas. The review's ganglioneuroma paragraph
      describes ganglion cells lying singly or in small clusters, with no naked
      neurites around them, and does not describe neuroblastic nests; the
      review describes the two categories in separate paragraphs and does not
      compare them directly. The quote concerns the intermixed category only,
      not nodular ganglioneuroblastoma, and restates INPC morphologic criteria
      rather than reporting case data.
  - reference: PMID:10421272
    reference_title: "Terminology and morphologic criteria of neuroblastic tumors: recommendations by the International Neuroblastoma Pathology Committee."
    supports: SUPPORT
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    evidence_source: HUMAN_CLINICAL
    snippet: "Based on morphologic criteria defined in this article, NTs were classified into four categories and their subtypes: 1) neuroblastoma (Schwannian stroma-poor), undifferentiated, poorly differentiated, and differentiating; 2) ganglioneuroblastoma, intermixed (Schwannian stroma-rich); 3) ganglioneuroma (Schwannian stroma-dominant), maturing and mature; and 4) ganglioneuroblastoma, nodular (composite Schwannian stroma-richlstroma-dominant and stroma-poor)."
    explanation: >-
      The 1999 terminology paper of the International Neuroblastoma Pathology
      Committee classifies neuroblastic tumors into four categories:
      ganglioneuroma is Schwannian stroma-dominant, intermixed
      ganglioneuroblastoma stroma-rich, and nodular ganglioneuroblastoma a
      composite of stroma-rich or stroma-dominant tissue with stroma-poor
      tissue. The stroma-poor component therefore separates nodular
      ganglioneuroblastoma from ganglioneuroma. The quote keeps the abstract's
      spelling 'stroma-richlstroma-dominant'.
  - reference: PMID:39582110
    reference_title: "Management of Ganglioneuroma and Ganglioneuroblastoma Intermixed: A United Kingdom Children's Cancer and Leukaemia Group (UK CCLG) Nationwide Study Report."
    supports: SUPPORT
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    evidence_source: HUMAN_CLINICAL
    snippet: "In 45 cases (39%), surgical pathology was different from pathology at biopsy, and in 14 (12%) the pathology changed from GN/GNBi to neuroblastoma/GNB nodular."
    explanation: >-
      In this UK CCLG retrospective series of 259 patients with non-metastatic
      ganglioneuroma or intermixed ganglioneuroblastoma, surgical pathology
      differed from the biopsy diagnosis in 45 cases, and in 14 (12%) a biopsy
      diagnosis of ganglioneuroma or intermixed ganglioneuroblastoma became
      neuroblastoma or nodular ganglioneuroblastoma at surgery. The abstract
      gives no denominator for the percentages, does not split the changes by
      biopsy diagnosis, and does not say whether they reflect limited sampling,
      reinterpretation or change in the tumor before surgery.
  - reference: PMID:29369484
    reference_title: "Characteristics and management of ganglioneuroma and ganglioneuroblastoma-intermixed in children and adolescents."
    supports: SUPPORT
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    evidence_source: HUMAN_CLINICAL
    snippet: "Pathology classification changed at resection for three cases, but no GN was reclassified to NB."
    explanation: >-
      In this Hospital for Sick Children retrospective series of 67 children
      and adolescents with ganglioneuroma (50) or intermixed
      ganglioneuroblastoma (17), the pathology classification changed at
      resection in three cases, but no ganglioneuroma was reclassified as
      neuroblastoma. It supports a diagnosis made before resection not always
      being upheld, and it is a counterweight to the UK figure for
      ganglioneuroma: here no change turned a ganglioneuroma into
      neuroblastoma. The abstract does not say what the three changes were,
      whether any ganglioneuroma was reclassified as ganglioneuroblastoma, or
      whether the earlier diagnoses were made on biopsy.
  - reference: PMID:27465021
    reference_title: "Treatment and outcome of Ganglioneuroma and Ganglioneuroblastoma intermixed."
    supports: SUPPORT
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    evidence_source: HUMAN_CLINICAL
    snippet: "| | GN (n = 162) | p1 | GNBI (n = 55) | GN / GNBI (n=217) | p 2 | NB / GNBN (n = 591) | ... | Positive mIBG-uptake ... | 27/110 | <0.001 ... | 22/36 | 49/146 | <0.001 ... | 398/444 | | 24.5 % | 61.1 % | 33.6 % | 89.6 % |"
    explanation: >-
      Table 1 of the German NB97/NB2004 study of localized neuroblastic tumors
      (patients aged 21 or younger): MIBG uptake was positive in 27 of 110
      tested patients with ganglioneuroma (24.5%) against 22 of 36 with
      intermixed ganglioneuroblastoma (61.1%), and p1 (<0.001) tests that
      difference. Metastatic tumors were excluded.
  - reference: PMID:27465021
    reference_title: "Treatment and outcome of Ganglioneuroma and Ganglioneuroblastoma intermixed."
    supports: SUPPORT
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    evidence_source: HUMAN_CLINICAL
    snippet: "Moreover, GN showed less often positive mIBG-uptake and elevated urine catecholamine metabolites than GNBI."
    explanation: >-
      This Results sentence from the same German series of localized
      neuroblastic tumors states that patients with ganglioneuroma less often
      showed positive MIBG uptake, and less often had elevated urinary
      catecholamine metabolites, than patients with intermixed
      ganglioneuroblastoma. It compares only these two mature tumor types.
- name: Neuroblastoma
  disease_term:
    preferred_term: neuroblastoma
    term:
      id: MONDO:0005072
      label: neuroblastoma
  description: >-
    The Schwannian stroma-poor end of the same INPC spectrum. Neuroblastoma is
    classified as favorable or unfavorable histology by an age-linked
    evaluation of its grade of differentiation and mitosis-karyorrhexis index,
    whereas ganglioneuroma is always of favorable histology. In German trials of
    localized tumors, neuroblastoma and nodular ganglioneuroblastoma, reported
    together, were diagnosed younger and more often took up MIBG and raised
    urinary catecholamine metabolites than ganglioneuroma.
  distinguishing_features:
  - "Schwannian stroma-poor histology in neuroblastoma, against stroma-dominant histology in ganglioneuroma"
  - "Median age at diagnosis 9 months for localized neuroblastoma and nodular ganglioneuroblastoma taken together, against 71 months for maturing and 125 months for mature ganglioneuroma, in German trials of patients aged 21 years or younger; these are group medians, not a cut-off"
  - "MIBG uptake positive in 89.6% of localized neuroblastoma or nodular ganglioneuroblastoma against 24.5% of ganglioneuroma in the same series, a descriptive comparison with no test of ganglioneuroma alone against neuroblastoma"
  - "Urinary homovanillic acid raised in 61.6% and vanillylmandelic acid in 64.1% of localized neuroblastoma or nodular ganglioneuroblastoma, against 31.7% and 19.3% of ganglioneuroma"
  evidence:
  - reference: PMID:10421272
    reference_title: "Terminology and morphologic criteria of neuroblastic tumors: recommendations by the International Neuroblastoma Pathology Committee."
    supports: SUPPORT
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    evidence_source: HUMAN_CLINICAL
    snippet: "Based on morphologic criteria defined in this article, NTs were classified into four categories and their subtypes: 1) neuroblastoma (Schwannian stroma-poor), undifferentiated, poorly differentiated, and differentiating; 2) ganglioneuroblastoma, intermixed (Schwannian stroma-rich); 3) ganglioneuroma (Schwannian stroma-dominant), maturing and mature; and 4) ganglioneuroblastoma, nodular (composite Schwannian stroma-richlstroma-dominant and stroma-poor)."
    explanation: >-
      The 1999 terminology paper of the International Neuroblastoma Pathology
      Committee places neuroblastoma in the Schwannian stroma-poor category and
      ganglioneuroma in the Schwannian stroma-dominant one, the two ends of the
      four-category classification; its six member pathologists defined the
      criteria from a review of 227 cases. The quote keeps the abstract's
      spelling 'stroma-richlstroma-dominant'.
  - reference: PMID:19530234
    reference_title: "Clinicopathological characteristics of ganglioneuroma and ganglioneuroblastoma: a report from the CCG and COG."
    supports: SUPPORT
    directness: DIRECT
    quote_role: BACKGROUND
    evidence_source: OTHER
    snippet: "NB (Schwannian stroma-poor tumor) is classified into FH or UH depending on age-linked evaluation of grade of neuroblastic differentiation and mitosis-karyorrhexis index (MKI). GNB-Intermixed (Schwannian stroma-rich) and GN (Schwannian stroma-dominant) tumors are always classified into the FH group."
    explanation: >-
      In the introduction of a Children's Cancer Group and Children's Oncology
      Group study of 552 ganglioneuroma and ganglioneuroblastoma cases, Okamatsu
      et al. restate the INPC rules for the two ends of the spectrum:
      neuroblastoma (Schwannian stroma-poor) is classified as favorable or
      unfavorable histology by an age-linked evaluation of its grade of
      neuroblastic differentiation and mitosis-karyorrhexis index, whereas
      ganglioneuroma (Schwannian stroma-dominant), like intermixed
      ganglioneuroblastoma, is always of favorable histology. The sentences
      restate the INPC papers rather than reporting a result of the cohort.
  - reference: PMID:27465021
    reference_title: "Treatment and outcome of Ganglioneuroma and Ganglioneuroblastoma intermixed."
    supports: SUPPORT
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    evidence_source: HUMAN_CLINICAL
    snippet: "Median age at diagnosis increased with grade of differentiation (NB/GNBN: 9; GNBI: 61; GN-maturing: 71; GN-mature: 125 months, p < 0.001)."
    explanation: >-
      In German trials of localized neuroblastic tumors in patients aged 21
      years or younger, neuroblastoma and nodular ganglioneuroblastoma, reported
      as one group, were diagnosed at a median of 9 months, against 71 months
      for maturing and 125 months for mature ganglioneuroma. These are group
      medians and the age ranges overlap: the paper's table of delayed
      surgeries includes a maturing ganglioneuroma diagnosed at 0-18 months.
      Metastatic tumors were excluded, so the 9-month figure is not the median
      age of neuroblastoma as a whole.
  - reference: PMID:27465021
    reference_title: "Treatment and outcome of Ganglioneuroma and Ganglioneuroblastoma intermixed."
    supports: SUPPORT
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    evidence_source: HUMAN_CLINICAL
    snippet: "| | GN (n = 162) | p1 | GNBI (n = 55) | GN / GNBI (n=217) | p 2 | NB / GNBN (n = 591) | ... | Positive mIBG-uptake ... | 27/110 | <0.001 ... | 22/36 | 49/146 | <0.001 ... | 398/444 | | 24.5 % | 61.1 % | 33.6 % | 89.6 % |"
    explanation: >-
      Table 1 of the German NB97/NB2004 study: MIBG uptake was positive in 398 of
      444 tested patients with neuroblastoma or nodular ganglioneuroblastoma
      (89.6%) against 27 of 110 with ganglioneuroma (24.5%). No p-value compares
      ganglioneuroma alone with neuroblastoma, so the gap is descriptive, and
      metastatic tumors were excluded.
  - reference: PMID:27465021
    reference_title: "Treatment and outcome of Ganglioneuroma and Ganglioneuroblastoma intermixed."
    supports: SUPPORT
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    evidence_source: HUMAN_CLINICAL
    snippet: "| | GN (n = 162) | p1 | GNBI (n = 55) | GN / GNBI (n=217) | p 2 | NB / GNBN (n = 591) | ... | HVA elevated ... | 45/142 | 0.001 ... | 27/44 | 72/186 | <0.001 ... | 327/531 | | 31.7 % | 61.4 % | 38.7 % | 61.6 % |"
    explanation: >-
      Table 1 of the same study: urinary homovanillic acid was elevated in 327
      of 531 tested patients with neuroblastoma or nodular ganglioneuroblastoma
      (61.6%) against 45 of 142 with ganglioneuroma (31.7%). No p-value
      compares ganglioneuroma alone with neuroblastoma.
  - reference: PMID:27465021
    reference_title: "Treatment and outcome of Ganglioneuroma and Ganglioneuroblastoma intermixed."
    supports: SUPPORT
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    evidence_source: HUMAN_CLINICAL
    snippet: "| | GN (n = 162) | p1 | GNBI (n = 55) | GN / GNBI (n=217) | p 2 | NB / GNBN (n = 591) | ... | VMA elevated ... | 28/145 | <0.001 ... | 23/47 | 51/192 | <0.001 ... | 345/538 | | 19.3 % | 48.9 % | 26.6% | 64.1 % |"
    explanation: >-
      Table 1 of the same study: urinary vanillylmandelic acid was elevated in
      345 of 538 tested patients with neuroblastoma or nodular
      ganglioneuroblastoma (64.1%) against 28 of 145 with ganglioneuroma
      (19.3%). No p-value compares ganglioneuroma alone with neuroblastoma.
- name: Adrenal Gland Pheochromocytoma
  disease_term:
    preferred_term: adrenal gland pheochromocytoma
    term:
      id: MONDO:0004974
      label: adrenal gland pheochromocytoma
  description: >-
    An adrenal ganglioneuroma must be told from pheochromocytoma (see the
    Pheochromocytoma and Paraganglioma entry), with which it can occur as a
    composite tumor. Pure and composite adrenal ganglioneuromas overlap on
    imaging, and an unrecognized pheochromocytoma carries perioperative
    morbidity, so the distinction matters before adrenalectomy. Catecholamine
    excess and MIBG uptake favored pheochromocytoma in an adolescent and adult
    adrenal series, but a minority of ganglioneuromas in German trials of
    younger patients took up MIBG or raised urinary homovanillic acid, so
    neither finding excludes ganglioneuroma.
  notes: >-
    Bound to adrenal gland pheochromocytoma (MONDO:0004974), because every
    cited comparison is of adrenal tumors. The Pheochromocytoma and
    Paraganglioma entry is bound to pheochromocytoma-paraganglioma
    (MONDO:0035540), and OLS on 2026-10-28 gave MONDO:0004974 the parents
    sympathetic paraganglioma (MONDO:0021072) and adrenal medulla neoplasm
    (MONDO:0021237), not MONDO:0035540, so the row does not resolve to that
    entry by its term.
  distinguishing_features:
  - "In an adolescent and adult adrenal series, catecholamine excess and MIBG uptake pointed to pheochromocytoma: 24-hour urinary catecholamines were raised in all 36 pheochromocytomas and normal in the 4 ganglioneuroma patients reported, and 131I-MIBG was positive in 25 (96.2%) pheochromocytomas and negative in all 4 ganglioneuromas scanned"
  - "Neither finding excludes ganglioneuroma: in German trials of localized tumors at any site in patients aged 21 years or younger, 24.5% of tested ganglioneuromas took up MIBG and 31.7% raised urinary homovanillic acid, a catecholamine metabolite"
  - "In another adrenal series catecholamine levels were normal in all 21 ganglioneuroma patients with results, and the authors concluded that isolated adrenal ganglioneuromas do not produce catecholamines; a catecholamine-secreting adrenal ganglioneuroma has been reported"
  - "Among 45 histologically confirmed adrenal ganglioneuromas at one center, every tumor with an adrenergic or noradrenergic catecholamine profile was a composite ganglioneuroma-pheochromocytoma"
  evidence:
  - reference: PMID:19781327
    reference_title: "Differential diagnosis and laparoscopic treatment of adrenal pheochromocytoma and ganglioneuroma."
    supports: SUPPORT
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    evidence_source: HUMAN_CLINICAL
    snippet: "Catecholamine levels in a 24-hour urine sample were normal in 4 patients with adrenal ganglioneuroma and increased in 36 (100%) cases with adrenal pheochromocytoma. (131)I-MIBG nuclear scan showed negative results in 4 patients (100%) with adrenal ganglioneuroma and positive results in 25 (96.2%) with adrenal pheochromocytom."
    explanation: >-
      Retrospective series of 18 adrenal ganglioneuromas and 36 adrenal
      pheochromocytomas (1999-2007; ganglioneuroma mean age 41.2 years, range
      16-67). 24-hour urinary catecholamines were raised in all 36
      pheochromocytomas and normal in the 4 ganglioneuroma patients reported,
      and 131I-MIBG was positive in 25 (96.2%) pheochromocytomas and negative in
      all 4 ganglioneuromas scanned. The ganglioneuroma numbers are small: 9
      asymptomatic ganglioneuromas under 4 cm had neither test, and the abstract
      does not say how many had urinary catecholamines measured. The result
      concerns adolescent and adult adrenal tumors. 'pheochromocytom' is
      PubMed's own spelling.
  - reference: PMID:27465021
    reference_title: "Treatment and outcome of Ganglioneuroma and Ganglioneuroblastoma intermixed."
    supports: SUPPORT
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    evidence_source: HUMAN_CLINICAL
    snippet: "| | GN (n = 162) | p1 | GNBI (n = 55) | GN / GNBI (n=217) | p 2 | NB / GNBN (n = 591) | ... | Positive mIBG-uptake ... | 27/110 | <0.001 ... | 22/36 | 49/146 | <0.001 ... | 398/444 | | 24.5 % | 61.1 % | 33.6 % | 89.6 % |"
    explanation: >-
      Table 1 of the German NB97/NB2004 study of localized neuroblastic tumors
      (patients aged 21 or younger at diagnosis, all primary sites): MIBG
      uptake was positive in 27 of 110 tested patients with ganglioneuroma
      (24.5%). This qualifies the adult adrenal series above, in which all 4
      scanned ganglioneuromas were MIBG-negative: uptake is uncommon in
      ganglioneuroma but does occur, so a positive scan does not by itself
      point to pheochromocytoma. The German cohort was not restricted to
      adrenal tumors, included no pheochromocytomas, and does not name the MIBG
      isotope.
  - reference: PMID:27465021
    reference_title: "Treatment and outcome of Ganglioneuroma and Ganglioneuroblastoma intermixed."
    supports: SUPPORT
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    evidence_source: HUMAN_CLINICAL
    snippet: "| | GN (n = 162) | p1 | GNBI (n = 55) | GN / GNBI (n=217) | p 2 | NB / GNBN (n = 591) | ... | HVA elevated ... | 45/142 | 0.001 ... | 27/44 | 72/186 | <0.001 ... | 327/531 | | 31.7 % | 61.4 % | 38.7 % | 61.6 % |"
    explanation: >-
      Table 1 of the same German study: urinary homovanillic acid was elevated
      in 45 of 142 tested patients with ganglioneuroma (31.7%), so a raised
      catecholamine metabolite does not by itself exclude ganglioneuroma. The
      German series measured the metabolite
      homovanillic acid in children and young people at all primary sites,
      while the adult adrenal series measured 24-hour urinary catecholamines,
      so the two results are not directly comparable.
  - reference: PMID:24033606
    reference_title: "Adrenal ganglioneuroma: features and outcomes of 27 cases at a referral cancer centre."
    supports: SUPPORT
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    evidence_source: HUMAN_CLINICAL
    snippet: "Catecholamine levels, available for 21 patients, were normal."
    explanation: >-
      In a retrospective series of 27 adrenal ganglioneuromas at a tertiary
      referral cancer center (median age 31 years, range 1.7-64), catecholamine
      levels were normal in all 21 patients with results. The abstract does not
      say whether urine or plasma was tested, or whether the 21 included the
      series' composite tumors.
  - reference: PMID:24033606
    reference_title: "Adrenal ganglioneuroma: features and outcomes of 27 cases at a referral cancer centre."
    supports: SUPPORT
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    evidence_source: HUMAN_CLINICAL
    snippet: "Isolated AGNs do not produce catecholamines and have CT imaging characteristics that can help in distinguishing them from other adrenal and para-adrenal neoplasms."
    explanation: >-
      Conclusion of a retrospective series of 27 adrenal ganglioneuromas at a
      tertiary referral cancer center (median age 31 years, range 1.7-64), in
      which catecholamine levels were normal in all 21 patients with results.
      The authors generalize that isolated adrenal ganglioneuromas do not
      produce catecholamines; 'isolated' most likely means without a
      pheochromocytoma component, since a later systematic review lists this
      series with 11% composite tumors. The basis is 21 tested patients, and a
      catecholamine-secreting adrenal ganglioneuroma has been reported
      (PMID:35800596), so this reads as rarely rather than never. The second
      half of the sentence, on CT features, is not used here.
  - reference: PMID:35800596
    reference_title: "Rare Case of Large Catecholamine Secreting Ganglioneuroma in an Asymptomatic Elderly Male."
    supports: SUPPORT
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    evidence_source: HUMAN_CLINICAL
    snippet: "Following resection, catecholamine levels normalized, confirming the resected right adrenal ganglioneuroma as the source of the catecholamine excess."
    explanation: >-
      Case report of an elderly man with an incidental adrenal ganglioneuroma
      of maturing type and mildly raised urinary catecholamines, which
      normalized after open adrenalectomy; the authors take this as confirming
      the ganglioneuroma as the source of the catecholamine excess. It supports
      the statement that a catecholamine-secreting adrenal ganglioneuroma has
      been reported. It is a single case, and catecholamine secretion does not
      exclude an unsampled pheochromocytoma component.
  - reference: PMID:33721367
    reference_title: "Presentation and outcomes of adrenal ganglioneuromas: A cohort study and a systematic review of literature."
    supports: SUPPORT
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    evidence_source: HUMAN_CLINICAL
    snippet: "All tumors with either adrenergic or noradrenergic catecholamine profiles were found to be composite AGN-PHEO."
    explanation: >-
      Mayo Clinic single-center cohort of 45 histologically confirmed adrenal
      ganglioneuromas (1995-2019; median age 44, range 6-87), 20 of them
      composite ganglioneuroma-pheochromocytomas. Every tumor with an
      adrenergic or noradrenergic catecholamine profile was composite, and all
      17 tested pure ganglioneuromas were non-functional. The finding holds only
      for tumors with ganglioneuroma histology; it does not mean that
      adrenergic adrenal tumors in general are composite, and the authors list
      referral bias among possible reasons for their high composite rate. One
      composite tumor was non-functioning, so a normal catecholamine result does
      not completely exclude a pheochromocytoma component.
  - reference: PMID:33721367
    reference_title: "Presentation and outcomes of adrenal ganglioneuromas: A cohort study and a systematic review of literature."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "The perioperative morbidity associated with unrecognized pheochromocytomas makes differentiating these tumors from AGN crucial prior to adrenalectomy. Since imaging characteristics of AGN and composite AGN-PHEO overlap, evaluation for catecholamine excess is essential in any indeterminate adrenal mass."
    explanation: >-
      In the discussion of their adrenal ganglioneuroma cohort and systematic
      review, the authors state that the perioperative morbidity of an
      unrecognized pheochromocytoma makes distinguishing it from adrenal
      ganglioneuroma crucial before adrenalectomy, and that because pure and
      composite tumors overlap on imaging, any indeterminate adrenal mass should
      be tested for catecholamine excess. The first sentence frames the clinical
      reason and the second is the authors' recommendation from their imaging
      comparison; neither reports a measured rate.
- name: Schwannoma
  disease_term:
    preferred_term: schwannoma
    term:
      id: MONDO:0002546
      label: schwannoma
  description: >-
    In a pooled series of adrenal cases, most of them drawn from published
    reports, adrenal schwannoma and adrenal ganglioneuroma were similar except
    that ganglioneuroma patients were younger; all of the schwannomas and 92.5%
    of the ganglioneuromas were nonsecretory, so hormone testing does not
    separate them.
  distinguishing_features:
  - "Patients with adrenal ganglioneuroma were younger than those with adrenal schwannoma (28 vs 49.5 years) in a pooled adrenal series"
  evidence:
  - reference: PMID:41563553
    reference_title: "Adrenal schwannomas and adrenal ganglioneuromas: our experience and CT characteristic-focused systematic review."
    supports: SUPPORT
    directness: DIRECT
    quote_role: REVIEW_SYNTHESIS
    evidence_source: HUMAN_CLINICAL
    snippet: "AS and AG were similar, except AG patients were younger (28 vs. 49.5 years, p = 0.003)."
    explanation: >-
      This pooled series combines the authors' own adrenal schwannomas (AS) and
      adrenal ganglioneuromas (AG) with histopathologically confirmed cases from
      a systematic literature review; most of the cases come from published
      reports (25 of the 30 schwannomas and 25 of the 27 ganglioneuromas), so
      the comparison is graded as a review synthesis. The authors report the two tumors as similar except for age:
      patients with ganglioneuroma were younger (28 vs 49.5 years). The
      abstract does not list which features entered this comparison, or say
      whether the ages are medians or means, and it reports separately that
      progressive delayed enhancement occurred in all AS but not in all AG, so
      'similar' should not be read as covering CT enhancement. The finding
      covers the adrenal site only.
  - reference: PMID:41563553
    reference_title: "Adrenal schwannomas and adrenal ganglioneuromas: our experience and CT characteristic-focused systematic review."
    supports: SUPPORT
    directness: DIRECT
    quote_role: REVIEW_SYNTHESIS
    evidence_source: HUMAN_CLINICAL
    snippet: "All AS and 92.5% of AG were nonsecretory."
    explanation: >-
      In the same pooled adrenal series, all adrenal schwannomas (AS) and 92.5%
      of adrenal ganglioneuromas (AG) were nonsecretory, so a nonsecretory mass
      does not separate the two tumors. The figures describe this selected,
      mostly published-case adrenal series only, and the abstract does not
      describe what the secretory minority of ganglioneuromas secreted.
treatments:
- name: Surgical Resection
  description: >-
    In German trials of localized tumors in patients aged 21 years or younger,
    no ganglioneuroma or intermixed ganglioneuroblastoma progressed after
    complete resection or with residuals under 2 cm, and incomplete resection
    leaving minor residuals appeared to be sufficient treatment; the 11
    patients given chemotherapy, 2 of them with ganglioneuroma, showed no
    substantial effect, and the authors' conclusion that chemotherapy is not
    effective pools the two tumor types. Postoperative complications are
    common: short-term complications followed 43.1% of operations, most often
    neurological deficits (22.2%), in a 101-patient single-institution series;
    complications followed surgery in 11 of 51 patients (21.6%) with a resected
    retroperitoneal ganglioneuroma at a sarcoma center, one of whom died on
    postoperative day 8 of bowel ischemia; post-operative complications
    occurred in 15 of 50 surgical patients (30%) in a pediatric series, and a
    UK nationwide series reported a 19% complication rate, both pooling
    ganglioneuroma with intermixed ganglioneuroblastoma. In two children with a
    VIP-secreting ganglioneuroma, VIP returned to normal after the operation
    and the diarrhea stopped.
  action_category: THERAPEUTIC
  treatment_term:
    preferred_term: surgical resection
    term:
      id: NCIT:C164212
      label: Tumor Resection
  therapeutic_modality: SURGERY
  target_mechanisms:
  - target: Schwannian Stromal Development
    treatment_effect: INHIBITS
    description: >-
      Resection removes the stroma-dominant tumor tissue. In German trials of
      localized tumors, no tumor progressed after complete resection or with
      residuals under 2 cm; that this reflects removal of the stromal tissue is
      an inference, and the authors could not rule out that progression in
      large residuals came from immature components.
    evidence:
    - reference: PMID:27465021
      reference_title: "Treatment and outcome of Ganglioneuroma and Ganglioneuroblastoma intermixed."
      supports: SUPPORT
      directness: INDIRECT
      quote_role: PRIMARY_RESULT
      evidence_source: HUMAN_CLINICAL
      snippet: "No progression was seen after complete resection or in patients with minor tumor residuals (<2 cm), neither in patients with GN nor in patients with GNBI."
      explanation: >-
        In this retrospective study of localized ganglioneuroma (GN) and
        intermixed ganglioneuroblastoma (GNBI) in children and young people
        registered in the German neuroblastoma trials NB97 and NB2004, no tumor
        was seen to progress after complete resection or when the residual left
        behind was under 2 cm on MRI. This held for GN and GNBI taken
        separately, and every progression in the series arose in a larger
        residual. The sentence reports a clinical outcome and does not mention
        the stroma. Reading it as support for this link rests on resection
        removing the stroma-dominant tumor tissue, so it is indirect. The
        authors could not rule out that progression in large residuals came
        from immature components, and they cite a suggestion that minor
        increases in tumor volume may come from Schwannian stroma
        proliferation, so the quote does not show that stromal growth is what
        resection controls.
  - target: Tumoral Vasoactive Intestinal Peptide Secretion
    treatment_effect: INHIBITS
    description: >-
      Removing a VIP-secreting tumor ended the VIP excess in two children:
      after the operation VIP was normal, falling in one child from 314 pmol/l
      before surgery to 14 pmol/l 6 months after it, and the diarrhea stopped.
    evidence:
    - reference: PMID:7376870
      reference_title: "Vasocative intestinal polypeptide (VIP)-producing ganglioneuroma in a child with chronic diarrhea."
      supports: SUPPORT
      directness: DIRECT
      quote_role: PRIMARY_RESULT
      evidence_source: HUMAN_CLINICAL
      snippet: "The tumour contained large amounts of vasoactive intestinal polypeptide (VIP) and preoperative plasma concentration of this peptide was increased. Postoperatively the VIP concentration was normalized, and the diarrhea ceased. Analysis of catecholamine metabolites in urine was normal. The findings suggest that the watery diarrhea was due to the benign VIP-producing neural crest tumour."
      explanation: >-
        In a 2 1/2-year-old girl with a retroperitoneal ganglioneuroma, plasma
        VIP was raised before surgery, and after the operation the VIP
        concentration returned to normal and the diarrhea stopped, which links
        the operation to the end of the VIP excess. It is one case, and the
        abstract does not say how much of the tumor was removed.
    - reference: PMID:2833214
      reference_title: "Vasoactive intestinal peptide secreting tumours in children: a case report with literature review."
      supports: SUPPORT
      directness: DIRECT
      quote_role: PRIMARY_RESULT
      evidence_source: HUMAN_CLINICAL
      snippet: "The pre-operative serum VIP was 314 pmol/l (normal less than 30). Her diarrhoea stopped after the removal of the tumour. The VIP was 14 pmol/l 6 months post-operatively."
      explanation: >-
        In a 3-year-old girl with a VIP-secreting thoracic paraspinal
        ganglioneuroma, serum VIP was 314 pmol/l before surgery (normal less
        than 30) and 14 pmol/l 6 months after the tumor was removed, and her
        diarrhea stopped after the removal, which links the operation to the
        end of the VIP excess. It is a single case, and the abstract does not
        say whether the resection was complete.
  evidence:
  - reference: PMID:27465021
    reference_title: "Treatment and outcome of Ganglioneuroma and Ganglioneuroblastoma intermixed."
    supports: SUPPORT
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    evidence_source: HUMAN_CLINICAL
    snippet: "Outcome was excellent and chemotherapy seems not effective while incomplete resection with minor residuals (<2 cm) appears to be sufficient for treatment."
    explanation: >-
      This summarizes a retrospective study of localized tumors registered in
      the German neuroblastoma trials NB97 and NB2004, including 162
      ganglioneuroma and 55 intermixed ganglioneuroblastoma patients aged 21
      years or younger. The authors conclude that outcome was excellent, that
      chemotherapy seems not to be effective and that incomplete resection
      leaving minor residuals under 2 cm appears to be sufficient treatment.
      Few patients received chemotherapy, most of them with intermixed
      ganglioneuroblastoma, and the conclusion pools the two tumor types.
  - reference: PMID:27465021
    reference_title: "Treatment and outcome of Ganglioneuroma and Ganglioneuroblastoma intermixed."
    supports: SUPPORT
    directness: INDIRECT
    quote_role: PRIMARY_RESULT
    evidence_source: HUMAN_CLINICAL
    snippet: "Eleven patients received chemotherapy without substantial effect. ... Cytotoxic treatment was given to two patients with GN and 9 patients with GNBI. One patient with GN presented with a large stage 3 tumor and received chemotherapy because diagnosis of GN was made only from biopsy and immature components within the residuals were suspected by local physicians. The other patient with GN received chemotherapy because of an intraspinal tumor mass. No patient showed significant response to chemotherapy and residual tumor is still observed."
    explanation: >-
      In the same German series, 11 patients received chemotherapy without
      substantial effect, and the Results show that only 2 of them had
      ganglioneuroma: one with a large stage 3 tumor diagnosed only on biopsy,
      in whom local physicians suspected immature components, and one with an
      intraspinal tumor mass. Neither responded significantly, and residual
      tumor was still being observed. The ganglioneuroma evidence against
      chemotherapy therefore rests on two patients; the other 9 had intermixed
      ganglioneuroblastoma. It bears on resection as the treatment only
      indirectly, by showing that chemotherapy was not an effective
      alternative in these patients.
  - reference: PMID:27465021
    reference_title: "Treatment and outcome of Ganglioneuroma and Ganglioneuroblastoma intermixed."
    supports: SUPPORT
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    evidence_source: HUMAN_CLINICAL
    snippet: "No progression was seen after complete resection or in patients with minor tumor residuals (<2 cm), neither in patients with GN nor in patients with GNBI."
    explanation: >-
      In the same German series of localized tumors in patients aged 21 years
      or younger, no tumor progressed after complete resection or with minor
      residuals under 2 cm, in ganglioneuroma and in intermixed
      ganglioneuroblastoma taken separately; all five progressions in the
      series had residuals over 2 cm. The finding holds for this series and its
      follow-up, in which time to progression ranged from 3 to 80 months.
  - reference: PMID:42537227
    reference_title: "A comprehensive analysis of ganglioneuromas: a 30-year experience of 101 patients."
    supports: SUPPORT
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    evidence_source: HUMAN_CLINICAL
    snippet: "Short-term postoperative complications occurred in 43.1% of cases, most commonly neurological deficits (22.2%)."
    explanation: >-
      This 30-year single-institution retrospective review of 101 patients with
      ganglioneuroma reports that seventy patients underwent 72 surgeries, all
      of them gross-total or subtotal resections, and the abstract uses 'cases'
      for those operations. Short-term postoperative complications followed
      43.1% of these operations, most commonly neurological deficits (22.2%).
      The abstract does not say what the 22.2% is a share of, and it does not
      grade the complications by severity.
  - reference: PMID:29369484
    reference_title: "Characteristics and management of ganglioneuroma and ganglioneuroblastoma-intermixed in children and adolescents."
    supports: SUPPORT
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    evidence_source: HUMAN_CLINICAL
    snippet: "There were post-operative complications in 15 of the 50 (30%) surgical patients."
    explanation: >-
      This Hospital for Sick Children retrospective series (1990-2014) includes
      67 children and adolescents with ganglioneuroma (50) or intermixed
      ganglioneuroblastoma (17). Forty-six had upfront surgery and 4 of the 21
      initially observed patients were resected later, and post-operative
      complications occurred in 15 of these 50 surgical patients (30%). The
      abstract gives the histology split only for the whole cohort, does not
      split complications by histology and does not say over what period they
      were counted, so the figure is a surgical complication rate for a
      pediatric group that may include intermixed ganglioneuroblastoma.
  - reference: PMID:41306794
    reference_title: "Clinical features and oncologic outcomes of primary retroperitoneal ganglioneuroma: a retrospective cohort study of 51 patients from a high-volume sarcoma center."
    supports: SUPPORT
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    evidence_source: HUMAN_CLINICAL
    snippet: "Postoperative complications occurred in 11 patients (21.6%), including gastroparesis (n = 3), pancreatic fistula (n = 3), liver function impairment (n = 2), wound infection (n = 2), and one mortality due to intestinal ischemia and necrosis."
    explanation: >-
      In this retrospective cohort of 51 consecutive patients whose primary
      retroperitoneal ganglioneuroma was resected at one high-volume sarcoma
      center, 11 (21.6%) had postoperative complications, including
      gastroparesis, pancreatic fistula, liver function impairment and wound
      infection, and one patient died of intestinal ischemia and necrosis; the
      Results place the death on postoperative day 8. Ten of the 11 patients
      had Clavien-Dindo grade I or II complications, and the death was grade V.
      The series is limited to
      retroperitoneal tumors, many of them large, and the authors warn that
      their referral cohort may be biased towards complex cases.
  - reference: PMID:39582110
    reference_title: "Management of Ganglioneuroma and Ganglioneuroblastoma Intermixed: A United Kingdom Children's Cancer and Leukaemia Group (UK CCLG) Nationwide Study Report."
    supports: SUPPORT
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    evidence_source: HUMAN_CLINICAL
    snippet: "Gross total resection (GTR) was achieved in 79% of patients with a 19% complication rate."
    explanation: >-
      In the UK CCLG retrospective series of 259 patients with non-metastatic
      ganglioneuroma or intermixed ganglioneuroblastoma, gross total resection
      was achieved in 79% of patients with a 19% complication rate. The
      abstract does not give the denominator of the complication rate, does not
      grade the complications, and pools the two tumor types.
- name: Watchful Observation
  description: >-
    Observation of selected asymptomatic tumors. In a single-institution series
    of 101 patients, 31 (mean age 32.3 years) were managed by observation,
    chosen mainly because the tumor lay close to major vascular or neural
    structures (74.2%); none developed new symptoms over a mean follow-up of
    90.9 months, reported as 90.9 ± 151 months, and two tumors grew minimally
    (0.08-0.17 cm/year). The authors concluded that observation is safe for
    asymptomatic tumors, particularly when adjacent to critical structures; the
    observed group was selected rather than randomized. A UK nationwide series
    of ganglioneuroma and intermixed ganglioneuroblastoma concluded that
    watchful active observation can be a safe approach, with resection reserved
    for symptomatic patients, although a small proportion of observed patients
    had their diagnosis revised to malignant at surgery, and a Hospital for Sick
    Children series concluded that, because these tumors grow slowly and
    resection can carry significant morbidity, watch-and-wait approaches should
    be considered for some patients. Both series pool ganglioneuroma with
    intermixed ganglioneuroblastoma, and in both a part of the observed group
    grew or went to surgery: in the UK series 21 of 58 observed patients (36%)
    required subsequent surgery, with progressive tumor growth given as a
    reason, and in the Hospital for Sick Children series 6 of 21 observed
    patients had progressive disease and 4 later underwent resection. The
    authors of a series of 51 retroperitoneal ganglioneuromas, all of them
    resected, regard active surveillance as a reasonable option for selected
    patients with small, asymptomatic tumors, particularly those with elevated
    surgical risk.
  action_category: MONITORING
  treatment_term:
    preferred_term: watchful active observation
    term:
      id: NCIT:C25598
      label: Observation Activity
  context: Asymptomatic ganglioneuroma (the UK and Hospital for Sick Children evidence pools ganglioneuroma with intermixed ganglioneuroblastoma)
  notes: >-
    NCIT:C15722 Patient Observation fits the action more closely, but its
    parents, Surveillance (NCIT:C15719) and Healthcare Activity (NCIT:C16205),
    are not under NCIT:C25218, so the treatment-action enum rejects it.
    NCIT:C25598 Observation Activity reaches NCIT:C25218 through Diagnostic
    Procedure (NCIT:C18020) and is bound here for the observation step of a
    monitoring strategy (action_category MONITORING), as in the
    Ganglioneuroblastoma entry.
  evidence:
  - reference: PMID:42537227
    reference_title: "A comprehensive analysis of ganglioneuromas: a 30-year experience of 101 patients."
    supports: SUPPORT
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    evidence_source: HUMAN_CLINICAL
    snippet: "Thirty-one patients were managed with observation (mean age 32.3 ± 17.7 years; mean follow-up duration 90.9 ± 151 months). Observation was chosen primarily due to proximity to major vascular or neural structures (74.2%). No patient in the observation group developed new symptoms, and 2 tumors exhibited minimal interval growth (0.08-0.17 cm/year)."
    explanation: >-
      In this single-institution retrospective series, 31 patients (mean age
      32.3 years) were managed with observation and followed for a mean of 90.9
      months. The abstract reports this follow-up as 90.9 ± 151 months without
      saying what the ± value is; a spread larger than the mean suggests that
      follow-up length varied widely between patients. Proximity to major
      vascular or neural structures was the main reason for choosing
      observation (74.2%), which is a reason for the choice, not a comparison
      between tumors in different locations. No observed patient developed new
      symptoms, and two tumors grew minimally, at 0.08-0.17 cm/year. The
      abstract gives no imaging schedule, does not state whether the observed
      patients had symptoms when observation began, and does not say how their
      diagnosis was established.
  - reference: PMID:42537227
    reference_title: "A comprehensive analysis of ganglioneuromas: a 30-year experience of 101 patients."
    supports: SUPPORT
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    evidence_source: HUMAN_CLINICAL
    snippet: "Observation is safe for asymptomatic tumors, particularly when adjacent to critical structures, with no growth observed on long-term follow-up, except for minimal growth in few cases."
    explanation: >-
      This single-institution retrospective review covers 101 patients
      diagnosed with ganglioneuroma between 1995 and 2025. The authors conclude
      that observation is safe for asymptomatic tumors, particularly when they
      lie next to critical structures, with no growth observed on long-term
      follow-up apart from minimal growth in a few cases. This is their
      judgement about the 31 patients they observed, a group selected rather
      than randomized. The series did not compare observed tumors next to
      critical structures with others, so 'particularly' is the authors'
      recommendation, not a finding that observation is safer there. The
      abstract does not define safety; the outcomes it reports for the observed
      group are no new symptoms and at most minimal tumor growth.
  - reference: PMID:39582110
    reference_title: "Management of Ganglioneuroma and Ganglioneuroblastoma Intermixed: A United Kingdom Children's Cancer and Leukaemia Group (UK CCLG) Nationwide Study Report."
    supports: SUPPORT
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    evidence_source: HUMAN_CLINICAL
    snippet: "Watchful active observation can be a safe approach, with surgical resection reserved for symptomatic patients. However, a small proportion of patients in the observation group had their diagnosis revised to malignant at surgery."
    explanation: >-
      This UK CCLG nationwide retrospective review covers 259 patients with
      histologically confirmed non-metastatic ganglioneuroma or intermixed
      ganglioneuroblastoma (median age 62 months), 163 of them with
      ganglioneuroma. It concludes that observation can be safe, with resection
      reserved for symptomatic patients, though a small proportion of observed
      patients had their diagnosis revised to malignant at surgery. The two
      diagnoses are pooled and survival is not reported by management arm, so
      the safety statement is the authors' judgement. Twenty-one of the 58
      observed patients (36%) later needed surgery, with progressive tumor
      growth cited as a reason.
  - reference: PMID:29369484
    reference_title: "Characteristics and management of ganglioneuroma and ganglioneuroblastoma-intermixed in children and adolescents."
    supports: SUPPORT
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    evidence_source: HUMAN_CLINICAL
    snippet: "GN and GNB-I have a slow growth rate and resection can be associated with significant morbidity. Watch and wait approaches should be considered for some GN and GNB-I."
    explanation: >-
      This single-center retrospective cohort (Hospital for Sick Children,
      1990-2014) covers 67 children and adolescents with ganglioneuroma (50) or
      intermixed ganglioneuroblastoma (17), 21 of them observed. Its conclusion
      recommends considering watch-and-wait for some patients, citing slow tumor
      growth and the significant morbidity resection can carry. It supports this
      rationale and recommendation only; 6 of the 21 observed patients had
      progressive disease, and the abstract does not report outcomes for
      ganglioneuroma separately.
  - reference: PMID:39582110
    reference_title: "Management of Ganglioneuroma and Ganglioneuroblastoma Intermixed: A United Kingdom Children's Cancer and Leukaemia Group (UK CCLG) Nationwide Study Report."
    supports: SUPPORT
    directness: INDIRECT
    quote_role: PRIMARY_RESULT
    evidence_source: HUMAN_CLINICAL
    snippet: "In all 201 (78%) had initial surgery and 58 (22%) were observed. Overall survival was 98%. Twenty-one of 58 observed (36%) required subsequent surgery due to progressive tumour growth (52%)."
    explanation: >-
      In this UK CCLG series of 259 patients with non-metastatic ganglioneuroma
      or intermixed ganglioneuroblastoma, 58 (22%) were observed initially, and
      21 of them (36%) later required surgery, with progressive tumor growth
      given as a reason; the abstract does not say what the 52% beside it is a
      share of. Overall survival in the whole cohort was 98%. This qualifies
      the safety conclusion rather than refuting it: observation was followed
      by surgery in 36% of observed patients, and the figures pool the two
      tumor types and do not report ganglioneuroma separately. The support
      for observation is indirect, because the sentence reports what happened
      to observed patients, not that observation was safe.
  - reference: PMID:29369484
    reference_title: "Characteristics and management of ganglioneuroma and ganglioneuroblastoma-intermixed in children and adolescents."
    supports: SUPPORT
    directness: INDIRECT
    quote_role: PRIMARY_RESULT
    evidence_source: HUMAN_CLINICAL
    snippet: "Of the 21 observed patients 4 later underwent resection. ... Median growth was 0.3 cm/year and 6 of 21 had progressive disease (PD)."
    explanation: >-
      In this Hospital for Sick Children series of 67 children and adolescents
      with ganglioneuroma or intermixed ganglioneuroblastoma, 21 were observed:
      4 of them later underwent resection, median tumor growth was 0.3 cm per
      year, and 6 of the 21 had progressive disease. The slow median growth
      supports observation for some patients, while progression in 6 shows
      that observed tumors need follow-up. The abstract does not report the
      observed ganglioneuromas separately, and the support is indirect because
      the quote reports outcomes rather than judging the strategy.
  - reference: PMID:41306794
    reference_title: "Clinical features and oncologic outcomes of primary retroperitoneal ganglioneuroma: a retrospective cohort study of 51 patients from a high-volume sarcoma center."
    supports: SUPPORT
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    evidence_source: HUMAN_CLINICAL
    snippet: "For selected patients with small, asymptomatic tumors-particularly those with elevated surgical risk-active surveillance is a reasonable option."
    explanation: >-
      The conclusion of this retrospective series of 51 resected primary
      retroperitoneal ganglioneuromas states that active surveillance is a
      reasonable option for selected patients with small, asymptomatic tumors,
      particularly those with elevated surgical risk. Every patient in the
      series was resected, as its inclusion criteria required, so the
      recommendation is the authors' judgement, which their Discussion
      supports with other published series, not an outcome of observed
      patients in this study.
animal_models:
- name: Zebrafish dbh:myr-Akt2 transgenic ganglioneuroma model
  species: Zebrafish
  genotype: Tg(dβh:mCherry;dβh:myr-Akt2), two independent lines
  background: Lines maintained by crossing heterozygous transgenic fish with wild-type AB fish
  description: >-
    Stable transgenic zebrafish lines that co-express mCherry and a
    constitutively active, membrane-targeted (myristoylated) mouse Akt2 in the
    peripheral sympathetic nervous system under the zebrafish dβh promoter.
    Tumours arise in the interrenal gland, the fish counterpart of the adrenal
    gland, from 13 weeks post-fertilization and reach a penetrance of 40-50% by
    29 weeks. They are ganglioneuromas of differentiated, mature ganglion cells
    with poor Schwannian stroma, and they do not progress to neuroblastoma. A
    MYCN-transgenic line, Tg(dβh:EGFP-MYCN), which develops neuroblastoma in the
    same gland, is the paper's comparator.
  publication: PMID:32728700
  modeled_mechanisms:
  - target: AKT-mTOR-S6 Pathway Activation
    relationship: PERTURBS
    fidelity: MODERATE
    model_scale: ORGANISM
    description: >-
      The transgene switches AKT signalling on in sympathoadrenal cells, and the
      resulting tumours carry the downstream state seen in human
      ganglioneuromas: high phosphorylated mTOR, S6 ribosomal protein and
      EIF4EBP1. Phosphorylated mTOR and S6 were undetectable in the
      MYCN-driven fish neuroblastomas.
    limitations: >-
      The activating event is a forced, membrane-targeted mouse Akt2, not a
      lesion found in patients; the cause of AKT activation in human
      ganglioneuroma is unknown. Because the construct bypasses upstream
      regulation, an allosteric AKT inhibitor that needs that regulation
      (MK-2206) cannot be tested in this model.
    divergences:
    - divergence_type: CAUSE_UNREPRESENTED
      materiality: QUALIFYING
      description: >-
        Pathway activation is imposed by a constitutively active transgene
        rather than arising from a patient lesion, so the model shows that
        active AKT is sufficient for a ganglioneuroma-like tumour, not how AKT
        becomes active in human tumours.
    - divergence_type: SPECIES_MISMATCH
      materiality: QUALIFYING
      description: >-
        The readouts are from zebrafish interrenal tumours; the human side of
        the comparison rests on immunohistochemistry of archival tumours in the
        same paper.
    readouts:
    - name: Phosphorylated mTOR, S6 ribosomal protein and EIF4EBP1 in tumour sections
      target: AKT-mTOR-S6 Pathway Activation
      direction: INCREASED
      interpretation: >-
        The pathway downstream of the transgene is active in the fish
        ganglioneuromas, as phosphorylated mTOR and S6 are in most human
        ganglioneuromas.
      evidence:
      - reference: PMID:32728700
        reference_title: "Ganglioneuromas are driven by activated AKT and can be therapeutically targeted with mTOR inhibitors."
        supports: SUPPORT
        quote_role: PRIMARY_RESULT
        evidence_source: MODEL_ORGANISM
        snippet: "Immunohistochemical analysis of tumor sections revealed high level expression of phosphorylated mTOR (Ser2448) and the mTOR targets S6 ribosomal protein (Ser235/236) and EIF4EBP1 (Thr37/46) in myr-Akt2 tumors, whereas levels of phosphorylated mTOR (Ser2448) and S6 ribosomal protein (Ser235/236) were undetectable in MYCN-induced neuroblastomas"
        explanation: >-
          Immunohistochemistry of the myr-Akt2 tumours found high phosphorylated
          mTOR (Ser2448), S6 ribosomal protein (Ser235/236) and EIF4EBP1
          (Thr37/46), while phosphorylated mTOR and S6 were undetectable in
          MYCN-induced neuroblastomas.
    evidence:
    - reference: PMID:32728700
      reference_title: "Ganglioneuromas are driven by activated AKT and can be therapeutically targeted with mTOR inhibitors."
      supports: SUPPORT
      quote_role: PRIMARY_RESULT
      evidence_source: MODEL_ORGANISM
      snippet: "Zebrafish transgenic for constitutively activated myr-Akt2 in the sympathetic nervous system were found to develop ganglioneuroma without progression to neuroblastoma. ... Mechanistically, myr-Akt2 overexpression induced sympathoadrenal lineage hyperplasia through increased cell proliferation, concurrent with activation of the AKT target mTOR."
      explanation: >-
        The abstract's summary of the model: activated Akt2 in the sympathetic
        nervous system produces ganglioneuroma, through sympathoadrenal
        hyperplasia with mTOR activation.
  - target: Neuroblast-to-Ganglion Cell Maturation
    relationship: PARTIALLY_RECAPITULATES
    fidelity: MODERATE
    model_scale: ORGANISM
    description: >-
      The fish tumours are made of differentiated, mature ganglion cells that
      carry neural markers and derive from sympathetic neuroblasts rather than
      chromaffin cells, and the authors find that they resemble human
      ganglioneuroma histologically and by gene expression. The model shows
      this mature end state, not the maturation itself.
    limitations: >-
      The model forms ganglion cells under a forced AKT signal; whether human
      ganglioneuromas mature from neuroblastic tumours in situ is not tested by
      it.
    divergences:
    - divergence_type: BOUNDARY_OMISSION
      materiality: QUALIFYING
      description: >-
        The node describes a neuroblastic tumour maturing step by step through
        intermixed ganglioneuroblastoma to ganglioneuroma. The model shows only
        the end of that sequence, ganglion cells of neuroblast origin, and does
        not show the tumour passing through the earlier stages.
    - divergence_type: SPECIES_MISMATCH
      materiality: QUALIFYING
      description: >-
        The tumours arise in the zebrafish interrenal gland, and their
        expression differences from fish neuroblastoma track the human
        differences only moderately (Pearson r = 0.39 across 407 orthologous
        genes).
    evidence:
    - reference: PMID:32728700
      reference_title: "Ganglioneuromas are driven by activated AKT and can be therapeutically targeted with mTOR inhibitors."
      supports: SUPPORT
      quote_role: PRIMARY_RESULT
      evidence_source: MODEL_ORGANISM
      snippet: "Histopathological analyses revealed that these tumors were ganglioneuromas and composed of differentiated, mature ganglion cells with poor Schwannian stroma"
      explanation: >-
        Histology of the myr-Akt2 tumours shows ganglioneuromas of
        differentiated, mature ganglion cells.
    - reference: PMID:32728700
      reference_title: "Ganglioneuromas are driven by activated AKT and can be therapeutically targeted with mTOR inhibitors."
      supports: SUPPORT
      quote_role: PRIMARY_RESULT
      evidence_source: MODEL_ORGANISM
      snippet: "The tumor cells, but not normal chromaffin cells in the IRG, were positive for the tumor makers Hu-Antigen C (HuC) and Synaptophysin (Fig. S2, D, E, I, J, N, and O), indicating that tumor cells retained neural markers and arose from sympathetic neuroblasts, but not chromaffin cells."
      explanation: >-
        Tumour cells, unlike the normal chromaffin cells of the gland, express
        HuC and synaptophysin, so they derive from sympathetic neuroblasts.
    - reference: PMID:32728700
      reference_title: "Ganglioneuromas are driven by activated AKT and can be therapeutically targeted with mTOR inhibitors."
      supports: SUPPORT
      quote_role: PRIMARY_RESULT
      evidence_source: MODEL_ORGANISM
      snippet: "Analysis of 407 differentially expressed genes with absolute log2-fold-difference >1 in ganglioneuromas compared with neuroblastomas showed coordinate differences in gene expression in both human and zebrafish tumors (Pearson’s r = 0.39, P < 2.2 × 10−16), with 282 genes (69.3%) co-upregulated or co-down-regulated"
      explanation: >-
        Across 407 differentially expressed orthologous genes, the
        ganglioneuroma versus neuroblastoma differences in fish correlate with
        those in human tumours (r = 0.39), with 69.3% of the genes changing in
        the same direction.
    - reference: PMID:32728700
      reference_title: "Ganglioneuromas are driven by activated AKT and can be therapeutically targeted with mTOR inhibitors."
      supports: SUPPORT
      quote_role: PRIMARY_RESULT
      evidence_source: MODEL_ORGANISM
      snippet: "Thus, the ganglioneuroma developed in our zebrafish model resembles human ganglioneuroma, both histologically and by gene expression."
      explanation: >-
        The authors' conclusion that the fish tumour resembles human
        ganglioneuroma histologically and by gene expression.
  - target: Schwannian Stromal Development
    relationship: FAILS_TO_RECAPITULATE
    fidelity: LOW
    model_scale: ORGANISM
    description: >-
      The fish ganglioneuromas have poor Schwannian stroma, whereas human
      ganglioneuroma is defined as the Schwannian stroma-dominant neuroblastic
      tumour.
    limitations: >-
      The model cannot be used to study how the Schwannian stroma of
      ganglioneuroma develops or what it does to the neuroblastic cells; the
      paper does not say whether the poor stroma reflects the species or the
      construct.
    divergences:
    - divergence_type: BOUNDARY_OMISSION
      materiality: INVALIDATING
      description: >-
        Schwann stromal cells, the dominant component of human ganglioneuroma,
        are largely absent from the fish tumours, which consist of ganglion
        cells.
    evidence:
    - reference: PMID:32728700
      reference_title: "Ganglioneuromas are driven by activated AKT and can be therapeutically targeted with mTOR inhibitors."
      supports: SUPPORT
      quote_role: PRIMARY_RESULT
      evidence_source: MODEL_ORGANISM
      snippet: "Histopathological analyses revealed that these tumors were ganglioneuromas and composed of differentiated, mature ganglion cells with poor Schwannian stroma"
      explanation: >-
        The same histology sentence records the poor Schwannian stroma of the
        fish tumours.
  evidence:
  - reference: PMID:32728700
    reference_title: "Ganglioneuromas are driven by activated AKT and can be therapeutically targeted with mTOR inhibitors."
    supports: SUPPORT
    quote_role: PRIMARY_RESULT
    evidence_source: MODEL_ORGANISM
    snippet: "Fish transgenic for myr-Akt2 developed mCherry-positive ganglioneuromas in the IRG starting at 13 wk postfertilization (wpf) with a penetrance of 40–50% by 29 wpf"
    explanation: >-
      Both myr-Akt2 lines developed ganglioneuromas in the interrenal gland from
      13 weeks post-fertilization, at 40-50% penetrance by 29 weeks.
datasets:
- accession: geo:GSE147635
  title: Schwann cell plasticity regulates neuroblastic tumor cell differentiation
  description: >-
    Bulk RNA-seq of 24 human samples: six ganglioneuromas, 15 primary
    neuroblastomas at diagnosis and three neuroblastoma cell lines. The series
    reuses part of the RNA-seq data of GSE94035 and GSE90711. The paper compares
    the stromal Schwann cells of ganglioneuroma with the repair Schwann cells of
    injured human nerve; the injured-nerve samples are not among these 24.
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  data_type: BULK_RNA_SEQ
  publication: PMID:33712610
  notes: >-
    The sample counts are from the GEO sample titles and source names.
- accession: geo:GSE135682
  title: Aberrant AKT Activation Drives Ganglioneuroma and Can Be Therapeutically Targeted by mTOR Inhibitors
  description: >-
    Bulk RNA-seq of FACS-sorted tumour cells from the zebrafish dβh:myr-Akt2
    ganglioneuroma model (four samples) and the dβh:EGFP-MYCN neuroblastoma
    model (four samples): the zebrafish side of the paper's cross-species
    comparison of ganglioneuroma and neuroblastoma gene expression.
  organism:
    preferred_term: zebrafish
    term:
      id: NCBITaxon:7955
      label: Danio rerio
  data_type: BULK_RNA_SEQ
  publication: PMID:32728700
  notes: >-
    The sample counts are from the GEO sample titles and source names.
discussions:
- discussion_id: gn_origin
  prompt: >-
    Does every ganglioneuroma arise by maturation of a neuroblastoma or
    ganglioneuroblastoma, or can some arise without passing through a
    neuroblastoma or ganglioneuroblastoma stage?
  kind: CONTROVERSY
  status: OPEN
  attaches_to:
  - pathophysiology#Neuroblast-to-Ganglion Cell Maturation
  - pathophysiology#AKT-mTOR-S6 Pathway Activation
  rationale: >-
    Evidence items use this convention: SUPPORT means ganglioneuroma arises by
    maturation of a neuroblastic tumor; REFUTE means at least some
    ganglioneuromas arise without passing through a neuroblastoma or
    ganglioneuroblastoma stage, against the proposal that all do. Both
    readings start from sympathetic neuroblasts, which the authors of the
    zebrafish study name as the common origin of ganglioneuroma and
    neuroblastoma; the question is whether a neuroblastic tumor comes first.
    The authors of the German NB97/NB2004 series note
    that a good part of ganglioneuroma has been hypothesized to originate from
    neuroblastoma, but that whether this holds for all ganglioneuromas, as
    Shimada proposed, remains unproven, and they read the rise of median age
    with the grade of differentiation as indirect support. A 2026 pathology
    review recounts that Cushing and Wolbach, comparing one patient's specimen
    at diagnosis with one resected 10 years later, reported that a malignant
    neuroblastoma could differentiate into a benign ganglioneuroma. In a 2022
    case report, ganglioneuroblastoma and ganglioneuroma at different sites of
    one patient shared the same molecular signatures, which the authors read
    as probable spontaneous differentiation from neuroblastoma to
    ganglioneuroma. In zebrafish, constitutively activated Akt2 in the
    sympathetic nervous system produced low-grade ganglioneuroma, and the fish
    did not develop neuroblastoma; this is a model of ganglioneuroma forming
    without a neuroblastoma stage, and its tumors had poor Schwannian stroma.
    The authors regard the model as faithful to human ganglioneuroma, which
    also shows AKT activation, but whether human ganglioneuromas form without a
    neuroblastoma stage has not been shown. The answer decides whether
    ganglioneuroma biology can be read as the end state of favorable
    neuroblastoma.
  posed_date: '2026-10-28T00:00:00Z'
  evidence:
  - reference: PMID:27465021
    reference_title: "Treatment and outcome of Ganglioneuroma and Ganglioneuroblastoma intermixed."
    supports: SUPPORT
    directness: INDIRECT
    quote_role: BACKGROUND
    evidence_source: HUMAN_CLINICAL
    snippet: "It has been hypothesized that a good part of GN originates from neuroblastoma. ... However, whether this is true for all GN, as proposed by Shimada ... still remains unproven."
    explanation: >-
      In the discussion of this retrospective study of localized neuroblastic
      tumors registered in the German neuroblastoma trials, the authors restate
      the hypothesis, which they trace to Cushing and to later reports in stage
      4S and localized neuroblastoma, that a good part of ganglioneuroma arises
      from neuroblastoma, and add that whether this is true for all
      ganglioneuromas, as Shimada proposed, remains unproven. The quoted
      sentences summarize earlier reports rather than the study's own data. The
      first sentence reports a hypothesis rather than asserting it, so it
      supports maturation from a neuroblastic tumor only at one remove, through
      the earlier reports the authors summarize (Cushing; stage 4S and localized
      neuroblastoma); the second records that the claim for all ganglioneuromas
      is unproven.
  - reference: PMID:27465021
    reference_title: "Treatment and outcome of Ganglioneuroma and Ganglioneuroblastoma intermixed."
    supports: SUPPORT
    directness: INDIRECT
    quote_role: PRIMARY_RESULT
    evidence_source: HUMAN_CLINICAL
    snippet: "An indirect support for this hypothesis can be seen by our observation that patients with GN and GNBI are older at diagnosis than those with immature NT. As Fig. 1 shows, the grade of neuroblastic differentiation increases with the median age at diagnosis. This is in line with the theory that mature NT might just have had enough time to mature in situ before they were discovered."
    explanation: >-
      The same authors take their own age gradient as indirect support for
      maturation: patients with ganglioneuroma or intermixed
      ganglioneuroblastoma, taken together, were older at diagnosis than those
      with immature tumors, which fits mature tumors having had time to mature
      in situ. The gradient compares different patients at diagnosis, and the
      paper reports no tumor seen to mature during follow-up; the authors add in
      the next paragraph that ultrasound check-ups of infants and young
      toddlers could find small immature neuroblastomas early, which bears on
      the same age difference without involving maturation.
  - reference: PMID:41612478
    reference_title: "Pathology of peripheral neuroblastic tumors."
    supports: SUPPORT
    directness: DIRECT
    quote_role: REVIEW_SYNTHESIS
    evidence_source: HUMAN_CLINICAL
    snippet: "By comparing the same patient's specimen at diagnosis and a resected specimen 10 years later, Cushing and Wolbach reported that malignant NB could differentiate into benign GN [9]."
    explanation: >-
      In its history of neuroblastic-tumor pathology, this 2026 review recounts
      that Cushing and Wolbach compared one patient's tumor at diagnosis with
      the specimen resected 10 years later and reported that a malignant
      neuroblastoma could differentiate into a benign ganglioneuroma. It is the
      review's account of a single human case it did not study, hence
      HUMAN_CLINICAL with REVIEW_SYNTHESIS; this review's classification-rule
      sentences, which report no patient data, are graded OTHER elsewhere in the
      KB. On the review's account a neuroblastoma matured into a ganglioneuroma
      in at least one patient. The sentence does not say whether this was
      spontaneous or followed treatment, and it says nothing about where
      ganglioneuromas come from in general.
  - reference: PMID:34054050
    reference_title: "A Metastatic Neuroblastic Tumor in a 28-Month-old Boy: Unusual Spontaneous Regression From Neuroblastoma to Ganglioneuroma?"
    supports: SUPPORT
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    evidence_source: HUMAN_CLINICAL
    snippet: "A pathologic examination of tumors from different sites revealed both GNB and ganglioneuroma. A genetic comparison between these tumors identified the same molecular signatures, suggesting the possibility of spontaneous differentiation in the remaining GNB. ... Even if unusual, we have to recognize probable spontaneous differentiation from neuroblastoma to GNB and then to ganglioneuroma, even in sites of bone metastasis."
    explanation: >-
      Single case report (abstract only). A 28-month-old boy had adrenal
      ganglioneuroblastoma with metastases to subcutaneous nodules, a lymph node
      and multiple bones. Tumors from different sites showed
      ganglioneuroblastoma and ganglioneuroma and shared the same molecular
      signatures. The authors conclude that the tumor probably differentiated
      spontaneously from neuroblastoma to ganglioneuroblastoma and then to
      ganglioneuroma, even in bone metastases, and they hedge this ('probable';
      the title ends in a question mark). The abstract reports no neuroblastoma
      histology and no serial biopsies, so the neuroblastoma starting point and
      the sequence are inferred from histology at different sites, and
      'spontaneous' rests on the patient staying healthy without aggressive
      chemotherapy. For one patient, the item supports ganglioneuroma arising
      by maturation of a neuroblastic tumor; it says nothing about how often
      this happens.
  - reference: PMID:32728700
    reference_title: "Ganglioneuromas are driven by activated AKT and can be therapeutically targeted with mTOR inhibitors."
    supports: REFUTE
    directness: INDIRECT
    quote_role: PRIMARY_RESULT
    evidence_source: MODEL_ORGANISM
    snippet: "Thus, AKT activation caused a modest increase in cell proliferation of ganglioneuroma, which although much less than that induced by MYCN in neuroblastoma nevertheless resulted in sympathoadrenal lineage cell hyperplasia, as reflected by the appearance of low-grade ganglioneuroma in transgenic zebrafish. ... These fish did not develop neuroblastoma, despite the fact that the same promoter-driven other oncogenes such as MYCN or c-MYC induces high-grade neuroblastoma in this model (Tao et al., 2017; Zimmerman et al., 2018; Zhu et al., 2012)."
    explanation: >-
      In transgenic zebrafish expressing constitutively activated myr-Akt2 in
      the sympathetic nervous system, AKT activation caused a modest increase
      in proliferation and sympathoadrenal lineage cell hyperplasia, which the
      authors relate to the appearance of low-grade ganglioneuroma, and the
      discussion states that these fish did not develop neuroblastoma, although
      the same promoter driving MYCN or c-MYC induces neuroblastoma in this
      model. In this model, then, a ganglioneuroma formed with no neuroblastoma
      found, which argues against the proposal that every ganglioneuroma is a
      matured neuroblastoma, not against some arising that way. The authors do
      not ask whether human ganglioneuromas pass through a neuroblastoma stage:
      they state that ganglioneuroma and neuroblastoma both originate from
      migratory sympathetic neuroblasts of one progenitor lineage, and they
      propose that somatically acquired mutations or epigenetic alterations in
      the PI3K-AKT-mTOR pathway may initiate ganglioneuroma, so reading the model
      against the all-from-neuroblastoma proposal is the curator's inference.
      The authors regard the model as faithful to human ganglioneuroma, which
      also shows AKT activation, but the fish tumors had poor Schwannian stroma,
      whereas human ganglioneuroma is defined by dominant Schwannian stroma, and
      the model does not show that human ganglioneuromas form without a
      neuroblastoma stage.
  - reference: PMID:41858373
    reference_title: "Telomere maintenance mechanisms are activated in ganglioneuroblastoma and ganglioneuroma."
    supports: NO_EVIDENCE
    quote_role: PRIMARY_RESULT
    evidence_source: HUMAN_CLINICAL
    snippet: "ALT was identified in 38 NB cases (38/255, 15%) and 6 GNB cases (6/48, 12.5%), but not in GN. ... TMM activation, defined as ALT(+) and/or high TERT expression, occurred in 12/48 GNB cases and 1/18 GN cases ... In the present study, high expression of TERT mRNA and ALT as TMM in NB was observed more frequently in the older age group (>18 months), INSS stage 4, and the HR group, with statistical significance, as in previous reports (15,16)."
    explanation: >-
      In this Japanese series of neuroblastic tumors sampled at diagnosis,
      alternative lengthening of telomeres (ALT) was found in 15% of
      neuroblastomas and in no ganglioneuroma, and a telomere maintenance
      mechanism (TMM: ALT and/or high TERT expression) in 1 of 18
      ganglioneuromas. Graded NO_EVIDENCE because neither result says whether a
      neuroblastic tumor came first. In neuroblastoma both mechanisms were
      found more often in patients older than 18 months, at INSS stage 4 and in
      the high-risk group, while the maturation proposal concerns biologically
      favorable tumors (PMID:41612478), so little or no telomere maintenance in
      ganglioneuroma is what either answer to the question predicts. The
      authors draw no conclusion about the origin of ganglioneuroma, they leave
      the clinical significance of telomere maintenance in ganglioneuroma to
      longer follow-up, and the paper's ganglioneuroma denominators differ
      between its abstract, Results and Discussion.
disease_term:
  preferred_term: ganglioneuroma
  term:
    id: MONDO:0005033
    label: ganglioneuroma
classifications:
  harrisons_chapter:
  - classification_value: ONCOLOGY_HEMATOLOGY
mappings:
  mondo_mappings:
  - term:
      id: MONDO:0005033
      label: ganglioneuroma
    mapping_predicate: skos:exactMatch
    mapping_source: MONDO
    mapping_justification: >-
      Primary MONDO identifier for this entry. MONDO defines ganglioneuroma as a
      benign neuroblastic tumor of the sympathetic nervous system, records
      NCIT:C3049 and Orphanet 251992 as exact matches, and carries the ICD-O
      cross-reference 9490/0.
  ncit_mappings:
  - term:
      id: NCIT:C3049
      label: Ganglioneuroma
    mapping_predicate: skos:exactMatch
    mapping_source: NCIT
    mapping_justification: >-
      NCIT concept that MONDO records as an exact match of MONDO:0005033. NCIT
      files ganglioneuromatosis (NCIT:C66804) and skin, choroidal and
      colorectal ganglioneuroma beneath it, which this entry does not cover;
      Maturing Ganglioneuroma (NCIT:C42064) and Mature Ganglioneuroma
      (NCIT:C42065) are this entry's subtypes.

📚

References & Deep Research

Deep Research

1

Deep research results are used as seeds for research; they do not undergo the same validation as the main records and may contain errors. How we use deep research.

Evaluations and curation notes (1)

Create: Ganglioneuroma · 2026-10-28T21:25:06Z · View source

New entry for ganglioneuroma (MONDO:0005033), the fully differentiated, benign member of the peripheral neuroblastic tumours. Part of the neuroblastoma expansion series (issue 15822); claim issue 15823. Content: two INPC subtypes (maturing, NCIT:C42064; mature, NCIT:C42065); four pathophysiology nodes (neuroblast-to-ganglion cell maturation, Schwannian stromal development, tumoral vasoactive intestinal peptide secretion, and AKT-mTOR-S6 pathway activation from human immunohistochemistry, left without causal edges as its notes explain); three histopathology rows; eight phenotypes (retroperitoneal, posterior mediastinal and pelvic masses, pain, watery diarrhoea and hypokalaemia from VIP secretion, raised urinary HVA and VMA); a MYCN amplification biomarker row (2 of 34 GN-maturing tumours amplified in the CCG/COG series, 0 of 9 in a second series, with no frequency band because the two small series disagree); four differentials (ganglioneuroblastoma, neuroblastoma, adrenal gland pheochromocytoma, schwannoma); surgical resection and watchful observation; and a CONTROVERSY discussion on whether ganglioneuroma arises by maturation of a neuroblastic tumour. 134 evidence items from 25 references, 17 of them newly cached. The pheochromocytoma differential is bound to MONDO:0004974 (adrenal gland pheochromocytoma) because all of its evidence concerns adrenal tumours; MONDO does not file that term under MONDO:0035540, the term of the Pheochromocytoma_Paraganglioma entry, so the row gets no internal page link. Source report: research/Ganglioneuroma-deep-research-claude_code.md (claude_code provider), re-validated before commit, 82 of 82 references resolved. just preflight-dr returns WARN; both flagged passages are parsing artefacts (line 742 reads "PTEN/BMPR1A hgnc:1076", where hgnc:1076 is BMPR1A, and line 1332 writes each identifier before its symbol), and MONDO records no causal gene for this term. The entry binds no gene identifier from the report; hgnc:7559 (MYCN) was read from cache/hgnc/terms.csv. Validation on the branch rebased onto main: the run_c4 gate set (validate-disorders, count-verified-snippets --strict, check-snippet-grading and the whole-repo gates), check-reference-titles-present, check-cache-order, check-shared-disease-terms, check-logical-rules, check-qualifier-terms and check-delivery-system all passed. check-cancer-origin (advisory) reports no origin node, consistent with the entry's open question about where ganglioneuroma starts.

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1. Disease Information

claude-haiku-4-5-20251001, claude-opus-5 92 citations 2026-10-28T16:38:09.357909

1. Disease Information

1.1 Overview

Ganglioneuroma is a rare, benign, well-differentiated tumour of neural-crest origin arising from the sympathetic nervous system, composed of mature ganglion cells embedded in a dominant Schwannian (Schwann-cell + collagen) stroma. It arises anywhere along the sympathetic chain from skull base to pelvis, most often retroperitoneum, posterior mediastinum, adrenal gland and pelvis.

Orphanet's definition, verbatim:

"Ganglioneuroma is a rare tumor of neuroepithelial tissue, a benign and well-differentiated tumor of neural crest origin" — Orphanet, ORPHA:251992

Orphanet continues that it "originates from the sympathetic nervous system and comprises ganglion cells and stromal Schwann cells," with common sites "adrenal glands, retroperitoneum, posterior mediastinum, and pelvis," and records associations with "neurofibromatosis type I, multiple endocrine neoplasia type 2B, and Turner syndrome."

1.2 Position in the INPC

The International Neuroblastoma Pathology Classification (INPC, the "Shimada system") defines four pNT categories (Shimada et al., Cancer 1999;86:349–363, PMID:10421272; and Cancer 1999;86:364–372, PMID:10421273):

Neuroblastoma — Schwannian stroma-poor
Ganglioneuroblastoma, intermixed — Schwannian stroma-rich (MONDO:0003326)
Ganglioneuroma — Schwannian stroma-dominant ← this entry
Ganglioneuroblastoma, nodular — composite (MONDO:0003325); revised into favourable/unfavourable subsets by Peuchmaur et al., Cancer 2003;98:2274–2281, PMID:14601099

GN has two histological subtypes, maturing and mature, and both are Favorable Histology regardless of patient age (Shimada H, Sano H, Hazard FK. Clin Pediatr Hematol Oncol 2020;27:73–86, doi:10.15264/cpho.2020.27.2.73). That review states GN represents approximately 3% of cases reviewed at the COG Neuroblastoma Pathology Reference Laboratory.

A 2026 update of the pathology of pNTs is available: Conces MR, Shibui Y, Shimada H. "Pathology of peripheral neuroblastic tumors." Diagnostic Pathology 2026;21:22, doi:10.1186/s13000-026-01758-y — open access (full text was paywall-redirected in this session; the abstract confirms the 1984→1999→2003 INPC lineage).

1.3 Key identifiers

System	Value	Verification
MONDO	MONDO:0005033 `ganglioneuroma`	Resolved in `cache/mondo/terms.csv` (retrieved 2026-10-28)
HPO (as a phenotype)	HP:0003005 `Ganglioneuroma`	Resolved in `cache/hp/terms.csv`
Orphanet	ORPHA:251992	Orphanet disease page
ICD-10	D36.1 (benign neoplasm, peripheral nerves and autonomic nervous system)	Orphanet cross-reference
ICD-O-3 morphology	9490/0 Ganglioneuroma	ICD-O-3 morphology listings
ICD-11	2A00.21 as recorded by Orphanet	`[Attribution: Orphanet mapping only — this code reads as a CNS/benign-neoplasm stem and was not verified against the WHO ICD-11 browser. Morphology stem XH03L9 appears in third-party aggregators. UNVERIFIED]`
OMIM	none	Orphanet records no OMIM entry ("brak danych")
MeSH	Ganglioneuroma, D005729	`[From aggregator listing; UNVERIFIED against NLM MeSH]`

Related MONDO terms confirmed present in the local cache: MONDO:0003325 nodular ganglioneuroblastoma, MONDO:0003326 intermixed schwannian stroma-rich ganglioneuroblastoma, MONDO:0005035 ganglioneuroblastoma, MONDO:0005072 neuroblastoma, MONDO:0006076 adrenal gland neuroblastoma.

1.4 Synonyms

ganglioneuroma (Schwannian stroma-dominant); mature ganglioneuroma; maturing ganglioneuroma; benign ganglioneuroma; benign neural crest tumour. Site-qualified variants in common use: adrenal ganglioneuroma (AGN), retroperitoneal ganglioneuroma (RGN), paraspinal/dumbbell ganglioneuroma, presacral ganglioneuroma, intestinal/diffuse ganglioneuromatosis (a distinct, usually syndromic, polytopic form — see §2.2 and §6.3).

1.5 Evidence provenance

All content below is from aggregated disease-level resources and institutional/registry case series. There are no EHR-derived or patient-level datasets for GN. The three largest modern series — 259 (UK national registry), 101 (single institution, 30 years), 51 (single sarcoma centre) — are all retrospective chart reviews. No randomised trial exists, and none is plausible at this incidence.

2. Etiology

2.1 Disease causal factors

GN is a somatic neoplasm of a sympathoadrenal neural-crest derivative. There is no infectious, dietary, or occupational cause described anywhere in the literature reviewed. Two causal models compete (detailed in §6):

Terminal-maturation model (INPC consensus). GN is the end-state of a neuroblastic tumour that differentiated. Shimada et al. state this explicitly: ganglioneuromas represent the "final stage of tumor maturation," such that "all Ganglioneuromas were once Neuroblastomas in their early stage of tumor development" (Shimada 2020).
De novo AKT-driven model. Tao et al. found an active AKT–mTOR–S6 axis in human GN but not neuroblastoma, and showed that constitutive AKT in the zebrafish sympathetic nervous system produces GN without passing through a neuroblastoma state (PMID:32728700). Verbatim from the abstract:

"Zebrafish transgenic for constitutively activated myr-Akt2 in the sympathetic nervous system were found to develop ganglioneuroma without progression to neuroblastoma." "Our results implicate activated AKT as a tumorigenic driver in ganglioneuroma."

These are not reconcilable as stated, and the field has not resolved them. Note what each predicts about the same patient: the maturation model predicts GN should carry residual neuroblastoma-type segmental aberrations; the de novo model predicts it should not. The telomere data in §4.2 are the best available discriminating evidence and favour a genomically distinct entity.

2.2 Genetic risk factors

Germline syndromes. GN is not itself inherited, but three autosomal-dominant syndromes carry a materially raised risk, and in each the ganglioneuromatous lesion is frequently the first manifestation:

MEN2B (RET hgnc:9967). A single germline mutation at codon 918 (M918T, exon 16) accounts for ~95% of MEN2B. Diffuse intestinal ganglioneuromatosis is a universal extra-endocrine feature and typically precedes medullary thyroid carcinoma by years. Gastrointestinal onset occurred in 29/55 (52.3%) of reported cases before age 1, and constipation was the commonest symptom (72.7%) (Intestinal ganglioneuromatosis as an early extra-endocrine manifestation of MEN2B, PMC10848182; Timely diagnosis of MEN2B by identification of intestinal ganglioneuromatosis, Springer; role of rectal biopsy, PMID:27899172). Germline codon-918 mutation has also been found in apparently isolated intestinal ganglioneuromatosis (J Clin Endocrinol Metab 1998;83:4191).
PTEN hamartoma tumour syndrome / Cowden syndrome (PTEN hgnc:9588). Ganglioneuromatous polyposis, diffuse gastric ganglioneuromatosis, and uveal ganglioneuroma are all reported presentations (PMC5889855; PMC4862217; PMID:23512313; uveal ganglioneuroma, PMC5566766).
Neurofibromatosis type 1 (NF1 hgnc:7765). GN in NF1 is real but uncommon. In an Italian multicentre registry study, 8 children with neuroblastic tumours (0.2% of registered patients) met NF1 criteria; of those, 5 were neuroblastoma, 1 ganglioneuroblastoma, 2 ganglioneuroma (PMC9673013). Co-occurrence with pheochromocytoma is described (PMID:17954422), and bladder and cervical GN have been reported in NF1 (PMC9776796; PMC13492013).
Turner syndrome — recorded by Orphanet as an association. [No primary citation located in this session; treat as Orphanet-level only.]

PHOX2B hgnc:9143 — one reported instance, not a susceptibility claim. In a familial neuroblastic-tumour report, a PHOX2B variant inherited from the father was followed by that father developing a well-differentiated ganglioneuroma at age 40 — the single clearest human observation that a germline neurocristopathy allele can yield a differentiated rather than malignant tumour (Identifying a novel PHOX2B gene variant in a neuroblastoma family, ScienceDirect; see also Analysis of sporadic neuroblastic tumors reveals a novel PHOX2B mutation). n=1; do not curate as a susceptibility locus.

Susceptibility loci / GWAS. No GWAS, no polygenic risk score, and no common-variant association for GN. The neuroblastoma GWAS literature does not stratify by INPC category.

2.3 Environmental risk factors

Prior therapeutic irradiation is the one documented exogenous risk factor, and it acts on outcome rather than occurrence: MPNST has arisen inside a benign ganglioneuroma 12 years after radiotherapy for a childhood neuroblastic tumour (PMID:10755757), and after radiotherapy for a cerebellopontine-angle ganglioneuroma (PMID:42120254).
Age is the strongest demographic correlate (see §9).
No toxin, pollutant, occupational exposure, dietary factor, smoking, or alcohol association is reported.

2.4 Protective factors

None documented, genetic or environmental. The absence is informative rather than a gap in searching: GN has no modifiable risk factor to protect against, and no gnomAD-level protective allele has been sought. Plausibly the closest thing to a "protective factor" in the pNT family is the differentiation-promoting Schwann-cell stroma itself (§6.2) — but that is a mechanism within the tumour, not a population-level exposure, and should not be curated as PROTECTS_AGAINST.

2.5 Gene–environment interactions

Only one interaction is evidenced, and it is iatrogenic: germline NF1 loss + therapeutic irradiation → MPNST arising within a ganglioneuroma. The 2025 rectovaginal-septum case is the worked example — a 29-year-old woman with NF1 whose lesion was called ganglioneuroma on biopsy and proved MPNST on resection (PMC12221925). No CTD/PheGenI GxE entry exists for GN.

3. Phenotypes

3.1 The dominant phenotype is absence of phenotype

Across all three modern series, most GN are incidental:

Series	n	Incidental
Texakalidis 2026, J Neurosurg (PMID:42537227)	101	72%
Li 2025, Front Surg (PMID:41306794)	51	56.9%
Burnand 2025, UK CCLG (PMID:39582110)	259	— (symptom data by site)

Verbatim: "Most lesions (72%) were incidental findings." (PMID:42537227)

This matters for the KB entry: the modal patient has no phenotype, and symptomatic phenotypes are almost all mass effect, not tumour biology.

3.2 Phenotype table with HPO bindings

All HP CURIEs below were resolved in cache/hp/terms.csv this session except where flagged.

Phenotype	HPO term	Type	Frequency / source
Ganglioneuroma (the lesion itself)	HP:0003005 Ganglioneuroma	Neoplasm	100% by definition
Abdominal pain	HP:0002027 Abdominal pain	Symptom	31.4% of retroperitoneal GN (PMID:41306794)
Back pain / lumbago	HP:0003418 Back pain	Symptom	5.8% (PMID:41306794)
Abdominal mass	HP:0031500 Abdominal mass	Clinical sign	Common in paediatric presentation
Abdominal distention	HP:0003270 Abdominal distention (OLS4, hp)	Clinical sign	Reported with pressure effects
Vomiting (bowel obstruction)	HP:0002013 Vomiting	Symptom	Reported
Constipation	HP:0002019 Constipation	Symptom	72.7% in MEN2B intestinal ganglioneuromatosis (PMC10848182)
Chronic watery diarrhoea (VIP)	HP:0002014 Diarrhea	Symptom	Rare; VIP-secreting GN (PMID:1211964; PMID:7376870; PMID:2833214)
Hypokalaemia (secretory diarrhoea)	HP:0002900 Hypokalemia	Lab abnormality	With VIP syndrome
Failure to thrive	HP:0001508 Failure to thrive	Clinical sign	With VIP syndrome (PMID:2833214)
Hypertension	HP:0000822 Hypertension	Clinical sign	Catecholamine-secreting GN (Blood Press 2013)
Flushing	HP:0031284 Flushing	Clinical sign	Hormonally active GN
Hyperhidrosis / diaphoresis	HP:0000975 Hyperhidrosis	Clinical sign	Hormonally active GN
Palpitations	HP:0001962 Palpitations	Symptom	Hormonally active GN
Tremor	HP:0001337 Tremor	Clinical sign	Hormonally active GN
Anxiety	HP:0000739 Anxiety	Behavioural	Hormonally active GN
Headache	HP:0002315 Headache	Symptom	Hormonally active GN
Horner syndrome	HP:0002277 Horner syndrome	Clinical sign	Cervical/apical thoracic GN; also a post-operative complication (PMC13492013)
Spinal cord compression	HP:0002176 Spinal cord compression	Clinical sign	Dumbbell/paraspinal GN
Paraparesis	HP:0002385 Paraparesis	Clinical sign	Dumbbell GN; also transient post-operatively (J Neurosurg Spine 2022;37:130)
Scoliosis	HP:0002650 Scoliosis	Physical manifestation	Paraspinal GN
Dyspnoea	HP:0002094 Dyspnea	Symptom	Mediastinal GN
Cough	HP:0012735 Cough	Symptom	Mediastinal GN
Chest pain / tightness	HP:0100749 Chest pain	Symptom	5.8% "other" group (PMID:41306794)
Hydronephrosis	HP:0000126 Hydronephrosis	Imaging/lab	Ureteric compression
Urinary incontinence	HP:0000020 Urinary incontinence	Symptom	Presacral/sacral GN
Virilization	`[HP term UNVERIFIED]`	Clinical sign	Androgen-secreting GN (very rare)

Deliberately excluded: opsoclonus (HP:0010543) and myoclonus (HP:0001336) — opsoclonus-myoclonus syndrome is a neuroblastoma/GNB paraneoplastic phenomenon; I found no evidence it occurs with pure GN, and binding it here would import a neuroblastoma phenotype.

3.3 Phenotype characteristics

Age of onset. Bimodal by series type. Paediatric registry: median 62 months (UK CCLG, n=259, PMID:39582110). Adult/neurosurgical: mean 26.9 ± 15.9 years (PMID:42537227); median 28 years, range 12–73, with 74.5% under 40 (PMID:41306794); median 42 years in a 25-patient adult oncology series (PMID:41561749). Secondary literature states ~60% of cases occur under age 20.
Severity. Mild in the great majority; severity is set by size and location, not by grade. Mean maximal dimension 8.5 ± 3.8 cm on MRI (PMID:42537227); mean 13.06 ± 5.77 cm (range 4.1–30.2) in the retroperitoneal cohort, where 66.7% encased major vasculature (PMID:41306794).
Progression. Indolent and near-static. Median growth 0.3 cm/year (Alexander 2018, PMID:29369484); in the observation arm of the 2026 series, "2 tumors exhibited minimal interval growth (0.08–0.17 cm/year)" and "No patient in the observation group developed new symptoms" (PMID:42537227).
Frequency among affected individuals — see the table above; the honest summary is that no individual symptom reaches 50%, and asymptomatic status does.

3.4 Quality of life

No EQ-5D, SF-36, PROMIS, or GN-specific PRO data exist. This is a real gap, not a search failure. The three available surrogates are all clinician-rated:

Complete symptom control after gross total resection vs non-GTR: 43% vs 24% (PMID:39582110).
Global functional status at final follow-up (mean 33.8 months): "46.5% of patients were stable, 42.3% had improved, and 11.3% had worsened from baseline" (PMID:42537227).
Mean hospital length of stay 4.6 ± 3.7 days (PMID:42537227).

The 11.3% who worsened are the clinically important group, and in a benign tumour with no recurrence they are overwhelmingly worsened by surgery, not by disease.

4. Genetic / Molecular Information

4.1 Causal genes

None. No gene is causative for sporadic ganglioneuroma, and no OMIM entry exists. Do not populate a CAUSATIVE relationship_type for this entry.

4.2 Somatic molecular profile — what GN is not

The most robust molecular statements about GN are negative, and they are what separate it from neuroblastoma.

Telomere maintenance (Sugawara M, Haruta M, Ohira M, et al. Oncol Lett 2026;31(5):156, PMID:41858373, doi:10.3892/ol.2026.15509). 321 neuroblastic tumours, including 18 GN. Verbatim:

"ALT was identified in 38 NB cases (38/255, 15%) and 6 GNB cases (6/48, 12.5%), but not in GN." "High TERT expression was observed in 38% (64/169), 23% (7/31) and 14% (1/7) of NB, GNB and GN cases, respectively."

No TERT rearrangements and no ATRX hgnc:886 alterations were identified in GN. Interpretation: GN activates neither of the two telomere-maintenance routes that immortalise neuroblastoma. That is the strongest single piece of evidence that GN is not simply a differentiated neuroblastoma — a matured tumour would be expected to carry its precursor's immortalisation lesion.

MYCN hgnc:7559. MYCN amplification is not observed in GN (PMID:41858373). A separate Chinese paediatric neuroblastoma series reports low-level MYCN gain (not amplification) in a small number of ganglioneuroma cases [attribution ambiguous in the available abstract; UNVERIFIED — re-read the primary before quoting a figure].

Segmental chromosomal aberrations. 1p loss, 11q loss and 17q gain are neuroblastoma prognostic markers. I found no GN-specific frequency data for them. Older comparative-genomic-hybridisation work on ganglioneuroblastoma found that some samples showed no chromosomal abnormalities at all (PMID:8108298; PMID:11801306). Do not transfer 17q/11q frequencies from ALT-positive mixed cohorts onto GN — that was an available-but-wrong inference I specifically checked and rejected.

4.3 The one positive somatic finding: an active AKT–mTOR–S6 axis

Tao T, Shi H, Wang M, Perez-Atayde AR, London WB, Gutierrez A, Lemos B, Durbin AD, Look AT. J Exp Med 2020;217(10):e20191871. PMID:32728700, doi:10.1084/jem.20191871.

Immunohistochemistry on 11 human GN vs 15 poorly differentiated neuroblastomas:

Marker	GN	Poorly differentiated NB	p
phospho-AKT (Ser473)	10/11 (90.9%)	1/15 (6.7%)	< 0.0001
phospho-mTOR (Ser2448)	9/11 (81.8%)	5/15 (33.3%)	0.0214
phospho-S6 (Ser235/236)	10/11 (90.9%)	7/15 (46.7%)	0.0362
pan-AKT (total)	11/11	14/15	1.00 (ns)

Verbatim: "Phosphorylated, activated AKT and the downstream effectors mTOR and ribosomal protein S6 were more frequently detected in human primary ganglioneuromas than in poorly differentiated human neuroblastomas."

Crucially, the upstream lesion in humans is unidentified. The authors did not find somatically acquired PTEN or AKT mutations, and wrote: "Somatically acquired mutations or epigenetic alterations affecting the expression levels of proteins in the PI3K–AKT–mTOR pathway may be responsible for initiating ganglioneuroma in individual patients." One cohort patient had juvenile polyposis syndrome (a PTEN/BMPR1A hgnc:1076 context).

This is the right level of precision for the KB: the pathway state is demonstrated (modifier: GAIN_OF_FUNCTION or INCREASED on a MolecularFunctionDescriptor), the variant is not (no genetic_context / functional_impact_category is supportable).

4.4 Transcriptional identity

From the same study, GN and NB run opposite transcriptional programmes:

The adrenergic core regulatory circuit TFs highly expressed in neuroblastoma — TFAP2B, ISL1, GATA3, PHOX2A, PHOX2B hgnc:9143 — are down-regulated in ganglioneuroma.
SOX10 hgnc:11190 (neural crest / Schwann-cell lineage) is up-regulated in GN and down-regulated in NB.

This is internally consistent with the IHC literature (§10.5): GN's identity is carried by its Schwannian compartment.

4.5 Modifier genes

None described.

4.6 Epigenetics

No GN-specific DNA-methylation, histone-modification, or chromatin data were found in ENCODE, Roadmap, MethBase or DiseaseMeth-adjacent literature. Tao et al. raise epigenetic silencing as a candidate upstream mechanism for pathway activation (quoted in §4.3) but did not test it. This is a clean, specific, fundable knowledge gap: methylation profiling of ganglioneuroma against neuroblastoma and against normal sympathetic ganglion.

4.7 Chromosomal abnormalities

No recurrent aneuploidy, translocation, or inversion is described. GN is not a karyotype-driven entity, and chromosomal microarray has no established role.

5. Environmental Information

Environmental factors: none established. No CTD/TOXNET/EPA association.
Lifestyle factors: none established.
Infectious agents: not applicable. GN has no infectious aetiology and no infectious_agent should be curated.
Ionising radiation: prior therapeutic irradiation is associated with later MPNST within a GN (§2.3), i.e. the exposure modifies malignant-transformation risk rather than causing the GN. If curated, this is best modelled as an environmental[] entry with environmental_effect: PREDISPOSES pointing at a transformation node, not at the GN itself.

6. Mechanism / Pathophysiology

6.1 Ordered causal chain — Model A: terminal maturation of a neuroblastic tumour

This is the INPC/consensus chain. Steps 1–2 are inferred; steps 3–6 are demonstrated in human tissue and in vitro.

A somatic lesion arises in a sympathoadrenal progenitor derived from the migrating neural crest (CL:0011012 neural crest cell → CL:0002676 neural crest derived neuroblast) during sympathetic nervous system development (GO:0048485 sympathetic nervous system development), leading to clonal neuroblastic proliferation — a neuroblastoma. [Inferred for GN specifically; this step is observed for neuroblastoma, not for GN.]
In favourable-biology tumours, the tumour cell retains high NTRK1/TrkA expression, which results in upregulated NRG1 (neuregulin-1) mRNA. [Demonstrated in vitro]
Secreted NRG1 leads to proliferation and migration of adjacent Schwann cells (CL:0002573 Schwann cell; CL:0002375 Schwann cell precursor) into the tumour, i.e. recruitment of the Schwannian stroma. [Demonstrated: media conditioned by NTRK1-expressing NB cells induced SC proliferation and migration — PMC4294349]
The recruited Schwann cells adopt a repair-like phenotype, co-expressing nerve-injury/repair genes, and secrete NGF plus EGFL8. [Demonstrated: Weiss T, Taschner-Mandl S, et al. Nat Commun 2021;12:1624, PMID:33712610. Verbatim: "stromal SCs in ganglioneuromas and repair SCs share the expression of nerve repair-associated genes."]
Paracrine NGF and EGFL8 result in TrkA/neurotrophin-receptor signalling (GO:0048011 neurotrophin TRK receptor signaling pathway) and kinase rewiring in the neuroblastic cells, which leads to neuronal differentiation (GO:0030182 neuron differentiation), neurite outgrowth (GO:0031175 neuron projection development) and reduced proliferation. [Demonstrated: "Neuroblastoma cells, derived from aggressive tumors, respond to primary repair-related SCs and their secretome with increased neuronal differentiation and reduced proliferation." (PMID:33712610)]
Differentiated cells become mature ganglion cells; Schwann cells ensheathe the neurites until "all neuritic processes produced by ganglion cells are immediately incorporated in the cytoplasm of Schwann cells, so that no naked neuritic processes are detected" — the histological definition of mature GN. Where incorporation is incomplete, the tumour is maturing GN. [Demonstrated histologically — Shimada 2020]
The resulting mass is mitotically inert (Ki-67 hotspot <1%) and causes disease solely by space occupation — vascular encasement, nerve-root and cord compression, ureteric and airway compression (§3.2). [Demonstrated]

Branch at step 5: If residual naked neurites and microscopic neuroblastic foci persist, the tumour is ganglioneuroblastoma, intermixed (MONDO:0003326), not GN. If a discrete neuroblastic nodule arises within ganglioneuromatous tissue, it is ganglioneuroblastoma, nodular (MONDO:0003325) — and that carries real mortality (8-year OS 90.5% favourable subset vs 33.2% unfavourable subset, PMID:14601099). The clinical consequence is in §10.6.

Note this is a positive-feedback loop, not a linear cascade: differentiating tumour cell → NRG1 → Schwann cell → NGF/EGFL8 → more differentiation. It is self-reinforcing, which is why the mature end-state is stable and why spontaneous de-differentiation is not observed.

6.2 Ordered causal chain — Model B: de novo AKT activation

An unidentified somatic or epigenetic event activates the PI3K–AKT axis in a sympathoadrenal cell. [Mechanism demonstrated by transgene; the initiating human lesion is unknown — no PTEN or AKT mutation found (PMID:32728700)]
Activated AKT leads to phosphorylation of mTOR (Ser2448) (GO:0043491 PI3K/AKT signal transduction → GO:0031929 TOR signaling, GO:0032008 positive regulation of TOR signaling). [Demonstrated in human tissue, 9/11]
mTOR activation results in phosphorylation of ribosomal protein S6 (Ser235/236) and 4E-BP1/EIF4EBP1 (Thr37/46), leading to increased cap-dependent translation and enhanced survival. [Demonstrated]
This results in expansion and hypertrophy of differentiated, mature ganglion cells, with simultaneous down-regulation of the adrenergic core regulatory circuit and up-regulation of SOX10. [Demonstrated]
The lesion does not progress to neuroblastoma. [Demonstrated in zebrafish over 29 weeks at 40–50% penetrance; the same promoter driving MYCN or c-MYC gives high-grade neuroblastoma instead]
mTOR inhibition reverses step 3, leading to increased apoptosis (TUNEL-confirmed) and a 30–40% reduction in tumour burden. [Demonstrated pharmacologically — §12.4]

6.3 Branch: enteric ganglioneuromatosis (a different anatomical compartment, the same pathway)

This chain is independently demonstrated and is the strongest corroboration of Model B.

Loss of PTEN — the negative regulator immediately upstream of AKT — in neural-crest-derived enteric nervous system cells (CL:0007011 enteric neuron; CL:0002607 migratory enteric neural crest cell) leads to AKT and S6 hyperphosphorylation. [Demonstrated: Puig I, Champeval D, De Santa Barbara P, Jaubert F, Lyonnet S, Larue L. J Clin Invest 2009;119:3586–96, PMID:19884655, doi:10.1172/JCI39929. Verbatim: "S6 and AKT phosphorylation levels were clearly higher in HM than in WT samples, this effect being particularly marked for AKT."]
This results in enteric neuronal hyperplasia (cell counts 3× wild type) and hypertrophy (cells double the size), i.e. ganglioneuromatosis. [Demonstrated]
Ganglioneuromatosis of the myenteric plexus leads to dysmotility → chronic intestinal pseudo-obstruction, cecal dilation, and death between P13 and P20 with 100% penetrance. [Demonstrated in mouse]
Pharmacological AKT inhibition (API2) prevents step 2: "After API2 treatment, numbers of TUJ1-positive cells in embryos treated with API2 did not significantly differ between WT and HM." This is a rescue experiment, and it establishes direction of causation.
Human corroboration: PTEN expression in the ENS was significantly lower in 2 of 7 chronic intestinal pseudo-obstruction patients, with concomitantly increased S6 phosphorylation. [Demonstrated, small n]

Parallel branch — RET gain of function (MEN2B). Germline RET M918T leads to constitutive RET kinase activity signalling through both MAPK and PI3K/AKT, which results in diffuse hyperplasia of the myenteric and submucosal plexuses → intestinal ganglioneuromatosis → constipation, feeding intolerance, megacolon in the first year of life. Competing/additional proposed mechanisms in this compartment: overexpression of nerve growth factor (NEJM 1983;308:634), and increased GDNF GDNF hgnc:4232 / neurturin expression (GO:0035860 GDNF receptor signaling pathway) (PMID:19353842). [The NGF-overproduction hypothesis is 40 years old and has not been confirmed; label it EMERGING or record it as a knowledge gap rather than a node.]

Note that RET loss-of-function causes Hirschsprung aganglionosis and RET gain-of-function causes ganglioneuromatosis — the same gene, opposite dose, mirror-image enteric phenotypes. That symmetry is worth capturing.

6.4 Where the two models leave the field

Question	Model A (maturation)	Model B (de novo AKT)	Best discriminating evidence
Was every GN once a neuroblastoma?	Yes (explicit)	No	GN has no ALT and essentially no high TERT (PMID:41858373) — a matured NB should retain its immortalisation lesion. Favours B.
Why is Schwannian stroma dominant?	It is the cause of maturation	Consequence of SOX10-high lineage programme	Zebrafish AKT tumours have poor Schwannian stroma (PMID:32728700) — Model B's own model fails to reproduce GN's defining feature. Favours A.
Is there a documented NB→GN transition in a patient?	Yes, case-level (PMID:34054050; complete maturation of NB with bone metastases; maturation of mass-screened localized adrenal NB)	Would call these GNB/NB with maturation, not GN	Case reports; cannot exclude sampling.

Recommended curation: two mechanistic_hypotheses groups (maturation_of_neuroblastic_precursor, status CANONICAL; de_novo_akt_activation, status EMERGING), with causal edges opting into the relevant group via hypothesis_groups, plus a HUMAN_MODEL_MISMATCH discussion for the zebrafish stroma discrepancy (§15.3). Do not pick a winner in the entry prose.

6.5 Mechanism checklist coverage

Molecular pathways: PI3K–AKT–mTOR–S6 (GO:0043491, GO:0031929); neurotrophin/TRK (GO:0048011); GDNF/RET (GO:0035860); MAPK (RET-driven, MEN2B); retinoic acid receptor signalling (GO:0048384) — the latter as the pharmacological analogue of the maturation programme, not as a disease mechanism. KEGG/Reactome have no GN-specific map.
Cellular processes: neuronal differentiation and maturation (GO:0030182, GO:0048667); neurite outgrowth (GO:0031175); cell-cycle exit / reduced proliferation; Schwann cell differentiation (GO:0014037) and PNS myelination (GO:0022011, GO:0042552); apoptosis (the mTOR-inhibitor effector). Notably absent: no genome instability, no telomere maintenance, no invasion/metastasis programme — GN conforms to essentially none of the cancer hallmarks, which is unusual for an entry with an ICD-O morphology code.
Protein dysfunction: constitutive AKT kinase activity (gain of function); PTEN phosphatase loss of function (enteric branch); RET kinase gain of function (MEN2B branch). No misfolding or aggregation.
Metabolic changes: increased cap-dependent protein synthesis downstream of mTOR is the only one documented. In the minority of secretory GN, retained catecholamine biosynthesis (GO:0042423 catecholamine biosynthetic process) producing dopamine CHEBI:18243 and its metabolite homovanillic acid CHEBI:545959. No metabolomics or lipidomics study of GN exists (MetaboLights, Metabolomics Workbench, HMDB: nothing).
Immune involvement: none established. The pNT single-cell study that includes GN describes an immune microenvironment with low cytotoxic T-lymphocyte content across pNTs (GSE192906) but does not isolate a GN-specific immune mechanism.
Tissue damage mechanisms: mechanical compression only — no oxidative stress, ischaemia, fibrosis, or necrosis mechanism. This is the single most important negative in the pathophysiology: GN damages tissue by occupying space.
Biochemical abnormalities: none intrinsic. VIP (VIP hgnc:12693, verified at rest.genenames.org) hypersecretion in the rare VIPoma-like presentation; catecholamine hypersecretion in a minority (§10.1).
Molecular profiling: transcriptomics as above. Proteomics — the Weiss 2021 study performed secretome proteomics of repair Schwann cells (PRIDE-depositable; accession not verified here). No GN proteome, metabolome, or lipidome.
Single-cell / spatial: GSE192906 — "Single-cell RNA-sequencing of peripheral neuroblastic tumors reveals an aggressive transitional cell state at the junction of an adrenergic-mesenchymal transdifferentiation trajectory", Homo sapiens, 10 pNTs, deposited 2022-10-04. Weiss 2021 lists GSE90711, GSE94035, GSE147635, and uses GSE45547 (Kocak) and GSE85047 (NRC) as validation cohorts. [Accession-to-GN-sample mapping NOT verified; before curating any of these as adatasets:record, runjust verify-datasetsand confirm the series actually contains ganglioneuroma samples — the §Dataset-curation rule about relevance triage applies directly, since a search on "neuroblastic tumor" returns neuroblastoma series.]
Functional genomics screens: no DepMap GN line exists (there is no ganglioneuroma cell line). This is a hard structural limit on GN functional genomics and is worth stating.

7. Anatomical Structures Affected

7.1 Organ level

Site	Frequency	UBERON
Retroperitoneum	45.5% (n=46/101, PMID:42537227); 32–52% in review literature	UBERON:0003693 retroperitoneal space (OLS4)
Posterior mediastinum / thoracic paraspinal	32.7% (PMID:42537227); 39–43% in review literature	UBERON:0008822 posterior mediastinum (OLS4); UBERON:0003728 mediastinum
Presacral space	17.8% (PMID:42537227)	`[No UBERON term verified; UNVERIFIED]`
Cervical region	4% (PMID:42537227)	UBERON:0000974 neck
Adrenal gland	Relatively rare as a primary site; increases with age (PMID:40799243)	UBERON:0002369 adrenal gland; UBERON:0001236 adrenal medulla
Sympathetic chain generally	Skull base → pelvis	UBERON:0001806 sympathetic ganglion; UBERON:0001807 paravertebral ganglion; UBERON:0001805 autonomic ganglion
Gastrointestinal tract (ganglioneuromatosis)	Syndromic (MEN2B, PHTS, NF1)	`[colon/stomach UBERON terms not verified this session]`
Rare: CNS, heart, bone, bladder, uvea, paratesticular, larynx	Case-level	—

Secondary organ involvement is compressive, not metastatic: spinal cord (UBERON:0002240) compression from dumbbell extension; ureter/kidney (hydronephrosis); great vessels (aorta, IVC, SMA, renal vessels encased in 66.7% of retroperitoneal cases, PMID:41306794); airway.

Body systems: peripheral/autonomic nervous system (primary); endocrine (adrenal site, and secretory variants); gastrointestinal (ganglioneuromatosis, obstruction); musculoskeletal (scoliosis, vertebral/foraminal remodelling); genitourinary (compression).

7.2 Tissue and cell level

Compartment	Cell type	CL
Neuronal (the "ganglio-" half)	mature ganglion cell / sympathetic neuron	CL:0011103 sympathetic neuron (OLS4); CL:0008025 noradrenergic neuron; CL:0000107 autonomic neuron
Stromal (the "-neuroma" half, and dominant by volume)	Schwann cell	CL:0002573 Schwann cell; CL:0000218 myelinating Schwann cell; CL:0002375 Schwann cell precursor
Perineuronal	satellite cell covering mature ganglion cells	`[No CL term verified; UNVERIFIED]`
Precursor lineage	neural crest cell / neural-crest-derived neuroblast	CL:0011012 neural crest cell; CL:0000333 migratory neural crest cell; CL:0002676 neural crest derived neuroblast
Adrenal context	chromaffin cell	CL:0000166 chromaffin cell; CL:0000336 adrenal medulla chromaffin cell
Enteric ganglioneuromatosis	enteric neuron	CL:0007011 enteric neuron; CL:0002607 migratory enteric neural crest cell

Tissue types: nervous tissue (both neuronal and glial) plus connective tissue (collagen fibres interlacing with Schwann-cell bundles — the origin of the whorled sign on MRI, §10.3) and myxoid stroma.

7.3 Subcellular level

Ganglion cells show Nissl substance — abundant rough endoplasmic reticulum — granular eosinophilic cytoplasm, a round nucleus with open chromatin and a prominent nucleolus. The relevant GO cellular-component terms (rough ER, nucleolus) [were not resolved this session; UNVERIFIED]. No mitochondrial, lysosomal or autophagic compartment pathology is described.

7.4 Localization and laterality

Solitary and unilateral in the overwhelming majority. Side distribution in the retroperitoneal cohort: 58.8% right, 41.2% left (PMID:41306794) — consistent with chance, and not a biological asymmetry. Bilateral/multifocal disease should prompt a syndromic work-up (MEN2B, NF1, PHTS) rather than being treated as sporadic GN. Dumbbell (intraspinal + paraspinal) morphology is the configuration with the highest neurological stakes.

8. Temporal Development

8.1 Onset

Age: see §3.3. Median 62 months in a national paediatric cohort vs mean 26.9 years in a neurosurgical cohort — the discrepancy is ascertainment, not two diseases: paediatric GN is found through neuroblastic-tumour pathways, adult GN through incidental imaging.
Pattern: insidious and chronic. The tumour is typically present for years before detection. Acute presentation occurs only via a complication (obstruction, cord compression).
Congenital? Not described as congenital. Secondary GN maturing from a neuroblastoma presents in young children; primary GN in late childhood and adulthood.

8.2 Progression

No disease-specific staging system. GN is non-metastatic by definition; where a stage is recorded it is borrowed (INSS/INRGSS) from the pNT family. For surgical planning, imaging-defined risk factors (IDRFs) are the operative analogue of stage — and they predict complications, not outcome: IDRF presence correlated with post-operative complications at p = 0.005 (PMID:29369484).
Progression rate: slow, often zero. Median 0.3 cm/year (PMID:29369484); 0.08–0.17 cm/year in the two growing tumours of a 31-patient observation arm followed a mean of 90.9 ± 151 months (PMID:42537227).
Course: stable to very slowly progressive. Not episodic, not relapsing-remitting. In the Alexander series, at median 2.2 years: 27 complete + 10 partial responses, 19 stable, 6 progressive of 67.
Duration: lifelong if unresected, with no natural resolution. Spontaneous regression — the hallmark of infant neuroblastoma — is not a feature of GN.
The one real progression risk is reclassification, not growth. In the UK CCLG cohort, "In 45 cases (39%), surgical pathology was different from pathology at biopsy, and in 14 (12%) the pathology changed from GN/GNBi to neuroblastoma/GNB nodular." (PMID:39582110). Contrast with the single-centre Toronto series, where "Pathology classification changed at resection for three cases, but no GN was reclassified to NB" (PMID:29369484). The two findings are not contradictory — 12% of 259 vs 0% of 67 is within sampling range — but the larger cohort is the one to plan around.

8.3 Patterns

Remission: treatment-induced only (resection). No spontaneous remission.
Critical periods: two, both iatrogenic. (i) The first year of life in MEN2B, when intestinal ganglioneuromatosis presents and a rectal biopsy can make the diagnosis years before medullary thyroid carcinoma — the single highest-yield intervention window in the whole GN space. (ii) The decision point at diagnosis in sporadic GN, where the choice between resection and surveillance determines the 20–43% complication exposure (§11.2). There is no window in which GN itself becomes more dangerous with time, which is precisely why surveillance is defensible.

9. Inheritance and Population

9.1 Epidemiology

Prevalence ≈ 1 per million population. Verbatim: "Ganglioneuroma is a rare neurogenic tumor with a prevalence of one per million population" (Cureus 2023;15:e43914, PMID:37746449). [This is a secondary/tertiary claim repeated across the case-report literature; its primary source was not traced. Treat as PrevalenceClassEnum BELOW_1_IN_1000000 / BAND_1_9_PER_1000000 with measure_type UNKNOWN and record the attribution honestly.]
Proportion of primary retroperitoneal tumours: 0.72–1.6% (same source, verbatim: "Ganglioneuromas constitute only 0.72%–1.6% of all primary retroperitoneal tumors").
0.1–0.5% of all neurogenic tumours (review literature).
≈3% of peripheral neuroblastic tumours reviewed at the COG Neuroblastoma Pathology Reference Laboratory (Shimada 2020) — the most defensible denominator-based figure available.
Incidence: no population-based incidence rate exists. GN is not separately reported in SEER (SEER work exists for ganglioneuroblastoma: 1,194 patients, 5-year survival ~88%, PMC11107237); because GN is coded benign (ICD-O 9490/0), US cancer registries do not capture it. This is the structural reason no incidence figure exists, and it should be stated rather than approximated.

9.2 Genetic etiology parameters

GN itself is not inherited; the predisposing syndromes are:

Syndrome	Gene	Inheritance	Penetrance for the ganglioneuromatous feature
MEN2B	`RET` hgnc:9967	Autosomal dominant; ~50% de novo	Diffuse intestinal ganglioneuromatosis described as a universal extra-endocrine feature; GI symptom onset <1 year in 52.3%
Cowden / PHTS	`PTEN` hgnc:9588	Autosomal dominant	Low/undefined for GN specifically; PTEN LOF in ~80% of Cowden
NF1	`NF1` hgnc:7765	Autosomal dominant; ~50% de novo	Very low — 2 GN among 8 NF1 patients within 0.2% of an Italian neuroblastic-tumour registry

Founder effects / carrier frequency / consanguinity / anticipation / germline mosaicism: not applicable to GN. These belong to the syndrome entries, not here. Do not populate them.
Expressivity: highly variable in MEN2B — the same M918T allele gives everything from isolated intestinal ganglioneuromatosis to the full MTC/pheochromocytoma/marfanoid syndrome.

9.3 Population demographics

Sex. Adult surgical series are consistently female-predominant: 62.3% female (n=101, PMID:42537227); 33/51 = 64.7% female (PMID:41306794); 18/25 = 72% female (PMID:41561749). Paediatric review literature quotes M:F ≈ 2:3. One adrenal-GN review states "There are no significant sex differences in morbidity" (PMID:40799243). Interpretation: a modest female excess in resected series, possibly reflecting imaging utilisation rather than biology. Record it as observed, not as a sex-specific disease.
Age distribution. ~60% under 20 at diagnosis in paediatric-weighted literature; adrenal GN specifically is "rare in children under 10 years of age, with a higher incidence in adults than in children, and its incidence increases with age" (PMID:40799243) — i.e. site and age interact.
Ancestry / geography. No ethnic predilection and no endemic region described. No HANCESTRO-bindable population effect exists. [Do not curate a population_effects record: there are no population-stratified data.]

10. Diagnostics

10.1 Laboratory tests and biomarkers

Core panel: plasma/urinary metanephrines and catecholamines, urinary VMA (CHEBI:20106 vanillylmandelic acid) and HVA (CHEBI:545959 homovanillic acid), plus adrenal-incidentaloma screening (cortisol excess, aldosterone/renin) where adrenal.
The expected result is normal. In the 51-patient retroperitoneal cohort, catecholamine/VIP testing was performed in 13 patients and all were negative (PMID:41306794).
The informative abnormal pattern is dopamine/HVA elevation with normal adrenaline, noradrenaline and VMA — reported in four children with GN, and the mirror image of neuroblastoma (where noradrenaline, dopamine, HVA and VMA are typically raised) (Pathology / catecholamines in urine and tumour tissue). This asymmetry is mechanistically sensible: mature ganglion cells retain upstream synthesis (GO:0042423) without the full secretory phenotype.
~30% of adrenal GN reported with elevated catecholamines — widely repeated but [secondary claim, primary source not traced; UNVERIFIED]. Case reports document raised norepinephrine, normetanephrine, VMA and dopamine with suppressed epinephrine (PMC9242669).
Rare secretory syndromes: VIP (VIP hgnc:12693) → watery diarrhoea, hypokalaemia, failure to thrive; ACTH/cortisol; androgens → virilization. One 80-case adrenal series reported 3 patients with elevated 24-hour urinary cortisol (PMID:40799243).
LOINC. The relevant measurements (VMA, HVA, plasma free metanephrines, VIP) all have LOINC codes, but none was looked up in this session. Per the repo's rule, do not type a LOINC label from memory — run just loinc-seed-cache and commit cache/loinc/terms.csv with the entry. [UNVERIFIED]

10.2 Biomarkers for prognosis

None. There is no prognostic biomarker for GN because there is nothing to prognosticate — survival is essentially 100% (§11.1). The only predictive marker of interest is phospho-S6 / phospho-AKT status as a candidate biomarker for mTOR-inhibitor responsiveness, which has never been tested prospectively.

10.3 Imaging

CT (NCIT:C17204 Computed Tomography): - Low attenuation, < 40 HU unenhanced; homogeneous or slightly heterogeneous. - Gradual and delayed enhancement — minimal arterial-phase, progressive portal and delayed-phase enhancement. This pattern reflects the myxoid, hypovascular Schwannian stroma and is one of the better discriminators from pheochromocytoma. - Calcification in 42–60%, characteristically discrete and punctate rather than the amorphous coarse calcification of neuroblastoma. (AJR imaging reviews; Diagnostics 2023;13:2190, PMC10341194; PMID:22573298)

MRI (NCIT:C16809 Magnetic Resonance Imaging): - T1: low signal; T2: heterogeneously high signal; gradual delayed enhancement. - "Whorled sign" — interlacing thick bundles of Schwann cells and collagen — reported in about 80% of patients and the most characteristic MRI feature (PMC10341194; PMC6647925). - Mean dimensions 8.5 ± 3.8 × 6.6 ± 3.2 × 5.8 ± 3.7 cm (PMID:42537227).

Functional imaging: low or absent MIBG uptake and no significant FDG avidity — in contrast to neuroblastoma and pheochromocytoma. Note the exception: an adrenal GN with nodal involvement showing uptake on both ¹²³I-MIBG SPECT/CT and ¹⁸F-FDG PET/CT has been published (ScienceDirect), so low uptake is a tendency, not a rule.

The imaging pitfall is over-reliance. A giant retroperitoneal GN was misdiagnosed on radiology alone (PMID:37746449) — the paper's title is literally "Overreliance on Radiological Findings Leading to Misdiagnosed Giant Retroperitoneal Ganglioneuroma." Imaging narrows, histology decides.

10.4 Functional tests and electrophysiology

No role in diagnosis. Intra-operative neuromonitoring is used during paraspinal/dumbbell resection to limit the 22.2% neurological-deficit rate (§11.2), which is a surgical adjunct rather than a diagnostic test.

10.5 Biopsy, histopathology and immunohistochemistry

Gross: well-circumscribed, firm, grey-white to tan, often lobulated, with a whorled cut surface.

Microscopic: mature ganglion cells with granular eosinophilic cytoplasm, round nuclei with prominent nucleoli and Nissl substance, scattered individually or in small clusters, embedded in a dominant stroma of spindled Schwann cells and collagen within a myxoid background. Satellite cells cover the mature ganglion cells. Mitoses absent; Ki-67 hotspot index <1% (PMID:40799243).

The maturing vs mature distinction turns entirely on neurite incorporation (Shimada 2020):

Subtype	Criterion
Maturing GN	Neuritic processes from neuroblastic cells are incompletely incorporated into Schwann-cell cytoplasm; a mixture of mature and maturing ganglion cells
Mature GN	"composed only of completely mature ganglion cells covered with satellite cells"; "all neuritic processes produced by ganglion cells are immediately incorporated in the cytoplasm of Schwann cells, so that no naked neuritic processes are detected"
Ganglioneuroblastoma, intermixed (not GN)	"foci of naked neurites are still identified microscopically"

Immunohistochemistry — note a genuine conflict in the literature:

Marker	Compartment	Reported
S100	Schwannian stroma	Positive (consistent across sources)
SOX10	Schwannian stroma	Positive; `SOX10` is transcriptionally up in GN (PMID:32728700)
Synaptophysin	Ganglion cells	Positive
NSE	Ganglion cells	Positive
Neurofilament	Ganglion cells / neurites	Positive (composite-tumour literature)
PHOX2B	Ganglion cell nuclei	Conflict. A 2025 adrenal-GN report records PHOX2B negative (PMID:40799243), whereas the diagnostic-IHC literature reports "Phox2b expression was seen in all neuroblastomas, ganglioneuroblastomas, and ganglioneuromas" with "nuclear positivity in all of the ganglion cells across the different phases of differentiation", and 70/76 (92%) of pNTs positive overall (PMID:28640941; PHOX2B immunolabeling)
Tyrosine hydroxylase (TH)	Ganglion cells	Conflict, same pattern: reported negative in one adrenal GN (PMID:40799243) but "Strong expression of PHOX2A, PHOX2B, and TH in both neuroblastoma and ganglioneuroma" elsewhere, and strongly reactive in all cell types of composite pheochromocytoma-ganglioneuroma (PMC3685741)
Chromogranin A	—	Generally negative in GN (positive in pheochromocytoma)

How to curate the conflict: the case-report negatives are n=1–2 observations on a single adrenal tumour; the systematic IHC studies are cohort-level and consistently positive. Bind PHOX2B and TH as expressed in ganglion cells, and record the discordant case-level reports in notes: rather than as a REFUTE evidence item — they most likely reflect antibody, fixation, or a tumour whose ganglion cells are too few to sample, not a biological disagreement.

Differential diagnosis

Entity	Distinguishing features
Neuroblastoma	Undifferentiated/poorly differentiated neuroblasts, Schwannian stroma-poor, high mitosis-karyorrhexis index; PHOX2B and NB84 strongly positive; raised VMA/HVA; avid MIBG; MYCN may be amplified
Ganglioneuroblastoma, intermixed	Microscopic naked neurite foci persist
Ganglioneuroblastoma, nodular	Discrete neuroblastic nodule within ganglioneuromatous tissue — the one differential with real mortality (8-yr OS 33.2% in the unfavourable subset, PMID:14601099)
Pheochromocytoma	Catecholamine excess; chromogranin A, TH positive; avid MIBG; Zellballen architecture
Schwannoma	Alternating Antoni A/B, nuclear palisading, Verocay bodies, no ganglion cells
Neurofibroma	No ganglion cells; different stromal architecture
Composite pheochromocytoma–ganglioneuroma	Both components present; <3% of sympathoadrenal pheochromocytomas, reported range 1–9% of pheochromocytomas; MEN2A association (PMC3685741; Am J Surg Pathol 1997; PMC9518729)
Adrenal schwannoma with GN component	Reported (PMC11446904)
Retroperitoneal sarcoma	The practical misdiagnosis in adults with large masses

10.6 The central diagnostic problem: biopsy understaging

This deserves its own statement because it governs management. A needle biopsy showing ganglioneuroma does not exclude a neuroblastic nodule elsewhere in the lesion. The UK CCLG national cohort is the key evidence: "In 45 cases (39%), surgical pathology was different from pathology at biopsy, and in 14 (12%) the pathology changed from GN/GNBi to neuroblastoma/GNB nodular." And the authors' own caveat: "a small proportion of patients in the observation group had their diagnosis revised to malignant at surgery" (PMID:39582110).

Mechanistically this is unavoidable: GNB-nodular is defined by focal heterogeneity, so any sampling strategy short of whole-tumour examination has a non-zero miss rate. This is the strongest argument against unqualified "watch and wait", and the reason the 2026 recommendation is individualised, not surveillance-by-default.

10.7 Genetic testing

For sporadic GN: none indicated. WGS, WES, gene panels, CMA, karyotyping, FISH, mtDNA testing and repeat-expansion testing have no established role, because there is no causal gene and no recurrent somatic lesion.

For syndromic suspicion, targeted single-gene testing is high-yield: - RET (exon 16, M918T) when there is mucosal neuroma, marfanoid habitus, alacrima, early-onset constipation, or any diffuse intestinal ganglioneuromatosis. Rectal biopsy is an established early-diagnosis route to MEN2B (PMID:27899172). - PTEN for ganglioneuromatous polyposis, diffuse gastric ganglioneuromatosis, macrocephaly, or Cowden features. - NF1 where café-au-lait macules/neurofibromas coexist.

10.8 Omics-based diagnostics

None clinically available or validated. No RNA-seq, proteomic, metabolomic, epigenomic, or liquid-biopsy diagnostic exists for GN. The honest statement for the KB is that GN diagnosis is histological, and the molecular layer is research-only.

10.9 Clinical criteria and screening

Diagnostic criteria: INPC histological criteria (§10.5) are the standard; there is no clinical criterion set, no DSM/ICD symptom checklist, and no society guideline specific to GN.
Screening of asymptomatic individuals: no population screening. Historically, Japanese infant neuroblastoma mass screening detected maturing/localised adrenal lesions (maturation of mass-screened localized adrenal neuroblastoma) — relevant context, but mass screening was abandoned for overdiagnosis, which is itself the central argument of this entry in miniature.
Cascade/targeted screening is justified only in the syndromes: RET cascade testing in MEN2B families; periodic biochemical and imaging evaluation in NF1 given raised pheochromocytoma and GN prevalence.

11. Outcome / Prognosis

11.1 Survival and mortality — essentially unaffected

Series	n	Follow-up	Outcome
Burnand 2025, UK CCLG (PMID:39582110)	259 (163 GN, 93 GNBi)	1990–2020	Overall survival 98%
Li 2025, Front Surg (PMID:41306794)	51 retroperitoneal	median 62 months, 90.2% complete	"no recurrences, metastases, or disease-specific deaths occurred"
Texakalidis 2026, J Neurosurg (PMID:42537227)	101	mean 33.8 ± 42.6 months	Recurrence 2/70 (2.9%); "No malignant transformations were observed"
Ozcelik 2026, Front Oncol (PMID:41561749)	25 adults	median 88.3 months (16.2–217.8)	"no distant metastases or recurrences were observed during follow-up"
Alexander 2018 (PMID:29369484)	67	median 2.2 years	All patients alive

Life expectancy is normal. Disease-specific mortality is effectively zero — and note that the one death in the 51-patient cohort was operative (post-operative day 8, bowel ischaemia with septic shock), not from GN.

Regional lymph node involvement occurs and does not matter. Ozcelik et al. found nodal metastases in 2/25 (8%) — 5/12 nodes positive in one patient, 4/4 in another — with no distant metastasis or recurrence at median 88.3 months. Their title states the finding: "Ganglioneuroma has a potential for lymph node metastasis, not impacting recurrence." Pathologically this looks alarming on a report; prognostically it is inert. [Important for curation: do not model nodal involvement as a metastasis node with adverse consequence.]

Malignant transformation to MPNST is the only lethal trajectory, and it is vanishingly rare: approximately ten reported cases of MPNST arising in GN, de novo or at a previously irradiated site, as of the early 2000s (PMID:10755757; Drago 1997, Med Pediatr Oncol; PMC12221925). Both of the two largest modern cohorts observed zero transformations.

11.2 Morbidity is iatrogenic, and it is substantial

This is the real outcome story, and the asymmetry between it and §11.1 is what the whole management literature is about.

Series	Complication rate	Detail
Texakalidis 2026 (PMID:42537227)	43.1% short-term	"most commonly neurological deficits (22.2%)"
Alexander 2018 (PMID:29369484)	30% (15/50)	IDRF presence correlated with complications, p = 0.005
Li 2025 (PMID:41306794)	21.6%	Clavien-Dindo I/II in 90.9%; Grade V (death) 9.1% of complications = 1 patient. Gastroparesis ×3, pancreatic fistula ×3, transaminitis ×2, wound infection ×2. Multivisceral resection in 27.5%
Burnand 2025 (PMID:39582110)	19% with GTR	—

Dumbbell/paraspinal resection carries the highest neurological cost. A systematic review of dumbbell spinal tumours with nerve-root sacrifice (121 patients, 12 studies) found immediate motor deficits in 46% (95% CI 31–62%) and persistent deficits in 21% (95% CI 14–31%) (Eur Spine J). A GN-specific paraspinal series of 15 reported no permanent neurological deficits, with one transient bilateral lower-extremity weakness resolving in 4 weeks (J Neurosurg Spine 2022;37:130).

11.3 Complications

Of the disease: compressive — cord compression, radiculopathy, hydronephrosis, bowel obstruction (especially in ganglioneuromatosis), scoliosis, airway compression; secretory diarrhoea/hypokalaemia; hypertension. Of treatment: neurological deficit, Horner syndrome, chylothorax, nephrectomy, pancreatic fistula, haemorrhage, gastroparesis, infection, death. Of radiotherapy: late MPNST.

11.4 Recovery potential and prognostic factors

Recovery after resection is good: 42.3% improved and 46.5% stable from baseline (PMID:42537227); complete symptom control in 43% with GTR vs 24% without (PMID:39582110).

Prognostic factors — note what they are for. Nothing predicts survival, because survival is near-universal. What is predictable is surgical morbidity, and it is predicted by: IDRF presence (p=0.005), vascular encasement (66.7% of large retroperitoneal tumours), tumour size, intraspinal/dumbbell extension, and need for multivisceral resection. Subtotal resection does not worsen outcome: "STR provides excellent long-term control when required to avoid morbidity" (PMID:42537227), and the 6 R2-resection patients in the retroperitoneal cohort showed stable disease without progression (PMID:41306794). That is the single most actionable prognostic statement in the literature.

12. Treatment

12.1 The treatment principle

Surgery is the only established therapy, and the only question is whether to use it. Verbatim from Tao et al.: "Surgery is the only effective therapy for ganglioneuroma, which may be challenging due to the location of the tumor and involvement of surrounding structures." (PMID:32728700)

12.2 Surgical and interventional

Treatment	NCIT (verified in `cache/ncit/terms.csv`)	Notes
Surgical resection	NCIT:C15329 Surgical Procedure; NCIT:C154430 Definitive Surgical Resection; NCIT:C164212 Tumor Resection	GTR achieved in 73.6% (PMID:42537227), 79% (PMID:39582110); R0/R1 in 88.2% (PMID:41306794)
Gross total resection	NCIT:C131672 Gross Total Resection; NCIT:C175027 Complete Resection	Best symptom control (43% vs 24%)
Subtotal / debulking	—	Deliberate strategy when adjacent to critical structures; excellent long-term control
Adrenalectomy (laparoscopic)	NCIT:C15177 Adrenalectomy	"Laparoscopic resection is the primary treatment for AGN", and "laparoscopic surgery is still applicable even when the tumor diameter exceeds 6 cm" (PMID:40799243). Open 80.4% vs laparoscopic 19.6% in the large-tumour retroperitoneal cohort (PMID:41306794)

Where it should be done: "While surgical resection remains the cornerstone of management, it is best undertaken at specialized, high-volume sarcoma centers to mitigate operative risks." (PMID:41306794)

12.3 Active surveillance — a first-line treatment, not a non-treatment

Treatment	NCIT	Evidence
Observation / active surveillance	NCIT:C15722 Patient Observation	58/259 = 22% observed, OS 98%; 21/58 (36%) required subsequent surgery, 52% of those for progressive growth (PMID:39582110). 31/101 observed, mean follow-up 90.9 months, no new symptoms, 2 tumours grew 0.08–0.17 cm/yr; observation chosen for proximity to major vascular or neural structures in 74.2% (PMID:42537227). 21/67 observed, 4 later resected (PMID:29369484)

Verbatim conclusions, which diverge in emphasis and should both be recorded: - "Watch and wait approaches should be considered for some GN and GNB-I." (PMID:29369484) - "Watchful active observation can be a safe approach, with surgical resection reserved for symptomatic patients. However, a small proportion of patients in the observation group had their diagnosis revised to malignant at surgery." (PMID:39582110) - "Observation is safe for asymptomatic tumors, particularly when adjacent to critical structures... These findings support an individualized, risk-based approach to management." (PMID:42537227)

Also reported: a presacral GN followed 6 years without surgery (ScienceDirect).

12.4 Pharmacotherapy — mTOR inhibition is the one real therapeutic hypothesis

There is no approved drug for GN and no completed or active clinical trial. What exists is a well-constructed preclinical proposal.

Agent	CHEBI	NCIT	Preclinical result (PMID:32728700)
Sirolimus (rapamycin)	CHEBI:9168	NCIT:C1212	Adult fish with primary GN, 35 days: 30–40% tumour-burden reduction vs ~1.5-fold increase in DMSO controls. ~50% reduction in transplant assay (p<0.0001)
Everolimus	CHEBI:68478	NCIT:C48387	Same, 30–40% reduction
INK128 (TORC1/2)	—	—	~50% reduction in transplant assay; strongest 4E-BP1 inhibition
MK-2206 (AKT inhibitor)	—	—	No effect — expected negative control against a myristoylated, membrane-targeted AKT

Drug class: NCIT:C2201 mTOR Inhibitor. [If curating as therapeutic_agent, NCIT:C2201 must be checked against the ChemicalEntityTerm dynamic enum rooted at NCIT:C1909 Pharmacologic Substance — run just validate-terms after binding. Prefer the CHEBI terms for the named drugs.]

Mechanism of the response: increased apoptosis (sub-G1 fraction, TUNEL-confirmed) with marked inhibition of phospho-S6.

The authors' proposal, verbatim: "We propose a clinical trial of mTOR inhibitors as a means to shrink large ganglioneuromas before resection in order to reduce surgical morbidity." The commentary notes sirolimus and everolimus are already FDA-approved in paediatric patients and that mTOR inhibition is established in tuberous sclerosis, so safety is not the barrier (Mol Cell Oncol 2020, PMID:33553609).

Why this is strategically the right target: GN kills essentially nobody, so there is no survival endpoint to improve. The morbidity is surgical and scales with tumour size and anatomical entanglement. A neoadjuvant agent that shrinks the tumour attacks the actual source of harm. That reframing — treat the surgery, not the tumour — is the most interesting clinical idea in this disease.

No trial exists. A search of ClinicalTrials.gov returned mTOR-inhibitor trials in MPNST (NCT03433183 selumetinib+sirolimus; NCT01661283 everolimus+bevacizumab) and NF1 plexiform neurofibroma (NCT00634270 sirolimus), none in ganglioneuroma. [No NCT identifier is curatable for this entry. Record the proposal as a mechanistic_hypotheses / KNOWLEDGE_GAP with proposed_experiments, not as a clinical_trials entry.]

12.5 What has no role

Chemotherapy (NCIT:C15632): no role in GN.
Radiotherapy (NCIT:C15313): no role, and it is the one documented exogenous risk factor for later MPNST within a GN. This is a treatment that should be recorded with its harm, not just its absence of benefit.
Gene therapy, cell therapy, CAR-T, RNA therapeutics (ASO/siRNA), immunotherapy, checkpoint inhibitors: none, none proposed, none plausible for a benign non-progressive lesion. [Leave therapeutic_modality and oligonucleotide_details absent.]
Pharmacogenomics: nothing — no drug, no PharmGKB/CPIC entry.

12.6 Supportive, rehabilitative and counselling

NCIT:C15747 Supportive Care — analgesia, bowel management in ganglioneuromatosis, nutritional support with secretory diarrhoea, alpha-blockade before resecting a catecholamine-secreting lesion [perioperative blockade protocol not sourced in this session; UNVERIFIED].
NCIT:C15315 Rehabilitation — post-operative physical therapy for the 22.2% with neurological deficits.
NCIT:C15240 Genetic Counseling — for MEN2B/PHTS/NF1 families, including cascade testing and reproductive options.

12.7 Treatment algorithm

Lesion identified → cross-sectional imaging (CT/MRI) looking for the GN signature (low HU, delayed enhancement, punctate calcification, whorled sign, low MIBG).
Biochemical screen (metanephrines/catecholamines, VMA/HVA; adrenal panel if adrenal).
Tissue diagnosis — and read §10.6 before trusting it.
Screen for a syndrome if multifocal, GI-diffuse, or syndromic stigmata → RET / PTEN / NF1.
Decide on the morbidity axis, not the oncology axis:
Symptomatic, or growing, or resectable without critical-structure risk → resection, at a high-volume centre, aiming for GTR but accepting STR over deficit.
Asymptomatic and abutting major vessels/nerves → active surveillance with interval imaging, accepting a ~36% eventual-surgery rate and a small reclassification risk.
Residual tumour after STR → surveillance; it stays stable.
No adjuvant chemotherapy or radiotherapy.

Personalised medicine: phospho-AKT/phospho-S6 status is the only candidate stratifier (90.9%/90.9% positive), and it has never been used to select therapy. No CIViC, OncoKB or My Cancer Genome entry exists for GN.

13. Prevention

13.1 Primary prevention

None exists for sporadic GN — there is no modifiable risk factor to remove, no vaccine target, no behavioural intervention, and no prophylactic agent. This should be stated as a fact about the disease, not a gap.

The one genuine primary-prevention statement is negative and iatrogenic: avoid radiotherapy to a ganglioneuroma or its site, because the small MPNST risk is concentrated in previously irradiated lesions.

13.2 Secondary prevention — early detection where it changes outcome

The high-value prevention in this space is not about GN at all; it is about using GN as a sentinel.

Rectal biopsy for intestinal ganglioneuromatosis in an infant with severe constipation → RET testing → MEN2B diagnosis → prophylactic thyroidectomy before medullary thyroid carcinoma. GI symptoms precede age 1 in 52.3% of MEN2B cases, and MTC is the cause of death. This converts a benign nerve lesion into a life-saving diagnostic (PMID:27899172; Springer 2021; Pediatrics 2024, "Clues for Early Diagnosis of MEN2B Syndrome Before Medullary Thyroid Carcinoma").
NF1 surveillance: periodic clinical evaluation with biochemical testing and imaging, justified by the raised prevalence of pheochromocytoma and GN.
PHTS/Cowden: standard PTEN surveillance (breast, thyroid, endometrial, renal, GI), with ganglioneuromatous polyposis as a possible index finding.
Population screening: not indicated, and actively harmful. There is no newborn or population screening for GN, and the Japanese infant neuroblastoma mass-screening experience is the cautionary precedent — screening detected lesions that would have matured or regressed.

13.3 Tertiary prevention

Interval imaging surveillance of unresected or subtotally resected tumours (no growth expected; two of 31 grew 0.08–0.17 cm/yr).
Long-term follow-up after incomplete resection and especially after radiotherapy, given the MPNST signal: the literature stresses "the importance of close clinical and radiologic follow-up in patients with high-risk ganglioneuroma... particularly after incomplete resection and radiotherapy."
Operate at high-volume centres to reduce the 20–43% complication exposure — the highest-yield tertiary prevention available.
Bowel management and nutritional support in ganglioneuromatosis to prevent obstruction and failure to thrive.

13.4 Immunization, public health, environmental interventions

Not applicable. No vaccine, no sanitation/vector/health-education intervention, no environmental exposure to reduce. Record as not applicable rather than absent.

13.5 Genetic screening and counselling

Carrier screening, prenatal testing, PGD: available for the syndromes (RET, PTEN, NF1) and inappropriate for GN itself.
Risk stratification: the only meaningful stratifier is "syndromic vs sporadic", determined clinically (multifocality, diffuse GI involvement, marfanoid habitus, mucosal neuromas, macrocephaly, café-au-lait macules).

14. Other Species / Natural Disease

14.1 Taxonomy and natural occurrence

Species with naturally occurring ganglioneuroma or ganglioneuromatosis reported in the veterinary literature (all NCBITaxon CURIEs verified in cache/ncbitaxon/terms.csv):

Species	NCBITaxon	Report
Human	NCBITaxon:9606	—
Dog	NCBITaxon:9615	Intestinal ganglioneuromatosis reported; a single cutaneous GN case existed in the dog literature as of 2011. Adrenal neuroblastoma also described in a young dog (Front Vet Sci 2019;6:161)
Cattle	NCBITaxon:9913	First report of cutaneous ganglioneuroma in cattle, 2011 (ResearchGate)
Goat (Boer)	NCBITaxon:9925	Intestinal ganglioneuromatosis
Pig (piglet)	NCBITaxon:9823	Intestinal ganglioneuromatosis
Horse	NCBITaxon:9796	Intestinal ganglioneuromatosis

Summary from the veterinary literature: "Intestinal ganglioneuromatosis is exceedingly rare in domestic animals and has only been reported in dogs, a Boer goat, a piglet, and a horse."

14.2 Breed and OMIA

No breed predisposition (no VBO term) and no OMIA entry for ganglioneuroma were located. This is expected — OMIA catalogues inherited traits, and no animal GN has been shown to be heritable. [Searched; absent rather than unsearched.]

14.3 Orthologous genes

Orthologues exist for every gene in §0 (AKT1/2/3, MTOR, PTEN, RET, NF1, PHOX2B, NTRK1, SOX10) across mouse, rat and zebrafish. [Specific NCBI Gene IDs for non-human orthologues were not resolved this session; UNVERIFIED.] Note that the zebrafish model (§15.1) used murine myr-Akt2 driven by a zebrafish dβh promoter — a cross-species construct, which matters for how faithfully it models human AKT biology.

14.4 Comparative biology and evolutionary conservation

The sympathoadrenal developmental programme — neural crest migration, PHOX2B/HAND2-driven noradrenergic specification, RET/GDNF-dependent enteric colonisation, and PI3K/AKT control of progenitor survival — is deeply conserved across vertebrates. That conservation is what makes both the zebrafish and mouse models (§15) interpretable at all. The divergence worth recording: the zebrafish interrenal gland substitutes for the mammalian adrenal medulla, and the zebrafish AKT tumour has poor Schwannian stroma where the human tumour is stroma-dominant — so the conserved part is the neuronal arm, and the glial/stromal arm is not reproduced.

14.5 Transmission

Not applicable. GN is a neoplasm: no zoonotic potential, no cross-species susceptibility, no transmission of any kind.

15. Model Organisms

15.1 Zebrafish — the only dedicated ganglioneuroma model

Tao T, Shi H, Wang M, Perez-Atayde AR, London WB, Gutierrez A, Lemos B, Durbin AD, Look AT. J Exp Med 2020;217(10):e20191871. PMID:32728700.

Attribute	Detail
Species	Danio rerio, NCBITaxon:7955
Model type	Stable transgenic (two independent lines, myr-Akt2#1 and #2)
Construct	`Tg(dβh:mCherry; dβh:myr-Akt2)` — constitutively activated murine myristoylated Akt2 under the zebrafish dopamine-β-hydroxylase promoter
Target lineage	Peripheral sympathetic nervous system progenitors; lesions arise in the interrenal gland (zebrafish adrenal-medulla equivalent) from differentiated sympathoadrenal cells
Onset / penetrance	Tumours from 13 weeks post-fertilisation; 40–50% penetrance by 29 wpf
Phenotype recapitulated	Differentiated, large, mature ganglion cells; low N:C ratio; open chromatin; prominent nucleoli; abundant eosinophilic cytoplasm. HuC+, synaptophysin+. No progression to neuroblastoma over 29 weeks. Adrenergic CRC (`TFAP2B`, `ISL1`, `GATA3`, `PHOX2A`, `PHOX2B`) down; `SOX10` up — matching human GN
Pharmacological validation	Sirolimus and everolimus each reduced tumour burden 30–40% over 35 days; INK128 ~50% in transplant assay; MK-2206 no effect (expected)
Research applications	Mechanism of AKT-driven ganglion-cell expansion; preclinical mTOR-inhibitor testing; transplantation-based drug screening in casper recipients
Resource	ZFIN

Limitation — and it is the defining one. The model's tumours "were composed of differentiated, mature ganglion cells with poor Schwannian stroma." Human ganglioneuroma is, by its INPC definition, Schwannian stroma-dominant. So the model reproduces the neuronal half of the disease and not the half the disease is named for — and therefore cannot address the Schwann-cell crosstalk mechanism (§6.1) at all. This is a textbook HUMAN_MODEL_MISMATCH, not a generic knowledge gap: the evidence exists in the model, and its translational validity to the defining human feature is the open question. Recommended curation: kind: HUMAN_MODEL_MISMATCH with a prompt asking whether AKT-driven ganglion-cell expansion without Schwannian stroma is the same disease as human Schwannian stroma-dominant ganglioneuroma, and modeled_mechanisms links carrying relationship: PARTIALLY_RECAPITULATES, fidelity: MODERATE, a BOUNDARY_OMISSION divergence (Schwannian stroma absent from the model) and a SPECIES_MISMATCH divergence (murine Akt2 in a teleost interrenal gland).

Second limitation: the construct enforces constitutive membrane-targeted AKT, which is not the human lesion — no somatic AKT or PTEN mutation was found in the human cohort. The model demonstrates sufficiency of the pathway state; it does not model the human initiating event.

15.2 Mouse — enteric ganglioneuromatosis

Puig I, Champeval D, De Santa Barbara P, Jaubert F, Lyonnet S, Larue L. J Clin Invest 2009;119(12):3586–96. PMID:19884655, doi:10.1172/JCI39929.

Attribute	Detail
Species	Mus musculus, NCBITaxon:10090
Model type	Conditional knockout: `Tyr:Cre/°; PTEN^F/F` (exon 5 floxed), homozygous = "HM"
Target lineage	Tyrosinase-expressing cells, which include enteric nervous system cells (plus melanoblasts and a subset of smooth-muscle precursors)
Phenotype	Enteric neuronal hyperplasia (3× cell count) and hypertrophy (2× cell size) = ganglioneuromatosis; chronic intestinal pseudo-obstruction with cecal dilation and empty colon; death P13–P20 with 100% penetrance
Pathway	"S6 and AKT phosphorylation levels were clearly higher in HM than in WT samples, this effect being particularly marked for AKT."
Rescue	AKT inhibitor API2 prevented the hyperplasia: TUJ1+ cell counts in treated HM embryos did not differ from WT, versus double WT in untreated HM
Human validation	PTEN expression significantly lower in 2/7 CIPO patients, with increased S6 phosphorylation
Resource	MGI, IMSR

Limitations: (i) the compartment is the enteric nervous system, so this is a model of intestinal ganglioneuromatosis, not of sympathetic-chain ganglioneuroma; (ii) the Cre driver is not ENS-specific (tyrosinase is also active in melanoblasts and cardiac/ductus smooth-muscle precursors), so the phenotype is not cell-autonomously attributed with certainty; (iii) perinatal lethality precludes any study of tumour natural history, growth rate, or ageing; (iv) human Cowden-syndrome tissue was not obtainable — "we were unable to obtain appropriate material for immunohistochemical analyses."

Why it still matters: it is the only rescue experiment in this entire disease. The API2 result establishes direction of causation from AKT activity to ganglion-cell expansion, which no human or zebrafish observation does.

15.3 Genetic model types available

Type	Available for GN?
Transgenic (overexpression)	Yes — zebrafish `dβh:myr-Akt2`
Conditional knockout	Yes — mouse `Tyr:Cre; Pten^F/F`
Knockout (constitutive)	Not for GN
Knock-in	Not for GN. `RET` M918T knock-in mice exist for MEN2B; `[their enteric ganglioneuromatosis phenotype was not characterised in this session — UNVERIFIED and a good follow-up]`
Humanised	None
Induced (drug/surgical/environmental)	None
Adjacent NF1/PTEN Schwann-cell models	`Dhh-Cre; Nf1^fl; Pten^fl` and `Pten`/EGFR Schwann-cell models produce neurofibroma and MPNST, not ganglioneuroma (PMID:22700876; PMC3539440) — informative for the transformation branch, not for GN itself

15.4 In vitro and cellular systems

There is no ganglioneuroma cell line. No ATCC/Cellosaurus entry, no DepMap model. GN is post-mitotic, which makes a line essentially impossible — a hard structural limit, and the reason all functional work uses neuroblastoma lines as surrogates.
Neuroblastoma + Schwann cell co-culture is the working in vitro model of the maturation mechanism: NTRK1-expressing NB cells, primary human repair Schwann cells, conditioned media, and recombinant EGFL8, with neurite outgrowth and proliferation as readouts (PMID:33712610; PMC4294349). Lines used across this literature include SH-SY5Y and SK-N-SH.
Retinoic-acid differentiation (CHEBI:15367 all-trans-retinoic acid; CHEBI:26536 retinoic acid) is the pharmacological proxy for maturation — ATRA causes a ~3-fold increase in TrkA expression and raises NTRK1/RET mRNA in NB lines (systematic ATRA analysis, PMC7053487). Important caveat for curation: ATRA-driven differentiation of a neuroblastoma line is not a model of ganglioneuroma — it is a model of neuroblastoma differentiation, which is only the same thing if Model A (§6.1) is correct. Grade any such evidence IN_VITRO with directness: INDIRECT.
Human nerve-injury tissue served as the repair-Schwann-cell comparator in Weiss 2021, which is an unusual and well-chosen control: it tests whether GN stroma resembles a physiological repair state rather than a neoplastic one. It does.

15.5 What the models collectively cannot do

Worth recording explicitly, because it defines the research frontier:

No model reproduces Schwannian stroma dominance — the disease's defining feature.
No model has the human initiating lesion, because that lesion is unknown.
No model of the sporadic human sympathetic-chain tumour exists in a mammal.
No model of malignant transformation (GN → MPNST).
No model permits long-term natural-history study — the mouse dies at P20 and the zebrafish is not followed beyond 29 wpf.

15.6 Resources

ZFIN (zebrafish), MGI / IMPC / KOMP / IMSR / EMMA / MMRRC (mouse), Alliance of Genome Resources, Cellosaurus and DepMap (both empty for GN).

Appendix A — Verified ontology term suggestions

Every CURIE below was resolved this session in cache/<prefix>/terms.csv, the EBI OLS4 API, or rest.genenames.org. Nothing here was written from memory. Items marked [UNVERIFIED] in the body are deliberately excluded from this table.

Disease: MONDO:0005033 ganglioneuroma · MONDO:0003326 intermixed schwannian stroma-rich ganglioneuroblastoma · MONDO:0003325 nodular ganglioneuroblastoma · MONDO:0005035 ganglioneuroblastoma · MONDO:0005072 neuroblastoma · MONDO:0006076 adrenal gland neuroblastoma

Phenotype (HP): HP:0003005 Ganglioneuroma · HP:0006747 Ganglioneuroblastoma · HP:0003006 Neuroblastoma · HP:0002666 Pheochromocytoma · HP:0002027 Abdominal pain · HP:0003418 Back pain · HP:0031500 Abdominal mass · HP:0003270 Abdominal distention · HP:0002013 Vomiting · HP:0002019 Constipation · HP:0002014 Diarrhea · HP:0002900 Hypokalemia · HP:0001508 Failure to thrive · HP:0000822 Hypertension · HP:0031284 Flushing · HP:0000975 Hyperhidrosis · HP:0001962 Palpitations · HP:0001337 Tremor · HP:0000739 Anxiety · HP:0002315 Headache · HP:0002277 Horner syndrome · HP:0002176 Spinal cord compression · HP:0002385 Paraparesis · HP:0010550 Paraplegia · HP:0002650 Scoliosis · HP:0002094 Dyspnea · HP:0012735 Cough · HP:0100749 Chest pain · HP:0000126 Hydronephrosis · HP:0000020 Urinary incontinence

Cell type (CL): CL:0011103 sympathetic neuron · CL:0008025 noradrenergic neuron · CL:0000107 autonomic neuron · CL:0002573 Schwann cell · CL:0000218 myelinating Schwann cell · CL:0002375 Schwann cell precursor · CL:0011012 neural crest cell · CL:0000333 migratory neural crest cell · CL:0002676 neural crest derived neuroblast · CL:0000166 chromaffin cell · CL:0000336 adrenal medulla chromaffin cell · CL:0007011 enteric neuron · CL:0002607 migratory enteric neural crest cell

Anatomy (UBERON): UBERON:0003693 retroperitoneal space · UBERON:0008822 posterior mediastinum · UBERON:0003728 mediastinum · UBERON:0002369 adrenal gland · UBERON:0001236 adrenal medulla · UBERON:0001806 sympathetic ganglion · UBERON:0001807 paravertebral ganglion · UBERON:0001805 autonomic ganglion · UBERON:0000974 neck · UBERON:0002240 spinal cord

Biological process (GO): GO:0048485 sympathetic nervous system development · GO:0007422 peripheral nervous system development · GO:0001755 neural crest cell migration · GO:0030182 neuron differentiation · GO:0045664 regulation of neuron differentiation · GO:0048667 cell morphogenesis involved in neuron differentiation · GO:0048663 neuron fate commitment · GO:0031175 neuron projection development · GO:0010975 regulation of neuron projection development · GO:0048011 neurotrophin TRK receptor signaling pathway · GO:0014037 Schwann cell differentiation · GO:0022011 myelination in peripheral nervous system · GO:0042552 myelination · GO:0043491 phosphatidylinositol 3-kinase/protein kinase B signal transduction · GO:0031929 TOR signaling · GO:0032008 positive regulation of TOR signaling · GO:0035860 glial cell-derived neurotrophic factor receptor signaling pathway · GO:0048384 retinoic acid receptor signaling pathway · GO:0042423 catecholamine biosynthetic process

Gene (HGNC, lowercase per repo convention): hgnc:391 AKT1 · hgnc:392 AKT2 · hgnc:393 AKT3 · hgnc:3942 MTOR · hgnc:9588 PTEN · hgnc:9967 RET · hgnc:7765 NF1 · hgnc:9143 PHOX2B · hgnc:427 ALK · hgnc:8031 NTRK1 · hgnc:7997 NRG1 · hgnc:7808 NGF · hgnc:11190 SOX10 · hgnc:4232 GDNF · hgnc:7559 MYCN · hgnc:11782 TH · hgnc:2689 DBH · hgnc:11730 TERT · hgnc:886 ATRX · hgnc:1076 BMPR1A · hgnc:12693 VIP (resolved at rest.genenames.org)

Chemical (CHEBI): CHEBI:33569 noradrenaline · CHEBI:33568 adrenaline · CHEBI:18243 dopamine · CHEBI:545959 homovanillic acid · CHEBI:20106 vanillylmandelic acid · CHEBI:9168 sirolimus · CHEBI:68478 everolimus · CHEBI:15367 all-trans-retinoic acid · CHEBI:26536 retinoic acid

Treatment (NCIT): NCIT:C15329 Surgical Procedure · NCIT:C154430 Definitive Surgical Resection · NCIT:C164212 Tumor Resection · NCIT:C131672 Gross Total Resection · NCIT:C175027 Complete Resection · NCIT:C15177 Adrenalectomy · NCIT:C15722 Patient Observation · NCIT:C15986 Pharmacotherapy · NCIT:C2201 mTOR Inhibitor · NCIT:C1212 Sirolimus · NCIT:C48387 Everolimus · NCIT:C15747 Supportive Care · NCIT:C15315 Rehabilitation · NCIT:C15240 Genetic Counseling · NCIT:C15313 Radiation Therapy · NCIT:C17204 Computed Tomography · NCIT:C16809 Magnetic Resonance Imaging

Taxon (NCBITaxon): NCBITaxon:9606 Homo sapiens · NCBITaxon:7955 Danio rerio · NCBITaxon:10090 Mus musculus · NCBITaxon:9615 Canis lupus familiaris · NCBITaxon:9913 Bos taurus · NCBITaxon:9925 Capra hircus · NCBITaxon:9823 Sus scrofa · NCBITaxon:9796 Equus caballus

Appendix B — Primary citations, with PMIDs and quotable abstract sentences

Each snippet below was read from the PubMed record or publisher page in this session and is an exact substring of that abstract. They are offered as candidate snippet: values; each still needs just fetch-reference PMID:<id> and just count-verified-snippets before commit.

PMID	Citation	Candidate exact quote
32728700	Tao T, et al. J Exp Med 2020;217(10):e20191871	"Zebrafish transgenic for constitutively activated myr-Akt2 in the sympathetic nervous system were found to develop ganglioneuroma without progression to neuroblastoma." · "Here, we found that an AKT-mTOR-S6 pathway was active in human ganglioneuroma but not neuroblastoma samples." · "Surgery is the only effective therapy for ganglioneuroma, which may be challenging due to the location of the tumor and involvement of surrounding structures."
33712610	Weiss T, Taschner-Mandl S, et al. Nat Commun 2021;12:1624	"Indeed, stromal SCs in ganglioneuromas and repair SCs share the expression of nerve repair-associated genes." · "Neuroblastoma cells, derived from aggressive tumors, respond to primary repair-related SCs and their secretome with increased neuronal differentiation and reduced proliferation."
19884655	Puig I, et al. J Clin Invest 2009;119:3586–96	"Intestinal ganglioneuromatosis is a benign proliferation of nerve ganglion cells, nerve fibers, and supporting cells of the enteric nervous system (ENS)..." · "S6 and AKT phosphorylation levels were clearly higher in HM than in WT samples, this effect being particularly marked for AKT."
39582110	Burnand KM, et al. Pediatr Blood Cancer 2025;72(2):e31445	"A total of 259 patients were identified (163 GN, 93 GNBi, median age 62 months)." · "In 45 cases (39%), surgical pathology was different from pathology at biopsy, and in 14 (12%) the pathology changed from GN/GNBi to neuroblastoma/GNB nodular." · "Watchful active observation can be a safe approach, with surgical resection reserved for symptomatic patients."
42537227	Texakalidis P, Gogoi R, Spinner RJ. J Neurosurg 2026;145(4):1223–9	"Most lesions (72%) were incidental findings." · "Short-term postoperative complications occurred in 43.1% of cases, most commonly neurological deficits (22.2%)." · "GNs demonstrate indolent behavior, low recurrence rates, and no observed malignant transformation in this large cohort." · "No patient in the observation group developed new symptoms, and 2 tumors exhibited minimal interval growth (0.08-0.17 cm/year)."
41306794	Li W, Xiao M, Miao C, et al. Front Surg 2025;12:1701114	"no recurrences, metastases, or disease-specific deaths occurred" · "While surgical resection remains the cornerstone of management, it is best undertaken at specialized, high-volume sarcoma centers to mitigate operative risks."
41858373	Sugawara M, Haruta M, Ohira M, et al. Oncol Lett 2026;31(5):156	"ALT was identified in 38 NB cases (38/255, 15%) and 6 GNB cases (6/48, 12.5%), but not in GN." · "High TERT expression was observed in 38% (64/169), 23% (7/31) and 14% (1/7) of NB, GNB and GN cases, respectively."
41561749	Ozcelik EE, et al. Front Oncol 2026;15:1632294	"no distant metastases or recurrences were observed during follow-up"
29369484	Alexander N, Sullivan K, Shaikh F, Irwin MS. Pediatr Blood Cancer 2018;65(5):e26964	"GN and GNB-I have a slow growth rate and resection can be associated with significant morbidity." · "Watch and wait approaches should be considered for some GN and GNB-I." · "There were post-operative complications in 15 of the 50 (30%) surgical patients."
10421272	Shimada H, et al. Cancer 1999;86:349–63 — "Terminology and morphologic criteria of neuroblastic tumors"	The four-category INPC definition (quote to be lifted from the fetched record)
10421273	Shimada H, et al. Cancer 1999;86:364–72 — "The International Neuroblastoma Pathology Classification (the Shimada system)"	3-year EFS 85% favourable vs 41% unfavourable histology
14601099	Peuchmaur M, et al. Cancer 2003;98:2274–81	"8-year event free survival rate: 86.1% vs. 32.2%; P = 0.0003; overall survival rate: 90.5% vs. 33.2%"
37746449	Cureus 2023;15:e43914	"Ganglioneuroma is a rare neurogenic tumor with a prevalence of one per million population" · "Ganglioneuromas constitute only 0.72%-1.6% of all primary retroperitoneal tumors"
40799243	Front Oncol 2025;15:1619030 — adrenal GN review	"AGN is rare in children under 10 years of age, with a higher incidence in adults than in children, and its incidence increases with age." · "Laparoscopic resection is the primary treatment for AGN."
33553609	Mol Cell Oncol 2020 — "Targeting ganglioneuromas with mTOR inhibitors"	Commentary on PMID:32728700
28640941	"PHOX2B reliably distinguishes neuroblastoma among small round blue cell tumours"	PHOX2B sensitivity/specificity in pNTs
—	Shimada H, Sano H, Hazard FK. Clin Pediatr Hematol Oncol 2020;27:73–86, doi:10.15264/cpho.2020.27.2.73	"composed only of completely mature ganglion cells covered with satellite cells" · "all neuritic processes produced by ganglion cells are immediately incorporated in the cytoplasm of Schwann cells, so that no naked neuritic processes are detected" · "all Ganglioneuromas were once Neuroblastomas in their early stage of tumor development"
—	Conces MR, Shibui Y, Shimada H. Diagnostic Pathology 2026;21:22, doi:10.1186/s13000-026-01758-y	Current INPC review; full text paywall-redirected in this session, fetch before curating from it

Appendix C — Explicit gaps and unverified items

Carried forward so nothing here is mistaken for an established fact.

ICD-11 code. Orphanet records 2A00.21; this was not verified against the WHO ICD-11 browser, and the morphology stem XH03L9 comes only from third-party aggregators.
MeSH D005729 taken from an aggregator listing, not NLM directly.
LOINC codes for VMA, HVA, metanephrines and VIP — none looked up. Do not type a LOINC label; use just loinc-seed-cache.
"~30% of adrenal GN have elevated catecholamines" — widely repeated secondary claim, primary source not traced.
"1 per million" prevalence and "60% under age 20" — both secondary/tertiary claims.
MYCN gain in GN — the one quantitative figure encountered (1.8%) has ambiguous attribution in the available abstract.
Turner syndrome association — Orphanet-level only, no primary citation located.
HPO term for virilization, UBERON term for presacral space, CL term for satellite cell, and GO cellular-component terms for Nissl substance/rough ER — all unresolved.
GEO accessions (GSE192906, GSE90711, GSE94035, GSE147635, GSE45547, GSE85047) — the GN-sample composition of each was not confirmed. Relevance triage is mandatory before curating any as a datasets: record.
PRIDE accession for the Weiss 2021 secretome proteomics — not resolved.
RET M918T knock-in mouse enteric phenotype — not characterised in this session; a likely fourth model organism.
Perioperative alpha-blockade protocol for secretory GN — not sourced.
Non-human orthologue NCBI Gene IDs — not resolved.
No GN-specific epigenomic, proteomic, metabolomic or lipidomic study exists. Searched; genuinely absent.
No GN-specific QoL instrument data exist. Searched; genuinely absent.
No clinical trial, past or present, in ganglioneuroma. Searched ClinicalTrials.gov; genuinely absent.

Sources

Reference Validation

Checked with linkml-reference-validator 0.4.0.

Outcome	Count
References checked	82
Resolved	82
Unresolved (possible confabulation)	0
Unverifiable	0
Quoted claims checked	1
Quoted claims found in source	1
Quoted claims not found in source	0
References weighed for topical relevance	82
On topic	29
Off topic	0

All extracted references resolved successfully.

Term Validation

Checked with linkml-term-validator 0.4.5, through the ols: adapter.

Outcome	Count
Terms checked	117
Resolved	116
Unresolved (possible confabulation)	0
Obsolete	0
Unverifiable	1
Terms whose name was checked	11
Terms named correctly	4
Terms named as a different term	2
Terms whose name is worth a second look	5

Terms the report names something else

These identifiers resolve, so nothing about them looks wrong, and the ontology calls them something unrelated to what the report calls them. That usually means the identifier is not the one the sentence needs:

MONDO:0005033 (5 mentions) - the report calls it "if available"; MONDO calls it ganglioneuroma
MONDO:0003325 (4 mentions) - the report calls it "composite", "Ganglioneuroblastoma, nodular — composite", "ganglioneuroblastoma, nodular"; MONDO calls it nodular ganglioneuroblastoma**

Terms whose name is worth a second look

The report's name for these is recognisably related to the term's own name without being one of them. A loose paraphrase reads the same way as a citation of the wrong sibling term - and so does a related synonym, which the ontology records precisely because it names something adjacent rather than the same thing - so these are listed rather than judged:

MONDO:0003326 (4 mentions) - the report calls it "Schwannian stroma-rich", "Ganglioneuroblastoma, intermixed — Schwannian stroma-rich", "ganglioneuroblastoma, intermixed"; MONDO calls it intermixed schwannian stroma-rich ganglioneuroblastoma**
CHEBI:9168 (2 mentions) - the report calls it "Sirolimus (rapamycin)"; CHEBI calls it sirolimus, and lists "sirolimusum" among its other names
NCBITaxon:9913 (2 mentions) - the report calls it "Cattle"; NCBITaxon calls it Bos taurus, and lists "domestic cattle" among its other names
NCBITaxon:9925 (2 mentions) - the report calls it "Goat (Boer)"; NCBITaxon calls it Capra hircus, and lists "goat" among its other names
NCBITaxon:9823 (2 mentions) - the report calls it "Pig (piglet)"; NCBITaxon calls it Sus scrofa, and lists "pig" among its other names

Terms named inconsistently

The report gives these identifiers more than one name of its own:

MONDO:0003326 - called "Schwannian stroma-rich", "Ganglioneuroblastoma, intermixed — **Schwannian stroma-rich", "ganglioneuroblastoma, intermixed"
MONDO:0003325 - called "composite", "Ganglioneuroblastoma, nodular — **composite", "ganglioneuroblastoma, nodular"

Prefixes with no resolver

Terms carrying these prefixes were not checked either way, because no configured ontology covers them. An unrecognised prefix may name an ontology this run could not reach as easily as one that does not exist, so nothing here is evidence of fabrication: ORPHA.

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Classifications

Mappings

Subtypes

Discussions and Knowledge Gaps

Pathophysiology

Histopathology

Pathograph

Phenotypes

Genetic Associations

Medical Actions

Diagnosis

Imaging Findings

Epidemiology

Clinical Burden

Differential Diagnoses

Related Datasets

Animal Models

Source YAML

References & Deep Research

Deep Research

1. Disease Information

1.1 Overview

1.2 Position in the INPC

1.3 Key identifiers

1.4 Synonyms

1.5 Evidence provenance

2. Etiology

2.1 Disease causal factors

2.2 Genetic risk factors

2.3 Environmental risk factors

2.4 Protective factors

2.5 Gene–environment interactions

3. Phenotypes

3.1 The dominant phenotype is absence of phenotype

3.2 Phenotype table with HPO bindings

3.3 Phenotype characteristics

3.4 Quality of life

4. Genetic / Molecular Information

4.1 Causal genes

4.2 Somatic molecular profile — what GN is not

4.3 The one positive somatic finding: an active AKT–mTOR–S6 axis

4.4 Transcriptional identity

4.5 Modifier genes

4.6 Epigenetics

4.7 Chromosomal abnormalities

5. Environmental Information

6. Mechanism / Pathophysiology

6.1 Ordered causal chain — Model A: terminal maturation of a neuroblastic tumour

6.2 Ordered causal chain — Model B: de novo AKT activation

6.3 Branch: enteric ganglioneuromatosis (a different anatomical compartment, the same pathway)

6.4 Where the two models leave the field

6.5 Mechanism checklist coverage

7. Anatomical Structures Affected

7.1 Organ level

7.2 Tissue and cell level

7.3 Subcellular level

7.4 Localization and laterality

8. Temporal Development

8.1 Onset

8.2 Progression

8.3 Patterns

9. Inheritance and Population

9.1 Epidemiology

9.2 Genetic etiology parameters

9.3 Population demographics

10. Diagnostics

10.1 Laboratory tests and biomarkers

10.2 Biomarkers for prognosis

10.3 Imaging

10.4 Functional tests and electrophysiology

10.5 Biopsy, histopathology and immunohistochemistry

10.6 The central diagnostic problem: biopsy understaging

10.7 Genetic testing

10.8 Omics-based diagnostics

10.9 Clinical criteria and screening

11. Outcome / Prognosis

11.1 Survival and mortality — essentially unaffected

11.2 Morbidity is iatrogenic, and it is substantial