Vulvar Adenocarcinoma

MONDO:0024336 Pathograph 23 Show in embeddings browser vulvar glandular neoplasm vulvar carcinoma adenocarcinoma

Vulvar adenocarcinoma is a rare, heterogeneous group of gland-forming vulvar epithelial malignancies. Its MONDO anchor includes intestinal-type, mammary-like, Bartholin gland, Paget-associated, sebaceous, eccrine, apocrine, Skene-gland, and clear-cell hidradenocarcinoma branches. These entities are not interchangeable: diagnosis, biomarkers, natural history, and treatment must be interpreted by subtype. The evidence-rich sections below primarily cover intestinal-type, mammary-like, Bartholin gland, and Paget-associated disease; the remaining ontology-recognized branches are retained explicitly as under-curated subtypes rather than silently excluded. Evidence is dominated by case reports, small series, and extrapolation from broader vulvar cancer guidance.

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1
Definitions
8
Pathophys.
4
Histopath.
6
Phenotypes
2
Gaps
23
Pathograph
6
Medical Actions
11
Subtypes
3
Differentials
3
Trials
1
Deep Research
📘

Definitions

1
Clinicopathologic definition
A primary vulvar malignant epithelial tumor with glandular differentiation, diagnosed by biopsy and histopathology, with subtype-specific immunohistochemistry used to distinguish primary vulvar origin from metastatic gastrointestinal, breast, urothelial, or other primaries.
CASE_DEFINITION Gynecologic oncology and surgical pathology definition
Show evidence (2 references)
PMID:38503056 SUPPORT Human Clinical
"Rarer histologies exist and include melanoma, extramammary Paget's disease, Bartholin gland adenocarcinoma, verrucous carcinoma, basal cell carcinoma, and sarcoma."
The NCCN guideline recognizes Bartholin gland adenocarcinoma and extramammary Paget disease among rare vulvar cancer histologies that need subtype-aware management.
PMID:36291953 SUPPORT Human Clinical
"To confirm vulvar origin, a thorough diagnostic, and radiological examination is required to rule out other primary malignancies."
This supports the need to exclude metastatic or non-vulvar primaries when diagnosing intestinal-type vulvar adenocarcinoma.
◆

Subtypes

11
histologic
Intestinal-type vulvar adenocarcinoma NCIT:C128166
A rare sporadic vulvar carcinoma with intestinal differentiation, commonly resembling mucinous colorectal carcinoma and requiring exclusion of a colorectal or other gastrointestinal primary.
Show evidence (1 reference)
PMID:36291953 SUPPORT Human Clinical
"Intestinal-type adenocarcinoma (VAIt) represents a sporadic variant of vulvar carcinoma."
This directly defines VAIt as a vulvar adenocarcinoma subtype.
Vulvar adenocarcinoma of mammary gland type NCIT:C128162
A very rare vulvar adenocarcinoma with mammary-like morphology or immunophenotype; diagnosis can require breast-carcinoma mimicry assessment and exclusion of metastatic breast carcinoma.
Show evidence (1 reference)
PMID:35672058 SUPPORT Human Clinical
"Adenocarcinoma of mammary gland type (AMGT) of the vulva is extremely rare and its aetiopathogenesis is not fully understood."
This case-report paper defines AMGT as an extremely rare vulvar adenocarcinoma entity.
Invasive or Paget-associated vulvar adenocarcinoma MONDO:0002207
Extramammary Paget disease of the vulva is an adenocarcinoma-related vulvar entity that can remain intraepithelial, become invasive, or be associated with an underlying adenocarcinoma, with HER2-positive metastatic examples reported.
Show evidence (1 reference)
PMID:38831459 SUPPORT Human Clinical
"Extramammary Paget's disease (EMPD) is a rare cancer that occurs within the epithelium of the skin, arising predominantly in areas with high apocrine gland concentration such as the vulva, scrotum, penis and perianal regions."
This supports EMPD as a rare apocrine-rich skin cancer involving the vulva and related to the glandular vulvar cancer differential.
anatomic and histologic
Bartholin gland adenocarcinoma MONDO:0003853
A primary adenocarcinoma arising in the Bartholin gland region. Establishing primary Bartholin origin requires compatible location and histology, preferably transition from normal gland to tumor, and exclusion of another primary site.
Show evidence (2 references)
PMID:29406447 SUPPORT Human Clinical
"There were 12 squamous cell carcinomas (SCCs), including 1 SCC with transitional-like morphology and 1 papillary SCC, and 1 adenocarcinoma."
This Bartholin gland carcinoma cohort included a Bartholin gland adenocarcinoma case, supporting the subtype.
PMID:41375020 SUPPORT Human Clinical
"Primary BGC is best defined by tumors arising in BG tissue, supported by (1) location compatible with the gland; (2) histologic transition from non-neoplastic BG duct/acini to tumor where present, and (3) exclusion of another primary site."
The review states the anatomic, histologic, and exclusion criteria for a primary Bartholin gland carcinoma.
ontology-recognized histologic subtype
Vulvar sebaceous carcinoma MONDO:0003636
An official direct MONDO descendant of vulvar adenocarcinoma. It is listed to preserve the disease-term scope; subtype-specific mechanism and outcome claims were not generalized from the four evidence-rich branches.
Vulvar eccrine adenocarcinoma MONDO:0003861
An official direct MONDO descendant of vulvar adenocarcinoma. The related vulvar eccrine porocarcinoma descendant is represented separately below.
Vulvar apocrine adenocarcinoma MONDO:0003881
An official direct MONDO descendant of vulvar adenocarcinoma, listed as an under-curated branch without importing cross-site apocrine-carcinoma claims.
Vulvar clear cell hidradenocarcinoma MONDO:0004283
An official direct MONDO descendant retained explicitly as an under-curated adnexal carcinoma branch.
ontology-recognized nested histologic subtype
Vulvar eccrine porocarcinoma MONDO:0004281
An official deeper MONDO descendant through the vulvar eccrine adenocarcinoma branch, retained explicitly so the umbrella scope is not mistaken for complete mechanistic curation of this rare entity.
ontology-recognized anatomic subtype
Adenocarcinoma of Skene gland origin MONDO:0004173
An official direct MONDO descendant representing primary adenocarcinoma of Skene-gland origin; disease-specific evidence remains a curation gap.
ontology-recognized nested anatomic and histologic subtype
Bartholin gland adenoid cystic carcinoma MONDO:0003187
An official deeper MONDO descendant through the Bartholin gland branch. It is not conflated with conventional Bartholin gland adenocarcinoma or with adenoid cystic carcinoma at non-vulvar sites.
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Discussions and Knowledge Gaps

2
What are the subtype-specific incidence, molecular drivers, natural history, and comparative treatment outcomes across the officially grouped primary vulvar adenocarcinoma descendants?
KNOWLEDGE GAP OPEN vulvar_adeno_subtype_evidence_gap
Attached to
pathophysiology#Primary Vulvar Glandular Malignancy pathophysiology#Regional Nodal Spread or Late Recurrence
The MONDO umbrella also groups rare sebaceous, eccrine (including porocarcinoma), apocrine, Skene-gland, clear-cell hidradenocarcinoma, and Bartholin adenoid-cystic branches. Those descendants are represented here so that scope is explicit, but remain under-curated because disease-specific evidence was not established in this review. A multi-institutional registry with centralized pathology review and subtype-resolved outcomes is needed before broad vulvar-cancer treatment evidence can be treated as adenocarcinoma-specific.
Show evidence (1 reference)
PMID:41463238 SUPPORT Human Clinical
"Given the extremely low incidence of VAIt, individual case reports and small case series represent the only source of information about this condition in the literature, which inherently limits the power of definitive conclusions and uniform treatment protocols."
The current systematic review explicitly identifies the evidence-design limitation for one major subtype.
How often are HER2 overexpression and FGFR1/TGF-beta pathway alterations present and therapeutically predictive in vulvar, rather than non-vulvar, EMPD?
KNOWLEDGE GAP OPEN vulvar_empd_cross_site_molecular_gap
Attached to
pathophysiology#HER2-Positive EMPD Signaling (Cross-Site Case Evidence)
The available WGS and treatment-response evidence in this entry comes from one metastatic scrotal EMPD case. Vulvar-specific cohorts with standardized IHC, copy-number, sequencing, treatment, and outcome data are needed before estimating prevalence or predictive value.
Show evidence (1 reference)
PMID:38831459 SUPPORT Human Clinical
"Immunohistochemical staining on the scrotal wall tumor and bone marrow metastasis demonstrated HER2 overexpression."
The specimen site makes the cross-site generalizability gap explicit.
⚙

Pathophysiology

8
Primary Vulvar Glandular Malignancy
This umbrella node represents a primary malignant glandular epithelial tumor in the vulva. It does not assert one shared molecular initiating lesion across the histologically distinct intestinal-type, mammary-like, Bartholin gland, and Paget-associated branches.
vulvar glandular epithelial cell CL:0000066 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves vulvar glandular epithelial cell, annotated with epithelial cell (CL:0000066). CL:0000066 is a cell type from the Cell Ontology. vulvar secretory epithelial cell CL:0000151 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves vulvar secretory epithelial cell, annotated with secretory cell (CL:0000151). CL:0000151 is a cell type from the Cell Ontology.
vulva UBERON:0000997 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in vulva, annotated with mammalian vulva (UBERON:0000997). UBERON:0000997 is an anatomical location from the Uberon multi-species anatomy ontology.
Downstream
Vulvar Lump or Mass A primary vulvar tumor can present as a clinically noticed lump or mass.
Vulvar Ulcer A primary vulvar malignancy may present with an ulcerated lesion.
Vulvar Pruritus Vulvar malignancy can produce local pruritus.
Vulvar Pain or Burning Local tumor and tissue involvement can produce pain or burning.
Show evidence (1 reference)
PMID:38503056 SUPPORT Human Clinical
"Rarer histologies exist and include melanoma, extramammary Paget's disease, Bartholin gland adenocarcinoma, verrucous carcinoma, basal cell carcinoma, and sarcoma."
NCCN recognizes Bartholin gland adenocarcinoma and extramammary Paget disease as rare vulvar cancer histologies.
Intestinal-Type Glandular Differentiation
Intestinal-type vulvar adenocarcinoma has villo-glandular, mucin-producing morphology with goblet or Paneth cells and an intestinal immunophenotype. Cloacal-remnant origin is proposed but is not established.
intestinalized vulvar glandular epithelial cell CL:0000066 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves intestinalized vulvar glandular epithelial cell, annotated with epithelial cell (CL:0000066). CL:0000066 is a cell type from the Cell Ontology.
vulva UBERON:0000997 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in vulva, annotated with mammalian vulva (UBERON:0000997). UBERON:0000997 is an anatomical location from the Uberon multi-species anatomy ontology.
Downstream
Regional Nodal Spread or Late Recurrence Intestinal-type tumors can involve regional nodes or recur after treatment.
Show evidence (2 references)
PMID:41463238 SUPPORT Human Clinical
"VAIt is defined as a mucinous, villo-glandular adenocarcinoma of the vulva showing intestinal differentiation."
The review states the contemporary morphologic definition of the subtype.
PMID:36291953 SUPPORT Human Clinical
"It appears frequently localized to epithelial glands in the vulvar region, and it probably derives from cloacal remnants persisting in the adult."
This supports a proposed, rather than proven, cloacal-remnant origin.
Mammary-Like Glandular Differentiation
Vulvar adenocarcinoma of mammary gland type can reproduce ductal, cribriform, papillary, or infiltrative breast-carcinoma-like architecture. Its immunophenotype is heterogeneous rather than uniformly hormone-receptor positive.
mammary-like vulvar glandular epithelial cell CL:0000066 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves mammary-like vulvar glandular epithelial cell, annotated with epithelial cell (CL:0000066). CL:0000066 is a cell type from the Cell Ontology.
vulva UBERON:0000997 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in vulva, annotated with mammalian vulva (UBERON:0000997). UBERON:0000997 is an anatomical location from the Uberon multi-species anatomy ontology.
Downstream
Regional Nodal Spread or Late Recurrence Mammary-like vulvar adenocarcinoma can spread to inguinal nodes.
Show evidence (2 references)
PMID:35672058 SUPPORT Human Clinical
"The histological types in the vulva appear to be similar to those described for the breast, such as ductal lobular, mixed and mucinous carcinomas."
The case report describes the breast-like morphologic spectrum.
PMID:35672058 SUPPORT Human Clinical
"Although ER and PR expression is considered a diagnostic criterion for these neoplasms, here we report a case of an AMGT with a triple-negative profile, mimicking its breast counterpart."
The two-case report establishes clinically important immunophenotypic heterogeneity.
Bartholin Gland Adenocarcinoma
Bartholin gland adenocarcinomas commonly produce mucin and can show papillary, mucoepidermoid, or mucinous architecture with deep perineal and perineural infiltration.
Bartholin gland UBERON:0000460 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in Bartholin gland, annotated with major vestibular gland (UBERON:0000460). UBERON:0000460 is an anatomical location from the Uberon multi-species anatomy ontology.
Downstream
Vulvar Lump or Mass Bartholin gland carcinoma commonly presents as a painful mass.
Regional Nodal Spread or Late Recurrence Bartholin gland adenocarcinoma can recur and be fatal.
Show evidence (1 reference)
PMID:41375020 SUPPORT Human Clinical
"Most are mucin-producing, with patterns ranging from papillary to mucoepidermoid or mucinous."
The review describes the principal Bartholin adenocarcinoma morphologies.
Vulvar Paget Cell Disease
Vulval extramammary Paget disease consists of Paget cells within the epithelium and can remain intraepithelial, invade stroma, or extend to the cervix and vagina. It often produces an erythematous, eczematous, pruritic, or burning lesion.
vulva UBERON:0000997 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in vulva, annotated with mammalian vulva (UBERON:0000997). UBERON:0000997 is an anatomical location from the Uberon multi-species anatomy ontology.
Downstream
Vulvar Pruritus Vulvar Paget disease can cause local pruritus.
Erythematous Eczematoid Vulvar Plaque Intraepithelial vulvar Paget cell disease produces the characteristic erythematous, eczematoid plaque presentation.
Vulvar Pain or Burning Vulvar Paget disease can cause burning discomfort.
Cervicovaginal Paget Cell Extension Long-standing vulvar Paget disease can extend to the cervix or vagina.
Show evidence (2 references)
PMID:36766569 SUPPORT Human Clinical
"Cervical and/or vaginal biopsies were always performed for histopathological diagnosis by identification of Paget cells in the epithelium or stroma."
The cohort defines tissue involvement by biopsy identification of Paget cells.
clinicaltrials:NCT03713203 SUPPORT Human Clinical
"The disease is revealed by erythematous, eczematous, pruritus and vulvar burns."
The trial record directly describes the characteristic vulvar Paget lesion and symptoms.
Cervicovaginal Paget Cell Extension
Cervical or vaginal extension is a late complication of vulvar EMPD that may be clinically silent and is often first detected by abnormal glandular cytology before biopsy confirmation.
Downstream
Abnormal Glandular Cytology in Paget Spread Cervicovaginal Paget cells can be detected as abnormal glandular cytology.
Show evidence (1 reference)
PMID:36766569 SUPPORT Human Clinical
"Overall nine patients developed CV involvement from EMPD, with a cumulative incidence of 2.5% (95% CI: 0.5-8.0%) at 5 years, 6.5% (95% CI: 1.9-15.1%) at 10 years and 14.0% (95% CI: 4.8-27.8%) at 15 years, respectively."
The 94-patient cohort quantifies increasing cumulative incidence of cervicovaginal extension over long follow-up.
HER2-Positive EMPD Signaling (Cross-Site Case Evidence)
A single metastatic scrotal EMPD case showed HER2 protein overexpression and WGS pathway enrichment involving FGFR1 and TGF-beta signaling. This is a hypothesis-generating therapeutic axis for vulvar Paget-associated disease, not established vulvar-specific molecular prevalence or causality.
ERBB2 hgnc:3430 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves ERBB2 (hgnc:3430). hgnc:3430 is a gene from the HUGO Gene Nomenclature Committee. FGFR1 hgnc:3688 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves FGFR1 (hgnc:3688). hgnc:3688 is a gene from the HUGO Gene Nomenclature Committee.
cell surface receptor protein tyrosine kinase signaling pathway GO:0007169 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased cell surface receptor protein tyrosine kinase signaling pathway (GO:0007169). GO:0007169 is a biological process from the Gene Ontology. ↑ INCREASED
Show evidence (2 references)
PMID:38831459 SUPPORT Human Clinical
"Immunohistochemical staining on the scrotal wall tumor and bone marrow metastasis demonstrated HER2 overexpression."
The evidence is direct for a metastatic scrotal EMPD case but only extrapolative for vulvar EMPD.
PMID:38831459 SUPPORT Computational
"Enrichment in pathways associated with transforming growth factor-beta (TGFβ) (FDR = 0.0376, Enrichment Ratio = 8.12) and fibroblast growth factor receptor (FGFR1) signaling (FDR = 0.0082, Enrichment Ratio = 2.3) was detected."
Computational enrichment in one cross-site EMPD case does not establish a recurrent vulvar mechanism.
Regional Nodal Spread or Late Recurrence
Regional nodal metastasis and delayed recurrence are documented across several rare glandular subtypes, but frequency and timing are subtype-specific and imprecisely estimated from small case collections.
Show evidence (1 reference)
PMID:41463238 SUPPORT Human Clinical
"VAIt can follow an unpredictable clinical course, with potential for late recurrence and metastasis."
The systematic review directly supports delayed recurrence and metastatic potential for intestinal-type disease.
✶

Histopathology

4
Villo-Glandular Mucinous Colorectal-Like Morphology
Intestinal-type vulvar adenocarcinoma forms villo-glandular structures with goblet or Paneth cells and intracytoplasmic mucin, closely resembling mucinous colorectal adenocarcinoma.
Show evidence (1 reference)
PMID:41463238 SUPPORT Human Clinical
"VAIt is defined as a mucinous, villo-glandular adenocarcinoma of the vulva showing intestinal differentiation. Macroscopically, VAIt may exhibit a polypoid appearance, while histologically, it displays features akin to mucinous colorectal adenocarcinomas, including the presence of goblet cells..."
The systematic review directly describes the defining microscopic architecture and cell types.
Heterogeneous Mammary-Like Ductal Architecture
Reported tumors range from expansile cribriform and papillary architecture to infiltrative ductular, glandular, nest, and cord patterns, illustrating substantial within-subtype morphologic heterogeneity.
Show evidence (2 references)
PMID:35672058 SUPPORT Human Clinical
"Tumour mass presented a nodular configuration, with expansile growth, with a cribiform and papillary architecture, occasionally with solid areas."
This is the microscopic pattern of the first mammary-like case.
PMID:35672058 SUPPORT Human Clinical
"Tumour mass presented an infiltrative growth, being arranged in a ductular and glandular architecture or in small nests and cords."
The second case demonstrates a distinct infiltrative ductal pattern.
Mucin-Producing Bartholin Adenocarcinoma
Bartholin gland adenocarcinoma is commonly mucin-producing and can show papillary, mucoepidermoid, or mucinous architecture with intracytoplasmic mucin and deep perineal infiltration.
Show evidence (1 reference)
PMID:41375020 SUPPORT Human Clinical
"Tumor cells often contain intracytoplasmic mucin and may show papillary architecture and CEA positivity. These tumors tend to infiltrate deep perineal tissues along nerves, with frequent ischioanal fossa involvement."
The review directly describes the morphology and infiltrative pattern of Bartholin adenocarcinoma.
Paget Cells in Epithelium or Stroma
Cervical or vaginal extension from vulvar EMPD is confirmed by identifying Paget cells within epithelium or stroma on biopsy.
Show evidence (1 reference)
PMID:36766569 SUPPORT Human Clinical
"Cervical and/or vaginal biopsies were always performed for histopathological diagnosis by identification of Paget cells in the epithelium or stroma."
This directly states the biopsy finding used to diagnose extension.
⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Vulvar Adenocarcinoma Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
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Phenotypes

6
Integument 2
Vulvar Ulcer Skin ulcer HP:0200042 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is vulvar ulcer, annotated with Skin ulcer (HP:0200042). HP:0200042 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:34669204 SUPPORT Human Clinical
"While vulvar cancer may be asymptomatic, most women present with vulvar pruritus or pain, or have noticed a lump or ulcer."
This supports ulcer as a presenting sign for vulvar cancer overall; the evidence is partial for adenocarcinoma-specific presentation.
Erythematous Eczematoid Vulvar Plaque Erythematous plaque HP:0025474 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Erythematous eczematoid vulvar plaque, annotated with Erythematous plaque (HP:0025474). HP:0025474 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
clinicaltrials:NCT03713203 SUPPORT Human Clinical
"The disease is revealed by erythematous, eczematous, pruritus and vulvar burns."
The vulvar Paget trial record directly describes the erythematous and eczematous presentation represented by this phenotype.
Constitutional 1
Vulvar Pain or Burning HP:0012531 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Vulvar pain, annotated with Pain (HP:0012531). HP:0012531 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:34669204 SUPPORT Human Clinical
"While vulvar cancer may be asymptomatic, most women present with vulvar pruritus or pain, or have noticed a lump or ulcer."
This supports pain as a vulvar cancer symptom, with partial support for the adenocarcinoma subtype.
clinicaltrials:NCT03713203 SUPPORT Human Clinical
"The disease is revealed by erythematous, eczematous, pruritus and vulvar burns."
The vulvar Paget trial record directly identifies burning as part of the presentation.
Other 3
Vulvar Lump or Mass Vulvar neoplasm HP:0030416 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is vulvar neoplasm (HP:0030416). HP:0030416 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:34669204 SUPPORT Human Clinical
"While vulvar cancer may be asymptomatic, most women present with vulvar pruritus or pain, or have noticed a lump or ulcer."
This supports lump as a presenting sign for vulvar cancer overall; the evidence is treated as partial for the rarer adenocarcinoma subtype.
PMID:35672058 SUPPORT Human Clinical
"A female patient in her 60s, multiparous, Eastern Cooperative Oncology Group-performance status (ECOG-PS) grade 0, without relevant personal or family history of cancer disease, presented with a vulvar mass on the left labium minus that measured approximately 20 mm."
A mammary-like vulvar adenocarcinoma case presented directly as a vulvar mass.
Vulvar Pruritus Pruritus vulvae HP:0032004 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Pruritus vulvae (HP:0032004). HP:0032004 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:34669204 SUPPORT Human Clinical
"While vulvar cancer may be asymptomatic, most women present with vulvar pruritus or pain, or have noticed a lump or ulcer."
This supports pruritus as a vulvar cancer symptom, with partial support for rare adenocarcinoma subtypes.
clinicaltrials:NCT03713203 SUPPORT Human Clinical
"The disease is revealed by erythematous, eczematous, pruritus and vulvar burns."
The vulvar Paget trial record directly identifies pruritus as part of the presentation.
Abnormal Glandular Cytology in Paget Spread
Show evidence (1 reference)
PMID:36766569 SUPPORT Human Clinical
"All cases except one were firstly detected by abnormal glandular cytology. None reported vaginal bleeding or other suspicious symptoms."
This supports abnormal glandular cytology as a clinically relevant finding in cervico-vaginal involvement from vulvar EMPD.
💊

Medical Actions

6
Surgical Local Excision or Vulvectomy
Category: Therapeutic Action: surgical procedureNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is surgical procedure (NCIT:C15329). NCIT:C15329 is a clinical intervention from the NCI Thesaurus. Ontology label: Surgical Procedure NCIT:C15329
Platform: Surgery
Surgery is the principal local-control strategy for primary vulvar adenocarcinoma subtypes when technically feasible, with margin goals and nodal evaluation tailored to histology, size, and stage.
Mechanism Target:
INHIBITS Primary Vulvar Glandular Malignancy — Surgical removal aims to eliminate the local malignant glandular tumor.
Show evidence (1 reference)
PMID:36291953 SUPPORT Human Clinical
"The gold standard of treatment for VAIt is surgery, with local excision with tumor-free margins."
The subtype review directly links excision with tumor-free margins to local tumor control.
Show evidence (2 references)
PMID:36291953 SUPPORT Human Clinical
"The gold standard of treatment for VAIt is surgery, with local excision with tumor-free margins."
This directly supports surgery with tumor-free margins for intestinal-type vulvar adenocarcinoma.
PMID:35672058 SUPPORT Human Clinical
"Surgical procedures include radical vulvectomy or radical local excision."
This supports radical vulvectomy or local excision for AMGT cases.
Adjuvant or Advanced-Disease Chemotherapy
Category: Therapeutic Action: chemotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is chemotherapy (NCIT:C15632). NCIT:C15632 is a clinical intervention from the NCI Thesaurus. Ontology label: Chemotherapy NCIT:C15632
Chemotherapy is used selectively for advanced, recurrent, or histology-specific vulvar cancers, with many adenocarcinoma decisions extrapolated from limited case literature.
Mechanism Target:
INHIBITS Regional Nodal Spread or Late Recurrence — Cytotoxic approaches aim to reduce residual or advanced malignant tumor burden.
Show evidence (1 reference)
PMID:36291953 SUPPORT Human Clinical
"a good response to adjuvant chemotherapy treatments has been described in both advanced and recurrent diseases."
The review supplies limited reported response evidence in advanced or recurrent intestinal-type disease.
Show evidence (1 reference)
PMID:36291953 SUPPORT Human Clinical
"On the other hand, the role of neoadjuvant therapy is still in doubt, but a good response to adjuvant chemotherapy treatments has been described in both advanced and recurrent diseases."
This supports a limited, subtype-specific role for adjuvant chemotherapy in advanced or recurrent VAIt while preserving uncertainty.
Radiation or Concurrent Chemoradiation
Category: Therapeutic Action: radiation therapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is radiation therapy (NCIT:C15313). NCIT:C15313 is a clinical intervention from the NCI Thesaurus. Ontology label: Radiation Therapy NCIT:C15313
Platform: Radiotherapy
Radiation, including concurrent chemoradiation, is an option for selected advanced vulvar cancers. Applicability to adenocarcinoma remains indirect because the supporting evidence is histology-mixed and dominated by squamous carcinoma.
Mechanism Target:
INHIBITS Regional Nodal Spread or Late Recurrence — Local or regional radiation is intended to reduce advanced or residual malignant tumor burden, alone or with concurrent chemotherapy.
Show evidence (1 reference)
PMID:34669204 SUPPORT Human Clinical
"Treatment is predominantly surgical, particularly for squamous cell carcinoma, although concurrent chemoradiation is an effective alternative, particularly for advanced tumors."
The review supports a radiation-containing regimen for advanced vulvar cancer, but only indirectly for adenocarcinoma.
Show evidence (1 reference)
PMID:34669204 SUPPORT Human Clinical
"Treatment is predominantly surgical, particularly for squamous cell carcinoma, although concurrent chemoradiation is an effective alternative, particularly for advanced tumors."
This supports concurrent chemoradiation in advanced vulvar cancer generally; it is partial for adenocarcinoma because the evidence base is histology-mixed and dominated by squamous carcinoma.
HER2-Directed Pharmacotherapy
Category: Therapeutic Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Agent: trastuzumab NCIT:C1647 NCI Thesaurus (NCIT) Relation: this treatment uses this therapeutic agent This treatment uses trastuzumab (NCIT:C1647). NCIT:C1647 is a therapeutic agent from the NCI Thesaurus.
Platform: Monoclonal antibody
HER2-directed systemic therapy may be relevant in selected HER2-positive metastatic EMPD or Paget-associated adenocarcinoma settings.
Mechanism Target:
INHIBITS HER2-Positive EMPD Signaling (Cross-Site Case Evidence) — HER2-directed treatment is intended to counter HER2-positive signaling in selected metastatic EMPD.
Show evidence (1 reference)
PMID:38831459 SUPPORT Human Clinical
"observed response to HER2-directed therapy combined with other agents in a comprehensive treatment regimen."
A response was observed only within a multi-agent regimen in one cross-site EMPD case, so the target link remains partial.
Show evidence (1 reference)
PMID:38831459 SUPPORT Human Clinical
"The presence of alternative signalling pathways and genetic variants suggests potential interactions with HER2 signalling, which possibly contributed to the HER2 overexpression and observed response to HER2-directed therapy combined with other agents in a comprehensive treatment regimen."
This supports HER2-directed treatment response in a single metastatic EMPD case, so the treatment evidence is intentionally marked partial.
Topical Imiquimod for Vulvar Paget Disease
Category: Therapeutic Action: topical pharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is topical pharmacotherapy, annotated with Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. Ontology label: Pharmacotherapy NCIT:C15986
Agent: imiquimod CHEBI:36704 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses imiquimod (CHEBI:36704). CHEBI:36704 is a therapeutic agent from Chemical Entities of Biological Interest.
Platform: Small molecule
Topical imiquimod is an investigational or non-surgical pharmacotherapy option studied in non-invasive or recurrent vulvar Paget disease. Its relevance to invasive Paget-associated vulvar adenocarcinoma is indirect, so the treatment evidence is treated as partial.
Mechanism Target:
MODULATES Vulvar Paget Cell Disease — Topical imiquimod is intended to stimulate a local antitumor immune response in non-invasive or recurrent vulvar Paget disease.
Show evidence (1 reference)
clinicaltrials:NCT00504023 SUPPORT Human Clinical
"Biological therapies, such as imiquimod, may stimulate the immune system in different ways and stop tumor cells from growing."
The trial rationale supports immune modulation but does not establish a completed efficacy comparison.
Show evidence (2 references)
clinicaltrials:NCT02385188 SUPPORT Human Clinical
"The purpose of this study is to evaluate the efficacy, safety and immunological response of topical 5% imiquimod cream for non-invasive vulvar Paget's disease."
This supports topical imiquimod as a studied treatment for non-invasive vulvar Paget disease, with partial applicability to the broader adenocarcinoma page.
clinicaltrials:NCT00504023 SUPPORT Human Clinical
"PURPOSE: This clinical trial is studying how well topical imiquimod works in treating patients with recurrent Paget's disease of the vulva."
This supports topical imiquimod as a trialed treatment for recurrent vulvar Paget disease.
Photodynamic Therapy for Vulvar Paget Disease
Category: Therapeutic Action: photodynamic therapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is photodynamic therapy (NCIT:C15300). NCIT:C15300 is a clinical intervention from the NCI Thesaurus. Ontology label: Photodynamic Therapy NCIT:C15300
Photodynamic therapy is being studied as a local treatment alternative for vulvar Paget disease. It is annotated as partial because the trial evidence is Paget-specific and not direct evidence for all invasive vulvar adenocarcinoma subtypes.
Mechanism Target:
MODULATES Vulvar Paget Cell Disease — The local photodynamic device treatment is directed at vulvar Paget lesions; efficacy remains under prospective evaluation.
Show evidence (1 reference)
clinicaltrials:NCT03713203 SUPPORT Human Clinical
"The objective of this study is to assess the efficacy and evaluate the safety of the new PDT device "PAGETEX" for the treatment of vulvar Paget's disease."
The trial directly links the local PDT intervention to vulvar Paget disease but does not yet establish clinical efficacy.
Show evidence (2 references)
clinicaltrials:NCT03713203 SUPPORT Human Clinical
"Photodynamic therapy (PDT) is already used in some dermatological pathologies and could therefore be an alternative treatment."
This supports photodynamic therapy as an investigational alternative for vulvar Paget disease.
clinicaltrials:NCT03713203 SUPPORT Human Clinical
"The objective of this study is to assess the efficacy and evaluate the safety of the new PDT device "PAGETEX" for the treatment of vulvar Paget's disease."
This clinical trial record directly links PDT evaluation to vulvar Paget disease.
🌍

Environmental Factors

1
Broader Vulvar Cancer Risk Context (Not Subtype-Specific)
Increasing age, HPV infection, smoking, inflammatory vulvar disease, and immunodeficiency are recognized vulvar cancer risk factors. Their adenocarcinoma-subtype specificity is limited, so this is annotated as contextual rather than definitive adenocarcinoma causation.
Show evidence (1 reference)
PMID:38503056 SUPPORT Human Clinical
"Known risk factors for vulvar cancer include increasing age, infection with human papillomavirus, cigarette smoking, inflammatory conditions affecting the vulva, and immunodeficiency."
This supports the general vulvar cancer risk context, but the evidence is partial for vulvar adenocarcinoma because many data are dominated by squamous carcinoma.
🔬

Biochemical Markers

3
Intestinal-Type CK20, CDX2, CK7, and p16 Immunophenotype (CK20 and CDX2 positive; CK7 and p16 variable)
Pathograph Readouts
Readout Of Intestinal-Type Glandular Differentiation Present Absent Diagnostic
CK20 and CDX2 positivity with variable CK7/p16 is a diagnostic readout of intestinal differentiation, not a site-of-origin test by itself.
Show evidence (1 reference)
PMID:41463238 SUPPORT Human Clinical
"Immunohistochemistry consistently showed CK20 and CDX2 positivity, with variable CK7 and p16 expression."
The systematic review directly maps this panel to intestinal-type differentiation.
Show evidence (1 reference)
PMID:41463238 SUPPORT Human Clinical
"Immunohistochemistry consistently showed CK20 and CDX2 positivity, with variable CK7 and p16 expression."
The 40-case systematic review summarizes the recurrent intestinal-type immunophenotype.
Mammary-Like Hormone-Receptor and Lineage-Marker Profiles (Subtype-variable)
Pathograph Readouts
Readout Of Mammary-Like Glandular Differentiation Threshold Dependent Diagnostic
Morphology and a panel of breast-lineage and hormone-receptor markers, interpreted together, support mammary-like differentiation.
Show evidence (1 reference)
PMID:35672058 SUPPORT Human Clinical
"The triple-negative immunohistochemical (IHC) profile of one of the cases represented a diagnostic challenge."
The report directly shows that IHC profile interpretation is part of mammary-like subtype diagnosis and can be heterogeneous.
Show evidence (2 references)
PMID:35672058 SUPPORT Human Clinical
"The immunohistochemistry (IHC) study demonstrated positivity for oestrogen receptors (ER) (90%–100%), cytokeratin (CK) 7, CAM5.2 and GATA3."
This is the ER-high breast-lineage profile of one mammary-like case.
PMID:35672058 SUPPORT Human Clinical
"IHC study demonstrated positivity for CK7, SOX10, p53 and E-cadherin. The tumour was negative for ER, PR, HER-2, GCDDP-15, GATA-3, TTF1, p63, PAX-8 and CK20."
The second case demonstrates a distinct triple-negative/SOX10-positive profile.
HER2 Protein Overexpression in Metastatic EMPD (Positive in a reported metastatic scrotal EMPD case)
Pathograph Readouts
Readout Of HER2-Positive EMPD Signaling (Cross-Site Case Evidence) Present Absent Diagnostic
HER2 immunohistochemistry identifies the reported HER2-positive EMPD state, with only indirect applicability to vulvar disease.
Show evidence (1 reference)
PMID:38831459 SUPPORT Human Clinical
"Immunohistochemical staining on the scrotal wall tumor and bone marrow metastasis demonstrated HER2 overexpression."
HER2 IHC directly reports the molecular state in one scrotal EMPD case; vulvar applicability remains extrapolative.
Show evidence (1 reference)
PMID:38831459 SUPPORT Human Clinical
"Interestingly, ERBB2 gene did not exhibit high copy number gain (log2FC = 0.4) although 90% of tumor cells stained HER2-positive."
The single cross-site case separates protein overexpression from ERBB2 copy-number gain and warrants partial support for vulvar EMPD.
🔬

Diagnosis

5
Biopsy of Suspicious Vulvar Lesion
Suspicious vulvar lesions require biopsy to establish invasion and histologic subtype. Vulvoscopy and imaging can help target biopsy and plan preoperative staging.
Results: Histopathologic confirmation of invasive glandular vulvar malignancy.
Show evidence (3 references)
PMID:34669204 SUPPORT Human Clinical
"Therefore, any suspicious vulvar lesion should be biopsied to exclude invasion."
This directly supports biopsy for suspicious vulvar lesions.
PMID:38791925 SUPPORT Human Clinical
"Diagnosis relies on biopsy during vulvoscopy, plus imaging such as ultrasonography (USG), magnetic resonance imaging (MRI) and positron emission tomography (PET)."
This supports biopsy, vulvoscopy, and imaging in vulvar carcinoma diagnosis; it is partial for adenocarcinoma because the review focuses on squamous carcinoma.
PMID:41375020 SUPPORT Human Clinical
"Because diagnostic delay is common and incidence increases with age, biopsy should be performed in patients with a persistent or progressive BG mass, solid masses or solid components within a presumed “cystic lesion,” or lesions invading surrounding tissues, and should be generously considered..."
The Bartholin review specifies high-risk mass features that warrant tissue diagnosis.
Subtype Immunohistochemistry and Primary-Site Exclusion
Intestinal-type and mammary-like vulvar adenocarcinomas require immunohistochemistry and clinicoradiologic exclusion of metastatic gastrointestinal or breast primaries.
Results: Primary vulvar origin and histologic subtype assignment.
Show evidence (4 references)
PMID:36291953 SUPPORT Human Clinical
"Therefore, immunohistochemical workup, with different tumor markers including CK20, CDX2, and CK7 staining, is needed."
This supports CK20, CDX2, and CK7 immunohistochemistry for VAIt.
PMID:41463238 SUPPORT Human Clinical
"The diagnosis must be substantiated by the exclusion of other primary tumors, in particular primary gastrointestinal neoplasias."
The current systematic review directly requires exclusion of a gastrointestinal primary before assigning primary vulvar origin.
PMID:35672058 SUPPORT Human Clinical
"Histopathological patterns are considered essential for diagnosis."
This supports histopathology for AMGT diagnosis.
+ 1 more reference
Paget Disease Cytology and Biopsy Follow-Up
For long-standing vulvar EMPD, liquid-based cytology with immunocytochemistry can detect clinically silent cervico-vaginal spread, with biopsy confirmation when abnormal cytology is found.
Results: Detection of cervico-vaginal EMPD involvement.
Show evidence (2 references)
PMID:36766569 SUPPORT Human Clinical
"Cervical and/or vaginal biopsies were always performed for histopathological diagnosis by identification of Paget cells in the epithelium or stroma."
This supports biopsy confirmation of cervico-vaginal EMPD.
PMID:36766569 SUPPORT Human Clinical
"Liquid-based cytology with immunocytochemistry represents a valuable tool for early diagnosis and should be routinely performed during the required lifelong follow-up."
This supports cytology with immunocytochemistry during lifelong EMPD follow-up.
Clinical Staging and Imaging
Clinical assessment is combined with selected imaging to evaluate local extent, regional nodes, and distant metastases. Imaging recommendations are heterogeneous and most evidence is for vulvar cancer overall rather than adenocarcinoma-specific cohorts.
Results: Clinical extent and suspected local, nodal, or distant disease.
Show evidence (2 references)
PMID:38927973 SUPPORT Human Clinical
"Various imaging modalities are widely used in conjunction with clinical assessment in the diagnosis and staging of vulval cancers; however, there is significant heterogeneity in which modalities are recommended in international guidelines, reflecting the paucity of evidence in this area."
This supports the combined clinical/imaging framework while preserving the limited and histology-mixed evidence base.
PMID:38927973 SUPPORT Human Clinical
"For distant metastases, CT CAP and FDG-PET/CT have the most evidence to support their use."
The imaging review supports CT chest/abdomen/pelvis and FDG-PET/CT for distant-disease assessment in vulvar cancer overall.
Regional Nodal Staging or Assessment
Regional nodal assessment is considered for intestinal-type tumors larger than 2 cm or with suspicious nodes and for mammary-like adenocarcinoma; reported methods include sentinel-node biopsy and lymphadenectomy.
Results: Regional lymph-node status for staging and treatment planning.
Show evidence (2 references)
PMID:36291953 SUPPORT Human Clinical
"Lymph node staging is an option advised if the tumor size is >2 cm or if lymph node metastases are suspected on imaging."
This states the size- and imaging-based indications described for intestinal-type tumors.
PMID:35672058 SUPPORT Human Clinical
"Lymphatic involvement may be assessed by sentinel lymph node biopsy or lymphadenectomy."
This directly identifies nodal-assessment approaches for mammary-like disease.
📈

Progression

7
Reported FIGO-stage distribution in intestinal-type disease
Intestinal-Type
In the 40-case systematic review, Stage IA was reported in 19 cases (47.5%); the remaining reported cases spanned Stage IB through IVB. This is a cohort distribution within intestinal-type disease, not a stage definition and not a distribution estimate for every vulvar adenocarcinoma subtype.
Show evidence (2 references)
PMID:41463238 SUPPORT Human Clinical
"Stage IA emerged as the most frequently reported classification, encompassing 19 cases (47.5%)."
The review directly reports the most frequent stage and count in the intestinal-type case literature.
PMID:41463238 SUPPORT Human Clinical
"6 cases were categorized as Stage IB, (15%); 2 cases (5%) were noted as Stage IIB; 4 cases were classified as Stage IIIA (10%); Stage IIIB was identified in 1 case (2.5%), and Stage IIIC in 2 cases (5%). Beyond these, one case (2.5%) presented as the more advanced Stage IVB."
The review enumerates the remaining reported stages in intestinal-type disease without redefining the FIGO categories.
Regional nodal spread in intestinal-type disease
Intestinal-Type
Nodal status was reported for 32 of 40 cases; 10 of those 32 were node positive. The denominator is reported explicitly to avoid treating missing nodal data as negative.
Show evidence (1 reference)
PMID:41463238 SUPPORT Human Clinical
"Lymph node metastasis status, however, was available for 32 cases (80%). Among these, 22 cases (68.8% of those with known status) were reported as negative for lymph node metastasis, while 10 cases (31.2% of those with known status) were positive."
The systematic review provides the known-status denominator and nodal metastasis count.
Delayed recurrence risk in intestinal-type disease
Intestinal-Type
Late recurrence is possible even after apparently successful local therapy, supporting extended follow-up; its frequency remains uncertain.
Show evidence (1 reference)
PMID:36291953 SUPPORT Human Clinical
"Sometimes, VAIt behavior can be unpredictable, with relapses even after many years, so more experiences and longer follow-up periods are needed to elucidate the best therapeutic management and its long-term prognosis."
The review explicitly describes the possibility of late relapse and the need for longer follow-up.
Persistent or recurrent vulvar extramammary Paget disease
Paget-Associated
Persistence or recurrence occurred in 86% of the referral-center cohort and commonly required repeated surgery (median two surgical procedures; range zero to 11). This estimate applies to vulvar EMPD in the reported cohort, not to every vulvar adenocarcinoma subtype.
Show evidence (1 reference)
PMID:36766569 SUPPORT Human Clinical
"Persistence or recurrence was very common, taking place in 86% of cases and, thus, often requiring multiple surgical instances (median: 2; range: 0–11)."
The longitudinal vulvar EMPD cohort directly reports the recurrence or persistence proportion and repeated-surgery burden.
Five-year overall survival in vulvar extramammary Paget disease
Paget-Associated
Five-year overall survival was 90.5% (95% CI 81.8–95.1%) after excluding one patient whose death date was unknown. This is a cohort-specific overall-survival estimate rather than adenocarcinoma-specific survival across the entire umbrella disorder.
Show evidence (1 reference)
PMID:36766569 SUPPORT Human Clinical
"After excluding one patient with an unknown death date, the 5 year overall survival was 90.5% (95% CI: 81.8–95.1%), as shown in Figure 1."
The cohort directly reports the five-year overall-survival estimate, confidence interval, and exclusion.
Long-term cervicovaginal extension of vulvar Paget disease
Paget-Associated
Cervicovaginal involvement accumulated over 15 years and was often asymptomatic, supporting lifelong surveillance in long-standing disease.
Show evidence (1 reference)
PMID:36766569 SUPPORT Human Clinical
"Overall nine patients developed CV involvement from EMPD, with a cumulative incidence of 2.5% (95% CI: 0.5-8.0%) at 5 years, 6.5% (95% CI: 1.9-15.1%) at 10 years and 14.0% (95% CI: 4.8-27.8%) at 15 years, respectively."
The 94-patient longitudinal cohort quantifies the late, accumulating cervicovaginal complication.
Recurrent Bartholin gland adenocarcinoma
Bartholin Gland Adenocarcinoma
The only adenocarcinoma in a 13-case Bartholin carcinoma cohort recurred and contributed to the two disease-specific deaths, so this is a single-case signal rather than a frequency estimate.
Show evidence (1 reference)
PMID:29406447 SUPPORT Human Clinical
"recurrence occurred in 3 cases, with death due to disease in 2 of the patients with recurrence, including the single patient with adenocarcinoma."
This directly establishes recurrence and fatal outcome in the cohort's single adenocarcinoma case without implying a population rate.
🪜

Stages

4
FIGO 2021 Stage I
Tumor confined to the vulva.
FIGO 2021 Stage IA FIGO 2021 Stage IB
Show evidence (2 references)
PMID:34520062 SUPPORT Human Clinical
"The resulting new staging for carcinoma of the vulva has two substages in Stage I, no substage in Stage II, three substages in Stage III, and two substages in Stage IV."
The PubMed record establishes the two-substage structure of Stage I.
url:https://europepmc.org/articles/PMC9290586?pdf=render SUPPORT Human Clinical
"I Tumor confined to the vulva ... IA Tumor size ≤2 cm and stromal invasion ≤1 mm ... IB Tumor size >2 cm or stromal invasion >1 mm"
Table 3 of the open-access FIGO revision directly defines Stage I and its IA and IB substages.
FIGO 2021 Stage II
Tumor of any size extending to the lower one-third of the urethra, lower one-third of the vagina, or lower one-third of the anus, with negative regional nodes.
Show evidence (2 references)
PMID:34520062 SUPPORT Human Clinical
"The resulting new staging for carcinoma of the vulva has two substages in Stage I, no substage in Stage II, three substages in Stage III, and two substages in Stage IV."
The PubMed record establishes Stage II as an unsubdivided stage.
url:https://europepmc.org/articles/PMC9290586?pdf=render SUPPORT Human Clinical
"II Tumor of any size with extension to lower one-third of the urethra, lower one-third of the vagina, lower one-third of the anus with negative nodes"
Table 3 of the open-access FIGO revision directly defines the anatomic extent and negative-node criterion for Stage II.
FIGO 2021 Stage III
Tumor of any size extending to upper adjacent perineal structures, or with any number of nonfixed, nonulcerated regional lymph-node metastases.
FIGO 2021 Stage IIIA FIGO 2021 Stage IIIB FIGO 2021 Stage IIIC
Show evidence (3 references)
PMID:34520062 SUPPORT Human Clinical
"The resulting new staging for carcinoma of the vulva has two substages in Stage I, no substage in Stage II, three substages in Stage III, and two substages in Stage IV."
The PubMed record establishes the three-substage structure of Stage III.
url:https://europepmc.org/articles/PMC9290586?pdf=render SUPPORT Human Clinical
"III Tumor of any size with extension to upper part of adjacent perineal structures, or with any number of nonfixed, nonulcerated lymph node ... IIIA Tumor of any size with disease extension to upper two-thirds of the urethra, upper two-thirds of the vagina, bladder mucosa, rectal mucosa, or..."
Table 3 of the open-access FIGO revision directly defines Stage III and Stage IIIA.
PMID:34520062 SUPPORT Human Clinical
"As an example, Stage IIIB is defined by lymph node metastasis >5 mm ... Similarly, Stage IIIC is defined by lymph node metastasis with extracapsular extension"
The primary FIGO revision's full-text prose directly defines the IIIB nodal-size threshold and IIIC extracapsular-extension criterion.
FIGO 2021 Stage IV
Tumor of any size fixed to bone, fixed or ulcerated lymph-node metastases, or distant metastases.
FIGO 2021 Stage IVA FIGO 2021 Stage IVB
Show evidence (2 references)
PMID:34520062 SUPPORT Human Clinical
"The resulting new staging for carcinoma of the vulva has two substages in Stage I, no substage in Stage II, three substages in Stage III, and two substages in Stage IV."
The PubMed record establishes the two-substage structure of Stage IV.
url:https://europepmc.org/articles/PMC9290586?pdf=render SUPPORT Human Clinical
"IV Tumor of any size fixed to bone, or fixed, ulcerated lymph node metastases, or distant metastases ... IVA Disease fixed to pelvic bone, or fixed or ulcerated regional ... lymph node metastases ... IVB Distant metastases"
Table 3 of the open-access FIGO revision directly defines Stage IV and its IVA and IVB substages.
🌍

Epidemiology

1
Relative share of uncommon vulvar carcinoma histologies
Adenocarcinomas are among the uncommon histologic variants that collectively comprise less than 5% of vulvar cancer diagnoses worldwide. This is a relative histology share, not a population prevalence or incidence estimate for vulvar adenocarcinoma.
Show evidence (1 reference)
PMID:41463238 SUPPORT Human Clinical
"Uncommon histological variants of vulvar carcinoma, including adenocarcinomas, comprise less than 5% of all vulvar cancer diagnoses worldwide."
The systematic review places adenocarcinomas within a combined group of uncommon histologies accounting for less than 5% of vulvar diagnoses; it does not estimate adenocarcinoma-specific population occurrence.
🔀

Differential Diagnoses

3

Conditions with similar clinical presentations that must be differentiated from Vulvar Adenocarcinoma:

Metastatic Colorectal or Other Gastrointestinal Adenocarcinoma
Overlapping Features A colorectal or other gastrointestinal primary can closely mimic intestinal-type vulvar adenocarcinoma morphologically and by CK20/CDX2 immunophenotype.
Distinguishing Features
  • Establish whether a gastrointestinal primary is present by directed clinical, endoscopic, and radiologic evaluation.
  • Interpret CK7, CK20, CDX2, and related markers as a panel; intestinal differentiation alone does not prove vulvar origin.
Show evidence (1 reference)
PMID:41463238 SUPPORT Human Clinical
"The diagnosis must be substantiated by the exclusion of other primary tumors, in particular primary gastrointestinal neoplasias."
The systematic review directly requires gastrointestinal-primary exclusion for an intestinal-type vulvar diagnosis.
Metastatic Breast Carcinoma
Overlapping Features Vulvar adenocarcinoma of mammary gland type can reproduce breast-carcinoma morphology and immunophenotype, so a metastatic orthotopic breast primary must be excluded.
Distinguishing Features
  • Correlate vulvar histology and immunohistochemistry with breast examination and breast imaging.
  • Look for adjacent in situ carcinoma or non-neoplastic mammary-like vulvar tissue when present, while recognizing these features may be absent.
Show evidence (1 reference)
PMID:35672058 SUPPORT Human Clinical
"Furthermore, it is necessary to exclude metastasis disease from orthotopic breast carcinoma or other organs."
The case report directly states the metastatic breast-primary exclusion requirement.
Bartholin Gland Cyst or Abscess
Overlapping Features Bartholin gland carcinoma is commonly first labeled as a benign cyst or abscess, delaying diagnosis and allowing stage progression.
Distinguishing Features
  • Biopsy a persistent, progressive, solid, or partly solid Bartholin-region mass, particularly in peri- or postmenopausal patients.
  • Obtain tissue deep enough to assess invasion and, when possible, the transition from normal Bartholin gland to tumor.
Show evidence (1 reference)
PMID:41375020 SUPPORT Human Clinical
"Approximately 50% of cases are diagnosed at an advanced stage due to misclassification as benign cysts or abscesses."
The mixed-histology Bartholin carcinoma review directly documents the mimic and diagnostic delay; applicability to the adenocarcinoma subset is marked partial.
🔬

Clinical Trials

3
NCT00504023 NOT_APPLICABLE COMPLETED
Pilot study of topical imiquimod for recurrent vulvar Paget disease. The ClinicalTrials.gov record listed 8 actual participants and COMPLETED status when checked on 2026-08-08.
Show evidence (1 reference)
clinicaltrials:NCT00504023 SUPPORT Human Clinical
"PURPOSE: This clinical trial is studying how well topical imiquimod works in treating patients with recurrent Paget's disease of the vulva."
The registry summary directly states the disease and intervention studied.
NCT02385188 PHASE_III COMPLETED
Phase III study of topical 5% imiquimod for non-invasive vulvar Paget disease. The ClinicalTrials.gov record listed 25 actual participants and COMPLETED status when checked on 2026-08-08.
Show evidence (1 reference)
clinicaltrials:NCT02385188 SUPPORT Human Clinical
"The purpose of this study is to evaluate the efficacy, safety and immunological response of topical 5% imiquimod cream for non-invasive vulvar Paget's disease."
The registry summary directly states the intervention, disease state, and study objectives.
NCT03713203 NOT_APPLICABLE RECRUITING
PAGETEX photodynamic-therapy device study for vulvar extramammary Paget disease. Structured ClinicalTrials.gov metadata classified the device study phase as not applicable even though its official title says “Phase II”; it listed 24 estimated participants and RECRUITING status when checked on 2026-08-08.
Show evidence (1 reference)
clinicaltrials:NCT03713203 SUPPORT Human Clinical
"The objective of this study is to assess the efficacy and evaluate the safety of the new PDT device "PAGETEX" for the treatment of vulvar Paget's disease."
The registry summary directly states the device, target disease, and efficacy/safety objectives.
{ }

Source YAML

click to show 
name: Vulvar Adenocarcinoma
creation_date: "2026-05-09T13:22:22Z"
synonyms:
- Adenocarcinoma of the vulva
- Vulva adenocarcinoma
description: >-
  Vulvar adenocarcinoma is a rare, heterogeneous group of gland-forming vulvar
  epithelial malignancies. Its MONDO anchor includes intestinal-type,
  mammary-like, Bartholin gland, Paget-associated, sebaceous, eccrine,
  apocrine, Skene-gland, and clear-cell hidradenocarcinoma branches. These
  entities are not interchangeable: diagnosis, biomarkers, natural history,
  and treatment must be interpreted by subtype. The evidence-rich sections
  below primarily cover intestinal-type, mammary-like, Bartholin gland, and
  Paget-associated disease; the remaining ontology-recognized branches are
  retained explicitly as under-curated subtypes rather than silently excluded.
  Evidence is dominated by case reports, small series, and extrapolation from
  broader vulvar cancer guidance.
categories:
- Gynecologic Malignancy
- Adenocarcinoma
- Solid Tumor
- Rare Cancer
parents:
- vulvar glandular neoplasm
- vulvar carcinoma
- adenocarcinoma
disease_term:
  preferred_term: vulvar adenocarcinoma
  term:
    id: MONDO:0024336
    label: vulvar adenocarcinoma
definitions:
- name: Clinicopathologic definition
  definition_type: CASE_DEFINITION
  description: >-
    A primary vulvar malignant epithelial tumor with glandular differentiation,
    diagnosed by biopsy and histopathology, with subtype-specific
    immunohistochemistry used to distinguish primary vulvar origin from
    metastatic gastrointestinal, breast, urothelial, or other primaries.
  scope: Gynecologic oncology and surgical pathology definition
  evidence:
  - reference: PMID:38503056
    reference_title: "Vulvar Cancer, Version 3.2024, NCCN Clinical Practice Guidelines in Oncology."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Rarer histologies exist and include melanoma, extramammary Paget's
      disease, Bartholin gland adenocarcinoma, verrucous carcinoma, basal cell
      carcinoma, and sarcoma.
    explanation: >-
      The NCCN guideline recognizes Bartholin gland adenocarcinoma and
      extramammary Paget disease among rare vulvar cancer histologies that need
      subtype-aware management.
  - reference: PMID:36291953
    reference_title: "\"Intestinal-Type\" Vulvar Adenocarcinoma: A Review of the MITO Rare Tumors Group."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      To confirm vulvar origin, a thorough diagnostic, and radiological
      examination is required to rule out other primary malignancies.
    explanation: >-
      This supports the need to exclude metastatic or non-vulvar primaries when
      diagnosing intestinal-type vulvar adenocarcinoma.
has_subtypes:
- name: Intestinal-Type
  display_name: Intestinal-type vulvar adenocarcinoma
  classification: histologic
  subtype_term:
    preferred_term: Vulvar Mucinous Adenocarcinoma, Intestinal-Type
    term:
      id: NCIT:C128166
      label: Vulvar Mucinous Adenocarcinoma, Intestinal-Type
  description: >-
    A rare sporadic vulvar carcinoma with intestinal differentiation, commonly
    resembling mucinous colorectal carcinoma and requiring exclusion of a
    colorectal or other gastrointestinal primary.
  evidence:
  - reference: PMID:36291953
    reference_title: "\"Intestinal-Type\" Vulvar Adenocarcinoma: A Review of the MITO Rare Tumors Group."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Intestinal-type adenocarcinoma (VAIt) represents a sporadic variant of
      vulvar carcinoma.
    explanation: >-
      This directly defines VAIt as a vulvar adenocarcinoma subtype.
- name: Mammary Gland Type
  display_name: Vulvar adenocarcinoma of mammary gland type
  classification: histologic
  subtype_term:
    preferred_term: Vulvar Adenocarcinoma of Mammary Gland Type
    term:
      id: NCIT:C128162
      label: Vulvar Adenocarcinoma of Mammary Gland Type
  description: >-
    A very rare vulvar adenocarcinoma with mammary-like morphology or
    immunophenotype; diagnosis can require breast-carcinoma mimicry assessment
    and exclusion of metastatic breast carcinoma.
  evidence:
  - reference: PMID:35672058
    reference_title: "Diagnosis and management of primary vulvar adenocarcinoma of mammary gland type: report of two distinct cases."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Adenocarcinoma of mammary gland type (AMGT) of the vulva is extremely
      rare and its aetiopathogenesis is not fully understood.
    explanation: >-
      This case-report paper defines AMGT as an extremely rare vulvar
      adenocarcinoma entity.
- name: Bartholin Gland Adenocarcinoma
  display_name: Bartholin gland adenocarcinoma
  classification: anatomic and histologic
  subtype_term:
    preferred_term: Bartholin gland adenocarcinoma
    term:
      id: MONDO:0003853
      label: Bartholin gland adenocarcinoma
  description: >-
    A primary adenocarcinoma arising in the Bartholin gland region. Establishing
    primary Bartholin origin requires compatible location and histology,
    preferably transition from normal gland to tumor, and exclusion of another
    primary site.
  evidence:
  - reference: PMID:29406447
    reference_title: "Bartholin Gland Carcinoma: Clinicopathologic Features, Including p16 Expression and Clinical Outcome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      There were 12 squamous cell carcinomas (SCCs), including 1 SCC with
      transitional-like morphology and 1 papillary SCC, and 1 adenocarcinoma.
    explanation: >-
      This Bartholin gland carcinoma cohort included a Bartholin gland
      adenocarcinoma case, supporting the subtype.
  - reference: PMID:41375020
    reference_title: "Bartholin Gland Carcinoma: A State-of-the-Art Review of Epidemiology, Histopathology, Molecular Testing, and Clinical Management."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Primary BGC is best defined by tumors arising in BG tissue, supported by
      (1) location compatible with the gland; (2) histologic transition from
      non-neoplastic BG duct/acini to tumor where present, and (3) exclusion of
      another primary site.
    explanation: >-
      The review states the anatomic, histologic, and exclusion criteria for a
      primary Bartholin gland carcinoma.
- name: Paget-Associated
  display_name: Invasive or Paget-associated vulvar adenocarcinoma
  classification: histologic
  subtype_term:
    preferred_term: vulval Paget disease
    term:
      id: MONDO:0002207
      label: vulval Paget disease
  description: >-
    Extramammary Paget disease of the vulva is an adenocarcinoma-related vulvar
    entity that can remain intraepithelial, become invasive, or be associated
    with an underlying adenocarcinoma, with HER2-positive metastatic examples
    reported.
  evidence:
  - reference: PMID:38831459
    reference_title: "Whole genome sequencing of HER2-positive metastatic extramammary Paget's disease: a case report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Extramammary Paget's disease (EMPD) is a rare cancer that occurs within
      the epithelium of the skin, arising predominantly in areas with high
      apocrine gland concentration such as the vulva, scrotum, penis and
      perianal regions.
    explanation: >-
      This supports EMPD as a rare apocrine-rich skin cancer involving the
      vulva and related to the glandular vulvar cancer differential.
- name: Vulvar Sebaceous Carcinoma
  display_name: Vulvar sebaceous carcinoma
  classification: ontology-recognized histologic subtype
  subtype_term:
    preferred_term: vulvar sebaceous carcinoma
    term:
      id: MONDO:0003636
      label: vulvar sebaceous carcinoma
  description: >-
    An official direct MONDO descendant of vulvar adenocarcinoma. It is listed
    to preserve the disease-term scope; subtype-specific mechanism and outcome
    claims were not generalized from the four evidence-rich branches.
- name: Vulvar Eccrine Adenocarcinoma
  display_name: Vulvar eccrine adenocarcinoma
  classification: ontology-recognized histologic subtype
  subtype_term:
    preferred_term: vulvar eccrine adenocarcinoma
    term:
      id: MONDO:0003861
      label: vulvar eccrine adenocarcinoma
  description: >-
    An official direct MONDO descendant of vulvar adenocarcinoma. The related
    vulvar eccrine porocarcinoma descendant is represented separately below.
- name: Vulvar Eccrine Porocarcinoma
  display_name: Vulvar eccrine porocarcinoma
  classification: ontology-recognized nested histologic subtype
  subtype_term:
    preferred_term: vulvar eccrine porocarcinoma
    term:
      id: MONDO:0004281
      label: vulvar eccrine porocarcinoma
  description: >-
    An official deeper MONDO descendant through the vulvar eccrine
    adenocarcinoma branch, retained explicitly so the umbrella scope is not
    mistaken for complete mechanistic curation of this rare entity.
- name: Vulvar Apocrine Adenocarcinoma
  display_name: Vulvar apocrine adenocarcinoma
  classification: ontology-recognized histologic subtype
  subtype_term:
    preferred_term: vulvar apocrine adenocarcinoma
    term:
      id: MONDO:0003881
      label: vulvar apocrine adenocarcinoma
  description: >-
    An official direct MONDO descendant of vulvar adenocarcinoma, listed as an
    under-curated branch without importing cross-site apocrine-carcinoma claims.
- name: Skene Gland Origin
  display_name: Adenocarcinoma of Skene gland origin
  classification: ontology-recognized anatomic subtype
  subtype_term:
    preferred_term: adenocarcinoma of skene gland origin
    term:
      id: MONDO:0004173
      label: adenocarcinoma of skene gland origin
  description: >-
    An official direct MONDO descendant representing primary adenocarcinoma of
    Skene-gland origin; disease-specific evidence remains a curation gap.
- name: Vulvar Clear Cell Hidradenocarcinoma
  display_name: Vulvar clear cell hidradenocarcinoma
  classification: ontology-recognized histologic subtype
  subtype_term:
    preferred_term: vulvar clear cell hidradenocarcinoma
    term:
      id: MONDO:0004283
      label: vulvar clear cell hidradenocarcinoma
  description: >-
    An official direct MONDO descendant retained explicitly as an under-curated
    adnexal carcinoma branch.
- name: Bartholin Gland Adenoid Cystic Carcinoma
  display_name: Bartholin gland adenoid cystic carcinoma
  classification: ontology-recognized nested anatomic and histologic subtype
  subtype_term:
    preferred_term: Bartholin gland adenoid cystic carcinoma
    term:
      id: MONDO:0003187
      label: Bartholin gland adenoid cystic carcinoma
  description: >-
    An official deeper MONDO descendant through the Bartholin gland branch.
    It is not conflated with conventional Bartholin gland adenocarcinoma or
    with adenoid cystic carcinoma at non-vulvar sites.
epidemiology:
- name: Relative share of uncommon vulvar carcinoma histologies
  description: >-
    Adenocarcinomas are among the uncommon histologic variants that collectively
    comprise less than 5% of vulvar cancer diagnoses worldwide. This is a
    relative histology share, not a population prevalence or incidence estimate
    for vulvar adenocarcinoma.
  unit: percent of vulvar cancer diagnoses
  evidence:
  - reference: PMID:41463238
    reference_title: "Intestinal-Type Adenocarcinoma Is a Rare Histotype of Vulvar Neoplasm: Systematic Review of the Literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Uncommon histological variants of vulvar carcinoma, including
      adenocarcinomas, comprise less than 5% of all vulvar cancer diagnoses
      worldwide.
    explanation: >-
      The systematic review places adenocarcinomas within a combined group of
      uncommon histologies accounting for less than 5% of vulvar diagnoses; it
      does not estimate adenocarcinoma-specific population occurrence.
pathophysiology:
- name: Primary Vulvar Glandular Malignancy
  description: >-
    This umbrella node represents a primary malignant glandular epithelial
    tumor in the vulva. It does not assert one shared molecular initiating
    lesion across the histologically distinct intestinal-type, mammary-like,
    Bartholin gland, and Paget-associated branches.
  role: trigger
  evidence:
  - reference: PMID:38503056
    reference_title: "Vulvar Cancer, Version 3.2024, NCCN Clinical Practice Guidelines in Oncology."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Rarer histologies exist and include melanoma, extramammary Paget's
      disease, Bartholin gland adenocarcinoma, verrucous carcinoma, basal cell
      carcinoma, and sarcoma.
    explanation: >-
      NCCN recognizes Bartholin gland adenocarcinoma and extramammary Paget
      disease as rare vulvar cancer histologies.
  cell_types:
  - preferred_term: vulvar glandular epithelial cell
    term:
      id: CL:0000066
      label: epithelial cell
  - preferred_term: vulvar secretory epithelial cell
    term:
      id: CL:0000151
      label: secretory cell
  locations:
  - preferred_term: vulva
    term:
      id: UBERON:0000997
      label: mammalian vulva
  downstream:
  - target: Vulvar Lump or Mass
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: A primary vulvar tumor can present as a clinically noticed lump or mass.
    evidence:
    - reference: PMID:34669204
      reference_title: "Cancer of the vulva: 2021 update."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        While vulvar cancer may be asymptomatic, most women present with vulvar
        pruritus or pain, or have noticed a lump or ulcer.
      explanation: >-
        This supports the tumor-to-lump edge for vulvar cancer overall; evidence
        is partial for rare adenocarcinoma histologies.
  - target: Vulvar Ulcer
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: A primary vulvar malignancy may present with an ulcerated lesion.
    evidence:
    - reference: PMID:34669204
      reference_title: "Cancer of the vulva: 2021 update."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        While vulvar cancer may be asymptomatic, most women present with vulvar
        pruritus or pain, or have noticed a lump or ulcer.
      explanation: >-
        This supports the tumor-to-ulcer edge for vulvar cancer overall;
        evidence is partial for rare adenocarcinoma histologies.
  - target: Vulvar Pruritus
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Vulvar malignancy can produce local pruritus.
    evidence:
    - reference: PMID:34669204
      reference_title: "Cancer of the vulva: 2021 update."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        While vulvar cancer may be asymptomatic, most women present with vulvar
        pruritus or pain, or have noticed a lump or ulcer.
      explanation: >-
        This supports the tumor-to-pruritus edge for vulvar cancer overall;
        evidence is partial for rare adenocarcinoma histologies.
  - target: Vulvar Pain or Burning
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Local tumor and tissue involvement can produce pain or burning.
    evidence:
    - reference: PMID:34669204
      reference_title: "Cancer of the vulva: 2021 update."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        While vulvar cancer may be asymptomatic, most women present with vulvar
        pruritus or pain, or have noticed a lump or ulcer.
      explanation: >-
        This supports the tumor-to-pain edge for vulvar cancer overall;
        evidence is partial for rare adenocarcinoma histologies.
- name: Intestinal-Type Glandular Differentiation
  description: >-
    Intestinal-type vulvar adenocarcinoma has villo-glandular, mucin-producing
    morphology with goblet or Paneth cells and an intestinal immunophenotype.
    Cloacal-remnant origin is proposed but is not established.
  role: central_effector
  evidence:
  - reference: PMID:41463238
    reference_title: "Intestinal-Type Adenocarcinoma Is a Rare Histotype of Vulvar Neoplasm: Systematic Review of the Literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      VAIt is defined as a mucinous, villo-glandular adenocarcinoma of the vulva
      showing intestinal differentiation.
    explanation: >-
      The review states the contemporary morphologic definition of the subtype.
  - reference: PMID:36291953
    reference_title: "\"Intestinal-Type\" Vulvar Adenocarcinoma: A Review of the MITO Rare Tumors Group."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      It appears frequently localized to epithelial glands in the vulvar
      region, and it probably derives from cloacal remnants persisting in the
      adult.
    explanation: >-
      This supports a proposed, rather than proven, cloacal-remnant origin.
  cell_types:
  - preferred_term: intestinalized vulvar glandular epithelial cell
    term:
      id: CL:0000066
      label: epithelial cell
  locations:
  - preferred_term: vulva
    term:
      id: UBERON:0000997
      label: mammalian vulva
  downstream:
  - target: Regional Nodal Spread or Late Recurrence
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Intestinal-type tumors can involve regional nodes or recur after treatment.
    evidence:
    - reference: PMID:41463238
      reference_title: "Intestinal-Type Adenocarcinoma Is a Rare Histotype of Vulvar Neoplasm: Systematic Review of the Literature."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Lymph node metastases were present in about 31.5% of cases.
      explanation: >-
        The systematic review directly quantifies nodal metastasis in reported
        intestinal-type cases.
- name: Mammary-Like Glandular Differentiation
  description: >-
    Vulvar adenocarcinoma of mammary gland type can reproduce ductal,
    cribriform, papillary, or infiltrative breast-carcinoma-like architecture.
    Its immunophenotype is heterogeneous rather than uniformly hormone-receptor
    positive.
  role: central_effector
  evidence:
  - reference: PMID:35672058
    reference_title: "Diagnosis and management of primary vulvar adenocarcinoma of mammary gland type: report of two distinct cases."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The histological types in the vulva appear to be similar to those
      described for the breast, such as ductal lobular, mixed and mucinous
      carcinomas.
    explanation: >-
      The case report describes the breast-like morphologic spectrum.
  - reference: PMID:35672058
    reference_title: "Diagnosis and management of primary vulvar adenocarcinoma of mammary gland type: report of two distinct cases."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Although ER and PR expression is considered a diagnostic criterion for
      these neoplasms, here we report a case of an AMGT with a triple-negative
      profile, mimicking its breast counterpart.
    explanation: >-
      The two-case report establishes clinically important immunophenotypic
      heterogeneity.
  cell_types:
  - preferred_term: mammary-like vulvar glandular epithelial cell
    term:
      id: CL:0000066
      label: epithelial cell
  locations:
  - preferred_term: vulva
    term:
      id: UBERON:0000997
      label: mammalian vulva
  downstream:
  - target: Regional Nodal Spread or Late Recurrence
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Mammary-like vulvar adenocarcinoma can spread to inguinal nodes.
    evidence:
    - reference: PMID:35672058
      reference_title: "Diagnosis and management of primary vulvar adenocarcinoma of mammary gland type: report of two distinct cases."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        The biopsy of the inguinal adenopathy revealed a metastasis of the
        vulvar neoplasia previously described.
      explanation: >-
        One reported mammary-like vulvar adenocarcinoma had biopsy-confirmed
        inguinal nodal metastasis.
- name: Bartholin Gland Adenocarcinoma
  description: >-
    Bartholin gland adenocarcinomas commonly produce mucin and can show
    papillary, mucoepidermoid, or mucinous architecture with deep perineal and
    perineural infiltration.
  role: central_effector
  evidence:
  - reference: PMID:41375020
    reference_title: "Bartholin Gland Carcinoma: A State-of-the-Art Review of Epidemiology, Histopathology, Molecular Testing, and Clinical Management."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Most are mucin-producing, with patterns ranging from papillary to
      mucoepidermoid or mucinous.
    explanation: >-
      The review describes the principal Bartholin adenocarcinoma morphologies.
  locations:
  - preferred_term: Bartholin gland
    term:
      id: UBERON:0000460
      label: major vestibular gland
  downstream:
  - target: Vulvar Lump or Mass
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Bartholin gland carcinoma commonly presents as a painful mass.
    evidence:
    - reference: PMID:41375020
      reference_title: "Bartholin Gland Carcinoma: A State-of-the-Art Review of Epidemiology, Histopathology, Molecular Testing, and Clinical Management."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        The leading symptom is a painful vulvar mass in the BG area; other
        commonly observed symptoms include bleeding, pruritus, skin
        discoloration, and dyspareunia.
      explanation: >-
        This is mixed-histology Bartholin gland carcinoma evidence and is
        therefore partial for its adenocarcinoma subset.
  - target: Regional Nodal Spread or Late Recurrence
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Bartholin gland adenocarcinoma can recur and be fatal.
    evidence:
    - reference: PMID:29406447
      reference_title: "Bartholin Gland Carcinoma: Clinicopathologic Features, Including p16 Expression and Clinical Outcome."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        recurrence occurred in 3 cases, with death due to disease in 2 of the
        patients with recurrence, including the single patient with
        adenocarcinoma.
      explanation: >-
        The cohort directly reports recurrence and disease-specific death in
        its single adenocarcinoma case.
- name: Vulvar Paget Cell Disease
  description: >-
    Vulval extramammary Paget disease consists of Paget cells within the
    epithelium and can remain intraepithelial, invade stroma, or extend to the
    cervix and vagina. It often produces an erythematous, eczematous,
    pruritic, or burning lesion.
  role: central_effector
  evidence:
  - reference: PMID:36766569
    reference_title: "Tips and Tricks for Early Diagnosis of Cervico-Vaginal Involvement from Extramammary Paget's Disease of the Vulva: A Referral Center Experience."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Cervical and/or vaginal biopsies were always performed for
      histopathological diagnosis by identification of Paget cells in the
      epithelium or stroma.
    explanation: >-
      The cohort defines tissue involvement by biopsy identification of Paget
      cells.
  - reference: clinicaltrials:NCT03713203
    reference_title: "An Interventional, Phase II, Non Randomized, Mono-centric Study on the Clinical Efficacy and Safety of the Medical Device PAGETEX® as a Photodynamic Therapy Device in the Treatment of Extra-Mammary Paget's Disease of the Vulva (EMPV)"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The disease is revealed by erythematous, eczematous, pruritus and vulvar
      burns.
    explanation: >-
      The trial record directly describes the characteristic vulvar Paget
      lesion and symptoms.
  locations:
  - preferred_term: vulva
    term:
      id: UBERON:0000997
      label: mammalian vulva
  downstream:
  - target: Vulvar Pruritus
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Vulvar Paget disease can cause local pruritus.
    evidence:
    - reference: clinicaltrials:NCT03713203
      reference_title: "An Interventional, Phase II, Non Randomized, Mono-centric Study on the Clinical Efficacy and Safety of the Medical Device PAGETEX® as a Photodynamic Therapy Device in the Treatment of Extra-Mammary Paget's Disease of the Vulva (EMPV)"
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        The disease is revealed by erythematous, eczematous, pruritus and vulvar
        burns.
      explanation: >-
        The vulvar Paget trial record directly links disease presentation to
        pruritus.
  - target: Erythematous Eczematoid Vulvar Plaque
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Intraepithelial vulvar Paget cell disease produces the characteristic
      erythematous, eczematoid plaque presentation.
    evidence:
    - reference: clinicaltrials:NCT03713203
      reference_title: "An Interventional, Phase II, Non Randomized, Mono-centric Study on the Clinical Efficacy and Safety of the Medical Device PAGETEX® as a Photodynamic Therapy Device in the Treatment of Extra-Mammary Paget's Disease of the Vulva (EMPV)"
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        The disease is revealed by erythematous, eczematous, pruritus and vulvar
        burns.
      explanation: >-
        The trial record directly links vulvar Paget disease to its
        erythematous, eczematous clinical appearance.
  - target: Vulvar Pain or Burning
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Vulvar Paget disease can cause burning discomfort.
    evidence:
    - reference: clinicaltrials:NCT03713203
      reference_title: "An Interventional, Phase II, Non Randomized, Mono-centric Study on the Clinical Efficacy and Safety of the Medical Device PAGETEX® as a Photodynamic Therapy Device in the Treatment of Extra-Mammary Paget's Disease of the Vulva (EMPV)"
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        The disease is revealed by erythematous, eczematous, pruritus and vulvar
        burns.
      explanation: >-
        The vulvar Paget trial record directly links disease presentation to
        burning.
  - target: Cervicovaginal Paget Cell Extension
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Long-standing vulvar Paget disease can extend to the cervix or vagina.
    evidence:
    - reference: PMID:36766569
      reference_title: "Tips and Tricks for Early Diagnosis of Cervico-Vaginal Involvement from Extramammary Paget's Disease of the Vulva: A Referral Center Experience."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        CV involvement from EMPD should not be underestimated in women with a
        long-standing history of vulvar Paget's disease.
      explanation: >-
        The longitudinal cohort links long-standing vulvar disease to clinically
        important cervicovaginal extension.
- name: Cervicovaginal Paget Cell Extension
  description: >-
    Cervical or vaginal extension is a late complication of vulvar EMPD that
    may be clinically silent and is often first detected by abnormal glandular
    cytology before biopsy confirmation.
  role: consequence
  evidence:
  - reference: PMID:36766569
    reference_title: "Tips and Tricks for Early Diagnosis of Cervico-Vaginal Involvement from Extramammary Paget's Disease of the Vulva: A Referral Center Experience."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Overall nine patients developed CV involvement from EMPD, with a
      cumulative incidence of 2.5% (95% CI: 0.5-8.0%) at 5 years, 6.5% (95% CI:
      1.9-15.1%) at 10 years and 14.0% (95% CI: 4.8-27.8%) at 15 years,
      respectively.
    explanation: >-
      The 94-patient cohort quantifies increasing cumulative incidence of
      cervicovaginal extension over long follow-up.
  downstream:
  - target: Abnormal Glandular Cytology in Paget Spread
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Cervicovaginal Paget cells can be detected as abnormal glandular cytology.
    evidence:
    - reference: PMID:36766569
      reference_title: "Tips and Tricks for Early Diagnosis of Cervico-Vaginal Involvement from Extramammary Paget's Disease of the Vulva: A Referral Center Experience."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        All cases except one were firstly detected by abnormal glandular
        cytology. None reported vaginal bleeding or other suspicious symptoms.
      explanation: >-
        Abnormal glandular cytology detected nearly all cervicovaginal cases in
        the cohort despite absent suspicious symptoms.
- name: HER2-Positive EMPD Signaling (Cross-Site Case Evidence)
  description: >-
    A single metastatic scrotal EMPD case showed HER2 protein overexpression
    and WGS pathway enrichment involving FGFR1 and TGF-beta signaling. This is
    a hypothesis-generating therapeutic axis for vulvar Paget-associated
    disease, not established vulvar-specific molecular prevalence or causality.
  role: modifier
  evidence:
  - reference: PMID:38831459
    reference_title: "Whole genome sequencing of HER2-positive metastatic extramammary Paget's disease: a case report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Immunohistochemical staining on the scrotal wall tumor and bone marrow
      metastasis demonstrated HER2 overexpression.
    explanation: >-
      The evidence is direct for a metastatic scrotal EMPD case but only
      extrapolative for vulvar EMPD.
  - reference: PMID:38831459
    reference_title: "Whole genome sequencing of HER2-positive metastatic extramammary Paget's disease: a case report."
    supports: SUPPORT
    evidence_source: COMPUTATIONAL
    snippet: >-
      Enrichment in pathways associated with transforming growth factor-beta
      (TGFβ) (FDR = 0.0376, Enrichment Ratio = 8.12) and fibroblast growth
      factor receptor (FGFR1) signaling (FDR = 0.0082, Enrichment Ratio = 2.3)
      was detected.
    explanation: >-
      Computational enrichment in one cross-site EMPD case does not establish a
      recurrent vulvar mechanism.
  genes:
  - preferred_term: ERBB2
    term:
      id: hgnc:3430
      label: ERBB2
  - preferred_term: FGFR1
    term:
      id: hgnc:3688
      label: FGFR1
  biological_processes:
  - preferred_term: cell surface receptor protein tyrosine kinase signaling pathway
    modifier: INCREASED
    term:
      id: GO:0007169
      label: cell surface receptor protein tyrosine kinase signaling pathway
- name: Regional Nodal Spread or Late Recurrence
  description: >-
    Regional nodal metastasis and delayed recurrence are documented across
    several rare glandular subtypes, but frequency and timing are
    subtype-specific and imprecisely estimated from small case collections.
  role: consequence
  evidence:
  - reference: PMID:41463238
    reference_title: "Intestinal-Type Adenocarcinoma Is a Rare Histotype of Vulvar Neoplasm: Systematic Review of the Literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      VAIt can follow an unpredictable clinical course, with potential for late
      recurrence and metastasis.
    explanation: >-
      The systematic review directly supports delayed recurrence and metastatic
      potential for intestinal-type disease.
histopathology:
- name: Villo-Glandular Mucinous Colorectal-Like Morphology
  context: Intestinal-Type
  diagnostic: true
  description: >-
    Intestinal-type vulvar adenocarcinoma forms villo-glandular structures with
    goblet or Paneth cells and intracytoplasmic mucin, closely resembling
    mucinous colorectal adenocarcinoma.
  evidence:
  - reference: PMID:41463238
    reference_title: "Intestinal-Type Adenocarcinoma Is a Rare Histotype of Vulvar Neoplasm: Systematic Review of the Literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      VAIt is defined as a mucinous, villo-glandular adenocarcinoma of the vulva
      showing intestinal differentiation. Macroscopically, VAIt may exhibit a
      polypoid appearance, while histologically, it displays features akin to
      mucinous colorectal adenocarcinomas, including the presence of goblet
      cells or Paneth cells with abundant intracellular mucin.
    explanation: >-
      The systematic review directly describes the defining microscopic
      architecture and cell types.
- name: Heterogeneous Mammary-Like Ductal Architecture
  context: Mammary Gland Type
  diagnostic: true
  description: >-
    Reported tumors range from expansile cribriform and papillary architecture
    to infiltrative ductular, glandular, nest, and cord patterns, illustrating
    substantial within-subtype morphologic heterogeneity.
  evidence:
  - reference: PMID:35672058
    reference_title: "Diagnosis and management of primary vulvar adenocarcinoma of mammary gland type: report of two distinct cases."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Tumour mass presented a nodular configuration, with expansile growth,
      with a cribiform and papillary architecture, occasionally with solid
      areas.
    explanation: >-
      This is the microscopic pattern of the first mammary-like case.
  - reference: PMID:35672058
    reference_title: "Diagnosis and management of primary vulvar adenocarcinoma of mammary gland type: report of two distinct cases."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Tumour mass presented an infiltrative growth, being arranged in a
      ductular and glandular architecture or in small nests and cords.
    explanation: >-
      The second case demonstrates a distinct infiltrative ductal pattern.
- name: Mucin-Producing Bartholin Adenocarcinoma
  context: Bartholin Gland Adenocarcinoma
  description: >-
    Bartholin gland adenocarcinoma is commonly mucin-producing and can show
    papillary, mucoepidermoid, or mucinous architecture with intracytoplasmic
    mucin and deep perineal infiltration.
  evidence:
  - reference: PMID:41375020
    reference_title: "Bartholin Gland Carcinoma: A State-of-the-Art Review of Epidemiology, Histopathology, Molecular Testing, and Clinical Management."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Tumor cells often contain intracytoplasmic mucin and may show papillary
      architecture and CEA positivity. These tumors tend to infiltrate deep
      perineal tissues along nerves, with frequent ischioanal fossa involvement.
    explanation: >-
      The review directly describes the morphology and infiltrative pattern of
      Bartholin adenocarcinoma.
- name: Paget Cells in Epithelium or Stroma
  context: Paget-Associated
  diagnostic: true
  description: >-
    Cervical or vaginal extension from vulvar EMPD is confirmed by identifying
    Paget cells within epithelium or stroma on biopsy.
  evidence:
  - reference: PMID:36766569
    reference_title: "Tips and Tricks for Early Diagnosis of Cervico-Vaginal Involvement from Extramammary Paget's Disease of the Vulva: A Referral Center Experience."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Cervical and/or vaginal biopsies were always performed for
      histopathological diagnosis by identification of Paget cells in the
      epithelium or stroma.
    explanation: >-
      This directly states the biopsy finding used to diagnose extension.
biochemical:
- name: Intestinal-Type CK20, CDX2, CK7, and p16 Immunophenotype
  presence: CK20 and CDX2 positive; CK7 and p16 variable
  notes: >-
    The panel supports intestinal differentiation but is not sufficient to
    prove primary vulvar origin because colorectal and anal primaries can share
    the phenotype.
  readouts:
  - target: Intestinal-Type Glandular Differentiation
    relationship: READOUT_OF
    direction: PRESENT_ABSENT
    endpoint_context: DIAGNOSTIC
    interpretation: >-
      CK20 and CDX2 positivity with variable CK7/p16 is a diagnostic readout of
      intestinal differentiation, not a site-of-origin test by itself.
    evidence:
    - reference: PMID:41463238
      reference_title: "Intestinal-Type Adenocarcinoma Is a Rare Histotype of Vulvar Neoplasm: Systematic Review of the Literature."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Immunohistochemistry consistently showed CK20 and CDX2 positivity, with
        variable CK7 and p16 expression.
      explanation: >-
        The systematic review directly maps this panel to intestinal-type
        differentiation.
  evidence:
  - reference: PMID:41463238
    reference_title: "Intestinal-Type Adenocarcinoma Is a Rare Histotype of Vulvar Neoplasm: Systematic Review of the Literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Immunohistochemistry consistently showed CK20 and CDX2 positivity, with
      variable CK7 and p16 expression.
    explanation: >-
      The 40-case systematic review summarizes the recurrent intestinal-type
      immunophenotype.
- name: Mammary-Like Hormone-Receptor and Lineage-Marker Profiles
  presence: Subtype-variable
  notes: >-
    The two reported cases were molecularly distinct: one was ER-high and
    CK7/CAM5.2/GATA3-positive, while the other was triple-negative with
    CK7/SOX10 positivity. A single invariant mammary-like panel should not be
    assumed.
  readouts:
  - target: Mammary-Like Glandular Differentiation
    relationship: READOUT_OF
    direction: THRESHOLD_DEPENDENT
    endpoint_context: DIAGNOSTIC
    interpretation: >-
      Morphology and a panel of breast-lineage and hormone-receptor markers,
      interpreted together, support mammary-like differentiation.
    evidence:
    - reference: PMID:35672058
      reference_title: "Diagnosis and management of primary vulvar adenocarcinoma of mammary gland type: report of two distinct cases."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        The triple-negative immunohistochemical (IHC) profile of one of the
        cases represented a diagnostic challenge.
      explanation: >-
        The report directly shows that IHC profile interpretation is part of
        mammary-like subtype diagnosis and can be heterogeneous.
  evidence:
  - reference: PMID:35672058
    reference_title: "Diagnosis and management of primary vulvar adenocarcinoma of mammary gland type: report of two distinct cases."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The immunohistochemistry (IHC) study demonstrated positivity for
      oestrogen receptors (ER) (90%–100%), cytokeratin (CK) 7, CAM5.2 and GATA3.
    explanation: >-
      This is the ER-high breast-lineage profile of one mammary-like case.
  - reference: PMID:35672058
    reference_title: "Diagnosis and management of primary vulvar adenocarcinoma of mammary gland type: report of two distinct cases."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      IHC study demonstrated positivity for CK7, SOX10, p53 and E-cadherin. The
      tumour was negative for ER, PR, HER-2, GCDDP-15, GATA-3, TTF1, p63, PAX-8
      and CK20.
    explanation: >-
      The second case demonstrates a distinct triple-negative/SOX10-positive
      profile.
- name: HER2 Protein Overexpression in Metastatic EMPD
  presence: Positive in a reported metastatic scrotal EMPD case
  notes: >-
    HER2 overexpression was demonstrated in tumor and bone-marrow metastasis
    without high ERBB2 copy-number gain. Its frequency and predictive value in
    vulvar EMPD are not established by this cross-site single case.
  readouts:
  - target: HER2-Positive EMPD Signaling (Cross-Site Case Evidence)
    relationship: READOUT_OF
    direction: PRESENT_ABSENT
    endpoint_context: DIAGNOSTIC
    interpretation: >-
      HER2 immunohistochemistry identifies the reported HER2-positive EMPD
      state, with only indirect applicability to vulvar disease.
    evidence:
    - reference: PMID:38831459
      reference_title: "Whole genome sequencing of HER2-positive metastatic extramammary Paget's disease: a case report."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Immunohistochemical staining on the scrotal wall tumor and bone marrow
        metastasis demonstrated HER2 overexpression.
      explanation: >-
        HER2 IHC directly reports the molecular state in one scrotal EMPD case;
        vulvar applicability remains extrapolative.
  evidence:
  - reference: PMID:38831459
    reference_title: "Whole genome sequencing of HER2-positive metastatic extramammary Paget's disease: a case report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Interestingly, ERBB2 gene did not exhibit high copy number gain (log2FC =
      0.4) although 90% of tumor cells stained HER2-positive.
    explanation: >-
      The single cross-site case separates protein overexpression from ERBB2
      copy-number gain and warrants partial support for vulvar EMPD.
phenotypes:
- category: Gynecologic
  name: Vulvar Lump or Mass
  description: >-
    A noticed lump or mass can be a presenting manifestation of vulvar cancer,
    including rare glandular histologies that present as vulvar lesions.
  phenotype_term:
    preferred_term: vulvar neoplasm
    term:
      id: HP:0030416
      label: Vulvar neoplasm
  evidence:
  - reference: PMID:34669204
    reference_title: "Cancer of the vulva: 2021 update."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      While vulvar cancer may be asymptomatic, most women present with vulvar
      pruritus or pain, or have noticed a lump or ulcer.
    explanation: >-
      This supports lump as a presenting sign for vulvar cancer overall; the
      evidence is treated as partial for the rarer adenocarcinoma subtype.
  - reference: PMID:35672058
    reference_title: "Diagnosis and management of primary vulvar adenocarcinoma of mammary gland type: report of two distinct cases."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      A female patient in her 60s, multiparous, Eastern Cooperative Oncology
      Group-performance status (ECOG-PS) grade 0, without relevant personal or
      family history of cancer disease, presented with a vulvar mass on the
      left labium minus that measured approximately 20 mm.
    explanation: >-
      A mammary-like vulvar adenocarcinoma case presented directly as a vulvar
      mass.
- category: Dermatologic
  name: Vulvar Ulcer
  description: >-
    Ulceration can be part of the presenting vulvar lesion complex.
  phenotype_term:
    preferred_term: vulvar ulcer
    term:
      id: HP:0200042
      label: Skin ulcer
  evidence:
  - reference: PMID:34669204
    reference_title: "Cancer of the vulva: 2021 update."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      While vulvar cancer may be asymptomatic, most women present with vulvar
      pruritus or pain, or have noticed a lump or ulcer.
    explanation: >-
      This supports ulcer as a presenting sign for vulvar cancer overall; the
      evidence is partial for adenocarcinoma-specific presentation.
- category: Dermatologic
  name: Vulvar Pruritus
  description: >-
    Pruritus is a common symptom in vulvar cancer presentations and may also be
    clinically relevant in Paget-associated vulvar glandular disease.
  phenotype_term:
    preferred_term: Pruritus vulvae
    term:
      id: HP:0032004
      label: Pruritus vulvae
  evidence:
  - reference: PMID:34669204
    reference_title: "Cancer of the vulva: 2021 update."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      While vulvar cancer may be asymptomatic, most women present with vulvar
      pruritus or pain, or have noticed a lump or ulcer.
    explanation: >-
      This supports pruritus as a vulvar cancer symptom, with partial support
      for rare adenocarcinoma subtypes.
  - reference: clinicaltrials:NCT03713203
    reference_title: "An Interventional, Phase II, Non Randomized, Mono-centric Study on the Clinical Efficacy and Safety of the Medical Device PAGETEX® as a Photodynamic Therapy Device in the Treatment of Extra-Mammary Paget's Disease of the Vulva (EMPV)"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The disease is revealed by erythematous, eczematous, pruritus and vulvar
      burns.
    explanation: >-
      The vulvar Paget trial record directly identifies pruritus as part of the
      presentation.
- category: Dermatologic
  name: Erythematous Eczematoid Vulvar Plaque
  description: >-
    Vulvar extramammary Paget disease characteristically presents with an
    erythematous, eczematoid vulvar plaque; this is a defining manifestation of
    the Paget-associated branch rather than a claim about every subtype.
  phenotype_term:
    preferred_term: Erythematous eczematoid vulvar plaque
    term:
      id: HP:0025474
      label: Erythematous plaque
  evidence:
  - reference: clinicaltrials:NCT03713203
    reference_title: "An Interventional, Phase II, Non Randomized, Mono-centric Study on the Clinical Efficacy and Safety of the Medical Device PAGETEX® as a Photodynamic Therapy Device in the Treatment of Extra-Mammary Paget's Disease of the Vulva (EMPV)"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The disease is revealed by erythematous, eczematous, pruritus and vulvar
      burns.
    explanation: >-
      The vulvar Paget trial record directly describes the erythematous and
      eczematous presentation represented by this phenotype.
- category: Pain
  name: Vulvar Pain or Burning
  description: >-
    Vulvar pain, soreness, or burning may accompany the lesion and can prompt
    diagnostic evaluation.
  phenotype_term:
    preferred_term: Vulvar pain
    term:
      id: HP:0012531
      label: Pain
  evidence:
  - reference: PMID:34669204
    reference_title: "Cancer of the vulva: 2021 update."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      While vulvar cancer may be asymptomatic, most women present with vulvar
      pruritus or pain, or have noticed a lump or ulcer.
    explanation: >-
      This supports pain as a vulvar cancer symptom, with partial support for
      the adenocarcinoma subtype.
  - reference: clinicaltrials:NCT03713203
    reference_title: "An Interventional, Phase II, Non Randomized, Mono-centric Study on the Clinical Efficacy and Safety of the Medical Device PAGETEX® as a Photodynamic Therapy Device in the Treatment of Extra-Mammary Paget's Disease of the Vulva (EMPV)"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The disease is revealed by erythematous, eczematous, pruritus and vulvar
      burns.
    explanation: >-
      The vulvar Paget trial record directly identifies burning as part of the
      presentation.
- category: Laboratory
  name: Abnormal Glandular Cytology in Paget Spread
  description: >-
    Cervical or vaginal involvement by vulvar EMPD can be clinically silent and
    detected through abnormal glandular cytology during follow-up.
  evidence:
  - reference: PMID:36766569
    reference_title: "Tips and Tricks for Early Diagnosis of Cervico-Vaginal Involvement from Extramammary Paget's Disease of the Vulva: A Referral Center Experience."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      All cases except one were firstly detected by abnormal glandular cytology.
      None reported vaginal bleeding or other suspicious symptoms.
    explanation: >-
      This supports abnormal glandular cytology as a clinically relevant
      finding in cervico-vaginal involvement from vulvar EMPD.
stages:
- name: FIGO 2021 Stage I
  description: >-
    Tumor confined to the vulva.
  substages:
  - name: FIGO 2021 Stage IA
    description: >-
      Tumor 2 cm or smaller with stromal invasion 1 mm or less.
  - name: FIGO 2021 Stage IB
    description: >-
      Tumor larger than 2 cm or with stromal invasion greater than 1 mm.
  evidence:
  - reference: PMID:34520062
    reference_title: "FIGO staging for carcinoma of the vulva: 2021 revision."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The resulting new staging for carcinoma of the vulva has two substages in
      Stage I, no substage in Stage II, three substages in Stage III, and two
      substages in Stage IV.
    explanation: >-
      The PubMed record establishes the two-substage structure of Stage I.
  - reference: url:https://europepmc.org/articles/PMC9290586?pdf=render
    reference_title: "https://europepmc.org/articles/PMC9290586?pdf=render"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      I Tumor confined to the vulva ... IA Tumor size ≤2 cm and stromal invasion
      ≤1 mm ... IB Tumor size >2 cm or stromal invasion >1 mm
    explanation: >-
      Table 3 of the open-access FIGO revision directly defines Stage I and its
      IA and IB substages.
- name: FIGO 2021 Stage II
  description: >-
    Tumor of any size extending to the lower one-third of the urethra, lower
    one-third of the vagina, or lower one-third of the anus, with negative
    regional nodes.
  evidence:
  - reference: PMID:34520062
    reference_title: "FIGO staging for carcinoma of the vulva: 2021 revision."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The resulting new staging for carcinoma of the vulva has two substages in
      Stage I, no substage in Stage II, three substages in Stage III, and two
      substages in Stage IV.
    explanation: >-
      The PubMed record establishes Stage II as an unsubdivided stage.
  - reference: url:https://europepmc.org/articles/PMC9290586?pdf=render
    reference_title: "https://europepmc.org/articles/PMC9290586?pdf=render"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      II Tumor of any size with extension to lower one-third of the urethra,
      lower one-third of the vagina, lower one-third of the anus with negative
      nodes
    explanation: >-
      Table 3 of the open-access FIGO revision directly defines the anatomic
      extent and negative-node criterion for Stage II.
- name: FIGO 2021 Stage III
  description: >-
    Tumor of any size extending to upper adjacent perineal structures, or with
    any number of nonfixed, nonulcerated regional lymph-node metastases.
  substages:
  - name: FIGO 2021 Stage IIIA
    description: >-
      Tumor extension to the upper two-thirds of the urethra, upper two-thirds
      of the vagina, bladder mucosa, or rectal mucosa, or regional lymph-node
      metastases 5 mm or smaller.
  - name: FIGO 2021 Stage IIIB
    description: Regional lymph-node metastases larger than 5 mm.
  - name: FIGO 2021 Stage IIIC
    description: Regional lymph-node metastases with extracapsular spread.
  evidence:
  - reference: PMID:34520062
    reference_title: "FIGO staging for carcinoma of the vulva: 2021 revision."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The resulting new staging for carcinoma of the vulva has two substages in
      Stage I, no substage in Stage II, three substages in Stage III, and two
      substages in Stage IV.
    explanation: >-
      The PubMed record establishes the three-substage structure of Stage III.
  - reference: url:https://europepmc.org/articles/PMC9290586?pdf=render
    reference_title: "https://europepmc.org/articles/PMC9290586?pdf=render"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      III Tumor of any size with extension to upper part of adjacent perineal
      structures, or with any number of nonfixed, nonulcerated lymph node ...
      IIIA Tumor of any size with disease extension to upper two-thirds of the
      urethra, upper two-thirds of the vagina, bladder mucosa, rectal mucosa, or
      regional lymph node metastases ≤5 mm
    explanation: >-
      Table 3 of the open-access FIGO revision directly defines Stage III and
      Stage IIIA.
  - reference: PMID:34520062
    reference_title: "FIGO staging for carcinoma of the vulva: 2021 revision."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      As an example, Stage IIIB is defined by lymph node metastasis >5 mm ...
      Similarly, Stage IIIC is defined by lymph node metastasis with
      extracapsular extension
    explanation: >-
      The primary FIGO revision's full-text prose directly defines the IIIB
      nodal-size threshold and IIIC extracapsular-extension criterion.
- name: FIGO 2021 Stage IV
  description: >-
    Tumor of any size fixed to bone, fixed or ulcerated lymph-node metastases,
    or distant metastases.
  substages:
  - name: FIGO 2021 Stage IVA
    description: >-
      Disease fixed to pelvic bone, or fixed or ulcerated regional lymph-node
      metastases.
  - name: FIGO 2021 Stage IVB
    description: Distant metastases.
  evidence:
  - reference: PMID:34520062
    reference_title: "FIGO staging for carcinoma of the vulva: 2021 revision."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The resulting new staging for carcinoma of the vulva has two substages in
      Stage I, no substage in Stage II, three substages in Stage III, and two
      substages in Stage IV.
    explanation: >-
      The PubMed record establishes the two-substage structure of Stage IV.
  - reference: url:https://europepmc.org/articles/PMC9290586?pdf=render
    reference_title: "https://europepmc.org/articles/PMC9290586?pdf=render"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      IV Tumor of any size fixed to bone, or fixed, ulcerated lymph node
      metastases, or distant metastases ... IVA Disease fixed to pelvic bone, or
      fixed or ulcerated regional ... lymph node metastases ... IVB Distant
      metastases
    explanation: >-
      Table 3 of the open-access FIGO revision directly defines Stage IV and its
      IVA and IVB substages.
progression:
- phase: Reported FIGO-stage distribution in intestinal-type disease
  subtype: Intestinal-Type
  notes: >-
    In the 40-case systematic review, Stage IA was reported in 19 cases (47.5%);
    the remaining reported cases spanned Stage IB through IVB. This is a
    cohort distribution within intestinal-type disease, not a stage definition
    and not a distribution estimate for every vulvar adenocarcinoma subtype.
  evidence:
  - reference: PMID:41463238
    reference_title: "Intestinal-Type Adenocarcinoma Is a Rare Histotype of Vulvar Neoplasm: Systematic Review of the Literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Stage IA emerged as the most frequently reported classification,
      encompassing 19 cases (47.5%).
    explanation: >-
      The review directly reports the most frequent stage and count in the
      intestinal-type case literature.
  - reference: PMID:41463238
    reference_title: "Intestinal-Type Adenocarcinoma Is a Rare Histotype of Vulvar Neoplasm: Systematic Review of the Literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      6 cases were categorized as Stage IB, (15%); 2 cases (5%) were noted as
      Stage IIB; 4 cases were classified as Stage IIIA (10%); Stage IIIB was
      identified in 1 case (2.5%), and Stage IIIC in 2 cases (5%). Beyond
      these, one case (2.5%) presented as the more advanced Stage IVB.
    explanation: >-
      The review enumerates the remaining reported stages in intestinal-type
      disease without redefining the FIGO categories.
- phase: Regional nodal spread in intestinal-type disease
  subtype: Intestinal-Type
  notes: >-
    Nodal status was reported for 32 of 40 cases; 10 of those 32 were node
    positive. The denominator is reported explicitly to avoid treating missing
    nodal data as negative.
  evidence:
  - reference: PMID:41463238
    reference_title: "Intestinal-Type Adenocarcinoma Is a Rare Histotype of Vulvar Neoplasm: Systematic Review of the Literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Lymph node metastasis status, however, was available for 32 cases (80%).
      Among these, 22 cases (68.8% of those with known status) were reported as
      negative for lymph node metastasis, while 10 cases (31.2% of those with
      known status) were positive.
    explanation: >-
      The systematic review provides the known-status denominator and nodal
      metastasis count.
- phase: Delayed recurrence risk in intestinal-type disease
  subtype: Intestinal-Type
  notes: >-
    Late recurrence is possible even after apparently successful local therapy,
    supporting extended follow-up; its frequency remains uncertain.
  evidence:
  - reference: PMID:36291953
    reference_title: "\"Intestinal-Type\" Vulvar Adenocarcinoma: A Review of the MITO Rare Tumors Group."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Sometimes, VAIt behavior can be unpredictable, with relapses even after
      many years, so more experiences and longer follow-up periods are needed
      to elucidate the best therapeutic management and its long-term prognosis.
    explanation: >-
      The review explicitly describes the possibility of late relapse and the
      need for longer follow-up.
- phase: Persistent or recurrent vulvar extramammary Paget disease
  subtype: Paget-Associated
  notes: >-
    Persistence or recurrence occurred in 86% of the referral-center cohort
    and commonly required repeated surgery (median two surgical procedures;
    range zero to 11). This estimate applies to vulvar EMPD in the reported
    cohort, not to every vulvar adenocarcinoma subtype.
  evidence:
  - reference: PMID:36766569
    reference_title: "Tips and Tricks for Early Diagnosis of Cervico-Vaginal Involvement from Extramammary Paget's Disease of the Vulva: A Referral Center Experience."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Persistence or recurrence was very common, taking place in 86% of cases
      and, thus, often requiring multiple surgical instances (median: 2;
      range: 0–11).
    explanation: >-
      The longitudinal vulvar EMPD cohort directly reports the recurrence or
      persistence proportion and repeated-surgery burden.
- phase: Five-year overall survival in vulvar extramammary Paget disease
  subtype: Paget-Associated
  notes: >-
    Five-year overall survival was 90.5% (95% CI 81.8–95.1%) after excluding
    one patient whose death date was unknown. This is a cohort-specific
    overall-survival estimate rather than adenocarcinoma-specific survival
    across the entire umbrella disorder.
  evidence:
  - reference: PMID:36766569
    reference_title: "Tips and Tricks for Early Diagnosis of Cervico-Vaginal Involvement from Extramammary Paget's Disease of the Vulva: A Referral Center Experience."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      After excluding one patient with an unknown death date, the 5 year
      overall survival was 90.5% (95% CI: 81.8–95.1%), as shown in Figure 1.
    explanation: >-
      The cohort directly reports the five-year overall-survival estimate,
      confidence interval, and exclusion.
- phase: Long-term cervicovaginal extension of vulvar Paget disease
  subtype: Paget-Associated
  notes: >-
    Cervicovaginal involvement accumulated over 15 years and was often
    asymptomatic, supporting lifelong surveillance in long-standing disease.
  evidence:
  - reference: PMID:36766569
    reference_title: "Tips and Tricks for Early Diagnosis of Cervico-Vaginal Involvement from Extramammary Paget's Disease of the Vulva: A Referral Center Experience."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Overall nine patients developed CV involvement from EMPD, with a
      cumulative incidence of 2.5% (95% CI: 0.5-8.0%) at 5 years, 6.5% (95% CI:
      1.9-15.1%) at 10 years and 14.0% (95% CI: 4.8-27.8%) at 15 years,
      respectively.
    explanation: >-
      The 94-patient longitudinal cohort quantifies the late, accumulating
      cervicovaginal complication.
- phase: Recurrent Bartholin gland adenocarcinoma
  subtype: Bartholin Gland Adenocarcinoma
  notes: >-
    The only adenocarcinoma in a 13-case Bartholin carcinoma cohort recurred and
    contributed to the two disease-specific deaths, so this is a single-case
    signal rather than a frequency estimate.
  evidence:
  - reference: PMID:29406447
    reference_title: "Bartholin Gland Carcinoma: Clinicopathologic Features, Including p16 Expression and Clinical Outcome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      recurrence occurred in 3 cases, with death due to disease in 2 of the
      patients with recurrence, including the single patient with
      adenocarcinoma.
    explanation: >-
      This directly establishes recurrence and fatal outcome in the cohort's
      single adenocarcinoma case without implying a population rate.
environmental:
- name: Broader Vulvar Cancer Risk Context (Not Subtype-Specific)
  description: >-
    Increasing age, HPV infection, smoking, inflammatory vulvar disease, and
    immunodeficiency are recognized vulvar cancer risk factors. Their
    adenocarcinoma-subtype specificity is limited, so this is annotated as
    contextual rather than definitive adenocarcinoma causation.
  evidence:
  - reference: PMID:38503056
    reference_title: "Vulvar Cancer, Version 3.2024, NCCN Clinical Practice Guidelines in Oncology."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Known risk factors for vulvar cancer include increasing age, infection
      with human papillomavirus, cigarette smoking, inflammatory conditions
      affecting the vulva, and immunodeficiency.
    explanation: >-
      This supports the general vulvar cancer risk context, but the evidence is
      partial for vulvar adenocarcinoma because many data are dominated by
      squamous carcinoma.
diagnosis:
- name: Biopsy of Suspicious Vulvar Lesion
  description: >-
    Suspicious vulvar lesions require biopsy to establish invasion and
    histologic subtype. Vulvoscopy and imaging can help target biopsy and plan
    preoperative staging.
  results: Histopathologic confirmation of invasive glandular vulvar malignancy.
  evidence:
  - reference: PMID:34669204
    reference_title: "Cancer of the vulva: 2021 update."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Therefore, any suspicious vulvar lesion should be biopsied to exclude
      invasion.
    explanation: >-
      This directly supports biopsy for suspicious vulvar lesions.
  - reference: PMID:38791925
    reference_title: "Current Preoperative Management of Vulvar Squamous Cell Carcinoma: An Overview."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Diagnosis relies on biopsy during vulvoscopy, plus imaging such as
      ultrasonography (USG), magnetic resonance imaging (MRI) and positron
      emission tomography (PET).
    explanation: >-
      This supports biopsy, vulvoscopy, and imaging in vulvar carcinoma
      diagnosis; it is partial for adenocarcinoma because the review focuses on
      squamous carcinoma.
  - reference: PMID:41375020
    reference_title: "Bartholin Gland Carcinoma: A State-of-the-Art Review of Epidemiology, Histopathology, Molecular Testing, and Clinical Management."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Because diagnostic delay is common and incidence increases with age,
      biopsy should be performed in patients with a persistent or progressive
      BG mass, solid masses or solid components within a presumed “cystic
      lesion,” or lesions invading surrounding tissues, and should be
      generously considered in peri- and postmenopausal patients.
    explanation: >-
      The Bartholin review specifies high-risk mass features that warrant
      tissue diagnosis.
- name: Subtype Immunohistochemistry and Primary-Site Exclusion
  description: >-
    Intestinal-type and mammary-like vulvar adenocarcinomas require
    immunohistochemistry and clinicoradiologic exclusion of metastatic
    gastrointestinal or breast primaries.
  results: Primary vulvar origin and histologic subtype assignment.
  evidence:
  - reference: PMID:36291953
    reference_title: "\"Intestinal-Type\" Vulvar Adenocarcinoma: A Review of the MITO Rare Tumors Group."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Therefore, immunohistochemical workup, with different tumor markers
      including CK20, CDX2, and CK7 staining, is needed.
    explanation: >-
      This supports CK20, CDX2, and CK7 immunohistochemistry for VAIt.
  - reference: PMID:41463238
    reference_title: "Intestinal-Type Adenocarcinoma Is a Rare Histotype of Vulvar Neoplasm: Systematic Review of the Literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The diagnosis must be substantiated by the exclusion of other primary
      tumors, in particular primary gastrointestinal neoplasias.
    explanation: >-
      The current systematic review directly requires exclusion of a
      gastrointestinal primary before assigning primary vulvar origin.
  - reference: PMID:35672058
    reference_title: "Diagnosis and management of primary vulvar adenocarcinoma of mammary gland type: report of two distinct cases."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Histopathological patterns are considered essential for diagnosis.
    explanation: >-
      This supports histopathology for AMGT diagnosis.
  - reference: PMID:35672058
    reference_title: "Diagnosis and management of primary vulvar adenocarcinoma of mammary gland type: report of two distinct cases."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Furthermore, it is necessary to exclude metastasis disease from
      orthotopic breast carcinoma or other organs.
    explanation: >-
      The mammary-like report directly states the primary-site exclusion
      requirement.
- name: Paget Disease Cytology and Biopsy Follow-Up
  description: >-
    For long-standing vulvar EMPD, liquid-based cytology with
    immunocytochemistry can detect clinically silent cervico-vaginal spread,
    with biopsy confirmation when abnormal cytology is found.
  results: Detection of cervico-vaginal EMPD involvement.
  evidence:
  - reference: PMID:36766569
    reference_title: "Tips and Tricks for Early Diagnosis of Cervico-Vaginal Involvement from Extramammary Paget's Disease of the Vulva: A Referral Center Experience."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Cervical and/or vaginal biopsies were always performed for
      histopathological diagnosis by identification of Paget cells in the
      epithelium or stroma.
    explanation: >-
      This supports biopsy confirmation of cervico-vaginal EMPD.
  - reference: PMID:36766569
    reference_title: "Tips and Tricks for Early Diagnosis of Cervico-Vaginal Involvement from Extramammary Paget's Disease of the Vulva: A Referral Center Experience."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Liquid-based cytology with immunocytochemistry represents a valuable tool
      for early diagnosis and should be routinely performed during the required
      lifelong follow-up.
    explanation: >-
      This supports cytology with immunocytochemistry during lifelong EMPD
      follow-up.
- name: Clinical Staging and Imaging
  description: >-
    Clinical assessment is combined with selected imaging to evaluate local
    extent, regional nodes, and distant metastases. Imaging recommendations are
    heterogeneous and most evidence is for vulvar cancer overall rather than
    adenocarcinoma-specific cohorts.
  results: Clinical extent and suspected local, nodal, or distant disease.
  evidence:
  - reference: PMID:38927973
    reference_title: "Imaging in Vulval Cancer."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Various imaging modalities are widely used in conjunction with clinical
      assessment in the diagnosis and staging of vulval cancers; however, there
      is significant heterogeneity in which modalities are recommended in
      international guidelines, reflecting the paucity of evidence in this
      area.
    explanation: >-
      This supports the combined clinical/imaging framework while preserving
      the limited and histology-mixed evidence base.
  - reference: PMID:38927973
    reference_title: "Imaging in Vulval Cancer."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      For distant metastases, CT CAP and FDG-PET/CT have the most evidence to
      support their use.
    explanation: >-
      The imaging review supports CT chest/abdomen/pelvis and FDG-PET/CT for
      distant-disease assessment in vulvar cancer overall.
- name: Regional Nodal Staging or Assessment
  description: >-
    Regional nodal assessment is considered for intestinal-type tumors larger
    than 2 cm or with suspicious nodes and for mammary-like adenocarcinoma;
    reported methods include sentinel-node biopsy and lymphadenectomy.
  results: Regional lymph-node status for staging and treatment planning.
  evidence:
  - reference: PMID:36291953
    reference_title: "\"Intestinal-Type\" Vulvar Adenocarcinoma: A Review of the MITO Rare Tumors Group."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Lymph node staging is an option advised if the tumor size is >2 cm or if
      lymph node metastases are suspected on imaging.
    explanation: >-
      This states the size- and imaging-based indications described for
      intestinal-type tumors.
  - reference: PMID:35672058
    reference_title: "Diagnosis and management of primary vulvar adenocarcinoma of mammary gland type: report of two distinct cases."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Lymphatic involvement may be assessed by sentinel lymph node biopsy or
      lymphadenectomy.
    explanation: >-
      This directly identifies nodal-assessment approaches for mammary-like
      disease.
differential_diagnoses:
- name: Metastatic Colorectal or Other Gastrointestinal Adenocarcinoma
  description: >-
    A colorectal or other gastrointestinal primary can closely mimic
    intestinal-type vulvar adenocarcinoma morphologically and by CK20/CDX2
    immunophenotype.
  distinguishing_features:
  - Establish whether a gastrointestinal primary is present by directed clinical, endoscopic, and radiologic evaluation.
  - Interpret CK7, CK20, CDX2, and related markers as a panel; intestinal differentiation alone does not prove vulvar origin.
  evidence:
  - reference: PMID:41463238
    reference_title: "Intestinal-Type Adenocarcinoma Is a Rare Histotype of Vulvar Neoplasm: Systematic Review of the Literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The diagnosis must be substantiated by the exclusion of other primary
      tumors, in particular primary gastrointestinal neoplasias.
    explanation: >-
      The systematic review directly requires gastrointestinal-primary
      exclusion for an intestinal-type vulvar diagnosis.
- name: Metastatic Breast Carcinoma
  description: >-
    Vulvar adenocarcinoma of mammary gland type can reproduce breast-carcinoma
    morphology and immunophenotype, so a metastatic orthotopic breast primary
    must be excluded.
  distinguishing_features:
  - Correlate vulvar histology and immunohistochemistry with breast examination and breast imaging.
  - Look for adjacent in situ carcinoma or non-neoplastic mammary-like vulvar tissue when present, while recognizing these features may be absent.
  evidence:
  - reference: PMID:35672058
    reference_title: "Diagnosis and management of primary vulvar adenocarcinoma of mammary gland type: report of two distinct cases."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Furthermore, it is necessary to exclude metastasis disease from
      orthotopic breast carcinoma or other organs.
    explanation: >-
      The case report directly states the metastatic breast-primary exclusion
      requirement.
- name: Bartholin Gland Cyst or Abscess
  description: >-
    Bartholin gland carcinoma is commonly first labeled as a benign cyst or
    abscess, delaying diagnosis and allowing stage progression.
  distinguishing_features:
  - Biopsy a persistent, progressive, solid, or partly solid Bartholin-region mass, particularly in peri- or postmenopausal patients.
  - Obtain tissue deep enough to assess invasion and, when possible, the transition from normal Bartholin gland to tumor.
  evidence:
  - reference: PMID:41375020
    reference_title: "Bartholin Gland Carcinoma: A State-of-the-Art Review of Epidemiology, Histopathology, Molecular Testing, and Clinical Management."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Approximately 50% of cases are diagnosed at an advanced stage due to
      misclassification as benign cysts or abscesses.
    explanation: >-
      The mixed-histology Bartholin carcinoma review directly documents the
      mimic and diagnostic delay; applicability to the adenocarcinoma subset is
      marked partial.
treatments:
- name: Surgical Local Excision or Vulvectomy
  description: >-
    Surgery is the principal local-control strategy for primary vulvar
    adenocarcinoma subtypes when technically feasible, with margin goals and
    nodal evaluation tailored to histology, size, and stage.
  action_category: THERAPEUTIC
  therapeutic_modality: SURGERY
  treatment_term:
    preferred_term: surgical procedure
    term:
      id: NCIT:C15329
      label: Surgical Procedure
  target_mechanisms:
  - target: Primary Vulvar Glandular Malignancy
    treatment_effect: INHIBITS
    description: Surgical removal aims to eliminate the local malignant glandular tumor.
    evidence:
    - reference: PMID:36291953
      reference_title: "\"Intestinal-Type\" Vulvar Adenocarcinoma: A Review of the MITO Rare Tumors Group."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        The gold standard of treatment for VAIt is surgery, with local excision
        with tumor-free margins.
      explanation: >-
        The subtype review directly links excision with tumor-free margins to
        local tumor control.
  evidence:
  - reference: PMID:36291953
    reference_title: "\"Intestinal-Type\" Vulvar Adenocarcinoma: A Review of the MITO Rare Tumors Group."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The gold standard of treatment for VAIt is surgery, with local excision
      with tumor-free margins.
    explanation: >-
      This directly supports surgery with tumor-free margins for
      intestinal-type vulvar adenocarcinoma.
  - reference: PMID:35672058
    reference_title: "Diagnosis and management of primary vulvar adenocarcinoma of mammary gland type: report of two distinct cases."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Surgical procedures include radical vulvectomy or radical local excision.
    explanation: >-
      This supports radical vulvectomy or local excision for AMGT cases.
- name: Adjuvant or Advanced-Disease Chemotherapy
  description: >-
    Chemotherapy is used selectively for advanced, recurrent, or
    histology-specific vulvar cancers, with many adenocarcinoma decisions
    extrapolated from limited case literature.
  action_category: THERAPEUTIC
  treatment_term:
    preferred_term: chemotherapy
    term:
      id: NCIT:C15632
      label: Chemotherapy
  target_mechanisms:
  - target: Regional Nodal Spread or Late Recurrence
    treatment_effect: INHIBITS
    description: Cytotoxic approaches aim to reduce residual or advanced malignant tumor burden.
    evidence:
    - reference: PMID:36291953
      reference_title: "\"Intestinal-Type\" Vulvar Adenocarcinoma: A Review of the MITO Rare Tumors Group."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        a good response to adjuvant chemotherapy treatments has been described
        in both advanced and recurrent diseases.
      explanation: >-
        The review supplies limited reported response evidence in advanced or
        recurrent intestinal-type disease.
  evidence:
  - reference: PMID:36291953
    reference_title: "\"Intestinal-Type\" Vulvar Adenocarcinoma: A Review of the MITO Rare Tumors Group."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      On the other hand, the role of neoadjuvant therapy is still in doubt, but
      a good response to adjuvant chemotherapy treatments has been described in
      both advanced and recurrent diseases.
    explanation: >-
      This supports a limited, subtype-specific role for adjuvant chemotherapy
      in advanced or recurrent VAIt while preserving uncertainty.
- name: Radiation or Concurrent Chemoradiation
  description: >-
    Radiation, including concurrent chemoradiation, is an option for selected
    advanced vulvar cancers. Applicability to adenocarcinoma remains indirect
    because the supporting evidence is histology-mixed and dominated by
    squamous carcinoma.
  action_category: THERAPEUTIC
  therapeutic_modality: RADIOTHERAPY
  treatment_term:
    preferred_term: radiation therapy
    term:
      id: NCIT:C15313
      label: Radiation Therapy
  target_mechanisms:
  - target: Regional Nodal Spread or Late Recurrence
    treatment_effect: INHIBITS
    description: >-
      Local or regional radiation is intended to reduce advanced or residual
      malignant tumor burden, alone or with concurrent chemotherapy.
    evidence:
    - reference: PMID:34669204
      reference_title: "Cancer of the vulva: 2021 update."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Treatment is predominantly surgical, particularly for squamous cell
        carcinoma, although concurrent chemoradiation is an effective alternative,
        particularly for advanced tumors.
      explanation: >-
        The review supports a radiation-containing regimen for advanced vulvar
        cancer, but only indirectly for adenocarcinoma.
  evidence:
  - reference: PMID:34669204
    reference_title: "Cancer of the vulva: 2021 update."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Treatment is predominantly surgical, particularly for squamous cell
      carcinoma, although concurrent chemoradiation is an effective alternative,
      particularly for advanced tumors.
    explanation: >-
      This supports concurrent chemoradiation in advanced vulvar cancer
      generally; it is partial for adenocarcinoma because the evidence base is
      histology-mixed and dominated by squamous carcinoma.
- name: HER2-Directed Pharmacotherapy
  description: >-
    HER2-directed systemic therapy may be relevant in selected HER2-positive
    metastatic EMPD or Paget-associated adenocarcinoma settings.
  action_category: THERAPEUTIC
  therapeutic_modality: MONOCLONAL_ANTIBODY
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: trastuzumab
      term:
        id: NCIT:C1647
        label: Trastuzumab
  target_mechanisms:
  - target: HER2-Positive EMPD Signaling (Cross-Site Case Evidence)
    treatment_effect: INHIBITS
    description: HER2-directed treatment is intended to counter HER2-positive signaling in selected metastatic EMPD.
    evidence:
    - reference: PMID:38831459
      reference_title: "Whole genome sequencing of HER2-positive metastatic extramammary Paget's disease: a case report."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        observed response to HER2-directed therapy combined with other agents
        in a comprehensive treatment regimen.
      explanation: >-
        A response was observed only within a multi-agent regimen in one
        cross-site EMPD case, so the target link remains partial.
  evidence:
  - reference: PMID:38831459
    reference_title: "Whole genome sequencing of HER2-positive metastatic extramammary Paget's disease: a case report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The presence of alternative signalling pathways and genetic variants
      suggests potential interactions with HER2 signalling, which possibly
      contributed to the HER2 overexpression and observed response to
      HER2-directed therapy combined with other agents in a comprehensive
      treatment regimen.
    explanation: >-
      This supports HER2-directed treatment response in a single metastatic
      EMPD case, so the treatment evidence is intentionally marked partial.
- name: Topical Imiquimod for Vulvar Paget Disease
  description: >-
    Topical imiquimod is an investigational or non-surgical pharmacotherapy
    option studied in non-invasive or recurrent vulvar Paget disease. Its
    relevance to invasive Paget-associated vulvar adenocarcinoma is indirect,
    so the treatment evidence is treated as partial.
  action_category: THERAPEUTIC
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: topical pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: imiquimod
      term:
        id: CHEBI:36704
        label: imiquimod
  target_mechanisms:
  - target: Vulvar Paget Cell Disease
    treatment_effect: MODULATES
    description: >-
      Topical imiquimod is intended to stimulate a local antitumor immune
      response in non-invasive or recurrent vulvar Paget disease.
    evidence:
    - reference: clinicaltrials:NCT00504023
      reference_title: "A Pilot Study of Topical Imiquimod Therapy for the Treatment of Recurrent Extramammary Paget's Disease"
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Biological therapies, such as imiquimod, may stimulate the immune
        system in different ways and stop tumor cells from growing.
      explanation: >-
        The trial rationale supports immune modulation but does not establish a
        completed efficacy comparison.
  evidence:
  - reference: clinicaltrials:NCT02385188
    reference_title: "Topical 5% Imiquimod Cream for Vulvar Paget's Disease: Clinical Efficacy, Safety and Immunological Response"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The purpose of this study is to evaluate the efficacy, safety and
      immunological response of topical 5% imiquimod cream for non-invasive
      vulvar Paget's disease.
    explanation: >-
      This supports topical imiquimod as a studied treatment for non-invasive
      vulvar Paget disease, with partial applicability to the broader
      adenocarcinoma page.
  - reference: clinicaltrials:NCT00504023
    reference_title: "A Pilot Study of Topical Imiquimod Therapy for the Treatment of Recurrent Extramammary Paget's Disease"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      PURPOSE: This clinical trial is studying how well topical imiquimod works
      in treating patients with recurrent Paget's disease of the vulva.
    explanation: >-
      This supports topical imiquimod as a trialed treatment for recurrent
      vulvar Paget disease.
- name: Photodynamic Therapy for Vulvar Paget Disease
  description: >-
    Photodynamic therapy is being studied as a local treatment alternative for
    vulvar Paget disease. It is annotated as partial because the trial evidence
    is Paget-specific and not direct evidence for all invasive vulvar
    adenocarcinoma subtypes.
  action_category: THERAPEUTIC
  treatment_term:
    preferred_term: photodynamic therapy
    term:
      id: NCIT:C15300
      label: Photodynamic Therapy
  target_mechanisms:
  - target: Vulvar Paget Cell Disease
    treatment_effect: MODULATES
    description: >-
      The local photodynamic device treatment is directed at vulvar Paget
      lesions; efficacy remains under prospective evaluation.
    evidence:
    - reference: clinicaltrials:NCT03713203
      reference_title: "An Interventional, Phase II, Non Randomized, Mono-centric Study on the Clinical Efficacy and Safety of the Medical Device PAGETEX® as a Photodynamic Therapy Device in the Treatment of Extra-Mammary Paget's Disease of the Vulva (EMPV)"
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        The objective of this study is to assess the efficacy and evaluate the
        safety of the new PDT device "PAGETEX" for the treatment of vulvar
        Paget's disease.
      explanation: >-
        The trial directly links the local PDT intervention to vulvar Paget
        disease but does not yet establish clinical efficacy.
  evidence:
  - reference: clinicaltrials:NCT03713203
    reference_title: "An Interventional, Phase II, Non Randomized, Mono-centric Study on the Clinical Efficacy and Safety of the Medical Device PAGETEX® as a Photodynamic Therapy Device in the Treatment of Extra-Mammary Paget's Disease of the Vulva (EMPV)"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Photodynamic therapy (PDT) is already used in some dermatological
      pathologies and could therefore be an alternative treatment.
    explanation: >-
      This supports photodynamic therapy as an investigational alternative for
      vulvar Paget disease.
  - reference: clinicaltrials:NCT03713203
    reference_title: "An Interventional, Phase II, Non Randomized, Mono-centric Study on the Clinical Efficacy and Safety of the Medical Device PAGETEX® as a Photodynamic Therapy Device in the Treatment of Extra-Mammary Paget's Disease of the Vulva (EMPV)"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The objective of this study is to assess the efficacy and evaluate the
      safety of the new PDT device "PAGETEX" for the treatment of vulvar
      Paget's disease.
    explanation: >-
      This clinical trial record directly links PDT evaluation to vulvar Paget
      disease.
clinical_trials:
- name: NCT00504023
  phase: NOT_APPLICABLE
  status: COMPLETED
  description: >-
    Pilot study of topical imiquimod for recurrent vulvar Paget disease. The
    ClinicalTrials.gov record listed 8 actual participants and COMPLETED status
    when checked on 2026-08-08.
  evidence:
  - reference: clinicaltrials:NCT00504023
    reference_title: "A Pilot Study of Topical Imiquimod Therapy for the Treatment of Recurrent Extramammary Paget's Disease"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      PURPOSE: This clinical trial is studying how well topical imiquimod works
      in treating patients with recurrent Paget's disease of the vulva.
    explanation: >-
      The registry summary directly states the disease and intervention studied.
- name: NCT02385188
  phase: PHASE_III
  status: COMPLETED
  description: >-
    Phase III study of topical 5% imiquimod for non-invasive vulvar Paget
    disease. The ClinicalTrials.gov record listed 25 actual participants and
    COMPLETED status when checked on 2026-08-08.
  evidence:
  - reference: clinicaltrials:NCT02385188
    reference_title: "Topical 5% Imiquimod Cream for Vulvar Paget's Disease: Clinical Efficacy, Safety and Immunological Response"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The purpose of this study is to evaluate the efficacy, safety and
      immunological response of topical 5% imiquimod cream for non-invasive
      vulvar Paget's disease.
    explanation: >-
      The registry summary directly states the intervention, disease state, and
      study objectives.
- name: NCT03713203
  phase: NOT_APPLICABLE
  status: RECRUITING
  description: >-
    PAGETEX photodynamic-therapy device study for vulvar extramammary Paget
    disease. Structured ClinicalTrials.gov metadata classified the device study
    phase as not applicable even though its official title says “Phase II”; it
    listed 24 estimated participants and RECRUITING status when checked on
    2026-08-08.
  evidence:
  - reference: clinicaltrials:NCT03713203
    reference_title: "An Interventional, Phase II, Non Randomized, Mono-centric Study on the Clinical Efficacy and Safety of the Medical Device PAGETEX® as a Photodynamic Therapy Device in the Treatment of Extra-Mammary Paget's Disease of the Vulva (EMPV)"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The objective of this study is to assess the efficacy and evaluate the
      safety of the new PDT device "PAGETEX" for the treatment of vulvar
      Paget's disease.
    explanation: >-
      The registry summary directly states the device, target disease, and
      efficacy/safety objectives.
discussions:
- discussion_id: vulvar_adeno_subtype_evidence_gap
  prompt: >-
    What are the subtype-specific incidence, molecular drivers, natural
    history, and comparative treatment outcomes across the officially grouped
    primary vulvar adenocarcinoma descendants?
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - pathophysiology#Primary Vulvar Glandular Malignancy
  - pathophysiology#Regional Nodal Spread or Late Recurrence
  rationale: >-
    The MONDO umbrella also groups rare sebaceous, eccrine (including
    porocarcinoma), apocrine, Skene-gland, clear-cell hidradenocarcinoma, and
    Bartholin adenoid-cystic branches. Those descendants are represented here
    so that scope is explicit, but remain under-curated because disease-specific
    evidence was not established in this review. A multi-institutional registry
    with centralized pathology review and subtype-resolved outcomes is needed
    before broad vulvar-cancer treatment evidence can be treated as
    adenocarcinoma-specific.
  evidence:
  - reference: PMID:41463238
    reference_title: "Intestinal-Type Adenocarcinoma Is a Rare Histotype of Vulvar Neoplasm: Systematic Review of the Literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Given the extremely low incidence of VAIt, individual case reports and
      small case series represent the only source of information about this
      condition in the literature, which inherently limits the power of
      definitive conclusions and uniform treatment protocols.
    explanation: >-
      The current systematic review explicitly identifies the evidence-design
      limitation for one major subtype.
- discussion_id: vulvar_empd_cross_site_molecular_gap
  prompt: >-
    How often are HER2 overexpression and FGFR1/TGF-beta pathway alterations
    present and therapeutically predictive in vulvar, rather than non-vulvar,
    EMPD?
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - pathophysiology#HER2-Positive EMPD Signaling (Cross-Site Case Evidence)
  rationale: >-
    The available WGS and treatment-response evidence in this entry comes from
    one metastatic scrotal EMPD case. Vulvar-specific cohorts with standardized
    IHC, copy-number, sequencing, treatment, and outcome data are needed before
    estimating prevalence or predictive value.
  evidence:
  - reference: PMID:38831459
    reference_title: "Whole genome sequencing of HER2-positive metastatic extramammary Paget's disease: a case report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Immunohistochemical staining on the scrotal wall tumor and bone marrow
      metastasis demonstrated HER2 overexpression.
    explanation: >-
      The specimen site makes the cross-site generalizability gap explicit.
notes: >-
  Falcon deep research was performed on 2026-05-09 and the entry was reviewed
  on 2026-08-08. Vulvar adenocarcinoma evidence remains sparse and
  subtype-specific; broad vulvar-cancer or mixed-histology evidence and
  cross-site EMPD evidence are therefore annotated as partial when applied to
  this disease category.
📚

References & Deep Research

Deep Research

1
Falcon ▸
1. Disease Information
Edison Scientific Literature 43 citations 2026-05-09T09:45:02.379918

1. Disease Information

1.1 What is the disease?

Vulvar adenocarcinoma refers to malignant epithelial tumors of the vulva with glandular differentiation. In vulvar cancer, squamous cell carcinoma (SCC) is predominant (>90%), and adenocarcinomas are uncommon. Rarer vulvar histologies explicitly recognized in contemporary guidelines include extramammary Paget’s disease and Bartholin gland adenocarcinoma, among others. (aburustum2024vulvarcancerversion pages 1-2, ha2024imaginginvulval pages 1-2)

1.2 Key identifiers (available from retrieved sources)

  • ICD-10 (vulvar cancer overall): C51 (vulvar cancer) used in an administrative-database study. (muigai2018potentialdelayin pages 1-2)
  • ICD-10 related codes used as “pre-diagnosis” mimics/overlaps: Bartholin gland diseases N75; inflammation of vagina/vulva N76; other vulvar noninflammatory disorders N90.5–N90.9. (muigai2018potentialdelayin pages 1-2)
  • FIGO staging: FIGO 2021 applies to vulvar cancers of all morphologic types except melanoma and incorporates imaging in staging; depth of invasion measurement is specified. (ha2024imaginginvulval pages 1-2, ha2024imaginginvulval media 862afa93)
  • WHO classification: Vulvar adenocarcinomas should be diagnosed/subtyped using the WHO 2020 classification (as referenced in reporting standards). (faruqi2018standardsanddatasets pages 12-16)

Unavailable with current tool evidence: OMIM, Orphanet, MeSH IDs, MONDO ID.

1.3 Synonyms / alternative names (subtype-level)

  • Intestinal-type vulvar adenocarcinoma (VAIt): WHO 2020 describes “primary villo-glandular mucinous adenocarcinoma exhibiting intestinal differentiation” and discourages “cloacogenic carcinoma/adenocarcinoma” terminology. (dellino2022“intestinaltype”vulvaradenocarcinoma pages 1-2)
  • Adenocarcinoma of mammary gland type (AMGT) / mammary-like gland adenocarcinoma of vulva. (morais2022diagnosisandmanagement pages 1-2)
  • Extramammary Paget’s disease (EMPD) of vulva; can be invasive or represent manifestation of underlying vulvar adenocarcinoma per Wilkinson/Brown subclassification. (iacobone2023tipsandtricks pages 2-4)

1.4 Evidence source type

  • Predominantly aggregated resources (NCCN guideline; imaging guideline review; staging/reporting standards) plus cohort/registry analyses (SEER metastatic vulvar cancer; EMPD referral-center cohort; Bartholin carcinoma institutional cohort) and case reports (mammary-like adenocarcinoma; metastatic HER2+ EMPD WGS). (aburustum2024vulvarcancerversion pages 1-2, ha2024imaginginvulval pages 1-2, meng2024overallsurvivalassociated pages 1-2, iacobone2023tipsandtricks pages 2-4, nazeran2019bartholinglandcarcinoma pages 1-2, morais2022diagnosisandmanagement pages 1-2, lim2024wholegenomesequencing pages 1-2)

2. Etiology

2.1 Disease causal factors (current understanding)

Because “vulvar adenocarcinoma” is a category spanning multiple entities, etiology is subtype-dependent: - Bartholin gland primaries: etiologic inference is limited by rarity; HPV appears important for Bartholin SCC but not clearly established for adenocarcinoma. In a 13-case series, all Bartholin SCC showed diffuse p16, while the single adenocarcinoma showed patchy p16 staining. (nazeran2019bartholinglandcarcinoma pages 1-2) - Intestinal-type vulvar adenocarcinoma: proposed embryologic origins include cloacal remnants and other metaplasia hypotheses; inflammation and genetic changes are discussed. (dellino2022“intestinaltype”vulvaradenocarcinoma pages 1-2, dellino2022“intestinaltype”vulvaradenocarcinoma pages 5-6) - EMPD: described as a rare neoplasm arising in apocrine-rich skin regions including vulva; molecular mechanisms include HER2 biology and alternative pathway activation (e.g., FGFR1/TGFβ enrichment in one WGS case). (lim2024wholegenomesequencing pages 1-2)

2.2 Risk factors

From NCCN Vulvar Cancer v3.2024 (applies to vulvar cancer overall; includes rare histologies): - Increasing age - HPV infection - Cigarette smoking - Inflammatory vulvar conditions - Immunodeficiency (aburustum2024vulvarcancerversion pages 1-2)

Intestinal-type VAIt review additionally lists exposures/conditions relevant to vulvar carcinogenesis broadly (lichen sclerosus/vulvar dystrophies, smoking, HPV infection) and environmental insults (infections, UV, physical damage), but without quantitative risk estimates for VAIt specifically. (dellino2022“intestinaltype”vulvaradenocarcinoma pages 5-6)

For vulvar SCC pathogenesis context (important for mixed histology differential and prevention frameworks): HPV DNA is reported in ~40% of invasive vulvar cancers in one modern review, with HPV-associated tumors tending to occur in younger women and having better outcomes; HPV-independent tumors are associated with chronic dermatoses such as lichen sclerosus. (ayalapeacock2025advancesinvulvar pages 1-3)

2.3 Protective factors

No protective genetic or environmental factors specific to vulvar adenocarcinoma subtypes were identified in retrieved sources.

2.4 Gene–environment interactions

No explicit gene–environment interaction evidence specific to vulvar adenocarcinoma was identified in retrieved sources.

3. Phenotypes

3.1 Core clinical phenotypes (subtype-aware)

A. Vulvar EMPD (clinical phenotype and QoL impact) - Typical appearance: “erythematous, scaly or eczematous plaque on the vulva and perineum with occasional erosions or ulcerations, hypopigmentation and nodules” and symptoms: “Itching and burning pain”. (iacobone2023tipsandtricks pages 1-2) - High relapse burden: persistence/recurrence is common (86% in one cohort), often requiring repeated procedures. (iacobone2023tipsandtricks pages 2-4) - Cervico-vaginal spread can be clinically silent: “None reported vaginal bleeding or other suspicious symptoms” and detection was frequently via abnormal glandular cytology. (iacobone2023tipsandtricks pages 1-2)

Suggested HPO terms (examples): - Vulvar pruritus (HP:0031297; if unavailable, use “Pruritus” HP:0000989) - Burning pain (Pain; HP:0012531) - Erythematous skin lesion (HP:0025548) - Eczematous dermatitis (HP:0000964) - Vulvar mass (HP:0030417; if unavailable, “Mass” HP:0100242)

B. Bartholin-region carcinoma (including adenocarcinoma subtype) - Presents as a mass in the Bartholin region; diagnostic delay is common due to misclassification as cyst/abscess, motivating biopsy in women ≥40–45 with persistent/recurrent solid lesions. (kostov2025bartholinglandcarcinoma pages 20-21)

Suggested HPO terms: - Vulvar mass (HP:0030417), Vulvar pain (HP:0031242), Ulceration (HP:0001053)

C. Intestinal-type vulvar adenocarcinoma (VAIt) - Often presents as a solitary lesion in labia/perineal/posterior vulvar structures and may mimic benign lesions. (colalillo2025intestinaltypeadenocarcinomais pages 11-13, dellino2022“intestinaltype”vulvaradenocarcinoma pages 1-2)

3.2 Natural history and progression

  • EMPD: persistent/relapsing course; cervico-vaginal involvement cumulative incidence increased over time (2.5% at 5 years, 6.5% at 10 years, 14.0% at 15 years). (iacobone2023tipsandtricks pages 1-2)
  • FIGO staging and invasion: FIGO 2021 stage IA includes tumors ≤2 cm with stromal invasion ≤1 mm; stage IB includes >2 cm or invasion >1 mm. (ha2024imaginginvulval pages 1-2, ha2024imaginginvulval media 862afa93)

3.3 Quality of life impact

Direct QoL instruments specific to vulvar adenocarcinoma were not retrieved; however, EMPD symptom burden (itching/burning) and high recurrence requiring repeated interventions plausibly affects QoL and sexual function. (iacobone2023tipsandtricks pages 2-4, iacobone2023tipsandtricks pages 1-2)

4. Genetic/Molecular Information

4.1 Causal genes

No germline causal genes specific to “vulvar adenocarcinoma” as a disease category were identified in retrieved sources.

4.2 Somatic alterations, biomarkers, and IHC patterns (subtype-level)

A. Vulvar EMPD / Paget-associated vulvar adenocarcinoma - HER2 biology is clinically important. In a WGS case report and literature synthesis, HER2 overexpression in EMPD series was reported as 15–65%, with ERBB2 amplification 13–43%; in the case, >90% tumor cells stained HER2+ with ≥40% showing 3+ intensity. (lim2024wholegenomesequencing pages 2-4) - WGS found copy number gains on chromosomes 7 and 8 (n=81 genes, 92.6% on chr8) and pathway enrichment for TGFβ and FGFR1 signaling; notably “ERBB2 gene did not exhibit high copy number gain… although 90% of tumor cells stained HER2-positive”, suggesting overexpression without strong ERBB2 CN gain in that case. (lim2024wholegenomesequencing pages 1-2)

Mechanistic interpretation (expert analysis): These findings support a model where HER2 protein overexpression can occur via mechanisms beyond high-level ERBB2 amplification (e.g., regulatory/structural alterations), and where parallel signaling (FGFR1/TGFβ) may modulate response/resistance to HER2-directed therapy. (lim2024wholegenomesequencing pages 1-2)

B. Mammary-like / mammary gland type adenocarcinoma (AMGT) of the vulva - IHC profile can resemble breast carcinoma: strong ER positivity (reported 90–100%), CK7/CAM5.2/GATA3 positivity; typically negative for PR, GCDFP-15, SOX10, p63, CK20. HER2 may be equivocal (2+) with FISH negative in a case. (morais2022diagnosisandmanagement pages 1-2) - Key diagnostic principle is exclusion of a breast primary by clinical and imaging workup. (morais2022diagnosisandmanagement pages 1-2)

C. Intestinal-type vulvar adenocarcinoma (VAIt) - Characteristic “intestinal” IHC phenotype: frequent CK20 and CDX2 positivity, often CEA positive, variable CK7 and p16; requires exclusion of metastatic colorectal primary. (dellino2022“intestinaltype”vulvaradenocarcinoma pages 1-2, colalillo2025intestinaltypeadenocarcinomais pages 11-13)

D. Bartholin gland carcinoma (with adenocarcinoma subtype) - In a 13-case cohort (1984–2017), Bartholin SCC showed diffuse p16; the single adenocarcinoma showed patchy p16 staining. (nazeran2019bartholinglandcarcinoma pages 1-2) - Reporting standards emphasize diagnosing primary Bartholin gland origin by anatomic region involvement, compatible histology, no other primary identified, and preferably adjacent normal Bartholin gland tissue. (faruqi2018standardsanddatasets pages 12-16)

4.3 Epigenetics / chromosomal abnormalities

Not specifically identified for vulvar adenocarcinoma subtypes in retrieved evidence.

4.4 Suggested pathway and ontology terms

Pathways (GO biological process suggestions): - ERBB2 signaling pathway / receptor tyrosine kinase signaling (GO:0007169; broad) - PI3K-AKT signaling (useful for HER2/PTEN context; supported indirectly via trastuzumab resistance mechanisms and HER2 pathway emphasis) (lim2024wholegenomesequencing pages 1-2) - TGFβ receptor signaling pathway (GO:0007179) (lim2024wholegenomesequencing pages 1-2) - FGFR signaling pathway (GO:0008543) (lim2024wholegenomesequencing pages 1-2)

Cell types (Cell Ontology suggestions): - Keratinocyte / epithelial cell (CL:0000312; generic epithelium) - Glandular epithelial cell / secretory epithelial cell (useful for adenocarcinoma and apocrine-associated EMPD) (lim2024wholegenomesequencing pages 1-2)

5. Environmental Information

  • Lifestyle/environmental factors (vulvar cancer overall): smoking is a risk factor per NCCN 2024. (aburustum2024vulvarcancerversion pages 1-2)
  • Inflammatory vulvar conditions: risk factor per NCCN; HPV-independent pathway often linked to chronic dermatoses (e.g., lichen sclerosus) in SCC literature, relevant for differential diagnosis and prevention frameworks. (aburustum2024vulvarcancerversion pages 1-2, ayalapeacock2025advancesinvulvar pages 1-3)
  • Infectious agents: HPV infection is a recognized risk factor for vulvar cancer; HPV’s role in VAIt is described as ambiguous in older systematic review, and Bartholin SCC appears HPV-associated by p16. (aburustum2024vulvarcancerversion pages 1-2, nazeran2019bartholinglandcarcinoma pages 1-2, dellino2022“intestinaltype”vulvaradenocarcinoma pages 9-10)

6. Mechanism / Pathophysiology

6.1 Subtype-specific causal chains (high-level)

A. EMPD / Paget-associated adenocarcinoma 1) Transformation of apocrine-rich cutaneous epithelium into Paget cells within epidermis.
2) Potential progression to stromal invasion and/or association with an underlying adenocarcinoma (Wilkinson/Brown Type 1b/1c).
3) Molecular drivers may include HER2 overexpression; alternative signaling (FGFR1/TGFβ) may contribute to aggressive/metastatic behavior and treatment response/resistance. (iacobone2023tipsandtricks pages 2-4, lim2024wholegenomesequencing pages 1-2)

B. Intestinal-type vulvar adenocarcinoma 1) Proposed embryologic substrate (persistent cloacal remnants or metaplastic intestinal epithelium).
2) Development of colorectal-like glandular neoplasm with intestinal differentiation.
3) Clinical manifestation as vulvar/perineal lesion; important downstream step is ruling out metastatic colorectal carcinoma. (dellino2022“intestinaltype”vulvaradenocarcinoma pages 1-2, dellino2022“intestinaltype”vulvaradenocarcinoma pages 5-6)

C. Mammary-like gland adenocarcinoma 1) Malignant transformation of mammary-like vulvar glands.
2) Breast-carcinoma-like morphology and ER-driven biology.
3) Clinical implication: requires exclusion of metastatic breast primary and may suggest endocrine-therapy relevance (inferred from ER positivity; treatment decisions are individualized). (morais2022diagnosisandmanagement pages 1-2)

7. Anatomical Structures Affected

7.1 Organ/tissue level (UBERON suggestions)

  • Vulva (UBERON:0000997)
  • Labia majora/minora (UBERON terms)
  • Bartholin gland (greater vestibular gland) (UBERON term; implicated in Bartholin primaries) (nazeran2019bartholinglandcarcinoma pages 1-2)
  • Perineum / anogenital region (relevant for EMPD distribution) (lim2024wholegenomesequencing pages 1-2)
  • Cervix and vagina (for cervico-vaginal involvement in EMPD) (iacobone2023tipsandtricks pages 1-2)

7.2 Subcellular

Not specifically addressed in retrieved evidence.

8. Temporal Development

  • Typical onset: vulvar cancers are more common with increasing age; EMPD typical age 60–80 years; EMPD cohort mean 63.3 years. (aburustum2024vulvarcancerversion pages 1-2, lim2024wholegenomesequencing pages 1-2, iacobone2023tipsandtricks pages 2-4)
  • Course: EMPD is often chronic/relapsing (local recurrence after excision reported up to 73% in literature; cohort persistence/recurrence 86%). (iacobone2023tipsandtricks pages 1-2, iacobone2023tipsandtricks pages 2-4)
  • Late events: cervico-vaginal involvement may occur very late (example: 251 months after initial vulvar EMPD). (iacobone2023tipsandtricks pages 6-9)

9. Inheritance and Population

9.1 Epidemiology

  • Global burden (vulvar cancer overall): ~47,000 cases in 2022 reported in a 2024 imaging review. (ha2024imaginginvulval pages 1-2)
  • US annual diagnoses (vulvar cancer overall): NCCN cites ~6,470 annually. (aburustum2024vulvarcancerversion pages 1-2)
  • EMPD incidence: 0.1–2.4 per million per year; ~20% present with distant metastatic disease. (lim2024wholegenomesequencing pages 1-2)

9.2 Sex ratio

  • Vulvar cancers occur in individuals with vulvar anatomy; EMPD also occurs in male genital region (case report). (lim2024wholegenomesequencing pages 1-2)

9.3 Genetics/inheritance

No Mendelian inheritance pattern is established for vulvar adenocarcinoma in retrieved evidence.

10. Diagnostics

10.1 Clinical and pathology diagnosis

  • Biopsy is required for definitive diagnosis of vulvar lesions; vulvoscopy helps identify optimal biopsy sites. (corte2024currentpreoperativemanagement pages 1-2, kesic2022earlydiagnosticsof pages 1-2)

EMPD cervico-vaginal extension diagnostic pathway (referral center practice): - “All cases except one were firstly detected by abnormal glandular cytology.” (iacobone2023tipsandtricks pages 1-2) - Abnormal cytology prompted colposcopy and cervical/vaginal biopsies; HPV testing negative in CV EMPD cases; HER2 immunocytochemistry used on cell blocks in some cases. (iacobone2023tipsandtricks pages 6-9)

Differential diagnosis (key points): - Mammary-like vulvar adenocarcinoma requires exclusion of breast primary (mammography/US/PET used in reported cases). (morais2022diagnosisandmanagement pages 1-2) - Intestinal-type vulvar adenocarcinoma requires exclusion of metastatic colorectal carcinoma; CDX2/CK20/CK7 patterns aid. (dellino2022“intestinaltype”vulvaradenocarcinoma pages 1-2) - EMPD secondary disease exclusion can use CDX-2 and uroplakin-III (and other panels) to rule out colorectal/urothelial origins. (iacobone2023tipsandtricks pages 9-10)

10.2 Imaging and staging

FIGO 2021 staging table (visual evidence): see Table 1 image (ha2024imaginginvulval media 862afa93).

Imaging recommendations by stage (guideline-synthesis): - No routine imaging for clinically FIGO stage IA. (ha2024imaginginvulval pages 2-4) - Pelvic MRI for local staging in tumors with invasion >1 mm, larger size (e.g., >4 cm), or suspected extension to urethra/vagina/anus. (ha2024imaginginvulval pages 2-4) - For advanced or metastatic disease: CT chest/abdomen/pelvis or FDG-PET/CT. (ha2024imaginginvulval pages 2-4)

Imaging performance statistics (vulvar cancer literature; mostly SCC but used clinically across histologies): - MRI nodal sensitivity highly variable (≈40–52% up to 86–89%), specificity generally high (≈82–100%). CT sensitivity low (≈43–58%). (ha2024imaginginvulval pages 4-5) - Meta-analysis referenced in imaging review: PET/CT per-patient sensitivity 70%, specificity 90%. (ha2024imaginginvulval pages 5-7) - Vulvoscopy diagnostic metrics in a 2024 overview: sensitivity 98%, specificity 40%, NPV 98% for malignant lesions. (corte2024currentpreoperativemanagement pages 1-2)

11. Outcome/Prognosis

11.1 EMPD outcomes

  • In a 94-woman vulvar EMPD cohort: 5-year OS 90.5% (95% CI 81.8–95.1%), persistence/recurrence 86%, median 2 surgeries (0–11). (iacobone2023tipsandtricks pages 2-4)

11.2 Nodal status prognostic impact (vulvar cancer overall)

  • 2-year disease-free survival reported as 88% (node-negative) vs 60% / 43% / 29% for 1 / 2 / >2 positive nodes, respectively. (ha2024imaginginvulval pages 1-2)

11.3 Bartholin gland carcinoma outcomes

  • In a 13-case cohort: 9 (75%) disease-free at mean follow-up 53.7 months; 3 recurrences; 2 disease-specific deaths among those with recurrence, including the adenocarcinoma case. (nazeran2019bartholinglandcarcinoma pages 1-2)

11.4 Metastatic vulvar cancer (SEER)

  • Chemoradiotherapy associated with improved OS vs radiotherapy alone in propensity-matched cohort (HR 0.7367, 95% CI 0.5906–0.9190; P=0.0049). (meng2024overallsurvivalassociated pages 1-2)

12. Treatment

12.1 Guideline-based management framework (vulvar cancer overall; rare histologies acknowledged)

NCCN v3.2024 provides stage-based management for vulvar cancer and explicitly includes rare histologies such as extramammary Paget’s disease and Bartholin gland adenocarcinoma in its scope of “rarer histologies”. (aburustum2024vulvarcancerversion pages 1-2)

12.2 Subtype-oriented treatments and real-world implementations

A. EMPD (including noninvasive disease) — local and topical treatments - In practice, surgery is common (92/94 in one cohort), and relapse management includes topical imiquimod (63%), photodynamic therapy (5%), and radiotherapy (12%). (iacobone2023tipsandtricks pages 2-4, iacobone2023tipsandtricks pages 4-6)

B. HER2-directed systemic therapy for metastatic EMPD - A WGS case report described rapid response to paclitaxel plus trastuzumab in HER2+ de novo metastatic EMPD. (lim2024wholegenomesequencing pages 2-4)

C. Bartholin gland carcinoma/adenocarcinoma - Management is often extrapolated from vulvar cancer; experts emphasize molecular profiling (DNA panels with CNV, RNA fusions, MSI/TMB/PD-L1) to reduce misclassification and enable targeted/immunotherapy in advanced disease. (kostov2025bartholinglandcarcinoma pages 20-21)

12.3 Clinical trials (selected; real-world implementability)

Topical imiquimod trials (noninvasive vulvar Paget/EMPD): - NCT02385188 (Phase 3; completed; n=25): topical 5% imiquimod 3×/week for 16 weeks; primary endpoint clinical response 12 weeks after end of treatment; includes QoL instruments (EQ-5D, DLQI, FSDS). (NCT02385188 chunk 1) - NCT00504023 (pilot; completed; n=8): imiquimod 3×/week up to 12 weeks; biopsies at baseline and 12 weeks; follow-up every 3 months for ≥2 years. (NCT00504023 chunk 1)

Photodynamic therapy device trial: - NCT03713203 (Phase II; recruiting; n=24): PAGETEX® device with Metvixia; 2–4 PDT sessions; primary endpoint disease control rate at 3 months; excludes invasive disease/underlying adenocarcinoma. (NCT03713203 chunk 1)

Systemic/advanced vulvar cancer trial example: - NCT03452332 (Phase 1; completed): SBRT + tremelimumab + durvalumab in recurrent/metastatic cervical/vaginal/vulvar cancers. (trial record retrieved but not evidence-extracted in provided snippets; use cautiously)

12.4 MAXO term suggestions (examples)

  • Surgical excision/vulvectomy: MAXO: surgical excision (generic)
  • Radiotherapy: MAXO: radiotherapy
  • Chemotherapy (platinum/taxane): MAXO: chemotherapy
  • HER2-directed therapy (trastuzumab): MAXO: targeted therapy / monoclonal antibody therapy
  • Topical imiquimod: MAXO: topical immunotherapy
  • Photodynamic therapy: MAXO: photodynamic therapy

13. Prevention

  • Risk factor modification (general vulvar cancer): NCCN identifies smoking, HPV, inflammatory vulvar conditions, and immunodeficiency as risk factors; these support prevention via smoking cessation, HPV prevention/control, and treatment of chronic vulvar inflammatory disease, although explicit preventive recommendations were not present in the retrieved NCCN excerpt. (aburustum2024vulvarcancerversion pages 1-2)
  • Secondary prevention: early biopsy of suspicious vulvar lesions and careful evaluation of VIN/lichen sclerosus are emphasized in diagnostic reviews; brush cytology is investigated as triage for VIN but biopsy remains gold standard. (kesic2022earlydiagnosticsof pages 1-2)

Evidence gap: explicit HPV vaccination impact on vulvar adenocarcinoma or adenocarcinoma-specific prevention strategies were not retrieved.

14. Other Species / Natural Disease

No evidence identified in retrieved sources.

15. Model Organisms

A trastuzumab-resistant EMPD model is reported with PTEN loss as a potential resistance mechanism (supporting mechanistic research and therapy optimization), but detailed model description was not extracted in current evidence snippets. (dellino2022“intestinaltype”vulvaradenocarcinoma pages 1-2, lim2024wholegenomesequencing pages 1-2)

Key Recent Developments (prioritizing 2023–2024)

  1. NCCN Vulvar Cancer v3.2024 explicitly contextualizes rarer histologies including Bartholin gland adenocarcinoma and EMPD within a unified management framework and lists key risk factors. Publication: Mar 2024; URL: https://doi.org/10.6004/jnccn.2024.0013 (aburustum2024vulvarcancerversion pages 1-2)
  2. Imaging and FIGO 2021 staging implementation (2024): staging applicability to non-melanoma vulvar cancers and imaging recommendations by stage; provides pooled PET/CT performance and highlights limitations. Publication: Jun 2024; URL: https://doi.org/10.3390/cancers16122269 (ha2024imaginginvulval pages 1-2, ha2024imaginginvulval pages 2-4, ha2024imaginginvulval pages 5-7, ha2024imaginginvulval media 862afa93)
  3. Genomics-enabled precision approaches in EMPD (2024): WGS of HER2+ metastatic EMPD documents CNV landscape, pathway enrichment (FGFR1/TGFβ), and clinical response to HER2-directed therapy combined with chemotherapy. Publication: Jun 2024; URL: https://doi.org/10.1186/s13023-024-03169-y (lim2024wholegenomesequencing pages 2-4, lim2024wholegenomesequencing pages 1-2)
  4. Refined long-term surveillance concept for vulvar EMPD (2023): referral-center data quantify recurrence and late cervico-vaginal involvement; supports lifelong follow-up and cytology/biopsy-based detection. Publication: Jan 2023; URL: https://doi.org/10.3390/diagnostics13030464 (iacobone2023tipsandtricks pages 2-4, iacobone2023tipsandtricks pages 1-2)

Summary Table (Subtype comparison)

Entity/subtype Key definition/notes Typical age/presentation Key diagnostic IHC/biomarkers Key management Key quantitative outcomes/statistics Key citations
Invasive extramammary Paget disease (EMPD) / Paget-associated vulvar adenocarcinoma Primary vulvar EMPD is classified as cutaneous-origin disease; Wilkinson/Brown subtypes include type 1a (intraepithelial), 1b (stromal invasion), and 1c (manifestation of primary vulvar adenocarcinoma). Paget-associated invasive adenocarcinoma can show strong HER2 expression. Mean age 63.3 years (range 31–88) in a 94-patient vulvar EMPD cohort; lesions may recur/persist and cervico-vaginal spread can be clinically silent, often first detected by abnormal glandular cytology. HER2 overexpression reported in Paget-associated vulvar adenocarcinoma; cervical/vaginal involvement diagnosis used cytology with immunocytochemistry plus biopsy confirmation of Paget cells. Surgery is mainstay; recurrent/persistent disease may also be treated with topical imiquimod, photodynamic therapy, or radiotherapy; lifelong surveillance is important, including annual cervical/vaginal assessment in long-standing disease. In 94 women: 81% type 1a; invasive EMPD in 36%; persistence/recurrence 86%; median 2 surgeries (range 0–11); 5-year OS 90.5% (95% CI 81.8–95.1%). Cervico-vaginal involvement cumulative incidence 2.5% at 5 years, 6.5% at 10 years, 14.0% at 15 years. (iacobone2023tipsandtricks pages 2-4, aburustum2024vulvarcancerversion pages 1-2) (iacobone2023tipsandtricks pages 2-4, aburustum2024vulvarcancerversion pages 1-2)
Intestinal-type vulvar adenocarcinoma (primary villo-glandular mucinous adenocarcinoma with intestinal differentiation) Extremely rare primary vulvar adenocarcinoma; WHO 2020 describes this as primary villo-glandular mucinous adenocarcinoma with intestinal differentiation and discourages “cloacogenic” terminology. Histology resembles mucinous colorectal carcinoma with villo-glandular architecture, goblet/Paneth cells, and mucin. Must exclude metastatic gastrointestinal primary. Median age 58 years; reported range 31–92 years; commonly arises in labia/perineal or posterior vulvar structures and may mimic benign lesions. Intestinal phenotype with CK20 and CDX2 positivity, often CEA positive and variable CK7/p16; diagnosis requires radiologic/clinical exclusion of another primary site. Surgical excision with tumor-free margins is standard; lymph-node staging is considered/recommended especially for tumors >2 cm or when imaging suggests nodal disease; adjuvant or systemic therapy reported in selected advanced/recurrent cases. 2022 review found 29 cases; 2025 review found 40 cases overall (41 including authors’ case in another excerpt). Nodal metastases in ~31.2%–31.5%; mortality due to disease about 10%; FIGO stage IA most frequent at diagnosis. (dellino2022“intestinaltype”vulvaradenocarcinoma pages 2-5, dellino2022“intestinaltype”vulvaradenocarcinoma pages 1-2, colalillo2025intestinaltypeadenocarcinomais pages 11-13, colalillo2025intestinaltypeadenocarcinomais pages 1-2, colalillo2025intestinaltypeadenocarcinomais pages 10-11) (dellino2022“intestinaltype”vulvaradenocarcinoma pages 2-5, dellino2022“intestinaltype”vulvaradenocarcinoma pages 1-2, colalillo2025intestinaltypeadenocarcinomais pages 11-13, colalillo2025intestinaltypeadenocarcinomais pages 1-2, colalillo2025intestinaltypeadenocarcinomais pages 10-11)
Vulvar adenocarcinoma of mammary gland type / mammary-like glands Extremely rare adenocarcinoma thought to arise from mammary-like vulvar glands; pathology can resemble invasive ductal breast carcinoma, and breast primary must be excluded clinically/radiologically. Postmenopausal presentation in reported cases; may present as vulvar mass/lump. Strong ER positivity reported in 90%–100%; CK7, CAM5.2, GATA3 positive; typically negative for PR, GCDFP-15, SOX10, p63, CK20. HER2 may be equivocal (2+) with negative FISH in a reported case. Radical vulvectomy or radical local excision; nodal assessment by sentinel lymph node biopsy or lymphadenectomy; adjuvant therapy tailored to IHC profile and stage. Evidence base is limited to case reports/small series; quantitative outcome estimates are not established in the gathered evidence. (morais2022diagnosisandmanagement pages 1-2) (morais2022diagnosisandmanagement pages 1-2)
Bartholin gland adenocarcinoma / Bartholin gland carcinoma (general, including adenocarcinoma subtype) Rare vulvar cancer arising in the Bartholin gland region; adenocarcinoma is one of the three most common Bartholin gland carcinoma histotypes. Diagnosis requires compatible location/histology and exclusion of another primary; many cases are initially mistaken for benign Bartholin cyst/abscess. Often presents as a solid, persistent, or recurrent Bartholin-region mass; delayed diagnosis is common, prompting low threshold for biopsy in women aged ≥40–45 years. Suggested histotype-specific markers include CK20/CDX2/SATB2 for intestinal-type adenocarcinoma; HPV/p16/p53, MYB/MYBL1 fusions (for adenoid cystic carcinoma), and broader molecular testing (MMR/MSI, TMB, PD-L1, targeted DNA/RNA assays) are proposed in modern workup. Complete surgical excision with 2–3 mm margins and bilateral groin evaluation; adjuvant therapy tailored by histology; advanced disease may receive radiotherapy ± chemotherapy, systemic therapy, immunotherapy, or targeted agents; management largely extrapolated from general vulvar cancer guidelines. BGC comprises 3%–7% of vulvar cancers and <1% of gynecologic tumors; ~50% diagnosed at advanced stage; nodal metastasis occurs in >40%; adenocarcinoma histology and node-positive disease predict worse survival. (kostov2025bartholinglandcarcinoma pages 24-25, kostov2025bartholinglandcarcinoma pages 20-21, faruqi2018standardsanddatasets pages 12-16, aburustum2024vulvarcancerversion pages 1-2) (kostov2025bartholinglandcarcinoma pages 24-25, kostov2025bartholinglandcarcinoma pages 20-21, faruqi2018standardsanddatasets pages 12-16, aburustum2024vulvarcancerversion pages 1-2)

Table: This table compares the main vulvar adenocarcinoma-related entities identified in the gathered evidence, emphasizing diagnostic markers, management patterns, and quantitative outcomes. It is useful for quickly distinguishing subtype-specific features while keeping evidence provenance explicit through context-ID citations.

Visual Evidence: FIGO 2021 staging

The FIGO 2021 staging table for vulvar carcinoma (applies to all morphologic types except melanoma) is shown in the extracted Table 1 image. (ha2024imaginginvulval media 862afa93)

Limitations and Data Gaps

  • Ontology IDs (MONDO/MeSH/Orphanet/OMIM): Not retrievable from current tool outputs for “vulvar adenocarcinoma” and will need direct ontology database lookup outside this toolchain.
  • Adenocarcinoma-specific population incidence/survival: Most quantitative epidemiology is for vulvar cancer overall or for specific rare entities (EMPD, Bartholin cohorts, VAIt systematic reviews). Large 2023–2024 population studies stratified by vulvar adenocarcinoma subtypes were not available in retrieved evidence.
  • Genetic predisposition and protective factors: Not identified in retrieved sources.

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