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Classifications

ICD-O Morphology

Harrison's Part

NIH Highlighted Topic

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Mechanistic Hypotheses

1

BDNF-Mediated Neurotropism Model of Perineural Invasion

bdnf_neurotropism EMERGING

Evidence balance 1 support

ACC uniformly expresses brain-derived neurotrophic factor, and BDNF-TrkB neurotrophin signalling is the leading candidate explanation for the tumor's unusual predilection for perineural spread. The supporting human evidence is immunohistochemical and correlative rather than functional: no study has yet shown that blocking BDNF or TrkB reduces perineural invasion in ACC. The alternative interpretation — that BDNF expression is a marker of the neural-adjacent microenvironment rather than a driver of neurotropism — has not been excluded.

Pathograph links

Biphasic Myoepithelial-Luminal Tumor Architecture -> Neurotropic Perineural Invasion INDIRECT UNKNOWN INTERMEDIATES The infiltrative biphasic tumor front advances preferentially along perineural planes.

Show evidence (1 reference)

PMID:12378520 SUPPORT Human Clinical

"Further studies are warranted to gain better understanding of this possible relationship."

The originating study explicitly frames the BDNF-neurotropism link as a possible relationship requiring further study, supporting EMERGING status.

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Discussions and Knowledge Gaps

2

Why does MYB-family activation, which is present in the great majority of ACCs and is the defining lesion of the disease, carry no prognostic information?

KNOWLEDGE GAP OPEN acc_myb_not_prognostic_gap

Attached to

pathophysiology#MYB-Driven Oncogenic Transcriptional Program

A systematic review of 36 studies found no consistent association between t(6;9)(MYB-NFIB) status and survival, while NOTCH1 mutation, TERT promoter mutation, solid histology, and perineural invasion all stratify outcome strongly. This implies that MYB activation is necessary for the ACC phenotype but that the clinically important variation lies in the cooperating lesions layered on top of it. Which cooperating events convert an indolent MYB-driven tumor into an aggressive one is not resolved.

Proposed experiments

Multi-region sequencing of matched indolent and aggressive ACC

exp_acc_multiregion_progression_sequencing

Sequence multiple regions of matched indolent and aggressive tumors from the same patient to identify progression-specific cooperating alterations against a constant MYB-fusion background, separating drivers of aggressiveness from the shared initiating lesion.

Isogenic dissection of cooperating lesions on a MYB-NFIB background

exp_acc_isogenic_cooperating_lesions

Express MYB-NFIB in isogenic salivary epithelial models with and without candidate cooperating lesions (NOTCH1 activation, TERT promoter mutation, chromatin-remodeler loss) and assay invasive and metastatic capacity to test which lesion supplies the aggressive phenotype.

Show evidence (1 reference)

PMID:30269389 SUPPORT Human Clinical

"A total of 11 studies attempted to determine the prognostic importance of the translocation, but no study found any significant association with survival rates"

Directly documents the absence of a prognostic association for the defining lesion of ACC, which is the gap this discussion records.

Is BDNF a causal driver of ACC neurotropism, or a marker of the neural-adjacent tumor microenvironment?

KNOWLEDGE GAP OPEN acc_bdnf_causal_vs_marker_gap

Attached to

pathophysiology#Neurotropic Perineural Invasion

Perineural invasion is the defining behaviour of ACC and independently predicts worse survival, yet the mechanistic evidence for its leading candidate mediator remains immunohistochemical and correlative more than two decades after the original observation. No study has shown that interrupting BDNF-TrkB signalling reduces perineural invasion in ACC. Because perineural spread is the direct cause of both cranial neuropathy and margin-positive resection, a genuinely causal mediator would be a high-value therapeutic target.

Proposed experiments

TrkB blockade in orthotopic ACC models with perineural readout

exp_acc_trkb_blockade_orthotopic

Apply pharmacological or genetic TrkB blockade in orthotopic ACC models and quantify perineural invasion histologically, testing whether interrupting the BDNF-TrkB axis reduces neurotropic spread.

ACC organoid-dorsal root ganglion co-culture under BDNF neutralisation

exp_acc_organoid_drg_coculture

Co-culture patient-derived ACC organoids with dorsal root ganglion explants under BDNF neutralisation to test whether directed migration toward nerve is BDNF-dependent.

Show evidence (1 reference)

PMID:12378520 SUPPORT Human Clinical

"Further studies are warranted to gain better understanding of this possible relationship."

The originating study itself frames the BDNF-neurotropism relationship as unresolved, which is the gap this discussion records.

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Pathophysiology

12

MYB-NFIB Fusion Oncogene Formation

A recurrent t(6;9)(q22-23;p23-24) translocation fuses the MYB proto-oncogene at 6q23 to the transcription factor gene NFIB at 9p23-24, producing chimeric transcripts in which MYB exon 14 is joined to the last coding exon(s) of NFIB. The rearrangement consistently deletes MYB exon 15 including the 3' UTR, which carries conserved binding sites for the repressive miR-15a/16 and miR-150 microRNAs. Loss of this post-transcriptional brake is the proximate mechanism of MYB overexpression. Reported prevalence varies widely across cohorts, largely reflecting assay methodology rather than true biological heterogeneity.

salivary gland cell CL:0009005

MYB hgnc:7545 NFIB hgnc:7785

Downstream

MYB-Driven Oncogenic Transcriptional Program Loss of 3' UTR-mediated repression leads to overexpression of MYB-NFIB transcripts and protein and activation of MYB target genes.

Show evidence (3 references)

PMID:19841262 SUPPORT Human Clinical

"the t(6;9)(q22-23;p23-24) translocation in adenoid cystic carcinomas (ACC) of the breast and head and neck consistently results in fusions encoding chimeric transcripts predominantly consisting of MYB exon 14 linked to the last coding exon(s) of NFIB"

Defines the recurrent t(6;9) translocation and the exon architecture of the MYB-NFIB fusion transcript that is the genomic hallmark of ACC.

PMID:19841262 SUPPORT Human Clinical

"The minimal common part of MYB deleted as the result of fusion was exon 15 including the 3'-UTR, which contains several highly conserved target sites for miR-15a/16 and miR-150 microRNAs."

Establishes loss of the MYB 3' UTR microRNA-binding sites as the molecular basis for escape from miR-15a/16 and miR-150 repression.

PMID:30269389 SUPPORT Human Clinical

"The prevalence of t(6;9)(MYB-NFIB) varied significantly (16%-100%), especially due to methodological heterogeneity among studies."

A systematic review quantifies the wide reported prevalence range of the fusion and attributes it to assay methodology; supports the claim that the fusion is recurrent but qualifies any single frequency figure.

MYBL1 Rearrangement and MYB Amplification

In tumors lacking the MYB-NFIB fusion, the same MYB-family transcriptional output is reached by alternative genetic routes: rearrangements of the second MYB-family gene MYBL1 (MYBL1-NFIB, MYBL1-ACTN1) or high-level amplification of MYB itself, each producing MYBL1 or MYB overexpression. These lesions are mutually exclusive with the MYB-NFIB fusion, making ACC a convergent phenotype at the level of MYB-family activation rather than a single-lesion disease.

MYBL1 hgnc:7547 MYB hgnc:7545

Downstream

MYB-Driven Oncogenic Transcriptional Program MYBL1 rearrangement or MYB amplification produces MYB-family overexpression and activation of the same downstream transcriptional program.

Show evidence (3 references)

PMID:29149504 SUPPORT Human Clinical

"we demonstrate that MYBL1 rearrangements and MYB amplification probably constitute alternative genetic drivers of breast AdCCs, functioning through MYBL1 or MYB overexpression."

Massively parallel sequencing of fusion-negative AdCC identifies MYBL1 rearrangement and MYB amplification as alternative drivers converging on MYB-family overexpression.

PMID:26851182 SUPPORT Other

"AdCCs can alternatively be driven by similar rearrangements involving a second MYB family gene, MYBL1, and that these two drivers act in remarkably similar ways"

Supports MYBL1 rearrangement as a mechanistically equivalent alternative driver to MYB-NFIB in ACC.

PMID:36465348 SUPPORT Human Clinical

"MYB and MYBL1 were found to belong to two different gene modules and were expressed in a mutually exclusive manner."

Single-cell transcriptomics confirms mutually exclusive MYB and MYBL1 expression modules, supporting them as alternative rather than additive drivers.

Super-Enhancer Translocation and MYB Positive Feedback Loop

Beyond creating a chimeric protein, the recurrent rearrangements act as regulatory translocations that juxtapose distal super-enhancers to the MYB locus. MYB protein then binds these translocated enhancers itself, establishing a self-sustaining positive feedback loop that locks in MYB overexpression. This enhancer dependency is the rationale for bromodomain (BET) inhibition in preclinical ACC models.

enhancer-driven positive regulation of MYB transcription GO:0045944 ↑ INCREASED

Downstream

MYB-Driven Oncogenic Transcriptional Program The enhancer feedback loop sustains high-level MYB expression and its downstream transcriptional program.

Show evidence (2 references)

PMID:26829750 SUPPORT Human Clinical

"we identify super-enhancer translocations that drive overexpression of the oncogenic transcription factor MYB as a recurrent theme in adenoid cystic carcinoma (ACC)"

Whole-genome sequencing and chromatin mapping identify super-enhancer translocations to the MYB locus as a recurrent mechanism of MYB overexpression in ACC.

PMID:26829750 SUPPORT Human Clinical

"MYB protein binds to the translocated enhancers, creating a positive feedback loop that sustains its expression."

Establishes the MYB autoregulatory positive feedback loop that sustains MYB overexpression in ACC.

MYB-Driven Oncogenic Transcriptional Program

Overexpressed MYB (or MYBL1), acting as a sequence-specific DNA-binding transcription factor, drives a transcriptional program promoting cell-cycle progression, survival, angiogenesis and adhesion. Critically, MYB binds lineage-specific enhancers and therefore drives different regulatory programs in the two cell compartments of the tumor: it cooperates with TP63 in myoepithelial cells and with a Notch program in luminal epithelial cells. This single-driver, two-program behaviour is the molecular explanation for the defining biphasic architecture of ACC.

MYB target gene transcriptional activation GO:0045944 ↑ INCREASED

MYB DNA-binding transcription factor activity GO:0003700 ↑ INCREASED

Downstream

Biphasic Myoepithelial-Luminal Tumor Architecture Lineage-specific MYB enhancer binding sustains distinct myoepithelial and luminal transcriptional programs within the same tumor.

Neurotropic Perineural Invasion The MYB-driven program supports the infiltrative, neurotropic phenotype that characterises ACC growth.

Show evidence (2 references)

PMID:19841262 SUPPORT Human Clinical

"Our data indicate that the MYB-NFIB fusion is a hallmark of ACC and that deregulation of the expression of MYB and its target genes is a key oncogenic event in the pathogenesis of ACC."

Establishes deregulated MYB target-gene expression as the key oncogenic event downstream of the fusion.

PMID:26829750 SUPPORT Human Clinical

"MYB also binds enhancers that drive different regulatory programs in alternate cell lineages in ACC, cooperating with TP63 in myoepithelial cells and a Notch program in luminal epithelial cells."

Directly supports the claim that a single MYB driver produces two distinct lineage-specific programs, underpinning the biphasic tumor architecture.

Intercalated Duct Cell of Origin and Premalignant Transition

Single-cell transcriptomic profiling of paracarcinoma and carcinoma tissue resolves the ACC epithelium into myoepithelial-like, intercalated duct-like, and duct-like cells. A subset of intercalated duct-like cells in paracarcinoma tissue carries copy-number alterations affecting MYB-family genes and EN1 and is identified as premalignant; pseudotime trajectory analysis shows these cells transitioning into frank malignant cells, implicating the intercalated duct cell as the cell of origin.

intercalated duct cell of salivary gland CL:4052048

Downstream

Biphasic Myoepithelial-Luminal Tumor Architecture Transformed intercalated duct-like cells give rise to the two-compartment tumor epithelium.

Show evidence (2 references)

PMID:36465348 SUPPORT Human Clinical

"part of intercalated duct-like cells with special copy number variations which altered with MYB family gene and EN1 transcriptomes were identified as premalignant cells"

Identifies a premalignant intercalated duct-like cell population defined by MYB-family copy-number alterations.

PMID:36465348 SUPPORT Computational

"Developmental pseudo-time analysis showed that the premalignant cells eventually transformed into malignant cells."

Pseudotime trajectory analysis supports progression of the premalignant intercalated duct-like population into malignant ACC cells.

Biphasic Myoepithelial-Luminal Tumor Architecture

The tumor is built from two interdependent epithelial compartments: abluminal myoepithelial-like cells and luminal ductal cells. These are arranged in cribriform, tubular, and solid patterns, with the cribriform "Swiss cheese" architecture produced by pseudocysts filled with basement-membrane-like material laid down by the myoepithelial compartment. The proportion of solid architecture is the basis of histological grading and tracks with aggressiveness.

BDNF-Mediated Neurotropism Model of Perineural Invasion

myoepithelial cell of salivary gland CL:0020066 luminal ductal tumor cell CL:0000068

major salivary gland UBERON:0001829

Downstream

Neurotropic Perineural Invasion The infiltrative biphasic tumor front advances preferentially along perineural planes.

Salivary Gland Neoplasm Tumor architecture arising in salivary ductal and myoepithelial lineages produces the characteristic salivary-gland neoplasm.

Neoplasm of Head and Neck At head-and-neck exocrine sites, the biphasic tumor architecture manifests as a locally infiltrative neoplasm.

Dysphagia Oropharyngeal and palatal tumors can impair swallowing through local mass effect and infiltration.

Show evidence (1 reference)

PMID:36465348 SUPPORT Human Clinical

"Three main types of the epithelial cells were identified into myoepithelial-like cells, intercalated duct-like cells, and duct-like cells by marker genes."

Single-cell profiling resolves the ACC epithelium into myoepithelial-like and ductal compartments, supporting the biphasic architecture.

NOTCH1 Pathway Hyperactivation

A distinct subgroup of ACC carries activating NOTCH1 mutations clustered in the negative regulatory region and the PEST (Pro-Glu-Ser-Thr-rich) domain — the same two hotspots exploited in T-cell acute lymphoblastic leukemia — which stabilise the Notch1 intracellular domain and drive constitutive pathway output. These alterations are strongly enriched in recurrent/metastatic relative to primary disease, indicating that Notch activation is a progression event as well as an initiating one.

NOTCH1 hgnc:7881

Notch signaling pathway GO:0007219 ↑ INCREASED

Downstream

Solid-Pattern Aggressive Disease Notch pathway activation drives the solid histologic phenotype and its accelerated clinical course.

Show evidence (2 references)

PMID:27870570 SUPPORT Human Clinical

"NOTCH1 mutations occurred predominantly (14 of 15 patients) in the negative regulatory region and Pro-Glu-Ser-Thr-rich domains, the same two hotspots seen in T-cell acute lymphoblastic leukemias, and led to pathway activation in vitro."

Localises ACC NOTCH1 mutations to the canonical activating hotspots and confirms functional pathway activation.

PMID:31483290 SUPPORT Human Clinical

"Compared with primary tumors, R/M tumors were enriched for alterations in key Notch (NOTCH1, 26.3% vs. 8.5%; NOTCH2, 4.6% vs. 2.3%; NOTCH3, 5.7% vs. 2.3%; NOTCH4, 3.6% vs. 0.6%) and chromatin-remodeling (KDM6A, 15.2% vs. 3.4%; KMT2C/MLL3, 14.3% vs. 4.0%; ARID1B, 14.1% vs. 4.0%) genes."

An integrated genomic analysis of 1,045 ACCs quantifies Notch-pathway and chromatin-remodeler enrichment in recurrent/metastatic versus primary tumors.

TERT Promoter Mutation as an Alternative Oncogenic Route

A minority of recurrent/metastatic tumors carry TERT promoter hotspot mutations that are mutually exclusive with both NOTCH1 mutations and MYB/MYBL1 fusions. Together with the MYB and Notch lesions these define four discrete molecular subgroups, indicating that ACC is reached by more than one oncogenic route rather than by a single obligatory pathway. The cited ACC genomic series establishes the lesion and its mutual exclusivity but does not measure telomerase activity or telomere length, so a downstream mechanism of telomere maintenance is not asserted here.

TERT hgnc:11730

Show evidence (2 references)

PMID:31483290 SUPPORT Human Clinical

"TERT promoter mutations (13.1% of R/M cases) were mutually exclusive with both NOTCH1 mutations (q = 3.3 × 10-4) and MYB/MYBL1 fusions (q = 5.6 × 10-3), suggesting discrete, alternative mechanisms of tumorigenesis."

Establishes TERT promoter mutation as a mutually exclusive, alternative oncogenic mechanism in ACC.

PMID:31483290 SUPPORT Human Clinical

"This network of alterations defined 4 distinct ACC subgroups: MYB+NOTCH1+, MYB+/other, MYBWTNOTCH1+, and MYBWTTERT+."

Defines the four molecular subgroups of ACC on which the multi-route model of tumorigenesis rests.

Neurotropic Perineural Invasion

Perineural invasion is the single most characteristic pathophysiological behaviour of ACC: tumor cells track along the perineural and endoneural spaces of named nerves, forming a target-like cuff around nerve fascicles and extending microscopically far beyond the grossly visible tumor margin, in many cases to the skull base. Brain-derived neurotrophic factor (BDNF), a neurotrophin involved in neurogenesis, is uniformly expressed by ACC and is the leading candidate mediator of this neurotropism. Perineural spread is the principal reason margin-negative resection is difficult and local recurrence is late and frequent.

nerve UBERON:0001021

Downstream

Cranial Neuropathy and Late Local Recurrence Tumor spread along cranial nerves produces neurological deficits and leaves microscopic residual disease after resection.

Show evidence (3 references)

PMID:12378520 SUPPORT Human Clinical

"This is accounted for histologically by its infiltrative capacity and distinct propensity for perineural invasion."

Attributes the lengthy clinical course and late local recurrence of ACC to its infiltrative capacity and perineural invasion.

PMID:12378520 SUPPORT Human Clinical

"Based on the results presented here, BDNF is unformly expressed by ACC and may play a causative role in its predilection for perineural invasion."

Immunohistochemistry in 29 primary ACCs shows uniform BDNF expression; the authors propose but do not prove a causative role, so this is marked PARTIAL.

PMID:17576903 SUPPORT Human Clinical

"Histopathologic evidence of PNS was present in 25 (66%) of 38 named nerves."

Quantifies the high histopathologic frequency of perineural spread along named nerves in ACC undergoing cranial base resection.

Solid-Pattern Aggressive Disease

NOTCH1-mutant tumors define a clinically distinct aggressive subgroup marked by solid histology, advanced stage at diagnosis, a higher rate of liver and bone metastasis, and substantially shorter relapse-free and overall survival than NOTCH1 wild-type disease. This subgroup is the target population for Notch-directed therapy.

Downstream

Late Haematogenous Metastasis The aggressive NOTCH-activated phenotype accelerates distant, particularly liver and bone, metastatic spread.

Show evidence (1 reference)

PMID:27870570 SUPPORT Human Clinical

"NOTCH1 mutations define a distinct disease phenotype characterized by solid histology, liver and bone metastasis, poor prognosis, and potential responsiveness to Notch1 inhibitors."

Directly establishes the NOTCH1-mutant clinical phenotype of solid histology, visceral and bone metastasis, and poor prognosis.

Cranial Neuropathy and Late Local Recurrence

Perineural tumor extension along the facial and trigeminal nerves and their named branches produces progressive motor and sensory cranial neuropathy, and leaves microscopic disease beyond the surgical field. The result is a characteristically long tail of local recurrence, with events occurring many years after apparently complete treatment and motivating long-term follow-up.

Downstream

Facial Palsy Facial-nerve involvement can produce progressive motor weakness.

Facial and Perineural Pain Invasion of sensory nerves produces pain in the involved distribution.

Paresthesia Sensory-nerve involvement produces numbness, tingling, or hypoesthesia.

Show evidence (2 references)

PMID:17576903 SUPPORT Human Clinical

"Perineural spread across the skull base is a frequent occurrence in patients with adenoid cystic carcinoma of the head and neck."

Confirms that perineural spread reaches the skull base frequently, the anatomical basis for cranial neuropathy and incomplete resection.

PMID:35931701 SUPPORT Other

"current treatment options for the localized disease are limited to surgery and radiation, which fails to prevent locoregional recurrences and distant metastases in over 50% of patients"

Quantifies the failure of local therapy to prevent locoregional recurrence and distant metastasis in more than half of patients.

Late Haematogenous Metastasis

ACC disseminates preferentially by the haematogenous rather than the lymphatic route, so regional nodal involvement is comparatively uncommon while distant metastasis — most often pulmonary, then bone and liver — is the dominant mode of failure. The defining feature is its latency: distant relapse typically appears several years after primary treatment and can occur more than a decade later, and patients may survive for years with established metastatic disease, so metastasis in ACC marks a chronic phase rather than an immediately terminal one.

lung UBERON:0002048

Downstream

Pulmonary Metastasis Haematogenous dissemination commonly seeds the lung after a prolonged disease-free interval.

Show evidence (3 references)

PMID:18343149 SUPPORT Human Clinical

"Adenoid cystic carcinoma is a rare tumour originating from the exocrine mucous glands, known for its high propensity for distant metastases."

Establishes the high propensity for distant metastasis that characterises ACC dissemination.

PMID:18343149 SUPPORT Human Clinical

"In 20 patients, at a median free interval time of 3 years (range 1-12), a distant metastasis relapse was observed."

Quantifies the multi-year and up to 12-year latency of distant metastatic relapse in a surgical ACC cohort.

PMID:18343149 SUPPORT Human Clinical

"Mean survival of patients having presented with distant metastases resulted as being 11 years (SE=2.2)."

Documents the prolonged survival after distant metastasis that distinguishes ACC from most metastatic carcinomas.

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Histopathology

4

Cribriform Pattern

The classic and most common architecture: nests of basaloid tumor cells punched through by rounded pseudocystic spaces ("Swiss cheese" appearance) containing basement-membrane-like and mucoid material produced by the myoepithelial compartment.

Show evidence (1 reference)

PMID:23463073 SUPPORT Other

"ACC has distinct histologic features, with cribriform and tubular growth patterns of basaloid cells displaying a predominantly myoepithelial cellular phenotype."

A disease-focused review identifies cribriform growth as a defining ACC histologic pattern.

Tubular Pattern

True ducts lined by an inner luminal epithelial layer and an outer myoepithelial layer. A predominantly tubular tumor corresponds to the lowest-grade, most favourable end of the histological spectrum.

Show evidence (1 reference)

PMID:23463073 SUPPORT Other

"ACC has distinct histologic features, with cribriform and tubular growth patterns of basaloid cells displaying a predominantly myoepithelial cellular phenotype."

A disease-focused review identifies tubular growth as a defining ACC histologic pattern.

Solid Growth Pattern

Sheets of basaloid cells without duct or pseudocyst formation, often with higher mitotic activity and comedonecrosis. The proportion of solid architecture drives histological grade; a solid-predominant tumor is the least favourable pattern and is enriched in NOTCH1-mutant disease.

Show evidence (2 references)

PMID:27180054 SUPPORT Human Clinical

"The solid pattern of AdCC showed gland differentiation but loss of myoepithelial differentiation with a higher proliferation and more aggressiveness as well as poorer prognosis compared with the cribriform-tubular subtypes"

Directly supports the solid pattern's altered differentiation and worse clinical behavior relative to cribriform-tubular ACC.

PMID:40025676 SUPPORT Human Clinical

"Twenty-nine patients were included, with a predominance of solid histology (86%)."

In a Notch-activated ACC cohort solid histology predominated, linking the solid pattern to Notch-pathway activation.

Perineural Invasion FREQUENT

Tumor cells within the perineural or endoneural space, classically forming a target-like cuff around a nerve fascicle. Present in the majority of named nerves examined in skull-base resection specimens and independently associated with worse disease-free and overall survival.

Show evidence (1 reference)

PMID:17576903 SUPPORT Human Clinical

"Histopathologic evidence of PNS was present in 25 (66%) of 38 named nerves."

Quantifies perineural spread in 66% of named nerves examined histopathologically, supporting a FREQUENT frequency band.

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Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.

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Phenotypes

7

Digestive 1

Dysphagia HP:0002015

Course: PROGRESSIVE

Show evidence (1 reference)

PMID:42371638 SUPPORT Human Clinical

"Presenting symptoms were mainly pain/discomfort (n = 31), followed by a palpable mass (n = 19) and dysphagia (n = 12)."

A 2026 systematic review directly documents dysphagia at presentation; support is PARTIAL because the cohort is limited to oropharyngeal ACC.

Head and Neck 1

Facial Palsy HP:0010628

Course: PROGRESSIVE

Show evidence (1 reference)

PMID:17576903 SUPPORT Human Clinical

"Adenoid cystic carcinoma of the head and neck frequently exhibits PNS across the skull base."

Indirect support: establishes frequent perineural spread across the skull base, the anatomical mechanism of cranial nerve palsy, but the snippet does not itself report facial palsy, so this is marked PARTIAL.

Nervous System 1

Paresthesia HP:0003401

Temporal: CHRONIC

Show evidence (1 reference)

PMID:36060029 SUPPORT Human Clinical

"Facial pain, nasal obstruction, and facial paresthesia were the most common symptoms."

A systematic review directly reports facial paresthesia among common symptoms of skull-base ACC; support is PARTIAL because this is an anatomically selected subset.

Neoplasm 1

Pulmonary Metastasis Neoplasm of the lung HP:0100526

Show evidence (1 reference)

PMID:18343149 SUPPORT Human Clinical

"Nine patients who presented isolated lung recurrence underwent complete lung metastasectomy."

Documents isolated pulmonary recurrence as a recognised and surgically addressed pattern of ACC metastasis.

Other 3

Salivary Gland Neoplasm HP:0100684

Course: PROGRESSIVE

Show evidence (2 references)

PMID:39410002 SUPPORT Human Clinical

"Adenoid cystic carcinoma (ACC) is a rare malignant tumor that mainly arises in the head and neck area."

A SEER registry study of 5,150 patients confirms the head and neck, dominated by salivary gland sites, as the principal primary site.

PMID:23463073 SUPPORT Other

"ACC is an uncommon neoplasm that most frequently arises in salivary glands and related tissue in the head and neck region."

Directly supports major and minor salivary glands as the typical sites of origin while preserving the existence of non-salivary primaries.

Neoplasm of Head and Neck HP:0012288

Show evidence (1 reference)

PMID:39199639 SUPPORT Human Clinical

"Eleven patients had primary salivary gland ACC and three primary lacrimal gland ACC"

Documents both salivary and lacrimal gland primaries within a head and neck ACC cohort.

Facial and Perineural Pain Pain in head and neck region HP:0046506

Temporal: CHRONIC

Show evidence (2 references)

PMID:12378520 SUPPORT Human Clinical

"distinct propensity for perineural invasion"

Indirect support: documents the perineural invasion that causes neuropathic facial pain; the snippet does not report the pain symptom itself, so this is marked PARTIAL.

PMID:42371638 SUPPORT Human Clinical

"Presenting symptoms were mainly pain/discomfort (n = 31), followed by a palpable mass (n = 19) and dysphagia (n = 12)."

A 2026 systematic review directly documents pain as the leading reported presenting symptom in oropharyngeal ACC; support is PARTIAL because the review is restricted to that anatomical subset.

🧬

Genetic Associations

5

MYB (MYB-NFIB Fusion)

Gene: MYB hgnc:7545 relationship_type: SOMATIC_DRIVER variant_origin: SOMATIC

Show evidence (2 references)

PMID:19841262 SUPPORT Human Clinical

"Our data indicate that the MYB-NFIB fusion is a hallmark of ACC"

Establishes the MYB-NFIB fusion as the defining genetic hallmark of ACC.

PMID:30269389 SUPPORT Human Clinical

"the best evidence available demonstrates that t(6;9)(MYB-NFIB) does not seem to be a prognostic determinant"

A systematic review of 36 studies finds no consistent association between the fusion and survival, supporting its diagnostic but not prognostic role.

NFIB (Fusion Partner)

Gene: NFIB hgnc:7785 relationship_type: SOMATIC_DRIVER variant_origin: SOMATIC

Show evidence (1 reference)

PMID:19841262 SUPPORT Human Clinical

"the t(6;9)(q22-23;p23-24) translocation in adenoid cystic carcinomas (ACC) of the breast and head and neck consistently results in fusions encoding chimeric transcripts predominantly consisting of MYB exon 14 linked to the last coding exon(s) of NFIB"

Directly establishes NFIB as the recurrent MYB fusion partner in ACC.

MYBL1 Rearrangement

Gene: MYBL1 hgnc:7547 relationship_type: SOMATIC_DRIVER variant_origin: SOMATIC

Show evidence (1 reference)

PMID:29149504 SUPPORT Human Clinical

"In two cases, we identified MYBL1 rearrangements (MYBL1-ACTN1 and MYBL1-NFIB), which were associated with MYBL1 overexpression."

Identifies the specific MYBL1 fusion partners and links them to MYBL1 overexpression in fusion-negative ACC.

NOTCH1 Activating Mutation

Gene: NOTCH1 hgnc:7881 relationship_type: SOMATIC_DRIVER variant_origin: SOMATIC

Show evidence (1 reference)

PMID:35931701 SUPPORT Other

"Approximately 20% of patients with ACC carry NOTCH-activating mutations that are associated with a distinct phenotype, aggressive disease, and poor prognosis."

Quantifies the prevalence of NOTCH-activating mutations and their association with aggressive disease.

TERT Promoter Mutation

Gene: TERT hgnc:11730 relationship_type: SOMATIC_DRIVER variant_origin: SOMATIC

Show evidence (1 reference)

PMID:31483290 SUPPORT Human Clinical

"TERT promoter mutations (13.1% of R/M cases) were mutually exclusive with both NOTCH1 mutations (q = 3.3 × 10-4) and MYB/MYBL1 fusions (q = 5.6 × 10-3), suggesting discrete, alternative mechanisms of tumorigenesis."

Quantifies TERT promoter mutation frequency and its mutual exclusivity with the other ACC drivers.

💊

Medical Actions

8

Surgical Resection

Action: Definitive Surgical Resection NCIT:C154430

Gross total resection with tumor-free margins is the principal local treatment when anatomically feasible. Achieving negative margins is difficult because microscopic perineural extension can reach beyond the visible tumor. In anterior craniofacial ACC, incomplete R2 resection did not improve on nonsurgical treatment, so the benefit should not be generalized to unresectable disease.

Show evidence (2 references)

PMID:39410002 SUPPORT Human Clinical

"In multivariable analysis, older age, male sex, thoracic cancer, the presence of regional and distal disease, receiving chemotherapy, not undergoing surgical resection, and being treated in the West vs. Northeast region were found to be independent predictors of poor survival."

In a 5,150-patient SEER analysis, not undergoing surgical resection is an independent predictor of poor survival, supporting surgery as the primary modality.

PMID:41941852 SUPPORT Human Clinical

"GTR followed by adjuvant RT, especially with proton therapy (PT), achieved the best local control. R2 resections provided no advantage over NST."

A large multi-institutional cohort supports gross total resection while warning against incomplete resection; support is PARTIAL because the study is retrospective and restricted to anterior craniofacial ACC.

Postoperative Radiotherapy

Action: Radiation Therapy NCIT:C15313

Radiotherapy combined with surgery is the standard local approach for many head-and-neck ACCs, particularly advanced or anatomically complex disease. Proton and carbon-ion techniques are emerging options for improving dose conformity; definitive proton therapy is supported for selected anterior craniofacial tumors when complete resection is not feasible.

Show evidence (3 references)

PMID:42229289 SUPPORT Other

"Although surgery combined with radiotherapy remains the standard local approach, treatment outcomes remain suboptimal in patients with unresectable tumors, advanced local disease, or anatomically complex lesions."

A contemporary review establishes surgery plus radiotherapy as the standard local approach while noting its limits in advanced disease.

PMID:42229289 SUPPORT Other

"Advances in radiotherapy, including MRI-guided radiotherapy, FLASH radiotherapy, and proton or carbon-ion therapy, are reshaping local treatment by improving dose precision, normal tissue sparing, and opportunities for treatment individualization."

Supports an emerging role for particle and advanced-photon techniques in local treatment, without treating all modalities as established standards.

PMID:41941852 SUPPORT Human Clinical

"For ACF-ACC, GTR plus modern RT provides the strongest local control, and R2 surgery should be avoided. PT is an effective definitive option for selected patients, supporting future response-guided treatment strategies."

Supports modern radiotherapy and selected definitive proton therapy in anterior craniofacial ACC; PARTIAL reflects the retrospective, site-restricted evidence.

Notch Inhibition (Gamma-Secretase Inhibitor)

Action: Pharmacotherapy NCIT:C15986

Agent: osugacestat (AL101) NCIT:C116872

AL101 (osugacestat) is a gamma-secretase inhibitor that blocks activation of all four NOTCH receptors, developed specifically for the NOTCH-activated ACC subgroup. It shows potent antitumor activity in NOTCH1-mutant ACC cell lines, organoids and xenografts, and in a retrospective clinical series of Notch-activated recurrent/metastatic ACC produced longer progression-free survival than prior systemic therapy — though responses remain partial and short-lived, and combination approaches are being explored.

Mechanism Target:

INHIBITS NOTCH1 Pathway Hyperactivation — Gamma-secretase inhibition blocks the proteolytic release of the Notch intracellular domain, shutting down the constitutive Notch transcriptional output produced by activating NOTCH1 mutations.

Show evidence (1 reference)

PMID:35931701 SUPPORT In Vitro

"treatment of the organoid model with AL101 resulted in down-regulation of NICD1"

Directly demonstrates suppression of activated NOTCH1 signaling in an ACC organoid model.

Show evidence (3 references)

PMID:35931701 SUPPORT Other

"we find that AL101 has potent antitumor effects in in vitro and in vivo models of ACC with activating NOTCH1 mutations and constitutively upregulated NOTCH signaling pathway"

The abstract summarizes activity across cell, organoid, and xenograft systems; OTHER avoids assigning this mixed preclinical statement to only one experimental source type.

PMID:35931701 SUPPORT Model Organism

"AL101 therapy induced potent TGI in both models with NOTCH1 gain-of-function mutations (110 and 74% for ACCx9 and ACCx11, respectively; p < 0.0001)"

Patient-derived xenografts provide separate in-vivo evidence of activity in NOTCH1 gain-of-function ACC.

PMID:40025676 SUPPORT Human Clinical

"NOTCH inhibitors demonstrate activity in NOTCH-activated ACC, surpassing the efficacy of observation or prior systemic therapies."

A 29-patient retrospective series supports clinical activity but with only 17% partial responses and 4.2-month median PFS, so support is PARTIAL.

Brontictuzumab (Anti-NOTCH1 Antibody)

Action: Pharmacotherapy NCIT:C15986

Agent: brontictuzumab NCIT:C103274

Brontictuzumab is a monoclonal antibody targeting NOTCH1. Tumor growth inhibition in ACC patient-derived xenografts occurred exclusively in the model carrying an activating NOTCH1 mutation, and an index patient with NOTCH1-mutant ACC had a partial response, providing preliminary evidence of genotype-restricted activity.

Mechanism Target:

INHIBITS NOTCH1 Pathway Hyperactivation — Antibody blockade of NOTCH1 prevents receptor activation in tumors dependent on activating NOTCH1 mutations.

Show evidence (1 reference)

PMID:27870570 SUPPORT Model Organism

"Significant tumor growth inhibition with brontictuzumab was observed exclusively in the ACC patient-derived xenograft model that harbored a NOTCH1 activating mutation."

Genotype-restricted activity in a NOTCH1-mutant xenograft directly links brontictuzumab treatment to the activated NOTCH1 mechanism.

Show evidence (2 references)

PMID:27870570 SUPPORT Model Organism

"Significant tumor growth inhibition with brontictuzumab was observed exclusively in the ACC patient-derived xenograft model that harbored a NOTCH1 activating mutation."

Patient-derived xenograft data show brontictuzumab activity restricted to NOTCH1-mutant ACC, establishing genotype-dependent benefit.

PMID:27870570 SUPPORT Human Clinical

"an index patient with NOTCH1-mutant ACC had a partial response to brontictuzumab"

A single-patient partial response provides preliminary human evidence only, so support is marked PARTIAL.

Lenvatinib

Action: Pharmacotherapy NCIT:C15986

Agent: lenvatinib CHEBI:85994

Lenvatinib is a multitargeted VEGFR/FGFR/PDGFR tyrosine kinase inhibitor used in recurrent or metastatic ACC. Activity is modest — partial responses in about 12% of evaluable patients — and toxicity frequently requires dose reduction, so it is best regarded as a disease-stabilising rather than tumor-shrinking option.

Show evidence (2 references)

PMID:32031693 SUPPORT Human Clinical

"Among 26 evaluable patients, 3 partial responses (11.5%) were reported."

Quantifies the modest objective response rate to lenvatinib in recurrent/metastatic ACC.

PMID:32031693 SUPPORT Human Clinical

"Lenvatinib appears to have modest activity in ACC."

The trial's own conclusion characterises lenvatinib activity in ACC as modest.

Axitinib

Action: Pharmacotherapy NCIT:C15986

Agent: axitinib CHEBI:66910

Axitinib improved progression-free survival compared with observation in progressive recurrent or metastatic ACC, but produced no objective responses; its demonstrated benefit is disease stabilization rather than tumor shrinkage.

Show evidence (1 reference)

PMID:34315722 SUPPORT Human Clinical

"With a median follow-up of 25.4 months, the 6-month PFS rate was 73.0% with axitinib and 23.0% with observation. Median PFS was longer in the axitinib arm (10.8 months vs. 2.8 months, P < 0.001). The ORR of axitinib was 0.0%, but the disease control rate was 100.0% with axitinib and 51.9% with..."

The first randomized ACC trial demonstrates a progression-free survival benefit but no objective responses, warranting PARTIAL support.

Rivoceranib

Action: Pharmacotherapy NCIT:C15986

Agent: rivoceranib NCIT:C152237

Rivoceranib, a VEGFR2 tyrosine-kinase inhibitor, has modest objective activity in progressive recurrent or metastatic ACC. Frequent grade 3 or worse toxicity and dose modification limit the certainty of net clinical benefit.

Show evidence (3 references)

PMID:37643133 SUPPORT Human Clinical

"Per investigator and BIRC, respectively, ORR was 15.3%"

The investigator and blinded-review response rates directly quantify the modest objective activity in this single-arm phase II study.

PMID:37643133 SUPPORT Human Clinical

"median progression-free survival was 9.0 months (95% CI, 7.3-11.5) and 9.0 months (95% CI, 7.7-11.5)."

A large international phase II study demonstrates nine-month median progression-free survival; its single-arm design warrants PARTIAL support.

PMID:37643133 SUPPORT Human Clinical

"Grade ≥3 treatment-related adverse events occurred in 56 patients (70.0%)"

The high rate of grade 3 or worse treatment-related adverse events tempers the phase II efficacy signal.

Pulmonary Metastasectomy

Action: Surgical Procedure NCIT:C15329

Resection of isolated pulmonary metastases is offered to selected patients after a long disease-free interval, but evidence is observational and the reported comparison with non-resection is vulnerable to selection bias.

Show evidence (1 reference)

PMID:18343149 SUPPORT Human Clinical

"Nine patients with a median free interval time of 5 years (range 1-12) underwent lung metastasectomy"

Documents pulmonary metastasectomy after a median five-year and up to 12-year disease-free interval; the comparison with non-resected patients was not statistically powered, so support is PARTIAL.

🔬

Biochemical Markers

3

MYB-NFIB Fusion Transcript

Show evidence (1 reference)

PMID:39199639 SUPPORT Human Clinical

"76.9% of the analyzed tumors displayed evidence of NFIB-MYB rearrangement at the 6q23.3 locus; 35% had mutations in NOTCH pathway genes"

Quantifies MYB-NFIB rearrangement detection rate alongside NOTCH pathway mutation rate in a clinically sequenced ACC cohort.

MYB Protein Overexpression

Show evidence (1 reference)

PMID:21164292 SUPPORT Human Clinical

"Strong Myb immunostaining is very specific for adenoid cystic carcinomas but is only present in 65% of all cases."

Directly establishes high specificity and the important 65% sensitivity limitation of MYB immunohistochemistry.

KIT (CD117) Expression

Show evidence (1 reference)

PMID:14681323 SUPPORT Human Clinical

"Overall, 94% (n = 62) of adenoid cystic carcinomas from various anatomic sites and of various histologic subtypes were positive for at least one of the KIT antibodies, and 77% (n = 50) of adenoid cystic carcinoma cases were positive for both antibodies."

Quantifies KIT immunoreactivity across anatomic sites and histologic subtypes, supporting its use as an ancillary rather than definitive marker.

🔬

Diagnosis

1

MYB rearrangement testing

Fluorescence in situ hybridization for MYB rearrangement can support an ACC diagnosis in the appropriate morphologic context, but a negative result does not exclude the disease.

fluorescence in situ hybridization NCIT:C17563

Show evidence (1 reference)

PMID:21164292 SUPPORT Human Clinical

"MYB translocation and expression are useful diagnostic markers for a subset of adenoid cystic carcinomas."

Supports FISH-detected MYB translocation as a subset-specific diagnostic adjunct and guards against treating a negative result as exclusionary.

🩻

Imaging Findings

1

Perineural spread to the skull base on MRI

High-resolution MRI is the preferred imaging method for defining named-nerve perineural spread toward the skull base and its extent before local therapy.

Mri Diagnostic

nerve UBERON:0001021

Show evidence (1 reference)

PMID:17576903 SUPPORT Human Clinical

"Magnetic resonance imaging had a higher sensitivity (100%) and specificity (85%)."

A histopathology-referenced cohort supports MRI's diagnostic performance for skull-base perineural spread.

📊

Prevalence

1

Worldwide

Unknown Rare

ACC is consistently characterised as a rare malignancy, accounting for a small fraction of head and neck cancers and roughly one in ten salivary gland neoplasms. Published incidence figures are on the order of a few cases per million per year, but the sources reviewed here state rarity qualitatively rather than reporting a directly quotable rate, so only the coarse class is recorded. A registry-derived numeric rate remains a curation gap.

Show evidence (1 reference)

PMID:39410002 SUPPORT Human Clinical

"Adenoid cystic carcinoma (ACC) is a rare malignant tumor that mainly arises in the head and neck area."

A SEER-based population study characterises ACC as rare, supporting the qualitative RARE prevalence class without asserting a numeric rate.

📊

Related Datasets

1

The mutational characterization of adenoid cystic carcinoma dbgap:phs000612

Adenoid cystic carcinoma (ACC) typically emanate from the major and minor salivary glands of the head and neck. ACCs have high rates of perineural invasion, locoregional recurrence, and distant metastasis. Here we report sequencing of 60 tumor/normal pairs and find substantial mutational diversity. On pathway analysis, a significant percentage of mutations involved chromatin remodeling, DNA damage, protein kinase A signaling, and FGF/IGF/PI3K signaling. Whole genome sequencing and FISH confirmed the MYB-NFIB translocation as the main structural variant in ACC.

Located via OmicsDI, which aggregates across omics repositories; this record comes from dbgap. Only repositories with no other discovery route in this project and with a working accession resolver are curated from OmicsDI -- GEO, ArrayExpress, PRIDE, MetaboLights and EGA hits are excluded as duplicates of dedicated passes. Matched because the disease is named in the dataset's own title ("Adenoid Cystic Carcinoma"). Retrieved 2026-08-02.

{ }

Source YAML

click to show

name: Adenoid Cystic Carcinoma
creation_date: "2026-07-31T00:00:00Z"
category: Cancer
categories:
- Salivary Gland Cancer
- Rare Cancer
parents:
- salivary gland carcinoma
disease_term:
  preferred_term: adenoid cystic carcinoma
  term:
    id: MONDO:0004971
    label: adenoid cystic carcinoma
description: >-
  Adenoid cystic carcinoma (ACC) is a rare epithelial malignancy that arises most
  often in the major and minor salivary glands, and also in the lacrimal gland,
  breast, tracheobronchial tree, skin, and uterine cervix. It is defined
  histologically by a biphasic population of ductal (luminal) and myoepithelial
  (abluminal, basaloid) cells arranged in cribriform, tubular, and solid
  patterns. Most tumors are driven by activation of the MYB family of
  transcription factors, classically through a t(6;9)(q22-23;p23-24)
  translocation producing a MYB-NFIB fusion that deletes the MYB 3' UTR and
  releases MYB from microRNA-mediated repression; MYBL1 rearrangements and
  high-level MYB amplification are alternative, convergent routes to the same
  MYB-driven transcriptional output. A distinct subgroup carries activating
  NOTCH1 mutations and shows solid histology, liver and bone metastasis, and
  markedly worse survival, while TERT promoter mutations mark a third, mutually
  exclusive oncogenic route. Clinically ACC is characterized by indolent but
  relentless growth, a striking propensity for perineural invasion, late
  haematogenous metastasis (predominantly to lung) that may appear more than a
  decade after treatment, and a comparatively low rate of regional lymph node
  involvement. It is largely refractory to conventional cytotoxic chemotherapy.
synonyms:
- ACC
- AdCC
- adenocystic carcinoma
- cylindroid adenocarcinoma
classifications:
  icdo_morphology:
    classification_value: Carcinoma
  harrisons_chapter:
  - classification_value: ONCOLOGY_HEMATOLOGY
  nih_research_priority:
  - classification_value: NIH_HT_42_rare_cancers_across_cancer_control_continuum
    notes: >-
      Rare salivary/exocrine gland malignancy (MONDO xref ICDO:8200/3) with no
      effective systemic therapy for recurrent or metastatic disease — a
      representative rare cancer for NIH Highlighted Topic 42.
prevalence:
- population: Worldwide
  measure_type: UNKNOWN
  prevalence_class: RARE
  notes: >-
    ACC is consistently characterised as a rare malignancy, accounting for a small
    fraction of head and neck cancers and roughly one in ten salivary gland
    neoplasms. Published incidence figures are on the order of a few cases per
    million per year, but the sources reviewed here state rarity qualitatively
    rather than reporting a directly quotable rate, so only the coarse class is
    recorded. A registry-derived numeric rate remains a curation gap.
  evidence:
  - reference: PMID:39410002
    reference_title: "Epidemiological Study of Adenoid Cystic Carcinoma and Its Outcomes: Insights from the Surveillance, Epidemiology, and End Results (SEER) Database."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Adenoid cystic carcinoma (ACC) is a rare malignant tumor that mainly arises
      in the head and neck area.
    explanation: >-
      A SEER-based population study characterises ACC as rare, supporting the
      qualitative RARE prevalence class without asserting a numeric rate.
pathophysiology:
- name: MYB-NFIB Fusion Oncogene Formation
  biological_scale: MOLECULAR
  description: >-
    A recurrent t(6;9)(q22-23;p23-24) translocation fuses the MYB proto-oncogene
    at 6q23 to the transcription factor gene NFIB at 9p23-24, producing chimeric
    transcripts in which MYB exon 14 is joined to the last coding exon(s) of
    NFIB. The rearrangement consistently deletes MYB exon 15 including the 3'
    UTR, which carries conserved binding sites for the repressive miR-15a/16 and
    miR-150 microRNAs. Loss of this post-transcriptional brake is the proximate
    mechanism of MYB overexpression. Reported prevalence varies widely across
    cohorts, largely reflecting assay methodology rather than true biological
    heterogeneity.
  genes:
  - preferred_term: MYB
    term:
      id: hgnc:7545
      label: MYB
  - preferred_term: NFIB
    term:
      id: hgnc:7785
      label: NFIB
  cell_types:
  - preferred_term: salivary gland cell
    term:
      id: CL:0009005
      label: salivary gland cell
  evidence:
  - reference: PMID:19841262
    reference_title: "Recurrent fusion of MYB and NFIB transcription factor genes in carcinomas of the breast and head and neck."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      the t(6;9)(q22-23;p23-24) translocation in adenoid cystic carcinomas (ACC)
      of the breast and head and neck consistently results in fusions encoding
      chimeric transcripts predominantly consisting of MYB exon 14 linked to the
      last coding exon(s) of NFIB
    explanation: >-
      Defines the recurrent t(6;9) translocation and the exon architecture of the
      MYB-NFIB fusion transcript that is the genomic hallmark of ACC.
  - reference: PMID:19841262
    reference_title: "Recurrent fusion of MYB and NFIB transcription factor genes in carcinomas of the breast and head and neck."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The minimal common part of MYB deleted as the result of fusion was exon 15
      including the 3'-UTR, which contains several highly conserved target sites
      for miR-15a/16 and miR-150 microRNAs.
    explanation: >-
      Establishes loss of the MYB 3' UTR microRNA-binding sites as the molecular
      basis for escape from miR-15a/16 and miR-150 repression.
  - reference: PMID:30269389
    reference_title: "t(6;9)(MYB-NFIB) in head and neck adenoid cystic carcinoma: A systematic review with meta-analysis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The prevalence of t(6;9)(MYB-NFIB) varied significantly (16%-100%),
      especially due to methodological heterogeneity among studies.
    explanation: >-
      A systematic review quantifies the wide reported prevalence range of the
      fusion and attributes it to assay methodology; supports the claim that the
      fusion is recurrent but qualifies any single frequency figure.
  downstream:
  - target: MYB-Driven Oncogenic Transcriptional Program
    description: >-
      Loss of 3' UTR-mediated repression leads to overexpression of MYB-NFIB
      transcripts and protein and activation of MYB target genes.
    causal_link_type: DIRECT
- name: MYBL1 Rearrangement and MYB Amplification
  biological_scale: MOLECULAR
  description: >-
    In tumors lacking the MYB-NFIB fusion, the same MYB-family transcriptional
    output is reached by alternative genetic routes: rearrangements of the second
    MYB-family gene MYBL1 (MYBL1-NFIB, MYBL1-ACTN1) or high-level amplification
    of MYB itself, each producing MYBL1 or MYB overexpression. These lesions are
    mutually exclusive with the MYB-NFIB fusion, making ACC a convergent
    phenotype at the level of MYB-family activation rather than a single-lesion
    disease.
  genes:
  - preferred_term: MYBL1
    term:
      id: hgnc:7547
      label: MYBL1
  - preferred_term: MYB
    term:
      id: hgnc:7545
      label: MYB
  evidence:
  - reference: PMID:29149504
    reference_title: "MYBL1 rearrangements and MYB amplification in breast adenoid cystic carcinomas lacking the MYB-NFIB fusion gene."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      we demonstrate that MYBL1 rearrangements and MYB amplification probably
      constitute alternative genetic drivers of breast AdCCs, functioning through
      MYBL1 or MYB overexpression.
    explanation: >-
      Massively parallel sequencing of fusion-negative AdCC identifies MYBL1
      rearrangement and MYB amplification as alternative drivers converging on
      MYB-family overexpression.
  - reference: PMID:26851182
    reference_title: "Adenoid Cystic Carcinoma Can Be Driven by MYB or MYBL1 Rearrangements: New Insights into MYB and Tumor Biology."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      AdCCs can alternatively be driven by similar rearrangements involving a
      second MYB family gene, MYBL1, and that these two drivers act in remarkably
      similar ways
    explanation: >-
      Supports MYBL1 rearrangement as a mechanistically equivalent alternative
      driver to MYB-NFIB in ACC.
  - reference: PMID:36465348
    reference_title: "Single-cell transcriptomic analysis of the tumor ecosystem of adenoid cystic carcinoma."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      MYB and MYBL1 were found to belong to two different gene modules and were
      expressed in a mutually exclusive manner.
    explanation: >-
      Single-cell transcriptomics confirms mutually exclusive MYB and MYBL1
      expression modules, supporting them as alternative rather than additive
      drivers.
  downstream:
  - target: MYB-Driven Oncogenic Transcriptional Program
    description: >-
      MYBL1 rearrangement or MYB amplification produces MYB-family overexpression
      and activation of the same downstream transcriptional program.
    causal_link_type: DIRECT
- name: Super-Enhancer Translocation and MYB Positive Feedback Loop
  biological_scale: MOLECULAR
  description: >-
    Beyond creating a chimeric protein, the recurrent rearrangements act as
    regulatory translocations that juxtapose distal super-enhancers to the MYB
    locus. MYB protein then binds these translocated enhancers itself,
    establishing a self-sustaining positive feedback loop that locks in MYB
    overexpression. This enhancer dependency is the rationale for bromodomain
    (BET) inhibition in preclinical ACC models.
  biological_processes:
  - preferred_term: enhancer-driven positive regulation of MYB transcription
    modifier: INCREASED
    term:
      id: GO:0045944
      label: positive regulation of transcription by RNA polymerase II
  evidence:
  - reference: PMID:26829750
    reference_title: "An oncogenic MYB feedback loop drives alternate cell fates in adenoid cystic carcinoma."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      we identify super-enhancer translocations that drive overexpression of the
      oncogenic transcription factor MYB as a recurrent theme in adenoid cystic
      carcinoma (ACC)
    explanation: >-
      Whole-genome sequencing and chromatin mapping identify super-enhancer
      translocations to the MYB locus as a recurrent mechanism of MYB
      overexpression in ACC.
  - reference: PMID:26829750
    reference_title: "An oncogenic MYB feedback loop drives alternate cell fates in adenoid cystic carcinoma."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      MYB protein binds to the translocated enhancers, creating a positive
      feedback loop that sustains its expression.
    explanation: >-
      Establishes the MYB autoregulatory positive feedback loop that sustains MYB
      overexpression in ACC.
  downstream:
  - target: MYB-Driven Oncogenic Transcriptional Program
    description: >-
      The enhancer feedback loop sustains high-level MYB expression and its
      downstream transcriptional program.
    causal_link_type: DIRECT
- name: MYB-Driven Oncogenic Transcriptional Program
  biological_scale: CELLULAR
  description: >-
    Overexpressed MYB (or MYBL1), acting as a sequence-specific DNA-binding
    transcription factor, drives a transcriptional program promoting cell-cycle
    progression, survival, angiogenesis and adhesion. Critically, MYB binds
    lineage-specific enhancers and therefore drives different regulatory programs
    in the two cell compartments of the tumor: it cooperates with TP63 in
    myoepithelial cells and with a Notch program in luminal epithelial cells.
    This single-driver, two-program behaviour is the molecular explanation for
    the defining biphasic architecture of ACC.
  molecular_functions:
  - preferred_term: MYB DNA-binding transcription factor activity
    modifier: INCREASED
    term:
      id: GO:0003700
      label: DNA-binding transcription factor activity
  biological_processes:
  - preferred_term: MYB target gene transcriptional activation
    modifier: INCREASED
    term:
      id: GO:0045944
      label: positive regulation of transcription by RNA polymerase II
  evidence:
  - reference: PMID:19841262
    reference_title: "Recurrent fusion of MYB and NFIB transcription factor genes in carcinomas of the breast and head and neck."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Our data indicate that the MYB-NFIB fusion is a hallmark of ACC and that
      deregulation of the expression of MYB and its target genes is a key
      oncogenic event in the pathogenesis of ACC.
    explanation: >-
      Establishes deregulated MYB target-gene expression as the key oncogenic
      event downstream of the fusion.
  - reference: PMID:26829750
    reference_title: "An oncogenic MYB feedback loop drives alternate cell fates in adenoid cystic carcinoma."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      MYB also binds enhancers that drive different regulatory programs in
      alternate cell lineages in ACC, cooperating with TP63 in myoepithelial
      cells and a Notch program in luminal epithelial cells.
    explanation: >-
      Directly supports the claim that a single MYB driver produces two distinct
      lineage-specific programs, underpinning the biphasic tumor architecture.
  downstream:
  - target: Biphasic Myoepithelial-Luminal Tumor Architecture
    description: >-
      Lineage-specific MYB enhancer binding sustains distinct myoepithelial and
      luminal transcriptional programs within the same tumor.
    causal_link_type: DIRECT
  - target: Neurotropic Perineural Invasion
    description: >-
      The MYB-driven program supports the infiltrative, neurotropic phenotype
      that characterises ACC growth.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
- name: Intercalated Duct Cell of Origin and Premalignant Transition
  biological_scale: CELLULAR
  description: >-
    Single-cell transcriptomic profiling of paracarcinoma and carcinoma tissue
    resolves the ACC epithelium into myoepithelial-like, intercalated duct-like,
    and duct-like cells. A subset of intercalated duct-like cells in
    paracarcinoma tissue carries copy-number alterations affecting MYB-family
    genes and EN1 and is identified as premalignant; pseudotime trajectory
    analysis shows these cells transitioning into frank malignant cells,
    implicating the intercalated duct cell as the cell of origin.
  cell_types:
  - preferred_term: intercalated duct cell of salivary gland
    term:
      id: CL:4052048
      label: intercalated cell of salivary gland
  evidence:
  - reference: PMID:36465348
    reference_title: "Single-cell transcriptomic analysis of the tumor ecosystem of adenoid cystic carcinoma."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      part of intercalated duct-like cells with special copy number variations
      which altered with MYB family gene and EN1 transcriptomes were identified
      as premalignant cells
    explanation: >-
      Identifies a premalignant intercalated duct-like cell population defined by
      MYB-family copy-number alterations.
  - reference: PMID:36465348
    reference_title: "Single-cell transcriptomic analysis of the tumor ecosystem of adenoid cystic carcinoma."
    supports: SUPPORT
    evidence_source: COMPUTATIONAL
    snippet: >-
      Developmental pseudo-time analysis showed that the premalignant cells
      eventually transformed into malignant cells.
    explanation: >-
      Pseudotime trajectory analysis supports progression of the premalignant
      intercalated duct-like population into malignant ACC cells.
  downstream:
  - target: Biphasic Myoepithelial-Luminal Tumor Architecture
    description: >-
      Transformed intercalated duct-like cells give rise to the two-compartment
      tumor epithelium.
    causal_link_type: DIRECT
- name: Biphasic Myoepithelial-Luminal Tumor Architecture
  biological_scale: TISSUE
  description: >-
    The tumor is built from two interdependent epithelial compartments: abluminal
    myoepithelial-like cells and luminal ductal cells. These are arranged in
    cribriform, tubular, and solid patterns, with the cribriform "Swiss cheese"
    architecture produced by pseudocysts filled with basement-membrane-like
    material laid down by the myoepithelial compartment. The proportion of solid
    architecture is the basis of histological grading and tracks with
    aggressiveness.
  cell_types:
  - preferred_term: myoepithelial cell of salivary gland
    term:
      id: CL:0020066
      label: myoepithelial cell of salivary gland
  - preferred_term: luminal ductal tumor cell
    term:
      id: CL:0000068
      label: duct epithelial cell
  locations:
  - preferred_term: major salivary gland
    term:
      id: UBERON:0001829
      label: major salivary gland
  evidence:
  - reference: PMID:36465348
    reference_title: "Single-cell transcriptomic analysis of the tumor ecosystem of adenoid cystic carcinoma."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Three main types of the epithelial cells were identified into
      myoepithelial-like cells, intercalated duct-like cells, and duct-like cells
      by marker genes.
    explanation: >-
      Single-cell profiling resolves the ACC epithelium into myoepithelial-like
      and ductal compartments, supporting the biphasic architecture.
  downstream:
  - target: Neurotropic Perineural Invasion
    description: >-
      The infiltrative biphasic tumor front advances preferentially along
      perineural planes.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    hypothesis_groups:
    - bdnf_neurotropism
  - target: Salivary Gland Neoplasm
    description: >-
      Tumor architecture arising in salivary ductal and myoepithelial lineages
      produces the characteristic salivary-gland neoplasm.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Neoplasm of Head and Neck
    description: >-
      At head-and-neck exocrine sites, the biphasic tumor architecture manifests
      as a locally infiltrative neoplasm.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Dysphagia
    description: >-
      Oropharyngeal and palatal tumors can impair swallowing through local mass
      effect and infiltration.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
- name: NOTCH1 Pathway Hyperactivation
  biological_scale: MOLECULAR
  description: >-
    A distinct subgroup of ACC carries activating NOTCH1 mutations clustered in
    the negative regulatory region and the PEST (Pro-Glu-Ser-Thr-rich) domain —
    the same two hotspots exploited in T-cell acute lymphoblastic leukemia —
    which stabilise the Notch1 intracellular domain and drive constitutive
    pathway output. These alterations are strongly enriched in
    recurrent/metastatic relative to primary disease, indicating that Notch
    activation is a progression event as well as an initiating one.
  genes:
  - preferred_term: NOTCH1
    term:
      id: hgnc:7881
      label: NOTCH1
  biological_processes:
  - preferred_term: Notch signaling pathway
    modifier: INCREASED
    term:
      id: GO:0007219
      label: Notch signaling pathway
  evidence:
  - reference: PMID:27870570
    reference_title: "Activating NOTCH1 Mutations Define a Distinct Subgroup of Patients With Adenoid Cystic Carcinoma Who Have Poor Prognosis, Propensity to Bone and Liver Metastasis, and Potential Responsiveness to Notch1 Inhibitors."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      NOTCH1 mutations occurred predominantly (14 of 15 patients) in the negative
      regulatory region and Pro-Glu-Ser-Thr-rich domains, the same two hotspots
      seen in T-cell acute lymphoblastic leukemias, and led to pathway activation
      in vitro.
    explanation: >-
      Localises ACC NOTCH1 mutations to the canonical activating hotspots and
      confirms functional pathway activation.
  - reference: PMID:31483290
    reference_title: "Genetic hallmarks of recurrent/metastatic adenoid cystic carcinoma."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Compared with primary tumors, R/M tumors were enriched for alterations in
      key Notch (NOTCH1, 26.3% vs. 8.5%; NOTCH2, 4.6% vs. 2.3%; NOTCH3, 5.7% vs.
      2.3%; NOTCH4, 3.6% vs. 0.6%) and chromatin-remodeling (KDM6A, 15.2% vs.
      3.4%; KMT2C/MLL3, 14.3% vs. 4.0%; ARID1B, 14.1% vs. 4.0%) genes.
    explanation: >-
      An integrated genomic analysis of 1,045 ACCs quantifies Notch-pathway and
      chromatin-remodeler enrichment in recurrent/metastatic versus primary
      tumors.
  downstream:
  - target: Solid-Pattern Aggressive Disease
    description: >-
      Notch pathway activation drives the solid histologic phenotype and its
      accelerated clinical course.
    causal_link_type: DIRECT
- name: TERT Promoter Mutation as an Alternative Oncogenic Route
  biological_scale: MOLECULAR
  conforms_to: "enabling_replicative_immortality#Telomere Maintenance Reactivation"
  description: >-
    A minority of recurrent/metastatic tumors carry TERT promoter hotspot
    mutations that are mutually exclusive with both NOTCH1 mutations and
    MYB/MYBL1 fusions. Together with the MYB and Notch lesions these define four
    discrete molecular subgroups, indicating that ACC is reached by more than one
    oncogenic route rather than by a single obligatory pathway. The cited ACC
    genomic series establishes the lesion and its mutual exclusivity but does not
    measure telomerase activity or telomere length, so a downstream mechanism of
    telomere maintenance is not asserted here.
  genes:
  - preferred_term: TERT
    term:
      id: hgnc:11730
      label: TERT
  evidence:
  - reference: PMID:31483290
    reference_title: "Genetic hallmarks of recurrent/metastatic adenoid cystic carcinoma."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      TERT promoter mutations (13.1% of R/M cases) were mutually exclusive with
      both NOTCH1 mutations (q = 3.3 × 10-4) and MYB/MYBL1 fusions (q = 5.6 ×
      10-3), suggesting discrete, alternative mechanisms of tumorigenesis.
    explanation: >-
      Establishes TERT promoter mutation as a mutually exclusive, alternative
      oncogenic mechanism in ACC.
  - reference: PMID:31483290
    reference_title: "Genetic hallmarks of recurrent/metastatic adenoid cystic carcinoma."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      This network of alterations defined 4 distinct ACC subgroups: MYB+NOTCH1+,
      MYB+/other, MYBWTNOTCH1+, and MYBWTTERT+.
    explanation: >-
      Defines the four molecular subgroups of ACC on which the multi-route model
      of tumorigenesis rests.
- name: Neurotropic Perineural Invasion
  biological_scale: TISSUE
  description: >-
    Perineural invasion is the single most characteristic pathophysiological
    behaviour of ACC: tumor cells track along the perineural and endoneural
    spaces of named nerves, forming a target-like cuff around nerve fascicles and
    extending microscopically far beyond the grossly visible tumor margin, in
    many cases to the skull base. Brain-derived neurotrophic factor (BDNF), a
    neurotrophin involved in neurogenesis, is uniformly expressed by ACC and is
    the leading candidate mediator of this neurotropism. Perineural spread is the
    principal reason margin-negative resection is difficult and local recurrence
    is late and frequent.
  locations:
  - preferred_term: nerve
    term:
      id: UBERON:0001021
      label: nerve
  evidence:
  - reference: PMID:12378520
    reference_title: "Perineural invasion in adenoid cystic carcinoma: Its causation/promotion by brain-derived neurotrophic factor."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      This is accounted for histologically by its infiltrative capacity and
      distinct propensity for perineural invasion.
    explanation: >-
      Attributes the lengthy clinical course and late local recurrence of ACC to
      its infiltrative capacity and perineural invasion.
  - reference: PMID:12378520
    reference_title: "Perineural invasion in adenoid cystic carcinoma: Its causation/promotion by brain-derived neurotrophic factor."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Based on the results presented here, BDNF is unformly expressed by ACC and
      may play a causative role in its predilection for perineural invasion.
    explanation: >-
      Immunohistochemistry in 29 primary ACCs shows uniform BDNF expression; the
      authors propose but do not prove a causative role, so this is marked
      PARTIAL.
  - reference: PMID:17576903
    reference_title: "The sensitivity and specificity of high-resolution imaging in evaluating perineural spread of adenoid cystic carcinoma to the skull base."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Histopathologic evidence of PNS was present in 25 (66%) of 38 named nerves.
    explanation: >-
      Quantifies the high histopathologic frequency of perineural spread along
      named nerves in ACC undergoing cranial base resection.
  downstream:
  - target: Cranial Neuropathy and Late Local Recurrence
    description: >-
      Tumor spread along cranial nerves produces neurological deficits and leaves
      microscopic residual disease after resection.
    causal_link_type: DIRECT
- name: Solid-Pattern Aggressive Disease
  biological_scale: ORGANISM
  description: >-
    NOTCH1-mutant tumors define a clinically distinct aggressive subgroup marked
    by solid histology, advanced stage at diagnosis, a higher rate of liver and
    bone metastasis, and substantially shorter relapse-free and overall survival
    than NOTCH1 wild-type disease. This subgroup is the target population for
    Notch-directed therapy.
  evidence:
  - reference: PMID:27870570
    reference_title: "Activating NOTCH1 Mutations Define a Distinct Subgroup of Patients With Adenoid Cystic Carcinoma Who Have Poor Prognosis, Propensity to Bone and Liver Metastasis, and Potential Responsiveness to Notch1 Inhibitors."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      NOTCH1 mutations define a distinct disease phenotype characterized by solid
      histology, liver and bone metastasis, poor prognosis, and potential
      responsiveness to Notch1 inhibitors.
    explanation: >-
      Directly establishes the NOTCH1-mutant clinical phenotype of solid
      histology, visceral and bone metastasis, and poor prognosis.
  downstream:
  - target: Late Haematogenous Metastasis
    description: >-
      The aggressive NOTCH-activated phenotype accelerates distant, particularly
      liver and bone, metastatic spread.
    causal_link_type: DIRECT
- name: Cranial Neuropathy and Late Local Recurrence
  biological_scale: ORGANISM
  description: >-
    Perineural tumor extension along the facial and trigeminal nerves and their
    named branches produces progressive motor and sensory cranial neuropathy, and
    leaves microscopic disease beyond the surgical field. The result is a
    characteristically long tail of local recurrence, with events occurring many
    years after apparently complete treatment and motivating long-term follow-up.
  evidence:
  - reference: PMID:17576903
    reference_title: "The sensitivity and specificity of high-resolution imaging in evaluating perineural spread of adenoid cystic carcinoma to the skull base."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Perineural spread across the skull base is a frequent occurrence in
      patients with adenoid cystic carcinoma of the head and neck.
    explanation: >-
      Confirms that perineural spread reaches the skull base frequently, the
      anatomical basis for cranial neuropathy and incomplete resection.
  - reference: PMID:35931701
    reference_title: "AL101, a gamma-secretase inhibitor, has potent antitumor activity against adenoid cystic carcinoma with activated NOTCH signaling."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      current treatment options for the localized disease are limited to surgery
      and radiation, which fails to prevent locoregional recurrences and distant
      metastases in over 50% of patients
    explanation: >-
      Quantifies the failure of local therapy to prevent locoregional recurrence
      and distant metastasis in more than half of patients.
  downstream:
  - target: Facial Palsy
    description: >-
      Facial-nerve involvement can produce progressive motor weakness.
    causal_link_type: DIRECT
  - target: Facial and Perineural Pain
    description: >-
      Invasion of sensory nerves produces pain in the involved distribution.
    causal_link_type: DIRECT
  - target: Paresthesia
    description: >-
      Sensory-nerve involvement produces numbness, tingling, or hypoesthesia.
    causal_link_type: DIRECT
- name: Late Haematogenous Metastasis
  biological_scale: ORGANISM
  conforms_to: "invasion_and_metastasis#Metastatic Colonization"
  description: >-
    ACC disseminates preferentially by the haematogenous rather than the
    lymphatic route, so regional nodal involvement is comparatively uncommon
    while distant metastasis — most often pulmonary, then bone and liver — is the
    dominant mode of failure. The defining feature is its latency: distant
    relapse typically appears several years after primary treatment and can occur
    more than a decade later, and patients may survive for years with established
    metastatic disease, so metastasis in ACC marks a chronic phase rather than an
    immediately terminal one.
  locations:
  - preferred_term: lung
    term:
      id: UBERON:0002048
      label: lung
  evidence:
  - reference: PMID:18343149
    reference_title: "Lung metastasis resection of adenoid cystic carcinoma of salivary glands."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Adenoid cystic carcinoma is a rare tumour originating from the exocrine
      mucous glands, known for its high propensity for distant metastases.
    explanation: >-
      Establishes the high propensity for distant metastasis that characterises
      ACC dissemination.
  - reference: PMID:18343149
    reference_title: "Lung metastasis resection of adenoid cystic carcinoma of salivary glands."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In 20 patients, at a median free interval time of 3 years (range 1-12), a
      distant metastasis relapse was observed.
    explanation: >-
      Quantifies the multi-year and up to 12-year latency of distant metastatic
      relapse in a surgical ACC cohort.
  - reference: PMID:18343149
    reference_title: "Lung metastasis resection of adenoid cystic carcinoma of salivary glands."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Mean survival of patients having presented with distant metastases resulted
      as being 11 years (SE=2.2).
    explanation: >-
      Documents the prolonged survival after distant metastasis that
      distinguishes ACC from most metastatic carcinomas.
  downstream:
  - target: Pulmonary Metastasis
    description: >-
      Haematogenous dissemination commonly seeds the lung after a prolonged
      disease-free interval.
    causal_link_type: DIRECT
mechanistic_hypotheses:
- hypothesis_group_id: bdnf_neurotropism
  hypothesis_label: BDNF-Mediated Neurotropism Model of Perineural Invasion
  status: EMERGING
  description: >-
    ACC uniformly expresses brain-derived neurotrophic factor, and BDNF-TrkB
    neurotrophin signalling is the leading candidate explanation for the tumor's
    unusual predilection for perineural spread. The supporting human evidence is
    immunohistochemical and correlative rather than functional: no study has yet
    shown that blocking BDNF or TrkB reduces perineural invasion in ACC. The
    alternative interpretation — that BDNF expression is a marker of the
    neural-adjacent microenvironment rather than a driver of neurotropism — has
    not been excluded.
  evidence:
  - reference: PMID:12378520
    reference_title: "Perineural invasion in adenoid cystic carcinoma: Its causation/promotion by brain-derived neurotrophic factor."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Further studies are warranted to gain better understanding of this possible
      relationship.
    explanation: >-
      The originating study explicitly frames the BDNF-neurotropism link as a
      possible relationship requiring further study, supporting EMERGING status.
histopathology:
- name: Cribriform Pattern
  finding_term:
    preferred_term: Cribriform Pattern
    term:
      id: NCIT:C35920
      label: Cribriform Pattern
  diagnostic: true
  description: >-
    The classic and most common architecture: nests of basaloid tumor cells
    punched through by rounded pseudocystic spaces ("Swiss cheese" appearance)
    containing basement-membrane-like and mucoid material produced by the
    myoepithelial compartment.
  evidence:
  - reference: PMID:23463073
    reference_title: "Adenoid cystic carcinoma: clinical and molecular features."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      ACC has distinct histologic features, with cribriform and tubular growth
      patterns of basaloid cells displaying a predominantly myoepithelial
      cellular phenotype.
    explanation: >-
      A disease-focused review identifies cribriform growth as a defining ACC
      histologic pattern.
- name: Tubular Pattern
  finding_term:
    preferred_term: Tubular Pattern
    term:
      id: NCIT:C35925
      label: Tubular Pattern
  description: >-
    True ducts lined by an inner luminal epithelial layer and an outer
    myoepithelial layer. A predominantly tubular tumor corresponds to the
    lowest-grade, most favourable end of the histological spectrum.
  evidence:
  - reference: PMID:23463073
    reference_title: "Adenoid cystic carcinoma: clinical and molecular features."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      ACC has distinct histologic features, with cribriform and tubular growth
      patterns of basaloid cells displaying a predominantly myoepithelial
      cellular phenotype.
    explanation: >-
      A disease-focused review identifies tubular growth as a defining ACC
      histologic pattern.
- name: Solid Growth Pattern
  finding_term:
    preferred_term: Solid Growth Pattern
    term:
      id: NCIT:C36182
      label: Solid Growth Pattern
  description: >-
    Sheets of basaloid cells without duct or pseudocyst formation, often with
    higher mitotic activity and comedonecrosis. The proportion of solid
    architecture drives histological grade; a solid-predominant tumor is the
    least favourable pattern and is enriched in NOTCH1-mutant disease.
  evidence:
  - reference: PMID:27180054
    reference_title: "Myoepithelial differentiation in cribriform, tubular and solid pattern of adenoid cystic carcinoma: A potential involvement in histological grading and prognosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The solid pattern of AdCC showed gland differentiation but loss of
      myoepithelial differentiation with a higher proliferation and more
      aggressiveness as well as poorer prognosis compared with the
      cribriform-tubular subtypes
    explanation: >-
      Directly supports the solid pattern's altered differentiation and worse
      clinical behavior relative to cribriform-tubular ACC.
  - reference: PMID:40025676
    reference_title: "Clinical Outcomes With Notch Inhibitors in Notch-Activated Recurrent/Metastatic Adenoid Cystic Carcinoma."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Twenty-nine patients were included, with a predominance of solid histology
      (86%).
    explanation: >-
      In a Notch-activated ACC cohort solid histology predominated, linking the
      solid pattern to Notch-pathway activation.
- name: Perineural Invasion
  finding_term:
    preferred_term: Perineural Invasion
    term:
      id: NCIT:C48260
      label: Perineural Invasion
  frequency: FREQUENT
  diagnostic: true
  description: >-
    Tumor cells within the perineural or endoneural space, classically forming a
    target-like cuff around a nerve fascicle. Present in the majority of named
    nerves examined in skull-base resection specimens and independently
    associated with worse disease-free and overall survival.
  evidence:
  - reference: PMID:17576903
    reference_title: "The sensitivity and specificity of high-resolution imaging in evaluating perineural spread of adenoid cystic carcinoma to the skull base."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Histopathologic evidence of PNS was present in 25 (66%) of 38 named nerves.
    explanation: >-
      Quantifies perineural spread in 66% of named nerves examined
      histopathologically, supporting a FREQUENT frequency band.
phenotypes:
- name: Salivary Gland Neoplasm
  category: Clinical
  description: >-
    A slowly enlarging mass of a major or minor salivary gland is a common
    presentation. ACC also occurs in other secretory glands, so this phenotype
    does not define every anatomical presentation.
  phenotype_term:
    preferred_term: Salivary gland neoplasm
    term:
      id: HP:0100684
      label: Salivary gland neoplasm
    clinical_course: PROGRESSIVE
  evidence:
  - reference: PMID:39410002
    reference_title: "Epidemiological Study of Adenoid Cystic Carcinoma and Its Outcomes: Insights from the Surveillance, Epidemiology, and End Results (SEER) Database."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Adenoid cystic carcinoma (ACC) is a rare malignant tumor that mainly arises
      in the head and neck area.
    explanation: >-
      A SEER registry study of 5,150 patients confirms the head and neck,
      dominated by salivary gland sites, as the principal primary site.
  - reference: PMID:23463073
    reference_title: "Adenoid cystic carcinoma: clinical and molecular features."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      ACC is an uncommon neoplasm that most frequently arises in salivary glands
      and related tissue in the head and neck region.
    explanation: >-
      Directly supports major and minor salivary glands as the typical sites of
      origin while preserving the existence of non-salivary primaries.
- name: Neoplasm of Head and Neck
  category: Clinical
  description: >-
    ACC most often presents as a head-and-neck tumor arising in major or minor
    salivary glands; lacrimal-gland primaries are another documented
    head-and-neck presentation.
  phenotype_term:
    preferred_term: Neoplasm of head and neck
    term:
      id: HP:0012288
      label: Neoplasm of head and neck
  evidence:
  - reference: PMID:39199639
    reference_title: "Molecular Analysis of Salivary and Lacrimal Adenoid Cystic Carcinoma."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Eleven patients had primary salivary gland ACC and three primary lacrimal
      gland ACC
    explanation: >-
      Documents both salivary and lacrimal gland primaries within a head and neck
      ACC cohort.
- name: Facial Palsy
  category: Clinical
  description: >-
    Progressive weakness of the facial musculature from perineural tumor
    extension along the facial nerve (CN VII) can occur with parotid or
    skull-base disease.
  phenotype_term:
    preferred_term: Facial palsy
    term:
      id: HP:0010628
      label: Facial palsy
    clinical_course: PROGRESSIVE
  evidence:
  - reference: PMID:17576903
    reference_title: "The sensitivity and specificity of high-resolution imaging in evaluating perineural spread of adenoid cystic carcinoma to the skull base."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Adenoid cystic carcinoma of the head and neck frequently exhibits PNS
      across the skull base.
    explanation: >-
      Indirect support: establishes frequent perineural spread across the skull
      base, the anatomical mechanism of cranial nerve palsy, but the snippet does
      not itself report facial palsy, so this is marked PARTIAL.
- name: Facial and Perineural Pain
  category: Clinical
  description: >-
    Pain or neuralgiform discomfort can accompany tumor involvement of sensory
    nerves; pain/discomfort is also a documented presenting symptom in
    oropharyngeal ACC.
  phenotype_term:
    preferred_term: Pain in head and neck region
    term:
      id: HP:0046506
      label: Pain in head and neck region
    temporality: CHRONIC
  evidence:
  - reference: PMID:12378520
    reference_title: "Perineural invasion in adenoid cystic carcinoma: Its causation/promotion by brain-derived neurotrophic factor."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      distinct propensity for perineural invasion
    explanation: >-
      Indirect support: documents the perineural invasion that causes neuropathic
      facial pain; the snippet does not report the pain symptom itself, so this
      is marked PARTIAL.
  - reference: PMID:42371638
    reference_title: "Clinical Features, Treatment, and Outcomes for Oropharyngeal Adenoid Cystic Carcinoma: A Systematic Review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Presenting symptoms were mainly pain/discomfort (n = 31), followed by a
      palpable mass (n = 19) and dysphagia (n = 12).
    explanation: >-
      A 2026 systematic review directly documents pain as the leading reported
      presenting symptom in oropharyngeal ACC; support is PARTIAL because the
      review is restricted to that anatomical subset.
- name: Paresthesia
  category: Clinical
  description: >-
    Numbness, tingling, and hypoesthesia in the territory of a nerve infiltrated
    by tumor, reflecting sensory fibre involvement by perineural spread.
  phenotype_term:
    preferred_term: Paresthesia
    term:
      id: HP:0003401
      label: Paresthesia
    temporality: CHRONIC
  evidence:
  - reference: PMID:36060029
    reference_title: "Adenoid Cystic Carcinoma (ACC) Infiltrating the Skull Base: A Systematic Review of Clinical Characteristics and Management Strategies."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Facial pain, nasal obstruction, and facial paresthesia were the most common
      symptoms.
    explanation: >-
      A systematic review directly reports facial paresthesia among common
      symptoms of skull-base ACC; support is PARTIAL because this is an
      anatomically selected subset.
- name: Pulmonary Metastasis
  category: Clinical
  description: >-
    The lung is a well-documented site of distant ACC recurrence. Pulmonary
    metastasis may appear only after a multi-year disease-free interval.
  phenotype_term:
    preferred_term: Neoplasm of the lung
    term:
      id: HP:0100526
      label: Neoplasm of the lung
  evidence:
  - reference: PMID:18343149
    reference_title: "Lung metastasis resection of adenoid cystic carcinoma of salivary glands."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Nine patients who presented isolated lung recurrence underwent complete
      lung metastasectomy.
    explanation: >-
      Documents isolated pulmonary recurrence as a recognised and surgically
      addressed pattern of ACC metastasis.
- name: Dysphagia
  category: Clinical
  description: >-
    Difficulty swallowing can be a presenting symptom of oropharyngeal ACC,
    including base-of-tongue primaries.
  phenotype_term:
    preferred_term: Dysphagia
    term:
      id: HP:0002015
      label: Dysphagia
    clinical_course: PROGRESSIVE
  evidence:
  - reference: PMID:42371638
    reference_title: "Clinical Features, Treatment, and Outcomes for Oropharyngeal Adenoid Cystic Carcinoma: A Systematic Review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Presenting symptoms were mainly pain/discomfort (n = 31), followed by a
      palpable mass (n = 19) and dysphagia (n = 12).
    explanation: >-
      A 2026 systematic review directly documents dysphagia at presentation;
      support is PARTIAL because the cohort is limited to oropharyngeal ACC.
biochemical:
- name: MYB-NFIB Fusion Transcript
  notes: >-
    Detection of the MYB-NFIB (or MYBL1) rearrangement by FISH, RT-PCR, or RNA
    sequencing is a useful molecular diagnostic adjunct for ACC. A negative
    result does not exclude ACC because only a subset carries the canonical
    translocation and alternative MYB-family alterations occur.
  evidence:
  - reference: PMID:39199639
    reference_title: "Molecular Analysis of Salivary and Lacrimal Adenoid Cystic Carcinoma."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      76.9% of the analyzed tumors displayed evidence of NFIB-MYB rearrangement
      at the 6q23.3 locus; 35% had mutations in NOTCH pathway genes
    explanation: >-
      Quantifies MYB-NFIB rearrangement detection rate alongside NOTCH pathway
      mutation rate in a clinically sequenced ACC cohort.
- name: MYB Protein Overexpression
  biomarker_term:
    preferred_term: Transcriptional Activator Myb
    term:
      id: NCIT:C17329
      label: Transcriptional Activator Myb
  notes: >-
    Strong nuclear MYB immunostaining is a specific diagnostic adjunct, but its
    limited sensitivity means that a negative stain does not exclude ACC.
  evidence:
  - reference: PMID:21164292
    reference_title: MYB expression and translocation in adenoid cystic carcinomas and other salivary gland tumors with clinicopathologic correlation.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Strong Myb immunostaining is very specific for adenoid cystic carcinomas
      but is only present in 65% of all cases.
    explanation: >-
      Directly establishes high specificity and the important 65% sensitivity
      limitation of MYB immunohistochemistry.
- name: KIT (CD117) Expression
  biomarker_term:
    preferred_term: Mast/Stem Cell Growth Factor Receptor Kit
    term:
      id: NCIT:C17328
      label: Mast/Stem Cell Growth Factor Receptor Kit
  notes: >-
    KIT (CD117) is expressed in the large majority of ACC and can serve as an
    ancillary immunohistochemical marker, although staining does not reliably
    distinguish ACC from every basaloid mimic.
  evidence:
  - reference: PMID:14681323
    reference_title: "Expression of KIT (CD117) in neoplasms of the head and neck: an ancillary marker for adenoid cystic carcinoma."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Overall, 94% (n = 62) of adenoid cystic carcinomas from various anatomic
      sites and of various histologic subtypes were positive for at least one of
      the KIT antibodies, and 77% (n = 50) of adenoid cystic carcinoma cases were
      positive for both antibodies.
    explanation: >-
      Quantifies KIT immunoreactivity across anatomic sites and histologic
      subtypes, supporting its use as an ancillary rather than definitive marker.
imaging_findings:
- name: Perineural spread to the skull base on MRI
  modality: MRI
  located_in:
    preferred_term: nerve
    term:
      id: UBERON:0001021
      label: nerve
  diagnostic: true
  description: >-
    High-resolution MRI is the preferred imaging method for defining named-nerve
    perineural spread toward the skull base and its extent before local therapy.
  evidence:
  - reference: PMID:17576903
    reference_title: "The sensitivity and specificity of high-resolution imaging in evaluating perineural spread of adenoid cystic carcinoma to the skull base."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Magnetic resonance imaging had a higher sensitivity (100%) and specificity
      (85%).
    explanation: >-
      A histopathology-referenced cohort supports MRI's diagnostic performance
      for skull-base perineural spread.
diagnosis:
- name: MYB rearrangement testing
  description: >-
    Fluorescence in situ hybridization for MYB rearrangement can support an ACC
    diagnosis in the appropriate morphologic context, but a negative result does
    not exclude the disease.
  diagnosis_term:
    preferred_term: fluorescence in situ hybridization
    term:
      id: NCIT:C17563
      label: Fluorescence In Situ Hybridization
  evidence:
  - reference: PMID:21164292
    reference_title: MYB expression and translocation in adenoid cystic carcinomas and other salivary gland tumors with clinicopathologic correlation.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      MYB translocation and expression are useful diagnostic markers for a subset
      of adenoid cystic carcinomas.
    explanation: >-
      Supports FISH-detected MYB translocation as a subset-specific diagnostic
      adjunct and guards against treating a negative result as exclusionary.
genetic:
- name: MYB (MYB-NFIB Fusion)
  gene_term:
    preferred_term: MYB
    term:
      id: hgnc:7545
      label: MYB
  variant_origin: SOMATIC
  relationship_type: SOMATIC_DRIVER
  notes: >-
    The somatic t(6;9) MYB-NFIB fusion is the genomic hallmark of ACC. It is a
    somatic, tumor-restricted event; ACC is not an inherited cancer syndrome.
    Notably, the fusion has not been shown to be prognostic — it defines the
    disease rather than stratifying it.
  evidence:
  - reference: PMID:19841262
    reference_title: "Recurrent fusion of MYB and NFIB transcription factor genes in carcinomas of the breast and head and neck."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Our data indicate that the MYB-NFIB fusion is a hallmark of ACC
    explanation: >-
      Establishes the MYB-NFIB fusion as the defining genetic hallmark of ACC.
  - reference: PMID:30269389
    reference_title: "t(6;9)(MYB-NFIB) in head and neck adenoid cystic carcinoma: A systematic review with meta-analysis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      the best evidence available demonstrates that t(6;9)(MYB-NFIB) does not
      seem to be a prognostic determinant
    explanation: >-
      A systematic review of 36 studies finds no consistent association between
      the fusion and survival, supporting its diagnostic but not prognostic role.
- name: NFIB (Fusion Partner)
  gene_term:
    preferred_term: NFIB
    term:
      id: hgnc:7785
      label: NFIB
  variant_origin: SOMATIC
  relationship_type: SOMATIC_DRIVER
  notes: >-
    NFIB at 9p23-24 is the reciprocal partner of MYB in the t(6;9) translocation.
    Its principal contribution appears to be removal of the MYB 3' UTR rather
    than a gain of NFIB function.
  evidence:
  - reference: PMID:19841262
    reference_title: "Recurrent fusion of MYB and NFIB transcription factor genes in carcinomas of the breast and head and neck."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      the t(6;9)(q22-23;p23-24) translocation in adenoid cystic carcinomas (ACC)
      of the breast and head and neck consistently results in fusions encoding
      chimeric transcripts predominantly consisting of MYB exon 14 linked to the
      last coding exon(s) of NFIB
    explanation: >-
      Directly establishes NFIB as the recurrent MYB fusion partner in ACC.
- name: MYBL1 Rearrangement
  gene_term:
    preferred_term: MYBL1
    term:
      id: hgnc:7547
      label: MYBL1
  variant_origin: SOMATIC
  relationship_type: SOMATIC_DRIVER
  notes: >-
    MYBL1 rearrangements (MYBL1-NFIB, MYBL1-ACTN1) drive the MYB-fusion-negative
    subset and are mutually exclusive with MYB alterations.
  evidence:
  - reference: PMID:29149504
    reference_title: "MYBL1 rearrangements and MYB amplification in breast adenoid cystic carcinomas lacking the MYB-NFIB fusion gene."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In two cases, we identified MYBL1 rearrangements (MYBL1-ACTN1 and
      MYBL1-NFIB), which were associated with MYBL1 overexpression.
    explanation: >-
      Identifies the specific MYBL1 fusion partners and links them to MYBL1
      overexpression in fusion-negative ACC.
- name: NOTCH1 Activating Mutation
  gene_term:
    preferred_term: NOTCH1
    term:
      id: hgnc:7881
      label: NOTCH1
  variant_origin: SOMATIC
  relationship_type: SOMATIC_DRIVER
  notes: >-
    Somatic gain-of-function NOTCH1 mutations cluster in the negative regulatory
    region and PEST domain. In the largest integrated series they occur in 8.5%
    of primary and 26.3% of recurrent/metastatic tumors, an approximately
    three-fold enrichment with progression (Ho et al., PMID:31483290). Figures
    around 13.7% (NOTCH1 alone) and 20.5% (broader Notch-pathway genes) come from
    a separate mixed primary-plus-recurrent cohort of 102 tumors and are not
    primary-restricted (Ferrarotto et al., PMID:27870570); the two denominators
    should not be compared directly. NOTCH1 mutation defines an aggressive
    solid-histology subgroup and is the actionable biomarker for Notch-directed
    therapy.
  evidence:
  - reference: PMID:35931701
    reference_title: "AL101, a gamma-secretase inhibitor, has potent antitumor activity against adenoid cystic carcinoma with activated NOTCH signaling."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Approximately 20% of patients with ACC carry NOTCH-activating mutations
      that are associated with a distinct phenotype, aggressive disease, and poor
      prognosis.
    explanation: >-
      Quantifies the prevalence of NOTCH-activating mutations and their
      association with aggressive disease.
- name: TERT Promoter Mutation
  gene_term:
    preferred_term: TERT
    term:
      id: hgnc:11730
      label: TERT
  variant_origin: SOMATIC
  relationship_type: SOMATIC_DRIVER
  notes: >-
    TERT promoter hotspot mutations occur in about 13% of recurrent/metastatic
    ACC and are mutually exclusive with both NOTCH1 mutation and MYB/MYBL1
    fusion, marking a third oncogenic route.
  evidence:
  - reference: PMID:31483290
    reference_title: "Genetic hallmarks of recurrent/metastatic adenoid cystic carcinoma."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      TERT promoter mutations (13.1% of R/M cases) were mutually exclusive with
      both NOTCH1 mutations (q = 3.3 × 10-4) and MYB/MYBL1 fusions (q = 5.6 ×
      10-3), suggesting discrete, alternative mechanisms of tumorigenesis.
    explanation: >-
      Quantifies TERT promoter mutation frequency and its mutual exclusivity with
      the other ACC drivers.
treatments:
- name: Surgical Resection
  description: >-
    Gross total resection with tumor-free margins is the principal local
    treatment when anatomically feasible. Achieving negative margins is
    difficult because microscopic perineural extension can reach beyond the
    visible tumor. In anterior craniofacial ACC, incomplete R2 resection did not
    improve on nonsurgical treatment, so the benefit should not be generalized
    to unresectable disease.
  therapeutic_modality: SURGERY
  treatment_term:
    preferred_term: Definitive Surgical Resection
    term:
      id: NCIT:C154430
      label: Definitive Surgical Resection
  evidence:
  - reference: PMID:39410002
    reference_title: "Epidemiological Study of Adenoid Cystic Carcinoma and Its Outcomes: Insights from the Surveillance, Epidemiology, and End Results (SEER) Database."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In multivariable analysis, older age, male sex, thoracic cancer, the
      presence of regional and distal disease, receiving chemotherapy, not
      undergoing surgical resection, and being treated in the West vs. Northeast
      region were found to be independent predictors of poor survival.
    explanation: >-
      In a 5,150-patient SEER analysis, not undergoing surgical resection is an
      independent predictor of poor survival, supporting surgery as the primary
      modality.
  - reference: PMID:41941852
    reference_title: "Outcomes of different treatment patterns for adenoid cystic carcinoma of the anterior craniofacial area: A multi-institutional study on 578 patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      GTR followed by adjuvant RT, especially with proton therapy (PT), achieved
      the best local control. R2 resections provided no advantage over NST.
    explanation: >-
      A large multi-institutional cohort supports gross total resection while
      warning against incomplete resection; support is PARTIAL because the study
      is retrospective and restricted to anterior craniofacial ACC.
- name: Postoperative Radiotherapy
  description: >-
    Radiotherapy combined with surgery is the standard local approach for many
    head-and-neck ACCs, particularly advanced or anatomically complex disease.
    Proton and carbon-ion techniques are emerging options for improving dose
    conformity; definitive proton therapy is supported for selected anterior
    craniofacial tumors when complete resection is not feasible.
  therapeutic_modality: RADIOTHERAPY
  treatment_term:
    preferred_term: Radiation Therapy
    term:
      id: NCIT:C15313
      label: Radiation Therapy
  evidence:
  - reference: PMID:42229289
    reference_title: "Advanced radiotherapy and systemic therapy in head and neck adenoid cystic carcinoma: Current progress and future integrated strategies."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Although surgery combined with radiotherapy remains the standard local
      approach, treatment outcomes remain suboptimal in patients with
      unresectable tumors, advanced local disease, or anatomically complex
      lesions.
    explanation: >-
      A contemporary review establishes surgery plus radiotherapy as the standard
      local approach while noting its limits in advanced disease.
  - reference: PMID:42229289
    reference_title: "Advanced radiotherapy and systemic therapy in head and neck adenoid cystic carcinoma: Current progress and future integrated strategies."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Advances in radiotherapy, including MRI-guided radiotherapy, FLASH
      radiotherapy, and proton or carbon-ion therapy, are reshaping local
      treatment by improving dose precision, normal tissue sparing, and
      opportunities for treatment individualization.
    explanation: >-
      Supports an emerging role for particle and advanced-photon techniques in
      local treatment, without treating all modalities as established standards.
  - reference: PMID:41941852
    reference_title: "Outcomes of different treatment patterns for adenoid cystic carcinoma of the anterior craniofacial area: A multi-institutional study on 578 patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      For ACF-ACC, GTR plus modern RT provides the strongest local control, and
      R2 surgery should be avoided. PT is an effective definitive option for
      selected patients, supporting future response-guided treatment strategies.
    explanation: >-
      Supports modern radiotherapy and selected definitive proton therapy in
      anterior craniofacial ACC; PARTIAL reflects the retrospective,
      site-restricted evidence.
- name: Notch Inhibition (Gamma-Secretase Inhibitor)
  description: >-
    AL101 (osugacestat) is a gamma-secretase inhibitor that blocks activation of
    all four NOTCH receptors, developed specifically for the NOTCH-activated ACC
    subgroup. It shows potent antitumor activity in NOTCH1-mutant ACC cell lines,
    organoids and xenografts, and in a retrospective clinical series of
    Notch-activated recurrent/metastatic ACC produced longer progression-free
    survival than prior systemic therapy — though responses remain partial and
    short-lived, and combination approaches are being explored.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: osugacestat (AL101)
      term:
        id: NCIT:C116872
        label: Osugacestat
  target_mechanisms:
  - target: NOTCH1 Pathway Hyperactivation
    treatment_effect: INHIBITS
    description: >-
      Gamma-secretase inhibition blocks the proteolytic release of the Notch
      intracellular domain, shutting down the constitutive Notch transcriptional
      output produced by activating NOTCH1 mutations.
    evidence:
    - reference: PMID:35931701
      reference_title: "AL101, a gamma-secretase inhibitor, has potent antitumor activity against adenoid cystic carcinoma with activated NOTCH signaling."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        treatment of the organoid model with AL101 resulted in down-regulation of
        NICD1
      explanation: >-
        Directly demonstrates suppression of activated NOTCH1 signaling in an
        ACC organoid model.
  evidence:
  - reference: PMID:35931701
    reference_title: "AL101, a gamma-secretase inhibitor, has potent antitumor activity against adenoid cystic carcinoma with activated NOTCH signaling."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      we find that AL101 has potent antitumor effects in in vitro and in vivo
      models of ACC with activating NOTCH1 mutations and constitutively
      upregulated NOTCH signaling pathway
    explanation: >-
      The abstract summarizes activity across cell, organoid, and xenograft
      systems; OTHER avoids assigning this mixed preclinical statement to only
      one experimental source type.
  - reference: PMID:35931701
    reference_title: "AL101, a gamma-secretase inhibitor, has potent antitumor activity against adenoid cystic carcinoma with activated NOTCH signaling."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      AL101 therapy induced potent TGI in both models with NOTCH1 gain-of-function
      mutations (110 and 74% for ACCx9 and ACCx11, respectively; p < 0.0001)
    explanation: >-
      Patient-derived xenografts provide separate in-vivo evidence of activity in
      NOTCH1 gain-of-function ACC.
  - reference: PMID:40025676
    reference_title: "Clinical Outcomes With Notch Inhibitors in Notch-Activated Recurrent/Metastatic Adenoid Cystic Carcinoma."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      NOTCH inhibitors demonstrate activity in NOTCH-activated ACC, surpassing
      the efficacy of observation or prior systemic therapies.
    explanation: >-
      A 29-patient retrospective series supports clinical activity but with only
      17% partial responses and 4.2-month median PFS, so support is PARTIAL.
- name: Brontictuzumab (Anti-NOTCH1 Antibody)
  description: >-
    Brontictuzumab is a monoclonal antibody targeting NOTCH1. Tumor growth
    inhibition in ACC patient-derived xenografts occurred exclusively in the
    model carrying an activating NOTCH1 mutation, and an index patient with
    NOTCH1-mutant ACC had a partial response, providing preliminary evidence of
    genotype-restricted activity.
  therapeutic_modality: MONOCLONAL_ANTIBODY
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: brontictuzumab
      term:
        id: NCIT:C103274
        label: Brontictuzumab
  target_mechanisms:
  - target: NOTCH1 Pathway Hyperactivation
    treatment_effect: INHIBITS
    description: >-
      Antibody blockade of NOTCH1 prevents receptor activation in tumors
      dependent on activating NOTCH1 mutations.
    evidence:
    - reference: PMID:27870570
      reference_title: "Activating NOTCH1 Mutations Define a Distinct Subgroup of Patients With Adenoid Cystic Carcinoma Who Have Poor Prognosis, Propensity to Bone and Liver Metastasis, and Potential Responsiveness to Notch1 Inhibitors."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Significant tumor growth inhibition with brontictuzumab was observed
        exclusively in the ACC patient-derived xenograft model that harbored a
        NOTCH1 activating mutation.
      explanation: >-
        Genotype-restricted activity in a NOTCH1-mutant xenograft directly links
        brontictuzumab treatment to the activated NOTCH1 mechanism.
  evidence:
  - reference: PMID:27870570
    reference_title: "Activating NOTCH1 Mutations Define a Distinct Subgroup of Patients With Adenoid Cystic Carcinoma Who Have Poor Prognosis, Propensity to Bone and Liver Metastasis, and Potential Responsiveness to Notch1 Inhibitors."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Significant tumor growth inhibition with brontictuzumab was observed
      exclusively in the ACC patient-derived xenograft model that harbored a
      NOTCH1 activating mutation.
    explanation: >-
      Patient-derived xenograft data show brontictuzumab activity restricted to
      NOTCH1-mutant ACC, establishing genotype-dependent benefit.
  - reference: PMID:27870570
    reference_title: "Activating NOTCH1 Mutations Define a Distinct Subgroup of Patients With Adenoid Cystic Carcinoma Who Have Poor Prognosis, Propensity to Bone and Liver Metastasis, and Potential Responsiveness to Notch1 Inhibitors."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      an index patient with NOTCH1-mutant ACC had a partial response to
      brontictuzumab
    explanation: >-
      A single-patient partial response provides preliminary human evidence only,
      so support is marked PARTIAL.
- name: Lenvatinib
  description: >-
    Lenvatinib is a multitargeted VEGFR/FGFR/PDGFR tyrosine kinase inhibitor used
    in recurrent or metastatic ACC. Activity is modest — partial responses in
    about 12% of evaluable patients — and toxicity frequently requires dose
    reduction, so it is best regarded as a disease-stabilising rather than
    tumor-shrinking option.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: lenvatinib
      term:
        id: CHEBI:85994
        label: lenvatinib
  evidence:
  - reference: PMID:32031693
    reference_title: "Patients with adenoid cystic carcinomas of the salivary glands treated with lenvatinib: Activity and quality of life."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Among 26 evaluable patients, 3 partial responses (11.5%) were reported.
    explanation: >-
      Quantifies the modest objective response rate to lenvatinib in
      recurrent/metastatic ACC.
  - reference: PMID:32031693
    reference_title: "Patients with adenoid cystic carcinomas of the salivary glands treated with lenvatinib: Activity and quality of life."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Lenvatinib appears to have modest activity in ACC.
    explanation: >-
      The trial's own conclusion characterises lenvatinib activity in ACC as
      modest.
- name: Axitinib
  description: >-
    Axitinib improved progression-free survival compared with observation in
    progressive recurrent or metastatic ACC, but produced no objective
    responses; its demonstrated benefit is disease stabilization rather than
    tumor shrinkage.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: axitinib
      term:
        id: CHEBI:66910
        label: axitinib
  evidence:
  - reference: PMID:34315722
    reference_title: "Randomized Phase II Study of Axitinib versus Observation in Patients with Recurred or Metastatic Adenoid Cystic Carcinoma."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      With a median follow-up of 25.4 months, the 6-month PFS rate was 73.0% with
      axitinib and 23.0% with observation. Median PFS was longer in the axitinib
      arm (10.8 months vs. 2.8 months, P < 0.001). The ORR of axitinib was 0.0%,
      but the disease control rate was 100.0% with axitinib and 51.9% with
      observation.
    explanation: >-
      The first randomized ACC trial demonstrates a progression-free survival
      benefit but no objective responses, warranting PARTIAL support.
- name: Rivoceranib
  description: >-
    Rivoceranib, a VEGFR2 tyrosine-kinase inhibitor, has modest objective activity
    in progressive recurrent or metastatic ACC. Frequent grade 3 or worse
    toxicity and dose modification limit the certainty of net clinical benefit.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: rivoceranib
      term:
        id: NCIT:C152237
        label: Rivoceranib
  evidence:
  - reference: PMID:37643133
    reference_title: "A Phase II Trial of Rivoceranib, an Oral Vascular Endothelial Growth Factor Receptor 2 Inhibitor, for Recurrent or Metastatic Adenoid Cystic Carcinoma."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Per investigator and BIRC, respectively, ORR was 15.3%
    explanation: >-
      The investigator and blinded-review response rates directly quantify the
      modest objective activity in this single-arm phase II study.
  - reference: PMID:37643133
    reference_title: "A Phase II Trial of Rivoceranib, an Oral Vascular Endothelial Growth Factor Receptor 2 Inhibitor, for Recurrent or Metastatic Adenoid Cystic Carcinoma."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      median progression-free survival was 9.0 months (95% CI, 7.3-11.5) and 9.0
      months (95% CI, 7.7-11.5).
    explanation: >-
      A large international phase II study demonstrates nine-month median
      progression-free survival; its single-arm design warrants PARTIAL support.
  - reference: PMID:37643133
    reference_title: "A Phase II Trial of Rivoceranib, an Oral Vascular Endothelial Growth Factor Receptor 2 Inhibitor, for Recurrent or Metastatic Adenoid Cystic Carcinoma."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Grade ≥3 treatment-related adverse events occurred in 56 patients (70.0%)
    explanation: >-
      The high rate of grade 3 or worse treatment-related adverse events tempers
      the phase II efficacy signal.
- name: Pulmonary Metastasectomy
  description: >-
    Resection of isolated pulmonary metastases is offered to selected patients
    after a long disease-free interval, but evidence is observational and the
    reported comparison with non-resection is vulnerable to selection bias.
  therapeutic_modality: SURGERY
  treatment_term:
    preferred_term: Surgical Procedure
    term:
      id: NCIT:C15329
      label: Surgical Procedure
  evidence:
  - reference: PMID:18343149
    reference_title: "Lung metastasis resection of adenoid cystic carcinoma of salivary glands."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Nine patients with a median free interval time of 5 years (range 1-12)
      underwent lung metastasectomy
    explanation: >-
      Documents pulmonary metastasectomy after a median five-year and up to
      12-year disease-free interval; the comparison with non-resected patients
      was not statistically powered, so support is PARTIAL.
discussions:
- discussion_id: acc_myb_not_prognostic_gap
  kind: KNOWLEDGE_GAP
  status: OPEN
  prompt: >-
    Why does MYB-family activation, which is present in the great majority of
    ACCs and is the defining lesion of the disease, carry no prognostic
    information?
  attaches_to:
  - pathophysiology#MYB-Driven Oncogenic Transcriptional Program
  rationale: >-
    A systematic review of 36 studies found no consistent association between
    t(6;9)(MYB-NFIB) status and survival, while NOTCH1 mutation, TERT promoter
    mutation, solid histology, and perineural invasion all stratify outcome
    strongly. This implies that MYB activation is necessary for the ACC phenotype
    but that the clinically important variation lies in the cooperating lesions
    layered on top of it. Which cooperating events convert an indolent MYB-driven
    tumor into an aggressive one is not resolved.
  proposed_experiments:
  - experiment_id: exp_acc_multiregion_progression_sequencing
    name: Multi-region sequencing of matched indolent and aggressive ACC
    description: >-
      Sequence multiple regions of matched indolent and aggressive tumors from
      the same patient to identify progression-specific cooperating alterations
      against a constant MYB-fusion background, separating drivers of
      aggressiveness from the shared initiating lesion.
  - experiment_id: exp_acc_isogenic_cooperating_lesions
    name: Isogenic dissection of cooperating lesions on a MYB-NFIB background
    description: >-
      Express MYB-NFIB in isogenic salivary epithelial models with and without
      candidate cooperating lesions (NOTCH1 activation, TERT promoter mutation,
      chromatin-remodeler loss) and assay invasive and metastatic capacity to
      test which lesion supplies the aggressive phenotype.
  evidence:
  - reference: PMID:30269389
    reference_title: "t(6;9)(MYB-NFIB) in head and neck adenoid cystic carcinoma: A systematic review with meta-analysis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      A total of 11 studies attempted to determine the prognostic importance of
      the translocation, but no study found any significant association with
      survival rates
    explanation: >-
      Directly documents the absence of a prognostic association for the defining
      lesion of ACC, which is the gap this discussion records.
- discussion_id: acc_bdnf_causal_vs_marker_gap
  kind: KNOWLEDGE_GAP
  status: OPEN
  prompt: >-
    Is BDNF a causal driver of ACC neurotropism, or a marker of the
    neural-adjacent tumor microenvironment?
  attaches_to:
  - pathophysiology#Neurotropic Perineural Invasion
  rationale: >-
    Perineural invasion is the defining behaviour of ACC and independently
    predicts worse survival, yet the mechanistic evidence for its leading
    candidate mediator remains immunohistochemical and correlative more than two
    decades after the original observation. No study has shown that interrupting
    BDNF-TrkB signalling reduces perineural invasion in ACC. Because perineural
    spread is the direct cause of both cranial neuropathy and margin-positive
    resection, a genuinely causal mediator would be a high-value therapeutic
    target.
  proposed_experiments:
  - experiment_id: exp_acc_trkb_blockade_orthotopic
    name: TrkB blockade in orthotopic ACC models with perineural readout
    description: >-
      Apply pharmacological or genetic TrkB blockade in orthotopic ACC models and
      quantify perineural invasion histologically, testing whether interrupting
      the BDNF-TrkB axis reduces neurotropic spread.
  - experiment_id: exp_acc_organoid_drg_coculture
    name: ACC organoid-dorsal root ganglion co-culture under BDNF neutralisation
    description: >-
      Co-culture patient-derived ACC organoids with dorsal root ganglion explants
      under BDNF neutralisation to test whether directed migration toward nerve
      is BDNF-dependent.
  evidence:
  - reference: PMID:12378520
    reference_title: "Perineural invasion in adenoid cystic carcinoma: Its causation/promotion by brain-derived neurotrophic factor."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Further studies are warranted to gain better understanding of this possible
      relationship.
    explanation: >-
      The originating study itself frames the BDNF-neurotropism relationship as
      unresolved, which is the gap this discussion records.
references:
- reference: PMID:14681323
  title: "Expression of KIT (CD117) in neoplasms of the head and neck: an ancillary marker for adenoid cystic carcinoma."
- reference: PMID:21164292
  title: MYB expression and translocation in adenoid cystic carcinomas and other salivary gland tumors with clinicopathologic correlation.
- reference: PMID:23463073
  title: "Adenoid cystic carcinoma: clinical and molecular features."
- reference: PMID:19841262
  title: "Recurrent fusion of MYB and NFIB transcription factor genes in carcinomas of the breast and head and neck."
- reference: PMID:27180054
  title: "Myoepithelial differentiation in cribriform, tubular and solid pattern of adenoid cystic carcinoma: A potential involvement in histological grading and prognosis."
- reference: PMID:26829750
  title: "An oncogenic MYB feedback loop drives alternate cell fates in adenoid cystic carcinoma."
- reference: PMID:27870570
  title: "Activating NOTCH1 Mutations Define a Distinct Subgroup of Patients With Adenoid Cystic Carcinoma Who Have Poor Prognosis, Propensity to Bone and Liver Metastasis, and Potential Responsiveness to Notch1 Inhibitors."
- reference: PMID:31483290
  title: "Genetic hallmarks of recurrent/metastatic adenoid cystic carcinoma."
- reference: PMID:34315722
  title: "Randomized Phase II Study of Axitinib versus Observation in Patients with Recurred or Metastatic Adenoid Cystic Carcinoma."
- reference: PMID:36060029
  title: "Adenoid Cystic Carcinoma (ACC) Infiltrating the Skull Base: A Systematic Review of Clinical Characteristics and Management Strategies."
- reference: PMID:36465348
  title: "Single-cell transcriptomic analysis of the tumor ecosystem of adenoid cystic carcinoma."
- reference: PMID:37643133
  title: "A Phase II Trial of Rivoceranib, an Oral Vascular Endothelial Growth Factor Receptor 2 Inhibitor, for Recurrent or Metastatic Adenoid Cystic Carcinoma."
- reference: PMID:41941852
  title: "Outcomes of different treatment patterns for adenoid cystic carcinoma of the anterior craniofacial area: A multi-institutional study on 578 patients."
- reference: PMID:42371638
  title: "Clinical Features, Treatment, and Outcomes for Oropharyngeal Adenoid Cystic Carcinoma: A Systematic Review."
datasets:
- accession: dbgap:phs000612
  title: The mutational characterization of adenoid cystic carcinoma
  description: Adenoid cystic carcinoma (ACC) typically emanate from the major and minor salivary glands of the head and neck. ACCs have high rates of perineural invasion, locoregional recurrence, and distant metastasis. Here we report sequencing of 60 tumor/normal pairs and find substantial mutational diversity. On pathway analysis, a significant percentage of mutations involved chromatin remodeling, DNA damage, protein kinase A signaling, and FGF/IGF/PI3K signaling. Whole genome sequencing and FISH confirmed the MYB-NFIB translocation as the main structural variant in ACC.
  notes: Located via OmicsDI, which aggregates across omics repositories; this record comes from dbgap. Only repositories with no other discovery route in this project and with a working accession resolver are curated from OmicsDI -- GEO, ArrayExpress, PRIDE, MetaboLights and EGA hits are excluded as duplicates of dedicated passes. Matched because the disease is named in the dataset's own title ("Adenoid Cystic Carcinoma"). Retrieved 2026-08-02.

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References & Deep Research

References

14

PMID:14681323

Expression of KIT (CD117) in neoplasms of the head and neck: an ancillary marker for adenoid cystic carcinoma.