Granular Cell Tumor

◆

Subtypes

3

Benign (conventional) granular cell tumor

The vast majority (~98%) of GCTs. Fulfils zero Fanburg-Smith malignancy criteria, has a low Ki-67 proliferation index (<5%), and is cured by complete excision with negative margins. Recurrence is ~2-8% with clear margins, rising to ~20% with positive margins.

Atypical granular cell tumor

Tumors fulfilling 1-2 Fanburg-Smith histologic criteria, with a Ki-67 index typically 5-10%. Behavior is intermediate/uncertain and warrants close follow-up.

Malignant granular cell tumor

Rare (~2%) variant fulfilling >=3 Fanburg-Smith criteria (necrosis, mitoses >2/10 HPF, spindling, nuclear pleomorphism, vesicular nuclei with prominent nucleoli, high nuclear-to-cytoplasmic ratio), with Ki-67 ~10-50%. Shows aggressive behavior, local recurrence up to ~32%, metastasis (lung, bone) in about half of cases (often within 2 years), and additional alterations in TP53 and PIK3CA. Median overall survival in metastatic disease is ~10 months.

⚙

Pathophysiology

5

ATP6AP1/ATP6AP2 Loss-of-Function Mutation

The genetic driver of most GCTs is a clonal, mutually exclusive, inactivating (truncating/frameshift/splice-site) somatic mutation in the V-ATPase accessory-protein genes ATP6AP1 (Xq28) or ATP6AP2 (Xp11.4). These are present in roughly 65-72% of GCTs across anatomic sites; other V-ATPase subunit genes (e.g., ATP6V0C, ATP6V1A, ATP6V0A4) are mutated in a minority. In multifocal disease, separate tumors carry distinct mutations, indicating independent clonal origins.

Schwann cell CL:0002573

Downstream

Impaired Vesicle Acidification Loss of functional V-ATPase accessory subunits impairs proton pumping into endosomes/lysosomes, raising luminal pH.

Oncogenic Signaling Activation Depletion of ATP6AP1/ATP6AP2 confers oncogenic properties, linking endosomal pH dysregulation to tumorigenesis.

Show evidence (3 references)

PMID:30166553 SUPPORT Human Clinical

"whole-exome sequencing and targeted sequencing analysis to reveal mutually exclusive, clonal, inactivating somatic mutations in the endosomal pH regulators ATP6AP1 or ATP6AP2 in 72% of GCTs"

The seminal study by Pareja et al. established mutually exclusive, clonal, inactivating ATP6AP1/ATP6AP2 mutations as the driver event in 72% of GCTs.

PMID:30597645 SUPPORT Human Clinical

"we identified mutations in genes encoding vacuolar H+ -ATPase (V-ATPase) components, including ATP6AP1 and ATP6AP2, in 33 (65%) GCTs"

An independent series of 51 GCTs confirmed recurrent V-ATPase component gene mutations (including ATP6AP1/ATP6AP2) in 65% of cases.

PMID:36534754 SUPPORT Human Clinical

"multifocal GrCT within an individual patient are molecularly distinct, while paired primary and metastatic GrCT share identical mutations"

Multifocal GCTs in one patient carry distinct V-ATPase mutations, indicating independent clonal origins, whereas matched primary/metastasis pairs share identical mutations.

Impaired Vesicle Acidification

V-ATPase dysfunction reduces acidification of endosomal and lysosomal compartments. The V-ATPase is a multisubunit proton pump that acidifies intracellular compartments; its impairment redistributes endosomal compartments and degrades lysosomal/autophagic function in the Schwann-cell lineage.

Schwann cell CL:0002573

vacuolar acidification GO:0007035 ↓ DECREASED proton transmembrane transport GO:1902600 ↓ DECREASED

Downstream

Endolysosomal Dysfunction and Autophagosome Accumulation Reduced luminal acidification impairs lysosomal substrate degradation and causes accumulation of endosomal/autophagic vesicles.

Show evidence (2 references)

PMID:30166553 SUPPORT In Vitro

"Silencing of these genes in vitro results in impaired vesicle acidification, redistribution of endosomal compartments, and accumulation of intracytoplasmic granules"

In vitro silencing of ATP6AP1/ATP6AP2 directly produces impaired vesicle acidification and endosomal redistribution.

PMID:30597645 SUPPORT Human Clinical

"These results suggest that V-ATPase function is impaired in GCTs not only by loss-of-function mutations of ATP6AP1 and ATP6AP2 but also through mutations of other subunits"

Mutations across multiple V-ATPase subunit genes converge on impaired V-ATPase (proton-pump) function in GCTs.

Endolysosomal Dysfunction and Autophagosome Accumulation

Defective acidification impairs degradation of intracellular substrates, leading to accumulation of autophagosomes/autophagolysosomes laden with myelin-derived material. These lysosome-rich vesicles are the intracytoplasmic granules that define GCT histology and recapitulate the cardinal phenotype of the tumor.

Schwann cell CL:0002573

lysosome organization GO:0007040 ⚠ ABNORMAL autophagy GO:0006914 ⚠ ABNORMAL endosome to lysosome transport GO:0008333 ⚠ ABNORMAL

Downstream

Granular Cell Tumor Morphology Accumulated lysosomal/autophagic granules produce the abundant eosinophilic, PAS-positive diastase-resistant granular cytoplasm.

Show evidence (2 references)

PMID:30166553 SUPPORT In Vitro

"accumulation of intracytoplasmic granules, recapitulating the cardinal phenotypic characteristics of GCTs and providing a novel genotypic-phenotypic correlation"

Granule accumulation downstream of V-ATPase loss recapitulates the cardinal phenotype of GCT, establishing the genotype-phenotype link.

DOI:10.1111/jop.13148 SUPPORT Human Clinical

"their intracytoplasmic granules are considered autophagosomes or autophagolysosomes and are consistent with myelin accumulation"

Ultrastructurally the defining GCT granules are autophagosomes/ autophagolysosomes consistent with myelin accumulation.

Oncogenic Signaling Activation

Beyond producing granules, loss of ATP6AP1/ATP6AP2 confers oncogenic properties. V-ATPase/lysosomal dysfunction enhances signaling through PDGFR-beta, Src-family kinases (SFKs), and STAT5a/b, and engages the PI3K-AKT-mTOR axis (especially in malignant GCT, which additionally acquires TP53 and PIK3CA alterations), driving proliferation and survival of the Schwann-lineage tumor cells. This signaling rationale underlies the activity of the multi-kinase inhibitor pazopanib.

Schwann cell CL:0002573

cell surface receptor protein tyrosine kinase signaling pathway GO:0007169 ↑ INCREASED cell population proliferation GO:0008283 ↑ INCREASED

Downstream

Neoplastic Schwann Cell Proliferation Sustained PDGFR-beta/SFK/STAT5 and PI3K-AKT signaling drives clonal expansion of the Schwann-lineage tumor cells.

Show evidence (2 references)

PMID:30166553 SUPPORT In Vitro

"depletion of ATP6AP1 or ATP6AP2 results in the acquisition of oncogenic properties"

Functional depletion of ATP6AP1/ATP6AP2 directly confers oncogenic properties on the cells.

PMID:37958362 SUPPORT Human Clinical

"antitumoral effects of pazopanib in GCT might be due to a loss-of-function of ATP6AP1/2 genes which consequently enhance signaling through several molecular pathways, such as SFKs, STAT5a/b, and PDGFR-β"

Loss of ATP6AP1/2 is proposed to enhance SFK, STAT5a/b, and PDGFR-beta signaling, providing the molecular rationale for pazopanib activity.

Neoplastic Schwann Cell Proliferation

The convergence of granule-forming endolysosomal dysfunction and oncogenic signaling yields a clonal proliferation of Schwann-derived granular cells, forming a non-encapsulated, often infiltrative nodule that is S100- and SOX10-positive. This tumor is the clinical lesion.

Schwann cell CL:0002573

Downstream

Soft Tissue Mass The proliferation presents clinically as a firm soft-tissue or submucosal nodule.

Neoplasm of the Tongue The tongue/oral cavity is the single most common intra-oral site of GCT.

Dysphagia Esophageal/aerodigestive GCTs can obstruct or impede swallowing.

Upper Airway Obstruction Laryngeal/tracheobronchial GCT can compromise the airway, which is potentially life-threatening in children.

Show evidence (2 references)

DOI:10.1111/jop.13148 SUPPORT Human Clinical

"GCTs are derived from Schwann cells"

GCTs are neuroectodermal neoplasms derived from Schwann cells.

PMID:37565535 SUPPORT Human Clinical

"Granular cell tumor (GCT) is a S100+ neoplasm with atypical and malignant variants"

GCT is an S100-positive neoplasm with atypical and malignant variants.

✶

Histopathology

1

Granular Cell Tumor Morphology VERY_FREQUENT

Non-encapsulated, often infiltrative nests and sheets of large polygonal cells with abundant eosinophilic, PAS-positive, diastase-resistant granular cytoplasm and small uniform nuclei. Pustulo-ovoid bodies of Milian (large eosinophilic granules with clear halos) are characteristic, and overlying pseudoepitheliomatous hyperplasia may mimic squamous cell carcinoma.

Show evidence (1 reference)

PMID:30166553 SUPPORT Human Clinical

"are characterized by abundant intracytoplasmic"

GCTs are characterized by abundant intracytoplasmic granules.

⬡

Pathograph

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

Referential integrity issues (1):

Target 'Granular Cell Tumor Morphology' (from 'Endolysosomal Dysfunction and Autophagosome Accumulation') not found in named elements

●

Phenotypes

4

Digestive 1

Dysphagia OCCASIONAL Dysphagia HP:0002015

Integument 1

Soft Tissue Mass VERY_FREQUENT Subcutaneous nodule HP:0001482

Course: PROGRESSIVE

Show evidence (1 reference)

PMID:36534754 SUPPORT Human Clinical

"Multifocal presentation is present in ~10% of cases"

Multifocal GCT presentation occurs in roughly 10% of cases.

Respiratory 1

Upper Airway Obstruction VERY_RARE Upper airway obstruction HP:0002781

Other 1

Neoplasm of the Tongue FREQUENT Neoplasm of the tongue HP:0100648

Show evidence (1 reference)

DOI:10.1111/jop.13148 SUPPORT Human Clinical

"mainly affect the skin of the upper limbs and trunks and the oral cavity"

GCTs mainly affect the skin of the upper limbs/trunk and the oral cavity.

🧬

Genetic Associations

3

ATP6AP1 (Somatic Inactivating (Loss-of-Function) Mutations)

Show evidence (2 references)

PMID:30166553 SUPPORT Human Clinical

"inactivating mutations of ATP6AP1 and ATP6AP2 are likely oncogenic drivers of GCTs"

Pareja et al. conclude inactivating ATP6AP1/ATP6AP2 mutations are likely oncogenic drivers of GCTs.

PMID:36534754 SUPPORT Human Clinical

"Twenty tumors showed mutations in ATP6AP1 (48%)"

In a multifocal GCT series, ATP6AP1 was the most frequently mutated gene (48% of tumors).

ATP6AP2 (Somatic Inactivating (Loss-of-Function) Mutations)

Show evidence (1 reference)

PMID:36534754 SUPPORT Human Clinical

"10 tumors had mutations in ATP6AP2 (24%)"

ATP6AP2 was mutated in 24% of tumors in a multifocal GCT series.

ATP6V0C and Other V-ATPase Subunits (Somatic Mutations (Minority))

Show evidence (1 reference)

PMID:30597645 SUPPORT Human Clinical

"seven other genes encoding V-ATPase components were also mutated, and three mutations in ATP6V0C occurred on the same amino acid (isoleucine 136)"

Additional V-ATPase subunit genes are mutated in GCT, including recurrent ATP6V0C isoleucine-136 mutations.

💊

Medical Actions

2

Complete Surgical Excision

Action: surgical excision MAXO:0000447

Complete surgical excision with negative (wide) margins is the standard of care for all resectable GCTs and is curative for the vast majority of benign tumors. Margin status is critical: positive margins are associated with substantially higher recurrence (~20% vs ~2-8% with clear margins).

Pazopanib

Action: targeted therapy Ontology label: Targeted Therapy NCIT:C93352

Agent: pazopanib CHEBI:71219

Pazopanib, an oral multi-target tyrosine kinase inhibitor (VEGFR, PDGFR, c-KIT), is the best-supported systemic therapy for advanced/metastatic malignant GCT, for which no standardized guideline exists. In a 2023 review of 10 reported cases it produced disease control in 8/10 (80%) and objective RECIST response in 4/10 (40%), well above the ~6% response rate of pazopanib in other soft-tissue sarcomas. Its rationale is the enhanced PDGFR-beta signaling downstream of ATP6AP1/2 loss.

Show evidence (2 references)

PMID:37958362 SUPPORT Human Clinical

"Eight out of ten patients (80%) experienced disease control with pazopanib, while four out of ten (40%) patients achieved an objective RECIST response"

Pazopanib achieved 80% disease control and 40% objective response in reported advanced/malignant GCT cases.

PMID:37958362 SUPPORT Human Clinical

"Pazopanib has been demonstrated to be active in advanced GCTs and may be considered as a preferable treatment option"

The review concludes pazopanib is active in advanced GCT and a preferable systemic option.

🔬

Biochemical Markers

3

S100 Protein Immunohistochemistry

Show evidence (1 reference)

PMID:30888637 SUPPORT Human Clinical

"distinguishing the two (S-100-positive in GCT and S-100-negative in CGCE)"

S-100 immunostaining distinguishes adult GCT (positive) from congenital granular cell epulis (negative).

SOX10 Immunohistochemistry

ATP6AP1/ATP6AP2 Molecular Testing

Show evidence (1 reference)

PMID:37565535 SUPPORT Human Clinical

"Frameshift and premature stop codons in ATP6AP1/2 are specific for granular cell lineage, and capable of excluding melanoma, in the absence of known melanoma-associated driver mutations"

ATP6AP1/2 truncating mutations are specific for granular-cell lineage and help exclude melanoma in ambiguous cases.

{ }

Source YAML

click to show

name: Granular Cell Tumor
creation_date: "2026-06-30T00:00:00Z"
category: Complex
disease_term:
  preferred_term: Granular Cell Tumor
  term:
    id: MONDO:0006235
    label: granular cell tumor
description: >-
  Granular cell tumor (GCT; Abrikossoff tumor) is an uncommon neuroectodermal
  soft-tissue neoplasm of Schwann-cell origin characterized by sheets and nests
  of large polygonal cells with abundant eosinophilic, periodic acid-Schiff
  (PAS)-positive, diastase-resistant granular cytoplasm. The granules are
  lysosome-rich autophagosomes/autophagolysosomes consistent with myelin
  accumulation, and tumor cells are typically S100- and SOX10-positive. GCTs
  most often arise in the skin/subcutis, tongue and oral cavity, breast,
  gastrointestinal tract (especially esophagus), and respiratory tract, and can
  occur at almost any anatomic site. The molecular hallmark is recurrent
  clonal, mutually exclusive, inactivating somatic mutations in the endosomal
  pH-regulating vacuolar H+-ATPase (V-ATPase) genes ATP6AP1 and ATP6AP2 (and,
  less often, other V-ATPase subunit genes such as ATP6V0C), found in roughly
  65-72% of GCTs. The vast majority of GCTs are benign and cured by complete
  surgical excision; a rare malignant variant (graded by the Fanburg-Smith
  criteria) is aggressive, metastasizes to lung and bone, and carries a poor
  prognosis. It is distinct from congenital granular cell epulis (congenital
  epulis of the newborn), which is S100-negative.
categories:
- Soft Tissue Neoplasm
- Mesenchymal Neoplasm
- Nerve Sheath Tumor
parents:
- nervous system neoplasm
has_subtypes:
- name: Benign GCT
  display_name: Benign (conventional) granular cell tumor
  description: >-
    The vast majority (~98%) of GCTs. Fulfils zero Fanburg-Smith malignancy
    criteria, has a low Ki-67 proliferation index (<5%), and is cured by
    complete excision with negative margins. Recurrence is ~2-8% with clear
    margins, rising to ~20% with positive margins.
- name: Atypical GCT
  display_name: Atypical granular cell tumor
  description: >-
    Tumors fulfilling 1-2 Fanburg-Smith histologic criteria, with a Ki-67
    index typically 5-10%. Behavior is intermediate/uncertain and warrants
    close follow-up.
- name: Malignant GCT
  display_name: Malignant granular cell tumor
  description: >-
    Rare (~2%) variant fulfilling >=3 Fanburg-Smith criteria (necrosis, mitoses
    >2/10 HPF, spindling, nuclear pleomorphism, vesicular nuclei with prominent
    nucleoli, high nuclear-to-cytoplasmic ratio), with Ki-67 ~10-50%. Shows
    aggressive behavior, local recurrence up to ~32%, metastasis (lung, bone)
    in about half of cases (often within 2 years), and additional alterations
    in TP53 and PIK3CA. Median overall survival in metastatic disease is
    ~10 months.
pathophysiology:
- name: ATP6AP1/ATP6AP2 Loss-of-Function Mutation
  description: >-
    The genetic driver of most GCTs is a clonal, mutually exclusive,
    inactivating (truncating/frameshift/splice-site) somatic mutation in the
    V-ATPase accessory-protein genes ATP6AP1 (Xq28) or ATP6AP2 (Xp11.4). These
    are present in roughly 65-72% of GCTs across anatomic sites; other V-ATPase
    subunit genes (e.g., ATP6V0C, ATP6V1A, ATP6V0A4) are mutated in a minority.
    In multifocal disease, separate tumors carry distinct mutations, indicating
    independent clonal origins.
  cell_types:
  - preferred_term: Schwann cell
    term:
      id: CL:0002573
      label: Schwann cell
  downstream:
  - target: Impaired Vesicle Acidification
    description: >-
      Loss of functional V-ATPase accessory subunits impairs proton pumping
      into endosomes/lysosomes, raising luminal pH.
    causal_link_type: DIRECT
  - target: Oncogenic Signaling Activation
    description: >-
      Depletion of ATP6AP1/ATP6AP2 confers oncogenic properties, linking
      endosomal pH dysregulation to tumorigenesis.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
  evidence:
  - reference: PMID:30166553
    reference_title: "Loss-of-function mutations in ATP6AP1 and ATP6AP2 in granular cell tumors."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "whole-exome sequencing and targeted sequencing analysis to reveal mutually \nexclusive, clonal, inactivating somatic mutations in the endosomal pH regulators \nATP6AP1 or ATP6AP2 in 72% of GCTs"
    explanation: >-
      The seminal study by Pareja et al. established mutually exclusive, clonal,
      inactivating ATP6AP1/ATP6AP2 mutations as the driver event in 72% of GCTs.
  - reference: PMID:30597645
    reference_title: "Frequent mutations of genes encoding vacuolar H(+) -ATPase components in granular cell tumors."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "we identified mutations in genes \nencoding vacuolar H+ -ATPase (V-ATPase) components, including ATP6AP1 and \nATP6AP2, in 33 (65%) GCTs"
    explanation: >-
      An independent series of 51 GCTs confirmed recurrent V-ATPase component
      gene mutations (including ATP6AP1/ATP6AP2) in 65% of cases.
  - reference: PMID:36534754
    reference_title: "Molecular Characterization of Multifocal Granular Cell Tumors."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "multifocal GrCT within an \nindividual patient are molecularly distinct, while paired primary and metastatic \nGrCT share identical mutations"
    explanation: >-
      Multifocal GCTs in one patient carry distinct V-ATPase mutations,
      indicating independent clonal origins, whereas matched primary/metastasis
      pairs share identical mutations.
- name: Impaired Vesicle Acidification
  description: >-
    V-ATPase dysfunction reduces acidification of endosomal and lysosomal
    compartments. The V-ATPase is a multisubunit proton pump that acidifies
    intracellular compartments; its impairment redistributes endosomal
    compartments and degrades lysosomal/autophagic function in the Schwann-cell
    lineage.
  cell_types:
  - preferred_term: Schwann cell
    term:
      id: CL:0002573
      label: Schwann cell
  biological_processes:
  - preferred_term: vacuolar acidification
    modifier: DECREASED
    term:
      id: GO:0007035
      label: vacuolar acidification
  - preferred_term: proton transmembrane transport
    modifier: DECREASED
    term:
      id: GO:1902600
      label: proton transmembrane transport
  downstream:
  - target: Endolysosomal Dysfunction and Autophagosome Accumulation
    description: >-
      Reduced luminal acidification impairs lysosomal substrate degradation and
      causes accumulation of endosomal/autophagic vesicles.
    causal_link_type: DIRECT
  evidence:
  - reference: PMID:30166553
    reference_title: "Loss-of-function mutations in ATP6AP1 and ATP6AP2 in granular cell tumors."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Silencing of these genes in vitro results in \nimpaired vesicle acidification, redistribution of endosomal compartments, and \naccumulation of intracytoplasmic granules"
    explanation: >-
      In vitro silencing of ATP6AP1/ATP6AP2 directly produces impaired vesicle
      acidification and endosomal redistribution.
  - reference: PMID:30597645
    reference_title: "Frequent mutations of genes encoding vacuolar H(+) -ATPase components in granular cell tumors."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "These results suggest that V-ATPase function is \nimpaired in GCTs not only by loss-of-function mutations of ATP6AP1 and ATP6AP2 \nbut also through mutations of other subunits"
    explanation: >-
      Mutations across multiple V-ATPase subunit genes converge on impaired
      V-ATPase (proton-pump) function in GCTs.
- name: Endolysosomal Dysfunction and Autophagosome Accumulation
  description: >-
    Defective acidification impairs degradation of intracellular substrates,
    leading to accumulation of autophagosomes/autophagolysosomes laden with
    myelin-derived material. These lysosome-rich vesicles are the
    intracytoplasmic granules that define GCT histology and recapitulate the
    cardinal phenotype of the tumor.
  cell_types:
  - preferred_term: Schwann cell
    term:
      id: CL:0002573
      label: Schwann cell
  biological_processes:
  - preferred_term: lysosome organization
    modifier: ABNORMAL
    term:
      id: GO:0007040
      label: lysosome organization
  - preferred_term: autophagy
    modifier: ABNORMAL
    term:
      id: GO:0006914
      label: autophagy
  - preferred_term: endosome to lysosome transport
    modifier: ABNORMAL
    term:
      id: GO:0008333
      label: endosome to lysosome transport
  downstream:
  - target: Granular Cell Tumor Morphology
    description: >-
      Accumulated lysosomal/autophagic granules produce the abundant
      eosinophilic, PAS-positive diastase-resistant granular cytoplasm.
    causal_link_type: DIRECT
  evidence:
  - reference: PMID:30166553
    reference_title: "Loss-of-function mutations in ATP6AP1 and ATP6AP2 in granular cell tumors."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "accumulation of intracytoplasmic granules, recapitulating the cardinal \nphenotypic characteristics of GCTs and providing a novel genotypic-phenotypic \ncorrelation"
    explanation: >-
      Granule accumulation downstream of V-ATPase loss recapitulates the
      cardinal phenotype of GCT, establishing the genotype-phenotype link.
  - reference: DOI:10.1111/jop.13148
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "their intracytoplasmic granules are considered autophagosomes or autophagolysosomes and are consistent with myelin accumulation"
    explanation: >-
      Ultrastructurally the defining GCT granules are autophagosomes/
      autophagolysosomes consistent with myelin accumulation.
- name: Oncogenic Signaling Activation
  description: >-
    Beyond producing granules, loss of ATP6AP1/ATP6AP2 confers oncogenic
    properties. V-ATPase/lysosomal dysfunction enhances signaling through
    PDGFR-beta, Src-family kinases (SFKs), and STAT5a/b, and engages the
    PI3K-AKT-mTOR axis (especially in malignant GCT, which additionally acquires
    TP53 and PIK3CA alterations), driving proliferation and survival of the
    Schwann-lineage tumor cells. This signaling rationale underlies the activity
    of the multi-kinase inhibitor pazopanib.
  cell_types:
  - preferred_term: Schwann cell
    term:
      id: CL:0002573
      label: Schwann cell
  biological_processes:
  - preferred_term: cell surface receptor protein tyrosine kinase signaling pathway
    modifier: INCREASED
    term:
      id: GO:0007169
      label: cell surface receptor protein tyrosine kinase signaling pathway
  - preferred_term: cell population proliferation
    modifier: INCREASED
    term:
      id: GO:0008283
      label: cell population proliferation
  gene_products:
  - preferred_term: PDGFR-beta
    term:
      id: NCIT:C30164
      label: Platelet-Derived Growth Factor Receptor Beta
  downstream:
  - target: Neoplastic Schwann Cell Proliferation
    description: >-
      Sustained PDGFR-beta/SFK/STAT5 and PI3K-AKT signaling drives clonal
      expansion of the Schwann-lineage tumor cells.
    causal_link_type: DIRECT
  evidence:
  - reference: PMID:30166553
    reference_title: "Loss-of-function mutations in ATP6AP1 and ATP6AP2 in granular cell tumors."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "depletion of ATP6AP1 or ATP6AP2 results in the \nacquisition of oncogenic properties"
    explanation: >-
      Functional depletion of ATP6AP1/ATP6AP2 directly confers oncogenic
      properties on the cells.
  - reference: PMID:37958362
    reference_title: "Antiangiogenics in Malignant Granular Cell Tumors: Review of the Literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "antitumoral effects of pazopanib in \nGCT might be due to a loss-of-function of ATP6AP1/2 genes which consequently \nenhance signaling through several molecular pathways, such as SFKs, STAT5a/b, \nand PDGFR-β"
    explanation: >-
      Loss of ATP6AP1/2 is proposed to enhance SFK, STAT5a/b, and PDGFR-beta
      signaling, providing the molecular rationale for pazopanib activity.
- name: Neoplastic Schwann Cell Proliferation
  description: >-
    The convergence of granule-forming endolysosomal dysfunction and oncogenic
    signaling yields a clonal proliferation of Schwann-derived granular cells,
    forming a non-encapsulated, often infiltrative nodule that is S100- and
    SOX10-positive. This tumor is the clinical lesion.
  cell_types:
  - preferred_term: Schwann cell
    term:
      id: CL:0002573
      label: Schwann cell
  downstream:
  - target: Soft Tissue Mass
    description: The proliferation presents clinically as a firm soft-tissue or submucosal nodule.
    causal_link_type: DIRECT
  - target: Neoplasm of the Tongue
    description: The tongue/oral cavity is the single most common intra-oral site of GCT.
    causal_link_type: DIRECT
  - target: Dysphagia
    description: Esophageal/aerodigestive GCTs can obstruct or impede swallowing.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
  - target: Upper Airway Obstruction
    description: >-
      Laryngeal/tracheobronchial GCT can compromise the airway, which is
      potentially life-threatening in children.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
  evidence:
  - reference: DOI:10.1111/jop.13148
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "GCTs are derived from Schwann cells"
    explanation: GCTs are neuroectodermal neoplasms derived from Schwann cells.
  - reference: PMID:37565535
    reference_title: "Utility of sequencing for ATP6AP1 and ATP6AP2 to distinguish between atypical granular cell tumor with junctional component and melanoma."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Granular cell tumor (GCT) is a S100+ neoplasm with atypical and \nmalignant variants"
    explanation: GCT is an S100-positive neoplasm with atypical and malignant variants.
histopathology:
- name: Granular Cell Tumor Morphology
  finding_term:
    preferred_term: Granular Cell Tumor
    term:
      id: NCIT:C3474
      label: Granular Cell Tumor
  frequency: VERY_FREQUENT
  diagnostic: true
  description: >-
    Non-encapsulated, often infiltrative nests and sheets of large polygonal
    cells with abundant eosinophilic, PAS-positive, diastase-resistant granular
    cytoplasm and small uniform nuclei. Pustulo-ovoid bodies of Milian (large
    eosinophilic granules with clear halos) are characteristic, and overlying
    pseudoepitheliomatous hyperplasia may mimic squamous cell carcinoma.
  evidence:
  - reference: PMID:30166553
    reference_title: "Loss-of-function mutations in ATP6AP1 and ATP6AP2 in granular cell tumors."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "are characterized by abundant intracytoplasmic"
    explanation: GCTs are characterized by abundant intracytoplasmic granules.
phenotypes:
- category: Neoplasm
  name: Soft Tissue Mass
  frequency: VERY_FREQUENT
  diagnostic: true
  description: >-
    GCTs typically present as a solitary, firm, slow-growing, often painless
    nodule (commonly 5 mm-2 cm) in the skin/subcutis or as a submucosal swelling.
    Multifocal disease occurs in roughly 10% of cases.
  phenotype_term:
    preferred_term: Subcutaneous nodule
    term:
      id: HP:0001482
      label: Subcutaneous nodule
    clinical_course: PROGRESSIVE
  evidence:
  - reference: PMID:36534754
    reference_title: "Molecular Characterization of Multifocal Granular Cell Tumors."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Multifocal presentation is present in ~10% of cases"
    explanation: Multifocal GCT presentation occurs in roughly 10% of cases.
- category: Neoplasm
  name: Neoplasm of the Tongue
  frequency: FREQUENT
  description: >-
    The tongue and oral cavity are the single most common intra-oral site of
    GCT; lesions are often submucosal, smooth-surfaced, and may appear yellowish.
  phenotype_term:
    preferred_term: Neoplasm of the tongue
    term:
      id: HP:0100648
      label: Neoplasm of the tongue
  evidence:
  - reference: DOI:10.1111/jop.13148
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "mainly affect the skin of the upper limbs and trunks and the oral cavity"
    explanation: GCTs mainly affect the skin of the upper limbs/trunk and the oral cavity.
- category: Gastrointestinal
  name: Dysphagia
  frequency: OCCASIONAL
  description: >-
    Esophageal GCT, an uncommon but recognized site, can cause difficulty
    swallowing.
  phenotype_term:
    preferred_term: Dysphagia
    term:
      id: HP:0002015
      label: Dysphagia
- category: Respiratory
  name: Upper Airway Obstruction
  frequency: VERY_RARE
  description: >-
    Laryngeal or tracheobronchial GCT can obstruct the upper airway and is
    potentially life-threatening, particularly in pediatric cases.
  phenotype_term:
    preferred_term: Upper airway obstruction
    term:
      id: HP:0002781
      label: Upper airway obstruction
biochemical:
- name: S100 Protein Immunohistochemistry
  biomarker_term:
    preferred_term: S100 protein
    term:
      id: NCIT:C29924
      label: S100 Calcium Binding Protein
  notes: >-
    Diffuse S100 positivity is the most important and consistent diagnostic
    marker of neural GCT; SOX10, CD68, inhibin-alpha, nestin, and calretinin are
    also typically positive. Rare non-neural GCT is
    S100-negative/vimentin-positive. S100 staining distinguishes adult GCT (S100-positive) from
    congenital granular cell epulis (S100-negative).
  evidence:
  - reference: PMID:30888637
    reference_title: "Congenital Granular Cell Epulis: Classic Presentation and Its Differential Diagnosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "distinguishing the two (S-100-positive in GCT and S-100-negative in CGCE)"
    explanation: >-
      S-100 immunostaining distinguishes adult GCT (positive) from congenital
      granular cell epulis (negative).
- name: SOX10 Immunohistochemistry
  biomarker_term:
    preferred_term: SOX10 transcription factor
    term:
      id: NCIT:C102893
      label: Transcription Factor SOX-10
  notes: >-
    SOX10 nuclear positivity supports the Schwann-cell/neural-crest lineage of
    GCT and is part of the supporting immunohistochemical panel.
- name: ATP6AP1/ATP6AP2 Molecular Testing
  notes: >-
    Frameshift and premature stop codons in ATP6AP1/ATP6AP2 are considered
    pathognomonic of granular-cell lineage and can be used diagnostically,
    particularly to distinguish atypical GCT with a junctional component from
    melanoma.
  evidence:
  - reference: PMID:37565535
    reference_title: "Utility of sequencing for ATP6AP1 and ATP6AP2 to distinguish between atypical granular cell tumor with junctional component and melanoma."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Frameshift and premature stop codons in ATP6AP1/2 are specific for \ngranular cell lineage, and capable of excluding melanoma, in the absence of \nknown melanoma-associated driver mutations"
    explanation: >-
      ATP6AP1/2 truncating mutations are specific for granular-cell lineage and
      help exclude melanoma in ambiguous cases.
genetic:
- name: ATP6AP1
  association: Somatic Inactivating (Loss-of-Function) Mutations
  notes: >-
    ATP6AP1 (V-ATPase accessory protein 1; Xq28) is the most frequently mutated
    gene in GCT. Mutations are somatic, clonal, and typically truncating/
    frameshift/splice-site (e.g., c.746_749del p.P249Hfs*4 in oral GCT). In
    multifocal series ATP6AP1 was mutated in ~40-48% of tumors. Mutations are
    mutually exclusive with ATP6AP2.
  evidence:
  - reference: PMID:30166553
    reference_title: "Loss-of-function mutations in ATP6AP1 and ATP6AP2 in granular cell tumors."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "inactivating \nmutations of ATP6AP1 and ATP6AP2 are likely oncogenic drivers of GCTs"
    explanation: >-
      Pareja et al. conclude inactivating ATP6AP1/ATP6AP2 mutations are likely
      oncogenic drivers of GCTs.
  - reference: PMID:36534754
    reference_title: "Molecular Characterization of Multifocal Granular Cell Tumors."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Twenty tumors showed mutations in ATP6AP1 \n(48%)"
    explanation: >-
      In a multifocal GCT series, ATP6AP1 was the most frequently mutated gene
      (48% of tumors).
- name: ATP6AP2
  association: Somatic Inactivating (Loss-of-Function) Mutations
  notes: >-
    ATP6AP2 (V-ATPase accessory protein 2 / prorenin receptor; Xp11.4) is the
    second most frequently mutated driver in GCT, with somatic loss-of-function
    mutations mutually exclusive with ATP6AP1 (~24% of tumors in a multifocal
    series).
  evidence:
  - reference: PMID:36534754
    reference_title: "Molecular Characterization of Multifocal Granular Cell Tumors."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "10 tumors had mutations in ATP6AP2 (24%)"
    explanation: >-
      ATP6AP2 was mutated in 24% of tumors in a multifocal GCT series.
- name: ATP6V0C and Other V-ATPase Subunits
  association: Somatic Mutations (Minority)
  notes: >-
    A minority of GCTs lack ATP6AP1/ATP6AP2 mutations but carry inactivating
    mutations in other V-ATPase subunit genes (e.g., ATP6V0C - with recurrent
    isoleucine-136 hits - ATP6V1A, ATP6V0A4), converging on the same impaired
    V-ATPase function. These are generally mutually exclusive with ATP6AP1/2.
  evidence:
  - reference: PMID:30597645
    reference_title: "Frequent mutations of genes encoding vacuolar H(+) -ATPase components in granular cell tumors."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "seven other genes encoding V-ATPase components were also \nmutated, and three mutations in ATP6V0C occurred on the same amino acid \n(isoleucine 136)"
    explanation: >-
      Additional V-ATPase subunit genes are mutated in GCT, including recurrent
      ATP6V0C isoleucine-136 mutations.
treatments:
- name: Complete Surgical Excision
  description: >-
    Complete surgical excision with negative (wide) margins is the standard of
    care for all resectable GCTs and is curative for the vast majority of benign
    tumors. Margin status is critical: positive margins are associated with
    substantially higher recurrence (~20% vs ~2-8% with clear margins).
  treatment_term:
    preferred_term: surgical excision
    term:
      id: MAXO:0000447
      label: surgical excision
- name: Pazopanib
  description: >-
    Pazopanib, an oral multi-target tyrosine kinase inhibitor (VEGFR, PDGFR,
    c-KIT), is the best-supported systemic therapy for advanced/metastatic
    malignant GCT, for which no standardized guideline exists. In a 2023 review
    of 10 reported cases it produced disease control in 8/10 (80%) and objective
    RECIST response in 4/10 (40%), well above the ~6% response rate of pazopanib
    in other soft-tissue sarcomas. Its rationale is the enhanced PDGFR-beta
    signaling downstream of ATP6AP1/2 loss.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: targeted therapy
    term:
      id: NCIT:C93352
      label: Targeted Therapy
    therapeutic_agent:
    - preferred_term: pazopanib
      term:
        id: CHEBI:71219
        label: pazopanib
  evidence:
  - reference: PMID:37958362
    reference_title: "Antiangiogenics in Malignant Granular Cell Tumors: Review of the Literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Eight out of ten patients (80%) experienced disease control with \npazopanib, while four out of ten (40%) patients achieved an objective RECIST \nresponse"
    explanation: >-
      Pazopanib achieved 80% disease control and 40% objective response in
      reported advanced/malignant GCT cases.
  - reference: PMID:37958362
    reference_title: "Antiangiogenics in Malignant Granular Cell Tumors: Review of the Literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Pazopanib has been demonstrated to be active in \nadvanced GCTs and may be considered as a preferable treatment option"
    explanation: >-
      The review concludes pazopanib is active in advanced GCT and a preferable
      systemic option.
notes: >-
  Granular cell tumor is distinct from congenital granular cell epulis
  (congenital epulis of the newborn; MONDO:0015528), a separate dismech entry
  curated as Congenital_Epulis.yaml: the epulis is S100-negative, arises on the
  neonatal maxillary alveolar ridge, arrests growth after birth, and is not
  associated with ATP6AP1/ATP6AP2 mutations or syndromes. GCTs may also arise in
  the setting of germline RAS-MAPK ("RASopathy") syndromes (Noonan, LEOPARD,
  neurofibromatosis type 1, Watson), but the recurrent driver mutations within
  the tumors themselves are somatic V-ATPase gene mutations.
references:
- reference: PMID:30166553
  title: "Loss-of-function mutations in ATP6AP1 and ATP6AP2 in granular cell tumors."
- reference: PMID:30597645
  title: "Frequent mutations of genes encoding vacuolar H(+)-ATPase components in granular cell tumors."
- reference: PMID:37958362
  title: "Antiangiogenics in Malignant Granular Cell Tumors: Review of the Literature."
- reference: PMID:36534754
  title: "Molecular Characterization of Multifocal Granular Cell Tumors."
- reference: PMID:30888637
  title: "Congenital Granular Cell Epulis: Classic Presentation and Its Differential Diagnosis."
- reference: PMID:37565535
  title: "Utility of sequencing for ATP6AP1 and ATP6AP2 to distinguish between atypical granular cell tumor with junctional component and melanoma."
- reference: DOI:10.1111/jop.13148
  title: "Whole‐exome sequencing reveals novel vacuolar ATPase genes’ variants and variants in genes involved in lysosomal biology and autophagosomal formation in oral granular cell tumors"

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References & Deep Research