Breast
Other benign tumors
Granular cell tumor
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PubMed Search: Granular cell tumor
Table of Contents
Definition / general | Essential features | Terminology | ICD coding | Epidemiology | Sites | Pathophysiology | Etiology | Clinical features | Diagnosis | Radiology description | Radiology images | Prognostic factors | Case reports | Treatment | Clinical images | Gross description | Gross images | Microscopic (histologic) description | Microscopic (histologic) images | Cytology description | Cytology images | Positive stains | Negative stains | Electron microscopy description | Molecular / cytogenetics description | Sample pathology report | Differential diagnosis | Additional references | Board review style question #1 | Board review style answer #1 | Board review style question #2 | Board review style answer #2Cite this page: Luceno S, Biernacka A. Granular cell tumor. PathologyOutlines.com website. https://www.pathologyoutlines.com/topic/breastgct.html. Accessed April 1st, 2025.
Definition / general
- Benign neuroectodermal tumor derived from Schwann cells and composed of epithelioid cells with abundant lysosome rich granular cytoplasm
Essential features
- Uncommon breast tumor with peripheral nerve sheath (Schwannian) differentiation
- Large epithelioid cells with bland nuclear features and abundant eosinophilic cytoplasm rich in granules (lysosomes)
- S100 is strongly and diffusely positive
- Must exclude other more aggressive neoplasms with granular appearance (melanoma, breast carcinoma)
Terminology
- Granular cell tumor (GCT)
- Historical terminology not recommended by the WHO
- Granular cell myoblastoma
- Abrikossoff tumor
- First described by A.I. Abrikosoff in 1926 as myoblastic myoma (Virchows Arch A Pathol Anat 1926;260:215)
Epidemiology
- Can occur anywhere in the body; breast accounts for 5 - 15% of all GCTs (J Surg Oncol 1980;13:301)
- Rare compared to other breast lesions: 1 per 1,000 breast tumors; 1 per 100 - 200 breast carcinomas (Breast J 2004;10:528)
- Women, wide age range (19 - 77 years) (Arch Pathol Lab Med 2011;135:890)
- More common in African Americans, in whom it occurs at a younger age (mean: 41 years) than in White Americans (mean age: 54 years) (Arch Pathol Lab Med 2011;135:890)
- Children and men are rarely affected (Clin Imaging 2018;52:334, Autops Case Rep 2019;9:e2019099, BMJ Case Rep 2019;12:e227805, J Ultrasound Med 2011;30:1295)
- May present with coincidental breast carcinoma or be associated with mastectomy scars (Arch Pathol Lab Med 2000;124:709)
Sites
- Skin and subcutaneous involvement is the most common
- Breast parenchyma can also be involved
- Most common in the upper inner quadrant near the supraclavicular nerve (in contrast, breast carcinomas are most common in the upper outer quadrant)
- Usually single but multicentricity has been reported in ~18% of patients (Breast J 2004;10:528)
- Occasionally bilateral
Pathophysiology
- Appears to derive from Schwann cells of peripheral nerves in the interlobular breast stroma
- Majority of GCTs (~60 - 70%, including breast tumors) harbor loss of function mutations in the ATP6AP1 and ATP6AP2 genes (mutually exclusive) located on the X chromosome, which may explain the higher prevalence in women (Nat Commun 2018;9:3533, Genes Chromosomes Cancer 2019;58:373)
- Encode vacuolar H+-ATPase components that regulate endosomal pH
- Impaired vesicular acidification and altered distribution of endosomes lead to massive accumulation of intracytoplasmic vesicles (correlating with histologic appearance)
- Exact oncogenic mechanism is not yet understood
Etiology
- Most cases, including multifocal, are sporadic
- Rare association with other conditions, including Bannayan-Riley-Ruvalcaba syndrome, neurofibromatosis type 1, Noonan syndrome and LEOPARD syndrome (Am J Med Genet A 2003;120A:286, Arch Dermatol 1990;126:1051, Eur J Pediatr Surg 2013;23:257, Clin Genet 2009;75:185)
Clinical features
- Majority of patients (~70%) present with a palpable breast lump and ~25% with an abnormality on a screening mammogram; ~4% detected on follow up of breast malignancy (Surg Oncol 2011;20:97)
- Most commonly, it is a solitary lesion; less commonly, multiple lesions are present in the breast or elsewhere (Breast J 2004;10:528)
- On clinical exam, there is an irregular and firm mass, which may retract skin, cause nipple inversion or adhere to the chest wall; it can mimic carcinoma (BMJ Case Rep 2013;2013:bcr2012008178)
- Usually painless; may be painful when it involves skin
- Lesions in the skin are indurated and flesh colored to red
- Colocalization of GCT and invasive breast carcinoma has been reported (Arch Pathol Lab Med 2002;126:731, Case Rep Oncol 2021;14:303)
Diagnosis
- Similar clinical and radiological features to breast carcinomas necessitate tissue diagnosis (BMJ Case Rep 2024;17:e258326, Cureus 2024;16:e57500, World J Clin Cases 2023;11:8044, Cureus 2024;16:e56774)
- Usually made by imaging guided core biopsy, occasionally fine needle aspiration
- GCT should be considered for neoplasms with abundant foamy, clear or granular cytoplasm
- Immunohistochemical studies are typically performed to support the diagnosis
- Excision is generally recommended
Radiology description
- Features on mammography
- Generally infer a suspicion of malignancy
- Common features include irregularity, spiculation, stellation, isodensity sometimes associated with hypodense rims, heterogenicity, variable circumscription and association with tendril-like extensions / desmoplasia
- Occasional skin thickening, local invasion and association with the pectoralis muscle
- Calcifications are usually absent
- Features on ultrasound
- Generally infer a suspicion of malignancy
- Common features include solid, heterogeneous, poorly defined masses with a high depth:width ratio
- Hypervascular echotexture, particularly peripherally, although this is not consistent
- Hypoechoic and display posterior shadowing with a coarse internal echo and high boundary echo
- Magnetic resonance imaging (MRI) / dynamic MR mammography may be useful in determining the extent of disease, the presence of aggressive features and contralateral screening; however, no specific features have been outlined and findings may mimic breast malignancy
- FDG PET: lack of increased glucose metabolism in keeping with a benign lesion
- References: Surg Oncol 2011;20:97, Radiol Bras 2020;53:105, J Korean Soc Radiol 2022;83:1195, Medicine (Baltimore) 2020;99:e23264, Br J Radiol 2007;80:970, J Nucl Med 1998;39:1398
Radiology images
Images hosted on other servers:
Digital mammography and ultrasound
MRI
Prognostic factors
- Most are benign (~99% of cases), with a low growth rate
- Since excision is recommended, the natural history of GCT that is not excised is unknown
- There is minimal risk of local recurrence, even when excised with positive margins (Arch Pathol Lab Med 2011;135:890)
- Exceptionally, GCT can show malignant behavior (in 1 - 2% of cases) (Am J Surg Pathol 1998;22:779)
- Rare malignant form can give rise to metastasis to axillary lymph nodes and distant dissemination (lung, liver or bone) (J Ultrasound Med 2011;30:1295)
Case reports
- 3 year old girl with GCT of the breast (Autops Case Rep 2019;9:e2019099)
- 45 year old woman with GCT of the breast (Indian J Surg Oncol 2020;11:321)
- 50 year old woman and 62 year old man both with GCT mimicking breast carcinoma (Cureus 2024;16:e57500)
- 58 year old woman with GCT (Indian J Surg Oncol 2015;6:446)
Treatment
- Treatment is local excision (Surg Oncol 2011;20:97)
- Local recurrence is rarely reported with incomplete excision
Clinical images
Images hosted on other servers:
Painless, discolored lesion
Ulcerated, painful lesion
Gross description
- Solid, homogeneous, tan-white and firm to hard mass (Breast J 2004;10:528, Breast J 2000;6:27)
- Borders can be well defined, circumscribed or ill defined, infiltrative
- Usually 1 - 3 cm, up to 5 cm
Gross images
Contributed by Salvatore Luceno, M.D., M.Sc. and Anna Biernacka, M.D., Ph.D.
Skin involvement
Solid mass
Microscopic (histologic) description
- Well demarcated but not encapsulated with a circumscribed or infiltrative border
- Cells arranged in cohesive sheets, clusters, fascicles and trabeculae form solid proliferation
- Infiltration into adjacent tissue in small nests; single cell infiltration is less common
- Cells are large, round to polygonal but may be spindle shaped
- Cell borders are indistinct with syncytial appearance or are well defined
- Cytoplasm is abundant, eosinophilic and finely granular due to the accumulation of lysosomes
- Smaller lysosomes are eosinophilic
- Larger lysosomes have surrounding halo (pustulo-ovoid bodies of Milian)
- PAS positive / diastase resistant
- In some tumors, cytoplasm appears clear and vacuolated
- Nuclei are centrally located, small, uniform and hyperchromatic, rarely vesicular
- Nucleoli may be inconspicuous or prominent
- Mitotic figures are rare (Surg Oncol 2011;20:97)
- Focal areas of nuclear pleomorphism or occasional mitoses should not be interpreted as evidence of malignancy
- Stroma may be dense collagenous / hyalinized / fibrous, may contain arborizing thin walled blood vessels, small nerve bundles and variable amounts of lymphocytes and plasma cells
- Perineural and perivascular involvement is frequent (J Clin Pathol 2014;67:19)
- Overlying epithelium may show pseudoepitheliomatous hyperplasia that may simulate squamous cell carcinoma (J Surg Oncol 1980;13:301)
- Malignant GCT (exceedingly rare, 1 - 2%) recognized by a set of histologic criteria (Am J Surg Pathol 1998;22:779)
- Necrosis
- Spindle cell morphology
- Vesicular nuclei with prominent nucleoli
- Increased mitotic activity (> 2 mitoses per 10 HPF at 200x magnification)
- High N:C ratio
- Significant nuclear pleomorphism
- Classified as atypical when 2 of 6 criteria are present and as malignant when 3 or more criteria are present (Breast J 2004;10:528, Arch Pathol Lab Med 2004;128:771)
- Large size (> 5 cm) is also of concern for malignancy
- Metastasis remains the only unequivocal sign of malignancy (Virchows Arch 2016;468:527)
Microscopic (histologic) images
Contributed by Salvatore Luceno, M.D., M.Sc. and Anna Biernacka, M.D., Ph.D.
Pseudoepitheliomatous hyperplasia
Infiltration around adnexal structures
Stromal inflammatory cells
Spindly cells in fascicles
Infiltration of dermal collagen
Focal nuclear atypia
Core needle biopsy
Infiltration of fat
Abundant cytoplasm, small nuclei
Proximity to nerve
Cytoplasmic granules (lysosomes)
S100
CD68
Cytokeratin AE1 / AE3
Cytology description
- Cellular aspirates with cohesive groups and single cells admixed with fragments of connective tissue (Breast J 2000;6:27, Diagn Cytopathol 2007;35:725, Surg Today 2004;34:760, Cytojournal 2014;11:28)
- Clusters may appear syncytial, while intact single cells have polygonal shapes
- Cytoplasm is abundant and granular with indistinct boundaries
- Nuclei are small and bland with finely granular chromatin and occasional small nucleoli; bare nuclei may be present
- Cell membranes appear delicate and fragile; cell disruption releases granules to the background
- Granules are blue with Romanowsky stains and red with the Papanicolaou stain
- No mitotic figures, no necrosis
- Differential diagnosis includes carcinomas (in particular apocrine) and xanthogranulomatous inflammatory lesions
Cytology images
Contributed by Salvatore Luceno, M.D., M.Sc. and Anna Biernacka, M.D., Ph.D.
Abundant and delicate cytoplasm
Granular background, naked nuclei
Resemblance to histiocytes
Nuclear features
Images hosted on other servers:
Nuclear & cytoplasmic features
Positive stains
- S100 (> 95% of cases), strong and diffuse in nuclear and cytoplasmic
- SOX10 (> 90%)
- CD68 (> 95%), CD63 (NKI-C3), nonspecific immunoreactivity in intracytoplasmic phagolysosomes
- Calretinin (~80%)
- Inhibin-α (~50%)
- Neuron specific enolase (~90%)
- CD56
- PAS (diastase resistant)
- Strong nuclear TFE3 and MITF (Hum Pathol 2015;46:1242, Am J Dermatopathol 2007;29:22)
- Focal CEA and vimentin
Negative stains
- Cytokeratins, EMA, mucins
- Estrogen and progesterone receptors (Breast J 2004;10:528)
- Androgen receptor, GCDFP-15
- HMB45, MelanA (Am J Dermatopathol 2007;29:22)
- PAX8
- GFAP
- Majority of muscle markers (desmin, myoglobin) are negative
- Beta catenin (majority has normal membrane pattern)
- NFP
- Ki67 proliferation index is typically low (< 2%) (Histopathology 1988;12:263, Arch Pathol Lab Med 2004;128:771)
Electron microscopy description
- Myelin figures, lysosomes
Molecular / cytogenetics description
- These tumors have a low mutation burden
- Frequent loss of function mutations in the ATP6AP1 and ATP6AP2 genes
Sample pathology report
- Breast, lumpectomy:
- Granular cell tumor (2 cm), completely excised (see comment)
- Comment: Sections show sheets of polygonal cells with abundant eosinophilic cytoplasm, round nuclei and inconspicuous nucleoli; no mitosis or atypia are seen. S100 is strongly and diffusely positive, whereas AE1 / AE3 is negative.
Differential diagnosis
- Invasive breast carcinomas, in particular apocrine, histiocytoid:
- Secretory carcinoma:
- Benign inflammatory lesions containing histiocytes (e.g., granulomatous mastitis, ruptured cysts, fat necrosis, ruptured breast implants and silicone):
- Histiocytes with foamy or vacuolated cytoplasm, increased inflammatory infiltrate, granulomas, giant cells
- Investigate clinical history
- Metastatic tumors (e.g., renal cell carcinoma, melanoma):
- Alveolar soft part sarcoma:
- Large, round to polygonal cells with well defined cell borders
- Vesicular chromatin with a prominent nucleolus
- Organoid and nest-like growth pattern with characteristic pseudoalveolar-like structures
Additional references
Board review style question #1
A 45 year old patient has a 1.5 cm poorly defined mass without calcifications on imaging. Tissue sampling was performed and the H&E stained section is shown in the image above. The lesional cells show strong diffuse staining with S100. Which of the following is the best diagnosis?
- Apocrine metaplasia
- Atypical ductal hyperplasia
- Granular cell tumor
- Invasive ductal carcinoma
Board review style answer #1
C. Granular cell tumor. Granular cell tumors are strong diffusely positivity for S100.
Answer A is incorrect because apocrine metaplasia of the breast is S100 negative, as they are of epithelial origin. Answer B is incorrect because breast epithelium is S100 negative and the image does not show hyperplastic epithelium with atypia. Answer D is incorrect because invasive ductal carcinoma originates in the breast epithelium, which is S100 negative.
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Reference: Granular cell tumor
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Board review style question #2
A 45 year old patient, status postbiopsy of a 2.3 cm breast mass, was found to have a granular cell tumor. Which of the following immunophenotype profiles best supports this diagnosis?
- CK7-, ER+
- S100-, ER+
- S100+, CK7-
- S100+, CK7+
Board review style answer #2
C. S100+, CK7-. Granular cell tumors are positive for S100 and negative for cytokeratins, including CK7.
Answer A is incorrect because granular cell tumors are ER-. Answer B is incorrect because granular cell tumors are S100+.
Answer D is incorrect because granular cell tumors are CK7-.
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Reference: Granular cell tumor
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