Image Quiz #195：S100 阳性的乳腺肿块Image Quiz #195: S100-positive breast mass

A 45 year old patient had a 1.5 cm poorly defined breast 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?

Select an answer:

1. Apocrine metaplasia
2. Atypical ductal hyperplasia
3. Granular cell tumor
4. Invasive ductal carcinoma

Answer

C. Granular cell tumor. Granular cell tumors show strong diffuse S100 positivity.

• A is incorrect: apocrine metaplasia of the breast is S100 negative, as they are of epithelial origin.
• B is incorrect: breast epithelium is S100 negative and the image does not show hyperplastic epithelium with atypia.
• D is incorrect: invasive ductal carcinoma originates in the breast epithelium, which is S100 negative.

Related topic: Granular cell tumor of the breast

Authors: Salvatore Luceno, M.D., M.Sc.; Anna Biernacka, M.D., Ph.D. · Last staff update: 15 September 2026 · PathologyOutlines topic

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)

ICD coding

• ICD-O
  • 9580/0 - granular cell tumor, NOS
  • 9580/3 - granular cell tumor, malignant

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

Digital mammography / ultrasound and MRI images from the original topic were hosted on other servers and were not archived locally.

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

Clinical images from the original topic were hosted on other servers and were not archived locally.

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

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

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

Cytology images from the original topic were not archived locally.

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

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: Keratin+
• Secretory carcinoma: GATA3+, MUC4+
• 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): Renal cell carcinoma:; PAX8+; Melanoma:; MelanA+, HMB45+
• 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

Practice question #1 and answer

Practice question #1 for this topic is Image Quiz #195 above; see the stem, choices A–D, and answer explanation at the top of this page.

Practice 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?

1. CK7-, ER+
2. S100-, ER+
3. S100+, CK7-
4. S100+, CK7+

Practice 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-.

Cite this page: Luceno S, Biernacka A. Granular cell tumor. PathologyOutlines.com website. https://www.pathologyoutlines.com/topic/breastgct.html. Accessed September 15th, 2026.

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