Granular Cell Tumor

Malignant granular cell tumor of somatic soft tissue can be staged according to the American Joint Committee on Cancer (AJCC) eighth-edition TNM staging system for soft tissue sarcoma of the trunk and extremities, although given the rarity of this entity, there is not current evidence demonstrating prognostic power for this approach.

Loss-of-function mutations affecting the V-ATPase accessory genes, ATP6AP1 (61%) and ATP6AP2 (11%), are found in 72% of granular cell tumors collectively. These genes play pivotal roles in endosomal pH regulation; loss-of-function mutations affecting these genes are found irrespective of anatomical site or whether the lesions are benign or malignant, and they have not been detected in other neoplasms. Therefore, loss-of-function ATP6AP1 or ATP6AP2 mutations appear to be pathognomonic for the diagnosis of granular cell tumor. Granular cell tumors lacking mutations in these genes have been reported to harbor mutations affecting other V-ATPase-related genes. Inactivation of either ATP6AP1 or ATP6AP2 in Schwann cells leads to the accumulation of intracytoplasmic granules that are characteristic of granular cell tumor. Analysis of the granules revealed that they display ultrastructural and immunophenotypic features of early and recycling endosomes. The mechanism by which loss-of-function mutations in endosomal regulatory proteins drive oncogenesis is currently unknown.

Granular cell tumors are uninodular, firm masses involving the skin/subcutis or submucosa, often with an overlying epithelial hyperplasia. On sectioning, the tumor has a yellowish, finely granular texture. Malignant granular cell tumors range in size from 1 to 18.2 cm, usually being > 5 cm. Grossly, tumors are pale grey and firm, often deeper (subcutaneous/intramuscular) than their benign counterparts.

Granular cell tumor has ill-defined borders and is composed of sheets, nests, and trabeculae of large, monotonous epithelioid to polygonal cells with intensely eosinophilic, granular cytoplasm. Cell borders may be indistinct, producing a syncytial appearance. Nuclei are usually centrally situated and range from uniformly small and mildly hyperchromatic to larger and vesicular with distinct nucleoli. Mitoses are variable in number but usually not prominent.

The finely granular appearance of the cytoplasm is due to massive accumulation of lysosomes including larger intracytoplasmic granules highlighted by clear halos. Perineural infiltration is common. For cutaneous granular cell tumor and granular cell tumor arising in sites such as the tongue and esophagus with overlying squamous epithelium, pseudoepitheliomatous hyperplasia is sometimes seen and when extensive can raise the consideration of squamous cell carcinoma.

Malignant granular cell tumors are rare and their features vary from overtly sarcomatous to morphologically bland on rare occasions. Histological features associated with malignancy include increased cellularity, prominent spindling, high N:C ratio, vesicular nuclei with prominent nucleoli, marked pleomorphism, increased mitotic activity (> 2 mitoses per 2 mm²), and geographical necrosis. Although most malignant granular cell tumors show necrosis and/or high mitotic activity, these parameters alone may not identify all tumors that metastasize.

Granular cell tumors are generally reactive for S100, SOX10, nestin, inhibin, and calretinin. Tumors are also positive for CD68, CD63 (NKI/C3), and NSE, probably nonspecific due to the cytoplasmic lysosomal content. MITF and TFE3 (in the absence of gene rearrangements) show diffuse nuclear reactivity in most cases, but HMB45 is uniformly negative and only very rarely is there focal reactivity for melan-A.

In FNA samples, the characteristic granular cytoplasm and bland nuclei are useful features, but carcinomas (particularly apocrine) and histiocytic processes must be considered.

Although granular cell tumor is benign in the vast majority of cases, local recurrence can sometimes be seen after incomplete excision. Malignant granular cell tumor has a 50% rate of metastasis. Local recurrence, metastasis, larger tumor size, and older patient age are adverse prognostic factors for malignant granular cell tumor.

Not clinically relevant

Essential: nests and sheets of epithelioid to polygonal cells; abundant, intensely eosinophilic, granular cytoplasm; positive for S100 and SOX10 by immunohistochemistry.