Granular Cell Tumors Workup

Updated: Dec 29, 2018
  • Author: Vladimir O Osipov, MD; Chief Editor: E Jason Abel, MD  more...
  • Print
Workup

Approach Considerations

Laboratory tests may be necessary to assess the functional effects of visceral lesions (eg, liver function tests in lesions along the biliary tree). However, the diagnosis of granular cell tumors centers on analysis of biopsy specimens.

Anatomic pathology

Gross features include pale white/yellow, nonencapsulated, and variably (well to poorly) circumscribed nodules with solid, fleshy cut surfaces that are devoid of liquefaction, necrosis, or bleeding. The overlying skin or mucosa is thickened and may have a cobblestone appearance. [15]

Microscopic features of benign granular cell tumors are remarkably uniform, regardless of the site. Granular cell tumors are sometimes located near a nerve twig, usually within the perineurium, and are variably circumscribed at the periphery. Approximately half of all granular cell tumors have poorly defined or infiltrative margins. The nodules are composed of large polyhedral cells arranged in sheets, nests, lobules, or trabeculae and are surrounded by variable stroma. A reticulin framework may be around individual cells or small groups of cells. Occasionally, granular cell tumors are extensively collagenized.

The tumor cells have abundant granular eosinophilic cytoplasm with centrally located vesicular or pyknotic nuclei. Markedly enlarged lysosomes in tumor cells may be observed as eosinophilic globules surrounded by a clear halo; some are extruded from cells and may be phagocytosed by histiocytes. In such cases, they are termed angulate bodies. Usually, the granules stain positive with periodic acid-Schiff (PAS) staining and are resistant to diastase. They also stain with Sudan black B and are magenta in trichrome preparations. Multinucleation, plentiful mitotic activity, nuclear pleomorphism, and prominent nucleoli are uncommon features. Squamous epithelium overlying the peripheral superficial lesions exhibits acanthosis and pseudoepitheliomatous hyperplasia.

Immunohistochemical findings

Granular cell tumors have an uncertain histogenesis. Many immunohistochemical and ultrastructural studies suggest a Schwann cell origin. [16]

The tumor cells stain positively for S-100 protein, neuron-specific enolase, and NK1-C3 in almost all cases. Positivity with stains for myelin-associated P0 and P2 proteins, myelin basic protein, and Leu-7 is less consistent. [17]

The tumor cells are nonimmunoreactive for epithelial, muscle, endothelial, and glial cell markers. This is useful for differentiating a granular cell tumor from other diagnostic possibilities.

Ultrastructural findings

Ultrastructural findings with granular cell tumors are highly characteristic. Pleomorphic secondary lysosomes are observed within the cytoplasm of tumor cells. [18, 19]

Features indicating neural derivation of granular cell tumors (eg, myelin residues, long-spacing collagen, arrays of neuritic processes among tumor cells) may be observed.

Variants

Gingival granular cell tumor of newborns is an extremely rare variant and manifests as a polypoid swelling situated exclusively over the lateral alveolar ridge, especially of the maxilla. More than 90% of patients are girls. [20] These lesions are likely to be reactive rather than neoplastic in nature, and, ultimately, they may be segregated from granular cell tumors. Lesions, noticed soon after birth, show the usual histopathologic features of granular cell tumors; however, the following differences from the adult counterpart are noted:

  • The lesions do not grow, and some regress

  • Recurrence has not been noted, even after incomplete resection

  • The lesions do not have a malignant counterpart

  • The lesions have a prominent plexiform network of capillaries and scattered inflammatory cells

  • Occasionally, lesions show entrapped odontogenic epithelium

  • Pseudoepitheliomatous hyperplasia of overlying squamous epithelium is less conspicuous or may be absent

  • The cells do not stain positively for the S-100 protein

  • Ultrastructurally, the lesional cells show a few histiocytic features, and giant lysosomes (globules/angulate bodies) are not observed.

The primitive polypoid granular cell tumor is another rare subset, which manifests as exophytic polypoid skin lesions at any site or in a person of any age. The lesions are characterized by nuclear pleomorphism, frequent mitoses, and poor immunohistochemical reactions. They are not aggressive tumors. Most likely, they represent a nonimmunoreactive phenotype of granular cell tumor. [21] In 2005, Lazar and Fletcher published a series of similar cases. Only one of 13 cases gave rise to a local lymph node metastasis. In this case, the patient had no recurrence and is currently disease-free 70 months after lymphadenectomy. [22]

Gross and microscopic features of malignant granular cell tumors  Histopathologic features of malignancy are unmistakable in some patients and do not pose any diagnostic difficulty. Some malignancies are identical to their benign counterparts (ie, small size, no local destruction, no infiltrative activity at the edge, bland cytology) and yet demonstrate malignant potential by way of metastases. [6, 23]

Therefore, with granular cell tumors larger than 3 cm, malignancy may be indicated by the following:

  • Locally destructive changes (eg, ulceration, necrosis, hemorrhage)

  • Infiltrative activity at the edges

  • Frequent mitoses

  • Vesicular nuclei with prominent nucleoli

Next:

Imaging Studies

Imaging studies may be necessary to detect deep-seated visceral lesions.

Previous
Next:

Procedures

Kobara et al reported that endoscopic imaging under direct view has potential diagnostic value for submucosal tumors in the gastrointestinal (GI) tract. The two granular cell tumors in this study were both white, cloudy, round, and elastic, with no visible tumor coating. Final pathological diagnosis was obtained by core biopsy using the submucosal endoscopy with mucosal flap method. [24]

Previous
Next:

Histologic Findings

See the image below.

Typical histology. Typical histology.
Previous
Next:

Staging

Universally recommended and accepted staging schemes specific for granular cell tumors do not exist. A general staging scheme developed by the American Joint Committee on Cancer for use with other soft tissue tumors may be followed.

Pathologic differential diagnoses

Some schwannomas and neurofibromas may show granular changes in parts, but the changes are never extensive enough to create a major diagnostic challenge. Moreover, schwannomas are encapsulated, and other stigmata of von Recklinghausen disease associated with neurofibromas are absent in patients with granular cell tumors.

Benign granular cell tumors may exhibit some superficial resemblance to rhabdomyomas and hibernomas. However, upon critical analysis, they do not show cytoplasmic striations or vacuoles and are negative for skeletal muscle markers and fat stains.

Intracranial granular cell tumors (the posterior pituitary is a noteworthy site for granular cell tumors) may be mistaken for granular variants of glial tumors but can be differentiated based on their negativity for glial fibrillary acid protein.

Granular cell variants of basal cell carcinoma, melanoma, leiomyoma, leiomyosarcoma, dermatofibrosarcoma, angiosarcoma, fibrous histiocytoma, and ameloblastoma can sometimes be indistinguishable from granular cell tumors if examined with routine light microscopy. A battery of immunohistochemical stains is needed to make a specific diagnosis. Granular cell tumors are positive for S-100 protein and negative for epithelial, melanocytic, smooth muscle, dendritic cell, and endothelial markers.

Malignant granular cell tumors can sometimes mimic alveolar soft part sarcoma because of their organoid growth pattern and periodic acid-Schiff (PAS)–positive intracellular crystalloids. The rhomboid crystalloids with their characteristic lattice pattern, observed ultrastructurally in alveolar soft part sarcoma, are absent in granular cell tumors.

Previous