Granular Cell Tumors

Synonyms and related keywords: granular cell myoblastoma, granular cell schwannoma, granular cell neurofibroma, granular neurogenic tumor, congenital epulis, gingival GCT, gingival granular cell tumors, malignant GCT, malignant granular cell tumors, malignant granular cell schwannoma, Abrikossoff tumor


INTRODUCTION

Background: The controversy regarding whether the formation of a granular cell tumor (GCT) is a metabolic, degenerative, or neoplastic process is now resolved; it is a neoplastic process. Lesions are of neural derivation, as supported by immunophenotypic and ultrastructural evidence. Granularity of tumor cells is due to the accumulation of secondary lysosomes in the cytoplasm. This change is rather nonspecific and can be observed in many non-neural tumors, including those arising from smooth muscle, connective tissue, neuroglia, endothelial, and epithelial cells. Features described within this article are those of neural granular cell tumors. Non-neural granular cell tumors are discussed only as differential diagnoses.

Pathophysiology: Granular cell tumors are typically solitary, smaller than 3 cm, and located in the dermis or subcutis and less frequently in the submucosa, smooth muscle, or striated muscle. Granular cell tumors are also found in the internal organs, particularly in the upper aerodigestive tract. Benign and malignant counterparts are known; the latter are rare, comprising fewer than 2% of all granular cell tumors (Franburg-Smith, 1998).

Frequency:

• Internationally: The lesion is uncommon. Exact figures are unavailable.

Mortality/Morbidity: Again, the lesion is uncommon, and, as with prevalence figures, mortality and morbidity rates are not available.

Race: Granular cell tumors appear to be more common in black persons. Multiplicity of lesions is definitely more common in black persons. Up to 10% of granular cell tumors are multiple (ie, 2-4).

Sex: A slight female predominance exists, with an estimated female-to-male ratio of approximately 3:2.

Age: Granular cell tumors affect persons of varying ages, and the range is wide. Most patients are middle-aged, with a peak incidence in the fourth through sixth decades of life.

CLINICAL

History:

• Benign lesions manifest as nonulcerated and usually painless nodules with an insidious onset and slow growth rate. They are rarely larger than 3 cm and usually have been noted for less than 6 months.

Physical:

• Any site is possible, although easily noticed surface lesions (ie, head, neck, trunk, extremities) are far more common than visceral lesions.

• The tongue is affected in approximately 25% of cases; breast involvement is also common.

• All together, parenchyma, subcutaneous tissue, and dermis account for approximately 15% of cases; a third are in the parenchyma.

• Origin in skeletal muscle is rare.

• Nodules, usually solitary, may be multiple in up to 10% of cases. (Two patients with 26 and 52 tumors are on record.)

• The lesions usually involve small- to medium-sized cranial or spinal nerves, although neurologic deficit is rare. No association with neurofibromatosis has been detected.

• Visceral involvement is encountered as mucosal or submucosal nodules in the esophagus, stomach, small and large intestines, larynx, bronchi, gall bladder, and biliary tract.

• The gastrointestinal tract harbors approximately 5% of all granular cell tumors.

• Lesions can be incidental findings, or they may give rise to obstructive or pressure symptoms when large enough and in a critical location.

• Clinical features of malignant lesions are as follows:

• Malignant granular cell tumors are rare. By convention, granular cell tumors are classified as malignant when their constituent cells show cytologic features of malignancy or when a morphologically benign granular cell tumor metastasizes to regional lymph nodes or distant sites or otherwise causes death.

• Malignancy is encountered more often in deep-seated lesions in adults, with a mean patient age of 50 years. Sex and race distribution of malignant tumors mirrors that of benign lesions. A history of long clinical duration and rapid recent growth has been observed in some cases, suggesting a possibility of malignant transformation from a preexisting benign granular cell tumor.

• The lesions are usually larger (ie, 4-15 cm) and may be locally destructive, thus causing symptoms (eg, pressure, obstruction, hemorrhage, ulceration, secondary infection) depending on the site. Metastases to regional lymph nodes and/or distant organs (most common site is the lungs) and concomitant symptoms may be present.

• Histopathologic features of malignancy are unmistakable in some patients and pose no diagnostic difficulty. Necrosis, nuclear pleomorphism, spindling and increased mitotic activity (>2 mitoses per 10 high power fields) are the features of malignancy. Some malignancies are identical to their benign counterparts (ie, small size, no local destruction, no infiltrative activity at the edge, bland histomorphology) and yet exhibit malignant potential by setting up metastases. Therefore, all lesions should undergo a careful and thorough examination.

Causes:

• The cause of granular cell tumors is unknown.

DIFFERENTIALS

Other Problems to be Considered:

Clinical differential diagnoses vary depending on the site of the granular cell tumor. Pathologic differential diagnoses are discussed in Workup.

WORKUP

Lab Studies:

• Laboratory tests may be necessary to assess the functional effects of visceral lesions (eg, liver function tests in lesions along the biliary tree).

• Anatomic pathology (Scheithauer, 1997)

• 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.

• 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 (Mazur, 1990)

• 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.

• 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 (Moscovic, 1967; Seo, 1984)

• These are highly characteristic. Pleomorphic secondary lysosomes are observed within the cytoplasm of tumor cells.

• 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 (Fletcher, 1995)

• 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 females. 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. These lesions are likely to be reactive rather than neoplastic in nature, and, ultimately, they may be segregated from granular cell tumors.

• The primitive polypoid granular cell tumor is another rare subset and manifests as an 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 (LeBoit, 1991). In 2005, Lazar and Fletcher published a series of similar cases. Only 1 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.

• Gross and microscopic features of malignant granular cell tumors (Kindblom, 1981; Fanburg-Smith, 1998)

• 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 exhibit malignant potential by way of metastases.

• Therefore, regarding granular cell tumors larger than 3 cm, locally destructive changes (eg, ulceration, necrosis, hemorrhage), infiltrative activity at the edges, frequent mitoses, and vesicular nuclei with prominent nucleoli may indicate the presence of malignancy.

Imaging Studies:

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

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, although 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 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.

TREATMENT

Medical Care: Radiation and chemotherapy are not needed for benign lesions and are not effective for malignant lesions.

Surgical Care: If resection is complete, local surgical excision is curative for benign granular cell tumors. Wide en bloc excision is recommended for malignant lesions.

Consultations: Seek consultation with a site-specific surgeon.

Diet: Generally, no diet restrictions are necessary.

Activity: Generally, no activity restrictions are necessary.

MEDICATION

The primary mode of treatment is surgical, not medical.


FOLLOW-UP

Complications:

• The main complications are recurrence, metastases, or both.

Prognosis:

• In benign lesions, recurrence rates are 2-8%, even when the resection margins are deemed free of tumor infiltration; they are 21-50% when the margins are positive for tumor.

• Malignant lesions are aggressive and difficult to eradicate with surgery. Metastases are usually detected within 2 years. Approximately 60% of patients die of the disease within 3 years of detection of the primary tumor.

• Ki-67 immunoreactivity of 10% or more tumor cells is an adverse prognostic factor.

MISCELLANEOUS

Medical/Legal Pitfalls:

• In submucosal granular cell tumors (eg, tongue, larynx, vulva), pseudoepitheliomatous hyperplasia of the overlying squamous epithelium may be misdiagnosed as squamous cell carcinoma (Peterson, 1974).

• Granular cell tumors of the breast may clinically, grossly, and microscopically simulate carcinomas of the breast. Granular cell tumors may produce skin or deep fascial fixation and hence may be clinically and grossly indistinguishable from scirrhous breast carcinoma. At the microscopic level, approximately 50% of granular cell tumors have a diffuse infiltrative pattern and induce a stromal response similar to that of scirrhous breast carcinoma. However, cytologically, granular cell tumors are distinguished based on eosinophilic cytoplasmic granules and small round nuclei with dense chromatin.

Special Concerns:

• No special concerns have been recorded related to pregnancy, pediatrics, or geriatrics.