Granular Cell Tumor (Myoblastoma)
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Introduction

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It is not clear whether or not granular cell tumor (granular cell myoblastoma, granular cell schwannoma) is a true neoplasm, a developmental anomaly, or a trauma-induced proliferation.  The basic cell of origin is now thought to be neural, although past reports frequently indicated an origin from striated muscle, or less frequently an origin from histiocytes, fibroblasts or pericytes.  The tumor is widely distributed throughout the body, but more than half of all cases occur in the oral cavity.  The other head and neck site likely to be involved is the larynx.

Malignant variants represent approximately 1% of all cases, with some representing neoplasia in Cowden syndrome (multiple hamartoma syndrome), but some consider these malignancies to be simply variants of the distinctive and rare alveolar soft part sarcoma, a look-alike malignancy composed largely of granular epithelioid cells organized in alveolar-like nests.  Once considered an organoid variant of malignant granular cell tumor or a malignant nonchromaffin paraganglioma, it also has immunohistochemical features of skeletal muscle. Its true histogenesis, however, remains debatable and it is included here only for purposes of convenience. Approximately one in four lesions occur in the head and neck region, usually the oral cavity, pharynx and orbit.  The most common location, however, is the thigh.

More than a third of all granular cell tumors occur on the lingual dorsum, usually as a sessile, painless, somewhat firm, immovable nodule less than 1.5 cm. in greatest diameter.  Lesions often demonstrate a pallor or a yellowish discoloration and typically have a smooth surface (Figure 1). When it occurs on the lingual dorsum, the surface papillae are separated one from another but do not usually disappear.

Other oral and pharyngeal sites of involvement include the soft palate, uvula, labial mucosa, oral floor and gingiva. There is no gender predilection for oral cases, but overall almost twice as many cases are diagnosed in women as in men. The lesion is typically diagnosed between the ages of 30 and 60, but it can arise at any age.  As many as 15% of patients will have granular cell tumors of multiple anatomic sites, with as many as 50 individual lesions in one patient.

Oral malignant granular cell tumor is rare but has been reported to grow rapidly, to become ulcerated and bosselated, and to achieve a size greater than 4-5 cm. by the time of diagnosis. It usually occurs in young adults.

Alveolar soft part sarcoma of the head and neck region accounts for 25% of all such sarcomas and has a decided predilection for children and young adults, especially females.  More peripheral lesions tend to occur in older individuals. Oral lesions are usually found in the tongue and the typical case is a slowly enlarging, asymptomatic, submucosal mass.

The granular cell of diagnostic necessity is a large polygonal, oval or bipolar cell with abundant, fine or coarsely granular eosinophilic cytoplasm, and a small, pale-staining or vesicular nucleus acentrically located in the cell (Figures 2 and 3). The cell membrane is moderately distinct, and some cells may contain large clumps of the granular cytoplasmic material, perhaps with clear haloes surrounding the clumps. Ultrastructural studies have described the cytoplasmic granules as autophagic vacuoles containing cellular debris, including mitochondria and fragmented endoplasmic reticulum, as well as myelin.

Granular cells often occur in ribbons separated by fibrous septa, giving the appearance of infiltrating or "invading" into underlying tissues, especially muscle, with the bipolar shape being more frequently noted at the leading edge (Figure 4). The cells may also appear to be streaming off from or metaplastically arising from underlying muscle fibers. Older lesions tend to become desmoplastic with a few scattered nests of granular cells in a densely fibrotic background.  Granular cells demonstrating nuclear enlargement, hyperchromatism and pleomorphism, or with mitotic activity or increased cellularity, are elements of the malignant variant of this tumor.

The more oval granular cells near the surface tend to occur in broad sheets with minimal background stroma. They have a remarkable resemblance to macrophages and are S-100 protein positive with immunostaining.  Immunohistochemistry will also be reactive for neuron-specific enolase (NSE), laminin and various myelin proteins. Staining is negative for neurofilament proteins and glial fibrillary acidic protein (GFAP). The interstitial cells stain for myelin protein.

The granular cells of oral/pharyngeal lesions typically extend to the surface epithelium, where they often induce a remarkable pseudoepitheliomatous hyperplasia. The pathologist must be very cautious about misdiagnosing this as well-differentiated squamous cell carcinoma and, almost by definition, a carcinoma-like surface lesion with underlying granular cells should be considered to be a benign, reactive change. No granular cell tumor of the mouth has yet been associated with a true squamous cancer and the lingual dorsum is one of the oral sites least likely to develop such a cancer. The inductive mechanism responsible for the pseudoepitheliomatous hyperplasia is poorly understood, but it is seen in several other head and neck lesions, most notably histoplasmosis and other deep fungal infections, median rhomboid glossitis (posterior atrophic candidiasis), and keratoacanthoma.

The malignant granular cell tumor has two distinct variations or subtypes. The first variant has a benign histopathology, not different from a typical granular cell tumor except for increased mitotic activity and mild nuclear pleomorphism. The clinical features of large size, rapid growth and surface ulceration must, therefore, be used to arrive at a malignant diagnosis, and the pathologist should carefully evaluate the lesional periphery for signs of true invasion. The second variant shows transition from typical benign granular cells to pleomorphic granular cells to pleomorphic nongranular spindle cells and giant cells with numerous mitotic figures. Malignant granular cell tumors are often negative for immunoreactivity for S-100 protein, NSE and vimentin.

The histopathology of alveolar soft part sarcoma is remarkably uniform from one tumor to the next, being characterized by organoid or nestlike clusters of epithelioid cells with a central loss of cellular cohesion resulting in a pseudoalveolar pattern.  Cell nests are separated by thin-walled, sinusoidal vascular spaces. While the clusters vary somewhat in size, they do not demonstrate the irregular alveolar pattern of alveolar rhabdomyosarcoma. The lesional cell is large and polygonal with a distinct cell border, a vesicular nucleus, and dense, abundant granular, eosinophilic or vacuolated cytoplasm. There is minimal variation in size and shape between cells and mitotic activity is sparse. Vascular invasion is a frequent finding. Reticulin stains will enhance the organoid arrangement of the tumor cells and the cells typically contain PAS-positive, diastase-resistant rod-shaped crystals.

Conservative excision is the treatment of choice for granular cell tumor. Recurrence is seen in fewer than 7% of cases thus treated, even if granular cells extend beyond the surgical margins of the biopsy sample.  A few reported metastasizing granular cell tumors have appeared to be histologically benign, and for this reason, tumors which recur, grow rapidly or reach a size greater than 5 cm. should be viewed with grave suspicion.

The malignant granular cell tumor and the alveolar soft part sarcoma are treated by wide surgical excision, but lung, brain and skeletal metastases tend to occur early and frequently in the former lesion, while occurring much later in the alveolar soft part sarcoma. Oral lesions carry a better prognosis than those elsewhere and the overall 5-year survival rate is approximately 65%.

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