Practice Essentials
Granular cell tumors (GCTs), also known as Abrikossoff tumors, are rare soft-tissue neoplasms that probably derive from Schwann cells, which are glial cells that surround neurons of the peripheral nervous system. [1, 2] These neoplasms can occur at any site, but most develop in the oral cavity, skin, and gastrointestinal tract. [3] Up to 10% are multifocal. [4] Most granular cell tumors are benign, although some may be locally aggressive. [5] Less than 2% are malignant, but these are aggressive and associated with a poor prognosis. [6, 7]
Granularity of the cells in these tumors 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.
Granular cell tumors of the mucosa and skin typically present as a firm, sometimes pigmented nodule. [8] The nodules are nonulcerated and usually painless, with an insidious onset and slow growth rate. See Presentation for more detail. Diagnosis of granular cell tumors centers on analysis of biopsy specimens; see Workup for more detail. Treatment is with surgical resection; radiation and chemotherapy are not needed for benign lesions and are not effective for malignant lesions. However, treatment with pazopanib may be considered in such cases. [9] See Treatment for more detail.
Etiology and Pathophysiology
Granular cell tumors are typically solitary and smaller than 3 cm. Up to 10% of granular cell tumors are multifocal (ie, two to four lesions). [4] Granular cell tumors are usually located in the dermis or subcutis and less frequently in the submucosa, smooth muscle, or striated muscle. They 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. [10]
Pareja et al identified loss-of-function mutations in ATP6AP1 or ATP6AP2 in 72% of granular cell tumors. Silencing of these genes in vitro results in impaired vesicle acidification, redistribution of endosomal compartments, and accumulation of intracytoplasmic granules, which are cardinal phenotypic characteristics of granular cell tumors. [11] Following whole-exome sequencing, RNA sequencing, and targeted sequencing of 51 granular cell tumor samples, Sekimizu et al reported identified loss-of-function mutations in 7 additional genes encoding vacuolar H+ -ATPase (V-ATPase) components. [12] Dehner et al reported that multifocal granular cell tumors in an individual patient are molecularly distinct; in some of these cases, different tumors may carry mutually exclusive mutations. [4]
Immunohistochemical study of 22 granular cell tumors by Kneitz et al reported moderate to strong staining for connexin 43 (Cx43) in all cases. Cx43 is the most broadly expressed gap junction protein, and elevated Cx43 levels have been demonstrated in a variety of skin and other tumors. These authors concluded that Cx43 may play an important role in the development of granular cell tumors. [1]
Epidemiology
Frequency
Granular cell tumors are uncommon. Exact figures are unavailable. Much of the literature on this neoplasm consists of reports of single cases.
Race-, sex-, and age-related demographics
Granular cell tumors appear to be more common in Black persons. Multiplicity of lesions is definitely more common in Black persons.
A slight female predominance exists. The female-to-male ratio is estimated at approximately 3:2. [10]
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. [3]
Prognosis
The prognosis for patients with granular cell tumors is as follows [10] :
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With benign lesions, recurrence rates are 2-8%, even when the resection margins are deemed free of tumor infiltration; recurrence rates are around 20% when the margins are positive for tumor.
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Malignant lesions are aggressive and difficult to eradicate with surgery. Local recurrences are as high as 32%, and metastases have been reported in half of the patients. Metastases are usually detected within 2 years.
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Of patients with malignant granular cell tumors, 39% die of the disease within 3 years after detection of the primary tumor.
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Adverse histopathologic prognostic factors include presence of necrosis, increased mitotic activity, spindling of tumor cells, vesicular nuclei with large nucleoli, and Ki-67 immunoreactivity of 10% or more tumor cells.
The main complication of benign lesions is recurrence. With malignant granular cell tumors, the main complications are recurrence, metastases, or both.
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Granular cell tumor simulating squamous cell carcinoma.
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Granular cell tumor underneath the squamous epithelium.
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S-100 immunohistochemical stain.
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Granular cell tumor. Typical histology.
