Granular Cell Tumors 

Updated: Dec 29, 2018
Author: Vladimir O Osipov, MD; Chief Editor: E Jason Abel, MD 

Overview

Practice Essentials

Granular cell tumors (GCTs), also known as Abrikossoff tumors, are rare soft-tissue neoplasms probably derived from Schwann cells.[1, 2]  

Most granular cell tumors are benign, although some may be locally aggressive.[3]  Less than 2% are malignant, but these are aggressive and associated with a poor prognosis.[4, 5]

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.

This article describes neural granular cell tumors. Non-neural granular cell tumors are discussed only as differential diagnoses.

Pathophysiology

Granular cell tumors are typically solitary and smaller than 3 cm. They are usually 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.[6]

Epidemiology

Frequency

The lesion is uncommon. Exact figures are unavailable. Much of the literature on granular cell tumors consists of reports of single cases.

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, two to four lesions).

Race-, sex-, and age-related demographics

A slight female predominance exists. The female-to-male ratio is estimated at approximately 3:2.[6]

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.

 

Presentation

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

Granular cell tumors may occur at any site, but easily noticed surface lesions (ie, head, neck, trunk, extremities) are far more common than visceral lesions. Other aspects of location are as follows:

  • 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 of those are in the parenchyma

  • Origin in skeletal muscle is rare

  • The lesions usually involve small- to medium-sized cranial or spinal nerves, although neurologic deficit is rare

  • Visceral involvement is encountered as mucosal or submucosal nodules in the esophagus,[7, 8] stomach, small and large intestines, larynx, bronchi, gallbladder, and biliary tract

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

  • Central nervous system granular cell tumors are extremely rare[9]

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

Nodules are usually solitary but may be multiple in up to 10% of cases (patients with 26 and 52 tumors are on record). Multiple granular cell tumors have been reported in patients with LEOPARD (lentigenes, electrocardiographic conduction anomalies, ocular hypertelorism, pulmonary stenosis, abnormalities of genitalia, retardation of growth, deafness) syndrome (Noonan syndrome), a rare autosomal dominant, disorder caused by a mutation in the protein tyrosine phosphatase, nonreceptor type 11 gene (PTPN11).[2, 10]

An association between multiple cutaneous granular cell tumors and neurofibromatosis has been suggested, but remains unproven.[11]

Malignant lesions

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.

Causes

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.[12]

 

DDx

Diagnostic Considerations

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

  • In submucosal granular cell tumors (eg, tongue, larynx, vulva), pseudoepitheliomatous hyperplasia of the overlying squamous epithelium may be misdiagnosed as squamous cell carcinoma.[13]  Coexistent granular cell tumors and squamous cell carcinomas of the head and neck have also been reported.[14]

  • 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. Cytologically, however, granular cell tumors are distinguished by the presence of eosinophilic cytoplasmic granules and small round nuclei with dense chromatin. See the images below.

Granular cell tumor simulating squamous cell carci Granular cell tumor simulating squamous cell carcinoma.
Granular cell tumor underneath the squamous epithe Granular cell tumor underneath the squamous epithelium.
S-100 immunohistochemical stain. S-100 immunohistochemical stain.
 

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

Imaging Studies

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

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]

Histologic Findings

See the image below.

Typical histology. Typical histology.

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.

 

Treatment

Approach Considerations

Treatment is with surgical resection. With benign granular cell tumors, local surgical excision is curative, if complete resection is achieved; however, recurrence is possible even withclear margins. Wide en bloc excision is recommended for malignant lesions.

Radiation and chemotherapy are not needed for benign lesions and are not effective for malignant lesions. However, case reports describe response to pazopanib in patients with metastatic disease.[4]

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.

 

Follow-up

Complications

The main complication of benign lesions is recurrence. With malignant granular cell tumors, the main complications are recurrence, metastases, or both.

Prognosis

Prognosis for patients with granular cell tumors is as follows[6] :

  • In benign lesions, recurrence rates are 2-8%, even when the resection margins are deemed free of tumor infiltration; they are around 20% when the margins are positive for tumor.

  • Malignant lesions are aggressive and difficult to eradicate with surgery. Local recurrences are as high as 32%, and metastases were reported in half of the patients. Metastases are usually detected within 2 years.

  • Of patients with malignant granular cell tumors, 39% die of the disease within 3 years after detection of the primary tumor.

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

 

Questions & Answers

Overview

What are granular cell tumors (GCTs)?

What is the pathophysiology of granular cell tumors (GCTs)?

What is the prevalence of granular cell tumors (GCTs)?

Which patient groups have the highest prevalence of granular cell tumors (GCTs)?

Presentation

Which clinical history findings are characteristic of granular cell tumors (GCTs)?

Where are granular cell tumors (GCTs) located?

Which physical findings are characteristic of granular cell tumors (GCTs)?

Which physical findings are characteristic of malignant granular cell tumors (GCTs)?

What causes granular cell tumors (GCTs)?

DDX

What should be considered in the diagnosis of granular cell tumors (GCTs)?

Workup

How are granular cell tumors (GCTs) diagnosed?

What is the anatomic pathology of granular cell tumors (GCTs)?

Which immunohistochemical findings are characteristic of granular cell tumors (GCTs)?

Which findings on ultrasound are characteristic of granular cell tumors (GCTs)?

What are gingival granular cell tumors (GCTs)?

What are primitive polypoid granular cell tumors (GCTs)?

Which gross and microscopic features are characteristic of malignant granular cell tumors (GCTs)?

Which is the role of imaging studies in the workup of granular cell tumors (GCTs)?

What is the role of endoscopy in the workup of granular cell tumors (GCTs)?

Which histologic findings are characteristic of granular cell tumors (GCTs)?

How are granular cell tumors (GCTs) staged?

What are the pathologic differential diagnoses of granular cell tumors (GCTs)?

Treatment

How are granular cell tumors (GCTs) treated?

What is the role of surgery in the treatment of granular cell tumors (GCTs)?

Which specialist consultations are beneficial to patients with granular cell tumors (GCTs)?

Follow-up

What are the possible complications of granular cell tumors (GCTs)?

What is the prognosis of granular cell tumors (GCTs)?