|Year : 2014 | Volume
| Issue : 5 | Page : 417-419
Red flag in granular cell tumors: Role of a pathologist
A Hemalatha1, Priya T Rajan1, CSBR Prasad1, M Ambikavathy2
1 Department of Pathology, Sri Devaraj Urs Medical College, Tamaka, Kolar, Karnataka, India
2 Department of Surgery, Sri Devaraj Urs Medical College, Tamaka, Kolar, Karnataka, India
|Date of Web Publication||5-Aug-2014|
Department of Pathology, Sri Devaraj Urs Medical College, Tamaka, Kolar, Karnataka
Source of Support: None, Conflict of Interest: None
Granular cell tumors (GCTs) are uncommon mesenchymal tumors of Schwann cell origin with malignant potential. A 50-year-old female presented with the complaints of swelling in right thigh since 1 year, associated with pain for 4 months. After clinical examination, imaging and histopathological examination diagnosis of malignant granular cell tumor (M-GCT)-Grade 1 (WHO grading of soft tissue tumors), stage-pT 2b N x M x was made. On immunohistochemistry tumor cells were positive for S-100 and Ki-67 expression was increased (>10%), confirming the histopathological diagnosis. M-GCTs though rare, are associated with local recurrence and metastasis. A thorough histopathological examination, grading and immunohistochemistry analysis is crucial for differentiation from benign soft tissue tumors. Fanburg-Smith et al. grading may aid in differentiating benign, atypical, and malignant variants. This case is reported for its rarity and to stress upon the importance of diagnosing malignancy in GCTs.
Keywords: Fanburg-Smith grading, Ki-67, malignant granular cell tumor
|How to cite this article:|
Hemalatha A, Rajan PT, Prasad C, Ambikavathy M. Red flag in granular cell tumors: Role of a pathologist. Clin Cancer Investig J 2014;3:417-9
| Introduction|| |
Soft tissue tumors are a group of neoplasms with varied appearances and prognostic potential. Among these tumors, granular cell tumors (GCTs), first described by Abrikossoff in 1926, are uncommon mesenchymal neoplasms of Schwann cell origin.  The benign counterpart of these tumors (B-GCTs) are known to occur throughout the body: In the head and neck region, the most common site is the tongue. Skin, subcutaneous tissue of trunk and upper extremities, breast, and female genital tract are the other sites of the tumor. ,,,,
Granular cell tumors are known to have malignant potential, and therefore a cautious and careful approach in diagnosis is of utmost importance malignant granular cell tumors (M-GCTs) were first described by Ravich et al. in 1945 and they constitute 1-2% of all GCTs. ,
Though metastasis is an important criterion to differentiate between benign and M-GCTs, even high grade tumors may not metastasize, making it difficult to differentiate between the two at the time of initial diagnosis. 
This differentiation is important as M-GCT should be treated by wide local excision with local lymph node sampling if any.
| Case report|| |
A 50-year-old woman presented to the surgical outpatient department of our hospital with a history of a swelling in her right thigh since over a year. It was associated with pain for the past 4 months. She did not complain of any restriction of mobility or paresis.
On clinical examination, a swelling in the anterolateral aspect of the right thigh measuring 15 cm × 10 cm × 5 cm was seen. The swelling was mobile, and firm in consistency.
Magnetic resonance imaging of the right thigh revealed a well lobulated soft tissue mass arising from the vastus lateralis and vastus intermedius without involving the bone. On fine-needle aspiration of the swelling, a diagnosis of fibroma was made. On a strong clinical suspicion of soft tissue sarcoma, wide local excision of the tumor was done, along with a part of the vastus lateralis and vastus intermedius, and sent to us.
On gross examination, a skin covered fibrofatty mass measuring 15 × 10.5 × 6 cm was seen.
The cut section revealed a grey-white irregular tumor measuring 8.5 × 8 × 4.5 cm. The tumor borders were irregular, the closest margin being 0.5 cm away from the surgically resected margin [Figure 1]a and b.
|Figure 1: (a) Cut section of grey-white irregular tumor measuring 8.5 × 8 × 4.5 cm surrounded by fibrofatty tissue. (b) The tumor borders were irregular, the closest margin being 0.5 cm away from the surgically resected margin|
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On histopathological examination, the tumor showed sheets of round to polygonal tumor cells with granular cytoplasm, round to oval vesicular nucleus with very prominent nucleoli. Mitotic index was 2-3 mitotic figures/10 high power fields. There were intracytoplasmic and extracellular eosinophilic globules. At the periphery of the tumor, infiltration into adipose tissue was seen. No necrosis/hemorrhage/lymphovascular invasion was seen [Figure 2]a and b. On immunohistochemistry, tumor cells were positive for S-100. Proliferation rate as determined by Ki-67 was over 10% [Figure 3]a and b.
|Figure 2: (a) Sheets of round to polygonal tumor cells with granular cytoplasm, round to oval vesicular nucleus with very prominent nucleoli (H and E, ×40). (b) Periphery of the tumor showing infiltration into adipose tissue (H and E, ×100)|
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|Figure 3: (a) Tumor cells positive for S-100 (immunohistochemistry [IHC], ×40). (b) Proliferation rate by Ki-67 >10% (IHC, ×40)|
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| Discussion|| |
Though both benign and M-GCT share common epidemiological features such as being more common in females than in males, occurring at the age of 40-69 years, the malignant ones are commonly larger and are frequently localized to the lower limb while the benign tumors are smaller and occur more commonly in the head and neck region and tongue.
On histopathological examination benign granular cell tumors may show features of multicentricity, focal pleomorphism, or recurrence, thereby searching the criteria for diagnosing them as benign. 
In some tumors metastasis to bone, nerve, peritoneal cavity, lung, and breast has been documented. Though metastasis is a definitive feature of malignancy, sometimes even when high grade tumors may not metastasize, and it is imperious to wait for patient to develop metastasis to make a diagnosis of M-GCT. ,,
In view of all these confusion Fanburg-Smith et al.,  described six important histological features to differentiate between malignant and benign granular cell tumors which includes pleomorphism, necrosis, spindling, vescicular nuclei with large nucleoli, increased mitotic activity, increased nucleocytoplasmic ratio.
Sonobe et al. divided M-GCT into two categories: Those that are malignant both histologically and clinically, and those that are benign histologically, but are clinically malignant. The patient in this case report was lost to follow-up and hence the metastasis of the tumor following excision could not be assessed. 
Initially, Abrikosoff suggested that granular cell tumors originate from skeletal muscle cells and so referred to them as myoblastomas; this suggestion probably arose from examination of tumors of the tongue in which infiltration between the striated muscle bundles gave the impression of a muscular origin. Recent studies suggest derivation from Schwann cells of the peripheral nerves, and the presence of S-100 protein supports this. 
All three categories of granular cell tumors display similar light microscopic, ultrastructural and immunohistochemical features. The immunoprofile showed positivity for S-100 and vimentin in almost all cases, as well as identical expression of CD57, NSE and CD68 in most cases.
Characteristic ultrastructural features included lysosomal complexes, interdigitating cytoplasmic processes, and external laminae. 
Statistically significant adverse prognostic features with regard to survival include local recurrences, metastasis, larger tumor size, older patient age, histological classification as malignant, presence of necrosis, increased mitotic activity, spindling of tumor cells, vesicular nuclei with large nucleoli, and Ki-67 values over 10%. 
Time interval between initial diagnosis and metastasis varied widely in different case reports. Crawford and de Bakey  have reported a patient in whom metastasis occurred 14 years after initial treatment. Mullins and Magner  have reported a case of a woman who first had a right flank subcutaneous mass, diagnosed as granular cell tumor, and then developing 2 years later a mass in the contralateral parotid gland. Another report was about a case of M-GCT in the popliteal cavity, which showed a metastatic focus after 2 years of initial diagnosis.
Differential diagnoses to be considered for granular cell tumors include granular cell features in carcinoma, ameloblastic lesions, leiomyoma, leiomyosarcoma, dermatofibroma, dermatofibrosarcoma protuberans, malignant fibrous histiocytoma, malignant peripheral nerve sheath tumor, angiosarcoma, melanoma as well as congenital gingival granular cell tumor. Immunohistochemistry helps in their differentiation. 
The treatment of choice for benign GCT is wide local excision. In the malignant variant, the treatment should additionally include wide local excision with regional lymph node dissection and radiological evaluation for metastasis. Radiotherapy and chemotherapy are used with variable success, but their effectiveness remains unproven. 
| Conclusion|| |
Malignant granular cell tumors can present as a diagnostic dilemma for pathologists, owing to the difficulties in differentiating them from other soft tissue tumors with overlapping features as well as from benign and atypical subtypes. This case is reported for its rarity and to highlight the need for cautious histopathological examination, use of Fanburg-Smith criteria and hence aid the clinicians in appropriate management and treatment.
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[Figure 1], [Figure 2], [Figure 3]