Fine-needle aspiration cytology of granular cell tumor: A report of two cases.

Granular cell tumors (GCTs) are uncommon soft tissue tumors, which are difficult to diagnose merely on clinical examination. Being an effective first-line investigation, the fine-needle aspiration cytology (FNAC) plays a significant role in its pre-operative recognition. However, as the tumor is likely to mimic certain other lesions, a cytopathologist needs to be aware of its characteristic cytomorphology. We report two cases of GCT who presented with subcutaneous swellings in the left lower back and the right-sided anterior abdominal wall for 6 and 2 months, respectively. Both the patients had a clinical diagnosis of lipoma/neurofibroma. FNAC was done in both. In the first case a cytodiagnosis of xanthogranuloma was suggested and GCT in the second. Subsequent histologic examination of both showed features of GCT. FNAC would aid in presumptive diagnosis of GCT.

Introduction

Granular cell tumors (GCT), previously referred to as ‘granular cell myoblastoma’ are rare mesenchymal tumors, comprising about 0.5% of all soft tissue tumors. These slow-growing, benign tumors of neural origin occur anywhere in the body are generally asymptomatic, usually solitary, although rarely multifocal.[1] The tongue is the most common site. Other sites are chest wall, upper extremities, skin and subcutaneous tissue, vulva, breast, larynx, bronchus, gastrointestinal tract, anus, bile ducts, pancreas, urinary bladder, uterus, brain, pituitary gland and soft tissues.[2]

GCT is treated by simple surgical excision, but its pre-operative diagnosis is inaccurate in most cases. Moreover, the cases that present as skin nodules or breast masses are likely to raise the suspicion of malignancy,[34] stressing the need for its accurate pre-operative recognition. As a simple, inexpensive, first-line investigative modality fine-needle aspiration cytology (FNAC) can play a major role,[5] and therefore a cytopathologist should be aware of the characteristic cytological features of this tumor.[678]

Case Reports

Case 1

A 37-year-old female presented with swelling over the left lower back for 6 months, and pain for 2 months. The swelling was firm, tender and measured 2.5 × 2.5 cm. The lesion was clinically diagnosed as a lipoma.

Case 2

A 53-year-old female presented with a subcutaneous swelling in the anterior abdominal wall, below the right costal margin for 2 months. It was firm, non — tender and measured 3 × 2 cm. A clinical differential diagnosis of neurofibroma and lipoma was considered.

In both the patients, a palpation-guided FNAC was performed. The smears were stained with May–Grünwald–Giemsa (MGG) stain and Papanicolaou method. Periodic acid-Schiff (PAS) stain was done on one of the air-dried smear of case-2. Subsequently, both the patients underwent excisional biopsy. The histological sections were stained with hematoxylin and eosin (H and E) and PAS stains, and immunohistochemistry (IHC) performed with S-100, CD-68 and neuron specific enolase (NSE).

Cytological Findings

Smears from case-1 showed large numbers of histiocytoid cells arranged in clusters, and lying singly with bland, round nuclei, uniformly distributed chromatin, and moderate-to-abundant, granular cytoplasm with indistinct cell borders and bare nuclei exhibiting minimal pleomorphism, along with a few neutrophils and lymphocytes in a blood-mixed lipoid background. The possibility of a xanthogranuloma was considered [Figure 1a–c], and biopsy was advised. Aspirate from case-2 showed somewhat similar features [Figure 1d] and cytoplasm revealed intense PAS-positive granularity. A diagnosis of ‘GCT’ was given.

Figure 1

FNA smear from case-1 (a) showing clusters and scattered, singly lying cells (MGG stain, ×100), (b) cells with histiocytoid appearance, indistinct cytoplasm (MGG, ×400), (c) singly scattered cells in a lipoid background (MGG, ×400), (d) smear from case-2 showing clusters of round-to-polygonal cells with abundant granular cytoplasm (MGG, ×400)

Histopathological Findings

Histological sections showed sheets of polygonal cells exhibiting eosinophilic, granular cytoplasm, and vesicular nuclei, some of them showing prominent nucleoli, separated by intervening fibrous septae [Figure 2]. The tumor cells were intensely PAS-positive (Inset of Figure 2a) and IHC revealed strong immunoexpression of S-100 protein, CD68, and NSE in both the cases (Inset of 2b–d) consistent with ‘GCT’.

Figure 2

Histologic section showing sheets of granular cells separated by fibrous septae (H and E, ×200) Inset, (a) shows PAS-positive cytoplasmic granules in neoplastic cells (PAS, ×400), inset (b-d) positive expression of S-100, CD 68 and NSE respectively (IHC, x200)

Discussion

GCTs primarily affect adults with a female predilection between the second and the sixth decades. They may also occur in children. Malignant GCT is rare and it is often difficult to distinguish from benign GCT.[9] GCTs of the subcutaneous tissue are relatively uncommon. The cytological features of GCT are well-described, and it is important for cytopathologists to be aware of these features.[7] In this context, it is noteworthy that our first case was interpreted as ‘xanthogranuloma’ as we had no previous cytological experience of this distinct entity, while the second case was diagnosed without any dilemma. Our experience of the first case, prompted us to use the PAS stain in the second case, which provided additional clue to the diagnosis. Naresh et al.[4] reported a case of GCT clinically suspected as breast cancer which was interpreted as a histiocyte-rich benign lesion of inflammatory origin on FNAC, which is similar to our first case. Clinical features of GCT are non-specific, which were evident in our cases as well. A correct pre-operative cytologic diagnosis obviates the need for biopsy.[10]

The differential diagnosis of GCT on FNAC includes malignant GCT, alveolar soft part sarcoma (ASPS), rhabdomyoma, histiocyte-rich lesion, metastatic carcinoma, epithelioid sarcoma, and melanoma. GCT of the breast are likely to be mistaken for apocrine metaplastic cells.[261112] The characteristic cytological features described for GCT are similar to those of our cases. Cases of GCT with intranuclear inclusions and cell clusters showing thin walled intersecting capillaries have also been documented.[67] As shown in our cases, both on cytology and histology, GCTs are PAS-positive, and immunohistochemically express S-100, NSE and CD68 indicating their neural origin.

Malignant GCT differs from benign GCT in that it exhibits necrosis, mitotic activity and nuclear atypia. ASPS also show cells with granular cytoplasm which are PAS-positive, with abundant cytoplasmic needle-like pink-colored, crystal and diastase-resistant granules.[12] Kim et al.[13] stressed the diagnostic value of transcription factor 3 (TFE3) immunostain for ASPS. Rhabdomyoma cells exhibit abundant eosinophilic cytoplasm, where special stains for skeletal muscle are of diagnostic assistance. Histiocytes are distinguished from GCT-cells in that they show bean-shaped nuclei. In GCT of the breast CD68 is positive, as these tumors are likely to arise from schwann cells and negative in apocrine metaplastic cells. S-100 protein is positive in GCT as they are closely associated with nerves.[912] GCT cells are negative for antibodies to cytokeratins AE1, AE3, desmin, MyoD1, myogenin, HMB-45, melan-A and MART-1, which helps to exclude metastatic carcinoma, epithelioid sarcoma, ASPS, and melanoma.[211]

Smith et al.,[14] while reporting a case of GCT of mediastinum, where the possibility of a benign neural tumor with granular cell features was considered, stressed the importance of combining FNAC with other ancillary studies for accurate diagnosis in unusual locations.

Conclusions

GCTs are rare and occur in a wide variety of sites with a wide spectrum of differential diagnoses that vary according to the site of occurrence. A cytopathologist has to be aware of their cytomorphologic features and differential diagnosis. A simple PAS stain is of great help in most cases. In difficult situations, judicious use of relevant markers on a cell block will be contributory to its final diagnosis.