by Dr J. Filipe, Dr D. V. Pereira and Dr S. André
Granular cell tumours of the breast are rare, mostly benign neoplasms derived from Schwann cells. Clinical and radiological features may be worrisome, raising the possibility of malignancy. The only method for diagnosis is histopathological evaluation of the lesion, mandatory for the appropriate management of patients.

Background

Granular cell tumours (GCTs) were first described in the tongue in 1926 by the Russian pathologist Abrikossoff, who suggested a myofibroblastic origin [1]. He also reported the first case of breast GCT in 1932 [2]. The 5th edition of the World Health Organization classification of breast tumors considers GCTs as mostly benign neoplasms with neuroectodermal origin, derived from Schwann cells [3]. Rare cases of granular cell malignant tumours are reported in the literature, associated with poor prognosis with lymph node and lung metastases [4].
Breast tumours represent 8% of all GCTs, which are more common in the head and neck, proximal extremities, gastrointestinal and respiratory tracts [3]. Usually, breast GCTs are single, but as many as 18% can be multicentric [3]. They arise more often in young adult African-American women, with earlier presentation in this population (mean age: 41|years as compared with 54|years in white-Americans) [3].
The majority of cases occur in the upper inner quadrant and it is suggested that GCTs grow through intracanalicular branches of the supraclavicular nerve, around Schwann cells [5].
Most cases are sporadic but breast GCTs have been reported in association with other conditions in Bannayan–Riley–Ruvalcaba syndrome, neurofibromatosis type|1 and Noonan syndrome (also known as LEOPARD syndrome) [3]. There are also reports of breast GCT associated with mastectomy scars and simultaneous GCT and breast carcinoma [3].
Loss-of-function mutations in ATP6AP1 and ATP6AP2 genes, involved in endosomal pH regulation, are frequently found in GCTs, leading to the accumulation of intracytoplasmic granules [3, 6]. These mutations are found irrespective of anatomic localization and are present in both benign and malignant tumours. As loss-of-function mutations in ATP6AP1 and ATP6AP2 genes were not yet described in other tumours, as far as it is known, they seem to be pathognomonic of GCTs [6].

Diagnosis

According to recommendations by EUSOMA (the European Society of Breast Cancer Specialists), in the preoperative phase, histopathology evaluation of core biopsy is the gold standard for GCT diagnosis [5], as clinical and radiological features of breast GCTs mimic breast carcinoma [3, 7].
In fact, GCTs present as irregular firm masses, typically superficial and mobile, but may rarely be adherent to the pectoralis fascia. They may cause skin thickening, retraction and nipple inversion [3]. On mammography, ultrasound and magnetic resonance imaging they are poorly defined masses with spiked margins but no microcalcifications [3, 7]. Despite these features usually associated with carcinomas only 1–2% of breast GCT cases show histological malignant change [3]. It is uncertain if malignant GCTs are malignant transformations from benign lesions or occur ‘de novo’ [4].

Pathologic findings

1. Macroscopic appearance

Grossly, GCTs are white or tan, firm and homogeneous, with regular or spiked margins, that can reach up to 5|cm (Fig.|1) [3].

2. Histopathologic features

Different sampling methods allow histological evaluation of GCTs: (1) needle-core biopsy (Fig.|2a); (2) vacuum-assisted breast biopsy (Fig.|2b); (3) surgical specimens, such as lumpectomies (Fig.|2c).
Histologically, breast GCTs are poorly defined tumours with infiltrative borders (Fig.|2c), composed of sheets, clusters or trabeculae of large, round and polygonal cells, separated by collagenous bands (Fig.|3a). The cells have indistinct borders and may have a syncytial pattern (Fig.|3b).
The hallmark feature is the presence of abundant eosinophilic cytoplasm with granular appearance (Fig.|3b). The nucleus is centrally located and it is usually round, small, hyperchromatic, rarely vesicular and with prominent nucleoli. Mitoses are usually absent. Perineural and perivascular invasion is frequently present. When GCTS are localized in the dermis, they may be associated with pseudoepitheliomatous hyperplasia. In small and superficial cutaneous biopsies, this sometimes can be confused with squamous cell carcinoma [3, 6].
The finely granular cytoplasm is derived from lysosome accumulation. Larger intracytoplasmic granules with clear haloes, named pustulo-ovoid bodies of Milian, are usually periodic acid–Schiff stain (PAS) positive and diastase resistant [3, 6].
The rare malignant GCTs morphologically vary from having a sarcomatous appearance to relatively bland features [6]. The histological criteria suggestive of malignancy are: increased cellularity, spindling, high nuclear to cytoplasm ratio, marked pleomorphism, vesicular nuclei with prominent nucleoli, more than two mitoses per 2|mm2 and geographical necrosis [4]. Larger tumours (>5|cm) and local recurrence are also features favouring malignancy [6].
Differential diagnosis
The histological differential diagnosis of breast GCTs includes reactive histiocytic lesions, dermatofibroma, epithelial tumours such as apocrine neoplasms and invasive carcinomas, melanocytic lesions (nevi and melanoma), hibernoma and alveolar soft part sarcoma [3, 6].
Morphological and immunohistochemical characterization are crucial in the differential diagnosis.
GCTs are strong and diffusely immunoreactive for S100 protein (Fig.|4a), CD68, CD63 antigen and neuron-specific enolase (NSE). The cells are also positive for transcription factor SOX-10 (SOX-10) (Fig.|4b), calretinin and inhibin A, and show diffuse nuclear expression of transcription factor E3 (TFE3) and microphthalmiaassociated transcription factor (MTIF). The cytoplasmatic granules are PAS positive and diastase resistant. Usually, there is no expression of cytokeratins (Fig.|4c), glial fibrillary acidic protein (GFAP), melanoma antigen recognized by T-cells 1 (Melan-A), HMB45- reactive antigen (HMB45), estrogen and progesterone receptors and receptor tyrosine-protein kinase erbB-2 (ERBB2) [3, 6].
S100 protein and SOX-10 are markers of Schwann cells but they may also be expressed in melanocytic lesions and primary breast carcinomas. The absence of cytokeratin expression excludes an epithelial lesion and the absence of Melan-A and HMB45 expression renders less likely a melanocytic lesion.
NSE is also a marker of neuroectodermal cells and is not specific for GCTs.
Inflammatory cells such as histiocytes can express CD68, as well as CD63 antigen; the last may also be present in neural derived tissue.
Dermatofibroma is also a benign infiltrative lesion commonly located at the dermis or subcutis with an identifiable grenz zone. It has spindle cells with scant cytoplasm and elongated nuclei dispersed among collagen bundles. Unlike GCTs, the cells are negative for S100 protein, SOX-10 and NSE.
Hibernoma is a benign, richly-vascularized adipose neoplasm composed by large brown fat cells with eosinophilic or pale multivacuolated cytoplasm that is granular with central nucleus, admixed with white adipose tissue. The cells are also positive for S100 protein, but staining is more variable. Unlike GCT, hibernoma is platelet endothelial cell adhesion molecule (CD31) positive.
Alveolar soft part sarcoma is a rare tumour of the soft tissue. It has an alveolar architecture and it is composed of large epithelioid polygonal cells with granular eosinophilic cytoplasm and prominent nucleoli. It has strong nuclear expression of TFE3, and may be focally positive for S100 protein; however, in contrast to GCTs, the cytoplasm has crystalline material and the cells are positive for actin and desmin. Furthermore, it is characterized by an ASPSCR1-TFE3 fusion gene.

3. Cytology

Fine-needle aspiration (FNA) is often inconclusive. Smears are hypercellular, with large polygonal cells with fragile membranes and abundant eosinophilic granular cytoplasm and small regular nuclei; no stromal or myoepithelial components are present (Fig.|5) [3, 8].
The cytoplasm features can frequently be interpreted as apocrine benign lesions, histiocytic lesions or even apocrine, lobular and secretory invasive carcinomas [3, 8]. In contrast to apocrine cells, the cells of GCTs are larger, with more granular cytoplasm and poorly defined borders. Some cases may also have prominent nuclear atypia. The use of cellblock and immunohistochemistry can be crucial.
Moreover, owing to the rarity of breast GCTs, pathologists lack experience in its cytological evaluation [8]. This method is no longer used for diagnosis of breast GCTs [5, 8].

Treatment

Treatment of GCTs relies on local excision [3, 5]. The best approach is lumpectomy (Fig.|2c) or even excision by vacuum-assisted breast biopsy in small lesions, a relatively safe and minimally invasive procedure (Fig.|2b) [3, 9]. Sentinel lymph node biopsy is not recommended but may be considered in the rare cases of malignant GCTs [5]. Metastasis have been described in 50% of malignant GCTs [6].
The recurrence rate is very low, even when excised with positive margins.
There is no need for adjuvant therapy in the benign cases, but long-term follow-up is recommended [5].

Summary

GCTs of the breast are rare neoplasms with neuroectodermal origin. Despite the fact that they are mostly benign tumours, they can mimic malignancies owing to their clinical and radiological features. Histopathology evaluation is the gold standard for diagnosis. Morphological and immunophenotypical features are characteristic, however differential diagnoses must be kept in mind.
Multidisciplinary approach is essential in breast tumours, and close contact between clinicians, radiologists and pathologists is vital for the correct management of patients.

The authors

Juliana Filipe* MD, Daniela Vinha Pereira MD, Saudade
André MD Serviço de Anatomia Patológica, Instituto Português
de Oncologia de Lisboa Francisco Gentil, Lisboa, Portugal

*Corresponding author
E-mail: jffilipe91@gmail.com