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Merkel cell carcinoma (MCC) is an uncommon cutaneous neuroendocrine carcinoma that requires confirmation by immunohistochemical stains to exclude histological mimics such as melanoma. Here we report a unique case of MCC that showed nuclear SOX10 staining, which, to the knowledge of the authors, is a phenomenon not previously described in the literature, and a potential diagnostic pitfall.
A 72-year-old female was referred to our hospital's plastics surgery unit for excision of a lesion on the nasal dorsum. The patient's medical history was notable for seropositive rheumatoid arthritis, previous basal cell carcinoma of the head and neck region, Barrett's oesophagus, hypercholesterolaemia and cigarette smoking (active smoker, greater than 100 pack year history). Medications included methotrexate, folic acid, hydroxychloroquine, prednisolone and aspirin.
The excised skin specimen (20×17×13 mm) showed a central, pale brown nodule measuring 15×13 mm. Microscopically, the nodule corresponded to a largely solid tumour infiltrating the dermis, subcutis and skeletal muscle as sheets, cords and nests, to a thickness of 9 mm (Fig. 1). The tumour cells were hyperchromatic basophilic cells possessing fine and coarse chromatin with small distinct nucleoli, high nucleus-cytoplasm ratios, scattered apoptotic bodies and mitotic figures. Some tumour nests were intimately associated with lymphocytes. No lymphovascular invasion, perineural infiltration or satellitosis was identified.
Fig. 1H&E stains showing tumour morphology at low (A), medium (B) and high power (C).
On immunohistochemistry, the tumour cells showed diffuse strong staining with AE1/AE3, CK20 (with focal perinuclear dot-like staining pattern) and EMA. Convincing neuroendocrine marker expression was present, including synaptophysin (diffuse, moderate staining), chromogranin (patchy but strong expression), INSM1 (variable intensity in the majority of tumour cells) and CD56 (scattered tumour cells). Merkel cell polyomavirus immunohistochemistry was negative, while diffuse moderate to strong staining (retained expression) was seen with Rb1 (pRb). Variable SOX10 staining (SP267 clone, Rabbit Monoclonal Primary Antibody; Cell Marque, USA) was seen in approximately half of the tumour cells, particularly at the periphery of cell clusters; notably, staining was significantly weaker than the positive internal controls (Fig. 2). A different SOX10 clone (EP268, Rabbit Monoclonal Antibody; Cell Marque) also showed variable weak to moderate nuclear staining in up to 5% of cells. No morphological difference was seen in the areas of SOX10 positivity. The tumour cells were entirely negative for S100, HMB-45, Melan-A and TTF-1.
Fig. 2SOX10 immunohistochemical stains using SP267 clone (A) and EP268 clone (B), highlighting strong nuclear staining in normal intradermal melanocytes contrasting with variable nuclear staining of tumour cells, with insets of corresponding H&E.
A diagnosis of Merkel cell carcinoma was made based on the overall morphological and immunohistochemical findings. The patient received local radiotherapy, with no clinical recurrence 1-year post-surgery.
MCC is a high grade primary neuroendocrine carcinoma of skin. It predominantly affects the head and neck region of elderly Caucasian males,
and is seen at disproportionately high rates in those on long term immunosuppression (such as our patient) and those with lymphoproliferative disorders.
Tumourigenesis is divided into two groups: those driven by Merkel cell polyomavirus (MCPyV) DNA integration, and those that are primarily related to ultraviolet (UV) radiation exposure.
Immunohistochemistry for Merkel cell polyomavirus is highly specific but not sensitive for the diagnosis of Merkel cell carcinoma in the Australian population.
Immunohistochemistry for Merkel cell polyomavirus is highly specific but not sensitive for the diagnosis of Merkel cell carcinoma in the Australian population.
Histologically, it has the appearance of a ‘small round blue cell tumour’, with sheets and nests of crowded monomorphic basaloid cells, typically centered in the dermis. The cells typically possess finely granular soi-disant salt and pepper chromatin characteristic of neuroendocrine tumours and have scant cytoplasm. Numerous mitotic figures and necrosis are common, reflecting the high grade nature of the tumour. Of note, tumours can show areas of divergent differentiation, including squamous and sarcomatoid patterns, mostly reported in tumours lacking MCPyV association.
Immunohistochemical stains are required to distinguish MCC from its histological differential diagnoses, which include metastatic small cell carcinoma, basal cell carcinoma, melanoma, lymphoma and other rarer small round blue cell tumours (such as Ewing's sarcoma and neuroblastoma). The characteristic expression profile is that of CK20 with perinuclear dot-like staining or diffuse cytoplasmic staining, and neuroendocrine marker expression (synaptophysin, chromogranin, CD56), although the latter may lack specificity.
Sox10—a marker for not only schwannian and melanocytic neoplasms but also myoepithelial cell tumors of soft tissue: a systematic analysis of 5134 tumors.
It shows strong nuclear staining in nerve sheath and melanocytic neoplasms but is not specific for these tumour types since it is also expressed in myoepithelial or basal cell-related neoplasms;
Sox10—a marker for not only schwannian and melanocytic neoplasms but also myoepithelial cell tumors of soft tissue: a systematic analysis of 5134 tumors.
Sox10—a marker for not only schwannian and melanocytic neoplasms but also myoepithelial cell tumors of soft tissue: a systematic analysis of 5134 tumors.
These cases included a 93-year-old male patient with MCC of the hand and a 62-year-old male patient with MCC of the arm. It is not known if these were UV-driven or polyomavirus-driven.
Our case also showed an unexpected finding of SOX10 staining. In contrast to previously reported cases, expression of SOX10 in our cases was nuclear and heterogeneous, and this was seen with two different clones. Other immunohistochemical stains, including diffuse CK20 staining with focal perinuclear dot-like staining, positive neuroendocrine markers (synaptophysin, chromogranin, CD56, INSM1) and diffuse strong staining with a pan-cytokeratin (AE1/3), were all characteristic of MCC and strongly supported the diagnosis. Lack of MCPyV positivity on immunohistochemistry suggests a UV radiation-driven pathogenesis in this tumour. Other melanocytic markers (S100, HMB-45, Melan-A) and a marker for metastatic small cell carcinoma (TTF-1) were negative, therefore excluding mimics and further supporting the diagnosis of MCC.
To the knowledge of the authors, this is the first report of nuclear SOX10 staining in MCC. This is an important finding to report since melanoma is frequently in the histological differential diagnosis for MCC, and SOX10 is often employed to exclude melanoma. Our case adds to the literature on unexpected SOX10 staining in Merkel cell carcinoma and highlights that reliance solely on SOX10 immunohistochemistry in the differential diagnosis of MCC versus melanoma may be a potential diagnostic pitfall. Therefore, SOX10 staining should be interpreted with caution and in the context of other morphological and immunohistochemical findings. The significance of this finding in relation to biological tumour behaviour (if any) is unclear; further case studies and series may reveal a currently undetermined utility and significance.
Conflicts of interest and sources of funding
The authors state that there are no conflicts of interest to disclose.
References
Albores-Saavedra J.
Batich K.
Chable-Montero F.
et al.
Merkel cell carcinoma demographics, morphology, and survival based on 3870 cases: a population based study.
Immunohistochemistry for Merkel cell polyomavirus is highly specific but not sensitive for the diagnosis of Merkel cell carcinoma in the Australian population.
Sox10—a marker for not only schwannian and melanocytic neoplasms but also myoepithelial cell tumors of soft tissue: a systematic analysis of 5134 tumors.
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