SOX10 Dot-Like Paranuclear Positivity in Merkel Cell Carcinoma

Abstract

To the Editor: Merkel cell carcinoma (MCC) is a rare primary neuroendocrine tumor of the skin that is categorized into Merkel cell polyomavirus positive and negative lesions.1 MCC typically shows a malignant small round blue cell morphology, and although not by any means specific, the tumor has a characteristic dot-like paranuclear CK20 staining pattern. Electron microscopy studies have shown that these CK20 + paranuclear structures are composed of intermediate filaments.2 In this article, we present 2 cases of MCC with perinuclear dot-like expression of SOX10. The first patient was a 93-year-old man with advanced dementia who initially presented with painful rapidly growing soft-tissue lesions involving the left elbow, left index finger, and anatomical snuffbox of the left hand. A biopsy of the index finger at the time was consistent with MCC (Figs. 1A, B). The lesion had positive immunohistochemical staining for CD56, dot-like staining for neurofilament and CK20 (Fig. 1C), whereas CK7, TTF1, desmin, and S100-protein were negative. A positron emission tomography–computed tomography at the time of diagnosis was concerning for metastasis to the epitrochlear lymph node. Given his poor functional status, the clinical team opted for palliative radiation therapy without any additional treatment, and he died 6 months after the diagnosis was rendered. The second patient was a 62-year-old man with enlarging masses of 1 year duration at the right elbow, axilla, and dorsal arm. A biopsy of the right axilla was consistent with MCC (Figs. 2A, B). The lesion had immunohistochemistry positive for CD56 and synaptophysin and dot-like positivity for CK20 (Fig. 2C) and neurofilament, whereas CK7, CD99, TTF1, desmin, and P63 were negative. Imaging at the time of diagnosis was concerning for involvement of the right axillary and epitrochlear lymph nodes. After receiving radiation therapy and 12 cycles of Avelumab, he remains in remission approximately 6 months since the diagnosis was rendered. In both cases, SOX10 (Rabbit Polyclonal Primary Antibody, prediluted; Cell Marque, Rocklin, CA) was ordered as part of the initial diagnostic workup, and although not a diagnostic pitfall as only nuclear reaction is considered positive, the perinuclear dot-like staining pattern (Figs. 1D and 2D) was a peculiar observation that we have not encountered before and has not been previously reported in the literature.FIGURE 1.: Patient 1, (A) low power [hematoxylin and eosin (H&E) stain, ×40], (B) medium power (H&E stain, ×200), (C) medium power (CK20 stain, ×200), (D) medium power (SOX10 stain, ×200) demonstrating perinuclear dot-like positivity.FIGURE 2.: Patient 2, (A) low power (H&E stain, ×40), (B) medium power (H&E stain, ×200), (C) medium power (CK20 stain, ×200), (D) medium power (SOX10 stain, ×200) demonstrating perinuclear dot-like positivity.The SOX10 gene is a member of the SRY-related HMG-box family, which has roles in the development and specification of neural crest cells and the maintenance of both Schwann cells and melanocytes. SOX10 is typically negative in both MCC and in cells infected with the Merkel cell polyomavirus.3 Although perinuclear dot-like SOX10 staining has not been reported in MCC, it has been noted in colorectal carcinoma, in a series performed by the anti-SOX10 manufacturer Cell Marque.4 The exact mechanism for the perinuclear dot-like staining in our cases is unclear. Recently, 2 studies documented dot-like CD99 expression in 14/14 (100%)5 and 16/33 (48%)6 cases of MCC, respectively. It is unclear whether the paranuclear SOX10 staining pattern we observed is mechanistically related to either CD99 or CK20 paranuclear dot-like staining patterns because none of the stains have an obvious correlate. A CD99 stain obtained in one of the cases presented here showed a membranous staining pattern, dissimilar from the dot-like pattern described in the aforementioned studies. Proposed mechanisms in the case of CD99 have included staining of the Golgi apparatus, cross-reactivity with intermediate filaments, or antigen mix-reactivity.7 Indeed, similar mechanisms have been proposed for CD99 perinuclear dot-like staining pattern seen in other lesions including serous carcinoma of the endometrium with Ewing sarcoma/peripheral primitive neuroectodermal tumor differentiation,8 solid pseudopapillary tumor of the pancreas,9 colonic adenomas and adenocarcinomas,7 and anaplastic large-cell lymphoma.10 It is possible that perinuclear dot-like staining of SOX10 in MCC is an underreported phenomenon. Although not a diagnostic pitfall, it is mechanistically an interesting observation.