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Background Distinguishing benign nodal nevus from metastatic melanoma can be diagnostically challenging, with important clinical consequences. Recently, the loss of epigenetic marker, 5‐hydroxymethylcytosine (5‐hmC) expression by immunohistochemistry has been found in melanomas and atypical melanocytic neoplasms. Methods About 41 metastatic melanomas and 20 nodal nevi were retrieved. Nuclear 5‐hmC (brown) and cytoplasmic Melan‐A Red (red) double immunohistochemical staining was performed. Results Total or partial loss of nuclear expression of 5‐hmC was noted in 40/41 metastatic melanomas; these tumor cells were strongly positive for Melan‐A Red, except in one case of desmoplastic melanoma. All cases of nodal nevus showed uniformly retained nuclear expression of 5‐hmC accompanied by strong Melan‐A Red cytoplasmic staining. In two cases containing both nodal nevus and metastatic melanoma, all tumor cells were positive for Melan‐A Red, but a nuclear expression of 5‐hmC was selectively absent only in the melanoma tumor cells. Conclusion Dual 5‐hmC/Melan‐A Red immunohistochemistry is highly specific in distinguishing nodal nevus from metastatic melanoma. Our protocol for brown and red chromogens used in this study provides excellent color contrast and is easy to interpret. Furthermore, this dual staining method allows the preservation of limited tumor tissue, which could be used for potential molecular studies.

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A 63-year-old white man with no significant previous medical or surgical history presented with painless jaundice after 3 weeks of dark urine, yellow stools, and a 9-pound weight loss. Bilirubin, aspartate transaminase, alanine transaminase, and alkaline phosphatase were elevated, and a computed tomography scan detected a 10-cm, ill-defined mass at the porta hepatis compressing the common bile duct. He underwent endoscopic retrograde cholangiopancreatography with stenting and ultrasound-guided biopsies. Histologic sections showed a neoplastic population of small ovoid cells with a high N:C ratio, nuclear hyperchromasia, "smoky" chromatin and abundant mitotic figures, and characteristic of high-grade neuroendocrine carcinoma (HGNECA). Immunohistochemistry showed synaptophysin, chromogranin, Golgi pattern CK20 reactivity, and strong diffuse expression of Merkel cell polyomavirus, supporting a diagnosis of Merkel cell carcinoma (MCC). A metastatic workup, including complete skin examination and positron emission tomography scan, revealed no other site of disease. Although this patient fits the classic demographic pattern for MCC, he lacks cutaneous involvement and significant risk factors for MCC including immunosuppression and concurrent or previous malignancy. Histologically, the differential diagnosis in this anatomical site is primary or occult metastatic organ-based small-cell HGNECA. Although pure nodal MCC accounts for a minute subset of MCC, it is almost exclusively described in superficial and extremity-draining nodal basins (eg, axillary or inguinal regions). Primary visceral nodal MCC accounts for fewer than 5 cases ever reported. This case illustrates the importance of recognizing the morphologic features characteristic of MCC, regardless of anatomical location, and the value of immunohistochemistry in diagnosis, which aid in differentiating it from non-MCC mimics. Development of targeted therapy has made distinction between MCC and non-MCC HGNECA increasingly important. This patient initially responded to PD-L1 inhibitor therapy but ultimately died with disease 10 months after diagnosis.

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