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Repigmentation of aging gray hair associated with unrecognized development and progression of amelanotic melanoma of the scalp: A physiological alert underlying hair rejuvenation

Dear Editor, Hair repigmentation in underlying melanoma is a rare event but may occasionally alert to the unnoticeable development and/or progression of the disease. We present, to our best knowledge, the first case of hair repigmentation and depigmentation along with the clinical course of advanced amelanotic melanoma on the scalp, which successfully responded to antiprogrammed death 1 (PD1) antibody monotherapy. An 80yearold Japanese man who presented with a 1month history of a scalp mass was referred to our department. Examination showed a 13.8 mm × 5.8 mm, nonpigmented, irregularshaped, reddish nodule on the right parietal scalp (Figure 1a,b). Notably, the skin lesion was overlain with brownblack hair surrounded by ordinary gray hair. There were multiple, small reddish nodules in the right temporal region (Figure 1a). Pathology of both skin lesions revealed a multilobulated sheet consisting of epithelioid cells with nuclear atypia, but almost without melanin except follicles, from the dermis to subcutis (Figure 1d– f). There was no continuity of the tumor nests with the epidermis and no follicular invasion. Immunostaining was positive for MelanA, S100, and HMB45, consistent with melanoma. Tumorinfiltrating lymphocytes mostly represented a CD8+/ PD1+ phenotype (Figure 1g,h), albeit with undetectable PD1 ligand expression of the tumor. Positron emission tomography showed multiple 18Ffluorodeoxyglucose (FDG) accumulations in the right cervical lymph nodes without organ metastases. Hence, the nodules on the right temporal skin were considered as intransit metastasis. He was diagnosed with stage IIIC malignant melanoma in (American Joint Committee on Cancer 8th edition). A BRAF mutation was not detected. He received the antiPD1 antibody pembrolizumab 2 mg/kg every 3 weeks. After five doses, the abnormal FDG uptake of right cervical lymph nodes disappeared completely. Moreover, his blackbrown hair covering the skin lesion returned to thin grayish hair with reduced size of the primary tumor and disappearance of intransit metastasis (Figure 1c). He has not experienced recurrence or metastasis after 1 year of the initial antiPD1 therapy. There have been only nine reported cases, including ours, of scalp melanoma with hair repigmentation.1– 3 Five of them (55.6%) were diagnosed as melanoma in situ, whereas our case was the most advanced stage of amelanotic phenotype. A proposed model for hair repigmentation associated with melanoma comprises two major cascades: (i) a direct melanin delivery from infiltrating melanoma cells to follicular keratinocytes; and (ii) an activation of KIT signalingdependent melanogenesis in hair bulbresidential melanocytes by neighboring melanoma cells.1 The latter scenario may be substantiated by the histology that perifollicular infiltration of melanoma cells was evident, similar to our case. Also, gray hairs other than the lesional scalp remained unchanged. Another explanation for hair repigmentation may include the tumoractivated transforming growth factor (TGF)β system; melanoma cells produce TGFβ to escape from the local immune surveillance,4 which promotes local invasion and/or metastasis. TGFβ maintains the immaturity of hair bulgeharboring melanocyte stem cells as a progenitor of local melanocytes.5 This was supported by immunostaining confirming TGFβ1expressing follicular epithelium adjacent to intense TGFβ1+ melanoma cells (Figure 1i). Any combination of these mechanisms would prime hair repigmentation and depigmentation in scalp melanoma. An abrupt hair colorrejuvenation in the elderly may reflect an underrecognized signature of advanced melanoma.