Tumoral Melanosis in the Setting of Targeted Immunotherapy for Metastatic Melanoma—A Single Institutional Experience and Literature Review

Abstract

Background: Tumoral melanosis clinically resembles metastatic melanoma, occurs in the context of regressed disease, and requires evaluation to rule out underlying melanoma and metastatic disease. Histopathology demonstrates a nodular infiltrate of melanophages in the dermis, subcutaneous tissue, deep soft tissue, or lymph nodes in the absence of viable melanocytes. Recent limited reports of tumoral melanosis in the context of immunotherapy with ipilimumab (monoclonal antibody targeting CTLA-4) as well as nivolumab and pembrolizumab (humanized monoclonal antibodies against programmed death 1 receptor) highlight a unique presentation representative of treatment-related tumor regression and an association with a favorable clinical response.Objective: To describe our experience with tumoral melanosis in the setting of immunotherapy for metastatic melanoma and elucidate the clinical and histopathological features.Methods: Retrospective case series from a single tertiary care institution. Results:We describe 10 cases of patients with metastatic melanoma who received treatment with immunotherapy before the development of tumoral melanosis. Length of time between the initiation of therapy and the onset of tumoral melanosis ranged from 2 to 20 months with a mean time of 10 months. At the end of the follow-up period, 8 patients were classified as having a complete or partial response to treatment with immunotherapy. One patient had progression of visceral and cutaneous disease on ipilimumab despite developing tumoral melanosis, and 1 patient had yet to undergo repeat imaging. Furthermore, at the end of follow-up, 3 patients were alive with no evidence of active disease, 5 patients were alive with disease, and 1 patient was deceased, although this patient died of a cardiovascular event unrelated to his underlying melanoma. Of the patients who were classified as alive with disease, 2 patients had minimal remaining disease, and 2 patients had an almost complete response on immunotherapy with recurrence of visceral metastases after immunotherapy was discontinued. One patient developed new peritoneal and cutaneous metastases on pembrolizumab despite development of tumoral melanosis. Conclusions:The underlying biologic mechanisms and prognostic implications of tumoral melanosis in the setting of immunotherapy remain to be elucidated. Further prospective studies with a larger cohort and prolonged follow-up are necessary to better understand the incidence, prevalence, and oncologic outcomes in patients with tumoral melanosis who receive immunotherapy.

Tumoral melanosis associated with nivolumab therapy for metastatic melanoma

“…Jurgens et al reported the largest series to date with ten cases. TM mainly appeared in the proximity of the primary tumor within two to twenty months after immunotherapy start [12]. Most cases described in this report showed a favorable clinical response, with nine out of ten patients being alive after the follow-up period [12].…”

“…Exceptionally, it has also been reported in regressed pigmented epithelial lesions [8]. As in our case, its metastatic appearance makes a skin biopsy necessary, with immunohistochemistry demonstrating positivity for CD68 and absence of neoplastic cells with SOX-10, HMB-45 and Melan-A [5][6][7][8][9][10][11][12]. The prognosis is still unclear due to the limited number of reported cases with long-term follow-up so far [5][6][7][8][9][10][11][12].…”

Cutaneous Events Associated with Immunotherapy of Melanoma: A Review

“…Tumoral melanosis usually presents as black or blue macules, papules or nodules clinically resembling a melanoma or cutaneous metastases. Because of this similarity, skin biopsy is essential for the diagnosis [ 35 ]. Histopathology of tumor melanosis demonstrates a large collection of melanophages and melanin pigment in subcutaneous tissue or dermis associated with the lack of melanocytes.…”

“…In the majority of cases reported so far, tumoral melanosis was found in proximity to the primary melanoma or in transit metastases [ 36 , 38 ], although three patients presented with tumoral melanosis at a distant site from the primary melanoma [ 35 ].…”

“…Hypothetically, these events would enhance melanoma destruction and the concomitant observed tumoral melanosis [ 39 ]. However, few patients also showed disease progression in spite of the development of tumoral melanosis during immunotherapy [ 35 , 43 ].…”