Tumoral Melanosis

SHEDDING LIGHT ON TUMORAL MELANOSIS

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By Warren R. Heymann, MD, FAAD
Oct. 9, 2024
Vol. 6, No. 41

Tumoral melanosis (TM) is a worrisome and confounding lesion for dermatologists and dermatopathologists alike. TM presents as darkly pigmented macules, papules, or nodules mimicking the appearance of a melanoma. Most cases are associated with either partial or complete regression of melanoma, although TM has been reported with solar lentigo, pigmented basal cell carcinoma, pigmented Bowen's disease, and mycosis fungoides. (1) This commentary will focus on melanoma-associated TM.

TM is defined histologically as a dense aggregate of melanophages with a complete absence of melanocytes. (2) The histological differential diagnosis includes dermal melanocytoses, pigmented epithelioid melanocytoma, deep penetrating nevus, primary dermal melanoma, and metastatic melanoma. (3) TM is differentiated from these cases by positive immunohistochemical staining of CD68 and negative melanocyte stains (Melan-A, HMB-45, and SOX-10). (2)

In their series of four TM cases, Alexandris et al. detailed the dermatoscopic findings of 'peppering,' whitish or pinkish structureless areas, and blue/grey areas. The latter feature was observed in all cases, while 'peppering' was seen in 50%. These dermatoscopic features result from dermal fibrosis and presence of dense melanophages. Shiny white structures, which are suggestive of malignancy and can only be observed with polarized dermatoscopy, were found in two out of four lesions, correlating to coarsecollagen bundles in the dermis. (4)

According to Pastukhova et al., "The pathophysiology of TM is thought to involve an immunologic response that infiltrates and destroys atypical melanocytic cells. It is theorized that tumor antigens expressed on the surface of melanoma cells potentiate cytotoxic CD8+ lymphocytes and subsequent destruction of the cutaneous melanocytic component." (3)

TM is distinct from diffuse melanosis (DM), which has a poor prognosis. DM demonstrates diffuse gray pigmentation affecting the entire skin and is frequently accompanied by melanuria. (5)

Images from reference 1.

There are two basic scenarios for TM — regression of advanced or metastatic melanoma or as a consequence of therapy. Jurgens et al assert, "The prognosis of tumoral melanosis is not well understood. The literature has demonstrated that focal regression within melanoma does not have a significant effect on morbidity or mortality; however, extensive regression in larger lesions may be associated with a poor prognosis. Thus, identification of tumoral melanosis in a patient with no known history of melanoma should prompt a thorough evaluation for metastatic disease. This stands in contrast to regression occurring in the setting of immunotherapy, where reports suggest that tumoral melanosis may be associated with tumor regression secondary to treatment response." (6) Modern immunotherapy (anti-CTLA-4 ipilimumab, PD1 inhibitors pembrolizumab and nivolumab, BRAF inhibitors such as dabrafenib, LAG-3 inhibitor relatlimab, and others) has revolutionized melanoma management. (7) Jurgens et al described 10 cases of patients with metastatic melanoma who received treatment with immunotherapy before the development of TM. The length of time between the initiation of therapy and the onset of TM 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. (6)

Talimogene laherparepvec (T-VEC) is a type I herpes simplex virus (HSV) genetically modified to preferentially replicate in tumor cells, enhance antigen loading of MHC class I molecules and express granulocyte-macrophage colony-stimulating factor (GM-CSF) to increase tumor-antigen presentation by dendritic cells. (8) Park et al. report six patients with metastatic cutaneous melanoma who were treated with T-VEC. Biopsies were performed after observing clinical responses in the injected tumors — TM was observed in all cases. Importantly, the authors note that to "accurately assess response to therapy and potentially decrease unnecessary additional T-VEC treatments, serial biopsy of 'stable' lesions should be considered to assess the presence or absence of viable tumor." (9)

In conclusion, TM is an enigmatic lesion requiring further scrutiny. Clinically, it is essential to attribute TM to either melanoma or its treatment. Such a determination helps in prognostication and possibly guiding therapy.

Point to Remember: The rare phenomenon of tumoral melanosis may become more common with advances in melanoma immunotherapy. Such cases may have a better prognosis than cases of TM due to regression from advanced disease. 

Our expert's viewpoint

Ata Moshiri, MD, MPH, FAAD
Assistant Professor, Ronald O. Perelman Department of Dermatology at NYU Grossman School of Medicine 
Associate Director, Dermatopathology Fellowship Program
Assistant Director, Dermatopathology Laboratory Operations

As highlighted by the commentary above, tumoral melanosis (TM) in the setting of melanoma is an interesting phenomenon with controversial clinical and prognostic implications. At its core, TM signifies the host immune system's ability to recognize and destroy melanocytes, replacing them with melanophages and other immune cells that clinically resemble residual melanoma. While TM was once a rare observation, the advent of systemic immunotherapy, oncolytic viral therapy, and effective tumor vaccines have made TM increasingly common in our patients with cutaneous metastases of their melanoma, and thus a source of confusion and consternation for the patients and everyone involved in their care.

How should one approach patients with black macules, papules, and/or nodules appearing in their skin around their melanoma scars during their immunotherapy treatment? In my view, this is one place where clinicopathologic correlation is critical to accurate counseling. As a dermatologist involved in delivering oncolytic viral therapy at a major cancer center, I received many consults for such patients with presumed progressive and refractory disease. Oftentimes, treatment had been withheld or changed based on such clinical assessments. Punch biopsies demonstrating TM and no viable melanoma helped to change the narrative entirely. Rather than despair, a finding of TM provided hope that the patient's newly activated lymphocytes were effectively fighting their cancer. Similarly, in patients receiving months or sometimes years of oncolytic viral therapy for "stable" disease, biopsies demonstrating TM allowed for discontinuation of additional (very expensive) injections. (9) While such responses are not always durable, and disease can recur after therapy is discontinued, TM signifies at least a temporary victory.

As dermatologists involved in cancer surveillance or treatment, we are uniquely positioned to provide clinicopathologic correlation to our patients and colleagues. Becoming familiar with TM and stressing the importance of biopsies to ascertain the presence or absence of viable disease is often necessary for informed clinical decision making and provides valuable histologic insights into the tumor microenvironment that, if correctly studied, may lead to further advances in immunomodulatory therapy for cancer.

1. Petit K, Hinrichs B, Chaudhary R. Gray-black macules in a patient with melanoma. JAAD Case Rep. 2022 Aug 23;28:113-115. doi: 10.1016/j.jdcr.2022.08.021. PMID: 36159718; PMCID: PMC9489873.

2. Massa A, Macchi S, Manuguerra R, Brusasco M, Aouadi M, Feliciani C, Satolli F. Is tumoral melanosis still a challenge? A case of tumoral melanosis without metastasis. Int J Dermatol. 2023 Dec;62(12):e618-e620. doi: 10.1111/ijd.16830. Epub 2023 Sep 6. PMID: 37670681.

3. Pastukhova E, El-Sayes Y, Nakonechny Q, Roy SF, Ghazawi FM. Chasing shadows: a series of tumoral melanosis mimicking melanoma. JAAD Case Rep 2024; DOI https://doi.org/10.1016/j.jdcr.2024.01.012

4. Alexandris D, Bobos M, Lallas A, Lazaridou E, Apalla Z. Clinical, dermatoscopic and histopathologic characteristics of tumoural melanosis: A case-series and literature review. J Eur Acad Dermatol Venereol. 2023 Dec 7. doi: 10.1111/jdv.19657. Epub ahead of print. PMID: 38059544.

5. Arias NM, Peñaranda JMS, Gaspar LS, Mosquera AC, Sánchez-Aguilar D. Tumoral melanosis associated with nivolumab therapy for metastatic melanoma. J Dtsch Dermatol Ges. 2022 Aug;20(8):1130-1131. doi: 10.1111/ddg.14809. Epub 2022 Jul 6. PMID: 35792091.

6. Jurgens A, Guru S, Guo R, Brewer J, Bridges A, Jakub J, Comfere N. Tumoral Melanosis in the Setting of Targeted Immunotherapy for Metastatic Melanoma-A Single Institutional Experience and Literature Review. Am J Dermatopathol. 2021 Jan 1;43(1):9-14. doi: 10.1097/DAD.0000000000001612. PMID: 32149829.

7. Heymann WR. Lagging ahead: LAG-3 checkpoint inhibition for advance melanoma. Dermatology World Insights and Inquiries 2022; volume 4, no. 2. https://www.aad.org/dw/dw-insights-and-inquiries/archive/2022/lag-3-checkpoint-inhibition-advanced-melanoma

8. Heymann WR. Oncolytic virotherapy and the dermatologist. Dermatology World Insights and Inquiries. March 8, 2018. https://www.aad.org/dw/dw-insights-and-inquiries/dermatopathology/oncolytic-virotherapy-and-the-dermatologist

9. Park SY, Green AR, Hadi R, Doolittle-Amieva C, Gardner J, Moshiri AS. Tumoral melanosis mimicking residual melanoma in the setting of talimogene laherparepvec treatment. J Immunother Cancer. 2022 Oct;10(10):e005257. doi: 10.1136/jitc-2022-005257. PMID: 36307152; PMCID: PMC9621191.

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Benjamin Hidalgo-Matlock
Skin Care Physicians of Costa Rica

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