Dermatology: Practical and Conceptual


Review | Dermatol Pract Concept. 2024;14(1):e2024008 1

Diffuse Melanosis Cutis as the First Sign 
of Recurrence of Low-Risk Melanoma: Case Report 

and Systematic Review
Anna Graziella Burroni1, Niccolò Capurro1, Franco Rongioletti2, Emanuele Cozzani1, 

Paolo Pronzato3, Astrid Herzum1, Antonio Guadagno4, Mattia Fabio Molle1, 
Giorgio Alberto Oddenino1, Aurora Parodi1

1 Section of Dermatology, Department of Health and Science (DissaL), Polyclinic Hospital San Martino, IRCCS, Università di Genova, Italy

2 Dermatology Clinic, Vita-Salute San Raffaele University, Milan, Italy

3 Medical Oncology 2 Unit, IRCCS Ospedale Policlinico San Martino, Genova, Italy

4 Division of Pathology, IRCCS Ospedale Policlinico San Martino, Genova, Italy

Key words: melanoma, melanosis, melanoma metastasis, pigmentation

Citation: Burroni AG, Capurro N, Rongioletti F, et al. Diffuse Melanosis Cutis as the First Sign of Recurrence of Low-Risk Melanoma: 
Case Report and Systematic Review. Dermatol Pract Concept. 2024;14(1):e2024008. DOI: https://doi.org/10.5826/dpc.1401a8

Accepted: May 6, 2023; Published: January 2024

Copyright: ©2024 Burroni et al. This is an open-access article distributed under the terms of the Creative Commons Attribution-
NonCommercial License (BY-NC-4.0), https://creativecommons.org/licenses/by-nc/4.0/, which permits unrestricted noncommercial use, 
distribution, and reproduction in any medium, provided the original authors and source are credited.

Funding: None.

Competing Interests: None.

Authorship: All authors have contributed significantly to this publication.

Corresponding Author: Niccolò Capurro MD, Section of Dermatology Polyclinic Hospital San Martino, IRCCS, largo R. Benzi 16131 
Genova, Italy. E-mail: capurro.niccolo@gmail.com

Introduction: Diffuse Melanosis Cutis (DMC) is a rare and late complication of metastatic malignant 
melanoma (MM) characterized by progressive pigmentation of skin and sometimes mucous mem-
branes. The distinctive feature is the widespread and progressive deposition of melanin precursors in 
the dermis.

Objectives: The purpose of this review is to define the clinical and demographic features of DMC and 
to promote a deeper insight into the clinical manifestation, histological findings, and pathophysiology 
behind DMC.

Methods: We have conducted a systematic review of the literature on published DMC in compliance 
with the Preferred Reporting Items for Systematic Reviews and Meta-Analysis. We also reported a case 
of DMC secondary to low-risk melanoma.

Results: Overall, including our case report, we reported 53 articles described 62 DMC patients. 
Breslow level of primary melanoma was reported having a mean value of 3.3 mm. The mean survival 
rate from onset of DMC resulted being 4.36 months.

ABSTRACT



2 Review | Dermatol Pract Concept. 2024;14(1):e2024008

Introduction

Diffuse Melanosis Cutis (DMC) is a rare and late complica-

tion of metastatic malignant melanoma (MM) characterized 

by progressive pigmentation of skin and sometimes mucous 

membranes.

The first properly documented case with photographic 

finding was described by Odel et al in 1937 [1].

There are few mentions of previous work in the litera-

ture referring to various reports of “melanosis” or “mela-

noderma,” however their exact correspondence with actual 

cases of DMC cannot be demonstrated.

The distinctive feature is the widespread and progres-

sive deposition of melanin precursors in the dermis, which 

gives the skin a discoloration variously defined as “blue-

gray”, “slate-gray” and “metallic-gray”. This pigmenta-

tion is almost unanimously described as more pronounced 

in the photo-exposed areas and with a caudo-cranial 

progression.

A clinical feature almost always associated with DMC 

is the presence of melanuria, due to the presence of melanic 

precursors in the urine, which typically becomes more ap-

parent with exposure of urine specimens to open air.

The essential histological finding of DMC is the presence 

of melanin in the dermis which has been described predom-

inantly within perivascular melanophages, but also as free 

scattered pigment.

It is essential to emphasize that in DMC the presence 

of neoplastic melanocytes in the dermis is never observed, 

making this clinical entity intrinsically different from cases 

of cutaneous metastases of metastatic malignant mela-

noma (MM).

Objective

This comprehensive review is dedicated to unraveling the 

clinical and demographic features of Diffuse Melanosis Cu-

tis (DMC), aiming to provide a better understanding of its 

clinical presentation, histological findings, and underlying 

pathophysiology. In addition to a detailed analysis of exist-

ing literature, we contribute valuable insights through the 

inclusion of a case report detailing DMC secondary to low-

risk melanoma. By offering a practical context alongside a 

careful exploration of various aspects, this study seeks to 

enrich the collective comprehension of DMC.

Case Report

A 63-year-old Caucasian man presented with a 3-week his-

tory of progressive skin and urine darkening. His past med-

ical history included a retro-auricular melanoma (pT1a, 

Breslow-depth 0.39 mm, Clark-level I, mitotic rate 0/mm2, 

no microsatellitosis, no regression) excised in 2014 and sub-

sequently subjected to wide local excision with free margins.

Clinical examination revealed a diffuse slate-gray hyper-

pigmentation affecting the entire skin, more pronounced on 

sun exposed areas (Figure 1).

Oral and conjunctival mucosal membranes and nail beds 

were normal. No lesions suggestive of primary or recurrent 

melanoma were evidenced at the site of previous melanoma 

excision, nor on other explorable mucosae and skin.

Hepatomegaly was present. Blood tests excluded hypo-

aldosteronism, hemochromatosis, lead, mercury, and silver 

nitrate poisoning. Urine analysis showed elevated values of 

5-S-Cysteinyldopa.

Total body computed tomography (CT) evidenced multiple 

osteolytic lesions of long bones, generalized lymphadenopathy 

and a 6 cm diameter liver mass in which an echo-guided needle 

biopsy disclosed the presence of protein S100+, HMB-45+ and 

BRAF+ (exon 15) pleomorphic cells, both epitheliomorphic 

Figure 1.        63-year-old caucasian patient with intense slate-gray 

pigmentation.

Conclusions: Among the most widely accepted etiopathogenetic hypotheses are deposition of melanic 
precursors in the dermis following tumor lysis, melanocyte proliferation induced by neoplastic growth 
factors, and the presence of diffuse dermal micro-metastases of MM. However, unanimous consensus 
on the proposed etiopathogenetic models of DMC is still lacking.



Review | Dermatol Pract Concept. 2024;14(1):e2024008 3

and spindle-shaped, with eosinophilic cytoplasms and nuclei 

with prominent nucleoli. Also, abundant brownish pigment 

was observed supporting the diagnosis of metastatic mela-

noma. A skin biopsy showed sparse melanophages containing 

melanic pigment in the superficial dermis, without any neo-

plastic proliferation. Immunohistochemistry was negative for 

pS100, Sox10, HMB45; positive for CD68 pgm1, supporting 

the diagnosis of diffused cutaneous melanosis (Figure 2).

Combination therapy with encorafenib and binimetinib 

was initiated but immediately discontinued because of acute 

iatrogenic liver failure. After supportive therapy and resto-

ration of liver function, second-line therapy with dabrafenib 

was initiated, with good tolerability.

The patient underwent disease progression, developing 

diffuse cerebral metastases 5 months after the diagnosis of 

DMC and died 8 months after the diagnosis of DMC.

Methods

A systematic review of the literature on published cases of 

diffuse melanosis cutis (DMC) was performed in compliance 

with the Preferred Reporting Items for Systematic Reviews 

and Meta-Analysis, through PubMed and Google Scholar [2].

Combinations of the following MeSH terms and key-

words were used to retrieve all the relevant articles: melanosis 

cutis, diffuse melanosis cutis, cutaneous melanosis. To iden-

tify eligible articles, titles and abstracts were screened and full 

texts when necessary. Also, references of the selected articles 

were screened manually to include possibly left-over articles.

Inclusion criteria were: articles focusing on DMC, case 

reports, case series, commentaries, reviews reporting new 

DMC cases. Conversely, studies reporting a definitive diag-

nosis other than DMC, and literature reviews without new 

DMC reports, were excluded.

Further analyzing the described cases of initially included 

articles, we eventually included only cases with definite 

DMC diagnosis, not reporting cases just presenting cutane-

ous metastasis.

Evidence extrapolated from the reviewed articles (Table 1) 

regarded: year of publication; number of studied patients; 

gender, age, ethnicity of patients; site of, Breslow level, Clark 

level, ulceration, mitotic rate of primary melanoma; lunge 

       Figure 2. (A) The epidermis shows solar lentigo-like characteristics while melanophages containing cytoplasmic melanin are visible in the 

dermis. (B) Perivascular and peri-adnexal distribution of macrophages. (C) High expression of CD68 pgm-1 by superficial dermal melano-

phages. (D) Negative immunohistochemical study for SOX-10 (D).



4 Review | Dermatol Pract Concept. 2024;14(1):e2024008

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Review | Dermatol Pract Concept. 2024;14(1):e2024008 5

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Review | Dermatol Pract Concept. 2024;14(1):e2024008 7

a Clark level of primary melanoma of III, IV or V. This is 

a documented case of DMC secondary to pt1a melanoma 

(Clark Level I).

Several pathogenetic mechanisms of DMC have been 

proposed among which, the most widely accepted, is that it 

is derived from circulating precursors of melanin, produced 

by melanoma, which are deposited at the dermal level and 

subjected to autoxidation. This hypothesis would also ex-

plain the presence of melanuria, frequently associated with 

DMC, in which the presence of melanic precursors in urine 

is extensively documented [56,57].

However, unanimous consensus on the proposed etio-

pathogenetic models of DMC is lacking.

Some authors suggest that skin pigmentation is  secondary 

to melanocyte proliferation induced by growth factors such 

as alpha-melanocyte stimulating hormone, hepatocyte 

growth factor and endothelin-1 released by neoplastic me-

lanocytes [58].

Others, hypothesize that neoplastic cell lysis induced by 

anticancer therapies would release melanic precursors with 

subsequent dermal deposition [59].

The latter hypothesis is not applicable to our case, as the 

onset of DMC was prior to therapy initiation. Also, the pres-

ence of cutaneous MM micro-metastases has been advocated 

as responsible for DMC [48]. However, this pathogenetic hy-

pothesis is disproved in our case by negative immunohisto-

chemistry indicating pigmentation is attributable only to the 

presence of dermal melanin and melanophages and not to 

neoplastic melanocytic clones.

DMC is to date considered a paraneoplastic manifesta-

tion of MM, burdened by a very poor prognosis. The average 

survival described in the literature from the onset of DMC is 

4 months, significantly lower than that of patients diagnosed 

with stage IV MM, but without DMC [56,60].

The reasons for the prognostic gap remain unclear to 

date; some authors speculate that MM complicated by DMC 

may be characterized by specific genetic mutations [61].

This would likely account for both the tendency of these 

MM to develop DMC and the worse prognosis, probably 

due to greater biological aggressiveness and less responsive-

ness to therapies.

References

1. Odel HM, Montgomery H, Horton BT. Diffuse melanosis second-

ary to malignant melanoma. Mayo Clinic Proc 1937:742-747.

2. PRISMA statement PRISMA (prisma-statement.org). Retrieved 

October 20, 2022, from http://www.prisma-statement.org/

3. Ritz ND. Diffuse melanosis, pericardial effusion, and melanu-

ria associated with malignant melanoma; case report with 

autopsy findings. Ann Intern Med. 1949(1):184-195. DOI: 

10.7326/0003-4819-30-1-184. PMID: 18106240.

metastasis; brain metastasis; melanuria; therapy, survival 

since DMC onset (in months); DMC in skin biopsy.

Results

A total of 185 articles were identified from the litera-

ture search since 1937 up to date. Ultimately, 52 articles 

about DMC, describing 61 DMC patients, satisfied above- 

described inclusion criteria and were included in the review 

(Table 1) [1,3-53].

Articles reported in previous literature reviews not satis-

fying the above-mentioned inclusion criteria were excluded. 

Overall, a female: male ratio of 1:1.8 and mean age at diag-

nosis of 53 years, median age of 50 years (86 and 20 years 

being the extremes) were reported.

Ethnic origin was reported for 52 patients: 98% were 

Caucasian, 2 % Japanese.

Regarding the primary melanoma, the most frequently 

affected site was the trunk (65%), followed by the limbs 

(21%) and head-and-neck (14%).

Breslow level of primary melanoma was reported in only 

20 cases, with a mean value of 3.3 mm.

Clark level also was reported in only 20 cases, 45% had 

Clark level IV, 30% level III and 25% level V.

Ulceration was not reported in the great majority of 

cases: only 2 articles mentioned ulceration. 100% of these 

had no ulceration.

Mitotic rate was reported only for two cases: 21/mm2 

and <1/mm2.

Overall, 40 patients were screened for lung metastasis: 

58% had lung metastasis, 42% had not.

Overall, 49 patients were screened for liver metastasis: 

92% had liver metastasis, 8% had not.

Overall, 29 patients were screened for brain metastasis: 

48% had brain metastasis, 52% had not.

Of 49 patients screened for melanuria, 96% had melanu-

ria, 4% had not.

The mean survival rate from onset of DMC was reported 

in 52 cases and resulted 4.36 months.

Of DMC patients 36 underwent skin biopsy to confirm 

the diagnosis.

Conclusions

Low-risk melanoma is defined as  melanoma with a tumor 

thickness of 0.8 mm or less or stage I melanoma. This group 

includes 70% of patients with cutaneous melanoma, and most 

of these patients is unlikely to develop recurrences [54,55].

DMC is a rare, late-term manifestation of MM.

To date, approximately 65 DMC cases have been de-

scribed in the literature all of which, when described, report 



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