10.5826/dpc.1401a8
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 membranes. 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.
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.
text/xml
2160-9381
3196
en
Aurora Parodi
https://creativecommons.org/licenses/by-nc/4.0
Dermatology Practical & Conceptual
pigmentation
Diffuse Melanosis Cutis as the First Sign of Recurrence of Low-Risk Melanoma: Case Report and Systematic Review
Text.Serial.Journal
https://dpcj.org/index.php/dpc
Review
2024-01-31
2023-02-24
2024-01-31
2024-02-21
e2024008
Dermatol Pract Concept
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 membranes. 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.
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.
Aurora Parodi
2024/01/31
10.5826/dpc.1401a8
e2024008
Section of Dermatology, Department of Health and Science (DissaL), Polyclinic Hospital San Martino, IRCCS, Università di Genova, Italy
2160-9381
pigmentation
en
e2024008
Sebaratnam DF, Martin LK, Venugopal SS, et al. Diffuse melanosis cutis in the setting of BRAF(V600E) metastatic melanoma. Int J Dermatol. 2014;53(11):1409-1411. DOI: 10.1111/ijd.12614. PMID: 25257244.
Diffuse Melanosis Cutis as the First Sign of Recurrence of Low-Risk Melanoma: Case Report and Systematic Review
https://dpcj.org/index.php/dpc/article/download/3196/2443
      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




  ABSTRACT             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.




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




Introduction                                                     Case Report
Diffuse Melanosis Cutis (DMC) is a rare and late complica-       A 63-year-old Caucasian man presented with a 3-week his-
tion of metastatic malignant melanoma (MM) characterized         tory of progressive skin and urine darkening. His past med-
by progressive pigmentation of skin and sometimes mucous         ical history included a retro-auricular melanoma (pT1a,
membranes.                                                       Breslow-depth 0.39 mm, Clark-level I, mitotic rate 0/mm2,
    The first properly documented case with photographic         no microsatellitosis, no regression) excised in 2014 and sub-
finding was described by Odel et al in 1937 [1].                 sequently subjected to wide local excision with free margins.
    There are few mentions of previous work in the litera-           Clinical examination revealed a diffuse slate-gray hyper-
ture referring to various reports of “melanosis” or “mela-       pigmentation affecting the entire skin, more pronounced on
noderma,” however their exact correspondence with actual         sun exposed areas (Figure 1).
cases of DMC cannot be demonstrated.                                 Oral and conjunctival mucosal membranes and nail beds
    The distinctive feature is the widespread and progres-       were normal. No lesions suggestive of primary or recurrent
sive deposition of melanin precursors in the dermis, which       melanoma were evidenced at the site of previous melanoma
gives the skin a discoloration variously defined as “blue-       excision, nor on other explorable mucosae and skin.
gray”, “slate-gray” and “metallic-gray”. This pigmenta-              Hepatomegaly was present. Blood tests excluded hypo-
tion is almost unanimously described as more pronounced          aldosteronism, hemochromatosis, lead, mercury, and silver
in the photo-exposed areas and with a caudo-cranial              nitrate poisoning. Urine analysis showed elevated values of
progression.                                                     5-S-Cysteinyldopa.
    A clinical feature almost always associated with DMC             Total body computed tomography (CT) evidenced multiple
is the presence of melanuria, due to the presence of melanic     osteolytic lesions of long bones, generalized lymphadenopathy
precursors in the urine, which typically becomes more ap-        and a 6 cm diameter liver mass in which an echo-guided needle
parent with exposure of urine specimens to open air.             biopsy disclosed the presence of protein S100+, HMB-45+ and
    The essential histological finding of DMC is the presence    BRAF+ (exon 15) pleomorphic cells, both epitheliomorphic
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      Figure 1. ​​​​​​​63-year-old caucasian patient with intense slate-gray
enrich the collective comprehension of DMC.                      pigmentation.


2                                                                            Review | Dermatol Pract Concept. 2024;14(1):e2024008
and spindle-shaped, with eosinophilic cytoplasms and nuclei               with the Preferred Reporting Items for Systematic Reviews
with prominent nucleoli. Also, abundant brownish pigment                  and Meta-Analysis, through PubMed and Google Scholar [2].
was observed supporting the diagnosis of metastatic mela-                     Combinations of the following MeSH terms and key-
noma. A skin biopsy showed sparse melanophages containing                 words were used to retrieve all the relevant articles: melanosis
melanic pigment in the superficial dermis, without any neo-               cutis, diffuse melanosis cutis, cutaneous melanosis. To iden-
plastic proliferation. Immunohistochemistry was negative for              tify eligible articles, titles and abstracts were screened and full
pS100, Sox10, HMB45; positive for CD68 pgm1, supporting                   texts when necessary. Also, references of the selected articles
the diagnosis of diffused cutaneous melanosis (Figure 2).                 were screened manually to include possibly left-over articles.
    Combination therapy with encorafenib and binimetinib                      Inclusion criteria were: articles focusing on DMC, case
was initiated but immediately discontinued because of acute               reports, case series, commentaries, reviews reporting new
iatrogenic liver failure. After supportive therapy and resto-             DMC cases. Conversely, studies reporting a definitive diag-
ration of liver function, second-line therapy with dabrafenib             nosis other than DMC, and literature reviews without new
was initiated, with good tolerability.                                    DMC reports, were excluded.
    The patient underwent disease progression, developing                     Further analyzing the described cases of initially included
diffuse cerebral metastases 5 months after the diagnosis of               articles, we eventually included only cases with definite
DMC and died 8 months after the diagnosis of DMC.                         DMC diagnosis, not reporting cases just presenting cutane-
                                                                          ous metastasis.

Methods                                                                       Evidence extrapolated from the reviewed articles (Table 1)
                                                                          regarded: year of publication; number of studied patients;
A systematic review of the literature on published cases of               gender, age, ethnicity of patients; site of, Breslow level, Clark
diffuse melanosis cutis (DMC) was performed in compliance                 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).


Review | Dermatol Pract Concept. 2024;14(1):e2024008                                                                                          3
4
                                                                                   Table 1. Summary table of clinical-demographic features of DMC cases reported in the literature.
                                                                      NUMBER                                                                                                                SURVIVAL
                                                                         OF        AGE                     BODY  BRESLOW    LUNG       LIVER     BRAIN                                     SINCE DMC
                                                       YEAR ARTICLE   PATIENTS   (YEARS) GENDER ETHNICITY   SITE   (mm)  METASTASIS METASTASIS METASTASIS MELANURIA        THERAPY         DIAGNOSIS
                                                       2019   [53]        1         47   F      CAUCASIAN HEAD-     NA   NO         YES        YES        NA        Vemurafenib,               12
                                                                                                          NECK                                                      Cobimetinib,
                                                                                                                                                                    Pembrolizumab
                                                       2019   [52]       1         47   NA       CAUCASIAN TRUNK    NA   YES        YES        YES        YES       Dabrafenib And             0,5
                                                                                                                                                                    Trametinib
                                                       2018   [51]       2         78   M        CAUCASIAN HEAD-      7  NO         YES        NO         YES       Pembrolizumab              1,2
                                                                                                           NECK
                                                       2018   [51]                 85   M        CAUCASIAN TRUNK    5.5  NO         YES        NO         YES       Pembrolizumab               2
                                                       2017   [50]       1         54   F        CAUCASIAN NA       NA   YES        YES        NO         YES       Dabrafenib, Trametinib     NA
                                                       2017   [49]       1         64   M        CAUCASIAN TRUNK    NA   YES        YES        NO         YES       None                        1
                                                       2017   [48]       1         72   M        CAUCASIAN TRUNK    >3   NO         NO         NO         YES       None                        8
                                                       2016   [47]       1         76   M        CAUCASIAN NA       NA   NO         YES        NO         NA        Dacarbazine,               16
                                                                                                                                                                    Ipilumumab
                                                       2016   [46]       1         77   M        CAUCASIAN NA       NA   YES        YES        NA         YES       None                       0,5
                                                       2015   [45]       1         35   M        CAUCASIAN TRUNK    0.8  YES        YES        YES        YES       Dabrafenib,                NA
                                                                                                                                                                    Ipilimumab
                                                       2015   [44]       1         43   F        CAUCASIAN TRUNK      3  NO         YES        NO         NA        Vindesine/Cisplatin         4
                                                       2011   [43]       1         45   F        CAUCASIAN TRUNK    NA   YES        YES        YES        YES       Polichemotherapy           11
                                                       2010   [42]       2         49   M        NA        NA       NA   NO         YES        NO         YES       Carboplatin-DTIC,           3
                                                                                                                                                                    YES-Ray Treatment
                                                       2010   [42]                 52   M        NA        TRUNK    0.82 YES        YES        YES        YES       Carboplatin-DTIC            2
                                                       2010   [41]       1         62   M        CAUCASIAN TRUNK      9  NO         NO         NO         YES       Dacarbazine                12
                                                       2009   [40]       1         54   M        CAUCASIAN NA       NA   NA         YES        NA         YES       None                       NA
                                                       2008   [39]       1         48   M        CAUCASIAN TRUNK    0.75 NA         YES        NA         YES       Dacarbazine                 3
                                                       2007   [38]       1         49   M        CAUCASIAN HEAD-    NA   NA         NA         NA         YES       NA                         NA
                                                                                                           NECK
                                                       2004   [37]       1         36   F        NA        TRUNK    NA   YES        YES        NO         NA        Temozolomide               11
                                                       2004   [36]       1         29   F        CAUCASIAN TRUNK     2.8 YES        NA         YES        YES       Interferon Alfa             2
                                                       2004   [35]       4         43   F        NA        HEAD-     3.2 NA         YES        NA         YES       Dacarbazine,                7
                                                                                                           NECK                                                     Carboplatin, Cisplatin




Review | Dermatol Pract Concept. 2024;14(1):e2024008
                                                       2004              52   M   CAUCASIAN LIMBS     >5    NA    YES   NA    YES   Dacarbazine                1,2
                                                       2004              71   M   NA        TRUNK      4    NA    YES   NA    NO    None                       0,2
                                                       2004   [35]       62   F   NA        NA        NA    NA    YES   NA    YES   Dacarbazine,               1,6
                                                                                                                                    POLICHEMOTERAPY
                                                       2002   [34]   1   65   M   NA          NA      NA    NA    NA    NA    NA    NA                          7
                                                       2001   [33]   1   35   F   CAUCASIAN   TRUNK    2    YES   YES   NO    YES   DBCT Regimen                6
                                                       2001   [32]   1   62   M   CAUCASIAN   LIMBS   3.1   NO    YES   YES   YES   Dacarbazine                 1
                                                       1999   [31]   1   77   M   CAUCASIAN   LIMBS   5.5   NO    YES   NA    NA    Combination                 7
                                                                                                                                    Chemotherapy
                                                       1998   [30]   1   78   M   JAPANESE  LIMBS     NA    YES   YES   NO    YES   DAV Regimen                 4
                                                       1997   [29]   1   86   F   CAUCASIAN NA        NA    NO    YES   YES   NO    Fludrocortisone            0,3
                                                       1996   [28]   1   58   M   CAUCASIAN TRUNK     NA    YES   YES   NA    YES   DTIC, Cisplatin,            6




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                                                                                                                                    BCNU, And Tamoxifen
                                                       1993   [27]   1   57   M   CAUCASIAN TRUNK     3.5   NA    NA    NA    NA    Dacarbazine,                5
                                                                                                                                    Interferone
                                                       1993   [26]   1   60   F   CAUCASIAN LIMBS     2.9   NO    NO    YES   YES   DTIC, CCNU And              6
                                                                                                                                    Vincristine
                                                       1993   [25]   1   79   M   CAUCASIAN HEAD-     NA    NA    YES   NA    NA    None                        2
                                                                                            NECK
                                                       1992   [24]   1   37   M   CAUCASIAN TRUNK     0.8   YES   YES   NA    YES   Interferone,                5
                                                                                                                                    Dacarbazine
                                                       1991   [23]   1   56   M   CAUCASIAN TRUNK     NA    NO    NO    NA    YES   Interferon Alfa and         4
                                                                                                                                    Cimetidine
                                                       1990   [22]   1   65   F   CAUCASIAN   NA      NA    NA    NA    NA    NA    NA                         NA
                                                       1990   [21]   1   60   M   CAUCASIAN   LIMBS   NA    NA    NA    NA    NA    NA                         NA
                                                       1989   [20]   1   34   F   CAUCASIAN   NA      NA    NA    NA    NA    NA    None                        6
                                                       1987   [19]   1   49   M   CAUCASIAN   TRUNK   1.5   YES   NA    NA    YES   None                       0,5
                                                       1986   [18]   2   31   M   CAUCASIAN   LIMBS   NA    NA    YES   NA    YES   Dtic                       3,2
                                                       1986   [18]       67   F   NA          TRUNK   NA    YES   YES   NA    YES   Interferon + Cimetinide    1,2
                                                       1984   [17]   1   44   M   CAUCASIAN   NA      NA    NA    NA    NA    YES   NA                          2
                                                       1981   [16]   1   59   M   NA          TRUNK   NA    YES   YES   NA    YES   Acarbazine And              4
                                                                                                                                    Lomustine
                                                       1980   [15]   1   23   M   CAUCASIAN TRUNK     NA    NA    YES   NA    YES   Dacarbazine,               12
                                                                                                                                    Vincristine, Lomustine
                                                                                                                                                              Continued




5
6
                                                                    Table 1. Summary table of clinical-demographic features of DMC cases reported in the literature. (Continued)
                                                                            NUMBER                                                                                                                         SURVIVAL
                                                                               OF        AGE                       BODY BRESLOW    LUNG       LIVER          BRAIN                                        SINCE DMC
                                                       YEAR ARTICLE         PATIENTS   (YEARS)   GENDER ETHNICITY   SITE  (mm)  METASTASIS METASTASIS      METASTASIS   MELANURIA        THERAPY          DIAGNOSIS
                                                       1980   [14]              1         70     M      CAUCASIAN NA       NA   YES        YES             YES          YES       NA                          2,5
                                                       1979   [13]              1         43     M      CAUCASIAN NA       NA   NA         YES             NA           YES       Dtic + Bleomycin             3
                                                       1975   [12]              1         20     F      CAUCASIAN TRUNK    NA   NA         YES             NA           YES       BCNU, Hydroxyurea,          0,5
                                                                                                                                                                                  DIC, And Vincristine
                                                       1974       [11]         1         58      M      CAUCASIAN TRUNK    NA     YES          YES         YES          YES       Telecobalt, Strontium      0,8
                                                                                                                                                                                  and X-Ray Irradiation
                                                       1973       [10]         1         39      F      CAUCASIAN LIMBS    NA     NO           YES         NO           YES       NA                          8
                                                       1972        [9]         1         39      F      CAUCASIAN LIMBS    NA     NO           YES         NO           YES       None                        8
                                                       1969        [8]         1         48      F      CAUCASIAN HEAD-    NA     YES          YES         YES          YES       Triethylene-                3
                                                                                                                  NECK                                                            Thiophosphoramide
                                                       1968       [7]          1         50      M      CAUCASIAN TRUNK    NA     NA           YES         NA           NA        Lomustine,                  9
                                                                                                                                                                                  Dacarbazine,
                                                                                                                                                                                  Actinomycin-D
                                                       1968       [6]          1         47      F      CAUCASIAN HEAD-    NA     YES          YES         YES          YES       Thiophosphoramide          1,2
                                                                                                                  NECK
                                                       1961       [5]          1         33      F      CAUCASIAN TRUNK    NA     YES          YES         YES          YES         None                      5
                                                       1954       [4]          3         41      M      CAUCASIAN TRUNK    NA     NO           NA          NA           YES         NA                       NA
                                                       1954                              33      M      CAUCASIAN TRUNK    NA     NA           NA          NA           YES         NA                        3
                                                       1954       [4]                    43      F      CAUCASIAN NA       NA     NA           NA          NA           YES         NA                       NA
                                                       1949       [3]          1         47      M      CAUCASIAN LIMBS    NA     YES          YES         NA           YES         None                      1
                                                       1937       [1]          1         36      M      CAUCASIAN TRUNK    NA     NA           NA          NA           NA          NA                       NA

                                                       NA = Not Available




Review | Dermatol Pract Concept. 2024;14(1):e2024008
metastasis; brain metastasis; melanuria; therapy, survival       a Clark level of primary melanoma of III, IV or V. This is
since DMC onset (in months); DMC in skin biopsy.                 a documented case of DMC secondary to pt1a melanoma
                                                                 (Clark Level I).

Results                                                             Several pathogenetic mechanisms of DMC have been
                                                                 proposed among which, the most widely accepted, is that it
A total of 185 articles were identified from the litera-         is derived from circulating precursors of melanin, produced
ture search since 1937 up to date. Ultimately, 52 articles       by melanoma, which are deposited at the dermal level and
about DMC, describing 61 DMC patients, satisfied above-­         subjected to autoxidation. This hypothesis would also ex-
described inclusion criteria and were included in the review     plain the presence of melanuria, frequently associated with
(Table 1) [1,3-53].                                              DMC, in which the presence of melanic precursors in urine
   Articles reported in previous literature reviews not satis-   is extensively documented [56,57].
fying the above-mentioned inclusion criteria were excluded.         However, unanimous consensus on the proposed etio-
Overall, a female: male ratio of 1:1.8 and mean age at diag-     pathogenetic models of DMC is lacking.
nosis of 53 years, median age of 50 years (86 and 20 years          Some authors suggest that skin pigmentation is ­secondary
being the extremes) were reported.                               to melanocyte proliferation induced by growth factors such
   Ethnic origin was reported for 52 patients: 98% were          as alpha-melanocyte stimulating hormone, hepatocyte
Caucasian, 2 % Japanese.                                         growth factor and endothelin-1 released by neoplastic me-
   Regarding the primary melanoma, the most frequently           lanocytes [58].
affected site was the trunk (65%), followed by the limbs            Others, hypothesize that neoplastic cell lysis induced by
(21%) and head-and-neck (14%).                                   anticancer therapies would release melanic precursors with
   Breslow level of primary melanoma was reported in only        subsequent dermal deposition [59].
20 cases, with a mean value of 3.3 mm.                              The latter hypothesis is not applicable to our case, as the
   Clark level also was reported in only 20 cases, 45% had       onset of DMC was prior to therapy initiation. Also, the pres-
Clark level IV, 30% level III and 25% level V.                   ence of cutaneous MM micro-metastases has been advocated
   Ulceration was not reported in the great majority of          as responsible for DMC [48]. However, this pathogenetic hy-
cases: only 2 articles mentioned ulceration. 100% of these       pothesis is disproved in our case by negative immunohisto-
had no ulceration.                                               chemistry indicating pigmentation is attributable only to the
   Mitotic rate was reported only for two cases: 21/mm2          presence of dermal melanin and melanophages and not to
            2
and <1/mm .                                                      neoplastic melanocytic clones.
   Overall, 40 patients were screened for lung metastasis:          DMC is to date considered a paraneoplastic manifesta-
58% had lung metastasis, 42% had not.                            tion of MM, burdened by a very poor prognosis. The average
   Overall, 49 patients were screened for liver metastasis:      survival described in the literature from the onset of DMC is
92% had liver metastasis, 8% had not.                            4 months, significantly lower than that of patients diagnosed
   Overall, 29 patients were screened for brain metastasis:      with stage IV MM, but without DMC [56,60].
48% had brain metastasis, 52% had not.                              The reasons for the prognostic gap remain unclear to
   Of 49 patients screened for melanuria, 96% had melanu-        date; some authors speculate that MM complicated by DMC
ria, 4% had not.                                                 may be characterized by specific genetic mutations [61].
   The mean survival rate from onset of DMC was reported            This would likely account for both the tendency of these
in 52 cases and resulted 4.36 months.                            MM to develop DMC and the worse prognosis, probably
   Of DMC patients 36 underwent skin biopsy to confirm           due to greater biological aggressiveness and less responsive-
the diagnosis.                                                   ness to therapies.


Conclusions                                                      References
Low-risk melanoma is defined as melanoma with a tumor             1. Odel HM, Montgomery H, Horton BT. Diffuse melanosis second-
thickness of 0.8 mm or less or stage I melanoma. This group          ary to malignant melanoma. Mayo Clinic Proc 1937:742-747.
                                                                  2. PRISMA statement PRISMA (prisma-statement.org). Retrieved
includes 70% of patients with cutaneous melanoma, and most
                                                                     October 20, 2022, from http://www.prisma-statement.org/
of these patients is unlikely to develop recurrences [54,55].
                                                                  3. Ritz ND. Diffuse melanosis, pericardial effusion, and melanu-
   DMC is a rare, late-term manifestation of MM.                     ria associated with malignant melanoma; case report with
   To date, approximately 65 DMC cases have been de-                 autopsy findings. Ann Intern Med. 1949(1):184-195. DOI:
scribed in the literature all of which, when described, report       10.7326/0003-4819-30-1-184. PMID: 18106240.




Review | Dermatol Pract Concept. 2024;14(1):e2024008                                                                            7
 4. Fitzpatrick TB, Montgomery H, Lerner AB. Pathogenesis of             20. Sexton M, Snyder CR. Generalized melanosis in occult primary
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    10.1038/jid.1954.22.                                                 21. Platin P, Sassolas B, Gavanou J, Guillet G. Quel est votre
 5. Goodall P, Spriggs AI, Wells FR. Malignant melanoma with mela-           ­diagnostic? Mélanodermie cutanée généralisée [What is your di-
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