10.5826/dpc.1301a57
Introduction: Mucosal melanoma  is a rare neoplasm. Late diagnosis is caused by occult anatomic sites and scarcity of symptoms. Novel biological therapies have now become available. Demographic, therapeutical and survival records on mucosal melanoma are scarce.
Objectives: To provide an 11-year retrospective clinical review of real-world data on mucosal melanomas managed in a tertiary referral center in Italy.
Methods: We included patients with histopathological mucosal melanoma diagnosis from January 2011 to December 2021. Data were collected until last known follow up or death. Survival analysis was performed. 
Results: Among 33 patients, we found 9 sinonasal, 13 anorectal and 11 urogenital mucosal melanomass (median age 82, females 66.7%). Eighteen cases (54.5%) presented with metastasis (p&lt;0.05). In the urogenital subgroup, only 4 patients (36.4%) had metastasis at diagnosis, all in regional lymph nodes. Sinonasal melanomas were surgically managed with a debulking procedure (44.4%); every case of anorectal and urogenital melanomas underwent radical surgery (30.8% and 45.5%). Fifteen patients were treated with biological therapy (p&lt;0.05). Radiation therapy was used in all melanomas of the sinonasal region (p&lt;0.05). Overall survival was longer for urogenital melanomas (26 months). Univariate analysis showed an increased hazard ratio for death in patients with metastasis. A negative prognostic value of metastatic status was reported by the multivariate model, while administration of first-line immunotherapy demonstrated a protective role.
Conclusions: At diagnosis, the absence of metastatic disease is the most relevant factor that influences the survival of mucosal melanomas. Moreover, the use of immunotherapy might prolong the survival of metastatic mucosal melanoma patients.
text/xml
2160-9381
2582
en
Caterina Longo
https://creativecommons.org/licenses/by-nc/4.0
Dermatology Practical & Conceptual
rare disease
Clinical Review of Mucosal Melanoma: The 11-Year Experience of a Referral Center
Text.Serial.Journal
https://dpcj.org/index.php/dpc
Original Article
2023-01-31
2022-05-09
2023-01-31
2023-02-27
e2023057
Dermatol Pract Concept
Introduction: Mucosal melanoma  is a rare neoplasm. Late diagnosis is caused by occult anatomic sites and scarcity of symptoms. Novel biological therapies have now become available. Demographic, therapeutical and survival records on mucosal melanoma are scarce.
Objectives: To provide an 11-year retrospective clinical review of real-world data on mucosal melanomas managed in a tertiary referral center in Italy.
Methods: We included patients with histopathological mucosal melanoma diagnosis from January 2011 to December 2021. Data were collected until last known follow up or death. Survival analysis was performed. 
Results: Among 33 patients, we found 9 sinonasal, 13 anorectal and 11 urogenital mucosal melanomass (median age 82, females 66.7%). Eighteen cases (54.5%) presented with metastasis (p&lt;0.05). In the urogenital subgroup, only 4 patients (36.4%) had metastasis at diagnosis, all in regional lymph nodes. Sinonasal melanomas were surgically managed with a debulking procedure (44.4%); every case of anorectal and urogenital melanomas underwent radical surgery (30.8% and 45.5%). Fifteen patients were treated with biological therapy (p&lt;0.05). Radiation therapy was used in all melanomas of the sinonasal region (p&lt;0.05). Overall survival was longer for urogenital melanomas (26 months). Univariate analysis showed an increased hazard ratio for death in patients with metastasis. A negative prognostic value of metastatic status was reported by the multivariate model, while administration of first-line immunotherapy demonstrated a protective role.
Conclusions: At diagnosis, the absence of metastatic disease is the most relevant factor that influences the survival of mucosal melanomas. Moreover, the use of immunotherapy might prolong the survival of metastatic mucosal melanoma patients.
Caterina Longo
2023/01/31
10.5826/dpc.1301a57
e2023057
Department of Dermatology, University of Modena and Reggio Emilia, Modena, Italy
2160-9381
rare disease
en
e2023057
Cinotti E, Chevallier J, Labeille B, et al. Mucosal melanoma: clinical, histological and c-kit gene mutational profile of 86 French cases. J Eur Acad Dermatol Venereol JEADV. 2017;31(11):1834-1840. doi:10.1111/jdv.14353
Clinical Review of Mucosal Melanoma: The 11-Year Experience of a Referral Center
https://dpcj.org/index.php/dpc/article/download/2582/1959
 Clinical Review of Mucosal Melanoma: The 11-Year
           Experience of a Referral Center
           Marco Spadafora1,2, Giacomo Santandrea1,3, Michela Lai1,2, Stafania Borsari2,
          Shaniko Kaleci4, Chiara Banzi5, Vincenzo Dario Mandato6, Giovanni Pellacani7,
                               Simonetta Piana3, Caterina Longo2,4


1 Clinical and Experimental Medicine PhD Program, University of Modena and Reggio Emilia, Modena, Italy
2 Centro Oncologico ad Alta Tecnologia Diagnostica, Azienda Unità Sanitaria Locale - IRCCS di Reggio Emilia, Reggio Emilia, Italy
3 Pathology Unit, Azienda Unità Sanitaria Locale - IRCCS di Reggio Emilia, Reggio Emilia, Italy
4 Department of Dermatology, University of Modena and Reggio Emilia, Modena, Italy
5 Medical Oncology Unit, Azienda Unità Sanitaria Locale - IRCCS di Reggio Emilia, Reggio Emilia, Italy
6 Unit of Obstetrics and Gynecology, Azienda Unità Sanitaria Locale - IRCCS, Reggio Emilia, Italy
7 Dermatology Clinic, Department of Clinical Internal, Anesthesiological and Cardiovascular Sciences, Sapienza University of Rome,
  Rome, Italy



Key words: mucosal melanoma, diagnosis, treatments, rare disease
Citation: Spadafora M, Santandrea G, Lai M, et al. Clinical Review Of Mucosal Melanoma: The 11-Year Experience Of A Referral Center.
Dermatol Pract Concept. 2023;13(1):e2023057. DOI: https://doi.org/10.5826/dpc.1301a57
Accepted: June 29, 2022; Published: January 2023
Copyright: ©2023 Spadafora 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: Caterina Longo, Department of Dermatology, University of Modena and Reggio Emilia, Italy. Azienda Unità
Sanitaria Locale – IRCCS di Reggio Emilia, Centro Oncologico ad Alta Tecnologia Diagnostica-Dermatologia, Reggio Emilia, Italy.
Phone: +390522295612 E-mail: longo.caterina@gmail.com




  ABSTRACT             Introduction: Mucosal melanoma is a rare neoplasm. Late diagnosis is caused by occult anatomic
                       sites and scarcity of symptoms. Novel biological therapies have now become available. Demographic,
                       therapeutical and survival records on mucosal melanoma are scarce.
                       Objectives: To provide an 11-year retrospective clinical review of real-world data on mucosal mela-
                       nomas managed in a tertiary referral center in Italy.
                       Methods: We included patients with histopathological mucosal melanoma diagnoses from January
                       2011 to December 2021. Data were collected until the last known follow-up or death. Survival anal-
                       ysis was performed.
                       Results: Among 33 patients, we found 9 sinonasal, 13 anorectal and 11 urogenital mucosal mela-
                       nomas (median age 82, females 66.7%). Eighteen cases (54.5%) presented with metastasis (p<0.05).




Original Article | Dermatol Pract Concept. 2023;13(1):e2023057                                                                       1
                     In the urogenital subgroup, only 4 patients (36.4%) had metastasis at diagnosis, all in regional lymph
                     nodes. Sinonasal melanomas were surgically managed with a debulking procedure (44.4%); every
                     case of anorectal and urogenital melanomas underwent radical surgery (30.8% and 45.5%). Fifteen
                     patients were treated with biological therapy (p<0.05). Radiation therapy was used in all melanomas
                     of the sinonasal region (p<0.05). Overall survival was longer for urogenital melanomas (26 months).
                     Univariate analysis showed an increased hazard ratio for death in patients with metastasis. A negative
                     prognostic value of metastatic status was reported by the multivariate model, while administration of
                     first-line immunotherapy demonstrated a protective role.
                     Conclusions: At diagnosis, the absence of metastatic disease is the most relevant factor that influences
                     the survival of mucosal melanomas. Moreover, the use of immunotherapy might prolong the survival
                     of metastatic mucosal melanoma patients.




Introduction                                                     mucosal melanoma arising in the urethra, vagina, rectum,
                                                                 and anus [8].
Melanoma is a malignant tumor arising from melano-                   Surgical excision with negative margins, which is the
cytes [1]. Although melanocytes are mostly localized in the      treatment of choice in mucosal melanomas, is often un-
skin, their precursors reach also endodermal and ectoder-        feasible because of an anatomically complex site of ori-
mal mucosae migrating from the neural crest [2]. Primary         gin [7,9]. Patients with unresectable or metastatic mucosal
mucosal melanoma arises from mucosal membranes lining            melanomas can be treated with the same regimen proposed
the head and neck (i.e. nasal and oral cavities), anorectal,     for cutaneous melanoma [10], although the frequency of
vulvovaginal, and urinary tract in order of frequency [3,4].     common driver BRAF is low compared to the cutaneous
The occult locations in which mucosal melanoma occurs            counterpart (50% vs 3-5%), with reduced usefulness of
preclude sun exposure as a predisposing risk factor; the eti-    targeted therapy [1]. Mutation of the KIT gene is detected
ologic factors driving tumorigenesis in mucosal melanoma         in about 25% of mucosal melanomas [1]; to date, guide-
have not been discovered yet [5]. Mucosal melanoma rep-          lines suggest KIT testing only when BRAF and, eventually,
resents 0.03% of all cancer diagnoses and 0.8-3.7% of all        NRAS, mutational status have been established; KIT tar-
melanomas [5,6], with a higher incidence in women than           geted therapy is usually administered as a second line ther-
men; different gender incidence is mainly due to vulvovagi-      apy [8]. In the last few years, immune checkpoint inhibitors
nal neoplasia, which represents alone 18% of mucosal mel-        (ICIs) have become a preferred first-line approach for pa-
anomas [1].                                                      tients with advanced or metastatic cutaneous melanoma.
    Most patients with mucosal melanoma are diagnosed in         A recent review [7] showed that anti-CTLA-4 antibody ip-
a metastatic stage because of the late occurrence of symp-       ilimumab has less efficacy as monotherapy than monoclo-
toms and the occult location of the primary tumor [7].           nal antibodies targeting the PD-1 and PD-L1, which have
The most common symptoms in nasal cavity melanomas               proven more effective in the treatment of MMs, with pro-
are unilateral nasal obstruction, mass lesion, and epistaxis     longed survival and acceptable toxicity. A sub-analysis of
while in the oral cavity symptoms such as swelling, ulcer-       mucosal melanomas performed in a five-year survival trial
ation, bleeding, pain, or tooth mobility can occur. Anorectal    showed similar data on efficacy [8,11]. The treatment regi-
melanomas usually manifest with rectal bleeding, anorectal       men currently authorized by Agenzia Italiana del Farmaco
discomfort, or prolapse of the tumor mass. In vulvovaginal       for advanced mucosal melanoma includes ipilimumab and
melanomas presenting symptoms are bleeding, vulvar mass,         anti-PD1 antibodies, while Imatinib is approved for unre-
pruritus, pain or irritation, micturition discomfort, and dis-   sectable metastatic melanoma in progression after immu-
charge [4].                                                      notherapy [8].
    There is no universal staging system for mucosal melano-         As primary mucosal melanoma is an exceedingly rare
mas. Head and neck mucosal melanomas are usually staged          neoplasm, demographic, histopathological, therapeutical,
according to the American Joint Committee on Cancer              and survival records on this topic are scarce. The current
(AJCC) criteria for head and neck cancer; vulvar melanoma        study aims to provide an 11-year retrospective clinical re-
can be staged following the AJCC criteria for cutaneous mel-     view of the real-world data on mucosal melanomas managed
anoma, while no staging criteria have been established for       in a tertiary referral center in Italy.




2                                                                     Original Article | Dermatol Pract Concept. 2023;13(1):e2023057
Methods                                                          the univariate and multivariate regression analyses were ex-
                                                                 pressed as Hazard ratio (HR) with it 95% confidence in-
This was a retrospective study performed between                 terval (CI). A p<0.05 was considered statistically significant.
01/01/2011 to 31/12/2021. This study was approved by
the Institutional Review Board of Azienda Unità Sanitaria
                                                                 Results
Locale – IRCCS di Reggio Emilia, Italy (protocol number
#2011/02347213).                                                 Demographic, Clinical, and Treatment Data
    We included consecutive patients with a histopatho-          Among 33 patients with primary mucosal melanomas who
logically confirmed diagnosis of mucosal melanomas. We           were included in our analyses, we found 9 melanomas of the
excluded recurrent tumors, unknown primary melanomas,            sinonasal region, 13 anorectal melanomas and 11 urogen-
and cases for which histological slides were not available for   ital melanomas (of which 10 vulvovaginal melanomas and
re-evaluation.                                                   1 bladder melanoma), as reported in Table 1 and Figure 1.
    Data from the first clinical or instrumental diagnosis to    Median age at diagnosis was 82 years (75-83), with no sub-
the date of each patient’s last known follow-up appointment      stantial differences by anatomical site. More women than
or death was obtained from digital medical records. We re-       men had mucosal melanoma (n= 22, 66.7%). Median fol-
corded patient age, gender, location of the lesion, presenting   low-up period was 11.5 months.
symptoms, site of metastasis at diagnosis if any (locoregional      Presenting symptoms for which physicians were con-
lymph node involvement, cerebral, visceral, or multiple me-      sulted by the patient were recorded in Table 2 (in our series
tastases when more than one of the previous sites was in-        dermatologists, otolaryngologists, gynecologists, and endos-
volved) and histopathological and molecular features (cell       copists); most patients were then managed by the Skin Can-
morphology, Breslow thickness and ulceration when not            cer Tumor Board.
compromised by fragmentation or orientation of biopsy               We observed that 18 cases of mucosal melanoma (54.5%)
specimen, and mutational status).                                out of 33 presented with metastasis at diagnosis (p<0.05)
    Surgery was recorded as debulking procedure or radical       and that 91% and 66% of patients with anorectal and sin-
treatment. Systemic treatments were categorized according to     onasal melanomas had at least one metastatic site at diagno-
current recommendations [8,10] as first-line biological treat-   sis. In urogenital melanomas, 4 out of 11 (36.4%) showed
ment (nivolumab, pembrolizumab, or imatinib), as first-line      metastases which were all diagnosed in locoregional lymph
chemotherapy when the patient was administered with sys-         nodes (inguinofemoral nodes) and no distant metastases.
temic therapy in the pre-biological era, and as ­second-line        Surgery: Clinical records reported that 39.4% of patients
treatments when therapy was switched to a different ther-        underwent surgical treatment (p<0.05). All the sinonasal
apy because of disease progression. We also recorded if the      melanomas which were surgically managed (44.4%) under-
patient underwent radiation therapy on the primary tumor,        went a debulking procedure, while every surgically managed
which was always managed with a cytoreductive-palliative         anorectal and urogenital melanoma had a radical intent pro-
purpose in our series [12].                                      cedure (30.8% and 45.5%). Most patients did not undergo
                                                                 surgery because of metastasis at diagnosis (n=14), detection
Statistics                                                       of different neoplasia at primary staging (n=2), unresectable
Statistical analysis was performed using STATA® software         tumor (n=3), age of the patient (n=1), death of the patient
version 17 (StataCorp, 4905 Lakeway Drive, College Sta-          before surgery (n=1).
tion, Texas 77845 USA). Descriptive statistics were pre-            Systemic treatment: We identified 15 patients treated
sented for baseline demographic clinical characteristics for     with systemic biological therapy as first-line treatment
the entire group, as well as for the groups of patients with     (p<0.05); 13 received nivolumab, 2 subjects were treated
different locations. Continuous variables were presented as      with pembrolizumab and 1 subject with imatinib. Only 1
the number of patients (N), mean, standard deviation (SD),       patient received first-line chemotherapy (cyclophosphamide,
­minimum (min), and maximum (max) and compared be-               vincristine, and dacarbazine combination treatment).
tween subgroups using Unpaired Student’s t-test; categorical        Furthermore, 5 patients were switched to a second-line
variables were presented as frequency (N, percentage [%])        systemic therapy; 3 of them were switched to ipilimumab, 1
and compared using Pearson’s chi‐squared test. Survival          to pembrolizumab and 1 to monotherapy with dacarbazine.
analysis was performed using the Kaplan-Meier method                Radiation therapy (RT): in our analysis, RT on the primary
and comparison between the survival curves was done us-          tumor has always been proposed as a ­cytoreductive-palliative
ing log-rank test. Univariate and multivariate analyses were     treatment; it was performed in all cases of sinonasal mela-
done using the Cox-regression hazard model. Data from            noma (p<0.05). Anorectal melanomas were treated with RT




Original Article | Dermatol Pract Concept. 2023;13(1):e2023057                                                                3
               Table 1. Comparison of demographic, clinical, and survival data in patients with
                         mucosal melanomas and stratification by the site of origin.
                                                      Mucosal                              Anorectal          Urogenital
                                                     melanomas           Sinunasal          (n=13,              (n=11,
                                                    (n=33, 100%)        (n=9, 27.3)         39.4%)             33.3%)          p-value
 Age at diagnosis, median (IQR)                       82 (75-85)         82 (75-83)        80 (72-87)         83 (80-85)        0.977
 Female                                                22 (66.7)          5 (55,6)           6 (46,2)          11 (100)         0.015
 Metastasis at diagnosis                               18 (54.5)          4 (44,4)          10 (76.9)           4 (36.4)
 Regional lymph nodes                                  8 (24.2)            0 (0.0)           4 (30.8)           4 (36.4)
 Visceral                                              4 (12.1)           3 (33.3)            1 (7.7)           0 (0.0)         0.021
 Cerebral                                               2 (6.1)            0 (0.0)           2 (15.4)           0 (0.0)
 ≥2 sites                                              4 (12.1)           1 (11,1)           3 (23.1)           0 (0.0)
 Surgical treatment                                    13 (39.4)          4 (44.4)           4 (30.8)           5 (45.5)
 Debulking                                             4 (12.1)           4 (44.4)            0 (0.0)           0 (0.0)         0.015
 Radical excision                                      9 (27.3)            0 (0.0)           4 (30.8)           5 (45.5)
 First-line biological therapy                         17 (51.5)          5 (55.5)           6 (46.2)           5 (45.5)
 Nivolumab                                             13 (39.4)          4 (44.4)           4 (30.8)           5 (45.5)
                                                                                                                                0.005
 Pembrolizumab                                          2 (6.1)           1 (11.1)            1 (7.7)           0 (0.0)
 Imatinib                                               1 (3.0)            0 (0.0)            1 (7.7)           0 (0.0)
 First-line chemotherapy                                1 (3.0)           1 (11.1)            0 (0.0)           0 (0.0)         0.253
 Second-line systemic therapy                          5 (15.1)           2 (22.2)           2 (15.4)           1 (9.1)
 Ipilimumab                                             3 (9.1)           2 (22.2)            1 (7.7)           0 (0.0)
                                                                                                                                0.383
 Pembrolizumab                                          1 (3.0)            0 (0.0)            1 (7.7)           0 (0.0)
 Dacarbazine                                            1 (3.0)            0 (0.0)            0 (0.0)           1 (9.1)
 Radiation therapy on the primary tumor                17 (51.5)           9 (100)           6 (46.2)           2 (18.2)        0.004
 Overall survival, median (IQR) months                 11 (6-25)         14 (6-22)           6 (2-11)         26 (11-34)        0.021
 Overall survival rate%, 12 months                         71                55                 54                100
 Overall survival rate%, 12 months                         54                37                 18                100
 Median follow-up period (months)                        11.5                 -                  -                    -

IQR: interquartile range




                                                          Mucosal Melanoma
                                                                n=33



                                Sinonasal                     Anorectal                      Urogenital
                                Melanoma                      Melanoma                       Melanoma
                               n=9 (27.3%)                   n=13 (39.4%)                   n=11 (33.3%)

                           Figure 1. Flow diagram showing mucosal melanoma subdivided by anatomical site of origin.


                 Table 2. Presenting symptoms of mucosal melanoma by anatomical region.
                                                                         Presenting symptoms (n)
 Site of primary melanoma
 Sinonasal                             Epistaxis (2), nasal obstruction (2), eyelid ptosis (1)
 Anorectal                             Rectorrhagia (4), tumor mass prolapse (2), anemia (2)
 Urogenital                            Tumor mass (6), pigmentation of external genitalia (1), vaginal bleeding (1)

n= number(s)



4                                                                            Original Article | Dermatol Pract Concept. 2023;13(1):e2023057
in 46.3% of cases while only 2 patients with urogenital mel-            cavities, melanocytes can be found both in the epithelium
anomas were treated with RT.                                            and in the stroma, mainly in the dark-skinned population.
      Survival data: Overall survival (OS), expressed as a me-               Delayed site-related detection of these melanomas can
dian value, was longer in urogenital melanomas (26 months),             explain their architecture, which is often nodular or polyp-
than sinonasal melanomas (14 months) and anorectal mela-                oid, and, at the same time, their thickness, which is usually
nomas (6 months).                                                       higher than most cutaneous melanomas.
      As reported in the Kaplan-Meier estimate (Figure 2), si-               Most mucosal melanomas are often associated with
nonasal and anorectal melanoma carried higher mortality in              an in situ lateral spread on the mucosal surface (Figure 3),
the first two years; anorectal melanoma had a high mortality            which is a supportive feature that the tumor is primitive.
rate over time while sinonasal melanoma reached a plateau.              Cytologically, mucosal melanomas are remarkably variable;
Urogenital melanoma showed longer survival in the first two             neoplastic cells can be spindle, rhabdoid, epithelioid, small,
years from diagnosis with delayed mortality.                            or giant pleomorphic (often multinucleated), thus causing
      The 24-month overall survival rate among mucosal mel-             challenging diagnostic problems in differentiating them
anoma patients was 54%. The 24-month overall mortality                  from lymphomas, carcinomas or sarcomas. Necrotic areas
for the location was 37% in sinonasal melanomas, 18% in                 are frequent and mitotic activity is usually high (Figure 4).
anorectal melanoma and 100% in urogenital melanoma.                     Due to their heterogeneous appearance, immunohisto-
The last observed exit from the estimate was 58 months                  chemical staining (S100, MART-1, HMB45 or SOX10) is
(Figure 2).                                                             often required to demonstrate the melanocytic origin of the
      The univariate analysis showed that metastasis at diag-           neoplasm.
nosis was significantly associated with mortality (Table 2).                 In our series, epithelioid features were prevalent (25 out
In the multivariate analysis, the risk factor significantly as-         of 33 cases). Two cases were composed of spindle hyperpig-
sociated with mortality was the presence of metastasis at               mented cells, two cases had a lymphocytic-like appearance,
diagnosis, while first-line immunotherapy demonstrated a                one was rhabdoid and, in three cases, the cytological pattern
protective role (Table 4).                                              of growth was mixed (Figure 5).
                                                                             Mean Breslow thickness in mucosal melanoma was 6.7
Histopathologic and Molecular Data                                      with no appreciable difference between different anatomical
Mucosal melanomas can occur in all sites where muco-                    sites; no Breslow thickness was reported in sinonasal mela-
sal melanocytes are present. While perianal, genital, and               nomas due to the sparse and fragmented nature of biopsy
perioral skin normally harbors melanocytes (and, conse-                 specimens. Tumor ulceration was noted in 11 samples. In
quently, these are sites of origin of benign and malignant              one case of vulvar melanoma, a residual melanocytic nevus
melanocytic tumors, albeit rare), melanocytes are usually               was found at the periphery of the tumor.
absent in the bladder mucosa. In the rare case of bladder                    No samples undergoing biomolecular analysis had BRAF
melanoma, a spread of melanocytes from the urethra could                or NRAS mutation, while 3 cases had c-KIT and 3 cases
explain its etiopathogenesis. In the nasal and paranasal                KRAS mutations.




 A)                       Kaplan–Meier survival estimate                B)                      Kaplan–Meier survival estimates
              1.00




                                                                                     1.00
                                                                                     0.75
              0.75




                                                                                     0.50
              0.50




                                                                                     0.25
                                                                                     0.00
              0.25




                                                                                            0           20                   40               60
                                                                                                             Analysis time
                                                                          Number at risk
                                                                       Sinonasal melanoma 9              3                   1                0
              0.00




                                                                       Anorectal melanoma 13             2                   0                0
                                                                       Urogeital melanoma 11             7                   2                0
                     0           20                   40          60
                                      Analysis time                                               Sinonasal melanoma     Anorectal melanoma
 Number at risk                                                                                   Urogintal melanoma
                     33          12                   3           0


Figure 2. Kaplan Meier estimates for overall survival. (A) OS in mucosal melanomas. (B) Stratification of the cohort by the site of the
primary tumor.



Original Article | Dermatol Pract Concept. 2023;13(1):e2023057                                                                                     5
               Table 3. Univariable model of risk factors for mortality in mucosal melanomas.
                                                                          HR 95% CI                              p-value
 Age at diagnosis                                                      1.02 (0.97-1.07)                           0.292
 Gender
 Female                                                                       ref.
 Male                                                                  1.93 (0.67-5.45)                           0.216
 Location
 Sinonasal                                                                    ref.
                                                                       1.90 (0.57-6.29)                           0.291
 Urogenital                                                            0.25 (0.05-1.09)                           0.066
 Metastasis at diagnosis
 No                                                                           ref.
 Yes                                                                   8.75 (1.79-42.76)                          0.007
 Site of metastasis at diagnosis
 Skin/regional lymph node                                                     ref.
 Visceral                                                              3.30 (0.34-31.96)                          0.302
 Cerebral                                                              6.21 (0.53-72.00)                          0.144
 ≥2 sites                                                              2.50 (0.22-27.95)                          0.456
 Surgery
 No                                                                           ref.
 Debulking                                                             0.19 (0.02-1.59)                           0.129
 Radical                                                               0.33 (0.09-1.16)                           0.085
 First-line biological therapy
 No                                                                           ref.
 Nivolumab                                                             0.88 (0.26-2.95)                           0.840
 Pembrolizumab                                                         1.16 (0.13-9.63)                           0.890
 Imatinib                                                              2.71 (0.31-23.21)                          0.362
 First-line chemotherapy
 No                                                                           ref.
 Yes                                                                   1.84 (0.23-14.66)                          0.561
 Second-line systemic therapy
 No                                                                           ref.
 Ipilimumab                                                            0.71 (0.09-5.68)                           0.752
 Pembrolizumab--
 Dacarbazine                                                           1.42 (0.17-11.30)                          0.740
 Cytoreductive-palliative radiation therapy
 No                                                                           ref.
 Yes                                                                   1.65 (0.56-4.90)                           0.360

HR: hazard ratio
CI: confidence interval


    Detailed descriptive data from histopathologic and mo-             Demographic data also confirm that mucosal melanoma has a
lecular data are reported in Table 5.                                  higher prevalence in females [9]; this result is largely driven by
                                                                       cases of vulvovaginal melanoma in the urogenital melanoma

Discussion                                                             subgroup. Surprisingly, we have no records of oral cavity muco-
                                                                       sal melanomas, which alone have been described as the second
This 11-year retrospective study shows that mucosal melanoma           most frequent location in the head and neck region [2,8,9].
is a tumor typically arising in the older population, with a me-          Histologically, most cases were made by epithelioid cells,
dian age of 82, not significantly influenced by site of origin [13].   regardless of the site of origin. In many cases, pleomorphic



6                                                                          Original Article | Dermatol Pract Concept. 2023;13(1):e2023057
             Table 4. Multivariable model of risk factors for mortality in mucosal melanomas.
                                                                 HR 95% CI                                     p-value
 Age at diagnosis                                           1.02 (0.96-1.09)                                    0.574
 Gender
 Female                                                             ref.
 Male                                                      3.33 (0.98-11.25)                                    0.107
 Metastasis at diagnosis
 No                                                                 ref.
 Yes                                                     26.55 (3.18-221.42)                                    0.001
 First-line biological therapy
 No                                                                 ref.
 Nivolumab                                                  0.10 (0.01-0.75)                                    0.025
 Pembrolizumab                                              0.04 (0.01-0.91)                                    0.044
 Imatinib                                                   0.09 (0.0-2.02)                                     0.133

CI: confidence interval




          Figure 3. Vulvar melanoma (A) Clinical overview of a nodular hyperpigmented lesion of the vulva. (B) Dermoscopy of
          the nodular part shows a blue-black structureless area with shiny white structures and negative pigment network at the
          implant base. (C) Dermoscopy of the flat part shows blue and black globules and blotches, a blue-white veil, and shiny
          white structures. (D) Histology: the neoplasm is largely ulcerated, shows discrete necrotic areas, and reaches 11 mm
          thickness according to Breslow. At a higher power view, vascular invasion of neoplastic cells is visible (arrow).



Original Article | Dermatol Pract Concept. 2023;13(1):e2023057                                                                     7
        Figure 4. Architectural features of mucosal melanoma in hematoxylin and eosin. (A) A sinonasal melanoma growing as a
        polypoid, edematous, and highly vascularized mass. Melanoma involves the entire polyp with multiple confluent nodules,
        reaching at least 1 mm Breslow thickness. The transitional respiratory epithelium is still recognizable all around. (B) A nod-
        ular melanoma arising at the interface between intestinal and squamous perianal epithelium. Breslow thickness is 14 mm
        (C) A vaginal nodular melanoma without any visible in situ component in the squamous vaginal epithelium. The tumor is
        superficially ulcerated, and Breslow thickness is 9 mm.



areas with bizarre, giant cells were present. Only two cases             reported by the multivariate model. These findings corrob-
of spindle cell melanomas were recorded, even if spindle cell            orate the evidence that diagnosing advanced-stage tumors
areas occurred in three cases with a mixed pattern of growth.            has a relevant influence on prognosis [14]. As previously dis-
The epithelioid features and the presence of melanin, which              cussed [9], the site of origin of neoplasia, mostly anatomically
in rare cases can be massive, simplified the diagnosis; vice             occult, is a relevant cause of late diagnosis. Incidence of mu-
versa, differential diagnosis resulted challenging in two cases          cosal melanomas in older age could be an additional cause,
of lymphoma-like melanoma (one anorectal and one genital)                as older people can delay seeking physician consultation.
and an immunohistochemical panel of stains was necessary                     The multivariate model also showed that the administra-
to rule out a lymphoproliferative process.                               tion of immunotherapy as a first-line treatment was a protec-
    More than half of mucosal melanomas (54.4%) mani-                    tive factor for death, with a statistical significance both for
fested with metastasis at diagnosis. Patients who were dis-              nivolumab and pembrolizumab. No significance has been
covered with metastasis have an increased HR for death                   obtained for imatinib, because of the small sample.
as highlighted by univariate analysis (Table 3); in addition,                It is interesting to highlight that, despite the small sam-
the prognostic value of metastatic status at diagnosis was               ple size in the current study, our data support the utility of



8                                                                             Original Article | Dermatol Pract Concept. 2023;13(1):e2023057
Figure 5. Unusual cytological features of mucosal melanoma in hematoxylin and eosin. (A) Pleomorphic areas in an epithelioid vulvar
­melanoma. Melanocytes are irregularly shaped, and nuclei are bizarre. The arrow indicates an abnormal mitotic figure. (B) A hyperpigmented
 genital melanoma, composed of middle-sized, mitotically active spindle cells. (C) A rectal melanoma made up of small, monomorphous
 lymphocytic-like cells. Immunohistochemical staining is necessary to confirm the melanocytic origin of the tumor (in the inset, HMB45
 diffusely stains the cells). (D) A rectal melanoma with a rhabdoid appearance. Neoplastic cells show a large, eosinophilic cytoplasm and
 peripherally located round nucleus.




immunotherapy to prolong survival in metastatic mucosal mel-           also reported [18,19] that females diagnosed with mucosal
anoma [7]. A recent international cohort study [15] remarked           melanomas have higher survival, unrelated to the site of or-
on the efficacy of the anti-PD1 agent in prolonging survival           igin; thus, the longer survival in this cohort could also be
in metastatic patients, even though to a lesser extent than in         driven by the prevalence of vulvovaginal melanoma in the
cutaneous melanoma. In fact, mucosal melanoma has been re-             subgroup. Surgical treatment with radical intent, undergone
ported to have a lower expression of PD-L1 than its cutaneous          by all patients with urogenital melanoma in our series, may
counterpart [16] and of being more ­tolerogenic [17] probably          be an additional factor influencing longer survival.
because of the absent mutagenic role of UV radiation that pre-             No case of male urogenital melanomas was reported in
vents a high tumor mutational load and immunogenicity.                 the database of the Pathology Unit of our hospital confirm-
                                                                       ing that mucosal melanoma of the male genital tract is a very
Urogenital Melanoma                                                    rare occurrence [4].
In our series, urogenital melanoma showed 4 cases of metas-                Urogenital melanomas in our database manifested as a
tasis in locoregional lymph nodes and no distant metastasis            vegetating mass, new pigmentation of the external genitalia,
at diagnosis. Moreover, urogenital melanoma is the sub-                or urogenital bleeding (Table 2).
group with the longer OS, with full survival at 24 months
and decreased survival only after 26 months (Figure 2). The            Anorectal Melanoma
absence at diagnosis of disseminated disease is probably the           Patients with anorectal melanoma showed a younger age at
most relevant factor that influences cohort survival. It was           diagnosis (Table 1).



Original Article | Dermatol Pract Concept. 2023;13(1):e2023057                                                                           9
           Table 5. Mucosal melanoma pathological data and stratification by the site of origin.
                                     Mucosal melanomas              Sinunasal            Anorectal                Urogenital
                                       (n=33, 100%)               (n=9, 27.3%)         (n=13, 39.4%)            (n=11, 33.3%)
 Breslow, n, mean ± SD (range)        10, 6.7 ±5.2 (0.6-17)             -            3, 7.1 ±5.3 (1.4-12)    7, 6.5 ±5.6 (0.6-17)
 Ulceration
 No                                            1 (3.0)               0 (0.0)                   0                     1 (9.1)
 Yes                                        11 (33.3)                0 (0.0)               5 (38.5)                 6 (54.5)
 Cytology
 Epithelioid cells                          25 (75.7)                9 (100)              10 (76.9)                 6 (54.5)
 Spindle cells                                 2 (6.1)               0 (0.0)                1 (7.6)                  1 (9.1)
 Small cells                                   2 (6.1)               0 (0.0)                1 (7.6)                  1 (9.1)
 Rhabdoid cells                                2 (6.1)               0 (0.0)                1 (7.6)                  0 (0.0)
 Mixed                                         3 (9.1)               0 (0.0)                0 (0.0)                 3 (27.2)
 LVI
 No                                          7 (21.2)               1 (11.1)                1 (7.7)                 5 (45.5)
 Yes                                         5 (15.2)               1 (11.1)               2 (15.4)                 2 (18.2)
 BRAF, wt                                   25 (75.8)               8 (88.9)              10 (76.9)                 7 (63.6)
 c-KIT
 V560D                                         3 (9.1)               0 (0.0)                1 (7.7)                 2 (18.2)
 wt                                          8 (24.2)               2 (22.2)               5 (38.5)                  1 (9.1)
 NRAS, wt                                    9 (27.3)               3 (33.3)               4 (30.8)                 2 (18.2)
 KRAS
 p.A146V                                       1 (3.0)               0 (0.0)                1 (7.7)                  0 (0.0)
 p.G12A                                        1 (3.0)              1 (11.1)                0 (0.0)                  0 (0.0)
 p.G12C                                        1 (3.0)               0 (0.0)                1 (7.7)                  0 (0.0)
 wt                                            1 (3.0)              1 (11.1)                0 (0.0)                  0 (0.0)

LVI: lymphovascular invasion



     Even though all patients surgically managed in this sub-          Additional evidence emerging from Kaplan-Meier analy-
group underwent a radical intent procedure, Kaplan-Meier            sis is that the mortality of sinonasal mucosal melanomas was
analysis showed the worst survival. This result is consistent       higher in the first 24 months and then decreased, reaching
with previous reports [15,18]. It is reasonable to suppose          a plateau (Figure 2). Factors that may influence this behav-
that a more widespread metastatic disease at diagnosis in this      ior, such as radiation therapy, administered to all cohort pa-
subgroup is the reason for this difference (Table 1). It was        tients, are still unclear and need to be further analyzed in a
demonstrated that anorectal melanoma has an intrinsically           larger sample.
aggressive behavior because of the high propensity to develop          Sinonasal melanomas in our series manifested with ep-
distant and brain metastases [18]; in our series, this subgroup     istaxis, nasal obstruction, and one case of eyelid ptosis
is the only one manifesting with 2 cases of cerebral metastasis     (Table 2).
and with 3 cases of multiple visceral metastases at diagnosis.
     Anorectal melanomas diagnosed in our clinics had pre-
                                                                    Conclusions
senting symptoms such as rectal bleeding, anemia, and pro-
lapse of the tumor mass (Table 2).                                  In conclusion, different strategies have to be developed to
                                                                    avoid late diagnosis; so far, there are no targeting cam-
Sinonasal Melanoma                                                  paigns or specific advice that can help physicians from dif-
In the sinonasal region, Breslow thickness is not easy to ap-       ferent specialties (i.e. gynecologists) to get early diagnoses
ply because of biopsy sampling. In fact, all surgical treat-        of this rare melanoma subsets. As promising results, the
ments proposed to this cohort of patients were debulking            use of immunotherapy might impact the natural history of
procedures that usually prevent obtaining a well-oriented           mucosal melanomas in improving overall or disease-free
full-thickness specimen for histopathological analysis.             survival.



10                                                                      Original Article | Dermatol Pract Concept. 2023;13(1):e2023057
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Original Article | Dermatol Pract Concept. 2023;13(1):e2023057                                                                           11
