Mucosal Melanoma of the Head and Neck

Melanoma of the Glans Penis and Urethra

Purpose Mucosal melanoma is an aggressive malignancy with a poor response to conventional therapies. The efficacy and safety of nivolumab (a programmed death-1 checkpoint inhibitor), alone or combined with ipilimumab (a cytotoxic T-lymphocyte antigen-4 checkpoint inhibitor), have not been reported in this rare melanoma subtype. Patients and Methods Data were pooled from 889 patients who received nivolumab monotherapy in clinical studies, including phase III trials; 86 (10%) had mucosal melanoma and 665 (75%) had cutaneous melanoma. Data were also pooled for patients who received nivolumab combined with ipilimumab (n = 35, mucosal melanoma; n = 326, cutaneous melanoma). Results Among patients who received nivolumab monotherapy, median progression-free survival was 3.0 months (95% CI, 2.2 to 5.4 months) and 6.2 months (95% CI, 5.1 to 7.5 months) for mucosal and cutaneous melanoma, with objective response rates of 23.3% (95% CI, 14.8% to 33.6%) and 40.9% (95% CI, 37.1% to 44.7%), respectively. Median progression-free survival in patients treated with nivolumab combined with ipilimumab was 5.9 months (95% CI, 2.8 months to not reached) and 11.7 months (95% CI, 8.9 to 16.7 months) for mucosal and cutaneous melanoma, with objective response rates of 37.1% (95% CI, 21.5% to 55.1%) and 60.4% (95% CI, 54.9% to 65.8%), respectively. For mucosal and cutaneous melanoma, respectively, the incidence of grade 3 or 4 treatment-related adverse events was 8.1% and 12.5% for nivolumab monotherapy and 40.0% and 54.9% for combination therapy. Conclusion To our knowledge, this is the largest analysis of data for anti-programmed death-1 therapy in mucosal melanoma to date. Nivolumab combined with ipilimumab seemed to have greater efficacy than either agent alone, and although the activity was lower in mucosal melanoma, the safety profile was similar between subtypes.

Comparative investigation of cell cycle and immunomodulatory genes in mucosal and cutaneous melanomas: Preliminary data suggest a potential promising clinical role for p16 and the PD-1/PD-L1 axis

Subtypes of melanoma, such as mucosal, uveal, and acral, are believed to result in worse prognoses than nonacral cutaneous melanoma. After a diagnosis of distant metastatic disease, however, the overall survival of patients with mucosal, uveal, acral, nonacral cutaneous, and unknown primary melanoma has not been directly compared. We conducted a single-center, retrospective analysis of 3,454 patients with melanoma diagnosed with distant metastases from 2000 to 2013, identified from a prospectively maintained database. We examined melanoma subtype, date of diagnosis of distant metastases, age at diagnosis of metastasis, gender, and site of melanoma metastases. Of the 3,454 patients (237 with mucosal, 286 with uveal, 2,292 with nonacral cutaneous, 105 with acral cutaneous, and 534 with unknown primary melanoma), 2,594 died. The median follow-up was 46.1 months. The median overall survival for those with mucosal, uveal, acral, nonacral cutaneous, and unknown primary melanoma was 9.1, 13.4, 11.4, 11.7, and 10.4 months, respectively. Patients with uveal melanoma, cutaneous melanoma (acral and nonacral), and unknown primary melanoma had similar survival, but patients with mucosal melanoma had worse survival. Patients diagnosed with metastatic melanoma in 2006-2010 and 2011-2013 had better overall survival than patients diagnosed in 2000-2005. In a multivariate model, patients with mucosal melanoma had inferior overall survival compared with patients with the other four subtypes. Additional research and advocacy are needed for patients with mucosal melanoma because of their shorter overall survival in the metastatic setting. Despite distinct tumor biology, the survival was similar for those with metastatic uveal melanoma, acral, nonacral cutaneous, and unknown primary melanoma. Uveal, acral, and mucosal melanoma are assumed to result in a worse prognosis than nonacral cutaneous melanoma or unknown primary melanoma. No studies, however, have been conducted assessing the overall survival of patients with these melanoma subtypes starting at the time of distant metastatic disease. The present study found that patients with uveal, acral, nonacral cutaneous, and unknown primary melanoma have similar overall survival after distant metastases have been diagnosed. These findings provide information for oncologists to reconsider previously held assumptions and appropriately counsel patients. Patients with mucosal melanoma have worse overall survival and are thus a group in need of specific research and advocacy.

PurposeTo investigate the frequency and characteristics of pulmonary metastases from malignant melanoma presenting as ground-glass opacity nodules (GGNs) on chest computed tomography (CT).Material and methodsA total of 354 patients with malignant melanoma who underwent chest CT for staging or follow-up were selected. We reviewed the CT images and enrolled 87 patients with lung metastases. Two radiologists evaluated the nodularity of the lung metastases (solid nodules or GGNs). Additionally, the tumor doubling time and disease type (mucosal, cutaneous, or acral melanomas) were analyzed.ResultsGGNs were observed in 13 of 87 (14.9%) patients. The tumor doubling time was 52.0 ± 33.5 days (range: 10.9–111 days) for GGNs and 43.8 ± 27.5 days (range: 9.4–115.3 days) for solid nodules. GGNs changed to solid nodules in 54.5% of patients with increased GGN metastasis. More patients in the GGN group (patients whose metastases included GGNs) had mucosal melanomas than acral melanomas (p = 0.0478); however, no significant difference was observed in the frequency of mucosal and cutaneous melanomas (p = 0.0670). Similarly, the proportion of patients in the GGN-dominant pattern group (patients with GGNs only or more GGNs than solid nodules) who had mucosal melanomas was more than that of patients with acral and cutaneous melanomas (mucosal melanoma vs. acral melanoma, p = 0.0342; mucosal melanoma vs. cutaneous melanoma, p = 0.0344).ConclusionsLung metastases from malignant melanoma sometimes appear as GGNs on CT, with a frequency of 14.9% in this study. If lung metastasis is observed as a GGN, the tumor doubling time may be useful for differentiating lung metastasis of malignant melanoma from lung adenocarcinoma.

e20016 Background: Mucosal melanoma (MM) of head and neck (H&N) is a relatively rare and different disease from cutaneous melanoma (CM). We aimed to define clinical features and outcomes of patients with MM of H&N and to emphasize its differences from CM. Methods: The medical records of patients (n= 41 for MM, n=94 for CM) between 2000 and 2010 were assesed. Results: In MM group, 21 patients had primary oral cavity (OCM) and 20 had sinonasal melanoma (SNM). The median age was 60 years and gender distribution was similar. Thirty-two (78%) of patients had stage I, 4 (10%) had stage II, and 5 (12%) patients had stage III disease. One and 5-year overall survival (OS) rates were 81% and 58%, and similar for SNM and OCM (p=0.67). Among CM patients, primary sites were face (53%), scalp (28%) and ear region (19%). Facial melanoma (FM) patients were older (p=0.001) than scalp (SM) or ear melanoma (EM). Male gender was more frequent among SM patients (81%) than FM (42%, p=0.001) and EM (50%, p=0.03). Most of FM patients had localized disease (84%), while most of EM (72%) and SM (46%) patients had advanced disease. One and 5-year OS rates of CM were 86% and 43%, respectively. Five-year OS rates were 72% for FM, 27% for EM and 17% for SM (FM v SM, p<0.001; FM v EM, p=0,012; EM v SM, p=0.40). Advanced disease (stage III and IV) had significant impact on OS (p=0.001) for only SM patients. In addition, male patients with CM had poorer prognosis than female patients (p=0.034). However, age of patient did not affect OS. MM group was older (median 60 v 54 years, p= 0.008) and had a higher rate of localized disease than CM (78% v 65%, p=0.06). Advanced disease had a significant impact on OS for both MM and CM (p= 0.03). OS rates of CM and MM were similar (p=0.53). Conclusions: Melanoma of H&N region is a very heterogeneous disease. MM has different clinicopathologic features from CM. Primary site of melanoma in this region is also important for prognosis and biological behaviour of tumour. Therefore, approaches to these melanomas should be different.

Mucosal melanoma of the head and neck is a rare and aggressive tumor entity with a poor prognosis. The standard treatment is radical tumor resection, with or without adjuvant radiation, where conventional chemotherapies in advanced stage or recurrent diseases have shown little benefit. Overexpression of the programmed cell death ligand 1 (PD-L1) is a common feature in human cancer. Although PD-L1 is an acknowledged prognostic biomarker for dismal prognosis in other tumors of the head and neck, expression and clinical relevance of PD-L1 in mucosal melanoma have not been addressed so far. We assessed PD-L1 expression using immunohistochemical staining in 23 tumor samples from patients with primary mucosal melanoma and correlated expression status with clinicopathological and outcome data. Tumors were derived from the nasal cavity (43.5%), nasal sinuses (43.5%), and the conjunctiva (13%). All patients had undergone surgery; 39% of all patients received adjuvant radiation and 13% were administered systemic interferon therapy. The probability of 1- and 5-year overall survival was 87 and 34.8%, respectively. The mean overall survival was 51 months and the mean recurrence-free survival was 23 months. Immunohistochemical staining showed PD-L1 expression in 13% (3/23) of mucosal melanoma. In contrast, prominent PD-L1 staining was detected in 100% of tissue sections from a control group of cutaneous melanoma (n=9). PD-L1 expression in mucosal melanoma was not correlated with age, sex, nor anatomical localization of the tumor. Interestingly, patients with PD-L1-positive mucosal melanoma had a significantly longer recurrence-free survival (P=0.026). In contrast to cutaneous melanoma and some other malignancies, a relevant PD-L1 overexpression in mucosal melanoma could not be confirmed.

Mucosal melanomas of the head and neck are rare and often diagnosed in the advanced stage. This study examines the incidence, survival and histology of mucosal melanoma compared to its cutaneous counterpart. This register-based cohort study reviews head and neck melanomas at Helsinki University Hospital, Finland, from 2002 to 2023. A total of 56 patients with mucosal and 714 with cutaneous melanoma were reviewed. The incidence of head and neck mucosal melanoma in the region was 1.55/million/year. The most common sites for mucosal melanomas were the nose and paranasal sinuses. Mucosal melanoma was more common in women, whereas cutaneous melanoma was more common in men (p > 0.05). A significant difference emerged in mortality between mucosal and cutaneous melanoma, as 5-year survival was only 12.0% in the mucosal melanoma group compared with 60.3% in the cutaneous melanoma group. Mucosal melanoma is a highly aggressive malignancy with poor survival; thus, prompt diagnosis is essential.

TPS9592 Background: Despite improved outcomes in melanoma with the introduction of checkpoint inhibitors (CPIs), ≈50% of patients do not respond. A subset of responders ultimately progress and have limited treatment options, underscoring a high unmet need for novel treatments with durable benefit. Patients with mucosal melanoma exhibit response rates and progression-free survival ≈2 times lower than those with cutaneous melanoma. Nemvaleukin alfa (nemvaleukin, ALKS 4230) is a novel, engineered cytokine that selectively binds to the intermediate-affinity interleukin-2 receptor complex to preferentially activate CD8+ T and natural killer cells, with minimal expansion of regulatory T cells. Nemvaleukin has been granted Orphan Drug designation for the treatment of mucosal melanoma by the US FDA. In the ARTISTRY-1 study, the intravenous (IV) recommended phase 2 dose (RP2D) for nemvaleukin monotherapy (6 µg/kg on days 1-5 of a 21-day cycle) demonstrated durable antitumor activity in patients with advanced melanoma, including mucosal melanoma, previously treated with a CPI (N = 46, overall response rate [ORR] 13.0% [95% CI 4.9-26.3], median duration of response 8.1 weeks [range 6.1-79.0]). In the ARTISTRY-2 study, the subcutaneous (SC) RP2D was identified as 3 mg every 7 days, which demonstrated pharmacodynamic effects consistent with those of IV delivery. Data from these studies support further evaluation of nemvaleukin monotherapy among patients with advanced mucosal or cutaneous melanoma. Additionally, a less frequent IV nemvaleukin dosing schedule is being evaluated in patients with advanced solid tumors in the ARTISTRY-3 study. Methods: ARTISTRY-6 (NCT04830124) is an ongoing phase 2, global, multicenter, open-label study that is currently enrolling. Eligible patients will have had prior anti–PD-(L)1 therapy with or without anti–CTLA-4 therapy, an Eastern Cooperative Oncology Group performance status of 0 or 1, and adequate hematologic reserve and hepatic and renal function. In Cohort 1, patients with advanced cutaneous melanoma will receive nemvaleukin at the SC RP2D of 3 mg every 7 days. In Cohort 2, patients with advanced mucosal melanoma will receive nemvaleukin at the IV RP2D of 6 µg/kg on days 1-5 of a 21-day cycle. In Cohort 3 (added as a protocol amendment), patients with advanced cutaneous melanoma will receive IV nemvaleukin in 1 of 2 less frequent dosing schedules of 1 or 2 doses per cycle. The dosing schedules for Cohort 3 will be determined when a less frequent IV RP2D has been established in ARTISTRY-3. Patients will receive nemvaleukin until progression or intolerable toxicity. The primary objective is to evaluate the antitumor activity of nemvaleukin monotherapy defined by ORR. Additional objectives include evaluation of safety, health-related quality of life, predictive biomarkers, pharmacokinetics, immunogenicity, and pharmacodynamic effects. Clinical trial information: NCT04830124 .

TPS9609 Background: Despite improved outcomes for melanoma patients with the introduction of checkpoint inhibitors (CPIs), ̃50% of patients do not respond. A subset of responders ultimately progress and have limited treatment options, underscoring a high unmet need for novel treatments with durable benefit. Patients with mucosal melanoma exhibit response rates and progression-free survival times ̃2 times lower than those with cutaneous melanoma. Nemvaleukin alfa (nemvaleukin, ALKS 4230) is a novel, engineered cytokine that selectively binds the intermediate-affinity interleukin-2 receptor complex to preferentially activate CD8+ T and NK cells with minimal expansion of regulatory T cells. Nemvaleukin has been granted Orphan Drug designation for the treatment of mucosal melanoma by the FDA. In ARTISTRY-1, the intravenous (IV) recommended phase 2 dose (RP2D) of 6 µg/kg nemvaleukin monotherapy demonstrated durable antitumor activity in patients with advanced melanoma, including mucosal melanoma, previously treated with a CPI. In ARTISTRY-2, the subcutaneous (SC) RP2D of 3 mg q7d was identified demonstrating pharmacodynamic effects consistent with IV delivery. Data support further evaluation of nemvaleukin monotherapy among patients with advanced mucosal and cutaneous melanoma. Methods: ARTISTRY-6 is a phase 2, global, multicenter, open-label study. Eligible patients have had prior treatment with an anti–PD-(L)1 therapy with or without anti–CTLA-4 therapy and have an ECOG performance status of 0 or 1 and adequate hematologic reserve and hepatic and renal function. Patients with advanced cutaneous (Cohort 1) and mucosal (Cohort 2) melanoma will receive nemvaleukin at the SC and IV RP2D, respectively. Patients will receive nemvaleukin until progression or intolerable toxicity. The primary objective is to evaluate the antitumor activity of nemvaleukin monotherapy defined by overall response rate. Additional objectives include the evaluation of safety, health-related quality of life, predictive biomarkers, pharmacokinetics, immunogenicity, and pharmacodynamic effects. Clinical trial information: NCT04830124.

Objective: Compared to the cutaneous melanoma, noncutaneous melanomas are relatively rare and have a distinct pattern of behavior. We performed this study to define the clinical characteristics and outcomes of patients with noncutaneous melanomas and emphasize how they differ from cutaneous melanomas. Methods: 216 patients who were diagnosed with noncutaneous melanoma were assessed and their medical records between 2000 and 2010 were retrieved from the cancer registry. 475 patients with cutaneous melanoma were used for comparison. Results: Of the 216 noncutaneous melanoma patients, 83 had mucosal melanoma, 101 had ocular melanoma and 32 had unknown primaries. For mucosal melanoma, the head and neck was the most common anatomic site (53%), followed by the gastrointestinal tract (37%), female genital (6%) and urinary tract (4%). The majority of the ocular melanomas (94%) originated in the uvea. 32 patients demonstrated a primary unknown disease with regional metastasis as the dominant behavior (72%). Age was found to be statistically significantly different among melanoma patients (p < 0.001). Younger patients had more cutaneous and unknown primary melanomas, whereas older patients had more ocular and mucosal melanoma. In subset analyses, we found significant differences between cutaneous and ocular (p = 0.038) or mucosal (p < 0.001) melanomas. The ratios of metastasis on admission were higher in patients with mucosal (27.7%) and unknown primary (28.1%) melanomas, and lower for ocular (3%) melanomas (p < 0.001). Patients with cutaneous melanoma had an intermediate (12%) ratio. Patients with ocular melanoma had better outcome than patients with other melanoma sites (p < 0.05). While overall survival for cutaneous melanoma was significantly negatively correlated with male gender (p < 0.001), advanced stages (p < 0.001) and old age (p = 0.005), stage IV disease was the only independent prognostic factor in patients with ocular melanoma (p = 0.006). No prognostic factor for outcome was found for either mucosal or unknown primary melanomas. Conclusion: The clinical presentations and prognoses of different primary sites of melanoma are distinctive. Therefore, approaches to these melanomas should be different.

Background: The incidence of each subtype of melanoma in different races and ethnicities is significant differences. Cutaneous melanomas dominate in the Caucasian population. In contrast, melanomas that occur in the Chinese population are mainly arising from non-cutaneous tissue (extremities and mucous). Here, we reported an analysis of genomic features in 97 acral, 52 cutaneous and 18 mucosal melanomas. Methods: Patients (pts) with melanoma were enrolled, and surgical tumor tissues were collected. Mutation profiling was performed by next-generation sequencing (NGS). Results: Comparing to cutaneous melanoma patients (Age 53±11.6), acral (Age 65±11.1, P&amp;lt;0.001) and mucosal (Age 64±9.7, P=0.01) melanomas occurred in older Chinese patients. Mutations were identified in 148 of melanoma patients (88.62%), including 85 acral (87.63%), 47 cutaneous (90.38%) and 16 mucosal (88.89%) melanomas. Mutations of BRAF (25/52) in cutaneous melanoma, NRAS in acral melanoma (22/97) and mucosal melanomas (5/18) were observed as the most commonly genetic variations in different subtype of melanoma, which always occurred mutual exclusivity. Furthermore, focal amplification of 11q13 (CCND1 and FGF3/4/19) was all abundant in acral melanoma (11.34%, 11/97), which was reported to affect the efficacy of immunotherapy. In total, occurrence of BRAF, NRAS, CDKN2A mutations and 11q13 amplification were significantly different in cutaneous and non-cutaneous melanomas, which suggested different pathogenesis. Conclusions: In summary, genomic characterization of melanomas may offer insights into tumorigenesis and identify potential therapeutic targets in this disease. Citation Format: Qiuyu Liu, Lingfei Kong, Weiran Wang, Danhua Wang, Tonghui Ma. Distinct genomic features of cutaneous, acral and mucosal melanomas in a Chinese retrospective cohort [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2223.

9016 Background: KIT gene mutations have recently been reported in mucosal and acral melanomas. While the KIT inhibitor imatinib is ineffective in the treatment of cutaneous melanoma, we observed a dramatic clinical response in a patient with a rectal melanoma harboring a KIT mutation. We therefore surveyed a series of melanoma subtypes for genomic alterations in KIT, BRAF and NRAS to determine what fraction of tumors might be amenable to kinase inhibitor therapy. Design: DNA from archival melanomas was amplified by PCR and the products were screened by denaturing HPLC for mutations in KIT exons 11, 13, 17; BRAF exon 15; and NRAS exons 1 & 2. Mutations were confirmed by direct sequencing. Immunohistochemistry for CD117 was performed on a subset of cases. KIT copy number was assessed by quantitative PCR assay in some cases. Results: KIT mutations included substitutions in exons 11 (W557R, K558N, V559A/D, L576P) or 17 (Y823D), and size-altering mutations in exon 11 (del 554–559; ins PYDHKWE at E583). Notably, all of these mutations occur in GI stromal tumors and nearly all (except Y823D) are sensitive to imatinib. Among mucosal melanomas, KIT mutations were more common in anorectal/vaginal melanomas (4/8; 50%) than in tumors of the head & neck (3/36; 8.3%). KIT mutations were rare in conjunctival and cutaneous tumors, and absent in choroidal tumors. There was no correlation between CD117 staining and KIT mutation status. There was a trend for KIT-mutant melanomas to have increased copy number (4/8; 50%) compared with KIT wild-type tumors (8/39; 20.5%). Conclusion: Our findings confirm that KIT mutations of the type known to be sensitive to imatinib occur in mucosal and acral melanomas. In addition, a substantial minority of these tumors have increased KIT copy number. NRAS mutations are also common in these tumors and would be predicted to be unresponsive to KIT inhibitor therapy. BRAF mutations are found in acral but not in mucosal melanomas. Genotyping can play an important role in the clinical management of these rare melanomas. Genomic Abnormalities in Melanoma Subtypes KIT mutations BRAF mutations NRAS mutations KIT copy number increase Acral 23% (3/13) 16.7% (2/12) 11.1% (1/9) 27.3% (3/11) Mucosal 15.2% (7/46) 0% (0/47) 26.3% (10/38) 25.0% (10/40) Cutaneous 1.8% (1/57) 30.3% (20/66) 10% (6/60) 9.1% (2/22) Conjunctival 7.7% (1/13) 26.7% (4/15) 0% (0/11) Not done Choroidal 0% (0/60) 0% (0/60) 0% (0/60) 0% (0/5) Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Novartis, Pfizer MolecularMD Novartis, Pfizer Novartis, Pfizer

Cutaneous, ocular, and mucosal melanomas are histologically indistinguishable tumors that are driven by a different spectrum of genetic alterations. With current methods, identification of the site of origin of a melanoma metastasis is challenging. DNA methylation profiling has shown promise for the identification of the site of tumor origin in various settings. Here we explore the DNA methylation landscape of melanomas from different sites and analyze if different melanoma origins can be distinguished by their epigenetic profile. We performed DNA methylation analysis, next generation DNA panel sequencing, and copy number analysis of 82 non-cutaneous and 25 cutaneous melanoma samples. We further analyzed eight normal melanocyte cell culture preparations. DNA methylation analysis separated uveal melanomas from melanomas of other primary sites. Mucosal, conjunctival, and cutaneous melanomas shared a common global DNA methylation profile. Still, we observed location-dependent DNA methylation differences in cancer-related genes, such as low frequencies of RARB (7/63) and CDKN2A promoter methylation (6/63) in mucosal melanomas, or a high frequency of APC promoter methylation in conjunctival melanomas (6/9). Furthermore, all investigated melanomas of the paranasal sinus showed loss of PTEN expression (9/9), mainly caused by promoter methylation. This was less frequently seen in melanomas of other sites (24/98). Copy number analysis revealed recurrent amplifications in mucosal melanomas, including chromosomes 4q, 5p, 11q and 12q. Most melanomas of the oral cavity showed gains of chromosome 5p with TERT amplification (8/10), while 11q amplifications were enriched in melanomas of the nasal cavity (7/16). In summary, mucosal, conjunctival, and cutaneous melanomas show a surprisingly similar global DNA methylation profile and identification of the site of origin by DNA methylation testing is likely not feasible. Still, our study demonstrates tumor location-dependent differences of promoter methylation frequencies in specific cancer-related genes together with tumor site-specific enrichment for specific chromosomal changes and genetic mutations. © 2021 The Authors. The Journal of Pathology published by John Wiley & Sons, Ltd. on behalf of The Pathological Society of Great Britain and Ireland.

Distinct genomic features in a retrospective cohort of mucosal, acral, and vulvovaginal melanomas