OBJECTIVE: Oral mucosal melanoma (OMM) is a rare but aggressive melanoma subtype. Due to its rarity, the genomic landscape of OMM remains unknown despite a relatively thorough understanding of the genetic profile of cutaneous melanoma (CM). In this study, we analyzed the genomic mutational profiles of Japanese patients with OMM and compared them with those of patients with nose/sinuses mucosal melanoma (NMM) and CM to identify potential therapeutic targets.
METHODS: We extracted clinical and genomic information of patients with OMM (n = 15), NMM (n = 63), and CM (n = 413) who underwent comprehensive genomic profiling tests under the National Health Insurance between June 2019 and November 2023 from the Center for Cancer Genomics and Therapeutics database.
RESULTS: The most frequent genomic alteration identified in OMM was RICTOR (40%) followed by CDK4 (33.3%), MDM2 (33.3%), KDR (30%), KIT (26.7%), and NF1 (26.7%). CDK4 and MDM2 were co-amplified. Gene alterations in MYC and NRAS were the highest in patients with NMM, followed by those with CM, and no MYC alteration was observed in patients with OMM. BRAF V600 mutation, which is frequently observed in patients with CM (23.2%) were only present in 1.6% of patients with NMM and none in patients with OMM.
CONCLUSIONS: This study clarified the genetic differences between OMM and NMM, and the first to report the frequent occurrence of RICTOR amplification in OMM. This analysis offers insights into the development of personalized therapeutics for OMM.

Immune checkpoint inhibitors (ICIs), including anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and anti-programmed death-1 (PD-1) antibodies, have initiated a new era in the treatment of malignant melanoma. ICIs can be used in various settings, including first-line, adjuvant, and neo-adjuvant therapy. In the scope of this review, we examined clinical studies utilizing ICIs in the context of treating oral mucosal melanoma, a rare disease, albeit with an extremely poor prognosis, with a specific focus on unraveling the intricate web of resistance mechanisms. The absence of a comprehensive review focusing on ICIs in oral mucosal melanoma is notable. Therefore, this review seeks to address this deficiency by offering a novel and thorough analysis of the current status, potential resistance mechanisms, and future prospects of applying ICIs specifically to oral malignant melanoma. Clarifying and thoroughly understanding these mechanisms will facilitate the advancement of effective therapeutic approaches and enhance the prospects for patients suffering from oral mucosal melanoma.

Oral mucosal melanoma is a type of pigment-producing cell malignancy that primarily affects the skin and oral mucosa, but can also affect the ears, eyes, gastrointestinal tract and vaginal mucosa. Oral mucosal melanoma has several different clinical manifestations. Even though it frequently manifests as a black-brown patch, macule, or nodular lesion with varying tones of red, purple or depigmented tissue, the clinical characteristics and pathobiological behaviour of oral mucosal melanomas differ from those of cutaneous melanomas. The prognosis for oral melanomas is exceedingly bad because they frequently exhibit no symptoms, which may delay diagnosis. The case of a 65-year-old male patient with a primary complaint of blackened gums in the right lower back region of the jaw is presented here.

OBJECTIVE: Primary head/neck mucosal melanomas (MMs) are rare and exhibit aggressive biologic behaviour and elevated mutational loads. The molecular mechanisms responsible for high genomic instability observed in head/neck MMs remain elusive. The DNA cytosine deaminase APOBEC3B (A3B) constitutes a major endogenous source of mutation in human cancer. A3B-related mutations are identified through C-to-T/-G base substitutions in 5\'-TCA/T motifs. Herein, we present immunohistochemical and genomic data supportive of a role for A3B in head/neck MMs.
RESULTS: A3B protein levels were assessed in oral (n = 13) and sinonasal (n = 13) melanomas, and oral melanocytic nevi (n = 13) by immunohistochemistry using a custom rabbit α-A3B mAb (5210-87-13). Heterogeneous, selective-to-diffuse, nuclear only, A3B immunopositivity was observed in 12 of 13 (92.3%) oral melanomas (H-score range = 9-72, median = 40) and 8 of 13 (62%) sinonasal melanomas (H-score range = 1-110, median = 24). Two cases negative for A3B showed prominent cytoplasmic staining consistent with A3G. A3B protein levels were significantly higher in oral and sinonasal MMs than intraoral melanocytic nevi (P < 0.0001 and P = 0.0022, respectively), which were A3B-negative (H-score range = 1-8, median = 4). A3B levels, however, did not differ significantly between oral and sinonasal tumours (P > 0.99). NGS performed in 10 sinonasal MMs revealed missense NRAS mutations in 50% of the studied cases and one each KIT and HRAS mutations. Publicly available whole-genome sequencing (WGS) data disclosed that the number of C-to-T mutations and APOBEC3 enrichment score were markedly elevated in head/neck MMs (n = 2).
CONCLUSIONS: The above data strongly indicate a possible role for the mutagenic enzyme A3B in head/neck melanomagenesis, but not benign melanocytic neoplasms.

Oral mucosal melanoma (OMM) is the subject of few studies, resulting in a lack of understanding. The aim of this study is to review the current literature on OMM. The term searched was \"oral mucosal melanoma\" between 01/01/2000 and 03/15/2021 in the PubMed Database (MEDLINE). Patients presenting with OMM and treated in our center between January 2009 and January 2020 were included in a case series. Demographics, location, risk factors, genetic mutations, treatment performed, and overall survival (OS) rates were evaluated. The PubMed database search yielded a total of 513 results, thirty-eight articles were finally included, which amounted to 2230 cases of OMM. 13 patients were included in the case series. A male-to-female ratio of 1.28:1.00 was found with a mean age at first diagnosis of 58.2 years old. Hard palate (1060 cases) and then gingiva (794 cases) were the two main locations. No risk factors could be identified. OMM were staged III or IV at diagnosis. Mutations were described as such: KIT in 14.6% of cases, BRAF in 7%, and NRAS in 5.6%. Treatment protocols varied but radical surgery was the cornerstone treatment associated with adjuvant therapies. Immunotherapy has not been evaluated for OMM. OS rates were 43.4% at 3 years, 33.1% at 5 year and 15.4% at 10 years. OMM show distinct features from cutaneous melanoma (CM): typical locations, no identified risk factors, different mutations profile, worse prognosis with advanced stage at diagnosis. Targeted therapies are still underused compared to CM.

Oral malignant melanomas are rare neoplasms of the oral cavity which present significant diagnostic ambiguity. The etiology is unclear though the stimulation of melanoblasts by genetic, epigenetic, and traumatic causes that have been proposed in etiopathogenesis. Clinically, it presents as a pigmented swelling or growth which remains asymptomatic until it advances to later stages. It is highly invasive and metastasizes quickly; hence, it has a very poor prognosis with a survival rate of only 7%. Early diagnosis of the neoplasm and thorough investigation is not only necessary for prompt treatment but also necessary for a favorable prognosis.

Primary mucosal melanomas are rare neoplasms that occur in the mouth, esophagus, nasopharynx, larynx, and anogenital mucosa. Mucosal melanomas are rare, accounting for approximately one percent of all melanomas. Of the mucosal melanomas that occur in the head and neck, oral mucosal melanomas compose approximately 25 percent. Here, we present a case of an amelanotic oral mucosal melanoma of the mucosal lip in a 77-year-old male patient with a history of non-Hodgkin\'s lymphoma and multiple basal and squamous cell carcinomas. The patient presented with a pink, nonpigmented, pedunculated mass on the left superior mucosal lip. Histopathologic examination of the biopsy specimen revealed a diagnosis of a superficial spreading type of malignant melanoma with a nodular component. The patient was referred to a tertiary care center for further management. Multiple risk factors exist for developing melanoma, including immunosuppression. Lymphoproliferative disorders, such as non-Hodgkin\'s lymphoma, lead to inherent immunosuppression, which can be exacerbated by chemotherapy treatments. Cases of oral mucosal melanoma have a poor prognosis due to delayed diagnosis, anatomic location, and aggressive behavior. Surgical resection is first-line therapy, with regional lymph-node dissection of the neck is recommended in most cases. Radiotherapy and targeted molecular therapy, such as c-KIT inhibitors, can also be used.

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Because of the poor prognosis and of oral mucosal melanoma, and patients\' short survival, large, randomised, clinical studies are difficult. We have investigated its demographic characteristics and analysed the effect of treatment, resection margins, and metastases on survival. We recorded age, sex, site of primary tumour, and types of treatment, survival, and metastases in 74 patients treated at the Department of Oral and Maxillofacial Surgery, Seoul National University Dental Hospital. Survival was analysed based on bony invasion, depth of invasion, and resection margins, and we found that it varied depending on the primary site (p=0.002), and declined with liver (p=0.001) or brain (p=0.033) metastases. The two-year survival according to the primary site was as follows: palate 85% (n=32), anterior maxillary gingiva 53% (n=13), mandible 58% (n=13), and posterior maxillary gingival 74% (n=10) and buccal mucosa 50% (n=4). The two-year survival was 34% (n=8) in patients with liver metastases and 23% (n=7) in patients with brain metastases. In cases of bony invasion (p=0.005), depth of invasion (p=0.042), unclear resection margin (p=0.023), or higher T stages (p=0.009), the survival declined considerably. Neck dissection did not affect survival (p=0.343). Survival of the patients given chemotherapy was significantly lower (p=0.013) and the two-year survival was 54.0%. The patients given radiotherapy showed no significant difference in survival compared with those not given radiotherapy (p=0.107). In conclusion, primary site, bony invasion, resection margins, depth of invasion and systemic metastases were critical to predict prognosis and selection of treatment of oral mucosal melanoma.

Circular RNAs (circRNAs) are known to be associated with carcinogenesis, and can serve as potential biomarkers for cancer diagnosis and therapeutic implications. However, little is known about their expression patterns in oral mucosal melanoma (OMM), an extremely rare cancer that is distinct from cutaneous melanoma for its clinical course and prognosis. To investigate circRNAs expression profile in OMM, we performed a circRNAs microarray to analyze 6 primary OMM samples with lymph nodes dissemination, and constructed a genome-wide circRNA profile. Our results revealed that 90 circRNAs were significantly dysregulated in the metastatic OMM tissues when compared to the paired adjacent tissues. Among them, hsa_circ_0005320, hsa_circ_0067531, hsa_circ_0008042 were significantly upregulated in primary tumor and metastatic lymph nodes compared to paired adjacent normal tissues and non-metastatic lymph nodes, whereas the expression of hsa_circ_0000869 and hsa_circ_0000853 were downregulated relatively. Gene Ontology (GO) and pathway analyses of differentially expressed circRNAs indicated that these identified circRNAs might play important roles in protein modification, protein binding and cellular metabolism in metastatic OMM. Functions of several selected circRNA were also identified. In addition, by using bioinformatics predictions, we further demonstrated that hsa_circ_0005320, hsa_circ_0067531 and hsa_circ_0000869 could serve as competing endogenous RNA (ceRNA), which might regulate tumorigenesis and metastatic of OMM by binding to specific microRNAs. Our results not only suggested that circRNAs might play critical roles in metastasis of OMM, but also provided critical information of circRNAs in regulating OMM progression. The findings would help us to develop potential biomarkers for clinical diagnosis and design therapeutic strategies for OMM.