Primary Oral Mucosal Melanoma Research Articles

Actionable Mutation Profile of Sun-Protected Melanomas in South America.

Melanomas that arise in sun-protected sites, including acral and oral mucosal melanomas, are likely under the control of unique, specific mechanisms that lead to mutagenesis through various pathways. In this study, we examined somatic mutations in tumors by targeted sequencing using a custom Ion Ampliseq Panel, comprising hotspots of 14 genes that are frequently mutated in solid tumors. Tumor DNA was extracted from 9 formalin fixation, paraffin-embedded sun-protected melanomas (4 primary oral mucosal melanomas and 5 acral lentiginous melanomas), and we identified mutations in the NRAS , PIK3CA , EGFR , HRAS , ERBB2 , and ROS1 genes. This study reveals new actionable mutations that are potential targets in the treatment of photo-protected melanomas. Additional studies on more of these melanoma subtypes could confirm our findings and identify new mutations.

Accurate Delineation of Mucosal Lesions in Treatment-Planning Computed Tomography Using Iodine Paste Markers for Oral Mucosal Melanoma

This technical report introduces the utility of iodine paste markers using endodontic materials for the accurate contouring of mucosal lesions of oral mucosal melanoma, which are difficult to delineate on imaging during the planning of carbon-ion radiation therapy (CIRT). The patient had a primary oral mucosal melanoma located in the palatal mucosa without palatal or maxillary bone invasion. A dental root canal filling material, which is a calcium hydroxide/iodoform nonhardenable paste, was used as a marker. We first performed treatment-planning computed tomography (CT) without an iodine paste marker for mucosal lesions. Subsequently, we placed an iodine paste marker on the palatal mucosal lesion to accurately delineate the mucosal lesions of the palate. Finally, we obtained a reference CT image with an iodine paste marker. Computed tomography without the marker was fused to the reference CT with markers during treatment planning, and the gross tumor volume was contoured. Thereafter, CIRT was delivered without markers. During CIRT, expected acute mucositis was observed in the area of the planning target volume, including melanosis, in accordance with the dose distribution. The use of iodine paste markers for localized mucosal lesions, which are difficult to delineate on CT and magnetic resonance imaging, may be useful for accurately contouring gross tumor volumes on treatment-planning CT.

Oral Mucosal Melanoma.

Primary oral mucosal melanoma (OMM) is a rare neoplasm accounting for the 0.2% to 0.8% of all melanomas. The aim of the present manuscript is (1) to describe 2 cases of primary OMM treated at our department, and (2) to perform a systematic literature review on primary OMM occurrence and treatment. Two cases of primary OMM were described. A systematic review is presented in order to assess the treatment options, recurrence, metastasis development, and survival rate of primary OMM. Two patients were referred for the development of a lesion of the hard palate and the maxillary gingival mucosa, respectively. An incisional biopsy was performed in both patients, followed by extensive surgical resection after a thorough consideration of patient history and systemic involvement. The literature search retrieved 447 primary OMM cases. In the 30% of cases, distant metastases were already present at the time of diagnosis. The management of primary OMM most frequently involved surgical treatment and adjuvant radiotherapy. Primary OMM still represents a challenge for the clinician, as the diagnosis is often performed when metastases have already developed. The prognosis is generally poor, thus highlighting the need for further investigations to improve early diagnosis.

Does BCL-2 Play Role in the Pathogenesis of Primary Oral Mucosal Melanoma?

Primary Oral Mucosal Melanoma represents 0.2 to 8% of all melanomas and 0.5% of all oral malignant neoplasia. The etiology still unknown, however, it has been suggested that head and neck mucosal melanomas change their genetic and metabolic pathways through intracellular cascades, which are associated with its etiopathogenesis mechanisms. The BCL2 protein is an integral part of the cell membrane, and it is also found in the cell nucleus, mitochondria, and endoplasmic reticulum. It is overexpressed in several malignant neoplasms, including cutaneouse ocular melanomas. Among all evaluated cases, we found positive immunostaining of BCL-2 in 26/34 (76.47%) and they had a membrane and cytoplasmic pattern, and the intensity was variable. According to our results and the findings of the literature, it can be suggested that BCL-2 has an important role in melanoma pathogenesis, including Primary Oral Mucosal Melanoma and also melanoma metastases. It seems that BCL-2 could be an adjunct marker for POMM and also a target for treatment development. New researches involving BCL-2 and a larger primary oral mucosal melanoma cohort could corroborate the present study

METABOLIC-RELATED AND STEM CELL MARKERS IN A SERIES OF PRIMARY ORAL MUCOSAL MELANOMAS AND ORAL NEVI

Primary oral mucosal melanomas (POMM) are rare and aggressive neoplasms arising in the melanocytes from the epithelial lining of the oral cavity, and currently few prognostic markers are described. Objective: In this study, we investigated the expression of glucose transporter 1 (GLUT1), antimitochondrial antibody (AMT), and stem cell markers (CD44) in a series of 3 POMM and 3 oral nevi. Methods: Immunostainings of GLUT1, CD44, and AMT were quantitatively assessed by digital analyses. Results: POMM showed a proliferation of epithelioid or fusiform variable-pigmented melanocytes. GLUT1, CD44, and AMT were negative in all nevi and strongly expressed in the melanomas. Conclusion: Our results suggest that overexpression of mitochondrial and stem cells markers can help confirm the diagnosis of melanomas and they can be associated with the aggressive behavior of these rare tumors.

Head and Neck: Primary oral mucosal melanoma

Head and Neck: Primary oral mucosal melanoma

NRAS and BRAF mutation frequency in primary oral mucosal melanoma

NRAS and BRAF mutation frequency in primary oral mucosal melanoma

Mutational Status of NRAS and BRAF Genes and Protein Expression Analysis in a Series of Primary Oral Mucosal Melanoma.

Primary oral mucosal melanoma is an extremely rare and aggressive tumor arising from melanocytes located in the mucosal epithelium of the oral cavity. Although malignant melanoma of oral mucosa shares some clinical features with its cutaneous counterpart, it has been associated with a worst prognosis; its etiopathogenesis are still only partially unraveled as there is no influence of UV radiation. It is known that the mitogen-activated protein kinase pathway mediates cellular responses to growth signals and its activation is an important phenomenon in melanoma. The aim of this study was to evaluate NRAS and BRAF genes, both components of mitogen-activated protein kinase molecular pathway, and compare with their protein expression. Point mutations of NRAS (codons 12, 13, and 61) and BRAF (codon 600) were screened by pyrosequencing method, and its results were associated to the protein expression of RAS and BRAF performed by immunohistochemistry. The authors observed mutation in BRAF 600 (3/14), NRAS codons 12 and 13 (2/14), and NRAS codon 61 (2/8). One case showed positive RAS protein expression, but no mutation was observed. Twelve in 14 cases showed positive BRAF protein expression: 3 cases showed BRAF mutation; 2 cases showed NRAS codon 61 mutation; 2 cases showed NRAS codons 12 and 13 mutation but not simultaneously. Although NRAS and BRAF mutation frequency and RAS protein expression are low, BRAF protein expression was intense; probably, NRAS and BRAF mutations are independent events and alternative molecular mechanisms in the primary oral mucosal melanoma tumorigenesis.

A Review of the Aetiopathogenesis and Clinical and Histopathological Features of Oral Mucosal Melanoma.

Oral mucosal melanoma is an uncommon, usually heavily melanin-pigmented, but occasionally amelanotic aggressive tumour with a poor prognosis. Despite radical surgery, radiotherapy, or chemotherapy, local recurrence and distant metastasis are frequent. Microscopical examination is essential for diagnosis, and routine histological staining must be supplemented by immunohistochemical studies. The aetiology is unknown, the pathogenesis is poorly understood, and the 5-year survival rate rarely exceeds 30%. In most cases, oral mucosal melanoma arises from epithelial melanocytes in the basal layer of the epithelium and less frequently from immature melanocytes arrested in the lamina propria. In both cases the melanocytes undergo malignant transformation, invade deeper tissues, and metastasize to regional lymph nodes and to distant sites. Very rarely metastasis from skin melanoma may give rise to oral mucosal melanoma that may be mistaken for primary oral mucosal melanoma. The pathogenesis of oral mucosal melanoma is complex involving multiple interactions between cytogenetic factors including dysregulation of the cKit signalling pathways, cell cycle, apoptosis, and cell-to-cell interactions on the one hand and melanin itself, melanin intermediates, and local microenvironmental agents regulating melanogenesis on the other hand. The detailed mechanisms that initiate the malignant transformation of oral melanocytes and thereafter sustain and promote the process of melanomagenesis are unknown.

Periodic acid-Schiff-positive loops and networks as a prognostic factor in oral mucosal melanoma.

The prognostic factors of oral mucosal melanoma (OMM), a rare and aggressive neoplasm, remain to be determined. The aim of this study is to investigate the prognostic significance of vasculogenic mimicry in OMM. The clinical data of 62 patients with primary OMM treated in Shanghai Ninth People's Hospital from April 2007 to April 2012 were retrieved and analyzed retrospectively. Staining of periodic acid-Schiff (PAS) and CD31 immunohistochemistry were performed to evaluate the prognostic value of PAS-positive patterns, blood lakes, and microvascular density. PAS-positive loops and networks (P<0.001) as well as blood lakes (P=0.040) were found to be predictors of overall survival (OS). The presence of PAS-positive loops and networks was an independent prognostic factor of poor OS in multivariate analysis (P=0.002). Although the presence of PAS-positive loops and networks was associated with hematogenous metastasis (P=0.041) and lymphogenous metastasis (P=0.041), it was not an independent predictor of both types of metastasis in multivariate analysis. Microvascular density was not associated with OS (P=0.627) and metastasis of OMM patients. PAS-positive loops and networks have a significant prognostic value in OMM. Detection of PAS-positive patterns may lead to better staging and serve as a prognostic parameter of OMM.

Primary Oral Mucosal Melanoma: a Short Review

Primary Oral Mucosal Melanoma (POMM) is a very rare entity and it develops from malignant transformation of melanocytes from mucosal epithelium. POMM has a very poor prognosis and aggressive behavior. It represents only 0.5% of all oral malignancies, accounting 0.2 to 8% of all melanomas, with an incidence of 1.2 cases per 10 million per year. POMM is asymptomatic in its early stages and usually not noticed by the patients, resulting in the delay in diagnosis. Immunoreactivity of melanoma cells to antibodies against: S-100 protein; Melan-A (MART-1) and HMB-45 (gp100) can be very useful to distinguish POMM from other malignancies. Others markers may indicate variations in its biologic behavior and prognosis, such as Ki-67; P53 and P16, and maybe useful for prognostic prediction.

Adhesion Molecules in Primary Oral Mucosal Melanoma

Primary oral mucosal melanoma is a rare aggressive tumor. Recent studies have demonstrated a correlation between increased tumor invasion and the metastatic phenotype and altered adhesion molecule expression profiles. The present study analyzed the expression of integrins, claudins, and immunoglobulin-like adhesion molecules in oral mucosal melanomas and correlated results with clinical parameters. Immunohistochemical analyses of the expression patterns of these molecules were performed on thirty-five cases of primary oral mucosal melanomas organized in a tissue microarray. The results were correlated with clinical and histological features of the cohort. A number of integrin subunits were negative and this was related with vascular invasion. Positivity of integrin beta-3 and CD166 (activated leukocyte cell adhesion molecule) was statistically associated with extensive vascular invasion (P < 0.05). Lower expression of CD54 (intercellular cell adhesion molecule) was associated with cases with extensive necrosis. Most cases with metastatic disease were negative for CD66 (carcinoembryonic antigen-related cell adhesion molecule). Several subunits of claudins were negative and, although not statistically significant, this lack of expression was partially associated with histological factors of poor prognosis. Altered patterns of adhesion molecule expression, mainly integrins and immunoglobulin-like proteins, may participate in the pathogenesis and outcome of oral mucosal melanomas.

The CDKN2A and MAP Kinase Pathways

The etiology and pathogenesis of oral mucosal melanomas are poorly understood, and no intraoral risk factors have been identified. Recent studies have postulated that DNA repair mechanisms and cell growth pathways are involved in the development of melanoma-particularly changes in the CDKN2A (p16-cyclinD-Cdk-pRb) and MAPK pathways (RAS, BRAF, MEK 1/2, and ERK 1/2 proteins). We examined the central components of the CDKN2A and RAS-RAF-MEK-ERK cascades by immunohistochemistry in a series of 35 primary oral melanomas by tissue microarray (TMA). We noted altered expression of the CDKN2A cascade proteins, although these modulations did not correlate significantly with clinical and pathological parameters. The expression of MAP kinase cascade proteins changed in most cases. We observed that 28.57% of cases were RAS-positive and that 82.85% and 74.28% of cases were positive for BRAF and ERK2, respectively; MEK2 and ERK1 were not expressed in 48.57% and 80% of cases, and all cases were negative for MEK1. The absence of RAS and ERK1 and positivity for BRAF and ERK2 were associated with higher histological grade, vascular invasion, and metastasis. Expression of MEK2 was significantly linked to vascular invasion (P = 0.043). The CDKN2A and MAPK pathways require further study in mucosal melanomas, but our results highlight the significance of important alterations, particularly with regard to histological indicators of poor prognosis in primary oral mucosal melanomas, independent of UV exposure.

Intraoral malignant melanoma

Primary oral mucosal melanoma is a rare aggressive neoplasm and accounts for only 0.2-8% of all reported melanomas. It is a malignant neoplasm of melanocytes that may arise from a benign melanocytic lesion or de novo from melanocytes within normal skin or mucosa. It is considered to be the most deadly and biologically unpredictable of all human neoplasms, having the worst prognosis. In this article, we report a case of oral melanoma in a 52-year-old female patient with a chief complaint of black discolouration of the maxillary gingiva and palate.

Primary oral mucosal melanoma (POMM): report of a clinical case and 17 cases of an oral pathology service (Irepo, Chile)

Primary oral mucosal melanoma (POMM): report of a clinical case and 17 cases of an oral pathology service (Irepo, Chile)

N‐Glycolyl GM3 ganglioside immunoexpression in oral mucosal melanomas of Chinese

The aim of this study was to determine the expression of N-Glycolyl GM3 (NeuGcGM3) ganglioside in oral mucosal melanomas. To assess the presence of cytidine monophospho-N-acetylneuraminic acid hydroxylase (CMAH) mRNA, an RT-PCR assay was performed in melanoma cell line (ME), an oral mucosal ME, and two fresh oral mucosal melanoma tissues. Expression of NeuGcGM3 ganglioside was evaluated by immunohistochemistry in 44 primary oral mucosal melanomas and 10 oral melanotic nevi. Also, the expression of NeuGcGM3 was examined in ME by immunocytochemistry. We first checked the expression of CMAH in ME and two fresh oral mucosal melanoma tissues. Presence of NeuGcGM3 ganglioside was evident in 37 of 44 cases (84.1%), showing a diffuse cytoplasmic and membranous staining. Patients with primary occurrence showed high levels of NeuGcGM3 ganglioside compared to patients with secondary occurrence. On the other hand, negative immunoreaction was evidenced in oral melanotic nevi. ME also presented the expression of NeuGcGM3 by immunocytochemistry. In this work, we for the first time evaluated the expression of 14F7 MAb immunorecognition in oral mucosal melanomas. Our results were in agreement with the assumption that NeuGcGM3 ganglioside may be considered as target for passive and active immunotherapy in oral mucosal melanomas expressing this molecule and indicate less risk of recurrence and a better prognosis. Moreover, ME provides a platform for more studies on the specific function of NeuGcGM3 in oral mucosal melanomas.

Primary Oral Mucosal Melanoma: Advocate a Wait-and-See Policy in the Clinically N0 Patient

Oral mucosal melanoma (OMM) is a rare disease associated with a very poor prognosis. Because well-established treatment protocols for OMM are in short supply, prognostic information regarding recent treatment modalities for this disease were sought. A retrospective chart review was performed of 61 patients who were treated for OMM from 1998 through 2005. The clinical features and treatment modalities were identified and correlated with the outcomes. There were 41 male and 20 female patients (ratio, 2.1:1) with a mean age of 54.1 years. The mean follow-up was 31.9 months, and the overall 2-year and 5-year survival rates were 51.1% and 30.3%, respectively. According to the seventh edition of the American Joint Committee on Cancer staging system, there were 31 patients (50.8%) with stage III tumors. A more advanced stage and a tumor of at least 2 cm were associated with worse survival (P < .001 and P = .036, respectively). Elective lymph node dissection and biochemotherapy were not associated with a higher total survival rate (P = .53 and P = .76, respectively). OMM has a male predilection. The seventh edition of the American Joint Committee on Cancer stage and tumor size are effective prognostic parameters for patients with OMM. The American Joint Committee on Cancer staging system provides useful information for predicting the ultimate outcome and should be used as the primary staging system. Elective node dissection and adjuvant biochemotherapy offer no additional advantage in increasing the patient survival rate. A wait-and-see policy is advocated for patients with clinical stage N0 cancer.

NRAS and BRAF mutation frequency in primary oral mucosal melanoma

Oral mucosal melanoma (OMM) is a fatal sarcoma of unknown etiology. Histological morphology and genetic events are distinct from those of its cutaneous counterpart. Mutation and up-regulation of c-kit has been identified in OMM which may activate downstream molecules such as RAS and RAF. These molecules are involved in the mitogen-activated protein kinase (MAPK) pathway leading to tremendous cell proliferation and survival. NRAS and BRAF mutation and protein expression have been studied in other melanoma subtypes. The purpose of this study was to determine RAS protein expression and NRAS and BRAF mutation in 18 primary OMM cases using immunohistochemistry and mutation analysis. Results showed that RAS is intensely expressed in both in situ and invasive OMMs. However, NRAS mutation was only observed in 2/15 polymerase chain reaction (PCR) amplified cases both of which were silent mutations. On the other hand, BRAF missense mutations were observed only in 1/15 cases with PCR amplification. NRAS and BRAF mutations were independent from previously reported c-kit mutations. The classical V600E BRAF mutation was not found; instead a novel V600L was observed suggesting that the oncogenic event in OMM is different from that in skin melanoma. The low frequency of NRAS and BRAF mutations indicate that these genes are not common, but probable events in OMM pathogenesis, most likely independent of c-kit mutation.

Primary Oral Mucosal Melanoma: A Series of 35 New Cases From South America

Oral mucosal melanoma is rare and reported to be more aggressive than its cutaneous counterpart. Due to the rarity of this entity, data on epidemiology, tumor behavior, treatment, follow-up, and survival of patients are mainly based on single case reports. The few existing series of patients show that oral mucosa melanoma has its peak between 41 and 60 years of age, and male to female ratio is 2:1. Preferred oral sites include hard palate and maxillary alveolar crests. Risk factors have not been clearly identified, and surgical treatment is still the treatment of choice for oral mucosal melanomas. The authors retrospectively studied 35 patients with primary melanoma of the oral cavity to report their clinical and pathological features, such as age, sex, site of the tumor, metastasis, treatment, response to therapy, and outcome. We found no significant sex predominance, and the mean age of the patients was 60.6 years, with a range from 9 to 91 years. The majority of the patients (71.42%) had palate commitment, and invasive histopathological aspect was observed in 80% of the specimens (grade 3). Long-distance metastasis was found in 60% of the cases. Fourteen patients were submitted to wide surgical resections, with local relapse being observed in 11 of them (78.5%). The authors suggest that improved outcome in oral malignant melanoma requires the development of new therapies and the prevention of distant metastasis.

C-kit protein expression correlated with activating mutations in KIT gene in oral mucosal melanoma

C-kit is a trans-membrane receptor tyrosine kinase (RTK) encoded by the proto-oncogene KIT located at 4q11-12. Gain-of-function mutations arising to c-kit activation independent of its ligand were observed in various tumors related to germ cells, mast cells, and interstitial cells of Cajal. C-kit also participates in melanocyte development; hence, its involvement in oral mucosal melanoma (OMM) tumorigenesis was investigated. Immunohistochemistry and mutation analysis were performed using 18 cases of human primary OMM. Results revealed 16 cases positive to c-kit protein. Atypical melanocytes expressed c-kit. All in situ components expressed c-kit, but only four cases exhibited intense expression in the invasive component. Missense mutations were observed in four cases, and two of those correlated with increased protein expression. C-kit expression in atypical melanocytes suggests the role of c-kit in the early stage of OMM tumorigenesis. C-kit protein expression correlated with activating mutations indicating the pertinent role of the proto-oncogene KIT in the tumorigenesis of OMM.