Primary Oral Melanoma Research Articles

IQGAP1 is an oncogenic target in canine melanoma.

Canine oral mucosal melanoma is an aggressive malignant neoplasm and is characterized by local infiltration and a high metastatic potential. The disease progression is similar to that of human oral melanomas. Whereas human cutaneous melanoma is primarily driven by activating mutations in Braf (60%) or Nras (20%), human mucosal melanoma harbors these mutations much less frequently. This makes therapeutic targeting and research modeling of the oral form potentially different from that of the cutaneous form in humans. Similarly, research has found only rare Nras mutations and no activating Braf mutations in canine oral melanomas, but they are still reliant on MAPK signaling. IQGAP1 is a signaling scaffold that regulates oncogenic ERK1/2 MAPK signaling in human Ras- and Raf- driven cancers, including melanomas. To investigate whether IQGAP1 is a potential target in canine melanoma, we examined the expression and localization of IQGAP1 in primary canine melanomas and canine oral melanoma cell lines obtained from the University of California-Davis. Using CRISPR/Cas9 knockout of IQGAP1, we examined effects on downstream ERK1/2 pathway activity and assayed proliferation of cell lines when treated with a peptide that blocks the interaction between IQGAP1 and ERK1/2. We observed that canine IQGAP1 is expressed and localizes to a similar extent in both human and canine melanoma by qPCR, Western blot, and immunofluorescence. Deletion of IQGAP1 reduces MAPK pathway activation in cell lines, similar to effects seen in human BrafV600E cell lines. Additionally, we demonstrated reduced proliferation when these cells are treated with a blocking peptide in vitro.

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.

Abstract: 14.50 Epidemiology And Survival Of Patients With Hard Palate Melanoma: A Population-Based Study

INTRODUCTION: Primary oral melanoma is an extremely rare and aggressive malignancy arising from the mucosal epithelium of the oral cavity. The majority of cases occur in the hard palate. However, disease presentation and survival have never been comprehensively studied. Our main goal was to analyze epidemiology, loco regional treatment patterns and survival outcomes of patients with primary hard palate melanoma in the United States, using the Surveillance, Epidemiology, and End Results (SEER) population based registry of the National Cancer Institute. MATERIALS AND METHODS: The SEER database was queried for melanoma cases (morphology codes=8720–8790) located in the hard palate (topography code C05.0-hard palate) diagnosed between 1973 and 2012. Demographic and clinicopathological information were extracted for each case. Overall survival rate was determined using the Kaplan-Meier method. Log.rank test was employed to compare overall survival between different subgroups and a Cox hazard regression analysis was performed to determine independent predictors of overall survival. RESULTS: We identified 83 cases of hard palate melanoma, 49 female and 34 males. The age distribution was: 13.3% < 50 years, 38.6% between 50 and 69 years, 48.2% >= 70. Surgery alone was performed in 48.2% of cases, radiation therapy alone in 6%, and the combination of surgery and radiation therapy 33.7%.Overall 5-year survival was 26.3%. Adjuvant radiation therapy was not associated with a longer overall survival as compared to surgery alone. CONCLUSIONS: Hard palate melanoma is a rare tumor with a low overall survival mostly affecting the elderly. Main treatment is surgical resection. Adjuvant radiotherapy does not confer an improved survival. The establishment of an international registry is advocated to better define treatment options.

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.

Primary Melanoma of the Oral Mucosa: A Case Report and Review of Literature

Primary oral melanoma is a rare neoplasm accounting for 0.5% of all oral malignancies. It has an aggressive behavior with a tendency of local invasion and distant metastases more readily than other malignant tumors of the oral cavity. Due to its rarity data on epidemiology, tumor behavior, treatment, follow up and survival of patients are mainly based on single case reports. Here we present a case of 85 years old female who presented with a hard palate blackish lesion and bilateral neck nodes enlargement, biopsy positive for malignant melanoma. With no evidence of extra oral primary melanoma evidence.

Immunohistochemical expression of cyclooxygenase-2 (COX-2) in oral nevi and melanoma.

Cyclooxygenase-2 (COX-2) catalyses the conversion of arachidonic acid to prostaglandin, and its overexpression has been demonstrated in different malignant tumors, including cutaneous melanoma. However, no data about the expression of this protein in oral melanocytic lesions are available to date. The aim of this study was to evaluate the immunohistochemical expression of COX-2 in oral nevi and melanomas, comparing the results with correspondent cutaneous lesions. COX-2 was evaluated by immunohistochemistry in 49 oral melanocytic lesions, including 36 intramucosal nevi and 13 primary oral melanomas, and in four cutaneous nevi and eight melanomas. All cases of oral and cutaneous melanomas were positive for COX-2. On the other hand, all oral and cutaneous melanocytic nevi were negative. COX-2 is highly positive in oral melanomas and negative in oral nevi and might represent a useful marker to distinguish melanocytic lesions of the oral cavity.

Primary Oral Melanoma: A Case Report and Literature Review

Primary Oral Melanoma: A Case Report and Literature Review

Abstract 5137: IQGAP1, an ERK1/2 MAPK scaffold, is an oncogenic target in canine melanoma

Abstract BACKGROUND: Human cutaneous melanoma is primarily driven by activating mutations in Braf (60%) or Nras (20%). However, human oral melanoma harbors these mutations much less frequently. Similarly, canine oral mucosal melanomas have not been found to have activating Braf or Nras mutations. This makes them an ideal model to study alternative means of ERK1/2 MAPK pathway activation as these tumors are still reliant on MAPK signaling. We have previously studied IQGAP1 as a tumor specific ERK1/2 MAPK scaffold and shown that it is required for cancer progression. METHODS: In this study, we utilized canine oral melanoma cell lines obtained from the University of California-Davis. We examined the expression and localization of IQGAP1, a signaling scaffold that regulates oncogenic ERK1/2 MAPK signaling in human cancer, and validate it as an oncogenic target in the canine melanoma model. Using a CRISPR/Cas9 knockout of IQGAP1, we examined effects on downstream pathway activation. Additionally, we assayed proliferation of these cell lines when treated with a peptide that blocks the interaction between IQGAP1 and ERK1/2. RESULTS: We observed that canine IQGAP1 is expressed and localizes to a similar extent in human and canine melanoma by qPCR, Western blot and immunofluorescence. Deletion of IQGAP1 from two canine oral melanoma cell lines using CRISPR-Cas9 genome editing reduces MAPK pathway activation, similar to effects seen in human BrafV600E cell lines. Additionally, we demonstrated reduced proliferation when these cells are treated with the WW blocking peptide in-vitro. We are currently investigating the expression and localization of IQGAP1 in primary canine oral melanoma compared to normal oral mucosa. CONCLUSION: Building on the above findings to explore alternative MAPK signaling in melanoma using the canine melanoma model may yield novel therapeutic strategies and novel means to target canine and human tumors that are resistant to current Braf and MEK targeted therapies. Citation Format: Ashley Zehnder, Becky Lee, Poornima Neela, Paul Khavari. IQGAP1, an ERK1/2 MAPK scaffold, is an oncogenic target in canine melanoma. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5137. doi:10.1158/1538-7445.AM2015-5137

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.

Primary malignant melanoma of oral cavity: A tertiary care center experience

Background:Primary mucosal malignant melanoma is an extremely rare, aggressive neoplasm accounting for 0.5% of all oral malignancies. Any pigmented lesion in oral cavity should have an index of suspicion, which should be investigated to detect the disease at an early stage and managed appropriately. Melanomas tend to invade locally into the tissue or metastasize more commonly than other malignant tumors of the oral cavity.Materials and Methods:We report a retrospective case series of eight patients suffering from primary oral malignant melanoma treated in our department between 2012 and 2014. The details were recorded from the departmental computerized database and patients on follow-up.Results:There were six male and two female patients with a mean age of 46.8 years. Hard palate was the most common affected site in oral cavity. Pigmented lesion\\ulcer was the most common presenting symptom. Majority of patients (5 patients) were diagnosed with Stage III (distant metastasis), two patients in Stage II, and one patient in Stage I. Three patients were treated with definitive surgery and five patients with palliative chemotherapy in view of distant disease. Following surgery, two of them required adjuvant chemoradiotherapy in view of nodal spread. Patients had a mean follow-up of 10.5 months (range: 8–26 months). Patients treated with definitive surgery had a mean survival rate of 16 months (range: 10–26 months), with local recurrence in one patient. Metastatic melanoma patients treated with palliative chemotherapy had a mean disease control rate of 5 months (range 5–9 months).Conclusion:Oral melanoma carries dismal prognosis with a 5-year survival rate of 5–20%. Early detection of the lesion, proper evaluation, and appropriate treatment are very important to cure the disease.

Clinicopathological characterization of primary oral and sinonasal melanoma in a referral centre in Mexico City: 2000–2012

In Mexico, there have been few studies on primary oral and sinonasal melanoma, an aggressive neoplasm with a low survival rate and few therapeutic alternatives. Further, there is limited information about its clinical and histopathological characteristics. The aim of this retrospective study was to describe the clinicopathological profile of these tumours in patients attending a major oncology reference centre in Mexico City over a 12-year period. Demographic and clinical data were obtained from the clinical charts, and histopathological features were evaluated. χ2, Fisher's exact, and Mann–Whitney U-tests were used for analysis; significance was set at P<0.05. Thirty-three cases were studied (73% sinonasal melanoma (SNM) and 27% oral melanoma (OM)); 58% were female and the median age was 66 (Q1–Q3 55.5–75) years. Compared with OM patients, SNM patients had a shorter time to diagnosis (16.7 vs. 11.7 months, P=0.022), were identified at earlier stages (33.3% vs. 58.3%, P=0.010), and all presented symptoms (66.7% vs. 100%, P=0.015). All samples showed vertical growth and 96.9% exhibited pleomorphism. A higher proportion of cases with pleomorphism developed metastases at follow-up than those without (60% vs. 12.5%, P=0.026). The present study provides valuable information that could form the basis of future studies in the search for advanced therapy modalities.

Intra-oral spitzoid Malignant Melanoma- unexpected diagnosis of a fibroepithelial polyp

Introduction: Primary malignant melanoma is a rare in the oral cavity. Primary oral melanoma represents 0.2-8% of all melanomas and accounts for 0.5% of all oral malignancies. The most frequent site of occurrence are the palate and maxillary gingivae accounting for 80% of all oral melanomas. Spitzoid melanoma is cutaneous malignancy and occurs commonly in on the head and extremities. Spitzoid melanoma shares many histopathologic features with Spitz nevus, it is one of the most difficult lesions to diagnose in dermatopathology. There is indeed uncertainty in the medical literature about how to diagnose melanocytic proliferations including Spitz nevus and spitzoid melanoma. Case: A fifty year male was referred with an asymptomatic intraoral lump of several months duration which was reported as slowly increasing in size. Excison biopsy was undertaken and histology revealed a compound, nonulcerated, poorly pigmented melanocytic lesion with mitotic and spitzoid changes. There was no inflammation, lymphovascular or perineural invasion. The lesion was diagnosed as an incompletely excised spitzoid melanoma. Further wide local excision with 5 mm margin was found to have a focus of Spitzoid melanoma. A second wide local excision was clear of residual tumour. CT staging skull base to diaphragm was clear of any metastatic disease and the patient remains disease free one year later. Conclusion: Intra-oral Spitzoid Melanoma is a rare. The management is surgical excision. Guidelines for its management however are not well established due to the small numbers of cases reported.

Primary Malignant Melanoma of the Oral Mucosa: Report of an Unusual Case

Primary oral malignant melanoma is an extremely rare tumor, representing 0.2% to 8% of all melanomas; accounting for 0.5% of all oral malignancies The prognosis for a patient with oral melanoma is dismal, with a 5-year survival rate of 5% to 20%. A case is reported of a malignant melanoma in the mouth of a 81 year old male. The patient had a history of a continuously growing exophytic hyperplastic mass of a dark color. Histological examination revealed a melanin-producing tumour. Surgery was not offered to our elderly and medically compromised patient. Instead he received radiation therapy as the primary treatment and immunotherapy as the adjuvant treatment.

Oral malignant melanoma: A report of two cases with BRAF molecular analysis.

Primary oral malignant melanoma is a rare condition, accounting for 1.3–1.4% of all melanomas, usually presenting with an aggressive clinical behavior. The present study reports the clinicopathological findings of two cases of oral malignant melanoma and discusses the epidemiology, diagnosis and current therapeutic approaches for this uncommon condition. In the first case the patient presented with a pigmented lesion located on the lower mucosal lip. The patient showed no nodal metastases and therefore, underwent a wedge resection. After seven months, the patient presented with neck lymph nodes and multiple visceral metastases. Molecular analysis of BRAF, using a pyrosequencing approach, revealed the presence of BRAF V600E mutation. The patient developed multiple visceral metastases, but refused treatment and was lost to follow-up. In the second case, no BRAF V600E mutation was found, but the patient exhibited a pigmented patch in the lower gingival mucosa, which was excised by surgical treatment. The patient was followed up by an oncologist, but did not undergo an additional therapy and is currently alive with no evidence of visceral metastases at one year following the diagnosis.

Primary oral melanoma presenting with cervical lymph node metastasis: A rare case report with emphasis on the role of FNA in the diagnostic approach

Primary oral melanoma presenting with cervical lymph node metastasis: A rare case report with emphasis on the role of FNA in the diagnostic approach

Primary Oral Malignant Melanoma: A Case Report and Review of Literature

Malignant melanoma is a neoplasm of melanocytic origin that arises from a benign melanocytic lesion or denovo from melanocytes within otherwise normal skin or mucosa. Primary malignant melanoma of the oral cavity is a rare neoplasm and is considered among the most deadly of all human neoplasms. This malignancy commonly affects male subjects and the average age for diagnosis of oral melanoma is 55 years. A biopsy is required to establish a diagnosis. Ablative surgery with tumor-free margins remains the treatment of choice. Described is a case of malignant melanoma of the maxillary gingiva in a 42-year-old female. Immunohistochemistry using HMB-45 and S100 was done for confirmatory diagnosis.

Primary malignant melanoma of maxilla: report of a case with discussion.

Primary oral malignant melanoma, very rare neoplasm of melanocytic origin, usually presents as a bluish black to tan-brown colored lesion Which is accounting for 0.2 to 8% of all melanomas, 1.6% of all head and neck malignancies, and 0.5% of all oral neoplasia. In general, the prognosis of oral melanoma is poor and worse than that of cutaneous melanoma. Here a case of oral malignant melanoma is presented, which was undetected during the first visit to a dental clinic. When a simple oral surgical treatment was carried out in that region, it resulted in the appearance of a massive pigmented lesion which was histopathologically diagnosed as malignant melanoma. This paper is presented to reemphasize the fact that any pigmented lesion in the oral cavity should be viewed with suspicion and proper investigation (biopsy) should be carried out to rule out any untoward experiences later.

Primary Oral Melanoma: A Case Report with Immunohistochemical Findings

Melanoma is a potentially aggressive and rare malign neoplasm of melanocytic origin. Only 1% occurs in oral mucosa, accounting for 0.5% of all oral malignancies being more aggressive when compared with the cutaneous counterpart. The tumor occurs more frequently in the hard palate and gingiva. Despite the advances in biological knowledge of melanoma, treatment and prognosis still have limitations, especially in head and neck melanomas, including oral melanomas. The aim of this study is to report a case of primary oral melanoma in a 54 year-old male patient. An asymptomatic pigmented lesion was located in the upper vestibular gingiva and an incisional biopsy was done. Cytomorphological findings revealed proliferation of pleomorphic epithelioid and plasmacytoid cells positive by immunohistochemistry for S-100 protein, HMB-45 and Melan-A, confirming the diagnostic of oral melanoma. This study showed the importance of the histopathological and immunohistochemical evaluation in order to determine the cytomorphologic aspects of oral melanoma to establish the final diagnosis.

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.

OP218: Immunohistochemical profile of primary oral malignant melanomas

Purpose Primary oral melanoma is an uncommon malignant tumor of melanocytic origin, with potentially aggressive capacity. Several immunohistochemical markers influencing invasiveness and metastatic dissemination of melanoma have been identified and used previously. Our aim was to analyze the immunohistochemical expression for cathepsin-D, c-kit, E-cadherin, cyclin D1, and MUM-1 in oral malignant melanomas. Material and Methods Immunoperoxidase staining was performed on formalin-fixed tissue specimens from oral melanoma specimens and oral melanocytic nevi lesions which were used as control group. The percentages of immunoreactive melanocytes were estimated and qualitatively abnormal immunoreactivity patterns were also tabulated. Results Cathepsin-D, c-kit, cyclin D1, and MUM-1 were highly expressed in oral melanomas, whereas negative or very weak expression of the above mentioned markers was recorded in oral melanocytic nevi lesions. E-cadherin was expressed uniform throughout the entire oral melanocytic nevi, whereas oral melanomas expressed heterogeneous E-cadherin staining. Furthermore oral melanomas showed qualitatively and quantitavely abnormal E-cadherin immunoreactivity, with gradual loss of staining and increasing lesional depth. The results indicate that cathepsin-D, c-kit, E-cadherin, cyclin D1, and MUM-1 may be involved in the development of oral melanomas, and eventually they may be useful in the differential diagnosis of oral malignant melanomas and oral melanocytic nevi lesions. Conclusions The above mentioned markers seems to correlate with oral melanoma development and have an important functional role in tumor development or progression. Melanoma has a wide spectrum of histologic features which mimic epithelial, hematologic, mesenchymal, and neural tumors. Immunohistochemistry has been the primary tool to distinguish melanomas from these other tumors. Use of immunohistochemical markers should therefore give additional information which cannot be determined by routine histopathology.