Non-cutaneous Melanoma Research Articles

Mucosal Melanoma of the Head and Neck

Overview Mucosal melanoma (MM) is a rare, very aggressive noncutaneous melanoma that affects the upper aerodigestive tract, genitourinary tract, and anal/rectal region.1 This portion of the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Head and Neck (H&N) Cancers only describes MMs of the H&N, which constitute fewer than 10% of melanomas of the H&N.1,2 Note that a separate NCCN Guideline is available for cutaneous melanoma (see NCCN Guidelines for Melanoma, available in this issue and online at www.NCCN.org). NCCN

Noncutaneous Melanoma Have Distinct Features from Each Other and Cutaneous Melanoma

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.

Frequency ofBRAFMutation and Clinical Relevance for Primary Melanomas

BackgroundThis study was conducted to clarify the frequency of the BRAF mutation in primary melanomas and its correlation with clinicopathologic parameters.MethodsWe analyzed the frequency of BRAF mutation in patients with primary cutaneous melanoma (n=58) or non-cutaneous one (n=27) by performing dual priming oligonucleotide-based multiplex real-time polymerase chain reaction to isolate and to purify the DNA from the formalin-fixed and paraffin-embedded tumors.ResultsThe BRAF mutation was found in 17.2% (10/58) of patients with primary cutaneous melanoma and 11.1% (3/27) of those with non-cutaneous melanoma. The frequency of BRAF mutation was not correlated with any clinicopathologic parameters with the exception of the patient age. The frequency of the BRAF mutation was significantly higher in patients younger than 60 years as compared with those older than 60 years (p=0.005).ConclusionsCompared with previous reports, our results showed that the frequency of the BRAF mutation was relatively lower in patients with primary cutaneous melanoma. Besides, our results also showed that the frequency of the BRAF mutation had an inverse correlation with the age. Further studies are warranted to exclude methodological bias, to elucidate the difference in the frequency of the BRAF mutation from the previous reports from a Caucasian population and to provide an improved understanding of the molecular pathogenesis of malignant melanoma.

Two cases of primary malignant melanoma of vagina

Primary malignant melanoma of the vagina is extremly rare disease. This disease is one of non-cutaneous melanomas and accounts for 0.3% of all malignant melanomas. The most common symptoms is vaginal bleeding because the disease is usually in advanced stage at first visit. An appropriate and effective treatment protocol has not been established. The prognosis is poorer than those of other vulvar melanomas. It has been known the tumor size is the most important prognostic factor determining the survival outcome. We reported two cases of primary malignant melanoma of the vagina with review of literature.

Dacarbazine-based chemotherapy as first-line treatment in noncutaneous metastatic melanoma

Malignant melanoma, a neoplastic disorder produced by malignant transformation of the melanocyte, is considered to be resistant to chemotherapy. Dacarbazine is one of the standard chemotherapeutic agents in Korea. This study is designed to analyze treatment outcome and delineate prognostic factors based on clinical parameters for patients with advanced malignant melanoma who had received dacarbazine-based chemotherapy. This is a multicenter, retrospective analysis of 95 patients with metastatic malignant melanoma who had received dacarbazine-based chemotherapy, from January 1997 to June 2010. After a median follow-up duration of 41 months (range, 2-191 months), median survival time from the start of treatment was 12.1 months [95% confidence interval (CI): 10.9-13.5]. The overall response rate was 26.3% (95% CI: 17.8-36.4). On univariate analysis, primary site [mucosa of head and neck, gastrointestinal (GI)/genitourinary tract > cutaneous+acral melanoma], metastases to liver, GI tract, and elevated lactate dehydrogenase adversely influenced on survival. At a multivariate level, independent poor prognostic factors were mucosal melanoma [P=0.001; hazard ratio (HR): 2.988; 95% CI: 1.534-5.821], metastasis to GI tract [P=0.040; HR: 2.108; 95% CI: 1.036-4.288], and elevated lactate dehydrogenase (P=0.047; HR: 1.695; 95% CI: 1.007-2.854). Dacarbazine-based chemotherapy seems to be a reasonable option in Asia where mucosal melanoma is more prevalent than in the West. The dacarbazine-based chemotherapy showed an overall response rate of 26.3% and an overall survival of 12.1 months without a significant difference in response rates between noncutaneous or cutnaeous melanoma.

Ocular Melanoma

Abstract Context—Intraocular melanoma of the ciliary body and choroid is the most common primary ocular malignant tumor in adults and the most common noncutaneous melanoma. Objective—To describe the most salient clinical features, histopathologic findings, and treatment modalities of intraocular melanoma, as well as the novel therapies currently being tested. Data Sources—Clinically, it is important to determine which lesions carry a worse prognosis so as to offer patients the best treatment modalities available. Tumor location, size, histopathology, cytogenetic abnormalities, and tumor profiling are all used in determining the risk of death from metastatic disease of uveal melanocytic lesions. Despite successful local tumor control, up to 50% of patients have metastatic disease within 15 years of diagnosis; there is no effective treatment for metastatic disease. Conclusions—Pathologists should be aware of the importance of tumor gross description, cellular histopathology classification, the use of fine-needle aspiration biopsy coupled with cytogenetics, and the new classification of uveal malignant melanomas that is based on chromosome 3 status.

“POSTERIOR FOSSA LESION 45 YEARS AFTER OCULAR TRAUMA”

We describe a patient who developed an isolated brain metastasis four years after his right eye was treated for conjunctival melanoma by excision and local chemotherapy. He had a history of ipsilateral ocular trauma by coal stuff while working in a mining industry. Conjunctival melanoma represents only 1.6% of all non-cutaneous melanoma. Metastasis of this kind of neoplasm to brain is a rare event, especially without evidence of prior or concurrent regional lymph node involvement.

Diagnostic utility of EWS break-apart fluorescence in situ hybridization in distinguishing between non-cutaneous melanoma and clear cell sarcoma

Clear cell sarcoma (CCS) is a rare soft tissue sarcoma with morphological similarities to malignant melanoma (MM), but with a distinct genetic background that includes the chromosomal translocation t(12;22)(q13;q12). Clear cell sarcoma is often misdiagnosed as MM because of similarities in target locations and immunophenotypes. Eighteen cases with MM in non-cutaneous sites were subjected to fluorescence in situ hybridization (FISH) to assess EWS gene breakage. Tissue microarrays were constructed using formalin-fixed, paraffin-embedded tissue and the EWSR1 (22q12) dual-color, break-apart rearrangement probe (Vysis) was used. Two patients were classified as CCS with EWS gene rearrangement, with a mean of 67.5% positive cells per sample according to break-apart FISH. The remaining 16 patients lacked break-apart signals of the EWS gene. The presence of type 1 (EWS exon 8-ATF1 exon 4) fusion transcripts was confirmed in FISH-positive patients by RT-PCR. Retrospective analysis revealed that the masses were located in the foot and buttock, respectively. Morphologically, tumor cells were not typical for those of CCS or MM. Break-apart FISH is an accurate and convenient method for differentiating between MM and CCS. Molecular detection of EWS gene rearrangement, either by break-apart FISH or RT-PCR, is mandatory in subjects with melanotic tumors of soft tissue.

Surgery of Primary Melanomas

Surgery remains the mainstay of melanoma therapy, regardless of the tumor site. Only the early diagnosis combined with proper surgical therapy currently gives patients affected by this malignancy the chance for a full cure. The main goal of surgical therapy is to provide the local control of the disease and to secure long-term survival of the patient without reasonable functional and esthetic impairment. The recommended method of biopsy—excisional biopsy, as an initial diagnostic and, to some extent, therapeutic procedure—is performed under local anesthesia as an elliptical incision with visual clear margins of 1–3 mm and with some mm of subcutaneous tissue. The extent of radical excision of the primary tumor (or scar after excisional biopsy) is based on the histopathologic characteristics of the primary tumor and usually consists of 1–2 cm margins with primary closure. The philosophy behind conducted randomized clinical trials has been to find the most conservative surgical approach that is able to guarantee the same results as more demolitive treatment. This has been the background of the trials designed to define the correct margins of excision around a primary cutaneous melanoma. Much less definition can be dedicated to the surgical management of patients with non-cutaneous melanomas.

Noncutaneous malignant melanoma: a prognostic model from a retrospective multicenter study

BackgroundWe performed multicenter study to define clinical characteristics of noncutaneous melanomas and to establish prognostic factors patients who received curative resection.MethodsOf the 141 patients who were diagnosed of non-cutaneous melanoma at 4 institutions in Korea between June 1992 and May 2005, 129 (91.5%) satisfied the selection criteria.ResultsOf the 129 noncutaneous melanoma patients, 14 patients had ocular melanoma and 115 patients had mucosal melanoma. For mucosal melanoma, anorectum was the most common anatomic site (n = 39, 30.2%) which was followed by nasal cavity (n = 30, 23.3%), genitourinary (n = 21, 16.3%), oral cavity (n = 14, 10.9%), upper gastrointestinal tract (n = 6, 4.7%) and maxillary sinus (n = 5, 3.9%) in the order of frequency. With the median 64.5 (range 4.3-213.0) months follow-up, the median overall survival were 24.4 months (95% CI 13.2-35.5) for all patients, and 34.6 (95% CI 24.5-44.7) months for curatively resected mucosal melanoma patients. Adverse prognostic factors of survival for 87 curatively resected mucosal melanoma patients were complete resection (R1 resection margin), and age > 50 years. For 14 ocular melanoma, Survival outcome was much better than mucosal melanoma with 73.3% of 2 year OS and 51.2 months of median OS (P = .04).ConclusionPrognosis differed according to primary sites of noncutaneous melanoma. Based on our study, noncutaneous melanoma patients should be treated differently to improve survival outcome.

9332 Non-cutaneous melanomas: not so rare entity – our experience at a centre in India

9332 Non-cutaneous melanomas: not so rare entity – our experience at a centre in India

Review: Therapeutic opportunities in noncutaneous melanoma

Recent evidence suggests that the biology of noncutaneous melanoma differs significantly from cutaneous melanoma and may provide therapeutic opportunity. The most frequent sites of origin of noncutaneous melanoma are the eye and mucosal surfaces. Although noncutaneous melanomas are an uncommon group of cancers (representing less than 10% of all melanomas) a greater understanding of their genetic and molecular abnormalites is being translated into novel treatment strategies. These developments are important because there is currently no effective systemic therapy for noncutaneous melanoma. Significant attention has been focused on the role of c-kit (KIT, CD117), a transmembrane receptor with tyrosine kinase activity. In vitro and ex vivo evidence suggests that c-kit is frequently expressed/over expressed/mutated in noncutaneous melanoma. Anti-tumour effects with c-kit inhibitors are seen in pre-clinical models. A variety of multitargeted kinase inhibitors which have activity against c-kit are currently in early phase clinical trials in metastatic ocular, mucosal and acral melanoma. The few case reports of significant clinical activity with targeted therapies provides hope that greater understanding of the biology of noncutaneous melanoma can be translated into effective treatment.

Malignant Melanoma: 10 Years Retrospective Study of Buddhist Tzu-chi General Hospital

Background: Retrospective review of melanoma in east Taiwan Aim and Objectives: To determine the characteristics and clinical outcome of patients with malignant melanoma in east Taiwan and survey the subtype of melanoma and survival between surgery and non-surgery group Materials and Methods: Thirty-six patients at Buddhist Tzu-Chi Hospital between May 1995 and April 2004 were included into study for clinical features and outcomes. Results: Of the 36 cases, there were 30 cases (84%) of acral lentiginous melanoma (ALM), one (2.7%) of nodular melanoma (NM), one (2.7%) of superficial spreading melanoma (SSM) and 4 cases (11.1%) of noncutaneous melanoma. Twenty-eight patients received surgery with or without lymph node dissection. Eight patients (male: female=7:1) took conservative treatment. Wide excision with therapeutic lymph node dissection was performed on 4 patients. Other sixteen patients received prophylatic LND after definite surgery. There's no significant difference in survival between surgery and surgery combined with lymph node dissection. The 5-year survival rates of patients with stageⅡ, Ⅲ, and Ⅳ, disease were 54%, 12.5%, & 0% respectively. The mean survival of the 36 cases was 2.56 years (0.024-12 years). Overall 5-year survival rate was 14% (5/36). All of these 5 patients received surgical excisions. There is significant difference between surgery and non-surgery group. Conclusion: Malignant melanoma is a highly lethal disease. Most of our patient possessed advanced stage at diagnosis and this account for poor 5-year survival in this series. Although uncommon in Taiwan, we strongly emphasize that more education for both general publics and physicians will promote early tumor detection and treatment, providing a better prognosis.

The safety of anti-tumour necrosis factor treatments in rheumatoid arthritis: meta and exposure-adjusted pooled analyses of serious adverse events

Objective:To evaluate the safety of biological treatments for rheumatoid arthritis (RA) using results from randomised controlled trials (RCT).Methods:The literature was searched to December 2007 for RCT evaluating inhibitors of tumour...

Jejuno-jejunal invagination due to intestinal melanoma

Cutaneous melanoma is one of the most studied neoplastic lesions in biology and clinical oncology. It has been well documented that this type of neoplasm presents a high metastatic rate, and is able to involve nearly every tissue. Non-cutaneous melanoma represents an unusual pattern of melanoma, and the small intestine is an uncommon anatomic localization. Herein we report an extremely rare clinical case of a young woman affected by a bleeding jejunal melanoma, whose early clinical presentation was an intestinal invagination.

Incidence of Noncutaneous Melanomas in the U.S.

Incidence of Noncutaneous Melanomas in the U.S.

BRAF and NRAS mutations are uncommon in melanomas arising in diverse internal organs

Background: Malignant melanoma arising from different body compartments may be associated with differing aetiological factors and clinical behaviour, and may manifest diverse molecular genetic profiles. Although many studies have focused...

The association between large congenital melanocytic naevi and cutaneous melanoma: preliminary findings from an Internet-based registry of 379 patients

There is ample evidence in the literature to support the fact that there is an increased risk of the development of melanoma in individuals with a large congenital melanocytic naevus (LCMN). The published melanoma risk estimates, by and large, do not distinguish between cutaneous and extracutaneous melanomas. It is currently not known to what extent each contributes to the overall cited melanoma risk estimates. In order to obtain a better understanding of the association between LCMN and cutaneous melanoma arising within an LCMN, we report the preliminary findings of a cross-sectional study of 379 patients, with a median age of 3 years, from the first self-referred, Internet-based registry of patients with LCMN. To date, no cutaneous melanoma has been reported; possible reasons for this finding are discussed. Further research is required to clarify the risk of the development of cutaneous melanoma separate from non-cutaneous melanoma and to identify subgroups of patients with LCMN at highest risk for the development of melanoma. This information will help to formulate appropriate decisions concerning the management of patients with LCMN.

Incidence of noncutaneous melanomas in the U.S.

Description of the epidemiology of noncutaneous melanoma has been hampered by its rarity. The current report was the largest in-depth descriptive analysis of incidence of noncutaneous melanoma in the United States, using data from the North American Association of Central Cancer Registries. Pooled data from 27 states and one metropolitan area were used to examine the incidence of noncutaneous melanoma by anatomic subsite, gender, age, race, and geography (northern/southern and coastal/noncoastal) for cases diagnosed between 1996 and 2000. Percent distribution by stage of disease at diagnosis and histology were also examined. Between 1996 and 2000, 6691 cases of noncutaneous melanoma (4885 ocular and 1806 mucosal) were diagnosed among 851 million person-years at risk. Ocular melanoma was more common among men compared with women (6.8 cases per million men compared with 5.3 cases per million women, age-adjusted to the 2000 U.S. population standard), whereas mucosal melanoma was more common among women (2.8 cases per million women compared with 1.5 cases per million men). Rates of ocular melanoma among whites were greater than eight times higher than among blacks. Rates of mucosal melanoma were approximately two times higher among whites compared with blacks. In contrast to cutaneous melanoma, there was no apparent pattern of increased noncutaneous melanoma among residents of southern or coastal states, with the exception of melanoma of the ciliary body and iris. Despite their shared cellular origins, both ocular and mucosal melanomas differ from cutaneous melanoma in terms of incidence by gender, race, and geographic area.

Trends in mortality from malignant melanoma in Sweden, 1970-1996.

The rise in melanoma-related mortality in Sweden has been less pronounced than the increase in incidence. Interventional activities aimed at early detection may have contributed to this discrepancy. Individuals with malignant melanoma as the underlying cause of death between 1970 and 1996 (n = 7177) formed the basis of this study. Annual age-standardized mortality rates were calculated using the direct method of standardization with the Swedish population of 1970 as reference. Temporal trends in the standardized rates were evaluated using a log-linear model. The effects of age, period, and cohort on the mortality trends were estimated using a Poisson regression model. Since the mid-1980s, melanoma-related mortality in Sweden has leveled off, with no further increase during the last 10-15 years. The contribution to the mortality from noncutaneous melanoma was proportionally stable (20-25%) during the studied period. In females, a significant decrease in mortality from cutaneous melanoma was shown for the period of 1987-1996 with an estimated annual decrease of -2.3% (95% confidence interval: -4.3 to -0.3). This trend appeared to be more pronounced in the Stockholm-Gotland region. The observed trends were best explained with the age-period model in both genders. Melanoma-related mortality in Sweden has leveled off since the mid-1980s. During the period 1987-1996, a statistically significant downward trend was observed for females. This trend coincides with increased preventional activities.