Melanoma with benign melanocytic naevus components: reappraisal of clinicopathological features and prognosis

The clinicopathological features and prognosis of primary cutaneous malignant melanoma with benign melanocytic naevus (BMN) components are still under debate. The purpose of this study was to characterize further the clinical and histopathological features of naevus-associated melanomas, with emphasis on the BMN components, and to examine their prognosis based on a large series. Following a histopathological review of 667 consecutive cases of primary cutaneous melanoma, 148 melanomas with BMN components (22.1%) were identified for further study. A control group of 519 melanomas without BMN components seen in a similar period were also studied. Clinically, patients with melanomas containing BMN components (n = 148; age range 25-86 years, mean age 54 +/- 16 years; male to female ratio 1:1.02) presented with tumours located mainly on the trunk (34.5%), followed by the upper extremities (24.3%), lower extremities (20.3%), and head and neck (14.2%). Compared with tumours without BMN components (n = 519; age range 19-89 years, mean age 57 +/- 15 years; male to female ratio 1:1.3), melanomas with BMN components occurred in slightly younger individuals (P = 0.027). Histopathologically, BMN components mainly showed features of acquired naevi (total 87 cases; dysplastic, 80 cases; banal, seven cases) or congenital naevi (total 57 cases; superficial, 56 cases; deep, one case), but a minority of these lesions (four cases) could not be further subcategorized. Generally, melanomas containing BMN components were relatively thinner than melanomas without BMN components (mean Breslow index 0.95 +/- 0.83 mm and 1.3 +/- 1.6 mm, respectively) (P = 0.015). The follow-up data available in 69 patients with naevus-associated melanomas consistently revealed a relatively good outcome (5 year metastasis-free survival rate 93.75%), although no statistical difference in prognosis was observed between this group and a subset of 283 melanomas patients without BMN components stratified by tumour thickness. We conclude that BMN components in naevus-associated melanomas constitute a heterogeneous group morphologically, consisting mainly of dysplastic and superficial congenital naevi. This finding indicates a more important role for superficial congenital naevus as a precursor lesion of naevus-associated melanomas than presently recognized. Patients with naevus-associated melanomas generally show a good clinical outcome, reflecting their small Breslow index.     

Mucosal Melanoma: a Literature Review

Purpose of review

Mucosal melanoma is of great interest due to its aggressive behavior and less favorable prognosis. The literature is mainly case reports and case series. Here, we will collect the knowledge on mucosal melanoma from the last decade and review the literature. The main focus is being site-specific clinical features, treatment, and prognosis.

Recent findings

The use of immunotherapy gain ground as for others subsets of melanoma. Anti-CTLA-4 and anti-PD-1/ PD-L1 blockade in mucosal melanoma have been evaluated in recent studies. Clinical trials are ongoing.

Summary

The etiology of mucosal melanomas remains unknown. Head and neck mucosal melanomas are most common. Wide excision surgery is the treatment of choice. The effect of adjuvant therapy on survival remains questionable due to the limited knowledge. Radiotherapy seems to give better local control. The overall five-year survival rate for mucosal melanomas is 0–45%. Recent data indicates that this may be improved by the immunotherapy in the years to come.

     

Temozolomide and interferon-alpha in metastatic melanoma: a phase II study of the Italian Melanoma Intergroup

Temozolomide (TMZ) is a new oral alkylating agent which has proven to be as active as dacarbazine (DTIC) in the treatment of melanoma, but with a lower toxicity. A multicentric phase II trial was conducted in an out-patient setting to determine the therapeutic activity and safety of TMZ in combination with interferon-alpha (IFN-alpha). From June 2000 to July 2001, 41 patients were recruited to receive TMZ 200 mg/m orally on days 1-5 every 28 days and with 5 MU IFN-alpha subcutaneously three times a week, continuously for eight cycles or until disease progression occurred. Of the 40 treated patients, two complete responses (5%) and three partial responses (7.5%) were observed, with a median duration of 4 months (range, 1.5-13.5 months). Thirteen patients (32.5%) had stable disease for a median of 2.5 months. Time to progression was 2.6 months and the median overall survival was 11.8 months. Nine patients (22.5%) developed brain metastases. The grade 4 toxicity observed in seven patients was of a transient haematological nature. This combination therapy is well tolerated but does not appear to increase the response rate or overall survival with respect to TMZ alone or to chemotherapeutic regimens. Further and more complex associations of these two drugs could be investigated in specific subsets of patients, in particular to evaluate its real efficacy in preventing brain metastases.     

Melanoma of unknown primary origin: A population-based study in the Netherlands

AimFew population-based studies have been published on melanoma of unknown primary origin (MUP). This study’s aim is to describe characteristics and survival of MUP patients in the Netherlands, based on nationwide data from the Netherlands Cancer Registry (NCR).MethodsPatient and tumour characteristics of MUP patients were retrieved from the NCR. Subgroups were made according to metastatic site: nodal or distant. Survival rates were calculated using the Kaplan–Meier method. To obtain a better insight in the composition and prognosis of the MUP group, the survival was compared to that of patients with melanoma of a known primary origin (MKP), tumour-node-metastasis (TNM) stage III and IV.ResultsOf all 33,181 melanoma patients diagnosed between 2003 and 2009, 2.6% (n = 857) were diagnosed with MUP. MUP patients with nodal metastases had a similar survival as MKP stage III with macroscopic nodal involvement. After stratification according to the number of involved lymph nodes, the survival of patients with nodal metastases with one involved lymph node was not significantly different between MUP and MKP. The survival of MUP patients with two or more involved lymph nodes was slightly worse than that of MKP stage III patients with macroscopic nodal involvement with two or more involved lymph nodes. MUP patients with distant metastases had a similar survival as MKP stage IV. After stratification according to number of metastatic sites and metastatic site category, the survival in MKP stage IV patients with (sub)cutaneous metastases was slightly worse than MUP distant patients with (sub)cutaneous metastases.ConclusionsThe results of this study imply that MUP patients form a heterogeneous group, and that MUP patients with nodal metastases could be classified as stage III melanoma with macroscopic nodal involvement, and MUP patients with distant metastases as stage IV melanoma.     

The EORTC Melanoma Group exchange program: evaluation of a multicenter monoclonal antibody study

In the framework of the European Organisation for Research and Treatment of Cancer (EORTC), the Immunology and Pathology Subgroups of the Malignant Melanoma Cooperative Group undertook a large multicenter monoclonal antibody (MAb) study. Fourteen laboratories from 7 European countries tested a panel of 23 MAbs for immunohistological staining reactivity for malignant and non-malignant lesions involving the melanocytic lineage. A standardized immunoperoxidase procedure was used and the results were evaluated using a standard protocol and data evaluation form developed in collaboration with the EORTC Data Center. According to this analysis, the antibodies in the panel could be classified into 3 main groups. The first group of MAbs includes those antibodies which stained the majority (greater than 80%) of all primary tumors, irrespective of their Breslow thickness and the majority of metastatic lesions. In addition, these MAbs stained a high percentage of cells within a given lesion. Several antibodies of Group I were likewise reactive with the majority of naevoblasts and with normal melanocytes. The second group of MAbs included antibodies reacting only with a limited number of primary melanomas and metastatic lesions. Antibodies of Group II reacted only weakly, if at all, with normal melanocytes or naevocytes. The percentage of cells within a malignant lesion stained by these MAbs was always rather low. The MAb group III detected surface structures whose expression appeared to be related to tumor progression; they did not react or reacted only weakly with naevi, and they all reacted with a small number of early primary melanomas (less than 0.75 mm). The number of lesions stained increased with increasing Breslow thickness. Our study suggests that the application of a panel of well defined MAbs might be of diagnostic and prognostic value in evaluating malignant melanoma.     

Melanoma in adolescents: a case-control study of risk factors in Queensland, Australia

The incidence of melanoma increases markedly in the second decade of life but almost nothing is known of the causes of melanoma in this age group. We report on the first population-based case-control study of risk factors for melanoma in adolescents (15-19 years). Data were collected through personal interviews with cases, controls and parents. A single examiner conducted full-body nevus counts and blood samples were collected from cases for analysis of the CDKN2A melanoma predisposition gene. A total of 201 (80%) of the 250 adolescents with melanoma diagnosed between 1987 and 1994 and registered with the Queensland Cancer Registry and 205 (79%) of 258 age-, gender- and location-matched controls who were contacted agreed to participate. The strongest risk factor associated with melanoma in adolescents in a multivariate model was the presence of more than 100 nevi 2 mm or more in diameter (odds ratio [OR] = 46.5, 95% confidence interval [CI] = 11.4-190.8). Other risk factors were red hair (OR = 5.4, 95%CI = 1.0-28.4); blue eyes (OR = 4.5, 95%CI = 1.5-13.6); inability to tan after prolonged sun exposure (OR = 4.7, 95%CI = 0.9-24.6); heavy facial freckling (OR = 3.2, 95% CI = 0.9-12.3); and family history of melanoma (OR = 4.0, 95%CI = 0.8-18.9). Only 2 of 147 cases tested had germline variants or mutations in CDKN2A. There was no association with sunscreen use overall, however, never/rare use of sunscreen at home under the age of 5 years was associated with increased risk (OR = 2.2, 95%CI = 0.7-7.1). There was no difference between cases and controls in cumulative sun exposure in this high-exposure environment. Factors indicating genetic susceptibility to melanoma, in particular, the propensity to develop nevi and freckles, red hair, blue eyes, inability to tan and a family history of the disease are the primary determinants of melanoma among adolescents in this high solar radiation environment. Lack of association with reported sun exposure is consistent with the high genetic susceptibility in this group.     

Melanoma metastasis is associated with enhanced expression of the syntenin gene

Primary cutaneous melanomas and melanoma metastases were examined for differential gene expression using subtractive suppression hybridization in a search for any genes associated with metastasis. Generating a subtracted library of candidate genes up-regulated in melanoma metastases, this library contained 8 different cDNAs, among them a cDNA fragment of the syntenin gene which was overexpressed in further independent melanoma resection specimens on cDNA Southern blots when compared to acquired melanocytic nevi from which melanomas are known to arise. Upon immunohistochemistry, the syntenin protein expression was detected in the cytoplasm of primary cutaneous melanomas and melanoma metastases. Melanoma metastases exhibited higher proportions of tumour cells positive for syntenin immunostaining in comparison to acquired melanocytic nevi or non-metastasizing primary melanomas which was statistically significant. In addition to melanoma, gastric cancer tissues exhibited a higher syntenin mRNA expression on a matched tumour/normal cDNA array than their normal counterparts which was statistically significant. Altogether, we here first describe the detection of the syntenin protein in resection specimens of melanocytic lesions. We conclude that melanoma metastasis is associated with increased expression of the syntenin gene which may participate in signal transduction and cell adhesion via the multifunctional protein-binding properties of its tandem PDZ domains.     

Melanoma computer-aided diagnosis: reliability and feasibility study.

BACKGROUND: Differential diagnosis of melanoma from melanocytic nevi is often not straightforward. Thus, a growing interest has developed in the last decade in the automated analysis of digitized images obtained by epiluminescence microscopy techniques to assist clinicians in differentiating early melanoma from benign skin lesions. PURPOSE: The aim of this study was to evaluate diagnostic accuracy provided by different statistical classifiers on a large set of pigmented skin lesions grabbed by four digital analyzers located in two different dermatological units. EXPERIMENTAL DESIGN: Images of 391 melanomas and 449 melanocytic nevi were included in the study. A linear classifier was built by using the method of receiver operating characteristic curves to identify a threshold value for a fixed sensitivity of 95%. A K-nearest-neighbor classifier, a nonparametric method of pattern recognition, was constructed using all available image features and trained for a sensitivity of 98% on a large exemplar set of lesions. RESULTS: On independent test sets of lesions, the linear classifier and the K-nearest-neighbor classifier produced a mean sensitivity of 95% and 98% and a mean specificity of 78% and of 79%, respectively. CONCLUSIONS: In conclusion, our study suggests that computer-aided differentiation of melanoma from benign pigmented lesions obtained with DB-Mips is feasible and, above all, reliable. In fact, the same instrumentations used in different units provided similar diagnostic accuracy. Whether this would improve early diagnosis of melanoma and/or reducing unnecessary surgery needs to be demonstrated by a randomized clinical trial.     

Melanoma in childhood: An EORTC-MCG multicenter study on the clinico-pathological aspects

Melanoma in children is rare. Nevertheless, it is imperative that clinicians be aware that melanoma does occur in childhood. Yet there is very little information available on the clinico-pathologic variations, and the prognostic parameters of melanoma in children. This report presents the results of a multicenter study of 102 lesions originally diagnosed as cutaneous melanoma, conducted among 5 Western European countries and collected during the period 1961–1994. Criteria for inclusion in the study included: (1) diagnosis of cutaneous melanoma; (2) age up to 16 years at diagnosis; and (3) availability of representative microscopic slides. On the basis of the histologic review only, 60 lesions were confirmed as melanoma, and 42 lesions initially diagnosed as melanoma were reclassified as nevi; 31 of the latter contained a predominance of spindle cells. The only significant parameter associated with the development of metastases or fatal outcome was thickness of more than 2.00 mm. The 5-year survival rate observed in this study was 84%. Based on these findings we conclude that considerable over-diagnosis of melanomas in children occurs. In order, therefore, to give consistent epidemiological data on melanomas in children and to improve proper recognition of their diagnostic features, both by clinicians and by pathologists, we propose to set up a central registry of melanomas in children in Europe, under the auspices of the European Organization for Research and Treatment of Cancer. © 1996 Wiley-Liss, Inc.     

Melanoma in a tattoo of the breast

Antitumor effect of oral bacille Calmette Guérin (BCG) administration was investigated by both animal experimentation and clinical trials. In animal experiments, orally administered BCG inhibited metastasis of syngeneic tumor from the initial site in caecum to mesenteric lymph nodes. Measurement of chemiluminescent intensity of adherent cells obtained from mesenteric lymph nodes of treated hosts revealed elevated activities of these cells. In the clinical trials it was found that marked histiocytosis occurred in mesenteric lymph nodes of stomach and colorectal cancer patients treated by the oral BCG. The 2-year survival rate of treated patients with stage IV stomach cancer (44.4%) was significantly higher than that of the untreated patients (6.3%). The results of the present study indicate that the oral BCG administration would be an effective local adjuvant therapy following radical surgery to treat patients with gastrointestinal cancer.     

Melanoma metastatic to the spine: a review of 133 cases

Although spine metastasis from melanoma is an uncommon event, it can pose a complex management problem. The presentation and natural history of melanoma metastatic to the spine has not been described in the medical literature. We have conducted a review of the records of 133 patients with melanoma metastatic to the spine in order to obtain retrospective data on demographic information, clinical presentation, disease course and survival. Patients with cutaneous, ocular and mucosal melanoma were all represented, but those with primary cutaneous tumours of the trunk were more prevalent than expected. Other sites of metastatic disease were present in nearly all patients and metastases to other skeletal sites were not unusual. Pain was the most common presenting symptom. The radiographic diagnosis was generally made easily by plain radiographs, computed tomography or magnetic resonance imaging, with the most frequent finding being a destructive lesion. Bone scan gave false-negative results 15% of the time. The median survival for the group was 4 months. It is concluded that melanoma metastatic to the spine represents a late event in the evolution of this illness. Palliation should be the goal of treatment, but symptom management should be individualized, bearing in mind the short anticipated survival of these patients.     

Melanoma of the skin: clinico-genetic studies

As a result of clinico-genealogical analysis of data on 691 skin melanoma patients, a classification of skin melanoma was elaborated which reflected the etiologic heterogeneity of the disease. Inheritable and non-inheritable forms of skin melanoma were identified. The inheritable tumor group included familial disease (2%) and tumors developing against the background of hereditary diseases and syndromes (32.7%). The data obtained served as basis for the identification of families with high genetic predisposition to skin melanoma development and for the assessment of individual risk of the disease in patients' relatives.