An immunoperoxidase study of S-100 protein in neoplastic cells in serous effusions. Use as a marker for melanoma

S-100 protein has been demonstrated on histologic sections in a number of neural and nonneural tissues, including a variety of neoplasms. Since pleural or peritoneal effusions are frequently the initial presentation of cancer, a study was undertaken to determine if S-100 protein in exfoliated cancer cells could be used as a marker for melanoma. Cells in 36 serous fluids obtained from 32 patients were retrospectively examined for S-100 protein by the peroxidase-antiperoxidase technique. All samples had been previously studied as Papanicolaou-stained cytology specimens, and 25 samples had been studied by transmission electron microscopy. All benign effusions were negative for S-100 protein. Malignant effusions were negative except for some that contained malignant melanoma cells: two of five pigmented melanomas and both cases of amelanotic melanoma. This study indicates that S-100 protein in malignant cells is a useful marker for malignant melanomas, especially the amelanotic type.     

Fine needle aspiration cytology of malignant melanoma of soft parts. Report of two cases

Two cases of malignant melanoma of soft parts were diagnosed by fine needle aspiration (FNA) biopsy. One case involved the right thumb of a 22-year-old woman; the other involved a submental mass in a 36-year-old man who had been previously diagnosed as having malignant melanoma of soft parts. The FNA smears showed discohesive polygonal or oval and fusiform cells with eccentric nuclei, irregular nuclear chromatin and prominent nucleoli. FNA cell block sections contained polygonal or fusiform cells with clear cytoplasm, eccentrically placed nuclei and prominent nucleoli. Ultrastructural and immunocytochemical studies on aspirated material supported the diagnosis of malignant melanoma.     

Cellular immunecompetence in patients with malignant melanoma

Summary The nonspecific immunecompetence of the peripheral blood lymphocytes of 29 patients with malignant melanoma and one with the benign condition of Riehl's melanosis was tested by means of a local xenogeneic graft-versus-host reaction and the E rosette test. The lymphocytes of 20 normal donors served as controls. Impairment of cellular immunecompetence was found in patients with invasive multiple primaries and those with invasive nodular malignant melanoma. Functional activity of T lymphocytes was normal in most of the patients who had an invasive melanoma with adjacent intraepidermal component of Hutchinson melanotic freckle or superficial spreading. In three cases with superficial spreading in which there had been an impairment of T cell function before removal of the tumor, there was an improvement following surgery. There was a clear correlation between the patient's cell-mediated immune response and the pathological type of the tumor, but not with the depth of invasion. It is suggested that cellular immunecompetence is a valuable parameter in the prognosis and treatment of malignant melanoma and should be measured in all patients with this type of tumor.     

Characteristics of malignant melanoma cells in the treatment with fast neutrons

The radioresistance of malignant melanoma cells has been explained by the wide shoulder of the dose-cell-survival curve of the cells exposed to photon beams. Fast neutrons, 30 MeV d-Be, were used to treat patients who had malignant melanoma in order to confirm the biological effects of high linear energy transfer (LET) radiation for tumor control. Seventy-two patients suffering from malignant melanoma participated in the clinical trials with fast neutrons between November 1975 and December 1986. Of 72 patients, 45 had melanoma of the skin, 20 had melanoma of the head and neck, and seven had choroidal melanoma. Five-year survival rate of the patients who had previously untreated melanoma of the skin was 61% and for patients who received postoperative irradiation, it was 35.7% whereas no patients who had recurrent tumor survived over 4 years. Of 22 patients who had melanoma of the skin, stage I, local control in four cases was achieved by irradiation alone, whereas local control was achieved in 17 of 18 patients who required salvage surgery after fast-neutron therapy. The results of pathological studies performed with specimens obtained from salvage surgery have shown that melanoma cells growing in intradermal tissue are radio-resistant, compared with cells growing in intraepidermal tissue. This might suggest that melanoma cells acquire radioresistance when the connective tissue is involved. Five-year survival rate of the patients who had locally advanced melanoma of the head and neck, previously untreated, was 15.4%. Radiation therapy with accelerated protons was suitable for patients suffering from choroidal melanoma.     

Comparison of immunohistochemical labelling of melanocyte differentiation antibodies melan-A, tyrosinase and HMB 45 with NKIC3 and S100 protein in the evaluation of benign naevi and malignant melanoma

A panel of three melanocyte differentiation antibodies has been compared with anti-S100 protein and NKIC3 in an assessment of benign and malignant melanocytic lesions.Anti-polyclonal S100 protein labelled all cases of primary cutaneous malignant melanoma, metastatic melanoma, desmoplastic melanoma and myxoid melanomas. In addition all benign and dysplastic naevi were positive. Conversely, HMB 45 was the least sensitive marker, labelling 24/31 primary cutaneous melanomas, 14/24 metastatic melanomas and only 1/6 desmoplastic melanomas. In the case of naevi, only junctional forms labelled consistently. Results for anti-melan-A and anti-tyrosinase were similar, although anti-tyrosinase proved slightly more sensitive in cases of malignant melanoma. NKIC3 revealed similar results to anti-tyrosinase, but had the disadvantage of reduced selectivity.It is concluded that anti-tyrosinase and anti-melan-A are useful additions to the panel of melanocytic monoclonal antibodies. In addition, both antibodies appear to have greater sensitivity for malignant melanoma than the conventionally used HMB 45 and could be considered as supportive markers to polyclonal anti-S100 protein in the diagnosis of malignant melanoma.     

MicroRNA let-7b targets important cell cycle molecules in malignant melanoma cells and interferes with anchorage-independent growth

A microRNA expression screen was performed analyzing 157 different microRNAs in laser-microdissected tissues from benign melanocytic nevi (n = 10) and primary malignant melanomas (n = 10), using quantitative real-time PCR. Differential expression was found for 72 microRNAs. Members of the let-7 family of microRNAs were significantly downregulated in primary melanomas as compared with benign nevi, suggestive for a possible role of these molecules as tumor suppressors in malignant melanoma. Interestingly, similar findings had been described for lung and colon cancer. Overexpression of let-7b in melanoma cells in vitro downregulated the expression of cyclins D1, D3, and A, and cyclin-dependent kinase (Cdk) 4, all of which had been described to play a role in melanoma development. The effect of let-7b on protein expression was due to targeting of 3'-untranslated regions (3'UTRs) of individual mRNAs, as exemplified by reporter gene analyses for cyclin D1. In line with its downmodulating effects on cell cycle regulators, let-7b inhibited cell cycle progression and anchorage-independent growth of melanoma cells. Taken together, these findings not only point to new regulatory mechanisms of early melanoma development, but also may open avenues for future targeted therapies of this tumor.     

miR-137 inhibits glutamine catabolism and growth of malignant melanoma by targeting glutaminase

Glutamine catabolism is considered to be an important metabolic pathway for cancer cells. Glutaminase (GLS) is the important rate-limiting enzyme of glutamine catabolism. miR-137 functions as a tumor suppressor in many human malignant tumors. However, the role and molecular mechanism of miR-137 and GLS in malignant melanoma has not been reported. In this study, we showed that miR-137 was decreased in melanoma tissue, and the low miR-137 level and high GLS expression are independent risk factor in melanoma. miR-137 suppressed the proliferation and glutamine catabolism of melanoma cells. GLS is crucial for glutamine catabolism and growth of malignant melanoma. We also demonstrated that miR-137 acts as a tumor suppressor in melanoma by targeting GLS. This result elucidates a new mechanism for miR-137 in melanoma development and provides a survival indicator and potential therapeutic target for melanoma patients.     

Fine needle aspiration cytology in recurrent amelanotic melanoma: a case report

BACKGROUND: Amelanotic melanoma can mimic a wide variety of epithelial and nonepithelial malignant tumors. Varied cytomorphology of melanoma has been described on exfoliative and fine needle aspiration cytology (FNAC). We report a case of recurrent amelanotic melanoma to highlight its varied cytomorphologic features, which may cause diagnostic problems on cytologic and on histologic examinations. CASE: A 63-year-old male presented with nodular swellings in the right anterior chest wall, right axilla and back. A nodule in the chest had been excised 6 months earlier. Clinically, the lesion was interpreted as recurrent soft tissue sarcoma. FNAC revealed malignant cells with highly varied morphology with plasmacytoid and pleomorphic malignant cells with occasional fibrocollagenous tissue strands showing adherent neoplastic cells. A cytologic diagnosis of pleomorphic malignant tumor was suggested, and the original histologic slides were reviewed; they showed a striking alveolar pattern that vaguely resembled an alveolar rhabdomyosarcoma. However, on immunohistochemistry, the tumor cells were S-100 and melan-A positive and desmin negative. A final diagnosis of amelanotic melanoma was made. CONCLUSION: Awareness of the highly varied cytomorphology of amelanotic melanoma minimizes the diagnostic difficulty on fine needle aspiration smears. Suitable immunohistochemical markers are of great value in difficult situations.     

Surgical considerations in the management of malignant melanoma of the ear

Malignant melanomas of the external ear are rare and are difficult lesions to treat because of the cosmetic importance and the reconstructive difficulty of their location. The literature suggests that these lesions have a worse prognosis than melanomas occurring elsewhere and that radical resection is the "correct" treatment. To clarify this issue, we examined 21 consecutive patients (19 male, 2 female) with malignant melanoma of the ear seen at the Yale-New Haven Hospital over the last 10 years. Nineteen patients had a diagnosis of primary malignant melanoma of the ear, one had a local recurrence, and one had an in-transit melanoma from an unknown primary site. The mean thickness of the lesions was 2.7 mm. Two patients had palpable nodes, which in both cases turned out to be histologically positive for tumor. All patients underwent local excision and reconstruction using chondrocutaneous or fasciocutaneous flaps or skin grafts. There was one local recurrence (0.5 mm original thickness); there were two patients with regional recurrences, both of whom died within a year with disseminated disease. Forty-three percent have been followed for 5 or more years and all are alive and free of disease. This suggests that malignant melanoma of the ear may be safely treated by conservative excision and reconstruction.     

Methylation and loss of Secreted Frizzled-Related Protein 3 enhances melanoma cell migration and invasion

Background

Wnt signaling is important in development and can also contribute to the initiation and progression of cancer. The Secreted Frizzled Related Proteins (SFRPs) constitute a family of Wnt modulators, crucial for controlling Wnt signaling. Here we investigate the expression and role of SFRP3 in melanoma.

Methodology/Principal Findings

We show that SFRP3 mRNA is down-regulated in malignant melanoma tumors as compared to normal/benign tissue. Furthermore, we found that SFRP3 expression was lost in the malignant melanoma cell lines, A2058, HTB63 and A375, but not in the non-transformed melanocyte cell line, Hermes 3A. Methylated CpG rich areas were detected in the SFRP3 gene in melanoma cell lines and their SFRP3 expression could be restored using the demethylating agent, 5′aza-deoxycytidine. Addition of recombinant SFRP3 to melanoma cells had no effect on viable cell numbers, but decreased cell migration and invasion. Wnt5a signaling has been shown to increase the migration and invasion of malignant melanoma cells, and high expression of Wnt5a in melanoma tumors has been connected to a poor prognosis. We found that recombinant SFRP3 could inhibit Wnt5a signaling, and that it inhibited melanoma cell migration and invasion in a Wnt5a-dependent manner.

Conclusion/Significance

We conclude that SFRP3 functions as a melanoma migration and invasion suppressor by interfering with Wnt5a signaling.     

Combined treatment of advanced malignant melanoma with coumarin and cimetidine

Summary Immunostimulant therapy with coumarin and cimetidine was evaluated in 17 patients with advanced malignant melanoma. Induction therapy with coumarin 100 mg daily was given for 8 weeks, whereupon cimetidine 1000 mg daily was added. No patients had been previously treated with cytotoxic drugs, and all patients had a good performance status. In 16 patients progressive disease was observed, and only 1 patient experienced no change in condition, lasting 30 weeks. We conclude that treatment with this schedule of coumarin and cimetidine is without effect in advanced malignant melanoma.     

Malignant melanoma of the cervix. Report of a case

A malignant melanoma of the cervix, a rare neoplasm, was found to have an unusual cytologic pattern, similar to that of a leiomyosarcoma. A biopsy sample was diagnosed as cervical malignant melanoma of the spindle cell type. Some neoplastic cells in the tissue contained melanin pigment, whereas none of the abnormal cells in the cervical scrapes, except for an abnormal giant cell, had visible cytoplasmic pigment. The abnormal cells in the cervical scrape specimen were spindle-shaped, as were their nuclei, which is why the cytologic pattern was interpreted as that of a leiomyosarcoma. Evidence from this and previously reported cases shows that malignant melanoma must be considered as a possible source of exfoliated abnormal nonpigmented spindle-shaped cells in a cervicovaginal cell sample.     

Synthesis and characterization of a (68)Ga-labeled N-(2-diethylaminoethyl)benzamide derivative as potential PET Probe for malignant melanoma

Radiolabeled benzamides have been reported to be attractive agents for targeting malignant melanoma as they bind melanin and display high accumulation in melanoma cells. Herein, we report the synthesis and bioevaluation of a novel (68)Ga-labeled benzamide as a potential PET agent for malignant melanoma. The novel radiotracer was synthesized in good radiochemical yields (80% decay corrected yield) and high specific radioactivity (10GBq/μmol). Cellular uptake of (68)Ga-SCN-NOTA-BZA was significantly higher in B16F10 cells (mouse melanoma) treated with L-tyrosine. Biodistribution and micro-PET studies of (68)Ga-SCN-NOTA-BZA in B16F10-bearing mice showed selective uptake into the tumor. The radiotracer was cleared via renal excretion without further metabolism. These results demonstrate that (68)Ga-SCN-NOTA-BZA is a potential PET probe for malignant melanoma.     

Acral lentiginous melanoma: Basic facts,biological characteristics and research perspectives of an understudied disease

Acral lentiginous melanoma is a histological subtype of cutaneous melanoma that occurs in the glabrous skin of the palms, soles and the nail unit. Although in some countries, particularly in Latin America, Africa and Asia, it represents the most frequently diagnosed subtype of the disease, it only represents a small proportion of melanoma cases in European‐descent populations, which is partially why it has not been studied to the same extent as other forms of melanoma. As a result, its unique genomic drivers remain comparatively poorly explored, as well as its causes, with current evidence supporting a UV‐independent path to tumorigenesis. In this review, we discuss current knowledge of the aetiology and diagnostic criteria of acral lentiginous melanoma, as well as its epidemiological and histopathological characteristics. We also describe what is known about the genomic landscape of this disease and review the available biological models to explore potential therapeutic targets.     

Experience with malignant melanoma of the head and neck

Data on 127 patients with malignant melanoma who had a minimum 5-year follow-up have been analyzed. A good, though not yet significant, correlation appears to exist between length of survival and the diameter and the thickness of the primary lesion, the level of the tumor invasion, and the type of melanoma. A further analysis of patients with Stage I disease lends support to the use of "prophylactic" node dissection when the primary lesions penetrate to levels 4 or 5, or when they are 1.5 mm or greater in thickness. Our current overall approach to the management of malignant melanoma of the head and neck is outlined.     

Malignant Melanoma—Profile of an Epidemic

Cutaneous malignant melanoma is occurring in epidemic proportions in the United States. To provide a profile of persons at risk and the epidemiologic features of malignant melanoma, we reviewed the records of 325 patients with cutaneous malignant melanoma seen at the University of Colorado Health Sciences Center between 1973 and 1983. Most patients had fair skin, brown or blonde hair, blue or green eyes, and had difficulty in suntanning. The majority of melanomas (72%) developed in preexisting nevi. In women, melanomas were most common on the extremities, and in men they occurred most frequently on the trunk, head or neck. The most frequently noted depth of invasion was Clark''s level IV. At diagnosis, most of the patients (77%) were at stage I. We conclude that malignant melanoma constitutes a major disease problem in the western United States that is largely preventable with appropriate physician and patient education.     

Epidemiologic data of malignant melanoma in Osijek-Baranya County (Eastern Croatia) during the period of 2000-2008

During the past several decades there has been a substantial increase in the incidence of malignant melanoma worldwide. The highest incidences were reported in New Zealand and Australia. In Europe the northern countries generally have a higher incidence. The aim of this retrospective study was to provide the incidence and mortality for all patients with malignant melanoma diagnosed in Osijek-Baranya County, Eastern Croatia, during 2000-2008. In the past 30 years in the Republic of Croatia the incidence of melanoma increased by 337%. During the period of 2000-2006 in Osijek-Baranja County, the incidence of melanoma increased by 13%. The incidence of melanoma increases with age, but in past decades melanoma is more often diagnosed in people aged 25-40. The mortality between 2000 and 2008 increased by 18%. The incidence of melanoma generally increases equally in men and women. The most common localization of skin melanoma in males was trunk and in females the lower extremities. Presently, in Osijek-Baranya County melanoma is 15th on the list of malignant tumors and represent 2% of all malignant tumors. In New Zealand, Australia and European northern countries mortality is reduced, as result of earlier diagnosis and education of risk groups. Unfortunately, in Osijek-Baranya County, in a comparison with these countries, the mortality is higher although incidence is the same or lower.     

Tanning Devices – Fast Track to Skin Cancer?

The use of UVB and/or UVA emitting devices for cosmetic tanning is widespread in Western populations including young people and is especially prevalent in females. Several epidemiological studies, although not all, have shown a significant relationship between the use of tanning devices and malignant melanoma after, in some cases, adjustment for confounding factors such as solar ultraviolet radiation (UVR) exposure. A relationship between solar exposure, especially intermittent exposure, and malignant melanoma is well established so it is not surprising that a similar connection has been reported for the use of tanning devices. Several epidemiological studies show that childhood exposure to sunlight is a risk factor for malignant melanoma and this may also be the case for the use of tanning devices, especially if sunburns are obtained. Some studies have evaluated the relationship between the use of tanning devices and non‐melanoma skin cancer and at least one has suggested an association. The use of tanning devices by a substantial minority of young people is a worrying trend in terms of a likely increased incidence of malignant melanoma, and possibly non‐melanoma cancers in the future. Although two recent reviews by epidemiologists conclude that a clear link between tanning devices and malignant melanoma is yet to be proven, there is a strong case for effective legislation to prohibit the use of tanning devices by people under 18 yr of age.     

Molecular markers in malignant cutaneous melanoma: Gift horse or one‐trick pony?

The management of malignant cutaneous melanoma is problematic. Current clinical prognostic factors do not adequately predict disease recurrence and overall survival in a significant subset of patients. Adjuvant therapies for melanoma are notoriously toxic and associated with significant morbidity. Furthermore, it has been difficult to predict which patients will respond best to these treatments, if at all. DNA and RNA biomarkers have been developed to help overcome these problems. Biomarkers have been shown to upstage patients with melanoma, but are the assays sensitive and specific enough for clinical use as predictors of disease outcome or treatment response? We review our experience with DNA and RNA biomarkers in terms of their prognostic and predictive capabilities in malignant melanoma and outline their likely role in the future of melanoma staging, surveillance, and treatment. © 2005 Wiley‐Liss, Inc.     

中国汉族人黑色素瘤家系临床特点分析

目的:探讨中国汉族人群恶性黑色素瘤家系发病情况及临床特点。方法:收集4个遗传性黑色素瘤家系进行家系调研和家系图谱绘制,并分析总结临床特点。结果:4个遗传性黑色素瘤家系共33人,确诊黑色素瘤患者10例,死亡2例。确诊患者平均年龄36岁。结论:中国汉族人群黑色素瘤家系具有发病年龄较轻,其中发病年纪越小其恶性程度越高、预后越差,而且黑色素瘤的高侵袭性同样具有明显家族遗传特点。