A case of epidermotropic metastatic malignant melanoma with multiple nodular lesions of the scalp

Epidermotropic metastatic malignant melanoma (EMMM) is a form of metastatic malignant melanoma that has dermal cell nests with epidermotropism and specific histopathological features. We report a patient with eight nodular lesions of the scalp with histopathological findings compatible with EMMM. The tumors developed one year before consultation and increased in size simultaneously. The histopathological findings of all eight tumors were very similar. The tumor cells were located mainly in the dermis and partly in the basal layer of the epidermis. They contained melanin pigments and were positive for anti-HMB45 antibody. The tumors did not respond to combination chemotherapy with dacarbazine, nimustine, vincristine, and interferon-beta. Therefore, all the tumors were surgically removed. No local relapse, distant metastasis or re-elevation of plasma 5-S-cysteinyldopa was identified during nine months of follow-up. Histopathologically, all eight tumors lacked apparent vascular invasion, which may be related to a slow clinical course of the present case.     

Unilateral dysplastic nevi associated with malignant melanoma.

A case of dysplastic nevi associated with malignant melanoma was reported. The case was characterized by unilateral distribution of dysplastic nevi. Multiple dysplastic nevi were observed only dorsally on the patient's left upper quadrant. To the best of our knowledge, the report of this form of dysplastic nevi is the first in Japan. In addition, dysplastic nevus cell nests were present in histologic contiguity with intraepidermal proliferation of melanoma in the radial growth phase. Histological evidence suggested that the melanoma in our case had probably been derived from the context of dysplastic nevus.     

Short-term morbidity associated with sentinel lymph node biopsy in cutaneous malignant melanoma

Guidelines for the surgical treatment of cutaneous primary malignant melanoma are well established; however, the approach to the treatment of the regional lymph nodes remains more controversial. In many centres, sentinel lymph node biopsy has been adopted as routine in the treatment of malignant melanoma for prognostic purposes, as it is not of proven therapeutic benefit. The Multicentre Selective Lymphadenectomy Trial II aims to determine the comparative benefits of subsequent completion lymphadenectomy versus observation in those found to have a positive sentinel node biopsy. Until results are available, the risks of the procedure must be weighed against the value of prognostic information gained from performing a sentinel node biopsy. In this retrospective analysis of sentinel lymph node biopsies at our institution, we show that in general, short-term morbidity associated with this procedure is low, but that morbidity is higher in a subgroup of people with higher weight or body mass index, and in those whose biopsy is located in the groin.     

恶性黑素瘤DNA甲基化的研究进展

恶性黑素瘤是一种皮肤起源的恶性肿瘤,其发生率和致死率在世界范围逐年上升.表观遗传学是一种涉及基因功能但不涉及DNA序列改变的遗传机制,DNA甲基化是其中最重要的机制之一,其作为连接表型与基因型重要纽带,是恶性黑素瘤发生发展中具有特异性和标志性的遗传学事件.通过逆转这些异常的甲基化状态实现更有针对性的治疗是新的研究方向.     

A localized variant of paraneoplastic pemphigus: acantholysis associated with malignant melanoma

We report a 72-year-old male patient with a nodular malignant melanoma that was associated with focal suprabasal acantholysis (FSA). This phenomenon, which is regarded as an incidental finding by dermatopathologists, may be associated with inflammatory and also neoplastic skin diseases. Haematoxylin and eosin stained sections from an erythematous plaque surrounding the patient's tumour showed FSA, direct immunofluorescence (DIF) and indirect immunofluorescence (IIF) on normal human skin, monkey oesophagus and rat urinary bladder were negative. On electron microscopy few desmosomes could be detected in the basal cell layer of the acantholytic areas and there was a nearly complete loss of these structures in the spinous cell layer. Only remnants of cytoplasmic plaques and keratin filaments could be observed in those areas. In contrast, adherens junctions appeared to be well preserved. An enzyme-linked immunosorbent assay (ELISA) using recombinant fusion proteins as antigens did not show circulating autoantibodies against desmoglein 1 (Dsg1) or desmoglein 3 (Dsg3). In contrast, immunoblotting revealed autoantibodies directed against keratinocyte antigens with a molecular weight of 85 kDa and 250 kDa, the first band corresponding to the molecular weight of comigrating plakoglobin. Immunoprecipitation with patient serum also revealed a 85-kDa band. We conclude that these autoantibodies, probably in conjunction with cofactors produced by the tumour, could play a part in the pathogenesis of this variant of FSA, for which we propose the term 'localized paraneoplastic pemphigus.'     

T‐cadherin loss induces an invasive phenotype in human keratinocytes and squamous cell carcinoma (SCC) cells in vitro and is associated with malignant transformation of cutaneous SCC in vivo

Background Cadherins play important roles in controlling keratinocyte growth, differentiation and survival. Atypical glycosylphosphatidylinositol‐anchored T‐cadherin (T‐cad) is highly expressed in the basal keratinocyte layer of skin. The role of T‐cad in keratinocyte biology and pathology is unclear. Objectives To define the role of T‐cad in the pathogenesis of cutaneous squamous cell carcinoma (SCC) through gain‐of‐function and loss‐of‐function studies in vitro and through examination of T‐cad expression patterns in human cutaneous SCC specimens in relation to histological classification of degree of tumour differentiation. Methods In vitro studies employed lentiviral‐mediated overexpression/silencing of T‐cad in normal human keratinocyte (HaCaT) and SCC (A431) cell lines, monolayer and multicellular spheroid culture models, cell morphology analyses and assays of random motility and invasion. Immunohistochemistry was performed on skin specimens from patients with actinic keratosis, Bowen disease or SCC. Results In vitro, silencing of T‐cad induced a morphologically elongated and disorganized cell phenotype, increased random motility and markedly enhanced invasive potential. Overexpression of T‐cad induced a morphologically spread and compact cell phenotype and blunted invasive potential. In vivo, regional loss of T‐cad expression was more frequent and prominent in SCC classified as moderately‐to‐poorly differentiated than in SCC classified as well differentiated. However, in both categories aberrant and/or absence of T‐cad expression was associated with histological features of a potentially more malignant and invasive phenotype of cutaneous SCC. Conclusions T‐cad is a controlling determinant of SCC phenotype and invasive behaviour and its loss is associated with the process of malignant transformation from noninvasive to invasive SCC.     

Loss of beta-catenin expression associated with disease progression in malignant melanoma

BACKGROUND: beta-catenin plays a crucial role in the function of cell adhesion molecules and also participates in growth regulatory signalling pathways that may be involved in malignant transformation. OBJECTIVES: To examine beta-catenin expression in lesions of melanocytic origin for associations with clinicopathological markers of disease progression and for its significance as a predictor of disease recurrence and prognosis. METHODS: beta-catenin expression was examined by immunoperoxidase staining in 50 melanocytic naevi and 91 primary and 50 metastatic melanomas. RESULTS: beta-catenin was expressed in 96% of melanocytic naevi, in 94% and 65%, respectively, of radial and vertical growth phase primary melanomas, and in 38% of metastatic melanomas. Benign and malignant melanocytic lesions had distinct patterns of beta-catenin localization. Most lesions expressing beta-catenin exhibited cytoplasmic staining; however, over 40% of benign lesions also displayed nuclear staining, which was present only in 10% of primary and 15% of metastatic melanomas. Absent or weak expression of beta-catenin in primary melanomas was associated with several markers of disease progression, including tumour thickness and presence of lymph node metastases. A similar but not statistically significant trend was observed for the association of beta-catenin expression with disease recurrence and prognosis. CONCLUSIONS: These results suggest that loss or downregulation of beta-catenin expression in melanoma cells plays a significant role in progression of the disease.     

DNA羟甲基化在恶性黑素瘤的进展

DNA羟甲基化指在TET蛋白酶家族催化下,将5甲基胞嘧啶氧化成5羟甲基胞嘧啶的过程,是DNA主动去甲基化的关键中间步骤,主要通过动态调节DNA甲基化水平,影响基因表达.DNA羟甲基化过程可被TET蛋白、三羧酸循环相关酶、维生素C、微小RNA等多种因素调控.研究发现,和血液系统恶性肿瘤及多种实体肿瘤类似,恶性黑素瘤中同样存在5羟甲基胞嘧啶含量降低,DNA羟甲基化调控因素异常等现象,提示DNA羟甲基化可能与恶性黑素瘤的发生发展及预后等相关.     

Cell elasticity is an important indicator of the metastatic phenotype of melanoma cells

The relationship between melanin pigmentation and metastatic phenotype of melanoma cells is an intricate issue, which needs to be unambiguously determined to fully understand the process of metastasis of malignant melanoma. Despite significant research efforts undertaken to solve this problem, the outcomes are far from being satisfying. Importantly, none of the proposed explanations takes into consideration biophysical aspects of the phenomenon such as cell elasticity. Recently, we have demonstrated that melanin granules dramatically modify elastic properties of pigmented melanoma cells. This prompted us to examine the mechanical effects of melanosomes on the transmigration abilities of melanoma cells. Here, we show for the first time that melanin granules inhibit transmigration abilities of melanoma cells in a number of granules dependent manner. Moreover, we demonstrate that the inhibitory effect of melanosomes is mechanical in nature. Results obtained in this study demonstrate that cell elasticity may play a key role in the efficiency of melanoma cells spread in vivo. Our findings may also contribute to better understanding of the process of metastasis of malignant melanoma.     

黑素瘤抑制性活性因子在黑素瘤不同阶段及基底细胞癌中的表达

目的：探讨黑素瘤抑制性活性因子（MIA）在黑素瘤及基底细胞癌中的表达及其作用。方法：应用sP免疫组化技术检测38份黑素瘤石蜡标本、35份基底细胞癌石蜡标本以及32份色素痣石蜡标本中MIA的表达水平。结果：MIA在所有色素痣以及基底细胞癌中均呈阴性表达，而在原位黑素瘤、侵袭性黑素瘤、有淋巴结转移的黑素瘤、无淋巴结转移的黑素瘤阳性表达率分别为21．4％、91．6％、94．1％和42．8％。结论：MIA在黑素瘤的发生发展中起重要作用，MIA有可能成为临床诊断、治疗黑素瘤的靶点。     

A case of pedunculated malignant melanoma of the vaginal mucosa.

We report an 84-year-old Japanese woman who presented with a pedunculated malignant melanoma of the vaginal mucosa. Mucosal melanoma is believed to be more common in Japan than other countries, but such tumors of the vulvovaginal region are quite unusual. In our patient, three tumors were connected by a narrow pedicle. Three black tumors measuring 5-10 mm in diameter with a common pedicle were seen on the vaginal mucosa at five o'clock from the cervix. The tumors were hanging from the narrow pedicle. On histologic examination, they were diagnosed as malignant melanoma. Resection was done with a distal margin of 3 cm from the tumors and a margin of 1 cm from the cervix. The patient has had no evidence of local recurrence or distant metastasis. In our patient, the three main tumors had a common pedicle, which seems to be a unique finding. Since pedunculated malignant melanomas are rare, making a clinical diagnosis is difficult. Although pedunculated melanomas are recognized as having a high malignant potential because these lesions are generally thick, a relatively good outcome is sometimes reported. In our patient, there was no tumor infiltration into the dermis of the pedicle, and this may be one reason for the good outcome at present. There has been no previous report of a mucosal melanoma consisting of three tumors like those in the present patient.     

A profile of invasive cutaneous malignant melanoma in Malta: 1993–2002

BACKGROUND: The incidence of malignant melanoma of the skin has risen in every part of the world where reliable cancer registration data are found. OBJECTIVE: Our study aims to describe the changing incidence of and survival from invasive cutaneous malignant melanoma in Malta, by analysing the data from the 211 cases that were registered at the Malta National Cancer Registry between 1993 and 2002. RESULTS: The age standardized incidence rates for invasive cutaneous malignant melanoma rose from 3.7 per 100,000 population per year for males and 5.1 for females in the first 5-year period, to 8.0 per 100,000 population per year for males and 5.9 for females in the second 5-year period. In both sexes, numbers of thin (< or = 1.0 mm) invasive melanomas increased significantly between 1993 and 2002; males also registered a significant increase in intermediate-thickness (1.01-4.0 mm) melanomas. The increase in numbers of thin and intermediate-thickness melanomas between the two 5-year periods was greatest in patients aged 60 years and over. The overall absolute 5-year survival rate for the first period was 74% and for the second period 92%. CONCLUSION: Numbers of reported cases of invasive cutaneous malignant melanoma in Malta have more than doubled during the 10-year study period. This is mostly due to a marked rise in the diagnosis of thin melanomas in both sexes, occurring mainly in patients aged 60 years and over. As thin melanomas are of low metastasizing potential, this has resulted in an increase in survival between the two 5-year study periods.     

Six cases of metastatic malignant melanoma with apparently occult primary lesions.

We report here six cases of malignant melanoma in which metastatic lesions were detected first. Of these, two cases showed some peculiar features: one exhibited widespread subcutaneous bleeding, probably due to venous rupture, and the other case had a rare primary lesion on the penis. In the Japanese literature, there have been 46 cases of malignant melanoma in which metastatic lesions were detected prior to the initial ones. The preferential site for metastasis was the lymph node (32 cases). The primary lesion was unknown in 35 patients. The outcomes were available for 36 of the 46 patients; 23 died, including 18 who died within two years.     

Blue naevus with satellitosis mimicking malignant melanoma

Blue naevus is an acquired benign melanocytic naevus. It is a firm, sharply defined dark blue to grey-black papule or nodule, which is likely to arise from the arrested dermal melanocytes in the dermis. In the last few years, blue naevus has attracted much attention due to the recognition of new entities and to its confusion with malignant melanoma. We report a 69-year-old man who developed a blue-black nodular lesion with satellitosis on his scalp. Although clinically it was thought to be a malignant melanoma, histopathological investigation and conservative methods such as dermatoscopy and power Doppler ultrasonography did not confirm this diagnosis. Histopathological examination excluded malignant melanoma, as there were no cellular atypia and mitotic activity in either the nodular lesion or the satellitosis. Doppler ultrasonography confirmed the benign nature of the lesion. Dermatoscopic examination showed homogeneous steel-blue pigmentation with individual blue globules, dots and some brown veils, and confirmed the histopathological diagnosis. To the best of our knowledge, our case is the third reported case of a blue naevus with satellitosis mimicking malignant melanoma.     

The risk for cutaneous malignant melanoma, melanoma in situ and intraocular malignant melanoma in relation to tobacco use and body mass index

BACKGROUND: The incidence of cutaneous malignant melanoma (CMM) and melanoma in situ (MIS) has been increasing during the last 50 years. Malignant melanoma (MM) is also the most common intraocular malignancy (IMM). Besides ultraviolet radiation, the cause of these tumours is largely unknown. OBJECTIVES: We designed a study to examine the effect of body mass index (BMI) and tobacco use on the risk for MM and MIS. METHODS: Analyses were performed on a nationwide cohort of 339 802 Swedish construction workers. Exposure information was collected prospectively by questionnaires combined with personal interviews. RESULTS: Follow up yielded a total of 7 663 400 person-years during which 1639 workers developed MM/MIS. The risk for MM/MIS was reduced in current or previous smokers compared with those who had never smoked, both when analysing all smoking tobacco products combined and when analysing cigarette and pipe smokers separately. The risk was further diminished with longer duration of smoking and greater quantity of tobacco smoked. The effect was more evident in CMM/MIS than in IMM. Snuff taking conferred a decreased risk for CMM/MIS, and a BMI over normal weight range conferred an increased risk for CMM. CONCLUSIONS: Tobacco smoking was found to be inversely associated with the risk for CMM and MIS. The mechanism of action is unknown but it has been suggested to be due to the immune suppressive effect that tobacco exerts which would be protective against deleterious immune reactions caused by, for example, the sun. Neither is the mechanism behind the higher risk for CMM due to being overweight known. One hypothesis is that it is an effect of a hormonal imbalance. Further studies are required to elucidate these mechanisms.     

A case of Werner syndrome with three primary lesions of malignant melanoma

Three primary lesions of malignant melanoma developed in a 44-year-old Japanese woman with Werner syndrome. One lesion was on the right large pudental lip and the others in distinct locations on her left sole. After the wide local excision of these tumors, the wound of the large pudental lip was sutured, and the defects on the sole were covered with skin grafts. After one course of chemotherapy consisting of dacarbazine, nimustine, vincristine sulfate and local injection of Interferon beta were performed, severe myelosupression occurred and continued for two months. Defective production of WRN protein was confirmed by Western blotting, although the three representative mutations in Japanese patients, mutations 1, 4 and 6, which include over 90% of the Japanese patients, were not detected. We also reviewed 26 cases of malignant melanoma associated with Werner syndrome (WS), including ours.     

Rapid growth of malignant melanoma in pregnancy

Malignant melanoma during pregnancy is a difficult problem as a variety of risks to both the mother and fetus must be weighed. We describe a rapidly progressive malignant melanoma diagnosed during pregnancy. There are no standarized guidelines for treatment; each case requires an individualized approach. We review the literature and present an algorithm to aid in approaching such patients.     

Radioimaging of malignant melanoma xenografts in nude mice using 111In-labeled monoclonal antibody against human malignant melanoma

By using ¹¹¹In-labeled monoclonal antibody (ZME-018) against human malignant melanoma, we examined its usefulness in radioimmunodetection of human melanoma xenografts in nude mice. Two human malignant melanoma cell lines were used in this study, KHm-1/4; and KHm-3/ps. KHm-1/4 cells express melanoma-associated antigen which is reactive with ZME-018, whereas KHm-3/ps cells do not. ZME-018 was conjugated with DTPA (diethylene triamine pentaacetic acid) first; then the conjugate was labeled with ¹¹¹In. After these procedures, labeled ZME-018 retained its binding activity against KHm-1/4 cells in vitro. Nude mice, bearing melenoma xenografts started from injections into the right hind legs, were i.p. or i.v. injected with ∽300 μCi (60 μg) of labeled ZME-018. Tumor images were taken with gamma camera at 24 hr intervals. Clear tumor images were obtained by 24 hrs after injection. The best imaging was obtained at 72 hrs with no background of internal organs. Specific localization was confirmed by the absence of imaging in the mice which received free ¹¹¹In only and also by using control mice bearing antigen-negative melanoma cells (KHm-3/PS). An example of tissue distribution of the labeled antibody in terms of tumor to tissue ratio at day 3 is as follows: tumor/intestine; 20/1, tumor/liver; 10/1, tumor/blood; 8/1, tumor/muscle; 8/1, tumor/heart; 3/1, tumor/kidney; 2/1. This study demonstrates the future applicability of ¹¹¹In-labeled monoclonal anti-melanoma antibody for radioimmunodetection of metastatic lesions in melanoma patients.     

Small malignant melanoma in patients with mycosis fungoides

An increased risk for a second malignancy has been reported in patients with mycosis fungoides. We describe two subjects with mycosis fungoides who developed small malignant melanoma after topical application of nitrogen mustard.     

Three cases of malignant melanoma arising on burn scars

It is well known that up to 2% of chronic burn scar lesions can transform into malignant tumors. Most of them are squamous cell carcinoma (SCC) and, more occasionally, basal cell carcinoma (BCC). The incidence of malignant melanoma (MM) is extremely low. To the best of our knowledge, there are only 23 such cases reported in the literature. We report here three cases of MM arising on burn scars and analyze the 23 cases reported previously. Case 1: a 74-year-old Japanese man sustained a burn injury on about 54% of his whole body surface when he was accidentally bathed in boiling oil at the age of 37 years old. Some small tumors developed on the burn scar on his right lumbar region. A wide excision of the tumor was performed. Case 2: a 51-year-old Japanese woman was injured on her right forearm and face by deep burns from a flame when she was 7 months old. She presented with a rapidly growing, painless black nodule on the dark skin lesion on her right forearm. She was treated with a wide excision followed by a full-thickness skin graft. Intravenous administration of one unit of OK-432 every week has been continued. Case 3: a 73-year-old Japanese woman was burned on her left leg and hand from a flame when she was 6 years old. A nodular lesion appeared within the ulcer two months previously and it was growing rapidly. This lesion was ulcerated on the top of its central area and was slightly reddish without any pigmentation. The patient was treated with a wide excision and a split-thickness skin graft. The 5-year survival rate of MM in an old burn scar is 53.6%. It is suggested that the prognosis of burn scar carcinoma is not worse than that of non-burn scar carcinoma.