Etiology of malignant melanoma--what do we know?

Cutaneous malignant melanoma is the cancer showing the highest rate of increase in Europe. Attempts to reduce this trend are based on epidemiological studies which show that the development of melanoma is influenced by both constitutional and behavioural factors. The author summarizes the current knowledge on etiologically important factors in cutaneous malignant melanoma. Constitutional factors such as inheritance, congenital nevi, atypical moles and hormones are discussed, as well as behavioural factors, with the emphasis on exposure to sun.     

Dynamics of cell-associated viremia and antibody response during the early phase of lentivirus infection in sheep

OBJECTIVE: To investigate the characteristic epiluminescent microscopic features of early lesions of malignant melanoma affecting glabrous skin, which is the most prevalent site of the neoplasm in nonwhite populations. DESIGN: The epiluminescent microscopic features of various kinds of melanocytic lesions affecting glabrous skin were investigated using a videomicroscope. All the diagnoses were determined clinically and histopathologically using the standard criteria. SETTING: A dermatology clinic at a university hospital. PATIENTS: The following 130 melanocytic lesions consecutively diagnosed at our department were examined: 16 lesions of acral lentiginous melanoma, 6 lesions of malignant melanoma in situ, and 108 lesions of benign melanocytic nevus (acquired or congenital). MAIN OUTCOME MEASURE: The incidence of each characteristic epiluminescent feature was compared among disease categories. RESULTS: On epiluminescent microscopy, malignant melanoma in situ and the macular portions of invasive malignant melanoma showed accentuated pigmentation on the ridges of the skin markings, which are arranged in parallel patterns on glabrous skin. This "parallel ridge pattern" was found in 5 (83%) of 6 lesions of malignant melanoma in situ and in 15 (94%) of 16 lesions of malignant melanoma. The parallel ridge pattern was rarely found in the lesions of benign melanocytic nevus. Most benign melanocytic nevi showed 1 of the following 3 typical epiluminescent patterns: (1) a parallel furrow pattern exhibiting pigmentation on the parallel sulci of [he skin markings (54%), (2) a latticelike pattern (21%), and (3) a fibrillar pattern showing filamentous or meshlike pigmentation (15%). The remaining 11 benign nevi (10%) showed a nontypical pattern. CONCLUSION: Because epiluminescent microscopic features of early malignant melanoma on glabrous skin are characteristic, we can effectively detect early lesions using this noninvasive method.     

Variants of melanoma

The current classification of malignant melanomas gives recognition to superficial spreading melanoma, lentigo maligna melanoma, acral lentiginous melanoma, and nodular types. In addition, neurotropic and desmoplastic types are recognized. The relativity inherent in the diagnosis of melanoma, provides the basis for the classification of melanomas on the basis of size. Lesions measuring 1 mm or less in vertical dimensions are unlikely to metastasize; they qualify as borderline melanocytic neoplasia of indeterminant malignant potential. The current classification has little relevancy to the category of variant nevi with the exceptions of malignant cellular blue nevus and melanoma arising in giant congenital nevi. A classification of variant melanomas as related to variant nevi is proposed. From a different perspective, a classification of melanomas with attention to nesting and cytological patterns in vertical growth is proposed: this alternate approach gives recognition to lesions that might otherwise be classified as "nevoid" melanomas. It also provides a default category for lesions that might otherwise be assigned to the Spitz nevus-like category. All of these tools for the manipulation of the real and virtual images of melanomas have been emphasized in the concept of minimal deviation melanoma.     

Dysplastic nevi and other risk markers for melanoma

Risk markers for cancer are genetic or behavioral attributes that are statistically associated with increased incidence of cancer. Risk may be assessed either in case-control studies, or in cohort studies in which individuals with particular attributes are followed and cancer risk is determined by direct observation. Both of these methods have been used to determine the major risk markers for melanoma. The single most important risk marker is the presence on the skin of dysplastic nevi. Dysplastic nevi may be regarded as intermediate lesions of tumor progression, in that approximately 30% of melanomas arise in association with a precursor nevus, which is most commonly dysplastic. However, paradoxically, because they are vastly more numerous than melanoma, most dysplastic nevi are stable lesions that do not progress. Additional important melanoma risk factors include a family and/or personal history of melanoma. A third major category of risk markers includes indicators of acute and chronic exposure to the sun, including freckles, actinic skin damage, and a history of sunburn. Evaluation of these markers in oncological patients and their first-degree relatives can identify a population of individuals whose risk for melanoma ranges from several-fold to more than 100-fold greater than that of random population members. Efforts directed at early diagnosis in these individuals can result in recognition of melanomas in their early, curable stages.     

Recognizing neoplastic skin lesions: a photo guide

Malignant lesions of the skin are common. Patients who develop squamous cell carcinoma and malignant melanoma often have recognizable precursor conditions. A few skin lesions resemble malignancies. Lesions that are growing, spreading or pigmented, or those that occur on exposed areas of skin are of particular concern. Knowing the similarities and differences between these lesions allows the primary physician to make a diagnosis in most cases by simple inspection and palpation. When in doubt, it is appropriate to perform an excisional biopsy of small lesions or punch biopsy of larger lesions. Removal of premalignant lesions will reduce the occurrence of malignant disease. Almost all skin cancers can be cured by early excision or destruction. For these reasons, physicians should be aware of the risk factors for skin cancer, educate patients about risk reduction and include skin inspection for premalignant and malignant lesions as a part of routine health maintenance examinations.     

Malignant melanoma from the dermatologic perspective

Early recognition and treatment of thin cutaneous melanomas (stages Ia and Ib) have contributed to a decreased case-fatality rate during the past several decades. The only known preventable risk factor for melanoma is sun protection in childhood, which directly affects the number of melanocytic nevi developing in an adult. Additional risk factors, clinical features, and the malignant potential of precursor lesions are discussed. The four major clinicopathologic subtypes of melanoma are described with recommendations for appropriate biopsy techniques for suspected melanoma. Nationwide skin cancer screenings by dermatologists and greater public awareness of the warning signs of melanoma have enhanced detection of early melanoma and have promoted chances for a cure.     

Pluripotential melanoblastoma, a unifying concept on malignancies arising in congenital melanocytic nevi: report of two cases

Congenital melanocytic nevi are benign lesions present at birth and considered to be caused by a maldevelopment of the neural crest. The malignant potential of the congenital melanocytic nevi have been extensively addressed by several authors, and malignant melanoma is the most frequent neoplasm arising in these lesions. The present report describes two patients with congenital melanocytic nevi in which malignant melanoma with undifferentiated areas showing rhabdomyoblastic differentiation developed. The findings suggest that these mixed neoplasms may be recapitulating the differentiation potential of the ectomesenchyme-neural crest cells. We advocate the term "melanoblastoma" when referring to them.     

Melanoma mimicking dermal and Spitz's nevus ("nevoid" melanoma)

We describe two examples of malignant melanoma that present with clinical and histopathologic characteristics resembling the benign acquired dermal nevus and the spindle and epithelioid cell nevus (Spitz's nevus), respectively. Both lesions were present on the trunk of adult patients. The clinical impression in both cases was dermal nevus. Histopathologically, these lesions were fairly well circumscribed and symmetrical; they exhibited an expansile dermal proliferation of atypical nevomelanocytes in nests and fascicles with only minimal intraepidermal involvement. These lesions which we will designate as "nevoid" melanoma can be misinterpreted as benign nevi because of the absence of prominent intraepidermal pagetoid spread and the pattern of apparent dermal maturation at the base of the tumor associated with a gradual diminution of cell size. These features mimic the maturation phenomena in banal dermal nevi and spindle and epithelioid cell nevi. The differential diagnosis includes other types of melanoma, and various benign entities characterized by a predominantly dermal proliferative process, such as deep penetrating nevus and cellular neurothekeoma. The recognition of nevoid melanoma is critical so that patients with these lesions receive appropriate therapy for malignant melanoma.     

Nursing staff perceptions of the use and reduction in the use of physical restraints

Substance P (SP) is a neuropeptide found in both the central and peripheral nervous system. In the skin, SP-containing neurons stimulate the release of histamine from connective tissue mast cells (MC). SP also can potentiate neoangiogenesis and induce dermal fibrosis. MC-derived histamine has potent vasoactive effects, is angiogenic, and promotes tissue fibroplasia. In addition to histamine, MC contain many other angiogenic factors and a variety of cytokines, growth factors, and proteolytic enzymes implicated in tissue remodeling, and normal as well as tumor-associated neoangiogenesis. Many MC-derived factors, including histamine, can enhance melanoma cell growth directly. MC often concentrate around cutaneous melanomas which also frequently are associated with angiogenesis and peritumoral fibrosis. The precise mediators of these responses have not been well defined. We evaluated by immunohistochemistry cutaneous lesions representing stages of progression of malignant melanoma and its precursor lesions for the expression of SP. SP was expressed in 17/25 (68%) primary invasive malignant melanomas, 2/5 (40%) metastatic melanomas, 6/10 (60%) melanomas in situ, 7/12 (58%) atypical (dysplastic) nevi, and 4/10 (40%) spindle and epithelioid cell (Spitz) nevi, but was not detected in any (0/11, 0%) acquired benign melanocytic nevi (p<0.05). Invasive melanomas were immunolabeled in both the intraepidermal and the dermal components of the lesions. For those atypical and Spitz nevi which expressed SP, most of the immunoreactive melanocytes were located at the dermal-epidermal junction overlying areas of papillary dermal fibrosis. The results show differential expression of SP among cutaneous melanocytic lesions and suggest that the expression of this neuropeptide together with other factors may contribute to some of the host responses associated with these lesions.     

Safety of long-term levodopa therapy in malignant melanoma

Levodopa therapy is contraindicated in malignant melanoma because of its apparent carcinogenic effects reported by physicians in the early 1970s. We discuss the case of a 74-year-old man with Parkinson's disease who was treated with levodopa and whose malignant melanoma was later diagnosed. Before development of malignant melanoma, the patient received an estimated 5.7 kg levodopa over 6 years. Therapy with levodopa was continued for > 10 years, with a total dose of approximately 4.3 kg levodopa (together with carbidopa.) Recurrence of the melanoma was not observed. Based on our experience with this patient and an extensive literature review, we conclude that the natural history of malignant melanoma is not adversely influenced by concurrent levodopa therapy. Levodopa therapy should not be withheld for fear of accelerating malignant melanoma in parkinsonian patients.     

Superior survival of young women with malignant melanoma

BACKGROUND: The Commission on Cancer data from the National Cancer Data Base (NCDB) relating to patients with malignant melanoma are used to examine patterns of long-term survival by patient gender and age, stage of disease, disease morphology, and anatomic subsite. METHODS: Five calls for data have yielded more than 3,700,000 cases of cancer for the years 1985 through 1993, including 23,341 cases of malignant melanoma between 1985 and 1989, from hospital cancer registries across the US, representing slightly less than a quarter of all melanoma cases diagnosed in the US between 1985 and 1989. RESULTS: Three statements can be made from this data: (1) There is little difference in the frequency of malignant melanoma between men and women with respect to stage of disease or morphology. However, differences between the genders do appear with respect to the anatomic subsite of melanotic tumors. (2) Overall, young women (45 years of age and under) enjoy superior survival rates when compared with older women (55 years of age and older) and men of any age. (3) The survival advantage held by young women is particularly pronounced among patients diagnosed with advanced stage disease. CONCLUSIONS: These data suggest that factors present in younger women may be critical in the superior survival rates seen among premenopausal women and might be hormonal in nature.     

Malignant melanoma

The incidence of malignant melanoma is increasing at a rate greater than any other cancer occurring in humans. In this era of managed care, patients with a suspicious pigmented lesion may first present to their primary care physician for evaluation. Therefore it is mandatory that the primary care physician be capable of distinguishing between benign and malignant pigmented lesions, know how to evaluate such patients, and know when to refer patients with suspicious or malignant pigmented lesions. Surgical removal remains the mainstay of treatment for patients with melanoma. Thus, to increase the cure rate for melanoma, both the public and nondermatologists need to be educated regarding the prevention and early detection of melanoma. Only in this way can the diagnosis of melanoma be made early before deep invasion has occurred and the patient placed at risk for systemic spread. In recent years, the surgical management of melanoma has become more conservative and rational. Limb amputation, arbitrary 5-cm margins of excision, and elective lymph node dissections are no longer performed. The recommended margins of excision are now based on objective pathologic and clinical data and are more conservative, and the sentinel node biopsy is now used to determine which high-risk patients should undergo a formal lymph node dissection. Although encouraging results are being seen with immunotherapy protocols, to date the only adjunctive therapy shown to increase survival in patients at high risk for systemic spread is alpha-interferon. With this drug, the improved survival is modest at best; it is expensive and a minority of patients can tolerate it in the doses recommended. Although response rates of 20% are seen with chemotherapy in patients with disseminated disease, these responses are short-lived, and there is no associated increased survival. Except for lentigo maligna, radiation therapy, even when its delivery is modified, still is useful only as an adjunct to surgery or for palliation.     

The importance of the ERCC1/ERCC4[XPF] complex for hypoxic-cell radioresistance does not appear to derive from its participation in the nucleotide excision repair pathway

BACKGROUND: The incidence of skin cancer is increasing at an alarming rate. OBJECTIVE: To discuss current epidemiologic data concerning the incidence, morbidity, environmental influences, predisposing, host conditions, precursor lesions, and prevention of melanoma and nonmelanoma (basal and squamous cell) skin cancer. METHODS: The current literature was reviewed in order to provide current epidemiologic data for melanoma, basal cell carcinoma (BCC), and squamous cell carcinoma (SCC). RESULTS: Skin cancer is exceedingly common and the incidence is rising rapidly. Although the mortality rate for nonmelanoma skin cancer (NMSC) is decreasing, that of melanoma is increasing. Both NMSC and melanoma are associated with significant morbidity. Whereas chronic sun exposure is the main cause of NMSC, the development of melanoma appears to be related to intense, intermittent sun exposure. Ozone depletion has contributed to rising incidence rates of both NMSC and melanoma. In contrast to NMSC, there is not a direct relationship between ultraviolet radiation and melanoma. Genetic susceptibility significantly increases the lifetime risk of acquiring melanoma. There is no precursor lesion for BCC. Precursor lesions for invasive SCC include actinic keratoses and SCC in situ. Melanoma may arise from benign nevi and dysplastic nevi. Prevention of melanoma and NMSC is extremely important since prognosis improves with early detection. Prevention may be achieved by educating patients and physicians how to detect skin cancers early and by decreasing or eliminating exposure to ultraviolet light. CONCLUSION: The incidence of skin cancer has reached epidemic proportions. Only through heroic efforts by health care professionals and the general public to prevent the development or progression of skin cancer will this epidemic be abated.     

Proto-oncogene c-kit expression in malignant melanoma: protein loss with tumor progression

The c-kit gene encodes a transmembrane receptor that has tyrosine kinase activity. c-kit plays a role in hematopoiesis, gametogenesis, and melanogenesis. c-kit is found in melanocytes, and there is evidence that expression is lost in melanoma. We studied 85 melanocytic lesions for c-kit by immunohistochemical techniques using a monoclonal antibody. The lesions included banal nevi, junctional and compound nevi with melanocytic dysplasia, nontumorigenic radial growth phase melanoma, tumorigenic vertical growth phase melanoma, and metastatic melanoma. We found intense membrane staining in normal melanocytes and mast cells. Staining in compound nevi was strongest in junctional and superficial dermal components, whereas dermal nevi showed weak reactivity. Dysplastic nevi stained strongly, particularly in junctional cells. In melanoma, strong reactivity was most prominent in radial growth phase disease, but there was little or no staining in vertical growth phase and metastatic melanomas. In summary, c-kit protein is expressed in normal melanocytes, benign nevi, dysplastic nevi and nontumorigenic melanoma, but expression is lost in tumorigenic primary melanomas and metastases. The role of c-kit loss in advanced melanoma requires additional investigation.     

Atypical mole syndrome: a brief overview for the primary care physician

Early detection of melanoma and identification of potential markers or precursor lesions can substantially improve survival. Several risk factors have been identified in the pathogenesis of this potentially lethal cancer. Numerous reports in the literature have confirmed a subset of persons with an increased risk of developing melanoma. These patients are identified by a distinctive clinical phenotype depicted by unusually appearing melanocytic nevi (moles) in association with an increased number of total body nevi. They may have a family history of atypical moles or melanoma. In order to facilitate the recognition of such individuals by the non-dermatologist, a brief overview and salient features of the atypical mole syndrome are presented.     

Expression of apoptosis regulators in cutaneous malignant melanoma

Metastatic malignant melanoma (MM) is usually incurable and responds poorly to chemotherapy. Because many cytotoxic drugs cause cell death by inducing apoptosis, an imbalance of apoptosis regulatory proteins may contribute to MM treatment resistance. We have previously shown reduced expression of Bcl-2 protein, a negative regulator of apoptosis, in MM as compared with benign nevi. It is hypothesized that other apoptosis regulators may be involved in survival of MM cells. We examined the expression of Bax, Bcl-2, Bcl-X, and Mcl-1 in human benign nevi, primary MM, and metastatic MM using immunohistochemistry. Results were confirmed with Western blotting. The proapoptotic protein, Bax, was surprisingly overexpressed in all MM samples compared with benign nevi. Interestingly, in most MM samples there was overexpression of Mcl-1 or Bcl-XL, both negative regulators of apoptosis. Increased expression of Mcl-1 and Bcl-XL was first observed in thin primary melanomas, suggesting that up-regulation of these proteins represents a relatively early event associated with malignant transformation in MM. As published previously, the majority of primary and metastatic MM exhibited reduced Bcl-2 levels. We conclude that the apoptosis inhibitors Bcl-XL or Mcl-1, alone or in combination, may circumvent the normal cell death pathway, contributing to the pathogenesis and treatment resistance in metastatic MM.     

Heterogeneous expression of immunotherapy candidate proteins gp100, MART-1, and tyrosinase in human melanoma cell lines and in human melanocytic lesions

In recent years, it has become evident that T cells can recognize peptides of melanocytic lineage antigens such as gp100, MART-1, and tyrosinase at the tumor cell surface and can subsequently destroy these cells. It is thus feasible to develop immunotherapeutic approaches based on the melanocytic marker profiles of melanoma cells. One of the predictors of the success rate of such a treatment is the extent of positive (target) tumor cells within the lesions of the patient. First, we investigated the presence of these three proteins in 18 human melanoma cell lines using RT-PCR and immunohistochemistry. In 11 cell lines, mRNA and protein of all three markers could be detected; in one cell line, only two markers were present, and six melanoma cell lines showed no evidence for these markers. Secondly, we stained frozen sections of 105 human melanocytic lesions, 13 common nevocellular nevi, 13 atypical nevi, 13 early primary melanomas (Breslow < 1.5 mm), 25 advanced primary melanomas (aPM; Breslow > or =1.5 mm), and 41 melanoma metastases (MM) with antibodies against glycoprotein 100, melanoma antigen recognized by T cells, and tyrosinase. In addition, we used the 3,4-dihydroxy-L-phenylalanine reaction to detect tyrosinase enzyme activity as a confirmation of the tyrosinase immunohistochemical results in a subset of the lesions. In the benign lesions, glycoprotein 100 was more prominently expressed in epidermal melanocytes, whereas melanoma antigen recognized by T cells was encountered in all or nearly all dermal melanocytes in all nevocellular nevi and atypical nevus lesions. Tyrosinase was found in a lower percentage of melanocytes, both in the epidermis and in the dermis within these lesions. With regard to heterogeneity of staining within the malignant lesions, we found that 54% (early primary melanomas), 48% (aPMs), and 56% (MM) of the lesions stained within the same staining category for all three proteins studied. Approximately 17% of the aPM and MM lesions did not show positive tumor cells for any of the three proteins. We conclude that a subgroup of patients with high expression should be selected for immunotherapeutic treatment approaches based on the presence of these proteins.     

Melanocytic nevi and risk of cutaneous malignant melanoma in southern Spain

The main objective of this study was to assess whether cutaneous malignant melanoma (CMM) shows a stronger relation with the melanocytic nevi count at the site where CMM was diagnosed than with the melanocytic nevi count at other sites, stratifying by histologic CMM type, in a southern Mediterranean population. Cases and controls were selected from a population in southern Spain in 1988-1993. The study population included 116 incident cases with non-familial CMM (International Classification of Diseases 9th Revision (ICD-9) code 172), and 116 controls matched 1:1 for sex and age (+/- 4 years). Data were collected by personal interview, and melanocytic nevi were counted over the entire body surface by clinical skin examination performed by a dermatologist. Crude and multiple risk factor-adjusted odds ratios and 95% confidence intervals were computed by conditional logistic regression analysis. After adjustment by skin type, unexposed skin color, and sun exposure, CMM was found to occur significantly more frequently in individuals with a high number of melanocytic nevi at the same site where CMM originated (odds ratio (OR) for >8 nevi = 12.0, 95% confidence interval (CI) 1.3-108.2). The ability to predict the number of melanocytic nevi on different anatomic sites on CMM, but excluding the CMM cases on each corresponding site, was also examined. A significant trend with the number of nevi on the anterior surface of thighs was found (OR for >4 nevi = 4.5, 95% CI 1.4-14.9). Melanocytic nevi count on the melanoma site was the variable most closely related to superficial spreading melanoma subtype (SSM) (OR for >8 nevi = 82.19, 95% CI 2.72-2,454). On the other hand, the number of melanocytic nevi on the melanoma site was unrelated to risk of CMM subtypes other than SSM. These results support the hypothesis that nevi are an important risk factor for melanoma, especially SSM, in populations with a darker ethnic background.     

Protein expression of the cell-cycle inhibitor p27Kip1 in malignant melanoma: inverse correlation with disease-free survival

In the present study we analyzed, by immunohistochemistry, a panel of human melanomas for protein expression of the cyclin-dependent kinase (cdk) inhibitor p27Kip1 and evaluated whether deregulated expression correlates with clinical outcome for this type of cancer. We found that p27Kip1 was strongly expressed by normal melanocytes and benign nevi, whereas in malignant melanoma, a heterogeneous expression pattern was observed. In the case of nodular melanomas, the level of p27Kip1 was found to correlate significantly with the thickness of the tumor, with less protein expressed in thicker lesions. We also found that patients having tumors with fewer than 5% p27Kip1-staining cells had a significantly higher risk of early relapse of their disease compared with those expressing moderate or high levels. In contrast, the level of p27Kip1 did not correlate with tumor thickness or disease-free survival in patients with superficial spreading melanomas, suggesting that p27Kip1 may play different roles in these two major pathological subgroups of malignant melanoma. Furthermore, p27Kip1 did not appear to have an influence on overall survival for either subgroup. When we examined the combined effect of p21WAF1/CIP1 (another cdk inhibitor) and p27Kip1 on clinical outcome, we found that analysis of these two cdk inhibitors together may have greater prognostic potential than either alone. In conclusion, our results suggest that virtually complete loss of p27Kip1 protein expression has potential importance as a prognostic indicator of early relapse in patients with nodular melanoma The results, furthermore, underscore the value of analyzing multiple cell cycle regulatory proteins to obtain the most reliable indication of prognosis.