Malignant melanoma

CONTEXT: The rapidly developing fields of melanoma research are revolutionizing the current concepts on melanoma etiology and pathogenesis and are introducing newer diagnostic techniques and potential therapeutic approaches. OBJECTIVES: To present the most current concepts on the etiology and pathogenesis of melanoma and to introduce the recent diagnostic techniques and the potential therapeutic approaches. METHODS: Data sources were reports on melanoma published in the English language literature and observations made using specimens available at Harvard University, Johns Hopkins Medical Center, Albany Medical College, Loyola University Medical Center, and University of Tennessee Health Science Center. RESULTS: Studies on melanoma containing chromosomal or genetic evaluation were selected for further analysis. Current clinical and pathologic categories with the reported genetic abnormalities were related to the latest information on pigment biology. The data extracted were used to develop a conceptual framework on the pathogenesis of melanoma; the generated model was then evaluated and used to suggest potential therapeutic approaches. CONCLUSIONS: (1) Melanoma is not genetically homogeneous, and the existing differences between the pathologic categories, particularly in areas such as type of growth phase (radial vs vertical growth), total vertical dimension, ulceration of primary tumor, and metastatic process, have profound prognostic and therapeutic implications. (2) Chromosomal aberrations and gene mutations are found in sporadic and familial melanomas; among the most important are those affecting the 9p21, which contains the p16 locus, a site known to be critical for normal progression of the cell cycle. Aberrant p16 expression is associated with more aggressive behavior. (3) Melanoma cells possess a remarkable repertoire of biosynthetic capacities represented by the production of hormones, growth factors, and their receptors that may sustain and accelerate tumor development and progression. For example, expression of the tumoral products alpha-melanocyte-stimulating hormone and adrenocorticotropic hormone is regulated in vitro by ultraviolet light, a known carcinogen. (4) Melanomas differ from other tumors in their intrinsic capability to express melanogenic enzymes with the corresponding structural proteins to actually synthesize melanin. Melanogenesis-related proteins are rapidly entering the clinical arena, being used not only as diagnostic markers, but also as potential targets for melanoma therapy.     

Malignant melanoma lately diagnosed

To assess the clinical impression that patients in Dublin were presenting with late, deep, poor prognosis lesions, a 10 year retrospective review of patients with malignant melanoma was performed. The pathological data on 186 patients was examined and clinical follow-up obtained on 151 of these (80%). The mean period of follow-up was 35 months. Females predominated in a ratio of 3:1. Incidence figures for the two five year periods (1976-80) and (1981-85) indicated a rise in the latter period of over 100%. There was a marked delay in presentation after the onset of symptoms i.e. new pigmented lesions or changes in pre-existing lesions (mean = 21 months). Only 45% of lesions were less than 1.5mm in depth. Females presented with a higher percentage of good prognosis lesions reflected in a superior five year survival figure of 70% compared with 43% for males. The results of this study suggest an increase in incidence and mortality from malignant melanoma in this country. Patients appear to be unaware of the significance of pigmented lesions, presenting late with deep poor prognosis tumours.     

Malignant melanoma in situ

There is general agreement that there are lesions which should be diagnosed as malignant melanoma in situ. The biologic behavior of the intraepidermal component of superficial spreading melanoma (the radial growth phase) has been demonstrated to have significantly different properties than those of the cells in the vertical growth phase. The central controversies regarding malignant melanoma in situ relate to the criteria for diagnosing melanoma and whether there are atypical melanocytic lesions which are neither nevi nor melanoma. I propose that reliable and reproducible objective criteria for melanoma have not been developed; rather, dermatopathologists use differing subjective criteria which result in diagnostic agreement in the vast majority of lesions. The controversy is over those lesions which are classified as melanoma by one set of criteria and not by others. I am also a proponent of the diagnosis of atypical melanocytic lesions, and have suggested an analogy to keratinocytic lesions in which this concept is well established. Studies of the sensitivity and specificity of the correlation between clinical and histologic features and the biologic behavior of melanocytic lesions are necessary to resolve these issues.     

Malignant melanoma in dermatoscopical picture

Dermatological investigation offers a more precise clinical diagnosis of malignant melanoma in 20-30% of cases. It gives a correct visualization of melanocytic structures up to dermatoepidermal junction in ten fold magnification. A less distinct picture can be obtained from medium corial structures. Lentigo maligna melanoma and superficially spreading melanoma can be well distinguished from other pigmented lesions. Dermatoscopy offers an inspirative view between a clinical and microscopical picture plane.     

Malignant melanoma of the conjunctiva

The clinicopathological features of 37 patients with invasive melanoma of the conjunctiva have been studied. Prognosis was closely related to the subsite and size of the primary tumour. Twenty of 21 patients with small localized bulbar neoplasms (95%) and four of six patients with diffuse bulbar melanomas (67%) have survived with no evidence of secondary spread. By contrast, only one of six patients with neoplasms involving the fornix (17%) and two of four (50%) with caruncular melanomas have survived. Metastatic spread was very uncommon in patients with melanomas less than 1.5 mm in maximum thickness, but the outcome of the disease in patients with tumours greater than 1.5 mm was not always bad. Treatment by local excision biopsy was followed by a high rate of conjunctival recurrence (59%). Exenteration of the affected eye guarded against the development of further orbital disease, but was not infrequently followed by the appearance of metastases. Many (62%) of the tumours appeared to have arisen in a pre-existing melanotic lesion or pigmented naevus of long-standing. Histologically, the tumours could be divided into those with an adjacent intra-epithelial component, manifest as atypical melanocytic hyperplasia in the conjunctival epithelium adjacent to the invasive melanoma, and those without (nodular melanoma). However, clear separation of the former group into the subtypes described for cutaneous melanomas proved impossible. Prognosis was not related to the type of melanoma, mitotic rate, cell type or degree of pigmentation.     

Malignant melanoma in stasis dermatitis

Two cases of malignant melanoma arising in established stasis dermatitis are described. One case was clinically thought to be melanocytic whereas the other was not. Histologically, both showed similar features with background varicose change of epidermal atrophy, sloughing of the epidermis, intense proliferation of small thick walled blood vessels, lymphocytic infiltrate and dermal fibrosis. In the superficial aspects of the biopsies there was little clue to the diagnosis of melanoma. In the deeper aspects of case 1, groups of melanocytes were present in the reticular dermis which mimicked benign naevus cells. S-100 protein staining confirmed the melanocytic nature of these lesions, their extent and the epidermal involvement. The latter features supported a malignant diagnosis. These lesions can be overlooked clinically as well as histologically.     

Malignant melanoma of the conjunctiva

One hundred thirty-one cases of conjunctival melanoma in which biopsies had been performed were studied to determine potential factors that might affect outcome in patients with these lesions. Two groups of lesions were identified: those associated with primary acquired melanosis (melanoma with PAM, 98 cases, 74.8 per cent) and those without primary acquired melanosis (melanoma without PAM, 33 cases, 25.2 per cent). The overall mortality rate in the 131 cases was 26 per cent (34 of 131); the mortality rate due to melanoma with PAM was 25.5 per cent (25 of 98), and that due to melanoma without PAM was 27.3 per cent (9 of 33). If PAM was associated with the lesion, the presence of atypical melanocytes within the epithelium (pagetoid invasion) was a sensitive indicator of subsequent metastasis. Tumor thickness may also be useful for predicting subsequent metastases. None of the histologic parameters studied proved useful for predicting outcome in patients who had melanomas without PAM. The presence or absence of nevi had no effect on prognosis.     

Malignant melanoma in Meckel's diverticulum

Meckel's diverticulum is a vestigial remnant of the omphalomesenteric duct, which is rarely affected by neoplasia. The authors report the first case of malignant melanoma in Meckel's diverticulum in a middle-aged man without skin or ocular lesions. Five other Meckel's diverticuli were evaluated histologically and by immunoperoxidase technics for neural crest elements, which could have given rise to this lesion.     

Malignant melanoma and charcot-marie-tooth disease

Two patients with Charco-Marie-Tooth disease subsequently developed cutaneous malignant melanoma. This constellation of diseases may be due to chance, but raises the possibility of a shared neural crest defect or genetic linkage.     

Malignant melanoma of the bronchus

A case of malignant melanoma of the bronchus is presented. The tumor obstructed the left main stem bronchus. Secondary pneumonia was probably caused by Hemophilus influenzae.     

Malignant melanoma of the anal canal

The clinical and pathological features of 15 cases of malignant melanoma of the anal canal are described.It would appear from this study that these tumours arise from squamous epithelium lining that part of the anal canal at or just above the line of the anal valves.     

Malignant melanoma metastatic to bone marrow

Bone marrow aspiration and biopsy is a useful means of detecting systemic involvement in patients with non haematological malignancy. Metastases of malignant melanoma may be detected in the bone marrow in a small percentage of patients. Two cases of malignant melanoma, with metastasis to marrow at the time of presentation, are described. In one case, bone marrow was the first site where the malignancy was identified. Subsequent investigations revealed an anal melanoma. In the second case, the patient had widespread dissemination from a tonsillar melanoma to many organs of the body, including bone marrow.