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BACKGROUND: Cellular tyrosine phosphorylation is regulated by two large families of enzymes. Protein tyrosine kinases (PTK) mediate addition, and protein tyrosine phosphatases (PTP), removal of phosphate from protein substrates. PTKs are oncogenes and PTPs have been hypothesized to function as tumour suppressor genes. OBJECTIVES: To determine changes in tyrosine phosphate and PTP activity that occur during melanoma progression. METHODS: Immunohistochemistry was used to study phosphotyrosine in melanocytic lesions. In addition, PTP activity of normal melanocytes and melanoma cell lines was measured using an enzyme-linked immunosorbent assay-based system. RESULTS: Melanocytes in normal skin and most (67%) benign naevi were not immunostained. Neither were early malignant lesions (80% of malignant melanoma in situ and radial growth phase melanomas) stained. However, most advanced melanomas (100% of vertical growth phase, and 90% of metastatic melanomas) were immunoreactive. When total PTP enzyme activity was assayed in normal melanocytes and malignant melanoma cell lines, there was a significant increase in activity associated with melanoma progression. CONCLUSIONS: Taken together, the data suggest increased phosphotyrosine signalling occurs during melanoma progression at the stage when cells first become competent for metastasis.

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We report two men who developed a transient perforating disorder characterized by transepidermal elimination of negatively birefringent needle-shaped crystals similar to monosodium urate. This striking clinical presentation has not previously been described and we propose that it be added to the group of diseases known as the primary perforating disorders.

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Ephrin-A1, formerly called B61, is a new melanoma growth factor; it is angiogenic and chemoattractant for endothelial cells. EPH-A2, or ECK (a receptor for ephrin-A1), is ectopically expressed in most melanoma cell lines; the pathology where this expression is first manifested and the possible role of the receptor in tumor progression are unknown. To determine these, we studied the expression of this ligand and receptor in biopsies of benign and malignant melanocytic lesions. EPH-A2 was not detected in normal melanocytes, benign compound nevi or advanced melanomas, though it was found in 2 of 9 biopsies of malignant melanoma in situ. Ephrin-A1 was present in occasional early lesions and in advanced primary melanomas (43%) and metastatic melanomas (67%). Expression of ephrin-A1 was induced in melanoma cells by pro-inflammatory cytokines. Our findings are consistent with 2 possible roles for ephrin-A1 in melanoma development: it may promote melanocytic cell growth or survival and induce vascularization in advanced melanomas. Both effects may be potentiated by inflammatory responses. Our data are consistent with earlier observations that an inflammatory infiltrate is associated with poor prognosis in thin primary melanomas.

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Papular mucinosis is a condition reported to be associated with abnormal serum paraproteins and plasma cell dyscrasias. We report a patient with papular mucinosis, without a serum paraprotein or bone marrow plasmacytosis, in whom the affected skin contained a prominent perivascular plasma cell infiltrate. Using in situ hybridization, for kappa and lambda light chain mRNA, these plasma cells were demonstrably monotypic for lambda light chain and, therefore, presumably monoclonal and putatively neoplastic. We suggest that the absence of a serum paraprotein and marrow plasmacytosis does not exclude the existence of a plasma cell neoplasm in patients with papular mucinosis. Such plasma cell populations may exist in the affected skin, although their true nature and behaviour remains to be determined.

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NM23 is a putative metastasis-suppressor gene for some human cancers. Here we have studied NM23 expression during melanoma progression using Northern blotting and immunocytochemistry. There was no significant difference in the average amounts of NM23 mRNA between cell lines derived from metastatic and primary melanomas. The level of NM23 mRNA was also determined for three pairs of poorly metastatic parental (P) and their highly metastatic variant (M) cell lines; the ratios for M/P were 1.2, 0.98 and 0.80. Next we used immunocytochemistry to study NM23 protein in normal skin, benign naevi and primary and metastatic melanomas. Melanocytes in all normal skin and benign samples were positive for NM23; however most primary melanomas (7/11) were not stained by the antibody. All metastatic melanoma samples (5/5) were positively stained. Findings were similar with an antiserum reactive with both forms of NM23 (H1 and H2), and with an antibody specific for NM23-H1. No relationship was apparent between NM23 immunoreactivity in primary tumours and their aggressiveness or prognosis. Hence, in contrast to the situation described for murine melanoma, the amount of NM23 mRNA or protein in human melanoma did not correlate inversely with metastasis.

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Sebaceous carcinomas are uncommon amongst cutaneous malignancies. These lesions can broadly be classified into 2 groups; (i) periorbital, which behave aggressively, and (ii) extraorbital, which are reported to metastasize rarely. A retrospective review has identified 12 cases of primary sebaceous carcinoma treated at Canniesburn Hospital over the decade from mid-1983 to mid-1993. Out of 7 cases with periorbital primary lesions, one patient died from metastatic disease and another developed local recurrence which was successfully excised. The series included an unusual case of metastasizing primary extraorbital sebaceous carcinoma.

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It has recently been reported that atypical fibroxanthoma (AFX) is a predominantly diploid lesion in contrast to malignant fibrous hystiocytoma (MFH) which is usually aneuploid. To test this hypothesis, DNA content quantification was undertaken on Feulgen-stained cytology and tissue section preparations from 10 cases of AFX by image analysis. The large atypical cells which characterize AFX were aneuploid in each case. Smaller spindle-shaped cells found in this lesion were diploid. The results suggest that AFX is indistinguishable from MFH by DNA content estimation and highlight an advantage of image analysis over flow cytometry.

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Pigmented lesions of palmar and plantar skin may cause diagnostic problems, partly because they are infrequently excised and also because some features of benign lesions in these sites may raise the suspicion of melanoma if considered alone. We have examined a series of benign melanocytic lesions and compared them with melanomas from these sites. The presence of severe melanocytic atypia was the most valuable feature in distinguishing between naevi and melanomas. Pagetoid infiltration of the epidermis by single atypical cells, or small groups of cells with abundant pale cytoplasm was seen only in melanomas, while transepidermal elimination of well-circumscribed nests was present only in benign lesions. A lymphocytic infiltrate was present in the dermis in 13 of 14 malignant lesions, but only two of the 26 naevi showed a sparse infiltrate: we suggest that the presence of a lymphocytic infiltrate should prompt a careful search for other features of malignancy. Other features examined, including elongation of rete ridges, pattern of melanocyte distribution at the dermo-epidermal junction, dermal sclerosis, and pigment in the stratum corneum or in the dermis, were seen in both naevi and melanomas and were not found to be useful in distinguishing benign from malignant lesions.

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Eosinophilic pustular folliculitis is a rare disorder previously reported predominantly in Japanese people who are otherwise healthy. Recently, the disorder has been noted in patients with acquired immune deficiency syndrome, as has eosinophilic folliculitis, a similar but distinct entity. The authors report a patient with eosinophilic folliculitis who was immunocompromised after high dose chemotherapy and bone marrow autograft for treatment of non-Hodgkin's lymphoma.

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Two cases of autoimmune bullous skin diseases in HIV-positive men are described. One man had bullous pemphigoid limited to his legs and the second man developed pemphigus herpetiformis. The possible association between autoimmune bullous diseases and HIV infection is discussed.

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To assess the effect of a pigmented lesion clinic on referral patterns and thickness of melanoma at presentation, we have compared data from the centralized pathology services of the adjacent health authorities of Wandsworth, and Merton and Sutton. Both districts were the subject of a CRC public awareness campaign in 1987, but only Wandsworth is served by a pigmented lesion clinic. All patients presenting with malignant melanoma were included; from 1981 to 1990 for Wandsworth, and from 1984 to 1990 for Merton and Sutton. The Breslow thickness and clinic source of all melanomas was documented. Approximately equal numbers of melanomas were seen in the two districts, with no obvious difference in the numbers of thin (< 1.5 mm thick) 'good prognosis' tumours. Both districts saw an increase in the total number of tumours, and the number of thin tumours, after the CRC publicity campaign. However, there was considerable cross-boundary referral to the pigmented lesion clinic in Wandsworth, with 60% of all melanomas coming from outside the district. The presence of a pigmented lesion clinic within a given district confers no obvious benefit with regard to the number of thin, 'good prognosis' melanomas being seen as a whole, but the cross-boundary referral pattern suggests that it fulfils a demand from both general practitioners (GPs) and patients, and it does provide a centralized source for the collection of much-needed data.

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Eosinophilic folliculitis is a recognized skin manifestation of human immunodeficiency virus (HIV) disease. Five cases of eosinophilic folliculitis occurring in HIV-negative patients treated for haematological malignancy are reported. In four cases this self-limiting, pruritic eruption, affecting the head and upper trunk, occurred 3 months after bone marrow transplantation, and the fifth case was a patient undergoing chemotherapy for Waldenström's macroglobulinaemia. This suggests that eosinophilic folliculitis is a consequence of disturbances of immune function, and is not specific for HIV infection.

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Pagetoid infiltration of the epidermis by melanocytes, also termed 'buckshot spread', is regarded by some as being essential for the confident histopathological diagnosis of primary cutaneous melanoma. We have reviewed 340 melanomas received over a 23 year period to assess the frequency of pagetoid infiltration and whether its presence bears any relationship with other histopathological features. Conspicuous pagetoid infiltration was present in 32.1% of the lesions and occasional melanocytes were observed within the stratum spinosum in a further 23.5% of cases. However, no melanocytes could be seen above the basal layer in 44.4% of the melanomas. The presence of pagetoid infiltration showed inverse correlation with tumour thickness, level of invasion, growth phase and mitotic count, and positive correlation with the presence and severity of regression. No association was found with the site of the primary lesion, melanocytic dysplasia or lentigo maligna in the adjacent epidermis, or with the presence of residual benign naevus cells in the epidermis. Thus, pagetoid infiltration of the epidermis was commonest in in situ or thin horizontal growth phase melanomas, and was conspicuous in only one-third of cases. While its presence is useful in the diagnosis of melanoma, its absence should not preclude it.

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In many centres the wide excision and split-skin grafting remains the standard therapy for primary cutaneous melanoma. One-hundred and thirty-seven primary cutaneous melanomas were seen in our department during a 3-year period; 25 patients were subsequently subjected to re-excision of scar following the initial excision biopsy. Lymphatic permeation, field change in the epidermal melanocytes and micrometastases were sought in the re-excision specimens in order to examine the pathological basis for this therapy. Two of the 25 primary melanomas included in this study were known to have been incompletely excised at the time of initial biopsy and both re-excision specimens included a few nests of atypical melanocytes adjacent to one edge of the biopsy wound. Examination of the re-excision specimens failed to demonstrate evidence of direct lymphatic permeation by melanoma, or of a field change in the epidermal melanocytes adjacent to the melanomas, although five specimens from sun-exposed sites showed slight melanocyte atypia. One re-excision specimen did include a single small group of melanocytes, less than 120 microns in size, in the dermis within 2 mm of the initial excision biopsy site of a melanoma 8.4 mm in thickness. These results support the view that more extensive local therapy than complete excision of primary cutaneous melanoma with a narrow margin of adjacent normal skin, is unlikely to benefit the patient.

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In primary cutaneous malignant melanoma, the vascularity of the dermis immediately deep to the lesion may relate to tumour aggressiveness and to prognosis. These newly formed dermal vessels are incorporated into the melanoma to form the tumour microcirculation. We have assessed the percentage vascular volume in a series of primary melanomas in order to investigate the relationship between tumour vascularity and maximum tumour thickness. For the 64 melanomas included in this study, there appeared to be a significant relationship between the percentage vascular volume and the maximum tumour thickness. This relationship was not influenced by the presence of necrosis, vascular invasion, regression, or lymphocytic infiltrate, nor by the growth phase of the tumour. However, the percentage vascular volume was very low in the occasional thick melanoma, at least one of which was associated with prolonged survival. It seems possible that a low tumour vascularity could correlate with a relatively favourable outcome in cutaneous melanoma.

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Clostridial mycotic aneurysms are unusual. We therefore record a fatal case of a ruptured clostridial mycotic aneurysm of the suprarenal aorta which developed several weeks after the resection of a segment of gangrenous small bowel.

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Basal melanocytes were counted and atypia assessed on an arbitrary scale in punch biopsies from the sun-exposed extensor aspect of the forearm of normal skin and from the covered skin of the buttock of patients with pigmented naevi and control subjects. The difference in melanocyte counts and in the presence of atypia between sun-exposed and covered skin was statistically highly significant. The only other difference was between melanocyte counts in covered skin from those with multiple atypical naevi and all other groups; the counts in the former were greater than those in the latter. No further difference was attributable to sun exposure, skin type or diagnostic group. Some degree of melanocyte atypia was seen in approximately half of the biopsies of sun-exposed skin, but atypia was seen in only six of 84 biopsies of covered skin. In each case atypia was present in the corresponding forearm biopsy and all six subjects had pigmented lesions (four with melanoma and two with multiple atypical naevi). It seems possible that while increased melanocyte counts in covered skin could correlate with the presence of atypical naevi, atypia of covered epidermal melanocytes could possibly relate to melanoma risk.

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