Overexpression and mutations of p53 in metastatic malignant melanomas.

Alterations of the p53 tumor suppressor gene are the most frequent genetic abnormalities in human malignancies, but the role of p53 in the etiology of malignant melanomas is unclear. Fifty unselected malignant melanomas were analyzed for p53 overexpression by immunohistochemistry using 3 monoclonal antibodies (MAbs). Fifteen tumors (29.4%) showed positive staining with at least 2 different antibodies. In the first 20 consecutive tumors exons 5-9 and adjacent splice sites of the p53 gene were analyzed by genomic sequencing. There were 4 mutations in 20 metastatic melanomas. Three of 4 mutations were C:G-->T:A transitions. A search of our database of p53 mutations revealed that out of 8 p53 mutations reported by others, 4 are C:G-->T:A transitions at dipyrimidine sites, and one is a tandem CC-->TT mutation. This mutational pattern is comparable with the pattern of p53 mutations in squamous cell and basal cell carcinomas of the skin and is related to exposure to ultraviolet B (UV-B) wavelength radiation. Taken together with a predominance of UV-induced mutations in the CDKN2/ p16 gene demonstrated in melanoma cell lines, our data support a role of sunlight exposure in the etiology of malignant melanoma. The low frequency of p53 mutants in melanomas compared with other types of skin cancers suggests that although mutations in this gene are likely to be involved in the development of some malignant melanomas, they do not play as large a role as in squamous and basal cell carcinomas of the skin.

Treatment of photoaged skin. Efficacy, tolerability and costs of available agents.

Photoaging is a cumulative degenerative process induced by solar irradiation with well defined clinical and histological correlates. Because of its huge psychological impact, there is much demand for effective treatment. Many well constructed trials confirm the clinical efficacy of topical tretinoin for improving fine wrinkling and mild to moderate hyperpigmentation; coarse wrinkling and severe hyperpigmentation respond less well. Histological improvement is well documented, but the precise relationship to clinical response is not clearly established. Tolerability can be a problem. Optimal concentrations are not firmly established and vary between patients. Claims that topical isotretinoin is better tolerated than tretinoin need to be confirmed with well constructed trials. Despite many claims, there have been no adequate trials documenting the efficacy of fish cartilage polysaccharide extracts or alpha-hydroxy acids. Careful patient selection with consideration of alternative treatments such as chemical peeling, dermabrasion and surgery is important to successful management of photoaging.

Kimura's disease and angiolymphoid hyperplasia with eosinophilia: new observations from immunohistochemical studies of lymphocyte markers, endothelial antigens, and granulocyte proteins.

Kimura's disease (KD) typically presents as large subcutaneous masses in young Oriental males. It is characterized by deep inflammation with vascular proliferation, lymphocytic nodules with subcutaneous germinal centers, fibrosis, and edema. In comparison, angiolymphoid hyperplasia with eosinophilia (AHLE) occurs in all races and the lesions usually are smaller and more superficial. The causes of these two diseases are debated. We compared histologic features of 4 cases of KD with 22 cases of ALHE and studied expression of endothelial antigens and lymphocyte markers as well as localization of eosinophil, mast cell, and neutrophil granule proteins in lesional tissue. T-cell lymphoid aggregates with well-formed B-cell germinal centers occurred in KD, and nodular and diffuse T-cell infiltration with small B-cell clusters occurred in ALHE. Endothelial proliferation was more pronounced in KD, lacking the atypical histiocytoid endothelial cells characteristic of ALHE. Many intact eosinophils infiltrated lesions in both diseases, although KD had less extracellular granule protein deposition than ALHE. Intact mast cells were seen in both diseases. There was neutrophil elastase staining of occasional scattered intact cells but no extracellular deposition. Compared with KD, ALHE is more varied in its clinical, histopathologic, and immunohistochemical features.

Henoch-Schönlein purpura: clinicopathologic correlation of cutaneous vascular IgA deposits and the relationship to leukocytoclastic vasculitis.

Significant cutaneous vascular IgA deposits are common in Henoch-Schönlein purpura but not in other vasculitides. The specificity for IgA vascular deposits for Henoch-Schönlein purpura is not well defined. To examine the specificity of IgA vascular deposits for this disease, we compared clinicopathologic features of 92 cases with IgA vascular deposits and a direct immunofluorescence impression of vasculitis with 90 similar cases without IgA deposits. Henoch-Schönlein purpura was diagnosed in 24% of cases with vascular IgA deposits on direct immunofluorescence examination. IgA deposits were frequent in erythema nodosum and venous stasis-related problems and in cryoglobulinemia, coagulopathic vasculopathies, and livedoid vasculitis. Of our cases, 78% exhibited vascular fluorescence with multiple conjugates. No histologic or immunofluorescence pattern alone was specific. The diagnostic specificity for Henoch-Schönlein purpura is improved if gastrointestinal involvement, upper respiratory infection, or age < 20 years is present. We propose diagnostic criteria for Henoch-Schönlein purpura incorporating clinical findings yielding sensitivity and specificity > 90%.

The sensitivity and specificity of direct immunofluorescence testing in disorders of mucous membranes.

BACKGROUND: Direct immunofluorescence testing is frequently used to diagnose inflammatory mucosal disorders, but its accuracy relative to histologic and clinical diagnosis has not been reported. OBJECTIVE: Our purpose was to compare diagnoses made on the basis of direct immunofluorescence, histologic features, and clinical impression and define optimal immunofluorescence criteria. METHODS: Direct immunofluorescence findings and diagnostic impressions for 500 unselected mucosal biopsy specimens were recorded, as were the histologic diagnosis, initial clinical impression, and final diagnosis made on the basis of all studies and follow-up. Sensitivity and specificity were calculated for each parameter by diagnosis and site. RESULTS: Direct immunofluorescence testing was superior for diagnosing pemphigus and pemphigoid and was slightly inferior to histologic evaluation for diagnosing lichen planus. Optimal criteria were IgG and C3 intercellular substance staining for pemphigus, linear C3 basement membrane zone deposits for pemphigoid, and shaggy fibrinogen basement membrane zone staining plus IgM cytoids for lichen planus. Direct immunofluorescence testing was diagnostic for several extraoral mucosal biopsy specimens. CONCLUSION: Direct immunofluorescence is a valuable diagnostic tool for diseases of the oral mucosa and other mucosal sites.

Expression of p53 protein in benign and malignant epidermal pathologic conditions.

BACKGROUND: p53 is an oncogene and a tumor-suppressor gene whose gene product regulates the cell growth cycle. Mutations in p53 are the most common genetic alterations in human cancer. OBJECTIVE: Our purpose was to define p53 expression and subcellular localization in normal and pathologic epidermis. METHODS: We examined sections of normal skin, psoriasis, squamous cell carcinoma (SCC), basal cell carcinoma (BCC), keratoacanthoma, and cultured epithelial cell lines with five antibodies to p53. RESULTS: Monoclonal antibody MAb421 and MAb1801 stained the cytoplasm of normal basal keratinocytes, suggesting that subcellular localization or sequestration of wild-type p53 regulates its activity. Polyclonal antibody reacted throughout normal epidermis, suggesting heterogeneity of species or conformational forms of p53 protein. Cytoplasmic reactivity to MAb421 was similar in normal epidermis, psoriasis, and cultured keratinocytes but was, diminished in SCC, BCC, and keratoacanthoma. CM-1 reactivity persisted in these tumors. Putative p53 mutations detected by MAb240 reactivity were present in 44% of SCC specimens. CONCLUSION: Epidermis expresses p53 and the gene may regulate epidermal keratinocyte growth and carcinogenesis.