Martin J. Trotter

Overexpression of the cyclin‐dependent kinase inhibitor p21WAF1/GIP1 in human cutaneous malignant melanoma

p2lWAFI/CIPI (p21) is an inhibitor of cyclin‐dependent kinases recently identified as the downstream effector of wild‐type p53‐me‐diated cell cycle arrest. The gene coding for p21 may function as a negative regulator of melanoma growth, progression, and metastasis. Using immunohistochemistry and Western blotting, we investigated the expression of p21 in human melanocytic proliferations. Immunohistochemical staining was performed on 13 common acquired nevi, 12 dysplastic nevi, 23 primary malignant melanomas, and 12 metastatic melanomas. Common acquired nevi showed minimal p21 staining (1.8±0.3%, mean±SEM). The percentage of positive nuclei was slightly elevated in dysplastic nevi (8.9±1.7%). Both primary malignant melanoma (29±3%) and metastatic melanoma (33±5%) demonstrated a significantly increased number of p21‐positive nuclei compared to benign lesions (p<0.001). p21 was strongly expressed even in actively proliferating lesions as confirmed by MIB‐1 labelling, and although the majority of p21‐positive cells likely represent a non‐proliferating population, staining was occasionally observed in cells undergoing mitosis, suggesting abnormal function of this cell cycle inhibitor in malignant melanoma. Overexpression of p21 in metastatic melanoma compared to common acquired nevi was confirmed by Western blot analysis of human tumor samples. These findings suggest that increased p21 expression relative to benign nevi is not sufficient to control melanoma growth in vivo.

Neutrophilic spongiosis in pemphigus herpetiformis.

Pemphigus herpetiformis is a rare pemphigus variant with light microscopic features that have historically been described as either “acantholytic dermatitis herpetiformis” or as “eosinophilic spongiosis in pemphigus”. The clinical features of this form of pemphigus are reminiscent of dermatitis herpetiformis; however, the direct immunofluorescence finding of epidermal intercellular IgG deposition is that of the pemphigus group. We report two patients with clinical presentations suggestive of dermatitis herpetiformis in whom the histopathologic features were those of a neutrophilic intraepidermal blistering disorder. Biopsies showed marked epidermal spongiosis with midepidermal acantholytic vesicles containing predominantly neutrophils and a few eosinophils. Direct immunofluorescence was positive for epidermal intercellular IgG; IgA deposition was not present. Neutrophilic spongiosis, in the absence of a prominent eosinophilic infiltrate, should be recognized as an early finding in some cases of pemphigus, and immunofluorescence studies are justified when this histologic feature is encountered in a skin biopsy.

Mitotic granuloma annulare: a clinicopathologic study of 20 cases

The finding of mitotic figures in granuloma annulare (GA) has not been emphasized in the literature. We describe 20 cases of a cellular, mitotically active variant of GA; we defined this group as cases having ≥ 1 mitosis per 10 hpf. Clinically, the lesions could not be distinguished from typical, localized GA: there were 9 males and 11 females with a mean patient age of 49±15 years (mean±SD), compared to 45±20 years in a randomly selected control group of 60 patients with GA, and no unusual sites of predilection were noted. Histologically, a classic, palisading granuloma pattern predominated (18/20 cases). Lesions were located in the mid‐dermis and tended to be more cellular than typical GA. The histiocytes comprising the lesion often had enlarged nuclei and prominent nucleoli. The number of mitoses per 10 hpf was 3.0±1.5 (range 1.0–7.2), control group 0.3±0.5; occasional atypical mitotic figures were observed. The proliferative nature of these lesions was confirmed using MIB‐1 staining; the percentage of MIB‐1 positive cells ranged from 5%–29% (mean 15±6%). Mitotic GA must be distinguished histologically from neoplastic processes, in particular epithelioid sarcoma. We conclude that histiocytes in clinically typical GA can exhibit an increased mitotic rate. Recognition of this variant is important in order to avoid overdiagnosis of a malignant condition.

Crusted scabies in association with human T-cell lymphotropic virus 1.

Background: Human T-cell lymphotropic virus 1 (HTLV-1) infection can lead to myelopathy/tropical spastic paresis and adult T-cell leukemia/lymphoma (ATLL). Infection with HTLV-1 has also been associated with clinically significant immunosuppression. Crusted scabies, also known as Norwegian scabies, is an uncommon presentation of scabies that may occur in conjunction with immunosuppression. Although crusted scabies has been reported in association with HTLV-1 infection, to our knowledge it has never been described in association with HTLV-1 associated myelopathy. Objective: The aim is to describe a case of HTLV-1 associated myelopathy and concomitant crusted scabies. Methods: This article includes a case report and a literature review. Conclusions: Crusted scabies is reported in association with HTLV-1 infection with or without concomitant ATLL. Crusted scabies should be considered in the differential diagnosis of a generalized cutaneous eruption in an HTLV-1 positive patient. Patients with crusted scabies from an HTLV-1 endemic population should be tested for a possible HTLV-1 infection. These patients may be at increased risk of progressing to ATLL.

Plaque-type multinucleate cell angiohistiocytoma.

Background: Multinucleate cell angiohistiocytoma (MCAH) is a rare cutaneous disorder that usually presents as papules or nodules. Objective: This article reports a case of MCAH that appeared clinically as a large cutaneous plaque. Methods and Results: A 74-year-old woman presented with a large painless, dusky red, indurated plaque measuring 12 × 6 cm on the trunk that was found on histopathologic examination to be a MCAH. Based on a literature review, this is the first reported case of MCAH presenting as a plaque rather than a papule or nodule. Conclusion: Multinucleate cell angiohistiocytoma may manifest clinically as a solitary cutaneous plaque.

Trichoepithelioma associated with cellular blue nevus.

Background: Epithelial elements, such as trichoepithelioma, are occasionally associated with melanocytic nevi. Objective: A case of trichoepithelioma in association with cellular blue nevus is reported. Methods and Results: A solitary, pigmented nodule was removed from the scalp of a middle-aged woman. Histopathologic examination demonstrated a circumscribed cellular blue nevus within which were embedded epithelial strands and cystic structures consistent with trichoepithelioma. Conclusion: Trichoepitheliomas have been described in relation to common acquired nevi, but an association with a blue nevus is rare. The intimate admixture of trichoepithelioma within the nodule of a nevus supports the concept of epithelial induction by melanocytic nevi.

Isolation and Partial Characterization of Potential Melanoma Suppressor Genes Using a Novel Subtractive Melanocyte Library

Background: There is increasing evidence that a tumour suppressor plays a role in the pathogenesis of cutaneous melanoma. Objective: Our objective was to isolate a melanoma-tumour suppressor gene. Methods: We constructed a novel subtractive library enriched for cDNAs expressed preferentially in normal melanocytes. Candidate genes were isolated using differential hybridization and were characterized further by Northern blot analysis. Results: Initially, 238 plaques were isolated, of which 57 contained insert cDNA. Ten of the cDNA clones demonstrated expression in normal melanocytes and were not present in at least one of four melanoma cell lines. Three of the clones showed no expression in melanocytes, but did hybridize with at least one of the melanoma lines. The remaining 44 clones were not expressed in either melanocyte or melanoma lines. Partial DNA sequence analysis of four selected clones revealed a cDNA representing the Ret Fused Gene (RFG) and two others highly homologous to tyrosinase-related protein (TRP1). Ret Fused Gene, a gene originally isolated from thyroid gland tumours, has been mapped to chromosome 10, whereas the TRP1 has been mapped to chromosome 9p. Both these genetic loci are known to be altered in melanoma. Conclusion: The method used is a powerful tool for the identification of genes important in the pathogenesis of skin diseases and is applicable to the study of a wide range of neoplastic and nonneoplastic conditions.