N. Scott McNutt

Dermatologic findings and manifestations of acquired immunodeficiency syndrome (AIDS)

We present a review of the spectrum of human T-lymphotropic virus type III (HTLV-III) infection with particular emphasis on cutaneous manifestations in 217 patients. Correlations are made with immunodeficiency as measured by absolute T-helper cell number. A classification is presented of these dermatologic findings.

Nevoid malignant melanoma: morphologic patterns and immunohistochemical reactivity

The term “nevoid malignant melanoma” (nevoid MM) is used here to describe rare nodular malignant melanomas that may escape detection in routine histological sections due to the lack of a prominent intraepidermal component, sharp lateral circumscription and evidence of partial maturation with descent in the dermis. Nevoid MM mimic ordinary compound or intradermal melanocytic nevi when the melanoma cells are small, or Spitzs nevi when the cells are large.

S100A6 Protein Expression is Different in Spitz Nevi and Melanomas

The Spitz nevus is a benign melanocytic lesion that can be identified reliably in many cases by conventional histopathological criteria. However, there are subsets of Spitz nevi and of malignant melanoma that closely resemble each other and represent diagnostic challenges. S100 proteins are of interest because of their involvement in neoplastic processes and their genes are clustered in chromosome 1q21. Chromosome 1 contains mutations in several types of tumors, including melanomas. The expression of different S100 proteins (A2, A6 and A8/A9 or A12) was examined in 42 Spitz nevi, 105 melanomas, and 73 melanocytic nevi to test the hypothesis that their expression differs among these entities and may contribute to the distinction between these entities. The results showed an up-regulation of S100A6 protein in Spitz nevi, melanomas, and melanocytic nevi but with a different percentage of positivity and pattern of immunoreactivity. The differences between these three entities were statistically significant (P < .001). All 42 Spitz nevi (100%) showed strong and diffuse S100A6 protein expression, both in junctional and in dermal components of the nevi. Thirty-three percent of melanomas expressed S100A6 (35/105). The expression was mainly weak (30/35) and patchy in the dermal component and was negative or minimal in the junctional component. Fifty-six percent of different subtypes of melanocytic nevi (41/73) expressed S100A6, almost all of them weakly (40/41) and in the dermal component. Normal intraepidermal melanocytes were negative. The melanocytic cells in these three entities did not express S100A2, S100A8/A9 or A12. However, an up-regulation of S100A2 and S100A8/A9 or A12 proteins was observed in normal keratinocytes in the epidermis overlying Spitz nevi and melanomas, without differences. In summary, a simple immunohistochemical test for S100A6 protein differentiated between Spitz nevi, melanomas, and melanocytic nevi. This marker could be used when the distinction is very difficult or controversial in routine studies, especially when there is a junctional component. Further molecular analyses of the S100A6 protein and gene should be performed to study the underlying genetic bases for such differences.

Primary cutaneous immunocytoma: A B-cell lymphoma that can easily be mistaken for cutaneous lymphoid hyperplasia

It has been estimated that immunocytomas comprise roughly 2% of all cutaneous lymphomas. We studied five patients with primary cutaneous immunocytomas who presented with cutaneous nodules or plaques. Many of the infiltrates were “top-heavy” and polymorphous with admixed eosinophils, macrophages, lymphoid follicles. and non-neoplastic lymphocytes. Other potentially confusing findings were one case each of spongiotic dermatitis and leukocytoclastic vasculitis. The neoplastic cells were often situated at the peripheries of nodules and ranged from those with nuclei that resembled small lymphocytes to others that resembled immunoblasts. Most had eccentrically placed nuclei and fan-shaped cytoplasm. Monotypic -light chain was found in all five cases, accompanied by -heavy chain in two cases, and mU-heavy chain in one. In situ hybridization detected only -mRNA in the four cases that yielded technically satisfactory results. The neoplastic cells did not express the B-cell antigen CD20; T-cells formed the centers of many nodules. Inappropriate staining for CD43 was evident in the neoplastic cells of one case. Because of reports of immunocytomas complicating acrodermatitis chronica atrophicans, we stained sections with an antiserum to Borrelia burgdorferi, which did not detect that organism. In situ hybridization did not detect EBER-I RNA of the Epstein-Barr virus, which can be present in immunocytomas in immunocompromised patients. One patient died of disease after failing chemotherapy; another is alive with disseminated disease, and three are in remission following excision of lesions alone in two patients and chemotherapy in one patient who had relapsed following both excision and radiation therapy.

Papulosquamous dermatoses of AIDS

We review the spectrum of papulosquamous disorders in the setting of infection with the human immunodeficiency virus (HIV). Included is a discussion of xerosis generalisata, seborrheic dermatitis, psoriasis, pityriasis rosea-like eruption, keratoderma blennorrhagicum, acquired ichthyosis, and erythroderma. Mechanisms of pathogenesis, including possible common pathways and relationships to underlying immunosuppression, are emphasized.

Immunohistochemical expression of BCL-2 in melanomas and intradermal nevi

The BCL‐2 gene is the prototype of a newly described family of oncogenes involved in tumorigenesis by blocking apoptosis, or programmed cell death. Overexpression of BCL‐2 protein was originally described in follicular B‐cell lymphomas bearing the 14;18 translocation. BCL‐2 overexpression has also been described in other lymphomas and more rarely in neoplasms outside the lymphoid tissue. The aim of this paper is to determine the immunohistochemical expression of BCL‐2 in intradermal nevi and primary invasive and metastatic melanoma. Formalin‐fixed and paraffin‐embedded tissues from 4 cutaneous melanoma metastases, 10 primary invasive melanomas, and 10 intradermal melanocytic nevi were immimolabeled with monoclonal antibodies directed against BCL‐2 protein (Dako, clone 124) and Ki‐67 antigen (Amac, clone MIB‐1), after antigen retrieval techniques. Morphologically normal epidermal melanocytes expressed BCL‐2, as did nevi and melanomas in virtually all cells. However, whereas the labeling in normal melanocytes and nevus cells showed a uniformly strong reactivity, melanoma cells showed a variable but mainly weak reactivity. Ki‐67 antigen expression was restricted to melanomas. The widespread expression of BCL‐2 suggests that this onco‐protein cannot be involved in the malignant transformation of melanocytic cells. It seems likely that the decreased BCL‐2 expression detected in melanomas may reflect one further step of tumor progression in melanocytic neoplasms.

The S100 family of multipurpose calcium-binding proteins

Antibodies reactive with S100 protein are useful markers in a diagnostic immunohistochemistry laboratory dealing with cutaneous tumors. However, S100 protein is not a single protein but instead a group of S100 proteins with diverse functions. S100 proteins constitute a family of acidic calcium‐binding proteins that are important in intracellular calcium metabolism. Recent evidence that some S100 proteins are secreted makes it likely that they are also involved in cell‐cell interactions. The exploration of the status of the different members of the S100 family may yield not only diagnostic clues but also relevant functional information about the cells. Considerable recent progress has been made in our understanding of S100 proteins. This review surveys some of these findings that may be either directly or indirectly relevant to cutaneous pathology.

Expression of the mast cell growth factor interleukin-3 in melanocytic lesions correlates with an increased number of mast cells in the perilesional stroma: implications for melanoma progression

The molecular events responsible for tumor progression in human cutaneous malignant melanoma remain unclear; however, critical to the process is the dysregulated proliferation of tumor cells and the development of new vascular channels which allow further growth and dissemination. Connective tissue mast cells (MC) have been implicated in tumor progression because they concentrate around tumors (including melanomas) prior to the formation of new blood vessels, and because they contain many chemical mediators, including basic fibroblast growth factor (bFGF), known to have mitogenic and angiogenic effects. Several MC chemotactic and mitogenic factors have been described including interleukin‐3 (IL‐3). In order to determine whether there is a differential expression of this MC chemotactic/mitogenic factor with tumor progression in vivo, we evaluated by immunohistochemistry 85 melanocytic lesions including primary invasive malignant melanoma (PIMM), melanoma in situ (MMIS), and ordinary intradermal benign melanocytic nevi (BMN) for expression of IL‐3. Nucleic acid in situ hybridization also was used to evaluate the melanocytic lesions for IL‐3‐specific mRNA transcripts. Intracellular IL‐3 protein was detected in 29/33 (88%) PIMM and 15/25 (60%) MMIS, but was not detected in any (0/27; 0%) BMN (p<0.0001). IL‐3‐specific mRNA transcripts were present in 3/4 PIMM and 2/10 MMIS in which IL‐3 protein was not identified, but were not detected in any BMN. IL‐3 mRNA or protein was not detected in normal melanocytes present in the perilesional epidermis of any of the specimens studied. Immunohistochemistry also was used to confirm the presence of IL‐3α‐specific receptors on human cutaneous MC. As demonstrated by others, a significantly increased number of MC was present in the perilesional stroma of PIMM and MMIS vis à vis BMN (p<0.0001). The results suggest that melanoma cells may attract MC in vivo by producing MC chemotactic/mitogenic factors such as IL‐3. The recruitment of MC and the subsequent release of their potent mitogenic and angiogenic factors such as bFGF may thus represent a tumor–host interaction which favors tumor progression.

Intermediate- and low-molecular-weight keratin detection with the monoclonal antibody MNF116. An immunohistochemical study on 232 paraffin-embedded cutaneous lesions

Immunohistochemical detection of certain low to intermediate molecular weight keratins often is impaired in routinely processed specimens due to masking of these antigens by formalin fixation. Despite standard enzymatic digestion, AE1:AE3 and CAM 5.2, two of the most currently utilized antikeratin antibody preparations, either stain weakly or fail to stain basal keratinocytes and tumors composed of basaloid keratinocytes in paraffin sections of formalin‐fixed tissue.

The intermediate filament peripherin is expressed in cutaneous melanocytic lesions

Peripherin is an intermediate filament involved in growth and development of the peripheral nervous system and is localized to neurons, some other cells derived from neural tube and neural crest, and some neuroendocrine cells (e.g. β cells of islets of Langerhans). Peripherin also has been demonstrated in neuroblastomas and cutaneous neuroendocrine (Merkel cell) carcinomas. The expression of peripherin by other cells derived from the neural crest is unknown.