Regulation of cutaneous malignancy by gammadelta T cells.

The localization of gammadelta T cells within epithelia suggests that these cells may contribute to the down-regulation of epithelial malignancies. We report that mice lacking gammadelta cells are highly susceptible to multiple regimens of cutaneous carcinogenesis. After exposure to carcinogens, skin cells expressed Rae-1 and H60, major histocompatibility complex-related molecules structurally resembling human MICA. Each of these is a ligand for NKG2d, a receptor expressed by cytolytic T cells and natural killer (NK) cells. In vitro, skin-associated NKG2d+ gammadelta cells killed skin carcinoma cells by a mechanism that was sensitive to blocking NKG2d engagement. Thus, local T cells may use evolutionarily conserved proteins to negatively regulate malignancy.

Th2 responses induced by epicutaneous or inhalational protein exposure are differentially dependent on IL-4.

Atopic individuals are predisposed to mounting vigorous Th2-type immune responses to environmental allergens. To determine the factors responsible, animal models that closely mimic natural modes of allergen exposure should prove most informative. Therefore, we investigated the role of IL-4, a known Th2-promoting cytokine, in generation of Th2 responses after exposure of either the skin or airway to soluble protein. Compared with wild-type (WT) mice, IL-4-deficient (IL-4(-/-)) mice showed markedly impaired Th2 activation after primary exposure to inhaled ovalbumin (OVA), with decreased OVA-specific IgG1 and IgE, and significantly fewer eosinophils in bronchoalveolar lavage (BAL) fluid after airway challenge. In contrast, IL-4(-/-) mice initially exposed to epicutaneous (e.c.) OVA mounted Th2 responses equivalent to responses in WT mice, with high numbers of eosinophils in BAL fluid. Because Th2 responses were not induced by e.c. OVA exposure in Stat6(-/-) mice (mice lacking signal transducer and activator of transcription 6), the role of IL-13 was tested. In vivo depletion of IL-13 prevented Th2 responses induced by e.c. OVA exposure in IL-4(-/-) mice. These data demonstrate a marked difference in the IL-4 dependence of Th2 responses generated at two anatomic sites of natural allergen encounter and identify the skin as a particularly potent site for Th2 sensitization.

Reassessment of histologic parameters in the diagnosis of mycosis fungoides.

The histologic diagnosis of mycosis fungoides (MF) can be difficult to establish and is based on interpretation of numerous subtle changes, most of which may be present to some degree in many inflammatory and neoplastic cutaneous conditions. To reassess the diagnostic criteria for making a histologic diagnosis of MF, we retrospectively reviewed histologic sections from 64 patients with mycosis fungoides (MF+) and compared the findings with sections from 47 patients who were biopsied to exclude MF and were shown not to have the disease (MF-). Patients were selected as MF+ or MF- independent of histologic findings based on the clinical course with at least 3 years of follow-up and immunophenotyping results. Following patient selection, at least two observers reviewed each slide without knowledge of final diagnosis and graded the intensity of approximately 25 histologic parameters. On univariate analysis, the following parameters were significant at beyond the p = 0.01 level: Pautrier's abscesses, haloed lymphocytes, exocytosis, disproportionate epidermotropism, epidermal lymphocytes larger than dermal lymphocytes, hyperconvoluted intraepidermal lymphocytes, and lymphocytes aligned within the basal layer. Haloed lymphocytes proved to be the most robust discriminator of MF from non-MF on multivariate analysis. These findings show that whereas many previously described features do discriminate between MF and inflammatory mimics, others are much less specific. Furthermore, few cases demonstrate all histologic features; for example, Pautrier's microabscesses were seen in only 37.5% of our cases. We conclude that a combination of specific histologic parameters can be used to establish a microscopic diagnosis of MF without the necessity of confirmatory immunophenotyping in the vast majority of cases.

Epithelioid cell histiocytoma. A report of 10 cases including a new cellular variant.

Epithelioid cell histiocytoma is a recently recognized lesion that is considered to be a variant of cutaneous fibrous histiocytoma (dermatofibroma). Ten cases are presented, including their light microscopic, immunohistochemical, and ultrastructural features. Eight of the cases are similar to those previously reported, presenting as elevated nodules arising on the extremities and composed of epithelioid histiocytes with overlying epidermal effacement. Two of the cases were composed of cells with the same morphologic and immunohistochemical characteristics as typical epithelioid cell histiocytoma, including factor XIIIa positivity, but these arose in the reticular dermis and exhibited prominent cellularity.

Cutaneous T-cell lymphoma. Refinement in the application of controversial histologic criteria.

The term cutaneous T-cell lymphoma was originally coined to encompass the spectrum of mycosis fungoides and Sézary syndrome. It has become increasingly evident that the histopathologic diagnosis of CTCL can be exceedingly challenging. A series of recent studies, however, have helped clarify the nature of the histologic findings in CTCL. Recently reported histologic data on mycosis fungoides, Sézary syndrome, and their variants is emphasized in this article, with special focus given to the findings in early lesions. A brief summary of lymphocyte immunophenotyping and the role of T-cell reception gene rearrangements in CTCL is included.

Under the microscope. Surgeons, pathologists, and melanocytic nevi.

Predicting the biologic behavior of melanocytic neoplasms (benign versus malignant) based on histology is one of the most difficult challenges in surgical pathology and dermatology. Success in the field of melanocytic neoplasia can be achieved by two means: performing excisions or biopsies that maximize the obtainable histologic information and providing sufficient history.

Subcutaneous Fusarium foot abscess in a renal transplant patient.

Fusarium species are ubiquitous plant and grain phytopathogens that rarely cause opportunistic infections in immunocompromised patients. While disseminated Fusarium infections are almost always fatal, localized infections may be responsive to a combination of systemic antibiotic therapy and surgical debridement. We present a diabetic renal transplant patient who developed a foot abscess due to Fusarium solani. Infection persisted despite aggressive surgical debridement and a 3-month course of intravenous liposomal amphotericin B.

Immunofluorescent analysis of the basement membrane zone in lichen planus suggests destruction of the lamina lucida in bullous lesions.

Lichen planus is an inflammatory dermatosis which is characterized histologically by an intense lymphocytic infiltrate at the dermal epidermal junction. This frequently results in disruption of the basement membrane zone, occasionally causing clinical blisters. In order to better understand the specific portion of the basement membrane zone which is disrupted by the lymphocytic infiltrate, we examined 7 cases of lichen planus with antibodies directed against anchoring filaments (GB3), the bullous pemphigoid antigen, anchoring fibrils (type VII collagen) and type IV collagen. In lesions without separation at the BMZ, all antibodies were strongly expressed, as in normal skin. In lesions with early separation, there was a focal decrease in GB3 staining, but types VII and IV collagen labelled normally. In lesions resulting in blisters, GB3 staining was essentially absent, and anti-types IV and VII collagen remained, but stained in a disrupted, less discrete pattern. The bullous pemphigoid antigen showed only slight deviation from the normal staining pattern. These findings suggest that the basement membrane zone in lichen planus is disrupted in the lamina lucida region. The lamina densa and sub-lamina densa zones remain intact even in bullous lesions of lichen planus.

Unilesional cutaneous T-cell lymphoma: clinical features, therapy, and follow-up of 10 patients with a treatment-responsive mycosis fungoides variant.

Ten patients, mean age 61 years, who presented with unilesional cutaneous T-cell lymphoma (CTCL) were studied. Lesional structure and distribution were similar to disseminated CTCL. Ablative therapy was successful in all patients. The relatively benign behavior of unilesional CTCL may reflect the prognostic importance of minimal tumor burden. Locally ablative therapy in the management of localized CTCL appears effective.

Epithelioid cell histiocytoma: a simulant of vascular and melanocytic neoplasms.

Epithelioid cell histiocytoma (ECH) is an unusual and still poorly recognized variant of benign fibrous histiocytoma. Epithelioid cell histiocytoma differs from most benign fibrous histiocytomas in five important ways: the predominance of epithelioid cells, relative lack of secondary elements (such as giant cells, foamy, or hemosiderin-laden macrophages), relative sharp circumscription, prominent vascularity, and centering in the papillary dermis in most cases. A strong resemblance to melanocytic and vascular lesions has been noted, and a recent case was reported with features suggesting endothelial origin. Fifteen new cases of ECH, including one example of the rare deep cellular variant, are presented herein, with emphasis on features mimicking vascular and melanocytic neoplasms. Labeling with endothelial markers, including previously unreported CD-31 labeling, showed abundant vascular staining, which may be challenging to interpret, but which does not indicate an endothelial origin of ECH.

Assessment of clonality in melanocytic nevi.

BACKGROUND: Melanocytic nevi are among the most common lesions in man; however; their pathogenesis remains largely unknown. While often held to be neoplastic, this hypothesis has not been conclusively verified. Alternatively, some authorities have held that melanocytic nevi are hamartomas. More practically, difficulty may be encountered in the histologic discrimination of melanocytic nevi from melanoma. It was reported that nevi may be differentiated from melanoma in females by polymerase chain reaction (PCR) analysis of loci of human androgen receptor gene on the X-chromosome. However, contradictory findings have also been reported, suggesting that both acquired nevi and melanoma are clonal. METHODS: Fifteen examples of melanocytic nevus were analyzed via PCR for pattern of X-chromosome inactivation as indicated by the methylation status of the human androgen receptor gene. RESULTS: Among 15 nevi analyzed, 11 cases provided informative polymorphism at the androgen receptor loci. Nine of these 11 cases revealed a non-random pattern of X-chromosome inactivation. CONCLUSIONS: These findings suggest that melanocytic nevi are clonal/neoplastic lesions. As such, they cannot be discriminated from melanoma on the basis of clonality.

T lymphocytes bearing the gamma/delta T-cell receptor in cutaneous lesions of dermatitis herpetiformis.

T lymphocytes bearing the gamma/delta T-cell receptor are a rare component of normal human GI epithelium and skin. Recently, however, an unusually high percentage of T lymphocytes with gamma/delta receptors has been described in gastrointestinal biopsies from patients with dermatitis herpetiformis, implicating the gamma/delta T cell subset in the pathogenesis of this disease. We investigated a possible role for this subset of lymphocytes in the pathogenesis of the cutaneous lesions of dermatitis herpetiformis. Using a standard immunoperoxidase technique, we labelled perilesional skin biopsies from patients with dermatitis herpetiformis and other inflammatory dermatoses with monoclonal antibodies to CD3, CD4, CD8, alpha/beta T cell receptor, gamma/delta T cell receptor, and IL-2 receptor. We found no differences in the percentage of gamma/delta positive T lymphocytes in skin lesions of dermatitis herpetiformis as compared to other selected inflammatory conditions. These findings suggest that the pathogenesis of the cutaneous lesions of dermatitis herpetiformis is not mediated through gamma/delta T cells, and that the cutaneous lesions may develop through mechanisms different from those operative in the gastrointestinal tract.

Immunohistochemical comparison of cutaneous lymphadenoma, trichoblastoma, and basal cell carcinoma: support for classification of lymphadenoma as a variant of trichoblastoma.

Cutaneous lymphadenoma is an uncommon basaloid epithelial tumor of uncertain histogenesis, most recently classified as a variant of trichoblastoma. Because characteristic immunohistochemical findings have been reported in trichoblastomas, we evaluated the staining patterns of five cutaneous lymphadenomas and compared the results to those of ten trichoblastomas and ten nodular basal cell carcinomas (BCCs), using antibodies to cytokeratin 20 (CK20), bcl-2, and CD34. In addition, because lymphadenomas contain intraepithelial S100-positive putative Langerhans cells, we compared staining of all tumor groups for S100 protein and CD1a. We also attempted to corroborate recent reports of CD30-positive activated lymphocytes in lymphadenomas. We identified CK20-positive Merkel cells in 3/5 lymphadenomas, 7/10 trichoblastomas, and none of the BCCs. Staining for bcl-2 accentuated the peripheral epithelial layer in all lymphadenomas and in 3/10 trichoblastomas, while the remaining trichoblastomas and all BCCs stained diffusely. There was stromal staining with CD34 in two lymphadenoma, 4 trichoblastomas, and 3 BCCs. All lymphadenomas featured numerous intraepithelial S100-positive cells which were also positive for CD1a in three cases tested. In addition, 8/10 trichoblastomas and 2/10 BCCs contained modest numbers of cells labelling for S100 and CD1a. Two of three lymphadenomas contained rare single cells resembling histiocytes faintly positive for CD30, and similar cells labelled for CD68. We conclude that the similar staining patterns of lymphadenomas and trichoblastomas support the classification of lymphadenoma as a variant of trichoblastoma. Staining with CD34 does not reliably distinguish between these tumors and BCCs. Lymphadenomas, trichoblastomas, and BCCs may all contain Langerhans' cells. The relationship between these cells and the striking lymphoid infiltrates seen in lymphadenomas is not clear. In our cases, the CD30-positive cells in lymphadenomas appear to represent histiocytes rather than activated lymphocytes.

Pointillist nevi.

BACKGROUND: Atypical melanocytic nevi and cutaneous melanoma are often marked by variation in color. However, there are examples of "benign" explanations for irregularities in pigmentation, such as perifollicular hypopigmentation or hyperpigmentation. OBJECTIVE: The purpose of this study was to correlate the clinical and histologic features of 3 unusual melanocytic nevi consisting exclusively of multiple, tiny, dark brown to black dots on a skin-colored background, which we have termed pointillist nevi. METHODS: Histologic examination was performed of the single pointillist nevus from each of 3 patients (all women; aged 28, 39, and 47 years). RESULTS: The diameters of the pointillist nevi were 2, 3.5, and 5.5 mm. Individual dots were approximately 0.1-0.25 mm. Each of the 3 nevi showed a different histologic correlate for the dots, either (1) discrete, densely pigmented, junctional melanocytic nests; (2) isolated dermal pigmented melanocytic nests; or (3) discrete clusters of melanophages in the papillary dermis. CONCLUSION: Pointillist nevi are benign melanocytic nevi with histologic correlates similar to those of the "brown globules" observed by dermoscopy in uniformly pigmented nevi. However, the dots seen in pointillist nevi can be visualized without magnification. The clinical and histologic features of pointillist nevi add to the spectrum of unusual patterns of pigmentation that may be encountered in benign melanocytic lesions.

Evaluation of T-cell receptor gene rearrangements in patients with recurrent patch/plaque (T2) CTCL (mycosis fungoides).

Cutaneous T-cell lymphoma is typically a clonal neoplasm of epidermotropic CD4+ T-lymphocytes that includes the entity mycosis fungoides (MF). After identification of patients with recurrent MF treated with total skin electron beam therapy (TSEBT) at the Yale University School of Medicine, this study attempted to compare T-cell receptor (TCR) gamma gene rearrangements via polymerase chain reaction (PCR) in both original and recurrent skin biopsies from these patients. Between 1974 and 1996, a total of 95 T2 MF patients were treated with TSEB, and four of these were identified for the study. Slides and tissue samples of both primary and recurrent skin biopsies for each patient were confirmed as being consistent with ME DNA for PCR was isolated from paraffin-embedded tissue samples. Using consensus primers that hybridize with conserved regions of the TCR gene, these regions of the genome were amplified. The PCR products were then analyzed by acrylamide gel electrophoresis. Of the primary and recurrent samples from four patients with a median disease-free interval (DFI) of 1222 days, only two showed evidence of a dominant TCR clone. A number of factors, including lack of sequence homology between the primers and the gene segments, the existence of multiple neoplastic cell lines, DNA degradation in the archival samples, and the presence of reactive as well as malignant lymphocytes, may have prevented the detection of dominant TCR rearranged clones in the samples. Despite the results of this study, TCR analysis via PCR and gel electrophoresis continues to be of utility in the evaluation of patients with MF when used in conjunction with other diagnostic modalities and in cases with nonspecific clinical, histopathological, and immunophenotyping findings.

Morphea limited to the superficial reticular dermis: an underrecognized histologic phenomenon.

Morphea (localized scleroderma) is a disease of unknown etiology, presenting as circumscribed areas of indurated skin. Histologically, most cases of morphea feature thickened collagen bundles in the deep reticular dermis, sometimes also extending into the superficial dermis or into the subcutis. We present six cases of morphea in which typical histologic features were restricted to the superficial dermis and contrast these with 27 additional biopsies of conventional morphea seen during the same time period. Sections were stained for elastic fibers, and dermal dendritic cells were labeled with antibodies to CD34 and Factor XIIIa. All six cases showed thickened collagen bundles restricted to the superficial dermis, sparing the deep dermis and without associated evidence of lichen sclerosus et atrophicus (LSA). Dermal elastic fibers were not appreciably decreased in number. There was loss of CD34-positive dermal spindle cells in each of our six superficial examples of morphea, which was restricted to the area of altered collagen in four of the six cases. This report highlights the distinctly uncommon phenomenon of morphea presenting solely as alteration of the superficial reticular dermis, without features of LSA. The selective loss of CD34-labeled spindle cells may provide information regarding the role of these putative immune accessory cells in morphea. Recognition of this manifestation of morphea may be helpful diagnostically.

Mycosis fungoides palmaris et plantaris or acral pagetoid reticulosis?

There has been ongoing debate about the nature of Woringer-Kolopp disease (unilesional pagetoid reticulosis). Despite the histologic resemblance to mycosis fungoides, these lesions are typically solitary and indolent. Recently, cutaneous plaques of epidermotropic lymphocytes restricted to acral sites resembling Woringer-Kolopp disease were reported to show T-cell clonality, leading to the designation mycosis fungoides palmaris et plantaris. We describe a similar case of recurrent plaques on palms and soles of a 45-year-old man that persisted for >14 years without other cutaneous or systemic disease. Histologically, the lesions were comprised of epidermotropic atypical lymphocytes with sparse dermal infiltrates. Immunohistochemically, the majority of intraepidermal lymphocytes labeled as CD8-positive suppressor/cytotoxic T cells and expressed alphaE beta7 (CD103), an integrin associated with epitheliotropism. Polymerase chain reaction studies revealed similar clonal gene rearrangements of T-cell receptors beta and gamma in tissue from both palm and sole. In view of these findings, the diagnosis of mycosis fungoides palmaris et plantaris may be appropriate. To date, however, the lesions have remained localized and continue to resolve spontaneously. As such, the behavior is similar to what has been described as pagetoid reticulosis. Long-term follow-up will be necessary to determine the biologic potential of this disease.

Polydipsia and hyponatremia induced by multiple neuroleptics but not molindone.

A 37 year old patient with chronic schizophrenia developed polydipsia and hyponatremia induced by several neuroleptics. We treated the patient successfully with molindone. The etiology of polydipsia with hyponatremia is discussed.