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.

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.

Induction of human tumor-loaded dendritic cells.

A preferred anti-cancer vaccine would be tumor-specific, simple to rapidly construct and safe to administer. It would permit immunization against a spectrum of the tumor's distinctive antigens, without requiring their prior identification. Toward these goals, we describe a modification of standard extracorporeal photopheresis (ECP) which initiates, within a single day, both monocyte-to-dendritic cell (DC) differentiation and malignant cell apoptosis. The transition of monocytes to immature DCs was identified by the expression of cytoplasmic CD83 and membrane CD36 in the absence of membrane CD14 staining, as well as induction of membrane CD83 expression. Differentiating DCs were avidly phagocytic and engulfed apoptotic malignant T cells. Differentiating DCs were capable of stimulating significant proliferation of normal alloreactive lymphocyte responders, indicting increased expression of membrane MHC class II molecules. This approach provides a clinically practical means of developing tumor-loaded cells that have initiated the transition to DCs without the requirement of exogenous cytokines, excessive cellular manipulation or isolation. Construction of DC vaccines using this methodology can be generalized to other diseases and may offer a novel approach for improved cancer immunotherapy.

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.

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.

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.

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.

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.

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.

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.

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.

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.

Biliary tract obstruction secondary to mycosis fungoides: a case report.

Mycosis fungoides is a cutaneous T-cell lymphoma that can disseminate to multiple organs. We report a patient who presented with obstructive jaundice caused by isolated involvement of the extrahepatic biliary tree by mycosis fungoides. Initially, endoscopic examinations and biopsies of the biliary tree and liver failed to reveal a cause for the obstructive symptoms. Finally, surgical resection of the gallbladder and extrahepatic ducts was performed. Examination revealed a dense, mixed lymphocytic infiltrate with atypical cells within the mucosa. Gene rearrangement studies confirmed the presence of a monoclonal T-cell population. The pattern of the gene rearrangement in the biliary tree was identical to that found in a previous skin biopsy that showed mycosis fungoides. Although liver involvement by mycosis fungoides is not uncommon, disease isolated to the extrahepatic biliary tree has not previously been reported. This case should alert clinicians and pathologists to yet another cause of obstructive jaundice.

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.

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.