Morphology of delayed-type hypersensitivity reactions in man. II. Ultrastructural alterations affecting the microvasculature and the tissue mast cells.

Profound alterations in the dermal microvasculature and the closely related fixed tissue mast cells were observed in allergic contact dermatitis reactions to dinitrochlorobenzene and urushiol in man. The vascular changes were of two types. The superficial capillary venule, a distinct anatomical and functional vessel system in the dermal papillae, developed interendothelial cell gaps, maximal at 3 days after skin test, which very likely were responsible for locally increased vascular permeability and consequent dermal edema. The products of degranulating tissue mast cells and infiltrating basophils may have been partly responsible for these changes. By contrast, vessels of the superficial venular plexus, oriented parallel to the cutaneous surface at the junction of the papillary and reticular dermis, were the site of diapedesis and perivascular cuffing by lymphocytes and other inflammatory cells. The superficial venular plexus vessels exhibited striking endothelial cell and pericyte hypertrophy, occasional necrosis of endothelial cells, endothelial cell mitoses, and an extensive and progressive laying down of new and abnormally disposed basal lamina. These changes, somewhat slower to develop than those affecting the superficial capillary venule, were present in all biopsies taken at 3 days or later and were accompanied by mast cell mitoses and the appearance of immature dermal mast cells. The basal lamina-alterations persisted and evolved for at least several weeks. The mechanisms initiating these vessel and mast cell changes have not been identified, but circumstantial evidence suggests that lymphocytes or their products or both may have been responsible.     

Atypical Spitz nevi/tumors: lack of consensus for diagnosis, discrimination from melanoma, and prediction of outcome.

The biological nature of Spitz nevi/tumors and their diagnostic distinction from, or relationship to, melanoma remain unresolved issues. In this report, a series of 30 melanocytic lesions removed from 28 patients, including atypical Spitz nevi/tumors and metastasizing Spitzoid tumors/melanomas, were evaluated by a panel of dermatopathologists to evaluate interobserver diagnostic concordance and to assess the prognostic power of histological criteria. For inclusion in the study, each lesion had to display some criteria for the Spitz nevus, and in addition one of the following was required: (1) definitive clinical outcome such as metastasis or death of disease, or (2) long-term follow-up if the patient remained disease free. Each lesion was reviewed independently and blinded as to the clinical data by 10 pathologists, who categorized them as (1) typical Spitz nevus/tumor, (2) atypical Spitz nevus/tumor, (3) melanoma, (4) tumor with unknown biological potential, or (5) other melanocytic lesion. There was limited discussion of criteria before the review. Evaluation of 17 Spitzoid lesions yielded no clear consensus as to diagnosis; in only one case did six or more pathologists agree on a single category, regardless of clinical outcome. Notably, however, some lesions that proved fatal were categorized by most observers as either Spitz nevi or atypical Spitz tumors. Conversely, seven or more pathologists scored 13 lesions as melanoma. These results illustrate (1) substantial diagnostic difficulties posed by many Spitz tumors, especially those with atypical features, even among experts, and (2) the lack of objective criteria for their distinction from melanoma and for gauging their malignant potential. Nevertheless, our observations do suggest that a biological relationship exists between the Spitz nevus/tumor and melanoma.     

Establishment of antitumor memory in humans using in vitro-educated CD8+ T cells

Although advanced-stage melanoma patients have a median survival of less than a year, adoptive T cell therapy can induce durable clinical responses in some patients. Successful adoptive T cell therapy to treat cancer requires engraftment of antitumor T lymphocytes that not only retain specificity and function in vivo but also display an intrinsic capacity to survive. To date, adoptively transferred antitumor CD8(+) T lymphocytes (CTLs) have had limited life spans unless the host has been manipulated. To generate CTLs that have an intrinsic capacity to persist in vivo, we developed a human artificial antigen-presenting cell system that can educate antitumor CTLs to acquire both a central memory and an effector memory phenotype as well as the capacity to survive in culture for prolonged periods of time. We examined whether antitumor CTLs generated using this system could function and persist in patients. We showed that MART1-specific CTLs, educated and expanded using our artificial antigen-presenting cell system, could survive for prolonged periods in advanced-stage melanoma patients without previous conditioning or cytokine treatment. Moreover, these CTLs trafficked to the tumor, mediated biological and clinical responses, and established antitumor immunologic memory. Therefore, this approach may broaden the availability of adoptive cell therapy to patients both alone and in combination with other therapeutic modalities.     

Somatic malignant transformation in a sacrococcygeal teratoma in a child and the use of F18FDG PET imaging

A 6-year-old female presented with a subcutaneous sacral mass. Biopsy revealed an adenocarcinoma most likely arising from a sacrococcygeal teratoma (SCT). CT imaging revealed a massive tumour consistent with SCT. F¹⁸FDG Positron Emission Tomography (PET) scan confirmed marked metabolic activity in the tumour mass and regional lymph node involvement. After chemotherapy repeat CT and PET studies revealed a poor response but no evidence of peritoneal or distant metastases. Radical abdomino-pelvic and gluteal surgery was performed with removal of the entire tumour confirmed as a moderately differentiated adenocarcinoma arising in an immature teratoma. Follow up imaging including PET scanning 5 months after her surgery revealed widespread peritoneal, hepatic and pulmonary metastases. Somatic malignant transformation of an SCT in a child of this age has not been previously reported.     

Autoantibodies to melanocytes and characterization of melanophages in patients affected by a new variant of endemic pemphigus foliaceus

Background: Melanin and melanophages are commonly seen under the basement membrane zone of the skin in patients affected by a new variant of endemic pemphigus foliaceus in El Bagre, Colombia (El Bagre‐EPF). Objective: Our study was conducted to determine the nature of these pigmentary alterations. Methods: We utilized clinical, histopathologic and immunologic techniques including direct and indirect immunofluorescence, immunohistochemistry, Bielschowsky staining and immunoelectron microscopy studies. Results: In the El Bagre‐EPF patients, we detected dermal melanin in melanophages and antigen‐presenting cells, in close proximity to neural and vascular markers. The melanophages consisted of a mixed population expressing CD68, myeloid/histoid antigen and S‐100 protein. By immunoelectron microscopy, the presence of autoantibodies in proximity to melanin granules was confirmed within the melanocytes utilizing 10‐nm gold particles. Conclusion: Dermal antigen‐presenting cells, including melanophages, seem to contain a diverse combination of molecules, representative of an immunologic process where these cells are engulfing both autoantigens and/or cellular debris in El Bagre‐EPF. Autoantibodies to discrete components of melanocytes were also identified; the clinical and immunologic significance of these findings remains unknown. Our work may provide a possible explanation of a darkened complexion in patients affected by endemic pemphigus foliaceus. Abreu Velez A M, Yi H, Googe PB Jr, Mihm MC Jr, Howard MS. Autoantibodies to melanocytes and characterization of melanophages in patients affected by a new variant of endemic pemphigus foliaceus.     

Two distinct cellular patterns in cutaneous necrotizing angiitis.

Two distinct cellular patterns of necrotizing angiitis involving venules in skin of patients with clinically identical cutaneous lesions were appreciated by the 1 -mum-thick section technique. In those individuals with serum hypocomplementemia, there was a perivenular inflitrate composed predominantly of neutrophils with fibrin deposition and nuclear debris. In patients with normal serum complement levels, in addition to an infiltrate of neutrophils and fibrin deposition, perivenular lymphocytes in various stages of activation were prominent. In both patterns the venules and not the arterioles were affected, mast cells exhibited various degrees of hypogranulation, and basophils and eosinophils were recognized only rarely. Lesions of different clinical age obtained from one hypocomplelmentemic patient and one normocomplementemic patient exhibited consistent cellular patterns, as did a single crop of lesions biopsied twice, 24 hr apart, in a patient with hypocomplementemia. No patient with hypocomplementemia became normocomplementemic or vice versa with persistence of lesions.