Dysplastic melanocytic nevi in histologic association with 234 primary cutaneous melanomas

Dysplastic melanocytic nevi (DMN) are irregularly pigmented lesions characterized by (1) atypical melanocytic hyperplasia in a lentiginous epidermal pattern (AMHL), (2) one or more dermal mesenchymal changes, and (3) frequently a dermal nevocellular nevus. In order to determine an association between DMN and cutaneous melanoma, the dominant histologic feature of DMN (namely, AMHL) was sought in histologic contiguity with 234 primary melanomas. Of these 234 cases, 9 were lentigo maligna melanomas. Of the remaining 225 cases, 49 (21.8%) were associated with AMHL in the same histologic section as (but beyond the most lateral margin of) intraepidermal and invasive melanoma. AMHL was directly associated with the presence of dermal nevocellular nevi in histologic contiguity with melanoma, and a greater number of histologic slides with melanoma available for review. AMHL was inversely associated with nodular melanoma. Most of the AMHL cases were not associated with familial melanoma, but the total number of familial cases was low. The histologic association between AMHL and melanoma in one fifth of cases in this series supports the hypothesis that at least some cutaneous melanomas may have an origin in DMN.     

Amino acid variations in hepatitis C virus p7 and sensitivity to antiviral combination therapy with amantadine in chronic hepatitis C

BACKGROUND: Formation of transmembrane ion channels by hepatitis C virus (HCV) p7 and abrogation of channel function by amantadine was demonstrated in vitro. The relevance of HCV p7 amino acid (aa) variations for response to antiviral therapy with amantadine is unknown. METHODS: HCV p7 was sequenced in 86 individuals who were infected with HCV genotype 1. Thirty-six of 86 patients received amantadine within an interferon-alpha (IFN-alpha)-based antiviral therapy. Helical wheel modelling for HCV p7 was performed. RESULTS: No significant correlation of overall aa variations within HCV p7 was observed with response to IFN-alpha-based therapy with amantadine in HCV genotype 1alpha/b infected patients. When analysis was restricted to non-conservative aa variations, a higher number of aa substitutions within complete HCV p7 and transmembrane helix 2 was associated with non-response in HCV-1b-infected patients receiving therapy with amantadine (P=0.015 and P=0.037, respectively), without amantadine (P=0.106 and P=0.118, respectively), and in the total cohort of HCV-1b-infected patients (P=0.00007 and P=0.011, respectively). Furthermore, substitution L20F was observed more often in non-responders than responders with HCV-1b infection and therapy with amantadine (P=0.099). By in silico modelling, aa 20 was located toward the p7 channel lumen. Substitution L20F may impair amantadine action by altering the shape of the ion channel pore. CONCLUSION: Substitution L20F within HCV p7 may be associated with non-response to combination therapy specifically with amantadine in HCV-1b-infected patients. Non-responders with HCV-1b infection showed higher numbers of non-conservative aa variations within HCV p7 than responders, irrespective of the application of amantadine.     

Infantile hemangiomas are arrested in an early developmental vascular differentiation state.

Infantile hemangiomas, the most common tumors of infancy, are vascular tumors characterized by rapid proliferation of endothelial cells during the first few months of postnatal life followed by slow spontaneous involution, whose molecular pathogenesis remains unclear. The recent identification of developmental expression of vascular lineage-specific markers prompted us to characterize infantile hemangiomas for the expression of lymphatic endothelial hyaluronan receptor-1 (LYVE-1), Prox-1, CD31 and CD34. We found that LYVE-1, a specific marker for normal and tumor-associated lymphatic vessels, was strongly expressed in tumor cells of infantile hemangiomas (n=28), but not in other vascular tumors including pyogenic granulomas (n=19, P<0.0001) or intramuscular hemangiomas (n=9), using LYVE-1/CD31 double immunostains. Whereas LYVE-1 expression was detected on the endothelial cells of all proliferating infantile hemangiomas, this lymphatic marker was absent from the lesional capillaries during involution in the majority of cases (P=0.0009). The majority of LYVE-1(+) endothelial cells also expressed CD34, but were negative for the lymphatic-specific homeobox protein Prox-1. Based on coexpression of both LYVE-1 and the blood vascular marker CD34, we propose that the endothelial cells in proliferating infantile hemangioma are arrested in an early developmental stage of vascular differentiation. The immature, incompletely differentiated immunophenotype of proliferating infantile hemangiomas may contribute to their rapid growth during the first few months of life.     

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.