Autoimmune-like pulmonary disease in association with parvovirus B19: a clinical, morphologic, and molecular study of 12 cases.

Parvovirus B19, the agent responsible for fifth disease, has been emerging as a significant pathogenetic factor in various acute vasculitic syndromes such as Wegener's granulomatosis, Henoch-Schönlein purpura, and Kawasaki disease. It has also been implicated in more chronic vasculopathic syndromes, specifically in the context of scleroderma and dermatomyositis. The basis of this association is likely multifactorial; implicated mechanisms include the virus's affinity for endothelium, resulting in a state of neoantigenicity through varied mechanisms as well as the induction of tumor necrosis factor alpha, a factor involved in the propagation of ANCA-positive vasculitic syndromes. The authors present a series of 12 patients with interstitial lung disease including idiopathic pulmonary fibrosis, scleroderma-associated pulmonary fibrosis, lymphocytic interstitial pneumonitis, and septal capillaritis. In all cases there was evidence of chronic parvovirus B19 infection based on serologic assessment and the isolation of B19 DNA on lung samples in all patients. Furthermore, in two cases there was in situ localization of B19 RNA and tumor necrosis factor alpha to endothelium and stromal cells. On pathologic examination, there were varying degrees of both septal fibrosis and inflammation along with evidence of septal capillary injury. In those cases categorized as representing either scleroderma or idiopathic pulmonary fibrosis, the immunofluorescent studies showed evidence of anti-endothelial cell antibody formation. The ANCA-associated syndromes were, as expected, negative by fluorescent analysis. Significantly elevated factor VIII levels, a standard serologic index of endothelial cell injury, were seen in four of the six patients tested. The antiphospholipid profile revealed antiphospholipids in 7 of the 11 patients tested. This report highlights a possible causal role for parvovirus B19 in the pathogenesis of select pulmonary disorders.

Idiopathic pulmonary fibrosis related to endothelial injury and antiendothelial cell antibodies.

Mechanisms underlying idiopathic pulmonary fibrosis are not well understood. This paper presents data supporting the hypothesis that microvascular endothelial cell injury and antiendothelial cell antibodies play roles in human idiopathic pulmonary fibrosis. Serologic and pathologic features of 40 patients diagnosed with idiopathic pulmonary fibrosis were evaluated. All patients had open lung biopsies indicating either usual or nonspecific interstitial pneumonitis. All biopsies had morphologic evidence of microvascular injury to the endothelium, and direct immunofluorescence testing revealed variable deposition of IgG, IgM, or IgA within septal microvasculature suggestive of humorally mediated microvascular injury. Ultrastructural studies revealed changes of endothelial cell injury and necrosis and evidence of repetitive episodes of microvascular injury characterized by basement membrane zone collagen deposition and lamellation. Serum samples demonstrated reactivity to multiple endothelial cell antigenic epitopes, and indirect immunofluorescent testing demonstrated a prominent pattern of fluorescence in pulmonary endothelial cell preparations. Serum samples were positive in 37/40 patients for antiphospholipid antibodies with one fourth having positive lupus anticoagulant tests accompanied by thrombotic episodes. In patients with idiopathic pulmonary fibrosis, Factor VIII levels and C-reactive protein levels were also elevated, supporting the presence of endothelial cell injury and inflammation. These data underscore a potential role for immune-based microvascular injury in the evolution of usual or nonspecific interstitial pneumonitis and indicate that those patients have evidence of microvascular injury and endothelial cell necrosis. The high prevalence of antiphospholipid antibodies in these patients may lead to an inherent thrombophilic tendency.

The absence of CD20 messenger RNA in recurrent cutaneous B-cell lymphoma following rituximab therapy.

BACKGROUND: Rituximab has been used to treat relapsed low-grade or advanced non-Hodgkin's lymphoma since 1997, targeting the CD20 antigen expressed by B cells. Single-agent rituximab therapy is safe and well tolerated. Recurrences showing a loss of CD20 expression following rituximab therapy have been reported. METHODS: Four patients with CD20-positive cutaneous B-cell lymphoma received rituximab therapy with subsequent recurrences. The biopsies were assessed for cytoplasmic CD20 expression; CD20 messenger RNA was also assessed where tissue was available. RESULTS: Cutaneous relapses occurring within 1.5-3 months following the last dose of rituximab were CD20 negative. In three cases, subsequent relapses showed renewed expression of CD20. Those biopsies demonstrating a loss of surface and cytoplasmic CD20 by immunohistochemistry also showed no evidence of messenger RNA for CD20 using an in situ polymerase chain reaction-based methodology. CONCLUSIONS: Rituximab may be associated with the emergence of CD20-negative B-cell clones, potentially rendering a tumor insensitive to this drug. Conversely, following cessation of the drug, a re-expression of CD20 within the neoplastic cells may occur allowing therapeutic intervention with this monoclonal antibody. The loss of CD20 expression appears to be a direct effect of the drug on CD20 messenger RNA synthesis.

De novo intraepidermal epithelioid melanocytic dysplasia as a marker of the atypical mole phenotype -- a clinical and pathological study of 75 patients.

BACKGROUND: We encountered a distinctive pattern of dysplastic intraepidermal melanocytic proliferation, which defies classification as a dysplastic melanocytic nevus, but in which the morphologic features fall short of a diagnosis of melanoma in situ. We designate such lesions as de novo intraepidermal epithelioid melanocytic dysplasia. METHODS: From 75 patients, 82 skin biopsies were encountered that showed this distinctive morphology. Hematoxylin- and eosin-stained histologic sections were studied and the features were correlated with personal and family histories of dysplastic nevi and melanoma. RESULTS: The diagnosis of de novo melanocytic dysplasia was made in 27 male patients and 48 female patients (mean age: 44 years). The histologic hallmark was a pagetoid (single-cell) array of moderately to severely atypical epithelioid melanocytes within the epidermis. Seventy-three lesions were located on sun-exposed skin and nine on sun-protected skin. In 41 patients, there was an atypical mole phenotype, whereas 20 patients had a prior or subsequent diagnosis of melanoma with five of 16 patients questioned revealing a family history of melanoma. CONCLUSIONS: De novo intraepidermal epithelioid melanocytic dysplasia is a distinct entity associated with an atypical mole phenotype and a personal and/or family history of melanoma.

Epstein--Barr virus-associated B-cell lymphoma in the setting of iatrogenic immune dysregulation presenting initially in the skin.

BACKGROUND: Epstein-Barr virus (EBV) has been implicated in B-cell lymphoma associated with iatrogenic immune dysregulation, primarily in the context of extracutaneous lymphoma. METHODS: We describe six patients, five transplant recipients receiving cyclosporine and one patient with rheumatoid arthritis receiving methotrexate, who developed cutaneous presentations of EBV-associated B-cell lymphoma. Human herpesvirus 8 (HHV8) and EBV thymidine kinase (vTK) expression were also explored. RESULTS: The cases comprised plasmablastic lymphoma (one case), plasmacytic marginal zone lymphoma (two cases), and diffuse large B-cell lymphoma (three cases). There was a monoclonal gammopathy in one and concurrent extracutaneous disease in two of the six patients. EBV-associated latent small nuclear RNA was detected in all cases with coexpression of HHV8 in one of the five cases and of vTK in three of the six cases. Three patients responded to a reduction in the immunosuppressive regimen and antiviral therapy. Recurrent disease developed in two, with one patient succumbing to multiorgan dissemination. CONCLUSIONS: EBV-associated cutaneous B-cell lymphoma is characterized by a long interval between the initiation of immunosuppression and the development of lymphoma. Although previous reports have reported an indolent clinical course, an aggressive clinical course may occur. HHV8 and lytic phase EBV antigens are detected in some cases, possibly suggesting a pathogenetic role.

Chondrodermatitis nodularis helicis as a marker of internal disease [corrected] associated with microvascular injury.

Chondrodermatitis nodularis helicis (CNH) is held to be an idiopathic degenerative process involving the upper dermis of the auricular rim. Chondrodermatitis typically occurs in elderly men where associations with underlying trauma and sun exposure have been postulated as potential inciting triggers. Its association as a marker of systemic disease is not well established. We describe 24 patients with CNH, in whom there were also significant underlying diseases largely associated with vascular injury including those of immune-based etiology and/or conditions which have been previously linked with granuloma annulare, another necrobiotic process of collagen. These patients with concomitant systemic disease were characteristically younger compared to the classic demographics described for CNH. In some cases, chondrodermatitis may represent an ischemic necrobiotic disorder of collagen, potentially defining an important sign of underlying systemic disease in younger patients.

Light-chain-restricted plasmacellular infiltrates in necrobiosis lipoidica -- a clue to an underlying monoclonal gammopathy.

BACKGROUND: Necrobiosis lipoidica (NL) is a member of the palisading granulomatous dermatitides that is associated, in most cases, with diabetes mellitus. However, there are an increasing number of cases of NL associated with other forms of systemic disease. We describe a novel case of NL associated with a light-chain-restricted plasmacellular infiltrate; subsequent investigations established an underlying monoclonal gammopathy. METHODS: Skin biopsy material was obtained and was processed in the usual fashion for hematoxylin and eosin (H and E) examination. Immunohistochemical staining was performed by utilizing kappa and lambda monoclonal antibodies (Dako Corporation, Carpentiera, CA, USA). Kappa and lambda in situ hybridization was also performed (Ventana Medical Systems, Tucson, AZ, USA). RESULTS: A 55-year-old woman with a 5-year history of bilateral thigh subcutaneous nodules underwent a skin biopsy, showing typical changes of NL; there was a concomitant prominent perivascular plasmacellular infiltrate. Kappa light chain restriction was observed amid the plasmacellular infiltrate. Bone marrow biopsy and immunophenotyping studies revealed a clonal plasmacytosis with kappa light chain restriction. CONCLUSIONS: Granulomatous inflammation, including NL, may be a cutaneous paraneoplastic expression of low-grade B-cell lymphoproliferative disease in the context of an underlying plasma cell dyscrasia.