Defining the temporal evolution of gut dysbiosis and inflammatory responses leading to hepatocellular carcinoma in Mdr2 -/- mouse model.

BACKGROUND: Emerging evidence implicates the gut microbiome in liver inflammation and hepatocellular carcinoma (HCC) development. We aimed to characterize the temporal evolution of gut dysbiosis, in relation to the phenotype of systemic and hepatic inflammatory responses leading to HCC development. In the present study, Mdr2 -/- mice were used as a model of inflammation-based HCC. Gut microbiome composition and function, in addition to serum LPS, serum cytokines/chemokines and intrahepatic inflammatory genes were measured throughout the course of liver injury until HCC development. RESULTS: Early stages of liver injury, inflammation and cirrhosis, were characterized by dysbiosis. Microbiome functional pathways pertaining to gut barrier dysfunction were enriched during the initial phase of liver inflammation and cirrhosis, whilst those supporting lipopolysaccharide (LPS) biosynthesis increased as cirrhosis and HCC ensued. In parallel, serum LPS progressively increased during the course of liver injury, corresponding to a shift towards a systemic Th1/Th17 proinflammatory phenotype. Alongside, the intrahepatic inflammatory gene profile transitioned from a proinflammatory phenotype in the initial phases of liver injury to an immunosuppressed one in HCC. In established HCC, a switch in microbiome function from carbohydrate to amino acid metabolism occurred. CONCLUSION: In Mdr2 -/- mice, dysbiosis precedes HCC development, with temporal evolution of microbiome function to support gut barrier dysfunction, LPS biosynthesis, and redirection of energy source utilization. A corresponding shift in systemic and intrahepatic inflammatory responses occurred supporting HCC development. These findings support the notion that gut based therapeutic interventions could be beneficial early in the course of liver disease to halt HCC development.

Podophyllin reaction mimicking Bowen's disease in a patient with delusions of verrucosis.

A 40-year-old woman presented with a delusion of warts on the forehead, for which she was applying podophyllin toxin. A skin biopsy was taken, which showed prominent mitotic figures in the basal and suprabasal layers of the epidermis and apoptotic keratinocytes. Histopathologically Bowen's disease was suspected, but was discounted after clinicopathological correlation was obtained and showed absence of epidermal atypia or disorganization. This case demonstrates the histological resemblance of podophyllin reaction to Bowen's disease. Differentiation of self-inflicted from organic skin disease may be difficult, especially where histopathological findings are confounded by cutaneous application of toxins.

Squamous cell carcinoma arising in an eccrine hidrocystoma.

This report describes the case of a 63 yr old male with an enlarging lesion on the left cheek. Excision biopsy showed a squamous cell carcinoma arising from an eccrine hidrocystoma. The eccrine hidrocystoma showed foci of squamous metaplasia and the sequence of squamous metaplasia complicated by squamous carcinoma is postulated. Squamous differentiation in eccrine neoplasia is discussed.

Primary intracerebral small lymphocytic non-Hodgkin's lymphoma with plasmacytoid differentiation, associated with prominent extracellular proteinaceous deposits.

A case of primary intracerebral non-Hodgkin's lymphoma in a 67-yr-old immunocompetent female is presented. The histopathological diagnosis was supported by immunohistochemical, flow cytometric and electron microscopic findings, and by clinical staging. This tumor is unusual in its morphological features of a low grade, small lymphocytic lymphoma with plasmacytoid differentiation (Working Formulation Classification), and its association with extensive, local, extracellular, proteinaceous deposits. Primary central nervous system non-Hodgkin's lymphomas are briefly discussed and it is postulated that the extracellular proteinaceous deposits in this case originated from immunoglobulins secreted by the neoplastic cells. To our knowledge the massive degree of local immunoglobulin deposition present in this primary central nervous system lymphoma has not been previously reported in the literature.

Cytologic features of ductal carcinoma in situ.

Fourteen cases of both palpable and non-palpable breast lesions reported as possible ductal carcinoma in situ (DCIS) on fine-needle biopsy (FNB) over a 12-mo period were retrieved from our files and compared to the subsequent histologic diagnosis. Although a definite cytologic pattern of highly cellular smears with high grade nuclei, dissociation, and background necrosis with microcalcifications emerged for comedo DCIS, it was not possible to differentiate these on cytologic grounds from high grade infiltrating carcinoma with necrosis unless mammographic findings were taken into account. Useful criteria for non-comedo low grade DCIS were high cellularity, low grade nuclei, and architectural features of papillary and three dimensional (3D) fragments, palisade arrangements, and monolayer sheets with punched out glandular lumina. We conclude that FNB has a definite role in the diagnosis of these lesions, with the limitation that invasive malignancy can never be excluded on cytologic criteria alone and clinico-radiological correlation is paramount.