BRAF V600E mutation has emerged as a marker of aggressive behavior in papillary thyroid carcinoma but its significance in microcarcinoma is not entirely clear. One-hundred and twenty-nine papillary thyroid microcarcinomas were tested for BRAF V600E mutation by single-strand conformation polymorphism, and their clinicopathologic features (age, sex, tumor size, multifocality, nodal metastases, histologic subtype, tumor cell morphology, architecture, tumor-associated stromal reaction, tumor interface to non-neoplastic thyroid (well circumscribed vs infiltrative), extrathyroidal extension, lymphovascular invasion, intratumoral multinucleated giant cells, and adjacent non-neoplastic thyroid pathology) were examined. Compared with tumors without the mutation (39/129, 30%), the mutated microcarcinomas (90/129, 70%) showed significantly higher prevalence of infiltrative tumor borders (78/90 vs 23/39, P ¼ 0.001), tumor-associated stromal desmoplasia/fibrosis and/or sclerosis (80/90 vs 25/39, P ¼ 0.002), classic nuclear features of papillary thyroid carcinoma (90/90 vs 35/39, P ¼ 0.008) and cystic change (43/90 vs 11/39, P ¼ 0.05). BRAF V600E mutation was more frequent in classic (75%), tall cell (91%), and other variants (470%) than in follicular variant (21%) of papillary thyroid microcarcinoma. Tumors without the mutation were significantly more likely to be solid, well circumscribed, and lacked desmoplasia/fibrosis or sclerosis. However, on multivariate analysis, only the follicular variant of papillary microcarcinoma was significantly associated with the absence of mutation (odds ratio (95% confidence interval): 0.09 (0.01-0.54)). Lymph node metastases (n ¼ 24) were more frequent in microcarcinomas with mutation than without (21/24 vs 3/24, P ¼ 0.02). All patients with lateral cervical node metastasis (n ¼ 9), and all but one tumor with extrathyroidal extension (n ¼ 17/18) showed BRAF V600E mutation. No significant differences were noted in age, sex, tumor size, multifocality, lymphovascular invasion, psammoma bodies, stromal calcification, intratumoral multinucleated osteoclastic-type giant cells, and lymphocytic infiltration between the two groups of tumors. BRAF V600E mutation is an early event in thyroid carcinogenesis, and is associated with distinctive morphology and aggressive features even in papillary thyroid microcarcinomas.

Background & objectivesHepatocellular carcinoma (HCC) is the second leading cause of cancer death worldwide. Several types of chronic liver disease predispose to HCC, and several different signalling pathways have been implicated in its pathogenesis, but no common molecular event has been identified. Ca2+ signalling regulates the proliferation of both normal hepatocytes and liver cancer cells, so we investigated the role of intracellular Ca2+ release channels in HCC.DesignExpression analyses of the type 3 isoform of the inositol 1, 4, 5-trisphosphate receptor (ITPR3) in human liver samples, liver cancer cells and mouse liver were combined with an evaluation of DNA methylation profiles of ITPR3 promoter in HCC and characterisation of the effects of ITPR3 expression on cellular proliferation and apoptosis. The effects of de novo ITPR3 expression on hepatocyte calcium signalling and liver growth were evaluated in mice.ResultsITPR3 was absent or expressed in low amounts in hepatocytes from normal liver, but was expressed in HCC specimens from three independent patient cohorts, regardless of the underlying cause of chronic liver disease, and its increased expression level was associated with poorer survival. The ITPR3 gene was heavily methylated in control liver specimens but was demethylated at multiple sites in specimens of patient with HCC. Administration of a demethylating agent in a mouse model resulted in ITPR3 expression in discrete areas of the liver, and Ca2+ signalling was enhanced in these regions. In addition, cell proliferation and liver regeneration were enhanced in the mouse model, and deletion of ITPR3 from human HCC cells enhanced apoptosis.ConclusionsThese results provide evidence that de novo expression of ITPR3 typically occurs in HCC and may play a role in its pathogenesis.

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We describe a time series analysis that differentiates the effects of variable larval supply and the mortality impact of shell disease on cohorts of the American lobster Homarus americanus in a southern New England, USA, coastal population. Prior to the onset of a shell disease epizootic in 1997, larval settlement alone fully explained 82% of the variation in the numbers of pre-recruit lobsters about to enter the Rhode Island lobster fishery. With the onset of shell disease, however, the model required an additional term for disease prevalence to provide a sufficient statistical fit to the observed data. Neither time trends in bottom temperature nor predatory fish provided significant additional explanatory power for variability in pre-recruit abundance. To our knowledge, this analysis constitutes the first demonstration in which cohorts of a benthic marine invertebrate have been successfully tracked from settlement to the threshold of a fishery by accounting for the joint effects of variable supply of new recruits and subsequent disease during post-settlement years. As such, it illustrates how factors altering the rate of post-settlement mortality over time can obscure predictive relationships between settlement and subsequent recruitment. A tight spawner-to-recruit linkage is therefore unlikely in coastal Rhode Island. The analysis underscores the value of maintaining parallel time series of different life stages, as well as the need to better quantify both pre-and post-settlement mechanisms that influence cohort success in marine populations.

Podoplanin, recognized by monoclonal antibody D2-40, may be a useful marker for follicular dendritic cell (FDC) tumors. Paraffin sections of 125 dendritic cell, histiocytic, and spindle cell lesions were studied, including 11 FDC tumors, 5 interdigitating dendritic cell tumors, 10 histiocytic sarcomas, 5 Langerhans cell histiocytosis, 5 sinus histiocytosis with massive lymphadenopathy, 5 inflammatory pseudotumors of lymph node or spleen, 9 nodal Kaposi sarcomas, 6 inflammatory myofibroblastic tumors (IMTs), 29 gastrointestinal stromal tumors (GISTs), and 10 cases each of malignant peripheral nerve sheath tumor, leiomyosarcoma, monophasic synovial sarcoma (SS), and solitary fibrous tumor. All FDC tumors and Kaposi sarcomas showed strong immunoreactivity for podoplanin (predominantly membranous). Podoplanin expression was only occasionally observed in the other tumor types, including 7 GISTs (24%), 2 IMTs (33%), and 3 SS (30%), and was generally weak and cytoplasmic. Reactivity for podoplanin was more common in spindle cell GISTs (5/13 [38%]) than in epithelioid or mixed-type GISTs (2/16 [13%]). Podoplanin is a highly sensitive marker for FDC tumors and may be useful to help confirm the diagnosis in conjunction with conventional FDC markers, particularly in the differential diagnosis of dendritic cell and histiocytic lesions.