Cyclin D1 and E2F-1 proteins are essential for the regulation of the G1/S transition through the cell cycle. Cyclin D1, a product of the bcl-1 gene, phosphorylates the retinoblastoma protein, releasing E2F-1, which in turn activates genes involved in DNA synthesis. Expression patterns of E2F-1 protein in thyroid proliferations have not been reported. This study used monoclonal antibodies for cyclin D1 and E2F-1 proteins to immunostain sections of normal thyroid, hyperplastic (cellular) nodules, follicular adenomas, follicular carcinomas, and papillary carcinomas. The proliferation rate was examined using an antibody specific for the Ki-67 antigen. Fluorescence in situ hybridization (FISH) methods and chromosome 11-specific probes were also employed to determine chromosome copy number and to assess for evidence of amplification at the 11q13 locus in papillary and follicular carcinomas with cyclin D1 overexpression. Concurrent overexpression of Ki-67, cyclin D1, and E2F-1 was found in the majority of benign and malignant thyroid lesions, compared with normal thyroid tissue. Cyclin D1 up-regulation was not due to extra copies of chromosome 11, or bcl-1 gene amplification. Malignant tumours showed the highest expression for all three markers, particularly papillary carcinomas. E2F-1 was detected at the same or slightly lower levels than cyclin D1. It was only found when cyclin D1 was overexpressed. Because cyclin D1 normally activates E2F-1, up-regulation of cyclin D1 may lead to E2F-1 overexpression in benign and malignant thyroid lesions.

The role of cell cycle protein expression in gestational trophoblastic disease is poorly understood. In this study we investigated the immunostaining patterns of G 1 restriction point and G 1 -S regulatory proteins E2F-1, Cdk2, cyclin E, p27 kip1 , and the proliferation marker Ki-67 on routinely processed sections of 29 hydatidiform moles (10 partial moles and 19 complete moles, including 9 persistent moles), 7 choriocarcinomas, and 7 normal placentas. Ki-67 trophoblast staining decreased with increasing gestational age of the placenta, and showed maximal expression in gestational trophoblastic disease. Cyclin-dependent kinase activity, as reflected by Cdk2 expression patterns, also decreased with placental maturation. E2F-1 was uniquely expressed by trophoblasts of moles and choriocarcinoma. Cyclin E was maximally expressed by complete moles and choriocarcinomas, and showed an inverse relationship with the cyclin-dependent kinase inhibitor p27 kip1 . Abnormal trophoblastic proliferations may be mediated through interactions of Cdk-2, E2F-1, cyclin E, and p27 kip1 . Overexpression of cyclin E was associated with more aggressive forms of gestational trophoblastic disease. However, we did not find distinguishing features between complete moles that spontaneously resolved after evacuation and persistent moles that required chemotherapy. The different expression patterns of cyclin E and E2F-1 in partial and complete moles may be useful in distinguishing these two entities. Furthermore, loss of p27 kip1 in malignant trophoblast may represent a necessary step in the development of choriocarcinoma.KEY WORDS: Cdk2, Choriocarcinoma, Cyclin E, E2F-1, Ki-67, p27 kip1 , Trophoblast.Mod Pathol 2001;14(10)

BACKGROUND Fine‐needle aspiration (FNA) of the thyroid is of limited value in discriminating between nonneoplastic and neoplastic lesions in approximately 5–29% of patients. Indeterminate lesions are due primarily to the overlapping cytologic features found in follicular lesions. In this report, the authors describe their experience with FNA biopsy of the thyroid, concentrating on the analysis of those aspirates placed in the follicular lesion category. METHODS A blinded, retrospective analysis of 92 patients who underwent FNA and were diagnosed with follicular lesions was performed by three of the authors (T.S.G., B.D.F., and M.O.) at a multihead microscope. A worksheet assessing a variety of cytologic and architectural features was filled out for each FNA patient. The reviewers then reached a consensus diagnosis. RESULTS The reviewers agreed with the reported FNA diagnosis of follicular lesion in 63 of the 92 patients studied. No distinguishing cytologic features predictive of the histologic outcome were found in any of these 63 patients. Seven patients were judged by the reviewers to have insufficient cells for evaluation. In the remaining 22 patients, the reviewers' diagnoses were in agreement with the histologic diagnoses in 17 patients. CONCLUSIONS The authors found that there is a gray area in the cytologic diagnosis of patients with thyroid lesions by FNA due to inherent similarities at the light microscopic level. However, increased specificity may be achieved by careful attention to cytologic features and morphologic detail. Skillful application of FNA techniques, with the recovery of an adequate sample, will further decrease both interpretive errors and the number of patients diagnosed with “follicular lesions.” Cancer (Cancer Cytopathol) 2000;90:335–341. © 2000 American Cancer Society.

These findings suggest that oxynto-cardiac mucosa occurs in a low damage environment and intestinal metaplasia in a high damage environment along the length of the columnar lined oesophageal segment. Aberrant proliferative patterns with Ki67 staining are not useful in differentiating reactive epithelia from low-grade dysplasia, but may prove useful in the diagnosis of high-grade dysplasia.

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