Retinoblastoma (Rb) mutation in thyroid neoplasia has been identified in a few molecular studies; however, the utility of Rb immunohistochemistry in distinguishing benign and malignant thyroid lesions has not been documented in formalin-fixed, paraffin-embedded tissues. The present study investigated Rb immunohistochemistry in a series of 111 formalin-fixed, paraffin-embedded benign and malignant thyroid lesions. All of the major histologic subtypes were included to detect any heterogeneity in Rb-1 expression that might influence the diagnostic utility of this technique or further elucidate the pathogenesis of thyroid neoplasia among the categories. Altogether, 34 follicular adenomas, 9 follicular carcinomas, 7 Hürthle cell adenomas, 5 Hürthle cell carcinomas, 23 papillary carcinomas (8 of which were follicular variants), 4 insular carcinomas, 4 anaplastic carcinomas, 6 medullary carcinomas, and 19 nodular goiters were analyzed. Avidinbiotin immunohistochemistry was performed using the Dako Rb-1 clone. Pronase digestion was introduced into the epitope retrieval protocol to eliminate false-positive cytoplasmic staining. Retinoblastoma (Rb) was the first discovered tumor-suppressor gene (1-3). It maps to chromosome 13q14 and encodes a 110 -114 KD nuclear protein that plays a major role in the regulation of cell growth arrest (4 -6). Rb protein product (P-Rb) is expressed in all cells, where it exists in an active hypophosphorylated and an inactive hyperphosphorylated state. In its active state, P-Rb serves as a brake on the advancement of cells from G1 to S phase of the cell cycle. When the cells are stimulated by growth factors, Rb protein is inactivated by phosphorylation, allowing the cells to transverse the G1-S checkpoint. Once cells enter the S phase, they are committed to divide. During the ensuing M phase, phosphate groups are removed from P-Rb by cellular phosphatases, thus regenerating the active hypophosphorylated form of the protein (5-8).The hypophosphorylated P-Rb achieves cell cycle arrest by forming a complex with the E2F family of transcription factors. These complexes bind to DNA and actively inhibit the transcription of S-phase genes, thereby preventing cell division (5-9). Germline loss or mutation of the Rb gene predisposes to the development of retinoblastoma and to a lesser extent osteosarcoma. Its role in the pathogenesis of retinoblastoma has been elegantly explained by Knudson's two-hit hypothesis (2). Furthermore, somatically acquired Rb mutations have been described in glioblastomas; sarcomas; small cell and non-small cell carcinomas of the lung; and breast, prostatic, and bladder carcinomas (10 -20).
The pathogenesis of ganciclovir-resistant cytomegalovirus (CMV) was investigated by analysing UL97 and gB sequences in tissues obtained from 4 immunocompromised patients with infections caused by ganalciclovir-resistant virus. UL97 and gB sequences were obtained by automated sequencing of CMV DNA amplified from lysates prepared from deparaffinized tissue sections. Patient 1 contained wild-type UL97 and gB3 sequences. Patient 2 harboured genetically distinct viruses in his lung: one with a ganciclovir-resistance UL97 mutation and a gB3 genotype, and another without UL97 mutations and a gB1 genotype. In patient 3, a ganciclovir-resistant UL97 mutant virus with a gB1 genotype was cultured from the lung, whereas the CMV in the brain did not contain mutations and its genotype was gB2. In patient 4, ganciclovir-resistance UL97 sequences were found in oesophageal tissue prior to the isolation of a ganciclovir-resistant CMV from the blood. All viruses in this patient had a gB3 genotype. CMV containing ganciclovir-resistance UL97 mutations may cause end-organ disease in immunocompromised individuals. In these subjects, CMV circulating in the blood may have similar or different UL97 and gB genotypes than the virus causing end-organ disease.
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