Retinoblastoma Expression in Thyroid Neoplasms

Abstract

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).

E2F-1 Transcription Factor Is Overexpressed in Oxyphilic Thyroid Tumors

“…The proliferative status and alterations of the cell cycle and retinoblastoma (Rb) pathway in oxyphilic and nonoxyphilic tumors have been assessed in several studies on thyroid cancer (7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21). Several studies on the proliferative activity of oxyphilic tumors demonstrated no differences from conventional follicular adenomas and carcinomas, both well differentiated and poorly differentiated (10,15,22).…”

Human thyroid tumours, the puzzling lessons from E7 and RET/PTC3 transgenic mice

“…Inactivation of these proteins results in a continuous growth of the thyroid, little affecting its differentiation, function and regulation (Iuliano et al, 2000). There is still a debate on RB1 function in human thyroid tumorigenesis with contradictory results on its loss or overexpression in papillary and follicular carcinomas vs adenomas (Anwar et al, 2000).…”

ONYX-411, a conditionally replicative oncolytic adenovirus, induces cell death in anaplastic thyroid carcinoma cell lines and suppresses the growth of xenograft tumors in nude mice

“…With respect to ATC, both RB and p53 status has been documented using various molecular techniques, 10,11,19 indicating that RB rather than p53 dysfunction occurs at higher frequency. The present study further emphasizes these observations, as eight of the nine cell lines tested had RB dysfunction, whereas only five of the nine cell lines exhibited p53 pathway dysfunction.…”

“…9 The RB pathway is impaired in its function in the majority of advanced human cancers, including ATC, regardless of whether RB itself is mutated or not. RB mutations in thyroid neoplasms have been documented in a small number of cases 10 and RB pathway dysfunction appears to be a common feature of thyroid cancer. 11 A number of strategies have been employed to target defects in this pathway with the hope of developing new therapeutics.…”