Anatomic Pathology / RET AND FOLLICULAR THYROID LESIONS

نویسندگان

  • Lisa A. Cerilli
  • Stacey E. Mills
  • Craig A. Rumpel
  • Thomas H. Dudley
  • Christopher A. Moskaluk
چکیده

We applied monoclonal antibodies against RET and cytokeratin 19 (CK19) to the following tumor sections: classic papillary carcinoma (PC), 16; Hürthle-type PC (HPC), 1; sclerosing PC with nodular fasciitis–like stroma (SPC), 1; PC, follicular variant (FVPC), 12; follicular adenoma (FA), 9; Hürthle cell adenoma (HA), 4; Hürthle cell carcinoma (HC), 3; and follicular carcinoma (FC), 7. CK19+ tumors included 16 PCs, 1 HPC, 1 SPC, 11 FVPCs, 7 FAs, 4 FCs, and 1 HC. RET+ tumors included 4 HAs, 3 HCs, 1 HPC, 12 PCs, 7 FVPCs, and 2 FAs. Reverse transcriptase–polymerase chain reaction (RT-PCR) revealed a RET transcript in 6 Hürthle cell lesions. RET immunoreactivity is less sensitive and specific for PC than CK19. CK19 is useful for identifying PC, although only lesions with diffuse, intense staining should be considered positive. The detection of RET protein by immunohistochemical analysis was corroborated by the presence of the RET transcript by RT-PCR. Further study is warranted to determine whether this represents activation by gene fusion or some other mechanism in this subset of thyroid neoplasms. Neoplasms of the thyroid frequently present diagnostic challenges. Although the question often focuses on whether criteria are sufficient to warrant a diagnosis of encapsulated follicular carcinoma (FC) as opposed to follicular adenoma (FA), the distinction of follicular lesions from the follicular variant of papillary carcinoma (PC) can be equally problematic. The separation of follicular variants of PC from other follicular lesions continues to rely solely on morphologic criteria. Differential cytokeratin profiles as detected by immunohistochemical analysis have been proposed as adjuvant diagnostic tests.1-5 Specifically, cytokeratin 19 (CK19) has become an accepted marker to help distinguish PC from FA.1-6 Because no single marker is completely sensitive or specific, additional agents to facilitate the distinction of the follicular variant of PC from follicular mimics continue to be sought. The sporadic form of PC of the thyroid is associated with an oncogenic form of RET, a tyrosine kinase involved in signal transduction. The RET gene is activated by rearrangement with one of several different genes, resulting in the fusion of the RET tyrosine-kinase domain to a 5' terminal region of one of the heterologous genes. This creates a RET/PTC product with constitutive kinase activity.7,8 The development of the RET/PTC oncogene is believed to be oncogenic for PC. Transgenic mice carrying the RET/PTC oncogene develop thyroid tumors with a papillary pattern and classic nuclear features identical to papillary tumors in humans.9,10 Interestingly, not all transgenic mice developed thyroid tumors, implying that the expression of the oncoprotein is necessary but not sufficient for tumorigenesis. Conversely, wide differences in the prevalence of RET/PTC rearrangements in human PC have been reported, ranging from 5% to 67%.11-18 Clearly tumorigenesis involves multiple Anatomic Pathology / ORIGINAL ARTICLE Am J Clin Pathol 2002;118:186-193 187 © American Society for Clinical Pathology “hits,” and other genetic lesions are likely involved in the development of some cases of PC. The diagnostic potential of the RET oncogene for pathologists lies in its reported specificity for PCs.14 Studies using in situ hybridization have detected RET messenger RNA in 43% of PCs and its absence in FCs, FAs, nodular hyperplasias, and normal thyroid.14,18 Close correlation between reverse transcriptase–polymerase chain reaction (RT-PCR) detection of RET/PTC and immunohistochemical detection of ret protein product has been observed.1,9 It follows that immunohistochemical detection of the RET protein may serve as a useful adjunct for the diagnosis of PC, particularly in variant forms that are challenging by routine light microscopy. By using immunohistochemical analysis and RT-PCR, we assessed a variety of follicular lesions for the presence of ret protein product. Materials and Methods

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تاریخ انتشار 2002