—  SYMPOSIUM #35  —

Controversies in Thyroid Pathology
Moderators: Dr. Thomas Giordano and Dr. Paul Komminoth

Section 5 - Controversies in Molecular Thyroid Pathology

Thomas J. Giordano
Department of Pathology
University of Michigan Health System


Background
Over the last 2 decades, our understanding of the molecular biology of follicular cell thyroid tumors has improved considerably to the point that the field is on the brink of a therapeutic transformation. Yet, there are many unanswered questions and issues that remain controversial. In this presentation, selected controversial issues regarding the molecular biology of follicular cell thyroid tumors are presented.

Papillary Carcinoma
Our increased understanding of the pathogenesis of papillary thyroid carcinoma (PC) reflects the fact that it is the most common malignant thyroid tumor. Much has been learned since the initial description of RET/PTC rearrangements [1, 2, 3]. It is now appreciated that several mutations in a variety of genes (i.e. RET/PTC, NTRK, NRAS, HRAS, KRAS, and BRAF) all function to activate the mitogen-activated protein kinase (MAPK) signaling pathways [4, 5]. The mutations are essentially mutually exclusive, providing strong evidence that a mutation in the pathway is required for the development of PC and that there is no benefit for the cancer cell of having more than mutation in the MAPK pathway. Yet, the mutations are not entirely equivalent. It has been known for some time that a correlation exists between specific mutations and various pathologic characteristics and clinical behavior. For example, the follicular variant of PC contains a high frequency of RAS mutations [6, 7]. Conversely, PCs with BRAF mutations usually have a classic or tall cell appearance and are associated with a more aggressive clinical course [8], although other reports are not in agreement [9, 10].

So some of the remaining questions include the following: What is the true significance of BRAF mutation? Should PC be considered one disease with variants or should the variants be considered as distinct entities? Should PC with different mutations be treated differently? What other mutations exist in well-differentiated PC?

Follicular Carcinoma
Our understanding of the pathogenesis of follicular thyroid carcinoma (FC) is less developed compared to that of PC. However, molecular studies are beginning to shed some light on this tumor. FCs contain 2 predominant mutations [11]. As with PC, these tumors contain point mutation of RAS genes. More recently, these tumors have been shown to contain a translocation between the PAX8 and PPARg genes, resulting in a fusion gene that expresses a fusion protein designated PPFP [12]. While it not exactly clear how this fusion protein contributes to the pathogenesis of FC, several recent studies have begun to shed light on the issue [13, 14, 15, 16] and will be discussed.

Meaning of PAX8-PPARg translocation
Another aspect to the PAX8-PPARg issue is whether this translocation is confined to FC or found in other tumor types such as follicular adenoma (FA) or PC. Several studies have found this translocation in FAs [17, 18, 19], raising the possibility of follicular carcinoma in situ, a controversial diagnostic entity. One could argue that tumors with this translocation are pathologically malignant by definition but have not yet manifested their ability to invade and metastasize.

Another unresolved issue is whether this translocation exists in PC. A recent study using FISH technology found the translocation in a significant percentage of the follicular variant of PCs [20]. However, other gene expression studies [13, 14] have found strikingly distinct gene expression profiles in FCs with the PAX8-PPARg translocation compared to a large cohort of other types of thyroid tumors including PC. Thus, there is conflicting data on this translocation depending on the technology employed.

So some of the remaining controversies in FC include the following questions?

Is the PAX8-PPARg translocation a true marker of malignancy? Is yes, does this provide support for a diagnostic entity of follicular carcinoma in situ? What is the best method for PAX8-PPARg screening?

Is the PAX8-PPARg translocation found in other types of thyroid tumors?

How does the PAX8-PPARg translocation contribute to neoplastic transformation?

RAS Mutations
RAS mutations have been found in a variety of thyroid tumors. Clearly, the follicular variant of papillary carcinoma is strongly associated with RAS mutations [6, 7] and they are also found in a subset of follicular carcinoma (those without the PAX8-PPARg translocation) [21]. This raises the following fundamental question: what is the relationship between the follicular variant of papillary carcinoma and follicular carcinoma with RAS mutations? Are they truly distinct diagnostic entities or might they represent the end of a single diagnostic spectrum? Recent gene expression profiles studies from our laboratory suggest that they are closely related but do have different gene expression profiles.

Conclusion
There remains much to learn regarding well-differentiated follicular cell thyroid carcinoma. However, the application of high-throughput comprehensive molecular technologies should help to resolve many of these issues in the coming years. Stay tuned for exciting developments!

Suggested Review Articles
  1. Kondo T, Ezzat S, Asa SL. Pathogenetic mechanisms in thyroid follicular-cell neoplasia. Nat Rev Cancer 2006;6(4):292-306.

  2. Kroll TG. Molecular events in follicular thyroid tumors. Cancer Treat Res 2004;122:85-105.

  3. Sobrinho-Simoes M, Preto A, Rocha AS, et al. Molecular pathology of well-differentiated thyroid carcinomas. Virchows Arch 2005;447(5):787-93.

  4. Tallini G. Molecular pathobiology of thyroid neoplasms. Endocr Pathol 2002;13(4):271-88.


References
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  2. Jhiang SM, Mazzaferri EL. The ret/PTC oncogene in papillary thyroid carcinoma. J Lab Clin Med 1994;123(3):331-7.

  3. Fusco A, Santoro M, Grieco M, et al. RET/PTC activation in human thyroid carcinomas. J Endocrinol Invest 1995;18(2):127-9.

  4. Kimura ET, Nikiforova MN, Zhu Z, Knauf JA, Nikiforov YE, Fagin JA. High prevalence of BRAF mutations in thyroid cancer: genetic evidence for constitutive activation of the RET/PTC-RAS-BRAF signaling pathway in papillary thyroid carcinoma. Cancer Res 2003;63(7):1454-7.

  5. Soares P, Trovisco V, Rocha AS, et al. BRAF mutations and RET/PTC rearrangements are alternative events in the etiopathogenesis of PTC. Oncogene 2003;22(29):4578-80.

  6. Di Cristofaro J, Marcy M, Vasko V, et al. Molecular genetic study comparing follicular variant versus classic papillary thyroid carcinomas: association of N-ras mutation in codon 61 with follicular variant. Hum Pathol 2006;37(7):824-30.

  7. Adeniran AJ, Zhu Z, Gandhi M, et al. Correlation between genetic alterations and microscopic features, clinical manifestations, and prognostic characteristics of thyroid papillary carcinomas. Am J Surg Pathol 2006;30(2):216-22.

  8. Xing M, Westra WH, Tufano RP, et al. BRAF mutation predicts a poorer clinical prognosis for papillary thyroid cancer. J Clin Endocrinol Metab 2005;90(12):6373-9.

  9. Liu RT, Chen YJ, Chou FF, et al. No correlation between BRAFV600E mutation and clinicopathological features of papillary thyroid carcinomas in Taiwan. Clin Endocrinol (Oxf) 2005;63(4):461-6.

  10. Kim TY, Kim WB, Song JY, et al. The BRAF mutation is not associated with poor prognostic factors in Korean patients with conventional papillary thyroid microcarcinoma. Clin Endocrinol (Oxf) 2005;63(5):588-93.

  11. Nikiforova MN, Lynch RA, Biddinger PW, et al. RAS point mutations and PAX8-PPARg rearrangement in thyroid tumors: evidence for distinct molecular pathways in thyroid follicular carcinoma. J Clin Endocrinol Metab 2003;88(5):2318-26.

  12. Kroll TG, Sarraf P, Pecciarini L, et al. PAX8-PPARg1 fusion oncogene in human thyroid carcinoma [corrected]. Science 2000;289(5483):1357-60.

  13. Lacroix L, Lazar V, Michiels S, et al. Follicular thyroid tumors with the PAX8-PPARg1 rearrangement display characteristic genetic alterations. Am J Pathol 2005;167(1):223-31.

  14. Giordano TJ, Au AY, Kuick R, et al. Delineation, functional validation, and bioinformatic evaluation of gene expression in thyroid follicular carcinomas with the PAX8-PPARg translocation. Clin Cancer Res 2006;12(7 Pt 1):1983-93.

  15. Foukakis T, Au AY, Wallin G, et al. The Ras effector NORE1A is suppressed in follicular thyroid carcinomas with a PAX8-PPARg fusion. J Clin Endocrinol Metab 2006;91(3):1143-9.

  16. Au AY, McBride C, Wilhelm KG, Jr., et al. PAX8-peroxisome proliferator-activated receptor gamma (PPARg) disrupts normal PAX8 or PPARg transcriptional function and stimulates follicular thyroid cell growth. Endocrinology 2006;147(1):367-76.

  17. Marques AR, Espadinha C, Catarino AL, et al. Expression of PAX8-PPARg1 rearrangements in both follicular thyroid carcinomas and adenomas. J Clin Endocrinol Metab 2002;87(8):3947-52.

  18. Cheung L, Messina M, Gill A, et al. Detection of the PAX8-PPARg fusion oncogene in both follicular thyroid carcinomas and adenomas. J Clin Endocrinol Metab 2003;88(1):354-7.

  19. Dwight T, Thoppe SR, Foukakis T, et al. Involvement of the PAX8/peroxisome proliferator-activated receptor gamma rearrangement in follicular thyroid tumors. J Clin Endocrinol Metab 2003;88(9):4440-5.

  20. Castro P, Rebocho AP, Soares RJ, et al. PAX8-PPARg rearrangement is frequently detected in the follicular variant of papillary thyroid carcinoma. J Clin Endocrinol Metab 2006;91(1):213-20.

  21. Fukushima T, Takenoshita S. Roles of RAS and BRAF mutations in thyroid carcinogenesis. Fukushima J Med Sci 2005;51(2):67-75.