Skip to main content
SpringerLink
Log in

Loss of heterozygosity mutations to tumor suppressor genes in cytologically atypical areas in chronic lymphocytic thyroiditis

  • Clinical Research
  • Published:
Endocrine Pathology Aims and scope Submit manuscript

Abstract

The relationship between chronic lymphocytic thyroiditis (CLT) and papillary thyroid carcinoma (PTC) is a subject of controversy. Some investigators suggest a causal relationship, whereas others regard the two as only a coincidental occurrence. An additional complicating factor is the presence of atypical nuclei frequently found within lymphoid infiltrates in CLT, which resemble those in PTC. The finding of the RET-PTC translocations in CLT has been reported by two independent groups of investigators, suggesting that the areas of nuclear atypia in CLT are neoplastic rather than reactive. In the present study, we report additional molecular findings that support the hypothesis that the atypical nuclear changes in CLT may be preneoplastic or neoplastic. We microdissected small areas with atypical nuclei in glands with CLT and observed loss-of-heterozygosity mutations of tumor suppressor genes. These genetic mutations are evidence of clonal preneoplastic or neoplastic changes in the follicular cells of CLT. The clinical malignant potential of these minute foci is likely to be very small but remains to be determined.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Ayala A, Sloane J, Wolma FJ Jr. Coexistent lymphoma, adenocarcinoma, and struma lymphomatosa. JAMA 204:829–831, 1968.

    Article  PubMed  CAS  Google Scholar 

  2. Mechler C, Bounacer A, Suarez H, et al. Papillary thyroid carcinoma: 6 cases from 2 families with associated lymphocytic thyroiditis harbouring RET/PTC rearrangements. Br J Cancer 85:1831–1837, 2001.

    Article  PubMed  CAS  Google Scholar 

  3. McLeod MK, East ME, Burney RE, et al. Hashimoto’s thyroiditis revisited: the association with thyroid cancer remains obscure. World J Surg 12:509–516, 1988.

    Article  PubMed  CAS  Google Scholar 

  4. Ott RA, Calandra DB, McCall A, et al. The incidence of thyroid carcinoma in patients with Hashimoto’s thyroiditis and solitary cold nodules. Surgery 98:1202–1206, 1985.

    PubMed  CAS  Google Scholar 

  5. Singh B, Shaha AR, Trivedi H, et al. Coexistent Hashimoto’s thyroiditis with papillary thyroid carcinoma: impact on presentation, management, and outcome. Surgery 126:1070–1076 (discussion 1076, 1077), 1999.

    Article  PubMed  CAS  Google Scholar 

  6. Tamimi DM. The association between chronic lymphocytic thyroiditis and thyroid tumors. Int J Surg Pathol 10:141–146, 2002.

    PubMed  Google Scholar 

  7. Holmes HB Jr, Kreutner A, O’Brien PH. Hashimoto’s thyroiditis and its relationship to other thyroid diseases. Surg, Gynecol Obstet 144:887–890, 1977.

    Google Scholar 

  8. Holm LE, Blomgren H, Lowhagen T. Cancer risks in patients with chronic lymphocytic thyroiditis. N Engl J Med 312:601–604, 1985.

    Article  PubMed  CAS  Google Scholar 

  9. Crile G Jr. Struma lymphomatosa and carcinoma of the thyroid. Surg Gynecol Obstet 147:350–352, 1978.

    PubMed  Google Scholar 

  10. Segal K, Ben-Bassat M, Avraham A, et al. Hashimoto’s thyroiditis and carcinoma of the thyroid gland. Int Surg 70:205–209, 1985.

    PubMed  CAS  Google Scholar 

  11. Strauss M, Laurian N, Antebi E. Coexistent carcinoma of the thyroid gland and Hashimoto’s thyroiditis. Surg Gynecol Obstet 157:228–232, 1983.

    PubMed  CAS  Google Scholar 

  12. Holm LE, Blomgren H, Lowhagen T. Cancer risks in patients with chronic lymphocytic thyroiditis. N Engl J Med 312:601–604, 1985.

    Article  PubMed  CAS  Google Scholar 

  13. Baloch ZW, LiVolsi VA. Follicular patterned lesions of the thyroid. Am J Clin Pathol 117:143–150, 2002.

    Article  PubMed  Google Scholar 

  14. Kumarasinghe MP, De Silva S. Pitfalls in cytological diagnosis of autoimmune thyroiditis. Pathology 31:1–7, 1999.

    Article  PubMed  CAS  Google Scholar 

  15. Musholt TJ, Musholt PB, Khaladj N, et al. Prognostic significance of RET and NTRK1 rearrangements in sporadic papillary thyroid carcinoma. Surgery 128:984–993, 2000.

    Article  PubMed  CAS  Google Scholar 

  16. Elisei R, Romei C, Vorontsova T, et al. RET/PTC rearrangements in thyroid nodules: studies in irradiated and not irradiated, malignant and benign thyroid lesions in children and adults. J Clin Endocrinol Metab 86:3211–3216, 2001.

    Article  PubMed  CAS  Google Scholar 

  17. Fusco A, Chiappetta G, Hui P, et al. Assessment of RET/PTC oncogene activation and clonality in thyroid nodules with incomplete morphological evidence of papillary carcinoma: a search for the early precursors of papillary cancer. Am J Pathol 160:2157–2167, 2002.

    PubMed  CAS  Google Scholar 

  18. Fischer AH, Bond JA, Taysavang P, et al. Papillary thyroid carcinoma oncogene (RET/PTC) alters the nuclear envelope and chromatin structure. Am J Pathol 153:1443–1450, 1998.

    PubMed  CAS  Google Scholar 

  19. Wirtschafter A, Schmidt R, Rosen D, et al. Expression of the RET/PTC fusion gene as a marker for papillary carcinoma in Hashimoto’s thyroiditis. Laryngoscope 107:95–100, 1997.

    Article  PubMed  CAS  Google Scholar 

  20. Sheils OM, O’Leary JJ, Uhlmann V, et al. ret/PTC-1 activation in Hashimoto’s thyroiditis. Int J Surg Pathol 8:185–189, 2001.

    Google Scholar 

  21. Nikiforov MN, Caudill CM, Biddinger PW, et al. Prevalence of RET/PTC rearrangements in Hashimoto’s thyroiditis and papillary thyroid carcinomas. Int J Surg Pathol 10:15–22, 2002.

    PubMed  Google Scholar 

  22. Sheils OM, Smyth P, Finn S, et al. RET/PTC rearrangements in Hashimoto’s thyroiditis [letter]. Int J Surg Pathol 10:167, 168, 2002.

    PubMed  CAS  Google Scholar 

  23. Nikiforov YE. RET/PTC rearrangements in Hashimoto’s thyroiditis [letter]. Int J Surg Pathol 10:168, 169, 2002.

    Google Scholar 

  24. Dockhorn-Dworniczak B, Franke WW, Schroder S, et al. Patterns of expression of cytoskeletal proteins in human thyroid gland and thyroid carcinomas. Differentiation 35:53–71, 1987.

    Article  PubMed  CAS  Google Scholar 

  25. Sahoo S, Hoda SA, Rosai J, et al. Cytokeratin 19 immunoreactivity in the diagnosis of papillary thyroid carcinoma: a note of caution. Am J Clin Pathol 116:696–702, 2001.

    Article  PubMed  CAS  Google Scholar 

  26. Baloch ZW, Abraham S, Roberts S, et al. Differential expression of cytokeratins in follicular variant of papillary carcinoma: an immunohistochemical study and its diagnostic utility. Hum Pathol 30:1166–1171, 1999.

    Article  PubMed  CAS  Google Scholar 

  27. Cheung CC, Ezzat S, Freeman JL, et al. Immunohistochemical diagnosis of papillary thyroid carcinoma. Mod Pathol 14:338–342, 2001.

    Article  PubMed  CAS  Google Scholar 

  28. Thiagalingam S, Foy RL, Cheng KH, et al. Loss of heterozygosity as a predictor to map tumor suppressor genes in cancer: molecular basis of its occurrence. Curr Opin Oncol 14:65–72, 2002.

    Article  PubMed  CAS  Google Scholar 

  29. Fan CY, Liu KL, Huang HY, et al. Frequent allelic imbalance and loss of protein expression of the DNA repair gene of hOGG1 in head and neck squamous cell carcinoma. Lab Invest 81:1429–1438, 2001.

    PubMed  CAS  Google Scholar 

  30. Van Deerlin VM, Leonard DG. Bone marrow engraftment analysis after allogeneic bone marrow transplantation. Clin Lab Med 20:197–225, 2000.

    PubMed  Google Scholar 

  31. Ott RA, McCall AR, McHenry C, et al. The incidence of thyroid carcinoma in Hashimoto’s thyroiditis. Am Surg 53:442–445, 1987.

    PubMed  CAS  Google Scholar 

  32. Ott RA, Calandra DB, McCall A, et al. The incidence of thyroid carcinoma in patients with Hashimoto’s thyroiditis and solitary cold nodules. Surgery 98:1202–1206, 1985.

    PubMed  CAS  Google Scholar 

  33. Maceri DR, Sullivan MJ, McClatchney KD. Autoimmune thyroiditis: pathophysiology and relationship to thyroid cancer. Laryngoscope 96:82–86, 1986.

    Article  PubMed  CAS  Google Scholar 

  34. Di Pasquale M, Rothstein JL, Palazzo JP. Pathologic features of Hashimoto’s-associated papillary thyroid carcinomas. Hum Pathol 32:24–30, 2001.

    Article  PubMed  Google Scholar 

  35. Kebebew E, Treseler PA, Ituarte PH, et al. Coexisting chronic lymphocytic thyroiditis and papillary thyroid cancer revisited. World J Surg 25:632–637, 2001.

    Article  PubMed  CAS  Google Scholar 

  36. LiVolsi VA. Surgical pathology of the thyroid. Philadelphia: W.B. Saunders, 1990.

    Google Scholar 

  37. Fusco A, Grieco M, Santoro M, et al. A new oncogene in human thyroid papillary carcinomas and their lymph-nodal metastases. Nature 328:170–172, 1987.

    Article  PubMed  CAS  Google Scholar 

  38. Jhiang SM, Caruso DR, Gilmore E, et al. Detection of the PTC/retTPC oncogene in human thyroid cancers. Oncogene 7:1331–1337, 1992.

    PubMed  CAS  Google Scholar 

  39. Lanzi C, Borrello MG, Bongarzone I, et al. Identification of the product of two oncogenic rearranged forms of the RET proto-oncogene in papillary thyroid carcinomas. Oncogene 7:2189–2194, 1992.

    PubMed  CAS  Google Scholar 

  40. Pierotti MA, Santoro M, Jenkins RB, et al. Characterization of an inversion on the long arm of chromosome 10 juxtaposing D10S170 and RET and creating the oncogenic sequence RET/PTC. Proc Natl Acad Sci USA 89:1616–1620, 1992.

    Article  PubMed  CAS  Google Scholar 

  41. Papotti M, Volante M, Giuliano A, et al. RET/PTC activation in hyalinizing trabecular tumors of the thyroid. Am J Surg Pathol 24:1615–1621, 2000.

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Medical Center, University of Pittsburgh, Pittsburgh, PA

    Jennifer L. Hunt MD, E. Leon Barnes MD, Patricia A. Swalsky BS, Cindy L. Trusky BS, E. Sasatomi MD, PhD & Sydney Finkelstein MD

  2. University of Pennsylvania Medical Center, Philadelphia, PA

    Zubair W. Baloch MD, PhD & Virginia A. LiVolsi MD

Authors
  1. Jennifer L. Hunt MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Zubair W. Baloch MD, PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. E. Leon Barnes MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Patricia A. Swalsky BS
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Cindy L. Trusky BS
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. E. Sasatomi MD, PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Sydney Finkelstein MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Virginia A. LiVolsi MD
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Jennifer L. Hunt MD.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Hunt, J.L., Baloch, Z.W., Barnes, E.L. et al. Loss of heterozygosity mutations to tumor suppressor genes in cytologically atypical areas in chronic lymphocytic thyroiditis. Endocr Pathol 13, 321–329 (2002). https://doi.org/10.1385/EP:13:4:321

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1385/EP:13:4:321

Key Words

Search

Navigation