Background. We report the case of a 74-year-old woman with BRAF and TERT promoter double-mutation, with an aggressive papillary thyroid carcinoma (PTC) with a focal undifferentiated component. Case presentation. PTC was diagnosed via cytological analysis and total thyroidectomy and lymph node dissection were performed 15 months before her death. Pathological diagnosis revealed stump-positive PTC pT4aN1bM1, Stage IVB. An initial radioiodine ablative dose (150 mCi) was administered. Thereafter, the mediastinal lymph node and multiple bilateral lung metastases were observed upon computed tomography. Six months later, recurrent lesions were irradiated with external beam radiation (39 Gy/13 fr). Within the next five months, she developed multiple-organ metastases. A month before death, recurrent lesions increased rapidly and an undifferentiated cancer was diagnosed upon biopsy. The multifocal disease was rendered inoperable. After gradual progression of respiratory failure, the patient died. During initial resection, a focal invasion component with severe nuclear atypia and spindle-shaped, giant cells were noted, thereby increasing the probability of focal undifferentiated transformation. A focal hobnail pattern and minor necrosis were observed. Upon autopsy, lung and multiple-organ metastases and massive mediastinal invasion were observed. The immunohistochemically undifferentiated lung cancer expressed vimentin, AE1/AE3, CK7, and p53, but not thyroglobulin, TTF-1, and Napsin A. Furthermore, a PTC component was observed in the lung, showing micropapillary architecture with a prominent hobnail pattern. Molecular analysis revealed a double-mutation in BRAF (V600E) and TERT (C228T) promoters. The Ki-67 labeling index of surgical papillary carcinoma tissue was 34%. BRAF mutations associated with p53 mutations triggered an additional TERT promoter mutation with upregulated Ki-67 in primary PTC, which can be a network of genetic alterations driving tumor progression and distant metastasis to the undifferentiated/anaplastic phenotype. Conclusions. The above mentioned molecular genetic features with the histologically hobnail component should be considered and tumor recurrence should be assessed carefully.
Akbota Targynova1, Zhanna Mussazhanova1,2, Nozomi Ueki2, Saltanat Bolsynbekova3, Zhanar Yeleubayeva4, Zhanna Kalmatayeva1, Raushan Issayeva1, Lazzat Sarsenova1, Raushan Umirova5, Dulat Serikbaiuly6, Aray K. Mukanova7, Madina R. Madiyeva7, Masahiro Nakashima2 1 Al-Farabi Kazakh National University, Faculty of Medicine and Health Care, Almaty, Republic of Kazakhstan; 2 Atomic Bomb Disease Institute, Department of Tumor and Diagnostic Pathology, Nagasaki University, Japan; 3 National Research Oncology Center, Department of Diagnostic Pathology and Laboratory, Nur-Sultan, Republic of Kazakhstan; 4 Kazakh Institute of Oncology and Radiology, Center of Morphological Examination, Almaty, Republic of Kazakhstan; 5 Asfendiyarov Kazakh National Medical University, Department of Obstetrics and Gynecology, Almaty, Republic of Kazakhstan; 6 National Research Oncology Center, Multidisciplinary surgery department, Nur-Sultan, Republic of Kazakhstan. 7 Semey Medical University, Department of Radiology, Semey, Republic of Kazakhstan.
1. American Cancer Society. Thyroid Cancer. 2016. 18.01.2021 2. Livolsi V.A. Papillary thyroid carcinoma: An update // Mod. Pathol. Mod Pathol, 2011. Vol. 24. P. S1–S9. 3. Siegel R. et al. Cancer treatment and survivorship statistics, 2012 // CA. Cancer J. Clin. Wiley, 2012. Vol. 62, № 4. P. 220–241. 4. Papp S., Asa S.L. When Thyroid Carcinoma Goes Bad: A Morphological and Molecular Analysis // Head Neck Pathol. Humana Press Inc., 2015. Vol. 9, № 1. P. 16–23. 5. Ragazzi M. et al. Update on anaplastic thyroid carcinoma: Morphological, molecular, and genetic features of the most aggressive thyroid cancer // International Journal of Endocrinology. Hindawi Limited, 2014. Vol. 2014. P. 1-13 6. Al-Qsous W., Miller I.D. Anaplastic transformation in lung metastases of differentiated papillary thyroid carcinoma: an autopsy case report and review of the literature // Ann. Diagn. Pathol. Ann Diagn Pathol, 2010. Vol. 14, № 1. P. 41–43. 7. Kaushal S. et al. Anaplastic transformation of metastatic papillary thyroid carcinoma at shoulder mimicking soft tissue sarcoma // Indian J. Pathol. Microbiol. Indian J Pathol Microbiol, 2011. Vol. 54, № 4. P. 796–799. 8. Besic N., Gazic B. Sites of metastases of anaplastic thyroid carcinoma: Autopsy findings in 45 cases from a single institution // Thyroid. Mary Ann Liebert Inc., 2013. Vol. 23, № 6. P. 709–713. 9. Kim T.H. et al. The association of the BRAFV600E mutation with prognostic factors and poor clinical outcome in papillary thyroid cancer: A meta-analysis // Cancer. Cancer, 2012. Vol. 118, № 7. P. 1764–1773. 10. Xing M. et al. BRAF mutation predicts a poorer clinical prognosis for papillary thyroid cancer // J. Clin. Endocrinol. Metab. J Clin Endocrinol Metab, 2005. Vol. 90, № 12. P. 6373–6379. 11. Yasuhiro I. et al. BRAF mutation in papillary thyroid carcinoma in a Japanese population: Its lack of correlation with high-risk clinicopathological features and disease-free survival of patients // Endocr. J. Endocr J, 2009. Vol. 56, №1. P. 89–97. 12. Kim T.Y. et al. The BRAFV600E mutation is not associated with poor prognostic factors in Korean patients with conventional papillary thyroid microcarcinoma // Clin. Endocrinol. (Oxf). Clin Endocrinol (Oxf), 2005. Vol. 63, № 5. P. 588–593. 13. Song Y.S., Lim J.A., Park Y.J. Mutation profile of well-differentiated thyroid cancer in asians // Endocrinology and Metabolism. Korean Endocrine Society, 2015. Vol. 30, № 3. P. 252–262. 14. Siegel R. et al. Cancer statistics, 2014 // CA. Cancer J. Clin. American Cancer Society, 2014. Vol. 64, № 1. P. 9–29. 15. Horn S. et al. TERT promoter mutations in familial and sporadic melanoma // Science. American Association for the Advancement of Science, 2013. Vol. 339, № 6122. P. 959–961. 16. Huang W. et al. Radical migration-addition of N-tert-butanesulfinyl imines with organozinc reagents // J. Org. Chem. J Org Chem, 2013. Vol. 78, № 22. P. 11229–11237. 17. Bell R.J.A. et al. The transcription factor GABP selectively binds and activates the mutant TERT promoter in cancer // Science. American Association for the Advancement of Science, 2015. Vol. 348, № 6238. P. 1036–1039. 18. Liu R., Xing M. TERT promoter mutations in thyroid cancer // Endocrine-Related Cancer. BioScientifica Ltd., 2016. Vol. 23, № 3. P. R143–R155. 19. Moon S. et al. Effects of Coexistent BRAFV600E and TERT Promoter Mutations on Poor Clinical Outcomes in Papillary Thyroid Cancer: A Meta-Analysis // Thyroid. Mary Ann Liebert Inc., 2017. Vol. 27, № 5. P. 651–660. 20. Liu C. et al. TERT promoter Mutation and Its Association with Clinicopathological Features and Prognosis of Papillary Thyroid Cancer: A Meta-analysis // Sci. Rep. Nature Publishing Group, 2016. Vol. 6, № 1. P. 36990. 21. Asioli S. et al. Papillary thyroid carcinoma with prominent hobnail features: A new aggressive variant of moderately differentiated papillary carcinoma. A clinicopathologic, immunohistochemical, and molecular study of eight cases // Am. J. Surg. Pathol. Am J Surg Pathol, 2010. Vol. 34, № 1. P. 44–52. 22. Motosugi U. et al. Thyroid papillary carcinoma with micropapillary and hobnail growth pattern: a histological variant with intermediate malignancy? // Thyroid: official journal of the American Thyroid Association. Thyroid, 2009. Vol. 19, № 5. P. 535–537. 23. Lubitz C.C. et al. Hobnail variant of papillary thyroid carcinoma: An institutional case series and molecular profile // Thyroid. Mary Ann Liebert Inc., 2014. Vol. 24, № 6. P. 958–965. 24. Solomon J.P., Wen F., Jih L.J. Anaplastic Transformation of Papillary Thyroid Cancer in the Retroperitoneum // Case Rep. Pathol. Hindawi Limited, 2015. Vol. 2015. P. 1–4. 25. Benedict M., Costa J. Metastatic Papillary Thyroid Carcinoma with Multifocal Synchronous Transformation to Anaplastic Thyroid Carcinoma // Case Rep. Pathol. Hindawi Limited, 2016. Vol. 2016. P. 1–5. 26. Riaz S. et al. Aggressive Disease Course of Papillary Thyroid Carcinoma with Focal Undifferentiated Component: A Case Report // Malecular Imaging Radionucl. Ther. Galenos Yayinevi, 2016. Vol. 25, № 3. P. 134–139. 27. Awan L.L. et al. Press Recurrence of Thyroid Cancer: From Papillary to Anaplastic // J Med Cases •. 2013. Vol. 4, № 8. P. 533–534. 28. Abe T. et al. Anaplastic transformation of papillary thyroid carcinoma in multiple lung metastases presenting with a malignant pleural effusion: A case report // J. Med. Case Rep. BioMed Central Ltd., 2014. Vol. 8, № 1. P. 1-5 29. Bejarano P.A. et al. Thyroid Transcription Factor-1, Thyroglobulin, Cytokeratin 7, and Cytokeratin 20 in Thyroid Neoplasms // Appl. Immunohistochem. Mol. Morphol. Ovid Technologies (Wolters Kluwer Health), 2000. Vol. 8, № 3. P. 189–194. 30. Nikiforov Y.E., Nikiforova M.N. Molecular genetics and diagnosis of thyroid cancer // Nature Reviews Endocrinology. Nat Rev Endocrinol, 2011. Vol. 7, № 10. P. 569–580. 31. Fagin J.A. et al. High prevalence of mutations of the p53 gene in poorly differentiated human thyroid carcinomas // J. Clin. Invest. The American Society for Clinical Investigation, 1993. Vol. 91, № 1. P. 179–184. 32. Ito T. et al. Unique association of p53 mutations with undifferentiated carcinoma of the thyroid // Nippon rinsho. Japanese journal of clinical medicine. 1994. Vol. 52, № 4. P. 1069–1074. 33. Ricarte-Filho J.C. et al. Mutational profile of advanced primary and metastatic radioactive iodine-refractory thyroid cancers reveals distinct pathogenetic roles for BRAF, PIK3CA, and AKT1 // Cancer Res. Cancer Res, 2009. Vol. 69, № 11. P. 4885–4893. 34. Gauchotte G. et al. BRAF, p53 and SOX2 in anaplastic thyroid carcinoma: Evidence for multistep carcinogenesis // Pathology. Lippincott Williams and Wilkins, 2011. Vol. 43, № 5. P. 447–452. 35. La Perle K.M.D., Jhiang S.M., Capen C.C. Loss of p53 promotes anaplasia and local invasion in ret/PTC1-induced thyroid carcinomas // Am. J. Pathol. American Society for Investigative Pathology Inc., 2000. Vol. 157, № 2. P. 671–677. 36. McFadden D.G. et al. p53 constrains progression to anaplastic thyroid carcinoma in a Braf-mutant mouse model of papillary thyroid cancer // Proc. Natl. Acad. Sci. U. S. A. National Academy of Sciences, 2014. Vol. 111, № 16. E1600-E1609 37. Matsuse M. et al. TERT promoter mutations and Ki-67 labeling index as a prognostic marker of papillary thyroid carcinomas: Combination of two independent factors // Sci. Rep. Nature Publishing Group, 2017. Vol. 7, № 1. P. 41752.
Количество просмотров: 97

Ключевые слова:

Библиографическая ссылка

Targynova A., Mussazhanova Z., Ueki N., Bolsynbekova S., Yeleubayeva Z., Kalmatayeva Z., Issayeva R., Sarsenova L., Umirova R., Serikbaiuly D., Nakashima M., Mukanova A.K., Madiyeva M.R. Anaplastic transformation of BRAF and TERT promoter double mutant Papillary Thyroid Carcinoma: clinical, morphological, and molecular genetic features // Nauka i Zdravookhranenie [Science & Healthcare]. 2021, (Vol.23) 5, pp. 248-256. doi 10.34689/SH.2021.23.5.026