Clinicopathologic features of RAS gene mutant thyroid tumors: an analysis of single institution_CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY

Authors：

ZHAO Qian , ZHOU Jun , WANG Chenglong , SUN Keyang , SU Xuling ,  LIU Zhiyan

Department of Pathology, Shanghai Sixth People’s Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200233, P. R. China;

Corresponding author：

LIU Zhiyan, Email: zhiyanliu@shsmu.edu.cn

Keywords：

thyroid tumor; RAS gene mutation; clinicopathologic feature

DOI：

10.7507/1007-9424.202410021

Video：

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Objective To analyze the clinicopathologic features of thyroid tumors with RAS gene mutation.Method The clinicopathologic data of thyroid tumor patients who underwent surgical treatment or biopsy and were diagnosed pathologically at the Department of Pathology of the Shanghai Sixth People’s Hospital Affiliated to Shanghai Jiao Tong University School of Medicine from January 2021 to June 2023, were collected. Results A total of 798 patients with thyroid tumors who met the inclusion criteria were collected, including 747 cases of follicular epithelial tumors and 51 cases of medullary thyroid carcinoma (MTC). Among 798 patients, the RAS gene mutations were detected in 36 cases (4.5%), including 25 (69.4%) patients with NRAS mutations, 8 (22.2%) patients with HRAS mutations, 3 (8.3%) patients with KRAS mutations, and 4 (1.1%) patients accompanied with TERT promoter mutations. Among 36 patients with RAS mutant thyroid tumors, the male to female ratio was 7∶11, with a median age of 48.5 years, with an average tumor diameter of 2 cm. The mutation rate of RAS gene in different histological types of thyroid tumors, from high to low, was highest in the thyroid follicular carcinoma (FTC, 25.9%), followed by differentiated high grade thyroid carcinoma (20.0%), anaplastic thyroid carcinoma (20.0%), noninvasive follicular thyroid neoplasm with papillary like nuclear features (18.2%), follicular variant of papillary thyroid carcinoma (FVPTC, 16.0%), and well-differentiated thyroid tumour of uncertain malignant potential (WT-UMP, 12.8%), the mutation rates of RAS gene in the FTC, FVPTC, and WT-UMP were significantly higher than that of the classical papillary thyroid carcinoma (P<0.001 1), and the mutation rate of RAS gene was the lowest in the classical papillary thyroid carcinoma (1.5%). A total of 35 patients were effectively followed up with an average follow-up period of 21.4 months, 6 of whom had cervical lymph node metastasis, 4 patients developed distant metastasis, and 1 patient with anaplastic thyroid carcinoma died. Conclusions RAS gene mutation can occur in thyroid follicular differentiated tumors and MTC. NRAS mutation is more common. The mutation rate is the highest in FTC, is the lowest in classical papillary thyroid carcinoma. Differential diagnosis combined with tissue morphology and other molecular changes can provide a reference for guiding treatment and evaluating prognosis.

Citation： ZHAO Qian, ZHOU Jun, WANG Chenglong, SUN Keyang, SU Xuling, LIU Zhiyan. Clinicopathologic features of RAS gene mutant thyroid tumors: an analysis of single institution. CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY, 2024, 31(11): 1307-1312. doi: 10.7507/1007-9424.202410021 Copy

1.	Baloch ZW, Asa SL, Barletta JA, et al. Overview of the 2022 WHO classification of thyroid neoplasms. Endocr Pathol, 2022, 33(1): 27-63.
2.	吕恬, 王佳峰, 徐加杰, 等. 《中国肿瘤整合诊治指南—CACA甲状腺癌诊治指南》外科部分解读. 中国普外基础与临床杂志, 2023, 30(2): 154-159.
3.	Asa SL, Baloch ZW, de Krijger RR. WHO classification of tumours series. Endocrine and neuroendocrine tumours. 5th ed. Lyon (France): IARC press, 2022.
4.	Park JY, Kim WY, Hwang TS, et al. BRAF and RAS mutations in follicular variants of papillary thyroid carcinoma. Endocr Pathol, 2013, 24(2): 69-76.
5.	Bray F, Ferlay J, Soerjomataram I, et al. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin, 2018, 68(6): 394-424.
6.	Xing M. Clinical utility of RAS mutations in thyroid cancer: a blurred picture now emerging clearer. BMC Med, 2016, 14: 12. doi: 10.1186/s12916-016-0559-9.
7.	Marotta V, Bifulco M, Vitale M. Significance of RAS mutations in thyroid benign nodules and non-medullary thyroid cancer. Cancers (Basel), 2021, 13(15): 3785. doi: 10.3390/cancers13153785.
8.	Hwang TS, Kim WY, Han HS, et al. Preoperative RAS mutational analysis is of great value in predicting follicular variant of papillary thyroid carcinoma. Biomed Res Int, 2015, 2015: 697068. doi: 10.1155/2015/697068.
9.	Jung CK, Bychkov A, Song DE, et al. Molecular correlates and nuclear features of encapsulated follicular-patterned thyroid neoplasms. Endocrinol Metab (Seoul), 2021, 36(1): 123-133.
10.	Coyne C, Nikiforov YE. RAS mutation-positive follicular variant of papillary thyroid carcinoma arising in a struma ovarii. Endocr Pathol, 2010, 21(2): 144-147.
11.	Kim M, Jeon MJ, Oh HS, et al. BRAF and RAS mutational status in noninvasive follicular thyroid neoplasm with papillary-like nuclear features and invasive subtype of encapsulated follicular variant of papillary thyroid carcinoma in Korea. Thyroid, 2018, 28(4): 504-510.
12.	Giordano TJ, Kuick R, Thomas DG, et al. Molecular classification of papillary thyroid carcinoma: distinct BRAF, RAS, and RET/PTC mutation-specific gene expression profiles discovered by DNA microarray analysis. Oncogene, 2005, 24(44): 6646-6656.
13.	Harahap AS, Subekti I, Panigoro SS, et al. Developing models to predict BRAF^V600E and RAS mutational status in papillary thyroid carcinoma using clinicopathological features and pERK1/2 immunohistochemistry expression. Biomedicines, 2023, 11(10): 2803. doi: 10.3390/biomedicines11102803.
14.	Harahap AS, Subekti I, Panigoro SS, et al. Profile of BRAF^V600E, BRAF^K601E, NRAS, HRAS, and KRAS mutational status, and clinicopathological characteristics of papillary thyroid carcinoma in Indonesian National Referral Hospital. Appl Clin Genet, 2023, 16: 99-110.
15.	Lim J, Lee HS, Park J, et al. Different molecular phenotypes of progression in BRAF- and RAS-like papillary thyroid carcinoma. Endocrinol Metab (Seoul), 2023, 38(4): 445-454.
16.	Cancer Genome Atlas Research Network. Integrated genomic characterization of papillary thyroid carcinoma. Cell, 2014, 159(3): 676-690.
17.	Jin M, Li Z, Sun Y, et al. Association analysis between the interaction of RAS family genes mutations and papillary thyroid carcinoma in the Han Chinese population. Int J Med Sci, 2021, 18(2): 441-447.
18.	Kure S, Wada R, Naito Z. Relationship between genetic alterations and clinicopathological characteristics of papillary thyroid carcinoma. Med Mol Morphol, 2019, 52(4): 181-186.
19.	Gopal RK, Kübler K, Calvo SE, et al. Widespread chromosomal losses and mitochondrial DNA alterations as genetic drivers in Hürthle cell carcinoma. Cancer Cell, 2018, 34(2): 242-255.
20.	Haroon Al Rasheed MR, Xu B. Molecular alterations in thyroid carcinoma. Surg Pathol Clin, 2019, 12(4): 921-930.
21.	Petric R, Gazic B, Besic N. Prognostic factors for disease-specific survival in 108 patients with Hürthle cell thyroid carcinoma: a single-institution experience. BMC Cancer, 2014, 14: 777. doi: 10.1186/1471-2407-14-777.
22.	Nagar S, Aschebrook-Kilfoy B, Kaplan EL, et al. Hurthle cell carcinoma: an update on survival over the last 35 years. Surgery, 2013, 154(6): 1263-1271.
23.	Landa I, Ibrahimpasic T, Boucai L, et al. Genomic and transcriptomic hallmarks of poorly differentiated and anaplastic thyroid cancers. J Clin Invest, 2016, 126(3): 1052-1066.
24.	Lin B, Ma H, Ma M, et al. The incidence and survival analysis for anaplastic thyroid cancer: a SEER database analysis. Am J Transl Res, 2019, 11(9): 5888-5896.
25.	Bychkov A, Hirokawa M, Jung CK, et al. Low rate of noninvasive follicular thyroid neoplasm with papillary-like nuclear features in Asian practice. Thyroid, 2017, 27(7): 983-984.
26.	Lyra J, Vinagre J, Batista R, et al. mTOR activation in medullary thyroid carcinoma with RAS mutation. Eur J Endocrinol, 2014, 171(5): 633-640.
27.	Hernandez-Prera JC. Molecular pathology of thyroid tumors: old problems and new concepts. Surg Pathol Clin, 2021, 14(3): 493-506.
28.	Landa I, Cabanillas ME. Genomic alterations in thyroid cancer: biological and clinical insights. Nat Rev Endocrinol, 2024, 20(2): 93-110.

1. Baloch ZW, Asa SL, Barletta JA, et al. Overview of the 2022 WHO classification of thyroid neoplasms. Endocr Pathol, 2022, 33(1): 27-63.
2. 吕恬, 王佳峰, 徐加杰, 等. 《中国肿瘤整合诊治指南—CACA甲状腺癌诊治指南》外科部分解读. 中国普外基础与临床杂志, 2023, 30(2): 154-159.
3. Asa SL, Baloch ZW, de Krijger RR. WHO classification of tumours series. Endocrine and neuroendocrine tumours. 5th ed. Lyon (France): IARC press, 2022.
4. Park JY, Kim WY, Hwang TS, et al. BRAF and RAS mutations in follicular variants of papillary thyroid carcinoma. Endocr Pathol, 2013, 24(2): 69-76.
5. Bray F, Ferlay J, Soerjomataram I, et al. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin, 2018, 68(6): 394-424.
6. Xing M. Clinical utility of RAS mutations in thyroid cancer: a blurred picture now emerging clearer. BMC Med, 2016, 14: 12. doi: 10.1186/s12916-016-0559-9.
7. Marotta V, Bifulco M, Vitale M. Significance of RAS mutations in thyroid benign nodules and non-medullary thyroid cancer. Cancers (Basel), 2021, 13(15): 3785. doi: 10.3390/cancers13153785.
8. Hwang TS, Kim WY, Han HS, et al. Preoperative RAS mutational analysis is of great value in predicting follicular variant of papillary thyroid carcinoma. Biomed Res Int, 2015, 2015: 697068. doi: 10.1155/2015/697068.
9. Jung CK, Bychkov A, Song DE, et al. Molecular correlates and nuclear features of encapsulated follicular-patterned thyroid neoplasms. Endocrinol Metab (Seoul), 2021, 36(1): 123-133.
10. Coyne C, Nikiforov YE. RAS mutation-positive follicular variant of papillary thyroid carcinoma arising in a struma ovarii. Endocr Pathol, 2010, 21(2): 144-147.
11. Kim M, Jeon MJ, Oh HS, et al. BRAF and RAS mutational status in noninvasive follicular thyroid neoplasm with papillary-like nuclear features and invasive subtype of encapsulated follicular variant of papillary thyroid carcinoma in Korea. Thyroid, 2018, 28(4): 504-510.
12. Giordano TJ, Kuick R, Thomas DG, et al. Molecular classification of papillary thyroid carcinoma: distinct BRAF, RAS, and RET/PTC mutation-specific gene expression profiles discovered by DNA microarray analysis. Oncogene, 2005, 24(44): 6646-6656.
13. Harahap AS, Subekti I, Panigoro SS, et al. Developing models to predict BRAF^V600E and RAS mutational status in papillary thyroid carcinoma using clinicopathological features and pERK1/2 immunohistochemistry expression. Biomedicines, 2023, 11(10): 2803. doi: 10.3390/biomedicines11102803.
14. Harahap AS, Subekti I, Panigoro SS, et al. Profile of BRAF^V600E, BRAF^K601E, NRAS, HRAS, and KRAS mutational status, and clinicopathological characteristics of papillary thyroid carcinoma in Indonesian National Referral Hospital. Appl Clin Genet, 2023, 16: 99-110.
15. Lim J, Lee HS, Park J, et al. Different molecular phenotypes of progression in BRAF- and RAS-like papillary thyroid carcinoma. Endocrinol Metab (Seoul), 2023, 38(4): 445-454.
16. Cancer Genome Atlas Research Network. Integrated genomic characterization of papillary thyroid carcinoma. Cell, 2014, 159(3): 676-690.
17. Jin M, Li Z, Sun Y, et al. Association analysis between the interaction of RAS family genes mutations and papillary thyroid carcinoma in the Han Chinese population. Int J Med Sci, 2021, 18(2): 441-447.
18. Kure S, Wada R, Naito Z. Relationship between genetic alterations and clinicopathological characteristics of papillary thyroid carcinoma. Med Mol Morphol, 2019, 52(4): 181-186.
19. Gopal RK, Kübler K, Calvo SE, et al. Widespread chromosomal losses and mitochondrial DNA alterations as genetic drivers in Hürthle cell carcinoma. Cancer Cell, 2018, 34(2): 242-255.
20. Haroon Al Rasheed MR, Xu B. Molecular alterations in thyroid carcinoma. Surg Pathol Clin, 2019, 12(4): 921-930.
21. Petric R, Gazic B, Besic N. Prognostic factors for disease-specific survival in 108 patients with Hürthle cell thyroid carcinoma: a single-institution experience. BMC Cancer, 2014, 14: 777. doi: 10.1186/1471-2407-14-777.
22. Nagar S, Aschebrook-Kilfoy B, Kaplan EL, et al. Hurthle cell carcinoma: an update on survival over the last 35 years. Surgery, 2013, 154(6): 1263-1271.
23. Landa I, Ibrahimpasic T, Boucai L, et al. Genomic and transcriptomic hallmarks of poorly differentiated and anaplastic thyroid cancers. J Clin Invest, 2016, 126(3): 1052-1066.
24. Lin B, Ma H, Ma M, et al. The incidence and survival analysis for anaplastic thyroid cancer: a SEER database analysis. Am J Transl Res, 2019, 11(9): 5888-5896.
25. Bychkov A, Hirokawa M, Jung CK, et al. Low rate of noninvasive follicular thyroid neoplasm with papillary-like nuclear features in Asian practice. Thyroid, 2017, 27(7): 983-984.
26. Lyra J, Vinagre J, Batista R, et al. mTOR activation in medullary thyroid carcinoma with RAS mutation. Eur J Endocrinol, 2014, 171(5): 633-640.
27. Hernandez-Prera JC. Molecular pathology of thyroid tumors: old problems and new concepts. Surg Pathol Clin, 2021, 14(3): 493-506.
28. Landa I, Cabanillas ME. Genomic alterations in thyroid cancer: biological and clinical insights. Nat Rev Endocrinol, 2024, 20(2): 93-110.

CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY

Clinicopathologic features of RAS gene mutant thyroid tumors: an analysis of single institution

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