World Journal of Surgery

, Volume 42, Issue 5, pp 1432–1439 | Cite as

Medullary Thyroid Carcinoma: Survival Analysis and Evaluation of Mutation-Specific Immunohistochemistry in Detection of Sporadic Disease

  • S. Jayakody
  • J. Reagh
  • M. Bullock
  • A. Aniss
  • R. Clifton-Bligh
  • D. Learoyd
  • B. Robinson
  • L. Delbridge
  • S. Sidhu
  • A. J. Gill
  • M. Sywak
Original Scientific Report
  • 114 Downloads

Abstract

Introduction

Medullary thyroid cancer (MTC) is a rare tumour of neuroendocrine origin with a more aggressive profile than differentiated thyroid cancer. Familial cases of MTC are associated with RET mutations whilst RAS mutations appear to be a frequent finding in RET negative tumours. The aims of this study were to analyse survival outcomes in MTC and to evaluate the role of RAS immunohistochemistry in the identification of sporadic disease.

Materials and methods

A retrospective cohort study of consecutive patients with MTC was undertaken. The primary outcome measures were overall survival and disease-free survival. Survival analysis was performed on the basis of sporadic and familial disease. Patients had routine RET testing using the capillary (Sanger) sequencing method. Histopathological MTC slides from 100 patients were tested for HRASQ61R, a common somatic RAS mutation in MTC, with mutation-specific immunohistochemistry (IHC).

Results

A total of 195 patients had surgical treatment of MTC in the period 1980 to 2016. There were 83 males and 112 females with a mean age of 53.0 years. A total of 39 (20%) patients had familial disease. Sporadic cases had a higher median pre-op calcitonin (969.5 vs. 257.5 pg/ml), greater mean primary tumour size (23.5 vs. 12.5 mm) and more distant metastases (12.8 vs. 10.3%). Multivariate analysis showed age (p = 0.005), Multiple Endocrine Neoplasia Type 2 (MEN2) status (p = 0.021) and distant metastasis (p = 0.002) to be significant independent predictors of survival. Significant independent predictors for disease-free survival were age (p = 0.015), MEN2 (p = 0.002), pre-op calcitonin (p = 0.033) and venous invasion (p = 0.001). The overall 5-year survival was 100% for familial MTC and 78% for sporadic MTC. The 10-year disease-free survival was 94% for familial MTC and 61% for sporadic cases. A total of 100 cases of MTC underwent mutation-specific IHC for HRASQ61R. Of these, 18 had confirmed MEN2. IHC had 100% specificity in excluding MEN2. Twelve (12%) of 100 patients stained positive for HRASQ61R mutation.

Conclusion

In the era of genetic testing, RET status significantly influences disease-specific survival in MTC. Mutation-specific IHC for HRASQ61R may have a role in the identification of patients presenting with sporadic disease.

Notes

Compliance with ethical standards

Conflict of interest

There are no conflicts of interest.

References

  1. 1.
    Wells SA Jr et al (2015) Revised american thyroid association guidelines for the management of medullary thyroid carcinoma. Thyroid 25(6):567–610CrossRefPubMedPubMedCentralGoogle Scholar
  2. 2.
    Ball DW (2000) Medullary thyroid carcinoma, in thyroid cancer. Springer, Berlin, pp 365–381Google Scholar
  3. 3.
    Leboulleux S et al (2004) Medullary thyroid carcinoma. Clin Endocrinol (Oxf) 61(3):299–310CrossRefGoogle Scholar
  4. 4.
    Wells SA Jr et al (2013) Multiple endocrine neoplasia type 2 and familial medullary thyroid carcinoma: an update. J Clin Endocrinol Metab 98(8):3149–3164CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Eng C et al (1996) The relationship between specific RET proto-oncogene mutations and disease phenotype in multiple endocrine neoplasia type 2: international RET Mutation Consortium analysis. JAMA 276(19):1575–1579CrossRefPubMedGoogle Scholar
  6. 6.
    Learoyd DL et al (1997) Genetic testing for familial cancer: consequences of RET proto-oncogene mutation analysis in multiple endocrine neoplasia, type 2. Arch Surg 132(9):1022–1025CrossRefPubMedGoogle Scholar
  7. 7.
    Bano G, Hodgson S (2016) Diagnosis and management of hereditary thyroid cancer. Recent Results Cancer Res 205:29–44CrossRefPubMedGoogle Scholar
  8. 8.
    Takahashi M (1994) Ret protooncogene and human-diseases—review. Int J Oncol 4(1):81–84PubMedGoogle Scholar
  9. 9.
    Krampitz GW, Norton JA (2014) RET gene mutations (genotype and phenotype) of multiple endocrine neoplasia type 2 and familial medullary thyroid carcinoma. Cancer 120(13):1920–1931CrossRefPubMedGoogle Scholar
  10. 10.
    American Thyroid Association Guidelines Task, F et al (2009) Medullary thyroid cancer: management guidelines of the American Thyroid Association. Thyroid 19(6):565–612CrossRefGoogle Scholar
  11. 11.
    Baumgartner-Parzer S et al (2005) Polymorphisms in exon 13 and intron 14 of the RET protooncogene: genetic modifiers of medullary thyroid carcinoma? J Clin Endocrinol Metab 90(11):6232–6236CrossRefPubMedGoogle Scholar
  12. 12.
    Louhibi L et al (2014) Demographic, clinical, and genetic characteristics of patients with medullary thyroid cancer in the past 16 years in Castilla-La Mancha. Endocrinol Nutr 61(8):398–403CrossRefPubMedGoogle Scholar
  13. 13.
    Wells SA, Santoro M (2009) Targeting the RET pathway in thyroid cancer. Clin Cancer Res 15(23):7119–7123CrossRefPubMedGoogle Scholar
  14. 14.
    Moura MM, Cavaco BM, Leite V (2015) RAS proto-oncogene in medullary thyroid carcinoma. Endocr Relat Cancer 22(5):R235–R252CrossRefPubMedGoogle Scholar
  15. 15.
    Taccaliti A et al (2011) Genetic alterations in medullary thyroid cancer: diagnostic and prognostic markers. Curr Genom 12(8):618–625CrossRefGoogle Scholar
  16. 16.
    Fernández-Medarde A, Santos E (2011) Ras in cancer and developmental diseases. Genes Cancer 2(3):344–358CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Boichard A et al (2012) Somatic RAS mutations occur in a large proportion of sporadic RET-negative medullary thyroid carcinomas and extend to a previously unidentified exon. J Clin Endocrinol Metab 97(10):E2031–E2035CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Moura MM et al (2011) High prevalence of RAS mutations in RET-negative sporadic medullary thyroid carcinomas. J Clin Endocrinol Metab 96(5):E863–E868CrossRefPubMedGoogle Scholar
  19. 19.
    Reagh J et al (2017) NRASQ61R mutation-specific Immunohistochemistry Also Identifies the HRASQ61R mutation in medullary thyroid cancer and may have a role in triaging genetic testing for MEN2. Am J Surg Pathol 41(1):75–81CrossRefPubMedGoogle Scholar
  20. 20.
    Turchini J et al (2017) NRASQ61R mutation-specific immunohistochemistry is highly specific for either NRASQ61R or KRASQ61R mutation in colorectal carcinoma. Appl Immunohistochem Mol Morphol 25(7):475–480CrossRefPubMedGoogle Scholar
  21. 21.
    Yamada T et al (2016) Utility of KRAS mutation detection using circulating cell-free DNA from patients with colorectal cancer. Cancer Sci 107(7):936–943CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Société Internationale de Chirurgie 2018

Authors and Affiliations

  • S. Jayakody
    • 1
  • J. Reagh
    • 3
    • 4
  • M. Bullock
    • 2
  • A. Aniss
    • 1
  • R. Clifton-Bligh
    • 2
  • D. Learoyd
    • 2
  • B. Robinson
    • 2
  • L. Delbridge
    • 1
  • S. Sidhu
    • 1
  • A. J. Gill
    • 3
    • 4
  • M. Sywak
    • 1
  1. 1.University of Sydney Endocrine Surgical UnitSydneyAustralia
  2. 2.Department of EndocrinologyRoyal North Shore HospitalSydneyAustralia
  3. 3.Cancer Diagnosis and Pathology Group, Kolling Institute of Medical ResearchRoyal North Shore HospitalSydneyAustralia
  4. 4.University of SydneySydneyAustralia

Personalised recommendations