The tissue expression pattern of CA 19.9 is associated with oncological features in medullary thyroid carcinoma

Abstract

Purpose

Elevated serum levels of carbohydrate antigen 19.9 (CA19.9), a well-established tumor marker in pancreatic neoplasms, has been proposed as a prognostic marker of tumor aggressiveness in medullary thyroid carcinoma (MTC). A hypothesis of C-cell dedifferentiation has been raised. Here, we evaluated the expression of CA19.9 and CD133, a stem cell marker, in MTC tissues.

Methods

MTC samples from patients attending a university-based hospital were evaluated for CA19.9 and CD133 expression by immunohistochemistry. Clinical data were retrieved from medical records.

Results

Tumor specimens from 70 MTC patients (57.1% hereditary) were evaluated. The age at diagnosis was 36.1 ± 16.3 years, and 58.6% were female; 53% of patients had cervical and 20% distant metastases. CA19.9 staining was detected in 87% of the samples, but no association was observed with biochemical markers, tumor size, local or distant metastases (All P > 0.05). Remarkable, CA19.9 expression was higher in the metastasis than in primary tumor samples (P = 0.0002). CD133 was expressed in 90.5% samples, but no correlation was found with CA19.9. Interestingly, we identified three distinct expression patterns to CA19.9: individual, focal, and diffuse cells. Sporadic MTC was associated with the individual cell pattern (70.6%), while the hereditary form with the focal expression pattern (63.9%; P = 0.04). Remarkably, the diffuse pattern was associated with larger tumor size and distant metastases (P = 0.032).

Conclusions

The majority of samples stained for CA19.9, suggesting it is an MTC cell-intrinsic feature. Three distinct expression patterns were identified, which were associated with the hereditary or sporadic form, larger tumor size, and presence of metastases.

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References

  1. 1.

    L. Davies, H.G. Welch, Increasing incidence of thyroid cancer in the United States, 1973-2002. JAMA 295(18), 2164–2167 (2006). https://doi.org/10.1001/jama.295.18.2164

    CAS  Article  PubMed  Google Scholar 

  2. 2.

    S.A. Hundahl, I.D. Fleming, A.M. Fremgen, H.R. Menck, A National Cancer Data Base report on 53,856 cases of thyroid carcinoma treated in the U.S., 1985-1995 [see commetns]. Cancer 83(12), 2638–2648 (1998). 10.1002/(SICI)1097-0142(19981215)83:12<2638::AID-CNCR31>3.0.CO;2-1 [pii]

    CAS  Article  Google Scholar 

  3. 3.

    M.R. Pelizzo, I.M. Boschin, P. Bernante, A. Toniato, A. Piotto, C. Pagetta, O. Nibale, L. Rampin, P.C. Muzzio, D. Rubello, Natural history, diagnosis, treatment and outcome of medullary thyroid cancer: 37 years experience on 157 patients. Eur. J. Surg. Oncol. 33(4), 493–497 (2007). https://doi.org/10.1016/j.ejso.2006.10.021

    CAS  Article  PubMed  Google Scholar 

  4. 4.

    A.L. Maia, S.M. Wajner, C.V. Vargas, Advances and controversies in the management of medullary thyroid carcinoma. Curr. Opin. Oncol. 29(1), 25–32 (2017). https://doi.org/10.1097/CCO.0000000000000340

    Article  PubMed  Google Scholar 

  5. 5.

    A. Laure Giraudet, A. Al Ghulzan, A. Auperin, S. Leboulleux, A. Chehboun, F. Troalen, C. Dromain, J. Lumbroso, E. Baudin, M. Schlumberger, Progression of medullary thyroid carcinoma: assessment with calcitonin and carcinoembryonic antigen doubling times. Eur. J. Endocrinol. 158(2), 239–246 (2008). https://doi.org/10.1530/EJE-07-0667

    CAS  Article  PubMed  Google Scholar 

  6. 6.

    J.A. Meijer, S. le Cessie, W.B. van den Hout, J. Kievit, J.W. Schoones, J.A. Romijn, J.W. Smit, Calcitonin and carcinoembryonic antigen doubling times as prognostic factors in medullary thyroid carcinoma: a structured meta-analysis. Clin. Endocrinol. 72(4), 534–542 (2010). https://doi.org/10.1111/j.1365-2265.2009.03666.x

    CAS  Article  Google Scholar 

  7. 7.

    J. Barbet, L. Campion, F. Kraeber-Bodere, J.F. Chatal, Prognostic impact of serum calcitonin and carcinoembryonic antigen doubling-times in patients with medullary thyroid carcinoma. J. Clin. Endocrinol. Metab. 90(11), 6077–6084 (2005). https://doi.org/10.1210/jc.2005-0044

    CAS  Article  PubMed  Google Scholar 

  8. 8.

    R. Lamerz, Role of tumour markers, cytogenetics. Ann. Oncol. 10(Suppl 4), 145–149 (1999).

    Article  Google Scholar 

  9. 9.

    V. Hess, B. Glimelius, P. Grawe, D. Dietrich, G. Bodoky, T. Ruhstaller, E. Bajetta, P. Saletti, A. Figer, W. Scheithauer, R. Herrmann, CA 19-9 tumour-marker response to chemotherapy in patients with advanced pancreatic cancer enrolled in a randomised controlled trial. Lancet Oncol. 9(2), 132–138 (2008). https://doi.org/10.1016/S1470-2045(08)70001-9

    CAS  Article  PubMed  Google Scholar 

  10. 10.

    N.R. Maisey, A.R. Norman, A. Hill, A. Massey, J. Oates, D. Cunningham, CA19-9 as a prognostic factor in inoperable pancreatic cancer: the implication for clinical trials. Br. J. Cancer 93(7), 740–743 (2005). https://doi.org/10.1038/sj.bjc.6602760

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  11. 11.

    O. Micke, F. Bruns, R. Kurowski, E. Horst, A.F. deVries, J.W. Hausler, N. Willich, U. Schafer, Predictive value of carbohydrate antigen 19-9 in pancreatic cancer treated with radiochemotherapy. Int J. Radiat. Oncol. Biol. Phys. 57(1), 90–97 (2003). S0360301603005248 [pii]

    CAS  Article  Google Scholar 

  12. 12.

    R. Passerini, M.C. Cassatella, S. Boveri, M. Salvatici, D. Radice, L. Zorzino, C. Galli, M.T. Sandri, The pitfalls of CA19-9: routine testing and comparison of two automated immunoassays in a reference oncology center. Am. J. Clin. Pathol. 138(2), 281–287 (2012). https://doi.org/10.1309/AJCPOPNPLLCYR07H

    CAS  Article  PubMed  Google Scholar 

  13. 13.

    R. Elisei, L. Lorusso, C. Romei, V. Bottici, S. Mazzeo, C. Giani, E. Fiore, L. Torregrossa, A.C. Insilla, F. Basolo, A. Guerini, A. Menghi, A. Poletti, L. Cugudda, P. Vitti, Medullary thyroid cancer secreting carbohydrate antigen 19-9 (Ca 19-9): a fatal case report. J. Clin. Endocrinol. Metab. 98(9), 3550–3554 (2013). https://doi.org/10.1210/jc.2013-1940

    CAS  Article  PubMed  Google Scholar 

  14. 14.

    S. Milman, K.D. Whitney, N. Fleischer, Metastatic medullary thyroid cancer presenting with elevated levels of CA 19-9 and CA 125. Thyroid 21(8), 913–916 (2011). https://doi.org/10.1089/thy.2010.0425

    Article  PubMed  Google Scholar 

  15. 15.

    R. Elisei, L. Lorusso, P. Piaggi, L. Torregrossa, G. Pellegrini, E. Molinaro, L. Agate, V. Bottici, F. Pani, A. Cacciato Insilla, F. Casella, R. Ciampi, I. Tognetti, G. Materazzi, F. Basolo, C. Romei, Elevated level of serum carbohydrate antigen 19.9 as predictor of mortality in patients with advanced medullary thyroid cancer. Eur. J. Endocrinol. 173(3), 297–304 (2015). https://doi.org/10.1530/EJE-15-0304

    CAS  Article  PubMed  Google Scholar 

  16. 16.

    R. Alencar, D.B. Kendler, F. Andrade, C. Nava, D. Bulzico, C.C.D. Pessoa, R. Corbo, F. Vaisman, CA19-9 as a Predictor of Worse Clinical Outcome in Medullary Thyroid Carcinoma. Eur. Thyroid J. 8(4), 186–191 (2019). https://doi.org/10.1159/000497201

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  17. 17.

    D.R. Siqueira, M. Romitti, A.P. da Rocha, L. Ceolin, C. Meotti, A. Estivalet, M.K. Punales, A.L. Maia, The RET polymorphic allele S836S is associated with early metastatic disease in patients with hereditary or sporadic medullary thyroid carcinoma. Endocr. Relat. Cancer 17(4), 953–963 (2010). https://doi.org/10.1677/ERC-09-0312

    Article  PubMed  Google Scholar 

  18. 18.

    S.A. Wells Jr., S.L. Asa, H. Dralle, R. Elisei, D.B. Evans, R.F. Gagel, N. Lee, A. Machens, J.F. Moley, F. Pacini, F. Raue, K. Frank-Raue, B. Robinson, M.S. Rosenthal, M. Santoro, M. Schlumberger, M. Shah, S.G. Waguespack, Revised American Thyroid Association guidelines for the management of medullary thyroid carcinoma. Thyroid 25(6), 567–610 (2015). https://doi.org/10.1089/thy.2014.0335

    Article  PubMed  PubMed Central  Google Scholar 

  19. 19.

    M.B. Amin, S. Edge, F. Greene, D.R. Byrd, R.K. Brookland, M.K. Washington, J.E. Gershenwald, C.C. Compton, K.R. Hess, D.C. Sullivan, J.M. Jessup, J.D. Brierley, L.E. Gaspar, R.L. Schilsky, C.M. Balch, D.P. Winchester, E.A. Asare, M. Madera, D.M. Gress, L.R. Meyer (Eds.), AJCC Cancer Staging Manual (8th edition) (Springer International Publishing, American Joint Commission on Cancer, 2017)

  20. 20.

    A.L. Maia, D.R. Siqueira, M.A. Kulcsar, A.J. Tincani, G.M. Mazeto, L.M. Maciel, Diagnosis, treatment, and follow-up of medullary thyroid carcinoma: recommendations by the Thyroid Department of the Brazilian Society of Endocrinology and Metabolism. Arq. Bras. Endocrinol. Metab. 58(7), 667–700 (2014)

    Article  Google Scholar 

  21. 21.

    S. Milman, J.L. Arnold, M. Price, A. Negassa, M.I. Surks, N. Fleischer, K.D. Whitney, Medullary thyroid cancer that stains negative for Ca 19-9 has decreased metastatic potential. Endocr. Pr. 21(6), 590–594 (2015). https://doi.org/10.4158/EP14357.OR

    Article  Google Scholar 

  22. 22.

    W. Zhu, T. Hai, L. Ye, G.J. Cote, Medullary thyroid carcinoma cell lines contain a self-renewing CD133+ population that is dependent on ret proto-oncogene activity. J. Clin. Endocrinol. Metab. 95(1), 439–444 (2010). https://doi.org/10.1210/jc.2009-1485

    CAS  Article  PubMed  Google Scholar 

  23. 23.

    Y. Bi, Y. Meng, H. Wu, Q. Cui, Y. Luo, X. Xue, Expression of the potential cancer stem cell markers CD133 and CD44 in medullary thyroid carcinoma: A ten-year follow-up and prognostic analysis. J. Surg. Oncol. 113(2), 144–151 (2016). https://doi.org/10.1002/jso.24124

    CAS  Article  PubMed  Google Scholar 

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Funding

This work has been made possible by grants from Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq), Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES), Fundo de Incentivo a Pesquisa (FIPE), and Programa de Apoio a Núcleos de Excelência (PRONEX)/Fundação de Amparo à Pesquisa do Estado do Rio Grande do Sul (FAPERGS).

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Contributions

Conception and design: C.V.F.V., A.L.M. Provision of study materials or patients: A.L.M. Collection and assembly of data: all authors. Data analysis and interpretation: C.V.F.V., L.C., R.S.S., A.L.M. Manuscript writing: C.V.F., L.C., R.S.S., and A.L.M. Final approval of manuscript: all authors.

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Correspondence to Ana Luiza Maia.

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Vargas, C.V.F., Ceolin, L., Scheffel, R.S. et al. The tissue expression pattern of CA 19.9 is associated with oncological features in medullary thyroid carcinoma. Endocrine (2020). https://doi.org/10.1007/s12020-020-02377-3

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Keywords

  • Medullary thyroid carcinoma
  • CA 19.9
  • CD133
  • C-cell dedifferentiation