Home Utility of proGRP as a tumor marker in the medullary thyroid carcinoma
Article
Licensed
Unlicensed Requires Authentication

Utility of proGRP as a tumor marker in the medullary thyroid carcinoma

  • Marina Parra-Robert , Aida Orois , Josep Maria Augé EMAIL logo , Irene Halperin , Xavier Filella and Rafael Molina
Published/Copyright: October 18, 2016
Become an author with De Gruyter Brill
Submit Manuscript Author Information
Clinical Chemistry and Laboratory Medicine (CCLM)
From the journal Clinical Chemistry and Laboratory Medicine (CCLM) Volume 55 Issue 3

Abstract

Background:

Medullary thyroid carcinoma (MTC) is a neuroendocrine tumor caused by a malignant transformation in the parafollicular C-cells of the thyroid, where calcitonin (CT) is released. Nowadays the main tumor markers (TM) used in the diagnosis and follow-up of MTC patients are CT and carcinoembryonic antigen (CEA). Nonetheless, progastrin releasing peptide (proGRP) has been recently proposed as a TM useful in the MTC. Our aims were to investigate the release of proGRP in thyroid tumors, its role in the assessment of advanced MTC and its utility in the differential diagnosis between MTC and non-MTC thyroid tumors.

Methods:

Serum samples from 22 patients with MTC and 16 with non-MTC were collected. Patients were classified into advanced cancer or no evidence of disease (NED). ProGRP was performed by Architect (Abbot Diagnostics), CT by Liaison (Diasorin) and CEA by Cobas E601(Roche Diagnostics).

Results:

ProGRP median concentration in advanced MTC was significantly higher (1398.4 pg/mL) when compared with non-MTC, either in advanced disease (24.9 pg/mL) or NED (14.6 pg/mL). In non-MTC patients, proGRP median concentration was below its cutoff level (50 pg/mL). Similar to CT, proGRP was able to detect 88.9% of MTC patients, but with a slightly lower specificity of 76.9%. Using proGRP together with CT the sensitivity increased to 100%.

Conclusions:

The low prevalence of this malignancy strongly recommends further collaborative studies, mainly focused on monitoring proGRP during tyrosine kinase inhibitors treatment for early detection of resistance and assessing its usefulness to avoid the observed false positive fluctuations that occur with CT and CEA.

Keywords: calcitonin; carcinoembryonic antigen (CEA); medullary thyroid carcinoma; progastrin releasing peptide (proGRP); thyroid tumor
Corresponding author: Josep Maria Augé, MD, Biochemistry and Molecular Genetics Department, Hospital Clinic, Villarroel, 170, 08036 – Barcelona, Spain

  1. Author contributions: All the authors have accepted responsibility for the entire content of this submitted manuscript and approved submission.

  2. Research funding: None declared.

  3. Employment or leadership: None declared.

  4. Honorarium: None declared.

  5. Competing interests: The funding organization(s) played no role in the study design; in the collection, analysis, and interpretation of data; in the writing of the report; or in the decision to submit the report for publication.

  6. Conflict of interest statement: The authors disclose no conflicts of interest.

References

1. Ganeshan D, Paulson E, Duran C, Cabanillas ME, Busaidy NL, Charnsangavej C. Current update on medullary thyroid carcinoma. Am J Roentgenol 2013;201:W867–76.10.2214/AJR.12.10370Search in Google Scholar

2. Hofstra RM, Landsvater RM, Ceccherini I, Stulp RP, Stelwagen T, Luo Y, et al. A mutation in the RET proto-oncogene associated with multiple endocrine neoplasia type 2B and sporadic medullary thyroid carcinoma. Nature 1994;367:375–6.10.1038/367375a0Search in Google Scholar

3. Mulligan LM, Kwok JB, Healey CS, Elsdon MJ, Eng C, Gardner E, et al. Germ-line mutations of the RET proto-oncogene in multiple endocrine neoplasia type 2A. Nature 1993;363:458–60.10.1038/363458a0Search in Google Scholar

4. Kebebew E, Ituarte PH, Siperstein AE, Duh QY, Clark OH. Medullary thyroid carcinoma: clinical characteristics, treatment, prognostic factors, and a comparison of staging systems. Cancer 2000;88:1139–48.10.1002/(SICI)1097-0142(20000301)88:5<1139::AID-CNCR26>3.0.CO;2-ZSearch in Google Scholar

5. Modigliani E, Cohen R, Campos JM, Conte-Devolx B, Maes B, Boneu A, et al. Prognostic factors for survival and for biochemical cure in medullary thyroid carcinoma: results in 899 patients. The GETC Study Group. Groupe d’etude des tumeurs a calcitonine. Clin Endocrinol (Oxf) 1998;48:265–73.10.1046/j.1365-2265.1998.00392.xSearch in Google Scholar

6. Pelizzo MR, Boschin IM, Toniato A, Pagetta C, Piotto A, Bernante P, et al. Natural history, diagnosis, treatment and outcome of papillary thyroid microcarcinoma (PTMC): a mono-institutional 12-year experience. Nucl Med Commun 2004;25:547–52.10.1097/01.mnm.0000126625.17166.36Search in Google Scholar

7. Trimboli P, Giovanella L, Crescenzi A, Romanelli F, Valabrega S, Spriano G, et al. Medullary thyroid cancer diagnosis: an appraisal. Head Neck 2014;36:1216–23.10.1002/hed.23449Search in Google Scholar

8. Trimboli P, Treglia G, Guidobaldi L, Romanelli F, Nigri G, Valabrega S, et al. Detection rate of FNA cytology in medullary thyroid carcinoma: a meta-analysis. Clin Endocrinol (Oxf) 2015;82:280–5.10.1111/cen.12563Search in Google Scholar

9. Machens A, Hauptmann S, Dralle H. Increased risk of lymph node metastasis in multifocal hereditary and sporadic medullary thyroid cancer. World J Surg 2007;31:1960–5.10.1007/s00268-007-9185-1Search in Google Scholar

10. Trimboli P, Giovanella L. Serum calcitonin negative medullary thyroid carcinoma: a systematic review of the literature. Clin Chem Lab Med 2015;53:1507–1514.10.1515/cclm-2015-0058Search in Google Scholar

11. Wells SA, Jr., Asa SL, Dralle H, Elisei R, Evans DB, Gagel RF, et al. Revised American Thyroid Association guidelines for the management of medullary thyroid carcinoma. Thyroid 2015;25:567–610.10.1089/thy.2014.0335Search in Google Scholar

12. Melvin KE. The paraneoplastic syndromes associated with carcinoma of the thyroid gland. Ann NY Acad Sci 1974;230:378–90.10.1111/j.1749-6632.1974.tb14472.xSearch in Google Scholar

13. Engelbach M, Gorges R, Forst T, Pfutzner A, Dawood R, Heerdt S, et al. Improved diagnostic methods in the follow-up of medullary thyroid carcinoma by highly specific calcitonin measurements. J Clin Endocrinol Metab 2000;85:1890–4.Search in Google Scholar

14. Moley JF, DeBenedetti MK, Dilley WG, Tisell LE, Wells SA. Surgical management of patients with persistent or recurrent medullary thyroid cancer. J Intern Med 1998;243:521–6.10.1046/j.1365-2796.1998.00333.xSearch in Google Scholar

15. Vierhapper H, Raber W, Bieglmayer C, Kaserer K, Weinhausl A, Niederle B. Routine measurement of plasma calcitonin in nodular thyroid diseases. J Clin Endocrinol Metab 1997;82:1589–93.10.1210/jcem.82.5.3949Search in Google Scholar

16. Ishikawa N, Hamada S. Association of medullary carcinoma of the thyroid with carcinoembryonic antigen. Br J Cancer 1976;34:111–5.10.1038/bjc.1976.133Search in Google Scholar

17. Niho S, Nishiwaki Y, Goto K, Ohmatsu H, Matsumoto T, Hojo F, et al. Significance of serum pro-gastrin-releasing peptide as a predictor of relapse of small cell lung cancer: comparative evaluation with neuron-specific enolase and carcinoembryonic antigen. Lung Cancer 2000;27:159–67.10.1016/S0169-5002(99)00100-2Search in Google Scholar

18. Mansson B, Ahren B, Nobin A, Bottcher G, Sundler F. Calcitonin, calcitonin gene-related peptide, and gastrin-releasing peptide in familial thyroid medullary carcinoma. Surgery 1990;107:182–6.Search in Google Scholar

19. Trimboli P, Seregni E, Treglia G, Alevizaki M, Giovanella L. Procalcitonin for detecting medullary thyroid carcinoma: a systematic review. Endocr Relat Cancer 2015;22:R157–R164.10.1530/ERC-15-0156Search in Google Scholar PubMed

20. Kameya T, Bessho T, Tsumuraya M, Yamaguchi K, Abe K, Shimosato Y, et al. Production of gastrin releasing peptide by medullary carcinoma of the thyroid. An immunohistochemical study. Virchows Arch A Pathol Anat Histopathol 1983;401:99–107.10.1007/BF00644793Search in Google Scholar PubMed

21. Modigliani E, Casanova S, Chayvialle JA, Bernard C, Franc B, Cohen R, et al. Immunoreactive gastrin-releasing peptide in medullary thyroid carcinoma. J Clin Endocrinol Metab 1990;71:831–5.10.1210/jcem-71-4-831Search in Google Scholar PubMed

22. Aoyagi K, Miyake Y, Urakami K, Kashiwakuma T, Hasegawa A, Kodama T, et al. Enzyme immunoassay of immunoreactive progastrin-releasing peptide (31–98) as tumor marker for small-cell lung carcinoma: development and evaluation. Clin Chem 1995;41:537–43.10.1093/clinchem/41.4.537Search in Google Scholar

23. Molina R, Filella X, Auge JM. ProGRP: a new biomarker for small cell lung cancer. Clin Biochem 2004;37:505–11.10.1016/j.clinbiochem.2004.05.007Search in Google Scholar PubMed

24. Yamaguchi K, Aoyagi K, Urakami K, Fukutani T, Maki N, Yamamoto S, et al. Enzyme-linked immunosorbent assay of pro-gastrin-releasing peptide for small cell lung cancer patients in comparison with neuron-specific enolase measurement. Jpn J Cancer Res 1995;86:698–705.10.1111/j.1349-7006.1995.tb02455.xSearch in Google Scholar PubMed PubMed Central

25. Korse CM, Holdenrieder S, Zhi XY, Zhang X, Qiu L, Geistanger A, et al. Multicenter evaluation of a new progastrin-releasing peptide (ProGRP) immunoassay across Europe and China. Clin Chim Acta 2015;438:388–95.10.1016/j.cca.2014.09.015Search in Google Scholar PubMed

26. Ide A, Ashizawa K, Ishikawa N, Ishii R, Ando T, Abe Y, et al. Elevation of serum pro-gastrin-releasing peptide in patients with medullary thyroid carcinoma and small cell lung carcinoma. Thyroid 2001;11:1055–61.10.1089/105072501753271752Search in Google Scholar PubMed

27. Inaji H, Komoike Y, Motomura K, Higashiyama M, Ohtsuru M, Funai H, et al. Demonstration and diagnostic significance of pro-gastrin-releasing peptide in medullary thyroid carcinoma. Oncology 2000;59:122–5.10.1159/000012148Search in Google Scholar PubMed

28. Takagi Y, Nakahara Y, Hosomi Y, Hishima T. Small-cell lung cancer with a rare epidermal growth factor receptor gene mutation showing “wax-and-wane” transformation. BMC Cancer 2013;13:529.10.1186/1471-2407-13-529Search in Google Scholar PubMed PubMed Central

29. Watanabe S, Sone T, Matsui T, Yamamura K, Tani M, Okazaki A, et al. Transformation to small-cell lung cancer following treatment with EGFR tyrosine kinase inhibitors in a patient with lung adenocarcinoma. Lung Cancer 2013; 82:370–2.10.1016/j.lungcan.2013.06.003Search in Google Scholar PubMed

30. Molina R, Auge JM, Alicarte J, Filella X, Vinolas N, Ballesta AM. Pro-gastrin-releasing peptide in patients with benign and malignant diseases. Tumour Biol 2004; 25:56–61.10.1159/000077724Search in Google Scholar PubMed

31. Molina R, Auge JM, Filella X, Vinolas N, Alicarte J, Domingo JM, et al. Pro-gastrin-releasing peptide (proGRP) in patients with benign and malignant diseases: comparison with CEA, SCC, CYFRA 21-1 and NSE in patients with lung cancer. Anticancer Res 2005; 25:1773–8.Search in Google Scholar

32. Guilloteau D, Perdrisot R, Calmettes C, Baulieu JL, Lecomte P, Kaphan G, et al. Diagnosis of medullary carcinoma of the thyroid (MCT) by calcitonin assay using monoclonal antibodies: criteria for the pentagastrin stimulation test in hereditary MCT. J Clin Endocrinol Metab 1990;71:1064–7.10.1210/jcem-71-4-1064Search in Google Scholar PubMed

33. Filella X, Ballesta AM, Fox M, Mitchell H, Molina R, Purstner P, et al. Multicentre clinical evaluation of the COBAS CORE CEA, CA 125 II and PSA tumor marker assays. Int J Biol Markers 1996;11:40–5.10.1177/172460089601100108Search in Google Scholar

34. Romei C, Elisei R, Pinchera A, Ceccherini I, Molinaro E, Mancusi F, et al. Somatic mutations of the ret protooncogene in sporadic medullary thyroid carcinoma are not restricted to exon 16 and are associated with tumor recurrence. J Clin Endocrinol Metab 1996;81:1619–22.Search in Google Scholar

35. Uchino S, Noguchi S, Adachi M, Sato M, Yamashita H, Watanabe S, et al. Novel point mutations and allele loss at the RET locus in sporadic medullary thyroid carcinomas. Jpn J Cancer Res 1998;89:411–8.10.1111/j.1349-7006.1998.tb00579.xSearch in Google Scholar PubMed PubMed Central

36. Alonso-Gordoa T, Diez JJ, Duran M, Grande E. Advances in thyroid cancer treatment: latest evidence and clinical potential. Ther Adv Med Oncol 2015;7:22–38.10.1177/1758834014551936Search in Google Scholar PubMed PubMed Central

37. Kurzrock R, Atkins J, Wheler J, Fu S, Naing A, Busaidy N, et al. Tumor marker and measurement fluctuations may not reflect treatment efficacy in patients with medullary thyroid carcinoma on long-term RET inhibitor therapy. Ann Oncol 2013;24:2256–61.10.1093/annonc/mdt177Search in Google Scholar PubMed

38. Postel-Vinay S, Schlumberger M, Soria JC. Tumour markers fluctuations in patients with medullary thyroid carcinoma receiving long-term RET inhibitor therapy: ordinary lapping or alarming waves foreshadowing disease progression? Ann Oncol 2013;24:2201–4.10.1093/annonc/mdt331Search in Google Scholar PubMed

39. Wells SA, Jr., Baylin SB, Linehan WM, Farrell RE, Cox EB, Cooper CW. Provocative agents and the diagnosis of medullary carcinoma of the thyroid gland. Ann Surg 1978;188:139–41.10.1097/00000658-197808000-00002Search in Google Scholar PubMed PubMed Central

40. Talmage RV, Grubb SA, Norimatsu H, Vanderwiel CJ. Evidence for an important physiological role for calcitonin. Proc Natl Acad Sci USA 1980;77:609–13.10.1073/pnas.77.1.609Search in Google Scholar PubMed PubMed Central

41. Kelley MJ, Becker KL, Rushin JM, Venzon D, Phelps R, Ihde DC, et al. Calcitonin elevation in small cell lung cancer without ectopic production. Am J Respir Crit Care Med 1994;149:183–90.10.1164/ajrccm.149.1.8111580Search in Google Scholar PubMed

42. Yiakoumakis E, Proukakis C, Raptis K, Korres A, Dondas N, Samaras V. Calcitonin concentrations in lung cancer and non-malignant pulmonary diseases. Oncology 1987;44:145–9.10.1159/000226466Search in Google Scholar PubMed

43. Schneider HG, Lam QT. Procalcitonin for the clinical laboratory: a review. Pathology 2007;39:383–90.10.1080/00313020701444564Search in Google Scholar PubMed

44. Copp DH, Cheney B. Calcitonin-a hormone from the parathyroid which lowers the calcium-level of the blood. Nature 1962;193:381–2.10.1038/193381a0Search in Google Scholar PubMed

45. Fragu P. Calcitonin’s fantastic voyage: from hormone to marker of a genetic disorder. Gesnerus 2007;64:69–92.10.1163/22977953-0640102004Search in Google Scholar

46. Cavalier E, Carlisi A, Chapelle JP, Delanaye P. Analytical quality of calcitonin determination and its effect on the adequacy of screening for medullary carcinoma of the thyroid. Clin Chem 2008;54:929–30.10.1373/clinchem.2007.100636Search in Google Scholar PubMed

47. Yamaguchi K, Abe K, Kameya T, Adachi I, Taguchi S, Otsubo K, et al. Production and molecular size heterogeneity of immunoreactive gastrin-releasing peptide in fetal and adult lungs and primary lung tumors. Cancer Res 1983;43:3932–9.Search in Google Scholar

Received: 2016-6-28
Accepted: 2016-9-19
Published Online: 2016-10-18
Published in Print: 2017-3-1

©2017 Walter de Gruyter GmbH, Berlin/Boston

Articles in the same Issue

  1. Frontmatter
  2. Editorials
  3. Targeting errors in microbiology: the case of the Gram stain
  4. Time for a holistic approach and standardization education in laboratory medicine
  5. Reviews
  6. Serum uric acid levels and risk of prehypertension: a meta-analysis
  7. Lactic acidosis: an update
  8. Mini Review
  9. Progress and impact of enzyme measurement standardization
  10. Opinion Paper
  11. Critical comments to a recent EFLM recommendation for the review of reference intervals
  12. IFCC Paper
  13. Quality Indicators in Laboratory Medicine: the status of the progress of IFCC Working Group “Laboratory Errors and Patient Safety” project
  14. Genetics and Molecular Diagnostics
  15. Evaluation and comparison of three assays for molecular detection of spinal muscular atrophy
  16. General Clinical Chemistry and Laboratory Medicine
  17. Risk analysis of the preanalytical process based on quality indicators data
  18. Analytical and clinical validation of the new Abbot Architect 25(OH)D assay: fit for purpose?
  19. Looking beyond linear regression and Bland-Altman plots: a comparison of the clinical performance of 25-hydroxyvitamin D tests
  20. Next-generation osmotic gradient ektacytometry for the diagnosis of hereditary spherocytosis: interlaboratory method validation and experience
  21. Diagnosis of sphingolipidoses: a new simultaneous measurement of lysosphingolipids by LC-MS/MS
  22. Monitoring nicotine intake from e-cigarettes: measurement of parent drug and metabolites in oral fluid and plasma
  23. Development of a rapid and quantitative lateral flow assay for the simultaneous measurement of serum κ and λ immunoglobulin free light chains (FLC): inception of a new near-patient FLC screening tool
  24. A real-world evidence-based approach to laboratory reorganization using e-Valuate benchmarking data
  25. Cancer Diagnostics
  26. Utility of proGRP as a tumor marker in the medullary thyroid carcinoma
  27. Cardiovascular Diseases
  28. Can non-cholesterol sterols and lipoprotein subclasses distribution predict different patterns of cholesterol metabolism and statin therapy response?
  29. Infectious Diseases
  30. Improving Gram stain proficiency in hospital and satellite laboratories that do not have microbiology
  31. Diabetes
  32. Volumetric absorptive microsampling at home as an alternative tool for the monitoring of HbA1c in diabetes patients
  33. Corrigendum
  34. EFLM Recommendation
  35. Corrigendum to: Recommendation for the review of biological reference intervals in medical laboratories
  36. Letters to the Editor
  37. Evaluation of the trueness of serum alkaline phosphatase measurement in a group of Italian laboratories
  38. Innovative software for recording preanalytical errors in accord with the IFCC quality indicators
  39. Mixing studies for abnormal coagulation screen – the current trend
  40. Identification of 5-fluorocytosine as a new interfering compound in serum capillary zone electrophoresis
  41. How to define reference intervals to rule in healthy individuals for clinical trials?
  42. Evaluation of the performance of INDEXOR® in the archive unit of a clinical laboratory: a step to Lean laboratory
  43. Evaluation of an automated chemiluminescent immunoassay for salivary cortisol measurement. Utility in the diagnosis of Cushing’s syndrome
  44. Analysis of hemolysis, icterus and lipemia in arterial blood gas specimens
  45. Comparison of three routine insulin immunoassays: implications for assessment of insulin sensitivity and response
https://doi.org/10.1515/cclm-2016-0572
Keywords for this article
calcitonin; carcinoembryonic antigen (CEA); medullary thyroid carcinoma; progastrin releasing peptide (proGRP); thyroid tumor

Articles in the same Issue

  1. Frontmatter
  2. Editorials
  3. Targeting errors in microbiology: the case of the Gram stain
  4. Time for a holistic approach and standardization education in laboratory medicine
  5. Reviews
  6. Serum uric acid levels and risk of prehypertension: a meta-analysis
  7. Lactic acidosis: an update
  8. Mini Review
  9. Progress and impact of enzyme measurement standardization
  10. Opinion Paper
  11. Critical comments to a recent EFLM recommendation for the review of reference intervals
  12. IFCC Paper
  13. Quality Indicators in Laboratory Medicine: the status of the progress of IFCC Working Group “Laboratory Errors and Patient Safety” project
  14. Genetics and Molecular Diagnostics
  15. Evaluation and comparison of three assays for molecular detection of spinal muscular atrophy
  16. General Clinical Chemistry and Laboratory Medicine
  17. Risk analysis of the preanalytical process based on quality indicators data
  18. Analytical and clinical validation of the new Abbot Architect 25(OH)D assay: fit for purpose?
  19. Looking beyond linear regression and Bland-Altman plots: a comparison of the clinical performance of 25-hydroxyvitamin D tests
  20. Next-generation osmotic gradient ektacytometry for the diagnosis of hereditary spherocytosis: interlaboratory method validation and experience
  21. Diagnosis of sphingolipidoses: a new simultaneous measurement of lysosphingolipids by LC-MS/MS
  22. Monitoring nicotine intake from e-cigarettes: measurement of parent drug and metabolites in oral fluid and plasma
  23. Development of a rapid and quantitative lateral flow assay for the simultaneous measurement of serum κ and λ immunoglobulin free light chains (FLC): inception of a new near-patient FLC screening tool
  24. A real-world evidence-based approach to laboratory reorganization using e-Valuate benchmarking data
  25. Cancer Diagnostics
  26. Utility of proGRP as a tumor marker in the medullary thyroid carcinoma
  27. Cardiovascular Diseases
  28. Can non-cholesterol sterols and lipoprotein subclasses distribution predict different patterns of cholesterol metabolism and statin therapy response?
  29. Infectious Diseases
  30. Improving Gram stain proficiency in hospital and satellite laboratories that do not have microbiology
  31. Diabetes
  32. Volumetric absorptive microsampling at home as an alternative tool for the monitoring of HbA1c in diabetes patients
  33. Corrigendum
  34. EFLM Recommendation
  35. Corrigendum to: Recommendation for the review of biological reference intervals in medical laboratories
  36. Letters to the Editor
  37. Evaluation of the trueness of serum alkaline phosphatase measurement in a group of Italian laboratories
  38. Innovative software for recording preanalytical errors in accord with the IFCC quality indicators
  39. Mixing studies for abnormal coagulation screen – the current trend
  40. Identification of 5-fluorocytosine as a new interfering compound in serum capillary zone electrophoresis
  41. How to define reference intervals to rule in healthy individuals for clinical trials?
  42. Evaluation of the performance of INDEXOR® in the archive unit of a clinical laboratory: a step to Lean laboratory
  43. Evaluation of an automated chemiluminescent immunoassay for salivary cortisol measurement. Utility in the diagnosis of Cushing’s syndrome
  44. Analysis of hemolysis, icterus and lipemia in arterial blood gas specimens
  45. Comparison of three routine insulin immunoassays: implications for assessment of insulin sensitivity and response
Sign up now to receive a 20% welcome discount
Institutional Access
How does access work?
Have an idea on how to improve our website?
Please write us.
© 2025 De Gruyter Brill
Downloaded on 18.9.2025 from https://www.degruyterbrill.com/document/doi/10.1515/cclm-2016-0572/html
Scroll to top button