title: Combined RET and Ki-67 assessment in sporadic medullary thyroid carcinoma: a useful tool for patient risk stratification.
abstract: OBJECTIVE
  Medullary thyroid carcinoma (MTC) derives from the parafollicular C cells, being sporadic in 75% of cases and familial in 25%, due to RET proto-oncogene germinal mutations. In sporadic forms, stage at diagnosis is the most important negative prognostic factor. The aim of this study was to evaluate the prognostic impact of molecular and immunohistochemical markers in sporadic MTC.
  
  
  METHODS
  We studied 60 patients with sporadic MTC. For each case, we sought RET somatic mutations in the primary cancer and in lymph node metastases. The primary cancer also underwent immunohistochemical examination for Ki-67.
  
  
  RESULTS
  A somatic RET mutation was found in 38% of patients, being M918T in 52% of them. We observed a statistically significant association between RET mutations and male gender (P<0.01), tumor size (P<0.05), lymph nodes (P<0.05) and distant metastases (P<0.001), advanced stage (P<0.05), increased risk of persistent disease (P=0.01), and low overall survival (P<0.01). High Ki-67 levels were similarly associated with extra-thyroid spread (P<0.05), lymph nodes (P<0.05) and distant metastases (P<0.001), advanced stage (P=0.01), and low overall survival (P=0.01). Combining somatic RET analysis with Ki-67 assessment seems to be useful for increasing the specificity of Ki-67 assessment alone and identifying patients with a more aggressive cancer: in our series, only the patients who died during the follow-up had both a somatic RET mutation and a Ki-67 expression level >50 cells/mm(2).
  
  
  CONCLUSIONS
  The combined evaluation of RET and Ki-67 could act as an adjuvant prognostic marker useful for ameliorating the initial risk stratification of patients with sporadic MTC.
authors.affiliation: Endocrinology Unit, Department of Medical and Surgical Sciences, University of Padova, Via Ospedale n.105, 35128 Padova, Italy. caterina.mian@unipd.it
authors.forename: Caterina
authors.initials: C
authors.lastname: Mian
authors.forename: Gianmaria
authors.initials: G
authors.lastname: Pennelli
authors.forename: Susi
authors.initials: S
authors.lastname: Barollo
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Cavedon
authors.forename: Davide
authors.initials: D
authors.lastname: Nacamulli
authors.forename: Federica
authors.initials: F
authors.lastname: Vianello
authors.forename: Isabella
authors.initials: I
authors.lastname: Negro
authors.forename: Giulia
authors.initials: G
authors.lastname: Pozza
authors.forename: Isabella Merante
authors.initials: IM
authors.lastname: Boschin
authors.forename: Maria Rosa
authors.initials: MR
authors.lastname: Pelizzo
authors.forename: Massimo
authors.initials: M
authors.lastname: Rugge
authors.forename: Franco
authors.initials: F
authors.lastname: Mantero
authors.forename: Maria Elisa
authors.initials: ME
authors.lastname: Girelli
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Opocher
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000097:blood / Q000378:metabolism; D018276:Carcinoma, Medullary / Q000453:epidemiology / Q000235:genetics* / Q000378:metabolism; D018278:Carcinoma, Neuroendocrine; D005091:Exons; D005260:Female; D005838:Genotype; D006801:Humans; D007150:Immunohistochemistry; D019394:Ki-67 Antigen / Q000235:genetics* / Q000378:metabolism; D008207:Lymphatic Metastasis / Q000473:pathology; D008297:Male; D008875:Middle Aged; D000090063:Proto-Oncogene Mas; D051096:Proto-Oncogene Proteins c-ret / Q000235:genetics* / Q000378:metabolism; D012372:ROC Curve; D018570:Risk Assessment; D016019:Survival Analysis; D013964:Thyroid Neoplasms / Q000453:epidemiology / Q000235:genetics / Q000378:metabolism; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D014408:Biomarkers, Tumor; D019394:Ki-67 Antigen; C000715470:MAS1 protein, human; D000090063:Proto-Oncogene Mas; D051096:Proto-Oncogene Proteins c-ret