title: Prevalence and clinical spectrum of nonsecretory medullary thyroid carcinoma in a series of 839 patients with sporadic medullary thyroid carcinoma.
abstract: BACKGROUND
  Medullary thyroid carcinoma (MTC) is characterized by the synthesis and secretion of calcitonin (Ct). MTC without Ct secretion has been reported on rare occasions. The aim of this study was to analyze the prevalence and clinical spectrum of nonsecretory MTC in two tertiary centers that cared for 839 patients with sporadic MTC.
  
  
  METHODS
  Clinical, biochemical, histological, and immunohistological findings, and somatic RET mutations were analyzed, and long-term follow-up was documented.
  
  
  RESULTS
  Seven patients with nonsecretory MTC were identified among 839 patients with sporadic MTC; thus, the prevalence rate of nonsecretory MTC was 0.83%. In these seven patients, Ct and carcinoembryonic antigen (CEA) levels were normal when MTC was initially diagnosed in the patients, despite advanced tumor stage. Ct and CEA levels remained undetectable in four patients; recurrence was indicated in one patient after 10 years of follow-up by routine anatomic imaging and increased CEA levels, and Ct levels became slightly elevated during follow-up, despite massive tumor load, in the remaining two patients. The diagnosis of MTC was confirmed by positive immunohistochemistry for Ct, CEA, and chromogranin A. A high Ki67 proliferation index (PI) (three patients) and a high proportion of RET 918-mutated cells (four patients), as well as poorly differentiated histology, were associated with aggressive biological behavior of the MTC. The prognosis for nonsecretory MTC varied between long-term survival (12.5 years) and rapid progression leading to death within 1.75 years after diagnosis.
  
  
  CONCLUSIONS
  The prevalence of nonsecretory MTC was low (0.83% of patients with MTC). Diagnosis was often made at a clinically advanced tumor stage. The histological and immunohistological characteristics and the clinical course and prognosis of nonsecretory MTC are markedly heterogeneous. A high Ki-67 PI and a large proportion of cells with RET 918 mutations are associated with a poor prognosis.
authors.affiliation: Endocrine Practice, Molecular Laboratory, Brueckenstrasse 21, Heidelberg, Germany. karin.frankraue@raue-endokrinologie.de
authors.forename: Karin
authors.initials: K
authors.lastname: Frank-Raue
authors.forename: Andreas
authors.initials: A
authors.lastname: Machens
authors.forename: Gudrun
authors.initials: G
authors.lastname: Leidig-Bruckner
authors.forename: Susanne
authors.initials: S
authors.lastname: Rondot
authors.forename: Christine
authors.initials: C
authors.lastname: Haag
authors.forename: Egbert
authors.initials: E
authors.lastname: Schulze
authors.forename: Angela
authors.initials: A
authors.lastname: Lorenz
authors.forename: Michael C
authors.initials: MC
authors.lastname: Kreissl
authors.forename: Henning
authors.initials: H
authors.lastname: Dralle
authors.forename: Friedhelm
authors.initials: F
authors.lastname: Raue
authors.forename: Kurt W
authors.initials: KW
authors.lastname: Schmid
mesh_terms: D000368:Aged; D014408:Biomarkers, Tumor / Q000378:metabolism; D018276:Carcinoma, Medullary / Q000175:diagnosis* / Q000453:epidemiology*; D018278:Carcinoma, Neuroendocrine; D049109:Cell Proliferation; D018450:Disease Progression; D005260:Female; D006801:Humans; D019394:Ki-67 Antigen / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D009154:Mutation; D015995:Prevalence; D011379:Prognosis; D051096:Proto-Oncogene Proteins c-ret / Q000378:metabolism; D013964:Thyroid Neoplasms / Q000175:diagnosis* / Q000453:epidemiology*; D016896:Treatment Outcome
chemical_list: D014408:Biomarkers, Tumor; D019394:Ki-67 Antigen; D051096:Proto-Oncogene Proteins c-ret