title: A Nationwide Study of Multiple Endocrine Neoplasia Type 2A in Norway: Predictive and Prognostic Factors for the Clinical Course of Medullary Thyroid Carcinoma.
abstract: Multiple endocrine neoplasia type 2A (MEN 2A) is an autosomal dominant syndrome caused by activating germline mutations in the RET (REarranged during Transfection) proto-oncogene. MEN 2A has a strong (>95%) and age-dependent (5-25 years) clinical penetrance of medullary thyroid carcinoma (MTC). Several major studies have analyzed the predictive and prognostic factors for MEN 2A to find indicators that predict the optimal timing of prophylactic thyroidectomy. The aims of this study were to describe all known RET positive MEN 2A patients diagnosed in Norway and to evaluate the clinical course of MTC, as well as its predictive and prognostic factors.
  
  
  
  This nationwide retrospective cohort study included data for 65 (14 index and 51 screening patients) out of a total of 67 MEN 2A patients with the RET gene mutation who were diagnosed in Norway since 1974. Data were collected by reviewing patient files. The variables analyzed were genotype, phenotype, preoperative basal calcitonin, age at thyroid surgery, central lymph node dissection and nodal status at primary surgery, number of surgical procedures, and biochemical cure. Of the 65 patients, 60 had undergone thyroid surgery. The median follow-up period was 9.9 years. The patients were divided into pre-RET-and RET-era, which included patients who had thyroid surgery before January 1, 1994, and after, respectively.
  
  
  
  In index and screening patients, MTC was found, respectively, in 100% and 45% of cases, central lymph node dissection at primary surgery was done for 64% and 52% of patients, and the median total number of surgical procedures was two (range 1-6) and one (range 1-4). At primary surgery, all patients (n = 13) with lymph node metastases had preoperative basal calcitonin levels ≥68 pg/mL, and all patients (n = 17) without central lymph node dissection and preoperative basal calcitonin <40 pg/mL were biochemically cured. Multivariate analysis showed that preoperative basal calcitonin was a significant predictive factor for MTC superior to age at thyroid surgery when analyzing the entire period (p = 0.009) and the RET-era separately (p = 0.021). Prognostic factors for biochemical cure were preoperative basal calcitonin, central lymph node dissection, and nodal status at primary surgery (p = 0.037, p = 0.002, and p = 0.005) when analyzing the entire period, but only nodal status at primary surgery when the RET-era was considered separately (p = 0.006).
  
  
  
  Preoperative basal calcitonin alone can serve as an indicator for optimal timing and the extent of thyroid surgery for MEN 2A patients that could be considered safe. The results are consistent with previously reported data.
authors.affiliation: 1 Department of Oncology, Section for Breast and Endocrine Surgery, Oslo University Hospital , Oslo, Norway .|2 Institute of Clinical Medicine, University of Oslo , Oslo, Norway .
authors.forename: Else Marie
authors.initials: EM
authors.lastname: Opsahl
authors.affiliation: 3 Department of Breast and Endocrine Surgery, Haukeland University Hospital , Bergen, Norway .|4 Department of Clinical Science, University of Bergen , Bergen, Norway .
authors.forename: Michael
authors.initials: M
authors.lastname: Brauckhoff
authors.affiliation: 1 Department of Oncology, Section for Breast and Endocrine Surgery, Oslo University Hospital , Oslo, Norway .
authors.forename: Ellen
authors.initials: E
authors.lastname: Schlichting
authors.affiliation: 5 Department of Breast and Endocrine Surgery, St. Olavs University Hospital , Trondheim, Norway .
authors.forename: Kristin
authors.initials: K
authors.lastname: Helset
authors.affiliation: 6 Division of Internal Medicine, University Hospital of North Norway , Tromsø, Norway .|7 Institute of Clinical Medicine, UIT, The Arctic University of Norway , Tromsø, Norway .
authors.forename: Johan
authors.initials: J
authors.lastname: Svartberg
authors.affiliation: 3 Department of Breast and Endocrine Surgery, Haukeland University Hospital , Bergen, Norway .
authors.forename: Katrin
authors.initials: K
authors.lastname: Brauckhoff
authors.affiliation: 8 Department of Medical Genetics, Oslo University Hospital , Oslo, Norway .
authors.forename: Lovise
authors.initials: L
authors.lastname: Mæhle
authors.affiliation: 9 Department of Medical Genetics, Haukeland University Hospital , Bergen, Norway .
authors.forename: Lars Fredrik
authors.initials: LF
authors.lastname: Engebretsen
authors.affiliation: 10 Department of Pathology, Oslo University Hospital , Oslo, Norway .
authors.forename: Eva
authors.initials: E
authors.lastname: Sigstad
authors.affiliation: 10 Department of Pathology, Oslo University Hospital , Oslo, Norway .
authors.forename: Krystyna K
authors.initials: KK
authors.lastname: Grøholt
authors.affiliation: 11 Centre for Cancer Biomarkers CCBIO, Department of Clinical Medicine, Section for Pathology, University of Bergen , Bergen, Norway .|12 Department of Pathology, Haukeland University Hospital , Bergen, Norway .
authors.forename: Lars Andreas
authors.initials: LA
authors.lastname: Akslen
authors.affiliation: 13 Department of Thoracic Surgery, Oslo University Hospital , Oslo, Norway .
authors.forename: Lars Hilmar
authors.initials: LH
authors.lastname: Jørgensen
authors.affiliation: 3 Department of Breast and Endocrine Surgery, Haukeland University Hospital , Bergen, Norway .|4 Department of Clinical Science, University of Bergen , Bergen, Norway .
authors.forename: Jan Erik
authors.initials: JE
authors.lastname: Varhaug
authors.affiliation: 2 Institute of Clinical Medicine, University of Oslo , Oslo, Norway .|14 Department of Medical Biochemistry, Oslo University Hospital , Oslo, Norway .
authors.forename: Trine
authors.initials: T
authors.lastname: Bjøro
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D014408:Biomarkers, Tumor / Q000097:blood; D002116:Calcitonin / Q000097:blood; D018276:Carcinoma, Medullary / Q000097:blood / Q000235:genetics / Q000473:pathology* / Q000601:surgery; D002648:Child; D002675:Child, Preschool; D018450:Disease Progression; D005260:Female; D006801:Humans; D008197:Lymph Node Excision; D008297:Male; D008875:Middle Aged; D018813:Multiple Endocrine Neoplasia Type 2a / Q000097:blood / Q000235:genetics / Q000473:pathology* / Q000601:surgery; D009664:Norway; D011379:Prognosis; D000090063:Proto-Oncogene Mas; D051096:Proto-Oncogene Proteins c-ret / Q000235:genetics*; D013964:Thyroid Neoplasms / Q000097:blood / Q000235:genetics / Q000473:pathology* / Q000601:surgery; D013965:Thyroidectomy; D055815:Young Adult
chemical_list: D014408:Biomarkers, Tumor; C000715470:MAS1 protein, human; D000090063:Proto-Oncogene Mas; D002116:Calcitonin; D051096:Proto-Oncogene Proteins c-ret; C099282:RET protein, human