title: A nationwide study on parathyroid carcinoma.
abstract: BACKGROUND
  Parathyroid carcinoma (PC) is rare and diagnostically challenging. Reported outcomes are rather poor and the incidence might be increasing.
  
  
  METHODS
  We performed a nationwide study on all cases (n= 32) diagnosed in 2000-2011 in Finland, and compared clinical and histopathological characteristics and outcome to atypical parathyroid (APA; n= 28) and parathyroid adenomas (PA; n= 72). The incidence in years 1955-1999 was compared to that in 2000-2013.
  
  
  RESULTS
  Preoperatively, calcium and parathyroid hormone concentrations were higher in PC compared to APA and PA (1.76, 1.56 and 1.44 mmol/l, p < .001; and 989, 355 and 160 μmol/l, p < .001, respectively). Calcium was ≤1.77 mmol/l for all PAs. Hospitalization (44% vs. 22% and 3%, respectively, p = .01), renal (50% vs. 48% vs. 22%, respectively, p = .01) and bone (47% vs. 15% vs. 38%, respectively p = .002) manifestations were more common. PC and APA tumors were larger than PA (p < .001). Histopathological characteristics of PC compared to PA are increased mitotic activity (p= .001), chief cells (p = .003), diffuse growth pattern (p < .001), higher Ki67 (p< .001) and negative parafibromin (p < .001). One PC (1/18) and one APA (1/16) patient had a CDC73 mutation. After 6.7 (2-13.9) years of follow-up, 9.4% of PC had residual, 21% recurrent disease and 12.5% died of disease. Overall mortality did not differ between subgroups (p = .094). Recurrent PC was characterized by vascular invasion, lymph node metastases, high mitotic activity, necrosis and negative parafibromin. Incidence increased from 1.42 (range 0.52-2.14) to 7.14 (range 3.42-10.38)/10.000.000/years; (p < .001).
  
  
  CONCLUSIONS
  PC associates with severe primary hyperparathyroidism and must be suspected if calcium ≥1.77 mmol/l. The prevalence of CDC73 germline mutations in PC and APA in Finland is 6%. PC has distinct histopathological characteristics and its incidence has increased over the past decades.
authors.affiliation: a The Division of Endocrinology , Abdominal Center, University of Helsinki and Helsinki University Hospital , Helsinki , Finland.
authors.forename: Eeva M
authors.initials: EM
authors.lastname: Ryhänen
authors.affiliation: b Department of Pathology , Huslab and University of Helsinki , Helsinki , Finland.
authors.forename: Helena
authors.initials: H
authors.lastname: Leijon
authors.affiliation: c Department of Internal Medicine , Tampere University Hospital , Tampere , Finland.
authors.forename: Saara
authors.initials: S
authors.lastname: Metso
authors.affiliation: d Department of Internal Medicine , Oulu University Hospital , Oulu , Finland.
authors.forename: Eija
authors.initials: E
authors.lastname: Eloranta
authors.affiliation: e Department of Internal Medicine , Satakunta Central Hospital , Pori , Finland.
authors.forename: Pirkko
authors.initials: P
authors.lastname: Korsoff
authors.affiliation: f Department of Internal Medicine , Central Finland Central Hospital , Jyväskylä , Finland.
authors.forename: Petteri
authors.initials: P
authors.lastname: Ahtiainen
authors.affiliation: g Department of Internal Medicine , North Carelia Central Hospital , Joensuu , Finland.
authors.forename: Päivi
authors.initials: P
authors.lastname: Kekäläinen
authors.affiliation: h Department of Internal Medicine , Kymenlaakso Central Hospital , Kotka , Finland.
authors.forename: Marjo
authors.initials: M
authors.lastname: Tamminen
authors.affiliation: i Department of Oncology , Turku University Hospital , Turku , Finland.
authors.forename: Raija
authors.initials: R
authors.lastname: Ristamäki
authors.affiliation: j Department of Internal Medicine , Vaasa Central Hospital , Vaasa , Finland.
authors.forename: Otto
authors.initials: O
authors.lastname: Knutar
authors.affiliation: k Department of Biostatistics , University of Turku , Turku , Finland.
authors.forename: Eliisa
authors.initials: E
authors.lastname: Löyttyniemi
authors.affiliation: a The Division of Endocrinology , Abdominal Center, University of Helsinki and Helsinki University Hospital , Helsinki , Finland.
authors.forename: Leo
authors.initials: L
authors.lastname: Niskanen
authors.affiliation: l Department of Surgery , University of Helsinki, Helsinki University Hospital , Helsinki , Finland.
authors.forename: Mika
authors.initials: M
authors.lastname: Väisänen
authors.affiliation: l Department of Surgery , University of Helsinki, Helsinki University Hospital , Helsinki , Finland.
authors.forename: Ilkka
authors.initials: I
authors.lastname: Heiskanen
authors.affiliation: a The Division of Endocrinology , Abdominal Center, University of Helsinki and Helsinki University Hospital , Helsinki , Finland.
authors.forename: Matti J
authors.initials: MJ
authors.lastname: Välimäki
authors.affiliation: m Institute of Clinical Medicine, Internal Medicine , University of Eastern Finland and Kuopio University Hospital , Finland.
authors.forename: Markku
authors.initials: M
authors.lastname: Laakso
authors.affiliation: l Department of Surgery , University of Helsinki, Helsinki University Hospital , Helsinki , Finland.|n Research Programs Unit, Translational Cancer Biology , University of Helsinki , Helsinki , Finland.
authors.forename: Caj
authors.initials: C
authors.lastname: Haglund
authors.affiliation: b Department of Pathology , Huslab and University of Helsinki , Helsinki , Finland.
authors.forename: Johanna
authors.initials: J
authors.lastname: Arola
authors.affiliation: a The Division of Endocrinology , Abdominal Center, University of Helsinki and Helsinki University Hospital , Helsinki , Finland.
authors.forename: Camilla
authors.initials: C
authors.lastname: Schalin-Jäntti
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000235:genetics; D005260:Female; D005500:Follow-Up Studies; D018095:Germ-Line Mutation; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D015994:Incidence; D008207:Lymphatic Metastasis; D008297:Male; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local / Q000453:epidemiology* / Q000473:pathology / Q000601:surgery; D010282:Parathyroid Neoplasms / Q000453:epidemiology* / Q000473:pathology / Q000601:surgery; D016105:Parathyroidectomy; D011379:Prognosis; D012189:Retrospective Studies; D025521:Tumor Suppressor Proteins / Q000235:genetics; D055815:Young Adult
chemical_list: D014408:Biomarkers, Tumor; C454900:CDC73 protein, human; D025521:Tumor Suppressor Proteins