Loss of parafibromin immunoreactivity is a distinguishing feature of parathyroid carcinoma.
OBJECTIVE
A reliable method for diagnosing parathyroid carcinoma has remained elusive over the years, resulting in its under-recognition and suboptimal therapy. Obtaining an accurate diagnosis has become an even more pressing matter with recent evidence that germline HRPT2 gene mutations are found in patients with apparently sporadic parathyroid carcinoma. There is a high prevalence of HRPT2 gene mutations and biallelic inactivation in parathyroid carcinoma. We hypothesize that loss of parafibromin, the protein product of the HRPT2 gene, would distinguish carcinoma from benign tissue.


METHODS
We generated a novel antiparafibromin monoclonal antibody and performed immunostaining on 52 definite carcinoma specimens, 6 equivocal carcinoma specimens, 88 benign specimens, and 9 hyperparathyroidism-jaw tumor (HPT-JT) syndrome-related adenomas from patients with primary hyperparathyroidism from nine worldwide centers and one national database.


RESULTS
We report that the loss of parafibromin nuclear immunoreactivity has 96% sensitivity [95% confidence interval (CI), 85-99%] and 99% specificity (95% CI, 92-100%) in diagnosing definite carcinoma. Inter-observer agreement for evaluation of parafibromin loss was excellent, with unweighted kappa of 0.89 (95% CI, 0.79-0.98). Two equivocal carcinomas misclassified as adenomas were highlighted by parafibromin immunostaining. One of these tumors has since recurred, satisfying criteria for a definite carcinoma. Similarly, eight of nine HPT-JT syndrome-related adenomas showed absent nuclear immunoreactivity.


CONCLUSIONS
Parafibromin is a promising molecular marker for diagnosing parathyroid carcinoma. The similar loss of parafibromin immunoreactivity in HPT-JT syndrome-related adenomas suggests that this is a pivotal step in parathyroid tumorigenesis.
Laboratory of Cancer Genetics, Van Andel Research Institute, Grand Rapids, Michigan 49503, USA.
Min-Han
MH
Tan
Carl
C
Morrison
Pengfei
P
Wang
Ximing
X
Yang
Carola J
CJ
Haven
Chun
C
Zhang
Ping
P
Zhao
Maria S
MS
Tretiakova
Eeva
E
Korpi-Hyovalti
John R
JR
Burgess
Khee Chee
KC
Soo
Wei-Keat
WK
Cheah
Brian
B
Cao
James
J
Resau
Hans
H
Morreau
Bin Tean
BT
Teh
D000911:Antibodies, Monoclonal / Q000276:immunology; D002460:Cell Line; D003937:Diagnosis, Differential; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry / Q000379:methods; D010282:Parathyroid Neoplasms / Q000378:metabolism / Q000473:pathology*; D011506:Proteins / Q000032:analysis* / Q000235:genetics / Q000276:immunology; D015203:Reproducibility of Results; D020539:Sequence Analysis, Protein; D025521:Tumor Suppressor Proteins
D000911:Antibodies, Monoclonal; C454900:CDC73 protein, human; D011506:Proteins; D025521:Tumor Suppressor Proteins; D049452:Green Fluorescent Proteins