Understanding the Genetic Basis of Parathyroid Carcinoma

Parathyroid carcinoma has always been difficult to diagnose pathologically. In fact, most parathyroid tumors which are classified as carcinoma do not recur after excision, and most parathyroid tumors which actually metastasize or recur repeatedly in the neck are not recognized as malignant at first presentation. In 2002, germline HRPT2 (also known as CDC73) mutation was reported as the cause of hyperparathyroidism-jaw tumor (HPT-JT) syndrome, an autosomal dominant hereditary tumor syndrome associated with a lifetime risk of parathyroid carcinoma approaching 15 %. Subsequently, bi-allelic inactivation or mutation of HRPT2 has been reported in the majority of parathyroid carcinomas that actually behave in a malignant manner but very rarely in sporadic benign parathyroid disease. Furthermore, germline testing for HRPT2 mutation in patients presenting with parathyroid carcinoma often identifies occult HPT-JT syndrome even in the absence of a family history or other syndromic manifestations. HRPT2 mutation testing is not readily available, and loss of expression of parafibromin (the protein encoded by HRPT2) as determined by immunohistochemistry has been used as a surrogate marker of HRPT2 mutation. Immunohistochemistry for parafibromin can be technically difficult and has been deployed by different investigators with variable enthusiasm and success. However, proponents have found immunohistochemistry for parafibromin useful to definitively confirm a pathological diagnosis of parathyroid carcinoma, predict a worse outcome in definite parathyroid carcinomas, triage formal genetic testing for HPT-JT syndrome, and predict the outcome of histologically atypical parathyroid adenomas.