The diagnostic role of HRPT2 mutations and parafibromin immunostaining in sporadic parathyroid carcinoma

Background and aim: Parathyroid carcinoma (PC) is a rare disease; its definitive diagnosis may be challenging, especially in case of absence of unequivocal diagnostic criteria (histopath- Langenbecks Arch Surg (2009) 394:407–416 409 ological vascular and extracapsular invasion of the adjacent tissues; distant metastases), with subsequent under-recognition and possibly under-treatment. In these cases a prolonged and strict follow up is required to assess the diagnosis. Recently, somatic inactivating mutations of HRPT2 (a gene encoding the Parafibromin, a nuclear protein with antiproliferative effects) have been described in most cases of sporadic PC. This study was aimed to assess the role of HRPT2 mutations and the usefulness of Parafibromin immunostaining in the diagnosis of sporadic PC. Methods: Somatic and germ-line mutations of HRPT2 gene and immunohistochemical evaluation of nuclear Parafibromin was assessed in three unequivocal PC, in 20 sporadic adenomas and ten normal parathyroids (control group). Results: Germ-line HRPT2 mutations were absent in all patients. Somatic HRPT2 mutations were absent in 100% of cases in the control group and in two PC patients, while a novel inactivating mutation of HRPT2 was found only in one PC. Nuclear Parafibromin staining was strongly evident in all cases in the control group; it was weakly and variably present in one PC and absent in the remaining two cases (sensitivity 66.7%, specificity 100% and accuracy 97%). Conclusions: Loss of nuclear Parafibromin staining may be a useful tool for the diagnosis of PC in most cases. However, since HRPT2 mutations may not be involved in a subset of PC, its negative predictive value may be limited.