The clinical features of parathyroid cancer are primarily due to hypercalcemia rather than to tumor mass or distant metastases, and therefore the challenge to the clinician is to distinguish this rare variant of PHPT from its much more common benign counterpart [1]. Several clinical manifestations may suggest a malignant lesion: male gender, young age, marked hypercalcemia, severe and concomitant bone disease, and renal involvement [2]. In addition, intraoperative findings can be helpful (large and stony-hard mass, adherence to the adjacent tissues, and most important, gross local infiltration), but they may be absent; frozen section is of little value. When considered together, the clinical features and the size of the parathyroid lesion at initial surgery raised the possibility of parathyroid carcinoma. The negative cervical exploration at the time of the second operation also raised doubts about the initial benign diagnosis.

As in many endocrine neoplasms, the histopathological distinction between benign and malignant parathyroid tumors is difficult and, in the absence of local invasion or metastases at initial surgery, a definite diagnosis cannot be established with certainty [3, 4]. Taken together, these considerations may account for diagnostic “underreading” in our patient of the initial parathyroid pathology. Misdiagnosis may have important psychological and clinical consequences. Indeed, the incorrect diagnosis of benign adenoma suggested a possible multiglandular disease at the time of recurrence, justifying a second neck operation, and delaying a more appropriate investigation and management. Several presenting features of our patient at initial evaluation might have suggested a malignant etiology of PHPT, but the course after surgery did not appear to counter the diagnosis of a benign parathyroid tumor. On the other hand, it is well known that parathyroid cancer is an indolent neoplasm with a relatively low malignant potential and both local recurrence and metastases may occur late in the course of the disease. Indeed our patient had a disease-free interval of 10 years between initial surgery and recurrence. This case illustrates the difficulty for an inexperienced endocrine pathologist to recognize a parathyroid carcinoma at initial surgery in the absence of local invasion or metastases. Moreover, when the clinical course of PHPT is at variance with the expected course, it may be valuable to have the slides reviewed again and eventually perform molecular analysis on pathologic tissue for CDC73/HRPT2 mutations and immunohistochemistry for parafibromin. This combined diagnostic approach could be of great utility in parathyroid tumors with equivocal histological features, since both the CDC73/HRPT2 gene inactivating mutation and loss of parafibromin immunostaining have been reported in up to 70 % of parathyroid cancers and in hyperparathyroidism–jaw tumor syndrome [5, 6].

Although there was no history of familial PHPT, the CDC73/HRPT2 mutation in our patient was unexpectedly germline and this prompted us to perform genetic analyses in first-degree relatives. The CDC73/HRPT2 mutation was detected in one of the two sons and in a liver specimen of the deceased father, who underwent partial hepatectomy for a benign nodule. The recognition of the carrier status in a kindred carrying a germline CDC73/HRPT2 mutation enabled the early detection of a parathyroid cancer in an apparently healthy subject [7]. Thus, a regular surveillance of subjects carrying a germline CDC73/HRPT2 mutation should be performed using serum calcium and PTH assays and neck ultrasound for early detection of affected individuals.