Primary hyperparathyroidism (PHPT) is a common endocrine disorder that is being diagnosed more frequently due to the increasing use of routine serum total calcium tests as part of medical examinations (1). The clinical presentation of PHPT is changing from a severe disease with renal stones and metabolic bone disease to mild asymptomatic disease (2). Parathyroid carcinoma (PC) comprises a very small proportion of PHPT cases. A meta-analysis of 20,225 cases of PHPT in the USA reported that PC occurred only in 0.74% of cases (3). Nevertheless, PC requires early recognition and complete resection because its prognosis is quite variable (4-6). The average time to the first recurrence is approximately 3-yr and intervals of up to 20-yr have been reported (7).

The current definitive treatment of PC is en-bloc resection, which avoids rupture and spillage of the tumor. Once the tumor has recurred, curative treatment is unlikely and the surgical complication rate is high, although PC patients typically have a prolonged survival (8). Therefore, it is desirable to distinguish benign disease such as parathyroid adenoma and hyperplasia from PC prior to surgery. Unfortunately, PC is frequently only diagnosed after surgery for hyperparathyroidism because the clinical presentation of PC and benign disease are strikingly similar.

In this retrospective study, we compared the clinical presentation of PC with benign disease and reevaluated the biochemical parameters that have been used to differentiate PC from benign disease at the time of the first operation.

We performed a retrospective review of electronic medical records in affiliated teaching hospitals of Seoul National University (Seoul National University Hospital, Seoul National University Bundang Hospital, and Seoul Metropolitan Government Borame Medical Center). The records were reviewed, over a 10-yr period from January 2000 to March 2011, of patients who had been diagnosed with hyperparathyroidism, parathyroid adenoma, parathyroid hyperplasia, PC, parathyroid tumor, or hypercalcemia. Patients with secondary or tertiary hyperparathyroidism, or other causes of hypercalcemia such as malignancy, vitamin D intoxication, immobilization, medications, hyperthyroidism, and other endocrine diseases, were excluded. Data collected from the records included the clinical features (hypercalcemia-related symptoms at the time of diagnosis, previous history of osteoporosis, fracture, and renal or urinary stone), laboratory data (serum levels of total calcium, phosphorous, intact parathyroid hormone [iPTH], creatinine, alkaline phosphatase [ALP], and 25-hydroxy vitamin D; 24 hr urinary calcium and phosphorus; and dual energy X-ray absorptiometry [DEXA]), and surgically proven pathology (adenoma, hyperplasia, and carcinoma). Serum iPTH was measured preoperatively by means of immunoradiometric assay (Cis Bio International, Gif-Sur-Yvette, Cedex, France). Follow-up duration, interval change of clinical features, and laboratory data after surgery were also included.

Descriptive statistics are reported as mean ± standard deviation, and confidence intervals were computed as two-tailed using 95% coverage. Categorical variables are reported as frequencies and proportions. Comparisons between continuous variables were performed using repeated measures ANOVA. Comparisons between categorical variables were performed using a chi-squared test. Univariate and multivariate analyses of variables were performed. Statistical analyses were done with SPSS version 18.0 (SPSS Inc., Chicago, IL, USA). P values < 0.05 were accepted as significant.

In this retrospective study of 194 patients with pathologically confirmed PHPT, the tumor size and serum ALP level were predictors of PC before the first operation. PC is an extremely rare tumor. In this study, only 11 patients were diagnosed with PC in Seoul National University's three affiliated teaching hospitals during a 10-yr period. The proportion of PC in patients with PHPT was relatively high in our study, 5.7% considering that previous studies reported that PC accounts for only 0.5%-5% of all patients with PHPT (3, 5, 11). This discrepancy could result from referral bias since the hospitals involved in the present study are referral centers.

There were no significant differences between PC and the benign disease in terms of clinical symptoms, bone loss or fracture, or nephrolithiasis. PC affects the classical target organs, such as bone and kidney, more severely than benign PHPT, since patients with PC commonly have profound hypercalcemia (8, 12-14). Although most PHPT patients in contemporary clinical practice are asymptomatic, some patients with benign PHPT present with more severe manifestations (2, 15, 16). In such patients, it may be extremely difficult to differentiate the clinical manifestations of malignancy from those of benign diseases. As the number of benign, symptomatic PHPT patients is progressively decreasing, the sample size of 194 patients in the present study would be unlikely to find a statistical difference between the clinical manifestations of malignant and benign PHPT.

Serum ALP level was higher in patients with PC than in those with benign disease (17), and our results suggest that a patient with serum ALP level less than 300 IU/L is unlikely to have carcinoma. Elevated serum ALP level in patients with PHPT may reflect the longstanding effect of PTH on the bone. This result is supported by the previous study that serum levels of PTH and ALP are useful for the prediction of PC (18). In this study, serum iPTH levels in patients with benign PHPT showed relatively wide distribution compared to serum ALP levels. This result suggests that serum ALP rather than serum iPTH could be predictive factors of PC. Persistent excess of PTH in the circulation causes an increase in the RANKL/OPG ratio, which is the main mechanism by which PTH stimulates osteoclastogenesis and bone resorption (19, 20). Histomorphometric studies have shown that PHPT commonly causes preferential cortical bone loss with preservation of cancellous bone (21, 22). Therefore, serum ALP might reflect the effects of PTH on the bone earlier than skeletal phenotypes such as bone mineral density or fractures.

The size of a parathyroid tumor may be an important factor in predicting PC in a patient with PHPT. In this study, 10 of 11 patients with PC had a parathyroid mass larger than 3.0 cm, and ROC analysis showed that the sensitivity and specificity for PC was 90.9% and 92.1%, respectively. This result is in agreement with previous findings that PC are usually larger than 3 cm and may be palpable (23). Interestingly, the median tumor size at the time of diagnosis in 286 cases of PC treated in the USA from 1985 to 1995 was approximately 3.3 cm (8). A palpable mass in the neck has been suggested as a strong predictive factor for PC (7, 11, 24), and particular attention should be paid to a hyperparathyroid patient with a parathyroid mass larger than 3.0 cm.

We also examined PTH as a potential factor to distinguish PC from benign causes of PHPT. In multivariate analysis, patients with PC did not show a statistically significant difference in serum levels of iPTH compared to those with benign PHPT. The relationship between preoperative serum PTH levels and the size of a parathyroid adenoma or carcinoma is controversial (25, 26). In the present study, serum iPTH levels were correlated with tumor size in patients with parathyroid adenoma but not in patients with PC. This difference may be resulted from the small number of patients with carcinoma. A recent report suggested that an N-terminal PTH distinct from iPTH can be recognized in a 3rd generation assay of whole PTH and that this form is overproduced in some patients with PC (27). Oncogenes and tumor suppressor genes involved in the control of the cell cycle have been linked to the pathogenesis of PC, including retinoblastoma (Rb), p53, breast carcinoma susceptibility (BRCA2), and cyclin D l/parathyroid adenomatosis gene 1 (CCND1/PRAD1) genes (28, 29). The excessive expression of CCND1 by the highly active PTH gene promoter in the parathyroid cell may contribute to excess cellular proliferation and development of PC. This result indicates that PC is frequently functional. Although CCND1 is overexpressed in more than 90% of cases of PC, its role in pathogenesis remains to be determined (30).

In conclusion, the results of this study suggest that the size of tumor and serum level of ALP may be helpful to predict PC in patients with PHPT before the primary operation.