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Primary hyperparathyroidism (P-HPT) is a common endocrine disorder that occurs as a result of adenomas (80-85%), hyperplasias (10-15%) or carcinomas (<1%) of the parathyroid glands. Molecular genetic analyses of heritable P-HPT syndromes have provided considerable insight into the understanding of sporadic parathyroid tumors and hyperplasias. This review will focus on the criteria for classification of parathyroid proliferative disorders and will highlight our understanding of these lesions at the molecular level. Advances in radiological imaging techniques together with the rapid intraoperative parathyroid hormone assay will be reviewed with respect to current treatment approaches for P-HPT.

Parathyroid neoplasms encompass a spectrum of proliferative lesions that include adenomas, atypical adenomas, and carcinomas. While the diagnosis of adenomas is usually straightforward, parathyroid carcinomas (PTCAs) often present considerable diagnostic challenges. Fibrosis and mitotic activity are common in PTCAs, but these features are not specific for malignancy. An unequivocal diagnosis of PTCA should be restricted to those tumors that invade adjacent soft tissues, thyroid gland, blood vessels, or perineural spaces or to those cases with documented metastases. Atypical adenomas include those tumors that share some of the features of PTCA but lack evidence of invasive growth. A variety of genetic abnormalities, including HRPT2 mutations, occur in PTCAs. Mutations of the HRPT2 gene, which encodes parafibromin, are responsible for the development of the hyperparathyroidism-jaw tumor syndrome and have also been implicated in the development of a high proportion of sporadic PTCAs. Correlative immunohistochemical studies have revealed nuclear parafibromin immunoreactivity in adenomas but absence or partial loss of staining in PTCAs. While parafibromin immunohistochemistry represents an important step in the ability to diagnose PTCA, additional studies will be required to test the validity of this approach and to determine the roles of other genes in the development of these tumors.

Background: Previous studies have established that calcitonin (CT) and the calcitonin generelated peptide (CGRP) are synthesized and stored in subsets of hyperplastic parathyroid cells that also contain chromogranin B (Schmid, KW, et al. Lab Invest 73:90, 1995). The purpose of the current study was to determine whether other generic but variably expressed neuroendocrine markers, i.e., synaptophysin (SYN) and CD57 (Leu7), are also present in normal, hyperplastic, and neoplastic parathyroid tissue and to assess their relationships to the presence of CT., Design: Immunoperoxidase stains for chromogranin A (CgA), chromogranin B (CgB), SYN, CD57, and CT were performed on 54 hyperplastic, 17 neoplastic (adenoma), and 16 normal parathyroid glands. Sequential sections were stained with antibodies to CgA, CgB, SYN, CD57, and CT using standard avidin-biotin-peroxidase techniques., Results: CgA was diffusely expressed in all normal, hyperplastic, and neoplastic glands. In hyperplasia, CgB was variably expressed in 6 cases (11%), SYN in 6 (11%), CD57 in 15 (28%), and CT in 8 (15%). In adenomas, CgB was variably expressed in 3 (17%), SYN in 3 (17%), CD57 in 4 (23%), and CT in 4 (23%). All normal glands were negative for CgB, SYN, and CT, while CD57 was variably expressed in 17%. Of the 12 glands that were CT positive, 8 were also positive for CgB, 2 for SYN, and 9 for CD57. Four glands that were strongly and diffusely positive for CT were CgB and SYN negative., Conclusions: CgB, SYN, and CD57 are markers for subsets of hyperplastic and neoplastic parathyroid glands. CT is also expressed in a significant proportion of hyperplastic and neoplastic parathyroid glands, and may be independent of the presence of CgB, SYN, or DD57. The significance of these findings in relationship to the abnormal calcium metabolism in patients with parathyroid hyperplasia remains to be determined.

Although histologic definition of follicular thyroid lesions is readily available, application of the diagnostic criteria and personal experience may lead to disagreement among pathologists. To investigate interobserver variation in assessment of encapsulated follicular lesions, eight pathologists (four American and four Japanese) reviewed the same hematoxylin and eosin-stained slide of each of 21 cases of thyroid lesions showing encapsulation and follicular growth pattern. In 10% of the cases, there was complete agreement. At least seven pathologists agreed on the diagnosis in 29% of the cases, and at least six in 76% of the cases. American and Japanese pathologists agreed among themselves in 33% and 52% of cases, respectively. The frequency of diagnosis of adenomatous goiter among Japanese pathologists (31%) was considerably higher than that among American pathologists (6%). In contrast, the frequency of diagnosis (25%) of papillary carcinoma among American pathologists was considerably higher than that (4%) among Japanese pathologists. Our analysis revealed three main factors affecting observer variation: 1) interpretation of the significance of microfollicles intimately related to capillaries within the tumor capsule, 2) evaluation of what constituted the type of nuclear clearing indicative of papillary carcinoma, and 3) absence of clear morphologic criteria for separation of adenomatous goiter and follicular adenoma. To reduce observer variation of encapsulated follicular lesions, it will be necessary to provide more explicit criteria for diagnosis.

Context.-Primary hyperparathyroidism (P-HPT) is one of the most common of all endocrine disorders. Eighty percent to 85% of cases are due to parathyroid adenomas while hyperplasia and carcinoma account for 10% to 15% and less than 1%, of cases, respectively. The past decade has witnessed remarkable advances in the understanding of the molecular basis of parathyroid hyperplasia and neoplasia. Additionally, imaging studies and the development of the intraoperative assay for parathyroid hormone have transformed the diagnosis and management of patients with these disorders. Objective.-To review the pathology of parathyroid lesions associated with P-HPT, their molecular and genetic bases, including heritable hyperparathyroidism syndromes, and their clinical diagnosis and management. Data Sources.-Review of pertinent epidemiology, pathology, radiology, and surgery literature on the diagnosis, classification, and treatment of P-HPT. Conclusions.-Although heritable causes of P-HPT including multiple endocrine neoplasia 1 and 2A and hyperparathyroidism-jaw tumor syndrome account for a minority of cases of P-HPT, advances in the characterization of the affected genes have provided insights into the genetic basis of sporadic parathyroid neoplasms. Alterations in cyclin D1 and loss of heterozygosity of chromosome 11q in adenomas and hyperplasias have provided support for clonality of these lesions. Parafibromin, the protein product of the HRPT2 gene responsible for hyperparathyroidism-jaw tumor syndrome, has been implicated in the development of sporadic parathyroid carcinomas and loss of immunohistochemical expression of this protein has been suggested to be of value in making the diagnosis of parathyroid carcinoma. Sestamibi scanning and ultrasound have revolutionized the planning of surgical approaches and the intraoperative parathyroid hormone assay has become the standard in guiding completion or extension of surgery. [ABSTRACT FROM AUTHOR]