Parathyroid ultrasonography in patients with primary hyperparathyroidism

Ultrasonography of the neck was performed in 42 consecutive patients with primary hyperparathyroidism (PHP). In 30 patients with subsequent neck exploration, ultrasonography localised 24 of 34 parathyroid tumours correctly (71%), and in 22 patients (73%) the diagnosis PHP was confirmed by identification of at least one parathyroid tumour. In 11 patients - who were not operated - ultrasonography disclosed a parathyroid tumour in four. Of all 42 patients, ultrasonography disclosed at least one parathyroid tumour in 26 (63%). The parathyroid tumours varied in echo pattern, and localisation difficulties were in particular related to associated nodular changes of the thyroid gland and the anatomic distribution of the enlarged parathyroid tissue.     

Parathyroid adenomas and glands in normocalcemic hyperparathyroidism. A light microscopic study.

Surgical exploration of the parathyroid glands was carried out in 84 patients who had recurrent kidney stones and serum calcium levels in the upper quartile and most of whom had hypercalciuria. Parathyroid adenoma(s) were found in 19 cases, hyperplasia in 39 cases, and normal parathyroid glands in 26 cases. Postoperatively, a clinical follow-up was carried out for 2 to 5 years. No relapse has occurred in the cases with adenoma(s) but did occur in 24% of the group with hyperplasia and in 48% of the group with normal glands. The histopathologic findings are described here, while the clinical results are given in another paper. The adenomas do not differ histologically from those giving rise to hypercalcemic hyperparathyroidism. The hyperplasia was of the chief cell type and was slight in most cases. The "normal" glands did not differ from other normal glands from euparathyroid subjects. There was no significant difference in weight and histopathologic appearance between the hyperplastic glands of patients who relapsed and those who did not. Nor did the normal glands of "cured" patients differ from those of patients with relapse. However, in both these groups, some histologic features seem to indicate a favorable outcome; in the group with hyperplasia, there were higher glandular and parencymal cell weight as well as predominance of light chief cells and small fibrotic areas. In the normal group, higher number of argyrophil cells and small fibrotic areas also seem to implicate a better prognosis.     

Parathyroid glands in primary hyperparathyroidism: an ultrastructural morphometric study of 25 cases.

In parathyroid glands removed from patients with primary hyperparathyroidism (pHPT), hyperplasias and adenomas cannot be distinguished from one another by light microscopy when only one gland is available for examination. When a second gland is available, it is necessary to establish whether it is normal, suppressed, or hyperplastic. This distinction may be difficult, and the main criterion is the amount of cytoplasmic lipid in the parenchymal cells. If the lipid is abundant, the gland is considered normal or suppressed, and if it is scanty, the gland is interpreted as hyperplastic. We have performed a morphometric ultrastructural study to test the reliability of this criterion. Twenty-five adenomatous glands removed from patients with pHPT, when compared with glands of normal size from euparathyroid patients, showed a significant increase in the parameters indicative of metabolic activity, namely the size of the Golgi apparatus, the amount of rough endoplasmic reticulum, and the length of plasmalemmas. In addition, the amount of cytoplasmic lipid was significantly reduced. Furthermore, 25 glands of normal size removed from the same patients with pHPT showed an amount of lipid similar to that of normal glands from euparathyroid patients. However, all the parameters indicative of metabolic activity were significantly higher than those in glands from euparathyroid patients and comparable to those found in adenomatous glands. These results suggest that in pHPT, normal-size glands are as active as adenomatous glands, regardless of a higher lipid content.     

Parathyroid hyperplasia in tertiary hyperparathyroidism: a pathological and immunohistochemical reappraisal

Thirty-one parathyroid glands from 11 patients with tertiary hyperparathyroidism were examined histologically and immunohistochemically to characterize better the nature of the accompanying parathyroid hyperplasia. The parathyroids showed varying degrees of nodular and diffuse hyperplastic involvement as well as apparently normal background tissue. The nodules were usually multiple within any one gland and, together with diffuse hyperplastic tissue, showed a varied cyto-architectural pattern. All glands studied showed both cellular argyrophilia and parathyroid hormone immunoreactivity. The staining pattern for parathyroid hormone ranged from negative or weak to strong, and from patchy to diffuse in hyperplastic tissue from different glands and within the same gland, regardless of the cell type. Apparently normal areas usually showed only patchy weak to moderately strong parathyroid hormone positivity. From the data obtained the most striking feature of the parathyroid glands in tertiary hyperparathyroidism is their extreme variability, both morphological and functional, as indicated by parathyroid hormone immunoreactivity. Furthermore, the generally lesser degree of parathyroid hormone immunoreaction observed in apparently normal parathyroid tissue may reflect suppression of hormone synthesis, with accompanying morphological regression to normal of pre-existent diffuse hyperplasia by autonomous hyperfunctioning nodules associated with tertiary hyperparathyroidism.     

Parathyroid glands in primary hyperparathyroidism: an ultrastructural study of 50 cases

Parathyroid glands from 50 cases of primary hyperparathyroidism were examined by light and electron microscopy in an attempt to elucidate the diagnostic role of electron microscopy in this disease. In the cases in which only one gland was removed at surgery, a final diagnosis by light microscopy was not possible. The electron microscopic findings for some of these single glands (e.g., ribosomal-lamellar complexes and groups of centrioles) suggested that they were adenomas. In cases in which two or more enlarged glands were removed, a correct final diagnosis could be made on the basis of the light microscopic findings alone, and electron microscopy provided no further significant information. Where one enlarged gland and one normally sized gland were removed, electron microscopy disclosed important findings in the normally sized glands. Specifically, light microscopic examination of normally sized glands suggested endocrine suppression, while electron microscopy showed chief cell activity, thereby changing the final diagnosis from adenoma to hyperplasia. The clinical follow-up assessment in some of these patients confirmed the electron microscopic findings. Therefore, the incidence of adenoma in patients with primary hyperparathyroidism should be critically re-evaluated by ultrastructural studies of the normal glands that should be removed with the enlarged ones.     

Parathyroid carcinoma: an overview

Parathyroid carcinoma is a rare tumor that is responsible for <1% of cases of hyperparathyroidism in most parts of the world. An increased incidence of this tumor has been reported in patients with the hyperparathyroidism-jaw tumor (HPT-JT) syndrome, but the etiology of most other cases is unknown. Parathyroid carcinomas tend to occur a decade earlier than adenomas, and the sex ratio approaches unity in contrast to the female preponderance of adenomas. Most patients with carcinomas present with marked hypercalcemia and are more likely to have associated bone and renal disease than those with adenomas. Although fibrosis and mitotic activity are common in carcinomas, these features are not specific for malignancy. The diagnosis of carcinoma should be restricted to those tumors that show invasion of blood vessels, perineural spaces, soft tissues, thyroid gland, or other adjacent structures or to tumors with documented metastases. Mutations of the HRPT2 gene (1q21-q32), which are responsible for the HPT-JT syndrome, have been implicated in the development of a high proportion of parathyroid carcinomas. A subset of patients with mutation-positive carcinomas have germline mutations of the HRPT2 gene. This finding suggests that some patients with apparent sporadic parathyroid carcinomas may have the HPT-JT syndrome or a variant of this syndrome. Because of the high frequency of local recurrence following incomplete excision, an en bloc resection is the preferred surgical approach for treatment of parathyroid carcinomas.     

Cellular immune responses in familial medullary thyroid carcinoma.

We studied prospectively 46 members of a kindred with familial medullary thyroid carcinoma to determine the importance of possible cellular immune reactivity to tumor antigen. We evaluated in vitro production of macrophage-migration-inhibitory factor and 3H-thymidine uptake by lymphocytes from patients, family members and normal subjects in response to extracts of medullary thyroid carcinoma and normal thyroid tissue. Lymphocytes from 12 of 18 patients with medullary thyroid carcinoma and four of seven patients with C-cell hyperplasia produced migration inhibitory factor or proliferated (or both) in response to tumor antigen. In contrast, cells from only two of 25 normal subjects and two of nine family members not genetically at risk for medullary thyroid carcinoma made migration inhibitory factor and proliferated to tumor antigen. Of particular interest, lymphocytes from six of 12 clinically normal family members genetically at risk for medullary thyroid carcinoma exhibited cellular immune reactivity to tumor antigen.     

Parathyroid hormone-like peptide in pancreatic endocrine carcinoma and adenocarcinoma associated with hypercalcemia.

Parathyroid hormone-like peptide (PLP) is produced by a number of tumors commonly associated with hypercalcemia as well as by nontumorous tissue, including some endocrine organs. We applied immunohistochemistry using the avidin-biotin-peroxidase technique to localize PLP in formalin-fixed, paraffin-embedded tissues of two human pancreatic carcinomas associated with hypercalcemia and normal blood parathyroid hormone levels. One tumor was endocrine and one was exocrine in differentiation. There was no evidence of bone metastasis in either case. We documented normalization of serum calcium level after removal of the pancreatic endocrine tumor. These observations support the suggestion that PLP production by pancreatic carcinoma may play a role in the development of hypercalcemia. However, the presence of PLP in tumors not associated with hypercalcemia indicates that other factors in addition to PLP are necessary for the manifestation of hypercalcemia. Hypercalcemia associated with exocrine pancreatic tumor has rarely been reported. Our exocrine pancreatic tumor appears to be the first reported case in which immunohistochemistry localized PLP. Since PLP has been localized to cells of exocrine ducts and ductules of normal pancreas, our results provide insight into the cell of origin of this tumor type.     

Genetic testing in familial isolated hyperparathyroidism: unexpected results and their implications

Familial hyperparathyroidism is not uncommon in clinical endocrine practice. It encompasses a spectrum of disorders including multiple endocrine neoplasia types 1 (MEN1) and 2A, hyperparathyroidism-jaw tumour syndrome (HPT-JT), familial hypocalciuric hypercalcaemia (FHH), and familial isolated hyperparathyroidism (FIHP). Distinguishing among the five syndromes is often difficult but has profound implications for the management of patient and family. The availability of specific genetic testing for four of the syndromes has improved diagnostic accuracy and simplified family monitoring in many cases but its current cost and limited accessibility require rationalisation of its use. No gene has yet been associated exclusively with FIHP. FIHP phenotypes have been associated with mutant MEN1 and calcium-sensing receptor (CASR) genotypes and, very recently, with mutation in the newly identified HRPT2 gene. The relative proportions of these are not yet clear. We report results of MEN1, CASR, and HRPT2 genotyping of 22 unrelated subjects with FIHP phenotypes. We found 5 (23%) with MEN1 mutations, four (18%) with CASR mutations, and none with an HRPT2 mutation. All those with mutations had multiglandular hyperparathyroidism. Of the subjects with CASR mutations, none were of the typical FHH phenotype. These findings strongly favour a recommendation for MEN1 and CASR genotyping of patients with multiglandular FIHP, irrespective of urinary calcium excretion. However, it appears that HRPT2 genotyping should be reserved for cases in which other features of the HPT-JT phenotype have occurred in the kindred. Also apparent is the need for further investigation to identify additional genes associated with FIHP.     

Recurrent hyperparathyroidism due to parathyroid carcinoma

The case is described of a woman who died with a functioning parathyroid carcinoma 19 years after removal of two parathyroid tumours, considered at the time to be benign. Following operation hyperparathyroidism subsided, with a short period of hypocalcaemia, and severe osteitis fibrosa cystica healed. Five years before death progressive renal failure developed with normal and later raised serum calcium levels. At necropsy a parathyroid carcinoma infiltrated the thyroid at the site of the previous operation and there was a solitary hepatic metastasis. A remaining parathyroid gland was nodularly hyperplastic and the bones showed evidence of active osteitis fibrosa. The relationship between parathyroid hyperplasia and neoplasia is discussed. Acceptable cases of parathyroid carcinoma are rare, but carcinoma is an important cause of recurrent hyperparathyroidism even months or years after removal of an ;adenoma'.     

Parathyroid mitogenic activity in plasma from patients with familial multiple endocrine neoplasia type 1

Hyperplasia of the parathyroid glands is a central feature of familial multiple endocrine neoplasia type 1. We used cultured bovine parathyroid cells to test for mitogenic activity in plasma from patients with this disorder. Normal plasma stimulated [3H]thymidine incorporation, on the average, to the same extent as it was stimulated in a plasma-free control culture. This contrasted with the results of the tests with plasma from patients with familial multiple endocrine neoplasia type 1, in which parathyroid mitogenic activity increased 2400 percent over the control value (P less than 0.001). Plasma from these patients also stimulated the proliferation of bovine parathyroid cells in culture, whereas plasma from normal subjects inhibited it. Parathyroid mitogenic activity in plasma from the patients with familial multiple endocrine neoplasia type 1 was greater than that in plasma from patients with various other disorders, including sporadic primary hyperparathyroidism (with adenoma, hyperplasia, or cancer of the parathyroid), sporadic primary hypergastrinemia, sporadic pituitary tumor, familial hypocalciuric hypercalcemia, and multiple endocrine neoplasia type 2 (P less than 0.05). Parathyroid mitogenic activity in the plasma of patients with familial multiple endocrine neoplasia type 1 persisted for up to four years after total parathyroidectomy. The plasma also had far more mitogenic activity in cultures of parathyroid cells than did optimal concentrations of known growth factors or of any parathyroid secretagogue. This mitogenic activity had an apparent molecular weight of 50,000 to 55,000. We conclude that primary hyperparathyroidism in familial multiple endocrine neoplasia type 1 may have a humoral cause.     

Parathyroid carcinoma associated with chronic renal failure and previous radiotherapy to the neck.

Carcinoma of the larynx was treated by irradiation followed by laryngectomy in a man who had been receiving regular haemodialysis for two years. At least one, and probably two, parathyroid glands were removed at this time, and the remaining two were removed three years later for tertiary hyperparathyroidism. A portion of one gland was implanted into the forearm. The forearm implant was resected the following year for recurrent hypercalcaemia. Six years later, again with recurrent hypercalcaemia, he died of bronchopneumonia. Metastatic parathyroid carcinoma was found in the apex of the left lung. The source of this parathyroid tissue and the possible role of irradiation in the pathogenesis of parathyroid cancer in this patient were investigated.