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Parathyroid cancer is rare but relatively frequent in Japan compared to Western countries. Surgical parathyroidectomy is the primary choice for radical treatment of primary hyperparathyroidism (pHPT), hence it is important to distinguish malignant from benign tumor in the determination of surgical indication as well as method of operation. However, it is not easy to diagnose parathyroid cancer prior to operation. In the present study, we analyzed the background data, biochemical data and bone mineral density (BMD) of 131 patients with pHPT (111 benign and 20 malignant). BMD of the lumbar spine and mid-radius was measured by dual-energy X-ray absorptiometry. Serum levels of calcium, alkaline phosphatase (ALP), and parathyroid hormone (PTH) were significantly higher in malignant group compared to benign one. The extent of elevation of mid PTH seemed to be higher than that of intact PTH in malignant group. Age-, gender-, and race-adjusted BMD of distal one-third of radius was significantly decreased in malignant group compared to benign one, although that of lumbar spine was not significantly different between the two groups, indicating that osteopenia was marked in the region which was rich in cortical bone in malignant group. On the other hand, serum levels of calcium, ALP, and mid PTH as well as age were selected as predictors of malignancy in univariate logistic regression analysis, while serum level of intact PTH was not selected. In conclusion, radial BMD was lower in malignant group compared to benign one in pHPT. Serum levels of calcium, ALP and mid PTH were useful to predict malignancy of affected parathyroid glands in pHPT patients.

Tumors of the thyroid and parathyroid glands may develop together or separately in patients who previously have been exposed to head and neck irradiation. Whether cranial irradiation confers an increased risk for pituitary adenoma remains unknown. We report the case of a 52-year-old woman who was treated during childhood for tinea capitis with scalp irradiation and later in life developed a prolactin-secreting tumor, a parathyroid adenoma, a benign thyroid lesion, and a basal cell carcinoma of the skin. She was treated successfully with bromocriptine and surgical removal of the parathyroid adenoma. Molecular analysis of the parathyroid tissue failed to demonstrate any abnormality of the multiple endocrine neoplasia Type 1 gene. This case report is the first to describe a prolactin-secreting tumor that developed in association with other endocrine neoplasia after head and neck irradiation. Our case suggests that multiple endocrine neoplasia may develop in a sporadic pattern after scalp irradiation.

Objective: To determine whether or not exposure to ionizing radiation as an adult increases the risk of developing parathyroid adenomas., Design and Patients: A cohort of 27 415 patients had received X-ray treatment to palliate pain originating from arthrosis and spondylosis from 1950 to 1964. In a subcohort of 8144 patients the cervical spine was the target, or one of the targets for the treatment. With the technique used it could be assumed that, as a rule, the parathyroid glands had been included in the treated volume. Patients with parathyroid adenomas were obtained from the Swedish Cancer Register from 1958 to 1995. The standardized incidence ratio (SIR) was calculated., Results: The number of person-years at risk was 180 492 in the cohort exposed at the cervical spine, and 412 994 in the control cohort irradiated only at other sites. The calculated dose in the parathyroid region in the study cohort was about 1 Gy. The observed number of parathyroid adenomas in the study cohort was 22, and 24 in the control cohort. Expected numbers based on population data were 12.0 and 24.7, respectively, giving an SIR of 1.83 (95% CI 1.14-2.76) and 0.97 (CI 0.62-1.45), respectively. Mean age at exposure was 48.9 years (SD 10.2) and at diagnosis 71.5 years (SD 8.3). The time from exposure to diagnosis varied from 2 to 34 years (median 26 years). The excess relative risk was about 0.8 per Gy., Conclusion: Exposure to ionizing radiation to the cervical spine in adult age seems to be associated with an increased risk of developing parathyroid adenomas.

Several authors have suggested that there is an excess risk of hyperparathyroidism, adenomas or hyperplasia after exposure to ionizing radiation. There is still, however, some uncertainty about this association, because these diseases are often asymptomatic and escape clinical detection if not specially searched for. This study is based on a pooled Swedish cohort of 27,925 persons with skin hemangiomas. The majority received radiation treatment in infancy between 1920 and 1965 in Stockholm and Gothenburg. The mean age at treatment was 6 months and the median thyroid dose was 0.20 Gy (range 0-28.5 Gy). Record linkage with the Swedish Cancer Register for the period 1958-1997 gave 43 cases of parathyroid adenoma in the cohort. Analyses of excess relative risk (ERR) models were performed using Poisson regression methods. Clinical records were scrutinized to determine if the childhood radiation exposure was known (biased cases) at the time of diagnosis. Seven of the cases of parathyroid adenoma were classified as biased cases. The standardized incidence ratio (SIR) was 2.10 (95% confidence interval 1.52-2.82) when all cases were included and 1.76 (95% CI 1.23-2.43) with the biased cases excluded. A linear dose-response model with stratification for sex fitted the data best. The ERR per gray was 3.84 (95% CI 1.56-8.99) with all cases and 1.56 (95% CI 0.36-4.45) with the biased cases excluded. There was a significant difference in the ERR per gray between the two subcohorts, probably because of different diagnostic activity in the regions. Our findings confirm that there is a dose-response relationship for radiation-induced parathyroid adenomas.

Objective: To determine whether patients with tertiary hyperparathyroidism due to single- or two-gland disease undergoing limited resection have similar long-term outcomes compared with patients with hyperplasia undergoing subtotal or total parathyroidectomy., Summary Background Data: Tertiary hyperparathyroidism occurs in less than 2% of patients after renal transplantation. Approximately 30% of these cases are caused by one or two hyperfunctioning glands. Nevertheless, the standard operation for this disease has been subtotal or total parathyroidectomy with autotransplantation., Methods: Seventy-one patients underwent surgery for tertiary hyperparathyroidism. At the time of surgery, 19 patients who had a single or double adenoma underwent limited resection of the enlarged glands only (adenoma group). The remaining 52 patients with three- or four-gland hyperplasia had subtotal or total parathyroidectomy with implantation (hyper group). Long-term cure rates between the two groups were compared., Results: In the adenoma group, 7 patients had a single adenoma and 12 underwent resection of a double adenoma. In the hyper group, 49 patients had subtotal and 3 had total parathyroidectomies. After surgery, 70 of 71 patients (99%) were cured of their hypercalcemia. The incidence of postoperative transient hypocalcemia was significantly higher in the hyper group (27% vs. 5%). No patients in either group had permanent hypocalcemia requiring long-term supplementation. With up to 16 years of follow-up, there have been no recurrences in the adenoma group, whereas three patients (6%) in the hyper group have had recurrent or persistent hyperparathyroidism., Conclusions: Patients with tertiary hyperparathyroidism who underwent limited resection of a single or double adenoma only had equivalent long-term cure rates compared with patients undergoing more extensive resections. Therefore, the authors recommend in patients with tertiary hyperparathyroidism and enlargement of only one or two parathyroid glands that the resection be limited to these abnormal glands only.

Primary hyperparathyroidism is the most common manifestation of MEN 1 syndrome. The management of these patients is complex due to the underlying disease process, which predisposes patients to persistent and recurrent disease. The surgical treatment of patients with MEN 1 and hyperparathyroidism can therefore be considered to be palliative in nature. The basic principles of surgery include (1) obtaining and maintaining normocalcaemia for the longest time possible, avoiding persistent/recurrent hypercalcaemia, (2) avoiding surgically induced hypocalcaemia, and (3) facilitating future surgery for recurrent disease. Two approaches have been described as the best practice for patients with hyperparathyroidism in MEN 1: subtotal parathyroidectomy, leaving a remnant of no more than 60 mg in the neck, and total parathyroidectomy with immediate autotransplantation of 10-20 1 mm(3) pieces of parathyroid tissue. Both approaches should be combined with efforts to exclude supernumerary glands and ectopic parathyroid tissue by including resection of fatty tissue from the central neck compartment and thymectomy in all patients. Cryopreservation of parathyroid tissue should be performed whenever facilities are available. In patients with persistent or recurrent disease, an attempt to obtain total elimination of cervical parathyroid tissue is justified, combined with cryopreservation of parathyroid tissue. As radical as surgery is for hyperparathyroidism in MEN 1, the surgeon must take steps to avoid permanent hypoparathyroidism, which in young patients may be worse than the disease itself.

We describe a sporadic case with familial adenomatous polyposis, multiple endocrine neoplasia type 1 (MEN1)-related tumors (an endocrine cell tumor of the pancreas and bilateral parathyroid tumors), and a papillary thyroid carcinoma. To clarify how mutations of the adenomatous polyposis coli ( APC ) gene and the MEN1 gene, responsible for familial adenomatous polyposis and MEN1, respectively, might have contributed to tumorigenesis in this case, we studied germline mutations in both genes and loss of heterozygosity at their genetic loci in multiple lesions. In addition, we performed immunohistochemistry for beta-catenin, associated with the function of the APC gene. A germline mutation was found in the APC gene but not in the MEN1 gene. Normal allelic loss at the APC gene locus was observed in bilateral parathyroid tumors. Immunohistochemical staining of beta-catenin demonstrated accumulation in the cytoplasm in addition to membrane staining in all analyzed tumors and a strong nuclear reaction in the endocrine cell tumor of the pancreas. The presence of normal allelic deletions of the APC gene in bilateral parathyroid tumors and nuclear staining of beta-catenin in the pancreatic tumor in addition to the germline mutations suggests that functional loss of the APC gene played an important role not only in familial adenomatous polyposis but also in the MEN1-related tumors in this case.

The development of hyperparathyroidism after radioactive iodine (RAI) therapy has been reported in 38 cases in the literature. However, the development of a parathyroid adenoma after RAI therapy for a hyperfunctioning multinodular goiter has not been reported. This report describes the pathologic and operative finding on a patient with both hyperthyroidism and hyperparathyroidism, which was diagnosed after previous RAI therapy for a toxic, multinodular goiter.

Objectives: To explore possible associations between the reproductive history amongst women and the risk of parathyroid adenoma (PA)., Design: Two nationwide Swedish registries. The Fertility Register included data on more than 3.4 million livebirths between 1943 and 1992 amongst Swedish females born 1925-72. The Cancer Register encompasses more than 1800 women with a diagnosis of PA 1960 until 1992., Setting: All women resident in Sweden 1960-92., Subjects: Cases were all 1800 women born 1925-72 reported to the Swedish Cancer Registry with a histopathological diagnosis of PA. Five controls were selected at random for each case by matching for the month and year of birth. Conditional logistic regression was used to estimate relative risks of PA., Main Outcomes: Parathyroid adenoma., Results: High parity (four or more live births) was associated with an increased risk of PA. Amongst women with a diagnosis of PA before menopause (i.e. the age of 50 years) there was an increased risk of PA with younger age at first childbirth. Nulliparous women were at increased risk for PA before menopause, and at decreased risk after menopause., Conclusions: There is an association between childbearing and the risk of PA, which has not previously been demonstrated, but the underlying biological mechanisms remain to be determined.

Parathyroid carcinoma is a very rare malignancy and the least common among endocrine malignat tumors. Its etiology is still unclear and some hypotheses have been suggested: previous external radiation to the neck, pregression from benign to malignant lesion, familial hyperparathyroidism. An early accurate diagnosis is very important since surgery is the most effective therapeutic approach to parathyroid carcinoma. Prognosis is quite variable and stress is laid on the early diagnosis and radical surgery which seem to be most favorable prognostic factors. An accurate follow-up should include frequent measurements of serum calcium and PTH levels to promptly detect recurrence or metastases which are usually associated with severe hyeprcalcemia.

The relationship between abnormal cell proliferation and aberrant control of hormonal secretion is a fundamental and poorly understood issue in endocrine cell neoplasia. Transgenic mice with parathyroid-targeted overexpression of the cyclin D1 oncogene, modeling a gene rearrangement found in human tumors, were created to determine whether a primary defect in this cell-cycle regulator can cause an abnormal relationship between serum calcium and parathyroid hormone response, as is typical of human primary hyperparathyroidism. We also sought to develop an animal model of hyperparathyroidism and to examine directly cyclin D1's role in parathyroid tumorigenesis. Parathyroid hormone gene regulatory region--cyclin D1 (PTH--cyclin D1) mice not only developed abnormal parathyroid cell proliferation, but also developed chronic biochemical hyperparathyroidism with characteristic abnormalities in bone and, notably, a shift in the relationship between serum calcium and PTH. Thus, this animal model of human primary hyperparathyroidism provides direct experimental evidence that overexpression of the cyclin D1 oncogene can drive excessive parathyroid cell proliferation and that this proliferative defect need not occur solely as a downstream consequence of a defect in parathyroid hormone secretory control by serum calcium, as had been hypothesized. Instead, primary deregulation of cell-growth pathways can cause both the hypercellularity and abnormal control of hormonal secretion that are almost inevitably linked together in this common disorder.

A 51-year-old male patient with chronic renal failure, who had required dialysis for 22 years, presented with a cervical mass. Laboratory data were consistent with secondary hyperparathyroidism due to chronic renal failure. Cervical exploration was performed with excision of four parathyroid glands and autotransplantation of the normal gland into the forearm. The cervical tumor of the right inferior gland demonstrated parathyroid carcinoma histologically. Adenoma of the right superior gland and hyperplasia of the left superior gland were also recognized. The left inferior gland was normal. A few cases of parathyroid carcinoma in patients on maintenance hemodialysis have been previously reported. However, this is the first report in which all four parathyroid glands revealed different pathological findings: carcinoma, adenoma, hyperplasia and normal gland. Chronic stimulation of the parathyroid glands to release parathyroid hormone might have caused the variety of findings in the four parathyroid glands.

Multiple endocrine neoplasia type 1 (MEN1) is an autosomal dominant disorder characterized by the combined occurrence of parathyroid, pancreatic endocrine, and anterior pituitary tumors. MEN1 has two characteristics; a hormone excess and a sometimes lethal outcome due to malignant tumors. The recent identification of the MEN1 gene has opened the door to a much deeper understanding of this syndrome. Germline MEN1 mutations have been identified in most MEN1 families. They were not found, however, in families with familial pituitary tumors. Thus, studies with the MEN1 gene helped to establish that mutation of some other gene(s) is likely causative of the MEN1 phenocopy. These recent advances provide for the identification of mutant MEN1 gene carriers who are at a high risk of developing MEN1. The protein encoded by the MEN1 gene has been shown to function in the regulation of JunD-activated transcription but much still remains to be elucidated.

Introduction: The role of vitamin D receptor (VDR) gene polymorphism in the pathogenesis of hyperparathyrodism is not clear yet. The aim of this study was to examine the role of BsmI VDR gene polymorphism in patients with primary hyperparathyrodism (PHP) secondary to adenomas., Material and Methods: Fifty-two postmenopausal women with PHP, mean age 64.5 years, were compared with a normal age-matched female population (n = 81)., Results: Distribution of BsmI polymorphism in PHP group was: Bb 54% (28/52); BB 21% (11/52); bb 25% (13/52). In the control group, the distribution in PHP group as follows: Bb 49% (40/81); BB 16% (13/81); bb 35% (28/81). No statistical differences were found between the two groups. In the PHP group, no statistical associations were found between different allelic distribution and age, creatinine, hematocrit, phosphorus, alkaline phosphatase (ALP), total calcium, serum parathyroid hormone (PTH), or gland weight. This data suggest that at least in this group, BsmI VDR gene polymorphism appears to be without relevance in clinical presentation and possibly tumorigenesis in PHP secondary to adenomas.

A 55-year old female patient on long-term hemodialysis began to suffer from pain in her knees and ankles. An ultrasonographic study showed enlargement of all four parathyroid glands. Serum parathyroid hormone and calcium levels were increased. Parathyroidectomy was performed. The right superior gland was enlarged and adherent to surrounding tissues. The other three glands were slightly enlarged. Histologically, the largest gland was a parathyroid carcinoma because capsular and vascular invasion were observed. To our knowledge, there have been only 13 cases of parathyroid carcinomas arising in patients with chronic renal failure reported in the English literature. To evaluate the characteristics of this tumor, we measured nuclear DNA and protein content using stains for HP (hematoporphyrin)/DAPI (4,6-diamidino-2-phenylindole dihydroporphyrin chloride). The nuclear DNA pattern was typically diploid or tetraploid. The cellular protein content was similar to that seen in the controls. The discrepancy between the histology, indicative of malignancy and the cytofluorometrical findings show that it is difficult to determine the prognosis for patients with secondary hyperparathyroidism and parathyroid carcinomas solely from the results of tumor DNA cytometry.

A review of all reports in the literature of parathyroid carcinoma (PTC) was undertaken to define an optimal management strategy for this rare condition. PTC is uncommon and its etiology of PTC is largely unknown although patients with familial hyperparathyroidism, multiple endocrine neoplasia type 1 and irradiation to the head and neck are at increased risk for developing the disease. PTC occurs with equal frequency in both sexes and is usually diagnosed in the fifth decade. En bloc resection of the carcinoma and the adjacent structures in the neck is the surgical treatment and is associated with an 8% local recurrence rate and a long term overall survival rate of 89% (mean follow up 69 months). In contrast simple parathyroidectomy results in a 51% local recurrence rate and 53% long-term survival rate (mean follow up 62 months). Adverse prognostic factors for survival were initial management with simple parathyroidectomy alone, the presence of nodal or distant metastatic disease at presentation and non-functioning PTC.

The presentation of parathyroid carcinoma in patients with chronic renal failure is rare, although with improvements in life expectancy associated with this condition there have now been 12 reported cases, including the first case we report here. It has been proposed that in these cases there has been a malignant transformation of benign parathyroid hyperplastic tissue. We also report the first case of parathyroid carcinoma associated with coeliac disease and suggest that the same mechanism may be responsible. We review the presentation, diagnosis, treatment and natural history of the disease.

Clonal analysis has shown that in renal hyperparathyroidism (2-HPT), parathyroid glands initially grow diffusely and polyclonally after which the foci of nodular hyperplasia are transformed to monoclonal neoplasia. There is a great deal of information about genetic abnormalities contributing to the tumourigenesis of parathyroid neoplasia in primary hyperparathyroidism. It is speculated that allelic loss of the MEN1 suppressor gene and overexpression of cyclin D1 induced by rearrangement of the parathyroid hormone gene may be the major genetic abnormality in sporadic parathyroid adenoma but not in 2-HPT. The pathogenesis of 2-HPT, abnormality of the Ca2+-sensing receptor (CaR) gene and the vitamin D receptor gene may possibly contribute to parathyroid tumourigenesis in 2-HPT. However, this is not yet clear and heterogeneous and multiple genetic abnormalities may be responsible for the progression of secondary parathyroid hyperplasia.

Background: Parathyroid disease occurs sporadically or as part of hereditary multiple endocrine neoplasia (MEN) syndrome. The aim of this study was to evaluate the possible role of the RET proto-oncogene not only in hereditary MEN 2-associated hyperparathyroidism but also in different forms of sporadic hyperparathyroidism., Methods: We investigated 22 patients with parathyroid disease whose family history and results of laboratory and clinical examinations excluded MEN 2 syndrome. DNA extractions of histologically confirmed tumor tissue of patients with primary hyperparathyroidism (n = 18), renal hyperparathyroidism (n = 2), and parathyroid carcinoma (n = 2) were performed. Using solid phase DNA sequencing, mutation analysis of polymerase chain reaction amplified products focused on exons 10, 11, and 16 of the RET proto-oncogene. Parathyroid tissue from four patients with known MEN 2A served as positive controls., Results: No mutations of the codons 609, 611, 618, 620, 634, and 918 were found in the sporadic parathyroid tumors analyzed. DNA sequencing revealed heterozygous mutations in codon 634 of the RET proto-oncogene in four parathyroid glands from four patients with MEN 2A., Conclusions: Mutations of the RET proto-oncogene contributing to MEN 2 syndromes are absent in sporadic parathyroid tumors. Our data in conjunction with the literature suggest at least three different modes of tumorigenesis in parathyroid disease.

We describe an 8-year-old boy who had asymptomatic hypercalcemia 4 years after radiotherapy involving the left orbit and lungs. A right parathyroid adenoma was diagnosed, and normocalcemia was achieved after its removal. Routine monitoring of serum calcium and phosphate levels is recommended for children after head and neck irradiation.

Aim: To analyse the causes and outcome of reoperations for persistent or recurrent primary hyperparathyroidism (HPT)., Materials and Methods: We reviewed the medical records of 38 patients who underwent reoperation between December 1965 and April 1997 for persistent or recurrent primary HPT. During this period of time, 1448 patients underwent operation for primary HPT, 294 for renal HPT and 58 for questionable disease, i. e. a total of 1800. In the 1448 cases of HPT, 22 patients were reoperated after a first cervicotomy in the institution, i. e. a first reoperation rate of 1.5%. Sixteen patients were referred after unsuccessful parathyroid surgery. Six patients were reoperated on twice and one patient seven times for a graft-dependent recurrence., Results: Reasons for failed parathyroid operations included tumour tissue in ectopic location (75%) or tumour tissue that had not been seen in normal position (19%), parathyreomatosis (2%), parathyroid cancer (2%) and graft-dependent hypercalcaemia (2%). Of the ectopic glands, 45 % were intrathymic, 12.5% intrathyroidal, 7.5% retro-oesophageal, 7.5% in the carotid sheath, 5% interthyrotracheal, 5% in the mediastinum (extrathymic), 5% in the aorto-pulmonary window, 2.5% undescended, 2.5% overdescended and 2.5% intertracheooesophageal. Of the patients, 38% had uniglandular lesions, 60% multiglandular lesions, and 2% parathyroid cancer. The histologically confirmed cause of HPT was adenoma in 50% of cases, hyperplasia in 38% and "normal" but overweight glands in 9.5%. Of the 38 patients studied, 15 presented one or more supernumerary glands (fifth to eighth gland). Reoperation was performed through a cervical incision in 82% of cases and using a mediastinal approach in 18% (8 median sternotomies, 1 thoracoscopy). The success rate of the reoperations was 92%. A total of 8% of patients suffered permanent unilateral vocal cord paralysis; 5% are definitely hypocalcaemic. The sensitivities of preoperative localization studies ranged from 69% for sestamibi scan and 63% for selective venous catheterization to 16% for computed tomography., Conclusion: Repeated parathyroidectomy can be avoided in more than 98% of patients if an experienced surgeon performs bilateral cervical exploration during the initial parathyroid operation. For patients with persistent or recurrent primary HPT, preoperative localization studies and a focused surgical approach can result in a 92% success rate with a minimal complication rate.

Reports of the coexistence of hyperparathyroidism and thyroid disease have raised the issue of a possible etiologic relationship. The present study tests the hypothesis that chronic elevation of thyroid-stimulating hormone (TSH) is related to the development of hyperparathyroidism. Four groups of 60 female rats were treated as follows: group 1, control; group 2, propylthiouracil (PTU) 0.0025%; group 3, PTU 0.0025% plus thyroxine, 5 microg two times per week; and group 4, only thyroxine. The animals' serum calcium, phosphorus, TSH, thyroxine, and parathyroid hormone (PTH) levels were evaluated at 0, 6, 12, and 18 months. Significant elevation of TSH was sustained throughout the 18 months in groups 2 and 3. The PTH levels were also significantly elevated in both group 2 and group 3 animals (P = 0.02). The histopathologic features of the parathyroids were evaluated at 18 months. In the group 2 (PTU only) animals, which had profound hypothyroid, 44% developed parathyroid adenomas. In the group 3 (PTU plus thyroxine) animals, who had mildly elevated TSH levels, 53% developed parathyroid adenomas. These findings are consistent with the hypothesis that prolonged TSH stimulation may lead to hyperparathyroidism in the rat model.

MEN (multiple endocrine neoplasia) type 2 syndrome is an inherited disease characterized by medullary thyroid carcinoma, pheochromocytoma, hyperparathyroidism and/or developmental anomalies. Germ-line mutations of the RET proto-oncogene have recently been identified as the underlying cause of the syndrome. Accordingly, several investigators have advocated prophylactic total thyroidectomy for medullary thyroid carcinoma at an early age in MEN 2 gene carriers identified by DNA analysis. Before applying this strategy in Japan, the biological behavior of each category of tumor in MEN 2 syndrome, and medullary thyroid carcinoma in particular, should be well understood. We conducted a nationwide questionnaire survey to clarify the clinicopathological features of MEN 2 in Japan, obtaining data for 230 patients diagnosed as having MEN 2. They included 84 males and 146 females, with a median age of 37.5 years (range 5-83). Patients were categorized as 179 with MEN 2A, 17 with MEN 2B, 12 with familial medullary thyroid carcinoma and 22 'other'. Medullary thyroid carcinoma, pheochromocytoma and parathyroid lesions occurred in 224 (97%), 132 (57%) and 25 (11%) patients respectively. Twelve patients (5.2%) died of medullary thyroid carcinoma and 11 patients died of other or unknown causes. Of 163 patients for whom follow-up data were obtained, 82 (50%) experienced recurrences of medullary thyroid carcinoma, including symptomatic recurrent tumors in 24 patients and elevated calcitonin levels alone in 54. In the era of RET mutational analysis for screening relatives of patients with MEN 2, these data provide useful information about surgical management for patients with MEN 2 in Japan.

Parathyroid carcinoma is a rare, reported to be less than 1% of patients with primary hyperparathyroidism. Recently, cell cycle regulators such as the retinoblastoma gene and p53 have been implicated in the pathogenesis of parathyroid carcinoma. Yet definite diagnosis remains difficult not only clinically but also pathologically. However, the clinical presentation, biochemical and hormonal findings, and appearance at the operation may possibly raise suspicion regarding the diagnosis. A radical en bloc resection at the primary operation is most important. Even after a successful initial operation parathyroid carcinoma carries an increased risk of recurrence. There is wide diversity in the interval between the initial operation and the manifestation of metastasis. Histopathology and DNA ploidy are valuable predictors of the clinical outcome. Because the severe hypercalcemia it engenders has catastrophic consequences, proper management of the recurrent hypercalcemia is also mandatory. The lung is the most common site of distant metastasis. Selected patients with pulmonary metastasis of parathyroid carcinoma can obtain significant benefit from aggressive surgical resection even when they have multiple or recurrent lesions. When hypercalcemia is refractory to surgical resection, medical treatment with bisphosphonate has a beneficial effect.

Background: Between 1980 and 1984, 312 (30%) of 1038 patients undergoing initial cervical exploration for primary hyperparathyroidism (pHPT) at our institution had proven renal stones., Methods: In this retrospective study we focused on clinical characteristics, biochemical tests, perioperative and pathologic findings, and immediate outcomes of operation, comparing findings in patients with and without renal stones., Results: Patients with renal stones were more often younger male patients, had serum phosphorus levels significantly lower (p < 0.02) and 24-hour urinary calcium excretion significantly higher (p < 0.0001) than patients without renal stones, and had a significantly higher (p < 0.05) proportion of abnormal glands weighing less than 250 mg. Relevant diagnostic preoperative variables were evaluated by means of multivariate analysis to determine whether they independently had predictive power with regard to renal stones. Male gender and younger age were significantly associated with the presence of renal stones, providing odds ratios of 2.5 and 1.4, respectively. In addition, the risk of having renal stones was significantly related to minimally elevated serum calcium levels (p < 0.05), serum phosphorus levels (p = 0.02), and 24-hour urine calcium excretion (p < 0.05)., Conclusions: In patients with renal stones the diagnosis of pHPT should be considered. If the diagnosis is confirmed, a liberal approach to cervical exploration should be taken.

This article provides an overview of the long-term carcinogenic effects of medical radiation exposure to the head and neck and focuses on studies that allow risk quantification. The thyroid gland in children is extremely sensitive to the tumorigenic effects of external radiation for many years after exposure. Risk of thyroid cancer decreases with increasing age at exposure, with little risk, if any, apparent among persons exposed as adults. Large risks of neural tumors have been reported after moderate- and high-dose radiotherapy in childhood; however, the magnitude of the risk at low doses and for adult exposures is unclear. Data on salivary gland tumors are limited but tend to support an association with radiation exposure. In contrast, the pituitary gland appears to be relatively resistant to the tumorigenic effects of radiation. Several cohort studies have reported an increased risk of hyperparathyroidism among irradiated populations. In summary, radiation exposure to the head and neck can result in tumors of the thyroid, salivary, and parathyroid glands, as well as the brain and central nervous system.

Temporally orderly activation of cyclin-dependent kinases (Cdks) governs progression and transitions of the cell cycle in eukaryotic cells. Binding of Cdks to cyclins and threonine phosphorylation in the Cdks are required to form fully active holo-Cdks. So far, 8 types of cyclins and 7 Cdks are known in mammals. Two types of the cyclins, D-(D1, D2, D3) and E-type cyclins, function in the G1 phase of the cell cycle. D-type cyclins form active complexes with Cdk 4 or Cdk 6 earlier than E-type cyclin does with Cdk 2. Overexpression of the cyclin D1 has been reported in human tumors including parathyroid adenomas with chromosomal abnormality, suggesting that overexpression of the cyclin D1 could abrogate cell cycle control in G1 phase and may contribute to generate tumor cells.

A totally thyroidectomized patient with thyroid and parathyroid carcinomas, which had developed after neck irradiation in childhood, became hypercalcemic due to pulmonary metastases. The hypercalcemia was ameliorated by intermittent iv administration of bisphosphonate for 3.5 years, but this gradually became refractory to the bisphosphonate treatment. After right thoracotomy for resection of pulmonary metastases, acute necrotizing pancreatitis developed. The patient was therefore placed on total parenteral nutrition supplemented with T4 and a restricted dose of magnesium. Thyroxine(T4) (30 micrograms/day, iv) was not sufficient to maintain euthyroidism, but a higher dose (60 micrograms/day) elicited mild hyperthyroidism to the same extent as that elicited by an oral dose of 100 micrograms/day. The present case showed that the appropriate iv dose of T4 in this thyroidectomized patient with acute pancreatitis was about 60% of the oral dose. Furthermore, bisphosphonates (pamidronate and alendronate) and magnesium depletion were very effective in controlling the hypercalcemia.

An unusual case of parathyroid adenoma is presented. This adenoma presented as a rapidly expanding neck mass in a normocalcemic patient. It was located far laterally in the neck, in association with the internal jugular vein and with a branchial cleft cyst. This case provides an unusual presentation of parathyroid adenoma. It also provides an elegant demonstration of developmental anatomy as well as the mechanism of parathyroid ectopia in the lateral aspect of the neck.

Persisting hypercalcemia after surgery for primary hyperparathyroidism is a challenge for the surgeon: once non-parathyroid causes for the hypercalcemia have been excluded the only remaining possible causes are ineffective surgery and a failed surgery. Between 1986 and 1994, 414 patients with primary hyperparathyroidism were operated upon, 32 of whom presented with persisting hypercalcemia; 24 of these patients had their first operation in another hospital. The cause for persisting hypercalcemia was a single adenoma in 27 patients (84%), double adenoma in 2 patients and primary hyperplasia in 2 patients. In 1 patient an unsuccessful revision operation was performed. In 17 patients the parathyroid glands had an atypical position. There were 11 patients who presented with recurrent hyperplasia. The reasons for recurrence were double adenoma in 2 patients and hyperplasia in 8 cases (73%). In 1 patient no pathologic gland was found. Although preoperative localization studies were positive in only 32%, the overall surgical success rate fortunately amounted to a satisfactory 95%.

Familial isolated hyperparathyroidism (FIHP) is a rare heritable disorder characterized by hypercalcemia, inappropriately high PTH levels, and isolated parathyroid tumors with no evidence of hyperfunction of any other endocrine tissues. To establish whether FIHP exists as a distinct disease entity or represents a variant of any of the known multiple endocrine neoplasia (MEN) syndromes, we tested 19 members of a large, well characterized family with FIHP in which the disease is transmitted through 4 generations in an autosomal dominant fashion. Fourteen DNA markers at 10 polymorphic loci closely linked to the MEN1 locus on the long arm of chromosome 11 and 5 markers close to the MEN2A gene on chromosome 10 were tested using Southern blot analysis and polymerase chain reaction-based techniques. Additionally, two polymorphic markers (Mir1 and Mir2) within the prepro-PTH gene on the short arm of chromosome 11 were analyzed using denaturant gradient gel electrophoresis. Linkage was clearly excluded between FIHP and the MEN1 and MEN2A loci as well as to the PTH gene. Comparison of constitutional and tumor genotypes showed that constitutional heterozygosity was retained for markers in the MEN1 and MEN2A regions as well as to the PTH gene in 4 tumors from 3 affected members. In 1 individual, a parathyroid carcinoma was found after recurrence of hypercalcemia. We, therefore, propose that autosomal dominant FIHP can occur as a genetically and clinically distinct entity with an increased risk of malignant transformation of parathyroid tumors.

Background: A case of familial parathyroid crisis resulting from presumptive cancer in a 14-year-old boy impressed the authors with its rarity and need for recognition., Methods: The authors performed a retrospective review of the relevant literature and described the case., Results: The case report cited is the eighth example of parathyroid cancer occurring in a child younger than 16 years of age. It represents the first example of malignant parathyroid crisis because of familial hyperparathyroidism and illustrates the demand for appropriate diagnosis and methods of management in parathyroid cancer., Conclusions: Familial hyperparathyroidism may become manifest in young patients, which justifies screening among affected families to avoid serious sequelae of disease. Parathyroid cancer is an example of a malignant neoplasm in the young and is managed best by en bloc resection of primary disease, appropriate neck dissection for nodal involvement, and aggressive resection for recurrence, if possible, to control the lethal effects of hypercalcemia; this permits prolonged survival even in discouraging situations.

In a 2.5-year carcinogenicity study, two groups, both including male and female Wistar rats, were fed two different diets with 4% and 16% fat. In addition to 4% soybean oil, the high-fat diet contained 12% mono- and diglycerides, of which 85% was stearic acid and 13% palmitic acid. There was no difference in food consumption, body weight, weight gain, and longevity between the two groups. A statistically significant increase in the incidence of tumors in the high-fat group was seen in fibroadenoma of the mammae (female, p = 0.05). No statistically significant difference was seen when the incidence of benign mammary tumors (adenomas and fibroadenomas) was combined, just as the overall incidence of mammary tumors (adenomas, fibroadenomas, and adenocarcinomas) was not significantly different between the groups. A statistically significant decrease in the incidence of tumors in the high-fat group was seen in adenoma of the parathyroid gland (male, p = 0.04) and medullary carcinoma of the adrenal gland (male, p = 0.04). Combining the incidence of benign and malignant tumors of the adrenal medulla led to a further increase in the level of significance (p = 0.02). The present study showed that a high-fat diet influenced the tumor incidence in certain organs of rats. However, the overall differences in tumor incidence between rats fed the low- and the high-fat diet are considered marginal. Therefore we were not able to confirm or deny the hypothesis that a high-fat diet promotes the development of cancer. It should be noted that, in our study, fat accounted for about 30% of the total energy in the high-fat diet. This is much below the amount of fat normally found in the western diet but corresponds well to the level recommended for human intake. In addition, the rats fed the high-fat diet did not gain more weight, even though no difference was recorded in food consumption (g/kg body wt) between the groups.

Very little is known about the pathogenesis of tuberous sclerosis. Over the past 10 years, however, increasing numbers of reports on adenomatous diseases in association with tuberous sclerosis have been published. A case of hypercalcaemia and parathyroid adenoma in association with tuberous sclerosis is presented, of which there has been one such report published previously. This association might be another manifestation of this complex disease: it is therefore recommended that plasma calcium concentrations should be measured in such patients.

An examination of registered cases of parathyroid tumor in Hiroshima Prefecture between 1974 and 1987 revealed 23 cases. An epidemiological study showed that the incidence of parathyroid tumors in Hiroshima Prefecture was significantly higher in the total exposed, especially among the proximally exposed (within 2,000 m from the hypocenter), than in the control nonexposed group (P less than 0.001). A similar trend was seen for parathyroid tumor associated with primary hyperparathyroidism.

Seventeen patients with parathyroid gland tumors underwent surgical resection at the Hiroshima University Hospital between 1956 and 1988. Three of them where born after the atomic bomb explosion, and 6 of the remaining 14 patients (42.9% of the total- a high proportion) were atomic bomb survivors. Because parathyroid gland tumors and hyperparathyroidism are assumed to develop in patients who have been exposed to radiation after a long latent period, it is necessary to anticipate the possible occurrence of these diseases in atomic bomb survivors. The present paper is the first to report surgically extirpated parathyroid gland tumors in atomic bomb survivors.

Parathyroid tumors in A-bomb survivors in Hiroshima have been studied. Thirteen cases of parathyroid tumor were confirmed from 4,136 autopsy cases between 1961 to 1977, and an elevated incidence of tumor with increase of dose (T65D) was demonstrated (P less than 0.01). A high proportion of 42.9%, 6 out of 14 parathyroid tumors extirpated at Hiroshima University Hospital between 1956 and 1988, were atomic bomb survivors exposed within 4.1 km from the hypocenter. From an epidemiological study using 23 parathyroid tumor cases detected in Hiroshima Prefecture between 1974 and 1987, an elevated incidence of parathyroid tumors with increase of dose (proximally exposed, other exposed and control nonexposed) was demonstrated (P less than 0.001).

To determine the effects of childhood irradiation on the parathyroid glands, a cohort of 4297 patients who received radiation to the tonsils before the age of 16 years has been followed-up prospectively. Among the 2923 patients who were located and provided information, 32 patients developed clinical hyperparathyroidism. The incidence of clinical hyperparathyroidism was 18.7 per 100,000 person-years below the age of 40 years and 171 per 100,000 person-years in the age range of 40 to 60 years. This represents a 2.9-fold (95% confidence interval, 1.6 to 4.3) and 2.5-fold (95% confidence interval, 1.1 to 3.9) increase in the incidence of hyperparathyroidism compared with that among the general population. In addition, 31% of the patients who developed hyperparathyroidism also developed thyroid cancer, which is higher than the 11.2% prevalence of thyroid cancer in the patients who received radiation therapy who did not develop parathyroid tumors. Patients with a history of head and neck irradiation should have their parathyroid glands evaluated on a regular basis.

Neonatal inbred Wistar albino rats were given either 5 or 10 microCi radioiodine (131I) within 24 hours of birth. After weaning, animals were placed on diets high, normal, or deficient in vitamin D3 (cholecalciferol) for periods up to 2 years. In animals aged 12 months and older, adenomas were found in 0 of 67 unirradiated controls, in 22 of 67 given 5 microCi 131I, and in 25 of 67 given to microCi 131I. The incidence of tumors in irradiated animals was highest (55%) in those on a low-vitamin D diet and lowest (20%) in those on a high-vitamin D diet. Plasma calcium levels were significantly increased by the high-vitamin D diet, but the low-vitamin D diet did not lead to any significant decrease as compared to the calcium levels of the normal vitamin D diet group. Small but significant calcium increases were found in tumor-bearing animals. These findings indicate that parathyroid tumors in the rat can be induced by radiation and that their incidence is strongly influenced by dietary vitamin D content. The possibility that metabolites of vitamin D3 may influence parathyroid growth and tumor formation directly is discussed.

73 patients with primary hyperparathyroidism are reviewed. The elevated serum calcium was the main diagnostic index but estimation of the parathyroid hormone was useful confirmatory evidence when raised. A normal level does not exclude the diagnosis being found in 32% of patients. Intravenous methylene blue was a useful adjunct to surgery. 95% of the patients had relief of their hypercalcaemia after a single operation. 78% of patients had stones and there was a marked reduction in further stone formation after surgery.