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Abnormal bone and parathyroid histology in carcinoma patients with pseudohyperparathyroidism.

Postmortem bone and parathyroid gland histology in nine hypercalcemic cancer patients without bone metastases was compared to bone and parathyroid histology in ten normocalcemia patients. Parameters of parathyroid function, including serum immunoreactive parathyroid hormone, acid base status, serum phosphate, and nephrogenous cyclic AMP were measured in the hypercalcemic group and compared to normals and to patients with primary hyperparathyroidism. Bone histology in all nine hypercalcemic cancer patients showed increased osteoclastic bone resorption and increased fibrous connective tissue in the bone marrow. Parathyroid glands were of normal size in all nine patients but contained little or no fat, one criterion of parathyroid hyperplasia. In the normocalcemic cancer patients only 2/10 had minimally increased bone resorption while 7/10 had decreased or absent stromal fat in the parathyroid glands. Despite the hyperplastic appearance of the parathyroid glands, serum biochemical parameters in the hypercalcemic cancer patients indicate a state of suppressed parathyroid function suggesting that the osteoclastic bone resorption is related to a humoral substance elaborated by the tumors which is distinct from parathyroid hormone.

Adult↗

Primary hyperparathyroidism in cats: seven cases (1984-1989).

The medical records of 7 hypercalcemic cats with primary hyperparathyroidism were evaluated. Mean age was 12.9 years, with ages ranging from 8 to 15 years; 5 were female; 5 were Siamese, and 2 were of mixed breed. The most common clinical signs detected by owners were anorexia and lethargy. A cervical mass was palpable in 4 cats. Serum calcium concentrations were 11.1 to 22.8 mg/dl, with a mean of 15.8 mg/dl calculated from each cat's highest preoperative value. The serum phosphorus concentration was low in 2 cats, within reference limits in 4, and slightly high in 1 cat. The BUN concentration was greater than 60 mg/dl in 2 cats, 31 to 35 mg/dl in 2 cats, and less than 30 mg/dl in 3 cats. Abnormalities were detected in serum alanine transaminase, aspartate transaminase, and alkaline phosphatase activities from 2 or 3 cats. Parathormone (PTH) concentrations were measured in 2 cats before and after surgery. The preoperative PTH concentration was within reference limits in 1 cat and was high in 1 cat. The PTH concentrations were lower after surgery in both cats tested. A solitary parathyroid adenoma was surgically removed from 5 cats, bilateral parathyroid cystadenomas were surgically resected in 1 cat, and a parathyroid carcinoma was diagnosed at necropsy in 1 cat. None of the cats had clinical problems with hypocalcemia after surgery, although 2 cats developed hypocalcemia without tetany, one of which was controlled with oral administration of dihydrotachysterol and the other with oral administration of 1,25 dihydroxyvitamin D. All 5 of the cta that underwent removal of an adenoma were alive at least 240 days after surgery.(ABSTRACT TRUNCATED AT 250 WORDS)

Adenoma↗

Parathyroid hormone related peptide and receptor expression in paired primary prostate cancer and bone metastases.

Parathyroid hormone-related peptide is a regulatory protein implicated in the pathogenesis of bone metastases, particularly in breast carcinoma. Parathyroid hormone-related peptide is widely expressed in primary prostate cancers but there are few reports of its expression in prostatic metastases. The aim of this study was to examine the expression of parathyroid hormone-related peptide and its receptor in matched primary and in bone metastatic tissue from patients with untreated adenocarcinoma of the prostate. Eight-millimetre trephine iliac crest bone biopsies containing metastatic prostate cancer were obtained from 14 patients from whom matched primary tumour tissue was also available. Histological grading was performed by an independent pathologist. The cellular location of mRNA for parathyroid hormone-related peptide and parathyroid hormone-related peptide receptor was identified using in situ hybridization with (35)S-labelled probe. Expression of parathyroid hormone-related peptide and its receptor was described as uniform, heterogenous or negative within the tumour cell population. Parathyroid hormone-related peptide expression was positive in 13 out of 14 primary tumours and in all 14 metastases. Receptor expression was evident in all 14 primaries and 12 out of 14 metastases. Co-expression of parathyroid hormone-related peptide and parathyroid hormone-related peptide receptor was common (13 primary tumours, 12 metastases). The co-expression of parathyroid hormone-related peptide and its receptor suggest that autocrine parathyroid hormone-related peptide mediated stimulation may be a mechanism of escape from normal growth regulatory pathways. The high frequency of parathyroid hormone-related peptide expression in metastases is consistent with a role in the pathogenesis of bone metastases.

Autoradiography↗

[Calcimimetics as a new chance for effective treatment of calcium metabolism disturbances].

Physiological principles are presented of calcium receptor (CaR) as well as agents affecting the receptor, defined as calcimimetics. Positive influence of type 1 and type 2 calcimimetics on calcium metabolism is discussed. The clinical indications for calcimimetics, especially type 2, in the future, seem to be hypercalcemia in the course of primary and secondary hyperparathyroidism as well as hypercalcemia in patients with parathyroid carcinoma.

Calcium↗

The predictive value of laboratory findings in patients with primary hyperparathyroidism.

BACKGROUND: Despite extensive preoperative imaging and intraoperative "gadgetry" to facilitate localization of abnormal parathyroid glands, the onus of identification and resection remains with the surgeon in the operating room. We pondered the relative usefulness of routine laboratory studies to the surgeon as predictive guides to the intraoperative findings in patients with primary hyperparathyroidism (HPT). STUDY DESIGN: Pre- and postoperative laboratory data were analyzed in 166 consecutive patients (1998 to 1999) undergoing successful cervical exploration for sporadic primary HPT and were correlated with the pathologic findings. Patients with secondary HPT, multiple endocrine neoplasia, familial HPT, and parathyroid carcinoma were not included in this study. RESULTS: One hundred eighteen women and 48 men (mean age = 63 years) with parathyroid adenoma (n = 155) and sporadic hyperplasia (n = 11) were evaluated. Mean parathormone (PTH) levels varied little with the pathology: adenoma = 9.6 pmol/L and hyperplasia = 10.2 pmol/L (p > 0.05). In patients with parathyroid adenoma, analysis of preoperative measures showed a positive correlation (r = 0.48, p < 0.0001) with PTH and gland weight. The correlation appeared to be the strongest in the tails of the distribution; in 22 of 23 (96%) cases with PTH levels lower than 6 pmol/L, the offending lesion or lesions were less than 400 mg; in all six cases with PTH levels higher than 18.0 pmol/L, the abnormal gland or glands weighed more than 800 mg. PTH levels between 6 and 18 pmol/L revealed mean adenoma weight of 757 mg (median = 420 mg; range = 50 to 5,500 mg). CONCLUSIONS: Extreme values of PTH in patients with single-gland parathyroid disease alert the surgeon to the likelihood of small or large parathyroid adenomas. Laboratory studies do not differentiate adenoma from hyperplasia, nor do they pinpoint the size of abnormal glands with moderate-range PTH values.

Adenoma↗

Ultrasonography and needle aspiration cytology in the diagnosis and management of parathyroid lesions.

To elucidate the diagnostic value of fine needle aspiration (FNA) cytology of ultrasonically suspected parathyroid lesions, we reviewed a series of 17 cases seen over the past two years. Patients with biochemically proven primary or secondary hyperparathyroidism were examined by ultrasonography using a 7.5-MHz linear transducer. Ultrasound-guided FNA cytologic examinations with Riu's stain were performed on 13 patients who had questionable ultrasonographic patterns. The aspirates were considered adequate in nine out of 13 cases (69%). The cytologic patterns, characterized by tight cohesion of naked nuclei with indistinct cell border showing hypermonomorphism and overlapping of nuclei, were noted in adenomatous and hyperplastic lesions. There were several different findings noted in the case of parathyroid carcinoma, including loose cohesion of nuclei, larger nuclear size, and prominent anisokaryosis. One patient with secondary hyperparathyroidism who previously had a neck exploration, received an ultrasonically-guided percutaneous alcohol injection to the parathyroid lesion after cytologic verification. The result was remarkable both in volume reduction and in clinical improvement. The results suggest that ultrasound-guided FNA cytologic examination with Riu's stain is safe, simple and helpful in the localization of parathyroid lesions prior to surgery or percutaneous alcohol ablation therapy.

Adenoma↗

Expression of parathyroid hormone-related protein in abnormal human parathyroids.

The expression of parathyroid hormone-related protein (PTHrP) in abnormal human parathyroids was investigated. Northern blot analysis of RNA extracted from human benign parathyroid adenomata (n = 4) revealed multiple PTHrP mRNA species ranging in size from 1.8 to 4 kb. The relative abundance of PTHrP mRNA expressed in two of the adenomata was similar to that of a tumour (DAF) associated with humoral hypercalcaemia of malignancy, whereas PTHrP mRNA was of low abundance in a third and was undetectable in the fourth. PTHrP-like immunoreactivity was detected in extracts of abnormal parathyroid tissue (benign adenoma (n = 7), hyperplasia (n = 5) and parathyroid carcinoma (n = 2] using a sensitive specific two-site immunoradiometric assay for human (h) PTHrP(1-86) and a radioimmunoassay for hPTHrP(1-34). Ratios of hPTHrP(1-86)- and hPTHrP(1-34)-like immunoreactivities relative to hPTH(1-84)-like immunoreactivity in the parathyroid tissue extracts were, on average, less than 1%. PTHrP bioactivity in the extracts could not be distinguished from that of PTH, by an osteosarcoma cell bioassay. We conclude that, despite reports of over-expression of PTHrP mRNA in parathyroid adenomata, the potential contribution of PTHrP to the total PTH-like activity of adenomata and other abnormal parathyroid tissue may be insignificant relative to PTH.

Adenoma↗

The two-hit theory of neoplasia: implications for the pathogenesis of hyperparathyroidism.

Knudson's two-hit or two-mutational-event hypothesis for the initiation of neoplasia suggests that two somatic mutations are necessary for initiation of sporadic neoplasms, and that a genetic plus a somatic mutation are required for hereditary neoplasms. Glucose-6-phosphate dehydrogenase (G6PD) studies of parathyroid tumors of 11 heterozygotes with hyperparathyroidism (HPT), including one with hereditary HPT, have shown both A and B isoenzymes. These findings suggest multicellular development of parathyroid tumors and are compatible with tumors being manifestations of either nonneoplastic hyperplasia or a genetic first mutational event. Parathyroid carcinoma may be the result of a second mutation in cells made susceptible by previous genetic or somatic mutations. Comparison of parathyroid cancer in families with hereditary HPT with sporadic cases from the literature reveals a generally younger onset with hereditary HPT compatible with the two-hit theory. Consideration of these age-of-onset and G6PD findings suggest that hyperparathyroidism may result from either non-neoplastic or mutational-induced processes even though no histologic distinctions have been observed in the hyperplasia associated with these processes.

Glucosephosphate Dehydrogenase↗

A Novel IVS2-1G>A mutation causes aberrant splicing of the HRPT2 gene in a family with hyperparathyroidism-jaw tumor syndrome.

HRPT2, the gene associated with hyperparathyroidism-jaw tumor (HPT-JT) syndrome, was previously mapped to 1q24-q32. It was recently cloned, and several germline mutations were found to predispose to HPT-JT syndrome. We sequenced the complete HRPT2 coding sequence and splice-junctional regions in a Korean family with HPT-JT syndrome and identified a novel germline mutation, IVS2-1G>A in intron 2, that caused the autosomal dominant trait of HPT-JT syndrome in this family. RT-PCR and sequencing of the transcripts revealed that this splicing mutation generated alternative splicing errors leading to the formation of two different transcripts, one with exon 3 deleted, the other lacking the first 23 bp of exon 3 due to the use of an internal splice acceptor in exon 3. Translation of both transcripts results in premature termination. In addition, we detected two novel somatic mutations of HRPT2 in malignant parathyroid tumors from the affected individuals. One, 85delG, causes premature termination; the other, an 18 bp in-frame deletion of 13_30delCTTAGCGTCCTGCGACAG, suggests that this region may be important in the development of the parathyroid carcinomas in HPT-JT syndrome. These findings provide further evidence that mutation of HRPT2 is associated with the formation of parathyroid tumors in HPT-JT syndrome.

Adult↗

Presence of neuron-specific enolase and somatostatin in human parathyroid tissues.

The association of parathyroid abnormalities with apudomas prompted us to examine parathyroid tissues for the presence of neuron-specific enolase and somatostatin. Enolase was present in extracts of 29 out of 29 parathyroid specimens; tissue content was significantly higher in adenoma than in hyperplasia tissues (p less than 0.005). Somatostatin was present in 14 of 33 specimens. Immunoreactive somatostatin measured in tissue extracts' fluids coeluted on Sephacryl chromatography along with synthetic somatostatin-14 in studies of two parathyroid carcinoma specimens. Since neuron-specific enolase has been found only in neural and neuroendocrine cells, our results suggest that human parathyroid glands may contain neuroendocrine elements. The differential content of neuron-specific enolase in adenoma versus hyperplasia specimens may be diagnostically useful in selected cases. The significance of the presence of somatostatin in some but not all parathyroid tumors requires further investigation. Taken together with our prior findings of gastrin and pancreatic polypeptide in some human parathyroid glands, we postulate that human parathyroid tumors contain neural crest elements.

Adenoma↗

[Mediastinal exploration by sternotomy in surgery of hyperparathyroidism. 36 cases].

Mediastinal exploration by sternotomy was carried out 36 times in 35 patients with evidence of hyperparathyroidism amongst a group of 1,461 operations for hyperparathyroidism between 1962 and 1987. The exploration was indicated 30 times as re-operation for hyperparathyroidism persistent after one or more negative cervicotomy procedures or recurrent, and 6 times from the outset, (5 in a context of acute hypercalcemia). Exploration was positive 20 times (16 adenomas, 2 hyperplasias, 2 metastases of a parathyroid carcinoma), but negative 16 times (3 diagnostic errors, 6 cervical lesions discovered subsequently, 7 explorations totally negative). The site of mediastinal parathyroid lesions is usually intrathymic (13 cases) but may sometimes (3 cases) be in the middle mediastinum. Pre-operative investigation to identify the site of a possible mediastinal lesion, in re-operation surgery, remains unreliable, the best investigation in this series being thoracic CT scan with 63% true positives. Thallium-Technetium subtraction isotope scan, carried out once with a good result, should now have a place amongst investigations. The principal post-operative complication is hypoparathyroidism which can be prevented by cryopreservation of a fragment of the lesion for possible subsequent reimplantation. Mediastinal exploration is rarely indicated in hyperparathyroid surgery and should be undertaken only after meticulous cervical exploration.

Adenoma↗

[Reoperation for persistent or recurrent primary hyperparathyroidism. Seventy-seven cases among 1888 operated patients].

AIMS: To analyse the results of re-operations for persistent (p) or recurrent (r) primary hyperparathyroidism (PHPT). PATIENTS AND METHODS: From 1965 throughout 2001, 1888 patients were operated on for PHPT. The cure rate after initial surgery was 97.6%. Seventy-seven (4.1%) were reoperated for p PHPT (n = 54) or r PHPT (n = 23). Thirty-two out of 77 (41%) had been primarily operated elsewhere. In 15 cases (20%) PHPT was genetically determined. The re-operation was undertaken on average 40.7 months after initial surgery (1 day-190 months). RESULTS: Two out of 77 were cases of familial hypocalciuric hypercalcaemia. Among the 75 patients reoperated for true PHPT, 23 (31%) had uniglandular disease (UGD) and 52 (69%) had multiglandular disease (MGD). There were two cases of recurrent parathyroid carcinoma. Overall 97 pathological glands were resected, 37% being orthotopic and 63% heterotopic. The re-operation was performed by a cervical approach in 80%, by a mediastinal approach in 15%, whereas 5% involved excision of antebrachial implants. In 96% of cases the parathyroid glands were in the cervical position. Among the preoperative localisations studies the sensitivity of scintigraphy utilising 2-methoxyisobutyl-isonitril (MIBI) was 61%. Utilising both MIBI and cervical ultrasound the sensitivity was 64%. Sixty-eight out of 75 (91%) were cured of their hypercalcaemia, but at the cost of permanent hypoparathyroidism in 9% of cases. No sporadic adenoma appears to have been missed. The seven failures after re-operation (9%) involved five cases of MGD, of which four were sporadic, two cases of carcinoma and one case of parathyreomatosis. 39 patients (51%) had more than four parathyroid glands and in 22/39 cases at least one supernumerary gland was pathological. CONCLUSION: The re-operations for PHPT were essentially due to MGD that was either sporadic or genetically determined. Often the offending supernumerary gland was not detected by imaging studies. Avoiding failures entails an initial bilateral cervicotomy with thymic exploration after MIBI scintigraphy to exclude a mediastinal focus.

Humans↗

Success of unilateral neck exploration for sporadic primary hyperparathyroidism.

BACKGROUND: Unilateral neck exploration for primary hyperparathyroidism (PHPTH) is controversial because of concern about missed multiglandular disease. METHODS: In patients with sporadic PHPTH our approach has been arbitrarily to surgically explore the right neck first unless preoperative or intraoperative evidence suggests left-sided parathyroid pathologic condition. When an adenoma is identified and a normal ipsilateral gland is confirmed on histologic examination, the contralateral side is not explored. A 15-year series of 371 patients with sporadic PHPTH was reviewed retrospectively to determine the efficacy of this strategy. RESULTS: At operation unilateral exploration was possible in 125 patients (34%). Of these 122 had a single adenoma and two patients had parathyroid carcinoma. One patient with unrecognized hyperplasia required subsequent subtotal parathyroidectomy. There were no major complications. Bilateral surgical exploration was required in 246 patients including 18 with hyperplasia, 4 with double adenomas, and 4 with parathyroid cancer. Bilateral surgical exploration failed in 18 patients (14 persistent and 4 recurrent PHPTH) and was complicated by one recurrent nerve palsy and two cases of permanent hypocalcemia. Operative time was significantly shorter in the unilaterally explored group. CONCLUSIONS: When possible, unilateral exploration for PHPTH is safe and effective, avoids obliterative scarring of the contralateral neck, and may reduce morbidity and operative time.

Adenoma↗

Clinical outcomes and fiscal consequences of bilateral neck exploration for primary idiopathic hyperparathyroidism without preoperative radionuclide imaging or minimally invasive techniques.

BACKGROUND: Radionuclide imaging-directed, minimally invasive parathyroid operation is promoted in the surgical literature and public domain as the fastest, most successful, and cheapest means of treating primary idiopathic hyperparathyroidism. The validity of these claims is unproven. This study reviews the treatment outcome results of a large series of patients treated with standard parathyroid operation without preoperative localization studies. Cost comparisons are made between this series and previous reports of selected patients in whom preoperative radionuclide imaging preceded minimally invasive parathyroid operation. METHODS: Diagnosis, treatment, and outcome data for 688 consecutive patients undergoing first neck exploration for primary idiopathic hyperparathyroidism were prospectively collected. All patients in our series underwent standard bilateral neck exploration without preoperative localization studies. Intraoperative methylene blue was used to aid identification of all parathyroid glands. Surgical findings, pathological diagnosis, operative time, length-of-stay, and treatment success data were collected. Cost data were calculated for our series using the identical calculations used in previous reports. Our outcome and calculated cost data were compared with previous reports by centers advocating scan-directed, minimally invasive parathyroid operation. RESULTS: Of 2,752 predicted total glands, 2,520 (91.6%) were identified using standard neck exploration without radionuclide localization studies. Single adenoma, with at least 1 normal gland, was found in 542 patients (78.8%), with 8 in a fifth gland. Multiple-gland hyperplasia was identified in 98 patients (14.2%) and of these 22 (3.2%) were double adenomas. Ten patients had parathyroid carcinoma (1.5%), and all received definitive surgical treatment during the primary operation. Cure rates were assessed by measurement of normal serum calcium and parathyroid hormone levels at 3 and 12 months after operation, and were 97.7% in our series. Mean operating time for the entire series was 65 minutes, decreased to 35 minutes in patients with single adenomas, and mean recovery room time was 30 minutes. Mean total costs for patients undergoing standard exploration for single adenoma was US dollars 1,107, and increased to US dollars 1,243 when patients with multigland disease, hyperplasia, or malignancy were included. CONCLUSIONS: Our series demonstrates operative times and treatment outcomes with costs that are approximately one-third less than those for scan-directed, minimally invasive operation for primary idiopathic hyperparathyroidism. Thus, claims that scan-directed parathyroid operation is the cheapest, fastest, and most successful means of treatment are not supported by these data.

Adenoma↗

[Radio-guided parathyroidectomy. A prospective study in 54 patients with primary hyperparathyroidism].

BACKGROUND: The contribution of nuclear-medical mapping using 99mTc-MIBI (MIBI) and the use of an intraoperative probe in primary hyperparathyroidism (I degrees HPT) surgery was evaluated prospectively in a series of patients undergoing parathyroidectomy. METHODS: Fifty-four patients, who were operated between May 1999 and July 2000, under-went a systematic preoperative evaluation using scintigraphy with a dual tracer 99Tc04/MIBI and image subtraction, and high-resolution neck ecotomography. Surgery was performed using a mini-invasive technique through an incision measuring 2-2.5 cm at the base of the neck in 46 patients; the other 8 patients underwent open surgery with bilateral exploration of the neck. MIBI was injected intravenously in the operating theatre following the induction of anesthesia and after 32 minutes on average, radioactivity was measured using a manual gamma probe. Radioactivity was also counted intraoperatively at the tip of the lung contralateral to the pathological gland, a parameter used as the base activity (B), in the presumed seat of the hyperfunctioning parathyroid (P), in correspondence with healthy thyroid tissue (T) and any associated thyroid nodes (N). Radioactivity was also recorded at the level of the empty parathyroid compartment after removal of the corresponding gland, and on the parathyroid removed ex vivo . RESULTS: The ratio between the three main parameters, T/B, P/B and P/T was respectively 1.6 (range=1.5 - 1.8), 2.7 (range=1.6-4.0) and 1.6 (range=1.1-2.8). In 4 cases (7.4%), the small size of the parathyroids, adjacent to thyroid nodes, meant that the parathyroid measurement of MIBI was smaller than the thyroid measurement. The histological finding was consistent with: single parathyroid adenoma in 49 cases, multiple adenomas in 3 cases, parathyroid carcinoma in 2 cases. Rapid intraoperative PTH normalised in all patients. CONCLUSIONS: The significant difference in radioactivity levels recorded in the patients, showed that the technique is useful to the surgeon as a means of intraoperative assay for hyperfunctioning parathyroids, even if it cannot obviously replace experience or the value of preoperative scientigraphic and ecotomographic imaging.

Adenoma↗

Hypercalcemia in patients with advanced chronic renal failure not yet requiring dialysis.

Six patients with progressive chronic renal failure not yet requiring dialysis and not consuming supplemental calcium or vitamin D developed hypercalcemia. Three had proven and 1 suspected tertiary hyperparathyroidism, 1 parathyroid carcinoma and 1 aplastic bone. None of the 3 patients who underwent bone biopsy had heavy bone aluminum staining. The patients with proven parathyroid-mediated hypercalcemia had marked elevation of C-terminal parathyroid hormone and alkaline phosphatase values and, when performed, radiographs consistent with osteitis fibrosa. When these findings are absent or the diagnosis is otherwise uncertain, a bone biopsy may provide a definitive diagnosis and guide management.

Adult↗

99mTc-MIBI radioguided surgery for limited invasive parathyroidectomy.

We report the preliminary results obtained with the intraoperative MIBI-guided gamma probe in a group of 9 patients with primary hyperparathyroidism (pHPT). These patients were selected for limited invasive parathyroid surgery on the basis of a preoperative imaging protocol consisting of a pertechnetate & perchlorate/MIBI scan combined with neck ultrasonography (US). In the operating room 50-70 MBq MIBI was injected 30 to 45 min before parathyroidectomy. The radioactivity was measured intraoperatively at three sites: parathyroid (P), thyroid (T), and background (B). The P/B, P/T, and T/B ratios were calculated. The T/B ratio was relatively constant (range, 1.5-1.8; mean, 1.6), while a wide variability was observed both for P/T ratio (range, 1.2-2.3; mean, 1.7) and P/B ratio (range, 2.1-4.0; mean, 2.9). At surgery single enlarged parathyroid glands were easily identified by means of intraoperative MIBI-guided gamma probe. Moreover, the gamma probe allowed us to perform a limited 2-2.5 cm neck incision in eight patients affected by parathyroid adenoma. In the remaining patient a parathyroid carcinoma was diagnosed and a bilateral neck exploration was performed. The intraoperative MIBI gamma probe seems to be a useful aid when limited invasive parathyroid surgery is performed.

Adenoma↗