Parathyromatosis: a rare yet important cause of persistent or recurrent hyperparathyroidism

BACKGROUND: Parathyromatosis is described by as small nodules of hyperfunctioning parathyroid tissue scattered in the soft tissues of the neck and/or mediastinum. Seeding of hypercellular parathyroid glands during surgical excision and overgrowth of parathyroid rests left behind during ontogenesis are the most likely causes of this rare phenomenon. To characterize the clinical presentation and management of this rare condition, we report on a patient with uremia and persistent hyperparathyroidism occurring after total parathyroidectomy. METHODS: The records of one man with parathyromatosis treated from 1989 to 1993 were reviewed. In addition, a review of the literature was undertaken. RESULTS: Findings at the patient's final operation (a median sternotomy) included multiple nodules of hyperplastic parathyroid tissue scattered throughout the thymus. The characteristics of this histologically benign tissue are consistent throughout various case reports in the literature. CONCLUSIONS: This case presentation shows the physiologic significance of parathyromatosis, particularly in the setting of kidney failure. The importance of meticulous handling of potentially hyperplastic parathyroid glands and routine cervical thymectomy among this subset of patients is emphasized.     

Surgical significance of supernumerary parathyroid glands in renal hyperparathyroidism

In secondary hyperparathyroidism (2HPT) fundamentally all parathyroid glands, including supernumerary glands, become hyperplastic, and stimulation of parathyroid glands continues after parathyroidectomy (PTx). Therefore supernumerary glands have special significance during surgery for 2HPT, whether persistent or recurrent HPT. In the present study 570 patients underwent initial total PTx with a forearm autograft. The frequency, type, location, histopathology, and clinical significance of the supernumerary glands were evaluated. At the initial operation 90 supernumerary glands were removed from 82 to 570 patients (14.4%); 12 patients (2.1%) required extirpation of supernumerary glands for persistent/recurrent HPT. Altogether 104 supernumerary glands were identified at operation in 94 of the 570 patients (16.5%). Among these 104 glands, 25 (24.0%) were of the rudimentary, or split, type and 79 (76.0%) of the proper type. Supernumerary glands were most frequently identified in the thymic tongue (53/104, 51.0%); 32 (60.4%) of these 53 glands were identified only microscopically. In 6 of the 570 cases (1.1%), reoperation was required for persistent HPT due to supernumerary glands located in the mediastinum, and 6 patients underwent neck reexploration for recurrence. Histopathologically, 61 of 104 (58.7%) supernumerary glands, including 36 glands recognized only microscopically, showed diffuse hyperplasia, and 43 (41.3%) displayed nodular hyperplasia. Residual small supernumerary glands with diffuse hyperplasia have the potential to be transformed to nodular hyperplasia during long-term hemodialysis. Therefore all parathyroid glands including supernumerary glands should, if possible, be removed at the initial operation. Routine removal of the thymic tongue and careful examination of the regions surrounding the lower poles of the thyroid, especially on the left side, are important steps in the surgical treatment.     

Altered adenylate cyclase kinetics in hyperfunctioning human parathyroid glands

Current evidence suggests that parathyroid gland adenylate cyclase is involved in the control of parathyroid hormone (PTH) secretion. Thus, the altered control of PTH release in hyperparathyroidism may relate to altered adenylate cyclase activation. Therefore, we examined adenylate cyclase kinetics in membrane preparations from hyperfunctioning human parathyroid glands and normal human and bovine parathyroid tissues. There were no differences in the affinity for ATP between enzymes of normal and pathological tissue. However, the enzyme in 10 hyperfunctioning glands showed increased affinity for Mg++. The activation constant for Mg++ (KaMg) of adenylate cyclase in normal human glands was 10.6 +/- 2 mM, a value not different from that of normal bovine parathyroid tissue (9.5 +/- 1 mM). In contrast, the adenylate cyclase in membrane preparations from three of four hyperplastic and six of seven adenomatous human glands showed a markedly reduced KaMg, ranging from 0.85-1.64 mM and from 1.58-6.46 mM, respectively. In one adenoma and one hyperplastic gland, the Ka of the enzyme for Mg++ was close to normal. The addition of guanylylimidodiphosphate or GTP to the incubation mixture increased, in a dose-dependent manner, the apparent KaMg of the enzyme in the abnormal tissue toward normal, suggesting a defective nucleotide regulatory site in the adenylate cyclase of hyperparathyroid glands. In addition, the hyperparathyroid gland enzyme was less susceptible to inhibition by calcium, requiring 0.7-1 mM Ca++ for 50% inhibition, whereas comparable inhibition of the normal adenylate cyclase was seen at 0.22-0.28 mM Ca++. We conclude that the abnormal control of PTH secretion in hyperparathyroidism may be related, at least in part, to alterations in the characteristics of parathyroid gland adenylate cyclase.     

Use of a press as support of the temporal bone in experimental otologic surgery]

Sixty-seven cases of neck exploration for suspected hyperparathyroidism were reviewed. Thirty-nine patients underwent removal of an adenoma with biopsy of one or more other parathyroid glands. In another group, nine patients underwent removal of the adenoma only. Both groups have had no recurrences of hyperparathyroidism in follow-up periods of two months to twelve years. The data presented indicate that removal of a parathyroid adenoma alone, without biopsy of other tissue, represents satisfactory treatment. Experience with hyperplastic glands is also reviewed. Subtotal parathyroidectomy was effective treatment in all patients, but a 30 per cent incidence of hypocalcemia was noted after this operation.     

Technetium 99m tetrofosmin parathyroid imaging. Results with double-phase study and SPECT in primary and secondary hyperparathyroidism

RATIONALE AND OBJECTIVES: The aim of our study was to evaluate the sensitivity, specificity, and positive predictive value (PPV) of technetium 99m (99mTc) tetrofosmin double-phase scintigraphy and single-photon emission computer tomography (SPECT) in preoperative localization of parathyroid adenoma in case of primary and secondary hyperparathyroidism (HPT). METHODS: Sixty-eight consecutive patients biochemically or sonographically suspected of parathyroid adenoma were included in our study. Apart from biochemical analysis of serum calcium, phosphate, and intact parathyroid hormone, double-phase scintigraphy was performed in each patient 5 and 45 minutes after injection of 370 MBq 99mTc tetrofosmin, followed by SPECT imaging. In consciousness of the scintigraphic results, ultrasound of the neck was performed as well to exclude false-positive results due to thyroid adenomas. RESULTS: Depending on the results of the biochemical analysis in combination with the results of the scintigraphic and ultrasound examination, the patients were classified retrospectively into three groups: group A with primary HPT (n = 35), group B with secondary HPT (n = 13), and group C without any biochemical suspicion of primary or secondary HPT (n = 20). In group A, double-phase study localized 25 of 36 (69.2%) parathyroid adenomas (one double adenoma) as against 34 of 36 (94.4%) with SPECT. Nine adenomas could be visualized only by SPECT. The reason for nonvisualization on planar scans was suspected to be an ectopic location in 2 cases (retrotracheal dislocation, retrovascular dislocation), a maximal diameter less than 15 mm (9-13 mm) in 6 cases, and oxyphilic-cell-poor cellularity in 1 case. Four false-positive retention (3 thyroid adenomas and 1 papillary thyroid carcinoma) were observed. SPECT showed a sensitivity of 94.4%, a specificity of 85%, and a PPV of 91.9% in biochemically suspected primary HPT. In group B, planar scintigraphy demonstrated 12 hyperplastic glands in 5 of 13 patients, and SPECT demonstrated 20 hyperplastic parathyroid glands in 8 out of 13 patients, which corresponds to a sensitivity of 38% and 61.5%, respectively. CONCLUSIONS: Technetium 99m tetrofosmin seems to be a promising alternative tracer with similar capabilities to 99mTc sestamibi in localization of parathyroid adenoma. SPECT showed clear advantages in terms of sensitivity over planar scintigraphy and should be used at least in cases with poor or no uptake in double-phase study. In endemic goiter areas, ultrasound of the neck should be performed to exclude false positive retention in thyroid adenomas. Technetium 99m tetrofosmin, like 99mTc sestamibi, is not ideal for localization of hyperplastic glands in secondary hyperparathyroidism because of low sensitivity.     

Nonadenomatous thymic unencapsulated parathyroid tissue as a cause of persistent primary hyperparathyroidism

Primary hyperparathyroidism may be caused by ectopic intrathymic parathyroid adenomas or hyperplastic parathyroid glands. The association of the ectopic inferior parathyroid glands and the thymus is due to their common embryologic origin from the third pharyngeal pouch. We report a case of primary hyperparathyroidism due to an unusual pathologic parathyroid gland formation: nonadenomatous thymic unencapsulated parathyroid tissue. Two unsuccessful neck exploration revealed only two normal parathyroid glands within the cervical area. Radiologic imaging studies failed to localize an ectopic parathyroid adenoma. Mediastinal exploration and thymectomy showed one small focus of unencapsulated hypercellular parathyroid tissue expanding peripherally along the septa of thymic adipose tissue. The hyperparathyroidism resolved with the surgical procedure.     

Effect of dose size on the pharmacokinetics of orally administered quinine

Parathyroid scintigraphy is useful in detecting residual hyperplastic parathyroid tissue in patients who continue to have hyperthyroidism after "total parathyroidectomy." Typically, only the neck and mediastinum are imaged. The authors report a case in which images of the forearm were helpful in detecting hyperplastic autologous transplanted parathyroid tissue.     

Diagnosis of dysfunctions of replanted parathyroid gland tissue by bilateral analysis of intact parathyroid hormones in cubital vein blood. A prospective study

AIM: In a prospective long-term follow-up study after operative therapy of hyperparathyroidism the value of bilateral determination of parathyroid hormone levels in cubital venous blood after total parathyroidectomy/autologous parathyroid gland reimplantation (musculus brachioradialis) for diagnosis of dysfunctioning grafted tissue is evaluated. PATIENTS AND MATERIAL: From August, 1, 1987 to March, 31, 1994 68 of 243 patients operated on for hyperparathyroidism underwent total parathyroidectomy. Autologous reimplantation of parathyroid gland was carried out simultaneously in 64 patients. Twice delayed reimplantation of cryopreserved tissue was carried out, and there was no reimplantation in two patients up to this day. Three patients were operated on for hyperfunctioning parathyroid autograft after former total parathyroidectomy/reimplantation. RESULTS: During follow-up 5 patients developed dysfunction of (reimplanted) parathyroid gland. Because of low or unprovable levels of intact parathormone the gradients of intact parathyroid hormone between grafted and nongrafted forearm were about 1:1 in postoperative hypoparathyroidism as well as in hypofunction of parathyroid gland. After successful replantation of cryopreserved parathyroid tissue gradients of intact parathyroid hormone increased (> 1:10). In hyperfunction of grafted parathyroid tissue hormone gradients were high (> 1:20 to 1:45,3) because of excessive high levels of intact parathormone in the cubital vein of the graft bearing arm. Successful reduction of parathyroid graft was followed by decrease of parathyroid hormone gradients. CONCLUSION: Regular follow-up of intact parathormone gradients together with intact parathyroid hormone levels and serumcalcium analysis allow the determination of parathyroid graft function. Also differentiation between graft dependent hyperparathyroidism and hyperfunctioning parathyroid tissue in the neck or mediastinum seems to be possible by bilateral determination of intact parathormone. Normal values or a normal range for intact parathyroid hormone gradients can not yet be defined.     

Parathyroid scintigraphy with Tc99m Sestamibi

BACKGROUND: Parathyroid scintigraphy with Tc99m Sestamibi, a tracer that is taken up by hyperfunctioning parathyroid tissue, has a high yield in the diagnosis of abnormal parathyroid growths. AIM: To assess the usefulness of parathyroid scintigraphy with Tc99m Sestamibi in patients with suspected hyperparathyroidism. PATIENTS AND METHODS: We analyzed retrospectively 29 patients with suspected hyperparathyroidism, in whom a scintigraphy with Tc99m Sestamibi was performed. RESULTS: Twenty four of 25 patients in whom hyperfunctioning parathyroid tissue was evidenced with scintigraphy, were operated. Histological diagnosis of the excised parathyroid gland, showed 23 adenomas and 1 hyperplasia. Anatomical location disclosed by scintigraphy was concordant with surgical findings in all cases, including a mediastinic adenoma. Of the four patients with negative scintigraphic findings, two had transitory PTH elevations and in two the presence of adenoma or hyperplasia could not be demonstrated with other diagnostic procedures. CONCLUSIONS: Parathyroid scintigraphy with Tc99m Sestamibi had an 86% sensitivity for the detection of hyperfunctioning parathyroid tissue in patients with elevated PTH.     

Depressed expression of calcium receptor in parathyroid gland tissue of patients with hyperparathyroidism

The factors involved in abnormal parathyroid cell secretory function and growth in patients with primary (I degree) and secondary (II degree) hyperparathyroidism are still incompletely understood. We compared the expression of the calcium-sensing receptor (CaR) at the gene message and the protein level in parathyroid tissue obtained from patients with I degree non-uremic or II degree uremic hyperparathyroidism with that in normal parathyroid tissue, using in situ hybridization and immunohistochemistry techniques. The expression of the CaR mRNA and protein was reduced in most cases of I degree adenoma and II degree hyperplasia, compared with strong expression normal parathyroid tissue. In II degree hyperparathyroidism, expression of both receptor mRNA message and protein was often particularly depressed in nodular areas, compared with adjacent non-nodular hyperplasia. Decreased Ca-R expression in adenomatous and hyperplastic parathyroid glands would be compatible with a less efficient control of PTH synthesis and secretion by plasma calcium than in normal parathyroid tissue.     

Revascularisation of human parathyroid tissue transplanted to athymic mice

The revascularisation process of transplanted human normal, hyperplastic and adenomatous parathyroid tissue was analysed at 2 and 4 days and 1, 2, 4, 7 and 12 weeks after transplantation to athymic mice. The transplants were examined by light and electron microscopy, immunohistochemistry and autoradiography. Vessels were detected by monoclonal antibodies specific for mouse and human endothelial cells. Immunohistochemistry demonstrated ingrowth of vessels from the host into the transplant and at one week numerous capillary sprouts were observed in the peripheral parts of the transplants. During the first week, peak levels of proliferation (labelling index) were observed in endothelial cells and capsular fibroblasts, and the proliferative capacity of endothelial cells was most pronounced in adenoma transplants. Fenestrated capillaries were observed in hyperplastic and adenomatous transplants, but not in transplants of normal tissue. In conclusion, revascularisation of transplanted human parathyroid tissue is enabled by ingrowth of vessels from the host into the transplant. The proliferative capacity of endothelial cells is higher and the process of maturation is faster in hyperplastic and adenomatous tissue compared to normal tissue.     

Growth and function of human parathyroid tissue transplanted to athymic mice

The morphology, cell proliferation and function of transplanted normal, hyperplastic and adenomatous human parathyroid tissue was studied after transplantation to athymic mice. The iPTH was evaluated in relation to morphology. Human parathyroid tissue collected during surgery for hyperparathyroidism was implanted subcutaneously into athymic mice (nu/nu-BALB/cA) and was analysed 1, 4, 7 and 12 weeks after transplantation. The transplants were examined by light and electron microscopy and by autoradiography after continuous infusion of 3H-thymidine. The relative amount of viable tissue was evaluated using a computer image analysing programme. Graft function was evaluated by measuring human iPTH in mouse serum. A transplant take ratio of 93% was observed. The proliferation rate in adenoma grafts at 12 weeks after transplantation was five and fifteen times that observed in normal and hyperplastic transplants, respectively. In normal and adenoma groups, a continuous increase in iPTH concentrations was observed, but in the hyperplastic group the iPTH remained on the same level. The secretion of iPTH in relation to the amount of transplanted tissue and the fraction of viable tissue was at the same level at 12 weeks in normal and adenomatous grafted animals. In conclusion, human parathyroid tissue was successfully transplanted and maintained its original structure. The growth potential, but not the iPTH secretion, was significantly higher in adenoma grafts compared to grafts from hyperplastic and normal glands.     

Intrathyroidal parathyroid glands can be a cause of failed cervical exploration for hyperparathyroidism

BACKGROUND: The incidence of intrathyroidal parathyroid glands remains controversial. The purpose of this study was to determine the incidence in a series of patients with hyperparathyroidism. METHODS: Three hundred nine patients underwent parathyroidectomy. Patients were divided into two groups: uniglandular disease versus hyperplasia. RESULTS: Eighteen of 309 patients (6%) had abnormal intrathyroidal parathyroid glands. The incidence was 3% (7 of 222) in patients with uniglandular disease versus 15% (11 of 73) in those with hyperplasia. With a mean follow-up of 54 months, 12 patients are eucalcemic, 5 have persistent hypocalcemia, and 1 has recurrent hypercalcemia. There were no recurrent laryngeal nerve injuries. CONCLUSIONS: These data suggest that an intrathyroidal adenoma is an uncommon cause of failure, whereas abnormal intrathyroidal parathyroid tissue may be a more common cause of failure in patients with hyperplasia.     

Detection of HPV and ras gene mutations in cervical smears from female genital lesions

BACKGROUND: Recurrent hyperparathyroidism may occur following parathyroid autotransplantation due to autogenous function of the muscle-engrafted tissue. Parathyroid lesions are uncommonly diagnosed on cytology. CASE: A 31-year-old female with chronic renal failure presented with an elevated parathyroid hormone level and a neck mass in the left sternocleidomastoid muscle, the site of a previous parathyroid autograft. Fine needle aspiration of the mass revealed high cellularity, with perivascularly arranged, three-dimensional, branching clusters; individual cells; and naked nuclei exhibiting anisonucleosis. A diagnosis of parathyroid graft hyperplasia was made by fine needle aspiration and subsequently by histopathologic examination. CONCLUSION: Fine needle aspiration is an effective tool for confirming the presence of parathyroid autograft hyperplasia, thus allowing the correct surgical approach.     

MIBI-scintigraphy. A simple and reliable method for localization of pathological parathyroid glands

99Tcm-sestamibi scintigraphy was used to localise enlarged parathyroid glands in 25 patients with primary hyperparathyroidism previously operated in the neck, 20 of whom had recurrent disease and five had previously undergone surgery for thyroid disorders. Of the 18 patients for whom positive scans were obtained, nine were operated on the scan findings being confirmed. Crucial information was provided in two cases of intrathyroidal and one case of intramediastinal localisation of the pathological gland were not operated on as the hypercalcaemia was only marginal or the symptoms were vague. Though preoperative localisation of pathological parathyroid glands is a prerequisite for neck exploration in patients with persistent or recurrent hypercalcaemia due to primary (or secondary) hyperparathyroidism, the procedure is not cost-effective before the initial operation.     

Minimally invasive radioguided parathyroidectomy in the reoperative neck

BACKGROUND: Operations for hyperparathyroidism (HPT) in a previously operated neck present a significant challenge and carry much higher morbidity rates than first-time operations. Our extensive experience with minimally invasive radioguided parathyroidectomy (MIRP) for first-time surgery for HPT has shown this method to be a directed approach to the offending adenoma, suggesting that the technique could be used to minimize reoperative neck surgery as well. METHODS: Over an 11-month period 24 consecutive patients with primary HPT who had undergone at least one previous neck operation were referred for re-exploration. All patients underwent preoperative sestamibi scanning; 21 localized sufficiently to undergo MIRP. RESULTS: All patients were cured after reoperation. Eighteen patients underwent MIRP under local anesthesia as outpatients; 3 MIRPs were done under general anesthesia. Average total operative time was 44 minutes, average incision length was 3.0 cm +/- 0.2 cm. Nineteen of the procedures were completed without any frozen sections. There were no complications. CONCLUSION: MIRP is extremely effective in patients with HPT who have undergone previous neck exploration for parathyroid or thyroid disease. The technique allows for such a directed dissection that smaller incisions and local anesthesia in an outpatient setting are routine.     

Neonatal primary hyperparathyroidism

The authors report on a case of severe primary hyperparathyroidism with clinical signs from birth. The boy was admitted because of poor somatomental development, hypotony, hepatosplenomegaly and osseous abnormalities, resembling those of rachitis. Laboratory data showed the typical findings of primary hyperparathyroidism. The authors performed parathyroidectomy with simultaneous heterotopic parathyroid tissue autotransplantation. Histology revealed parathyroid chief cell hyperplasia. Because of the hypercalcaemia and clinical signs persisting after the operation they removed the parathyroid autografts. Since this later was ineffective they performed a left sided neck dissection on the side of the excessive parathormone production. The child became hypocalcaemic necessitating calcium and vitamin D administration. He is now 17 months after the last operation. His somatomental development is accelerated. In connection with the case the authors surveyed the literature of this rare entity.     

Parathyroid detection in secondary hyperparathyroidism with 123I/99mTc-sestamibi subtraction single photon emission computed tomography

123I/99mTc-sestamibi subtraction single photon emission computed tomography (SPECT) has been proposed to detect hyperplastic parathyroid tissue, but the clinical usefulness of this technique in secondary hyperparathyroidism is uncertain. The purpose of this study was to evaluate preoperative parathyroid localization using 123I/99mTc-sestamibi subtraction SPECT in patients with renal failure and secondary hyperparathyroidism. Nineteen patients with chronic renal failure and secondary hyperparathyroidism underwent 123I/99mTc-sestamibi subtraction SPECT imaging preoperatively. None of these patients had undergone previous neck surgery. The location, weight, and histopathological results of all identified parathyroid glands were recorded. Surgery was considered successful in all patients, with resection of a total of 74 hyperplastic parathyroid glands. 123I/99mTc-sestamibi subtraction SPECT correctly identified 57 of these parathyroid glands (77% sensitivity). The mean weight among the true positive glands (n = 57) was 1031 mg (range, 45-7900 mg), and that among the false negative glands (n = 17) was 465 mg (range, 20-1800 mg). This difference between the mean weights was statistically significant (P = 0.018). There was a positive correlation between parathyroid weight and detectability with 123I/99mTc-sestamibi subtraction SPECT (Spearman correlation = 0.28; P = 0.0167). 123I/99mTc-sestamibi subtraction SPECT is able to correctly localize hyperplastic parathyroid glands in patients with renal failure and secondary hyperparathyroidism, but there is a fairly weak relationship between preoperative detection rate and anatomical parathyroid gland size.     

Parathyroid lesions localized by radionuclide subtraction and ultrasound

Radionuclide subtraction technique and gray-scale echography were used to localize parathyroid lesions in 6 patients with primary hyperparathyroidism. In 3 cases, surgery verified the scintigraphic findings. All lesions weighed less than 1 g, with the smallest weighing 350 mg. These procedures provide complementary information in preoperative localization of hyperfunctioning parathyroid tissue.     

Management of hyperparathyroidism in an endemic goiter area

In an endemic goiter area patients with hyperparathyroidism (HPTH) frequently also have thyroid abnormalities. In a retrospective study of 95 patients with HPTH we assessed the diagnostic accuracy of imaging techniques (ultrasonography or radionuclide scanning) for preoperative localization of parathyroid adenomas. Altogether 86% of our patients had goiter, requiring thyroid resections in 37%. For 19 patients the parathyroid exploration was the second or third cervical operation, most of them due to goiter. We found that the overall rate of transient and permanent recurrent nerve paralysis is considerably increased in patients with previous neck surgery (26% vs. 7%). The combination of ultrasonography and radionuclide scanning can lead surgeons to the site of parathyroid lesions responsible for HPTH in 85% of cases, although frequent nodular goiters can produce pitfalls for correct imaging in iodine-deficient countries. In endemic goiter areas preoperative localization studies can be recommended in patients with primary HPTH--for evaluation of thyroid pathology possibly leading to resection or its accuracy in localizing parathyroid adenomas. These studies also seem justified in patients with previously unsuccessful neck explorations for HPTH.