Biomedical subjects
Publications and source records attributed to E Paloyan.
Primary hyperparathyroidism is commonly associated with Hashimoto's thyroiditis. The raised TSH levels might induce hyperparathyroidism, as suggested by some experimental data. It might also explain the development of hyperparathyroidism after neck irradiation and lithium therapy.
In a consecutive series of 234 patients with differentiated thyroid carcinoma of follicular cell origin (Hürthle cell tumors excluded), a radioactive iodine (131I) scan was obtained 3 to 6 months after thyroidectomy and 4 weeks after cessation of thyroid hormone treatments, only if extrathyroidal tumor extension or nodal or distant metastases were present. Twenty-one patients (9%) with 131I uptake of 3% or more (group 1) were treated with 150 to 200 mCi of 131I. Forty-four patients (19%) with less than 3% uptake (group 2) and 169 patients (72%) without evidence of metastases or extrathyroidal spread (group 3) were treated only with thyroid hormone. All patients initially underwent total thyroidectomy and modified neck dissection if cervical lymph node metastases were present. Three patients in group 1 and one patient in group 2 had recurrent tumor with a mean follow-up of 8.9 and 8.4 years. There were no recurrences in group 3 with a mean follow-up of 7.2 years. Death rate from thyroid carcinoma was 5% in group 1 (one patient) and 0% in groups 2 and 3. In conclusion, 131I scanning and therapy may be omitted in patients with differentiated thyroid carcinoma in the absence of local tumor extension or regional or distant metastases. Therapy with 131I is not demonstrated to be of benefit in this population of patients.
A kindred with multiple endocrine neoplasia type IIA was studied. In four of five fully documented cases, patients presented with adrenal medullary disease during the second or third decade; in three cases, medullary thyroid carcinoma was not diagnosed until the fourth decade. This kindred seems to have an aggressive variant of adrenal medullary disease in which clinical presentation is early, metastasis occurs, and oncological cure is uncommon. Early detection and operation were important, and symptoms were controlled with operations and alpha- and beta-adrenergic blockade in uncured members.
The physiologic relationship between the thyroid and parathyroid glands remains poorly understood. A high incidence of coexistent thyroid disease and primary hyperparathyroidism has been well documented. Elevation of serum 1,25-dihydroxyvitamin D3 (vitamin D) has been detected in some patients with primary hyperparathyroidism. A report of specific binding sites and uptake of vitamin D by the thyrotrophs of the anterior pituitary indicates that vitamin D may modulate production or secretion of thyroid-stimulating hormone (TSH). To test this concept, we investigated the influence of elevated serum levels of vitamin D on basal and stimulated TSH. Vitamin D was administered by subcutaneously implanted sustained-release pellets at four dosages. Thyrotropin releasing hormone (TRH) stimulation tests were performed at time zero, 72 hours, 1 week, 2 weeks, and 5 weeks. Animals administered vitamin D became significantly hypercalcemic and demonstrated elevations of vitamin D, which peaked at 72 hours and remained elevated for 2 weeks after pellet implantation. TRH-stimulated TSH levels were significantly elevated at 72 hours and at 1 week and returned to normal after 5 weeks. Parathyroid hormone levels were suppressed at 72 hours and at 1 week and displayed significant elevation at 2 weeks. These results provide in vivo evidence for an interaction and a possible regulatory role of 1,25 on pituitary TSH secretion and parathyroid function.
Laidlaw coined the term nesidioblastosis in 1938 to characterize the neodifferentiation of the islet cells of Langerhans from pancreatic duct epithelium. It is well recognized in the pediatric population as a frequent cause of persistent neonatal hypoglycemia. However, its occurrence in adults is presumed to be rare and, therefore, it is not appreciated as a cause of hyperinsulinism. Three women, aged 29, 42, and 63, with adult onset hyperinsulinism secondary to nesidioblastosis are reported. All three patients required near-total pancreatectomy. The preoperative findings were consistent with hyperinsulinemic hypoglycemia as with insulinomas. Results of pancreatic imaging studies were normal in two patients and one patient had a pancreatic examination by computerized tomography and magnetic resonance imaging, with false-positive results. Two of the three patients had previously undergone a 50 per cent distal pancreatectomy in which the resected specimens were interpreted as normal in one patient and consistent with nesidioblastosis in the second. Both patients subsequently developed recurrent symptomatic hyperinsulinemic hypoglycemia that persisted despite dosage adjustments in diazoxide therapy. The oldest patient underwent a 95 per cent pancreatectomy at the initial surgical exploration because an insulinoma could not be identified. The other patients underwent a completion 95 per cent pancreatectomy. In both, histochemical examination of each specimen disclosed nesidioblastosis, characterized by clusters of islet cells interspersed throughout the exocrine tissue.
The purpose of the present investigation was to determine whether there is a correlation between the serum levels of thyroid stimulating hormone (TSH), parafollicular cell (C) population in the thyroid and calcitonin (CT) secretion in aging Long-Evans (L-E) rats. Serum TSH and CT values were determined in 50 male rats at ages 2, 6, 12, 18 and 24 months and 50 female rats at 18, 21 and 24 months. The animals were sacrificed at the end of the experiment to evaluate thyroid C cell pathology. Male rats showed an increase in the serum TSH values at 6 and 12 months of age, a decline at 18 months and a significant increase from 18 to 24 months of age. In female rats, a significant increase in serum TSH concentration was also noted from 18 to 24 months of age. In both sexes, 24 month old animals with thyroid C cell hyperplasia (CH+ group) had a significantly higher level of serum TSH as compared to animals with normal distribution of C cells (CH- group). Concentration of serum CT showed a progressive increase with age in both sexes. Male rats with thyroid C cell pathology had significantly higher levels of serum CT at 24 months of age as compared to rats with normal C cell distribution. In female rats, however, serum CT concentrations in two groups were not statistically significant. We conclude from these studies that in aged L-E rats, serum TSH concentration has an influence on thyroid C cell population.
Differentiated carcinoma of the thyroid gland is regarded as an indolent disease. However, this notion is dispelled when the population is stratified according to age, gross and microscopic tumoral characteristics and according to the occurrence of local and distant metastases in the early postoperative period. The adverse effect of local and distant recurrences on survival time has been emphasized in multiple series from the United States and Europe. However, the critical question that has yet to be answered is whether or not inadequately treated differentiated carcinomas of the thyroid gland seemingly cured in younger patients will recur as aggressive, malignant tumors when the same patients reach the graying golden years. A provisional answer to this question may indeed be found in the incidence of early postoperative nodal and distant recurrence rates. Some authors have concluded that the extent of operative treatment does not have a major influence on the course of differentiated carcinoma of the thyroid gland. This conclusion prompted the present follow-up study of 250 patients with differentiated carcinoma of the thyroid gland to examine the clinical course and results of therapy. We report a cumulative mortality rate of 2.4 per cent and a recurrence rate of 1.6 per cent, consisting of a 1.2 per cent incidence of cervical nodal recurrence and a distant recurrence rate of 0.4 per cent (one patient), after a median follow-up period of seven years and a mean of six years. Since there were no differences in treatment and outcome in 191 patients we studied who had papillary and 59 who had follicular carcinoma, they were analyzed as a single group for this report. Total thyroidectomy was the minimal treatment of all operable patients. In addition, 21.0 per cent required a modified dissection of the neck and 8.4 per cent of the patients had postoperative radioactive iodine administered to ablate either remnants of normal tissue or previously undetected metastases to cervical nodes or lungs. Potential factors contributing to improved local and distant recurrence rates included early detection of disease, especially in children who had irradiation and who were recalled and screened (34 per cent in this series); the use of needle aspiration cytologic study, leading to earlier diagnosis and treatment; total thyroidectomy, and the effective use of radioactive iodine administered as a single large dose within the first six months after thyroidectomy.
Of 522 patients with hyperparathyroidism operated on from 1973 to 1987 at our institution, there were seven (1.3%), each with an ectopic, hyperfunctioning mediastinal parathyroid adenoma, who required median sternotomy. In three of these seven patients, the tumor was located in the aorticopulmonary window. A 61-year-old woman with primary hyperparathyroidism had a preoperative thallium-technetium subtraction scan that showed thallium uptake at the base of the heart without any uptake in the neck. After further workup and without prior neck exploration, a parathyroid adenoma was found in the aorticopulmonary window through a median sternotomy. Six months later, serum calcium, phosphorus, and parathyroid hormone values remain normal. Two other cases of parathyroid adenoma in the aorticopulmonary window are presented. Of these two patients, the thallium scan was a key element in the immediate mediastinal exploration of one, who was transferred from another hospital comatose and intubated, in acute hypercalcemic crisis. Since mediastinal parathyroid tumors that necessitate median sternotomy occur in less than 2% of patients with primary hyperparathyroidism, we do not advocate routine preoperative localization studies before an initial cervical operation; localization, however, may be justified in selected cases, such as in critically ill patients or in instances of acute hyperparathyroidism, when the first operation needs to be curative.
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Over a period of 32 years from 1954 to 1986, 65 patients under the age of 21 years, 52 girls and 13 boys, were operated for nodular thyroids: the overall incidence of carcinoma was 37 per cent. It was 46 per cent in those patients presenting with a solitary nodule. Among the 24 patients with a malignancy, the carcinoma was of the papillary variety in 63 per cent, follicular in 25 per cent and medullary in 12 per cent. Two thirds of the patients had metastatic disease at the time of presentation. All patients with thyroid carcinoma were treated with total thyroidectomy. Other measures included neck dissection and radioactive iodine. When the eight patients with a history of head and neck irradiation and the three patients with medullary carcinoma were excluded, the incidence of carcinoma was 28 per cent. In summary, in spite of the decline in radiation associated cases, the incidence of carcinoma in nodular thyroid disease in the population under 21 years, remains at the relatively high figure of 28 per cent.
Over a period of 25 years (1961-1986), 30 consecutive patients were operated upon for solitary "HOT" nodules. The autonomy of these nodules was substantiated by cytomel nonsuppressibility on 131I or 123I scanning, or TSH stimulated enhancement of the remaining suppressed thyroid tissue (n = 24); or as a solitary toxic hot nodule with suppression of the remaining thyroid tissue (n = 6). Seventeen of these patients were euthyroid and 13 were thyrotoxic and required preoperative preparation with antithyroid medication. Five patients had a history of head and neck irradiation. The population consisted of 24 women and six men. Their ages ranged from 14 to 68 years. The tumors ranged in size from 1.5 to 7 cm. The pathologic findings consisted of "colloid" adenoma in nine patients, follicular adenoma in 19 patients, and a follicular carcinoma in two patients, for an incidence of 6 per cent. It is of interest that neither of the patients with thyroid carcinoma were toxic or had a history of radiation exposure. These findings support the concept that the incidence of carcinoma in truly autonomous "HOT" thyroid nodules is not negligible.
The question of thyroid neoplasia following high-dose radiation treatment to the neck and mediastinum for malignant neoplasms such as Hodgkin's lymphoma in children and young adults has been raised recently. Five patients, 19 to 39 years old, were operated on for thyroid neoplasms that developed following cervical and mediastinal radiation therapy for Hodgkin's lymphoma. Three patients had papillary carcinomas and two had follicular adenomas. The latency period between radiation exposure and the diagnosis of thyroid neoplasm ranged from eight to 16 years. This limited series provided strong support for the recommendation that children and young adults who are to receive high-dose radiation therapy to the head, neck, and mediastinum should receive suppressive doses of thyroxine prior to radiation therapy in order to suppress thyrotropin (thyroid-stimulating hormone) and then be maintained on a regimen of suppression permanently.
The merit of the preoperative localization of parathyroid tumors with thallium-technetium subtraction imaging is a subject of current debate in the treatment of primary hyperparathyroidism. Eighty patients with hyperparathyroidism underwent preoperative subtraction scintigraphy with 201Tl Cl and 99mTcO4; scan results were correlated with the operative identification and histopathology of the resected parathyroid tissue. The true-positive, false-positive and false-negative rates of these scans were compared between patients with tumors in normal and ectopic anatomic locations and between patients undergoing an initial and reoperative neck exploration. The scan was clearly valuable in patients with one or more prior neck explorations. True-positive scans were obtained in seven (77%) of nine such patients. The scan was also valuable in patients who had ectopic tumors (six mediastinal, seven intrathyroid, and two in the carotid sheath). Twelve (80%) of these 15 ectopic tumors were correctly localized either prior to their first operation or before subsequent explorations. In contrast, only 33 (50%) of 65 patients had a true-positive scan prior to their first operation and when the tumor was not in an ectopic location. In summary, in this series, the thallium-technetium scan was correct in only 50 per cent of patients undergoing an initial operation. However, it was positive in 77 per cent of patients who had at least one prior neck exploration and in 80 per cent of patients with an ectopic parathyroid tumor. These results support the selective use of this valuable imaging and localization tool.
This study was undertaken to determine the effects of estrogen and testosterone on baseline and thyrotropin-releasing hormone (TRH)-stimulated serum thyroid-stimulating hormone (TSH) levels in rats. Seven groups of 20 rats each were studied: intact males (group I), intact females (group II), castrated males (group III), castrated females (group IV), castrated males with testosterone replacement (group V), castrated females with testosterone supplement (group VI), and intact females with testosterone supplement (group VII). Two weeks after initiation of these hormone treatments, blood samples for TSH levels were obtained before and 10 minutes after TRH injection. Testosterone levels were also determined to verify hormone release. The results of these studies indicated that (1) testosterone has a primary, stimulatory role in the control of TSH concentration in that it causes elevation of both baseline and TRH-stimulated TSH levels, (2) endogenous estrogens have no such direct effect on TSH levels, and (3) in the presence of testosterone, endogenous estrogens partially inhibit the TSH-elevating effect of the androgen. As TSH stimulation is considered requisite for thyroid carcinogenesis, the different effects of testosterone and estrogen on TSH levels, demonstrated in this study, may in part explain differences in incidence and prognosis of thyroid carcinoma observed between the sexes in both rats and human beings.
Iatrogenic vocal cord paralysis is a well-publicized complication of thyroid and parathyroid operations. Less appreciated is the improvement of vocal cord function after resection of a thyroid or parathyroid tumor. Over the last 22 years, 14 patients presented with vocal cord paresis in the presence of thyroid or parathyroid tumors. Of these 14 patients, nine had complete resolution of paresis following resection of the thyroid or parathyroid tumors: three had a thyroid carcinoma impinging upon the nerve, three had large colloid goiters, two had a follicular adenoma and one had a parathyroid adenoma displacing the nerve. In five of the 14 patients the vocal cord paralysis persisted after operation. In three, the pathology accounted for the vocal cord paralysis and was not amenable to operative improvement: one patient had an unresectable anaplastic thyroid carcinoma, one patient had long-standing idiopathic unilateral vocal cord paralysis, and one patient had laryngeal adenoid cystic carcinoma with thyroid invasion. The fourth patient had an extensive thyroid hemangioma. The paralysis persisted after resection. The fifth patient had long-standing idiopathic vocal cord palsy. A preoperative vocal cord paresis in a patient with thyroid or parathyroid disease does not indicate permanent loss of recurrent nerve function, even in the presence of carcinoma. In this series, vocal cord function was restored in 9 of 10 patients with resectable thyroid or parathyroid tumors.
The incidence of thyroid carcinoma in Hashimoto's thyroiditis has been a widely debated issue. Previous authors have reported on this topic by analyzing series of patients with Hashimoto's thyroiditis or patients with thyroid carcinoma, but not both of those populations in the same series. The population consists of a consecutive series of 800 patients operated on for thyroid nodules not associated with a radiation history. Among 161 patients with the diagnosis of thyroid carcinoma, 61 (38%) had coexistent Hashimoto's thyroiditis. In comparison, among 161 sex- and age-matched patients with colloid nodules in the same population, 18 (11%) had Hashimoto's thyroiditis. Furthermore, in the series as a whole, the incidence of Hashimoto's thyroiditis in 423 patients with colloid nodules was 10 per cent. From the perspective of the Hashimoto's thyroiditis population in the same series of 800 thyroidectomies, among 267 patients with Hashimoto's thyroiditis 61 (23%) had coexistent carcinoma. In comparison, among 267 age- and sex-matched patients with colloid nodules there were only ten coexistent carcinomas for an incidence of 4 per cent. The high incidence of carcinoma of the thyroid in Hashimoto's thyroiditis lends credence to the hypothesis that Hashimoto's thyroiditis is a predisposing factor in the development of thyroid carcinoma.
An earlier study from our laboratory demonstrated that the incidence of thyroid C cell neoplasia in aging Long-Evans rats was high. When radioactive iodine was administered to 8-week-old Long-Evans rats, this incidence was reduced, although thyroid follicular cell neoplasia was increased. The aim of this study was to determine whether iodine-131 (131I) administered to an aged population of Long-Evans rats with established C cell hyperplasia would have a C cell ablative effect as pronounced as that observed in studies of young rats. For this study, 180 18-month-old Long-Evans rats (90 male and 90 female) were used. Baseline serum calcitonin levels were determined, and control and experimental groups containing equal numbers of animals were designated. 131I was administered by intraperitoneal injection to the experimental group, while equal volumes of saline solution were given to the control group. Blood samples for determination of serum calcitonin levels were obtained at 6-week intervals until the rats were 24 months old. Thyroid glands were then removed, and tissues were fixed, sectioned, and stained with hematoxylin and eosin and with peroxidase-antiperoxidase (PAP) using an anticalcitonin antibody. Examination of thyroid tissues showed that the incidence of C cell neoplasia was significantly reduced in irradiated animals as compared with nonirradiated controls (chi 2 analysis, p less than 0.05). PAP staining demonstrated diminished intracytoplasmic calcitonin in the radiation-treated group. Analysis of serum calcitonin levels over time showed significantly lower levels in the irradiated rat group than in the nonirradiated group (p less than 0.006).
When male Long-Evans rats at age 8 weeks were radiation treated (40 microCi Na131I), thyroid follicular adenomas and carcinomas were observed at age 24 months with a high incidence of 94%. Castration of males prior to irradiation significantly reduced this tumor incidence to 60%. When testosterone (T) was replaced in castrated, irradiated male rats, differentially increased incidences of thyroid tumors occurred, depending on the time interval for hormone replacement. Immediate (age 2-6 mo) or early (age 6-12 mo) T replacement at approximate physiologic levels led to thyroid follicular tumor incidences of 100 and 82%, respectively, whereas intermediate (12-18 mo) or late (18-24 mo) T treatment led to only 70 and 73% incidences, respectively. Continuous T replacement (2-24 mo) in castrated irradiated male rats raised thyroid tumor incidence to 100%. Since elevated thyroid-stimulating hormone (TSH) is a reported requisite for development of radiation-associated thyroid tumors, the effects of T on serum TSH levels were examined. Mean serum TSH values in all irradiated animal groups were significantly elevated above age-matched nonirradiated animals at 6, 12, 18, and 24 months. Serum TSH levels were higher in continuous T-replaced irradiated castrates than in intact, irradiated males, whereas such intact male TSH levels were greater than those for irradiated castrates without T treatment. Interval T replacement in castrated male rats was generally associated with increased serum TSH levels during the treatment interval and with lowered TSH levels after discontinuation of T treatment, particularly in irradiated rats. However, when irradiated, castrated males received late T replacement (age 18-24 mo), there was no elevation of TSH at the end of the treatment interval. Thus an indirect effect of T via early stimulation of TSH may be at least partly responsible for the high incidence of irradiation-induced thyroid tumors in rats.