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Objective: To evaluate the effects of parathyroidectomy on the nonspecific symptoms associated with primary hyperparathyroidism, with an emphasis on distinguishing sleepiness from muscle weakness., Methods: We conducted a prospective cohort study of consecutive patients presenting for parathyroidectomy for the treatment of primary hyperparathyroidism. Twenty-three patients underwent assessment preoperatively and postoperatively. The Functional Outcomes of Sleep Questionnaire (FOSQ), the Epworth Sleepiness Scale (ESS), and a questionnaire of disease-specific symptoms were administered preoperatively, 2 weeks postoperatively, and 4 to 6 months postoperatively. The FOSQ assesses how sleepiness alters daytime performance, and the ESS reflects the degree of daytime sleepiness., Results: All 23 patients achieved normocalcemia postoperatively. Although no significant changes were found in the overall scores for the FOSQ and ESS after parathyroidectomy, there was a significant decline in the overall mean incidence of disease-specific symptoms postoperatively (P

Background: Bronchioloalveolar carcinoma (BAC) is a well-differentiated lung adenocarcinoma that has a tendency to spread chiefly within the confines of the lung by aerogenous and lymphatic routes and may therefore be amenable to local therapy. However, a high rate of local recurrence after lung transplantation was recently reported. We describe two patients with unresectable and recurrent extensive BAC limited to the lung parenchyma who underwent lung transplantation with curative intent., Methods: Patients were chosen to receive lung transplants for BAC if they met the following criteria: (1) recurrent or unresectable BAC limited to the lung parenchyma without nodal involvement and (2) suitable candidate for lung transplantation., Results: The first patient relapsed in the lungs at 9 months after transplantation. The pattern of disease suggested contamination of the new lungs at the time of implantation. Repeat lung transplantation was performed, with cardiopulmonary bypass and irrigation of the remaining upper airway. This patient has had no evidence of local or systemic tumor recurrence at more than 4 years since the second transplantation. The second patient underwent transplantation using the modified technique and expired 16 months after transplantation of other causes. An autopsy showed no evidence of recurrent BAC in the lungs or of metastatic lesions at any site., Conclusions: Lung transplantation may be an option for unresectable or recurrent BAC confined to the lungs. Isolation of the diseased lungs and the use of cardiopulmonary bypass during surgery may be important in this disease and should be studied further.

The treatment of metastatic differentiated thyroid carcinoma is currently at a crossroad. The stunning effect of imaging doses of RAI on subsequent treatment doses is being recognized. Alternatives to RAI imaging for diagnostic purposes are being tested; these include ultrasonography for local and cervical nodal remnants/recurrences, Sestamibi and other isotope scanning that do not require the discontinuation of TSH suppression, and the measurement of circulating thyroglobulin that is rapidly becoming the cornerstone of the detection and the treatment follow-up of metastatic carcinoma.

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.

Phosphate administration increases both parathyroid hormone (PTH) secretion and parathyroid size in rats, but the relative contribution of hypertrophy and hyperplasia is unknown. Accordingly, we reexamined parathyroid histology in a previously published experiment [6], quantitatively rather than qualitatively. Ninety female Long-Evans rats were divided into six groups; three were given a normal diet, and three a high phosphate diet (Ca/P 1:7). One group from each arm was killed after 1, 2, and 3 months. Quantitative microscopy was performed on the parathyroid section with the largest area from each animal, without knowledge of its experimental status. Total gland area and total number of cell profiles did not change significantly in the control rats, but increased progressively in the phosphate-loaded rats. At 3 months, the difference was +194% for gland area and+151% for profile number (P < 0.0001), much more than could be accounted for by suppression of apoptosis. Mean nuclear profile area and mean cell profile area (including associated connective tissue as well as cytoplasm) were both significantly increased at 1 month (P < 0.0001). The differences persisted, but their magnitudes (about +16%) did not change further. This time course was consistent with the morphologic expression of increased PTH secretory activity. We conclude that phosphate administration to adult rats increases both size and number of parathyroid cells, the latter due to increased cell proliferation. Phosphate-stimulated parathyroid growth could be due to either hypocalcemia or decreased calcitriol production; increased cell division may also be linked to increased hormone secretion, regardless of its cause. The relative importance of these different mechanisms remains to be determined.

Failure of embryologic development of a lobe of the thyroid gland is a rare anomaly. In order to characterize this unusual entity, we report our experience in seven patients with thyroid hemiagenesis involving the left lobe in five and the right lobe in two patients. The diagnosis was made as a result of evaluation and treatment of a thyroid nodule (4), diffuse thyroid enlargement with thyrotoxicosis (2), and a simple goiter in a patient with a prior history of radiation treatment for facial acne. In five patients thyroid scintigraphy demonstrated unilateral absence of function, four of whom had an ultrasound exam of the neck that revealed a corresponding absence of thyroid tissue. In one patient the diagnosis was made incidentally on a screening ultrasound exam of the neck. Thyroid hemiagenesis was unsuspected preoperatively in one patient with Graves' disease because of marked hyperplasia of a single thyroid lobe and isthmus. Thyroid hemiagenesis was confirmed in four patients who underwent thyroidectomy. The presence of a thyroid isthmus was established in six patients. Postoperatively, all patients were treated with thyroid hormone. Associated thyroid pathology included adenoma (1), follicular carcinoma (1), colloid nodule (2), Graves' disease (2), and a simple goiter (1). In conclusion, the diagnosis of thyroid hemiagenesis should be considered in any patient with unilateral absence of function on thyroid scintigraphy and confirmed by ultrasonography. Recognition of this rare congenital anomaly is important to avoid unnecessary contralateral neck exploration with its potential morbidity and to insure that all patients receive careful follow-up and appropriate thyroid hormone therapy when necessary.

The incidence of autoimmune disease of the thyroid approaches 10% in women. This autoimmune state, which predisposes to the development of thyroid neoplasia, especially in patients with subclinical hypothyroidism, combined with tumor growth and immunologic factors that occur in the pregnant state, account for the significant incidence of nodular thyroid disease in pregnancy. Thyroid carcinoma of follicular cell origin in a young woman can generally be expected to pursue a slow course with ample time for preoperative preparation and operative treatment. However, the pregnant state should be considered an exception and thyroid nodular disease with suspicious aspiration cytologic features should be managed with a certain degree of urgency. In an excellent article on the subject of pregnancy as a predisposing factor in thyroid neoplasia, Rosen and Walfish present a series of 30 patients with thyroid neoplasia arising during pregnancy. The incidence of thyroid carcinoma was 43% and the incidence of adenoma 37%, for an 80% overall incidence of neoplasia. Furthermore, during the course of the pregnancy, 20% of the patients showed marked increase in nodular growth, including a 26-year-old primiparous woman who developed a small nodule in the first trimester which proved to be cellular on needle aspiration biopsy. In spite of thyroid hormone treatment, the nodule grew markedly in the last trimester. At postpartum operation, the patient was found to have a papillary carcinoma with extensive unilateral neck and mediastinal node disease, which was clinically occult. These authors stress the importance of the operative treatment of thyroid neoplasia of pregnancy, either in the second trimester or immediately after delivery. We agree.

Parathyroid autotransplantation was first described in 1907 by Halsted. However, this simple and effective method of preserving parathyroid function has been used with increasing frequency only during the past 25 years. Beginning in the late 1960s, our group has transplanted normal parathyroid tissue into the ipsilateral sternocleidomastoid muscle whenever these glands could not be preserved in situ with adequate blood supply. In addition, if the blood supply of all four parathyroid glands appeared compromised, cryopreservation of parathyroid tissue was performed in case the autotransplanted tissue did not function after surgery. Since 1970, 393 patients underwent a total thyroidectomy. Parathyroid glands that could not be saved in situ were biopsied to confirm their identity by frozen section and then autotransplanted. Of the 393 patients who underwent a total thyroidectomy, 261 patients required transplantation of one or more glands. Among those 261 patients who underwent selective parathyroid autotransplantation, 33 (13%) required temporary calcium and vitamin D supplementation. Of these 33 patients, 2 (less than 1%) had permanent hypoparathyroidism and are receiving long-term vitamin D therapy.

In contrast to a few follicles arranged in a wedge-shaped segment at the periphery of a lymph node, a significant amount of thyroid tissue in a cervical lymph node is considered evidence of metastatic thyroid carcinoma. In a consecutive series of 243 patients with papillary carcinomas, 52 presented with lateral cervical masses that proved to be lymph nodes with metastatic thyroid carcinoma, in the absence of readily palpable thyroid nodularity. The metastatic disease was demonstrated by excisional biopsy in 40 patients and fine needle aspiration cytology in 12 patients. Thirty-two (of the 52) underwent further diagnostic work-up, consisting of radionuclide scintigraphy and ultrasonography, with the demonstration of abnormalities consistent with a thyroid neoplasm in 75 per cent (24/32) of these patients. The remaining 20 patients had no additional studies except for chemical thyroid function evaluation. The operative treatment in all 52 patients was total thyroidectomy and unilateral or bilateral modified neck dissections, when extensive cervical adenopathy was encountered. Papillary thyroid carcinoma, ranging in size from 2 to 14 mm, was found in the lobe ipsilateral to the presenting cervical node metastasis, in all specimens. In addition, contralateral cervical lymph node metastases were found in five (10%) of these patients, with no evidence of thyroid carcinoma in the corresponding thyroid lobe. With a mean follow-up period of 9 years, all patients are alive with no evidence of recurrence.(ABSTRACT TRUNCATED AT 250 WORDS)

The coexistence of hyperparathyroidism and thyroid tumors and/or chronic thyroiditis has raised the possibility of an etiologic relationship. The present study was designed to test the hypothesis that the chronic elevation of thyroid-stimulating hormone (TSH) is related to the development of hyperparathyroidism. Three groups of 24 rats each were treated for 12 weeks as follows: group 1 received propylthiouracil (PTU) in their deionized water; group 2 received PTU and thyroid hormone to suppress TSH and to serve as a control group for possible direct effects of PTU; and group 3 was not treated at all and served as another control group. At 12 weeks, 95% of group 1 rats (PTU only) showed hyperplasia of the parathyroids with a 30% mean increase in circulating parathormone.

Recurrent hyperparathyroidism (HPT) occurs in a small percentage of patients undergoing parathyroidectomy for primary HPT and is usually due to inadequate excision of hyperfunctioning parathyroid tissue in the neck, a missed ectopic and hyperplastic parathyroid, or, less commonly, parathyroid carcinoma and parathyroid autografts. In order to determine the incidence, clinical characteristics, and outcome of patients with recurrent HPT due to parathyroid autografts, we reviewed our experience with 604 consecutive patients operated on for primary HPT between 1965 and 1989. One hundred of these patients received parathyroid autografts consisting of portions of one or more parathyroid glands. Three patients with autografts, placed in the sternocleidomastoid muscle, developed recurrent HPT due to their autografts for an incidence of 3 per cent. Recurrent disease was diagnosed between 62 and 113 months with an average of 89 months. The autotransplants in all three of these patients were from hyperplastic or adenomatous parathyroid tissue. Two patients had a history of neck irradiation. Preoperative thallium scans accurately localized the hyperfunctioning parathyroid tissue in all three patients. At operation, the hyperfunctioning autografts had grown into a discrete mass with a single vascular pedicle and were resected. Histologic examination disclosed either hyperplastic or adenomatous tissue, and corresponded to the histology and location of the original tissue transplanted in each case. Follow-up ranges from 12 to 67 months, with an average of 48 months. All patients remain cured and none require oral calcium supplementation. We conclude that graft-dependent recurrent HPT is due to the autotransplantation of hyperplastic or adenomatous parathyroid tissue and that thallium scanning is instrumental for diagnosis and localization.(ABSTRACT TRUNCATED AT 250 WORDS)

Background: The diagnosis of thyroid carcinoma during the course of lobectomy for a dominant nodule occasionally cannot be rendered on the basis of frozen section. Once the diagnosis of carcinoma is made, the question of completion thyroidectomy arises. The decision to perform completion thyroidectomy and the timing, safety, and efficacy of this procedure are reviewed., Methods: During the past 25 years (1965 to 1990), we operated on 351 consecutive patients with thyroid carcinoma. One hundred of these patients (84 women and 16 men) were initially treated by unilateral thyroid lobectomy for the previously stated reasons. Histopathologic examination of the permanent sections of the initial thyroid lobectomy specimen demonstrated papillary carcinoma in 70 patients and follicular carcinoma in 30 patients. Within a few months, a completion thyroidectomy was performed., Results: The completion thyroidectomy specimen contained papillary carcinoma in 33 (47%) of the 70 patients with papillary carcinoma and 10 (33%) of the 30 patients with follicular carcinoma. Overall, 43 of these 100 patients harbored thyroid carcinoma in the contralateral lobe. Complications of completion thyroidectomy were transient recurrent nerve paresis in two patients and temporary hypoparathyroidism in three patients, requiring calcium and vitamin D therapy for a few months., Conclusions: Although the significance and treatment of papillary carcinoma are debated on the basis of size and grade of the primary lesion and age and sex of the patients, once the diagnosis is made in one lobe we believe that a completion thyroidectomy should be considered, not only for papillary carcinomas but also for follicular carcinomas because 47% (papillary) to 33% (follicular) of these patients will harbor the neoplasm in the contralateral lobe.

Primary hyperparathyroidism (PHPT) is increasing in incidence and detection, primarily because of the aging of our population and the widespread use of automated serum calcium determination. As a result, a substantial number of "early" cases or "biochemical" PHPT are being detected. The indications for parathyroidectomy in such early cases of PHPT are currently under debate, primarily because of economic issues. These factors underscore the importance of research into the basic mechanisms and natural history of PHPT. We investigated an animal model of diet-induced PHPT that retains two crucial aspects of PHPT: elevation of endogenously produced parathyroid hormone (PTH), accompanied by gross and microscopic changes in the native parathyroid glands. Female Long-Evans rats were divided into six groups of 15 each and fed a control diet (Ca/P of 1:2) or a high-phosphate diet (Ca/P of 1:7) for 1-, 2-, or 3-month intervals. Compared with the control animals, serum PTH levels were elevated at all three time intervals in the experimental group, whereas serum calcium levels were decreased at all time intervals. Serum creatine levels were also elevated at all time intervals, whereas serum phosphorus levels did not change. Parathyroid histopathologic studies demonstrated no change at 1 month, whereas nine of 15 experimental animals showed mild hyperplasia at 2 months and 13 of 14 showed mild to moderate hyperplasia with gland enlargement at 3 months compared with control animals. Histopathologic examination of the kidneys showed no change at 1 month but focal parenchymal inflammation with calcium deposition at 2 and 3 months in the experimental groups. In conclusion, the high-phosphate diet successfully induced the earliest changes of PHPT: elevated PTH levels and parathyroid hyperplasia. However, because renal function was mildly compromised early on, some element of early secondary (renal) hyperparathyroidism may have supervened quickly. Because this model is simple, it may be useful to investigate this complex syndrome further, as well as its natural history and the complications it produces in other organs such as the kidneys.

Anaplastic thyroid carcinoma, in contrast to well-differentiated thyroid carcinoma, has a dismal prognosis, and little progress has been made in improving survival for this disease. We reviewed our experience during a 23-year period to identify risk factors and possible methods to improve outcome. Between 1966 and 1989, 340 patients with thyroid carcinoma underwent operation. Of these, 17 (5%) were undergoing operative treatment of anaplastic or undifferentiated thyroid carcinoma. The female/male ratio was 3.5:1, and mean age at presentation was 63 years. The most common presenting symptoms included neck mass, voice change, or dysphagia. Unusual presentations included symptomatic bradycardia from compression of the vagus nerve and superior vena cava syndrome. Four patients had a history of well-differentiated thyroid carcinoma. Nine patients had been diagnosed or treated in the past for "goiter" or a neck mass, and four patients had concurrent differentiated thyroid carcinoma associated with the anaplastic tumor. Thus 13 (76%) of 17 patients had a previous thyroid disorder, benign or differentiated malignant, and eight (47%) of 17 patients had previous or concurrent differentiated thyroid carcinoma. At the time of presentation, six patients had unilateral true vocal cord paralysis. At operation, 14 patients had local extension of the tumor and four required tracheostomy. Only five of 12 patients showed response to postoperative radiation therapy. Overall median survival was 12 months, and 13 (76%) of 17 patients died. The two patients alive longer than 12 months had only small foci of anaplastic carcinoma in association with well-differentiated carcinoma. Anaplastic thyroid carcinoma is a locally and systemically aggressive disease, with long-term survival seen only in those with well-localized anaplastic tumor. The major risk factor in this series is a history of previous benign or malignant thyroid disease. Because of this, a more aggressive approach to thyroid masses may be warranted. Long-standing goiters or benign nodules should be followed carefully and considered for resection if they grow or do not respond to medical therapy, and total thyroidectomy for malignant disease may obviate the subsequent development of anaplastic carcinoma. This method of early diagnosis and resection of abnormal thyroid tissue seems to be the only method currently available to improve the nearly uniform fatality of this disease.

Thyroid and parathyroid disease after head and neck irradiation in infancy and childhood is well known. Patients irradiated for facial acne were older and received a comparatively lower dose of radiation. These mitigating factors suggest a decreased incidence of thyroid and parathyroid disease in these patients. Over the past 28 years (1961 through 1989), 347 consecutive patients were operated on for radiation-associated thyroid and/or parathyroid disease. One hundred and ten patients in this group were irradiated for treatment for adolescent facial acne vulgaris. The interval between radiation exposure and thyroidectomy ranged from 7 to 57 years (mean, 30 years). The overall incidence of thyroid carcinoma was 31% (34 of 110 patients). Regional metastases in 10 patients (29%) were treated with modified radical neck dissection. Hyperparathyroidism, detected in 31% (34 of 110 patients) of this population, was treated with sub-total parathyroidectomy in all cases. The association of thyroid carcinoma and hyperparathyroidism after adolescent radiation exposure for acne vulgaris appears to be more than coincidental. The incidence of thyroid and parathyroid disease may be independent of the timing and dosage of radiation treatment. These thyroid and parathyroid tumors may develop decades after the initial radiation exposure.

Many advances have been made in the diagnosis and treatment of patients with Cushing's disease. Currently, partial or total transsphenoidal resection of the pituitary gland is the surgical approach favored by many authorities, with cure rates of 80% to 90% reported for selected patients. However, long-term follow-up is still needed for this treatment modality, and recurrence rates of up to 50% have been reported. In addition, less favorable results are seen with this approach when there is recurrence after initial transsphenoidal surgery or when there is not a single microadenoma responsible for the disease of the pituitary gland. We report a series of 14 patients who were treated with bilateral adrenalectomy and autotransplantation. Follow-up is 4 to 14 years. Four patients show iodocholesterol uptake at the site of autotransplantation. Of these, three patients have been weaned from cortisone for 12, 10, and 2 years. The fourth patient, after being weaned from all medications, underwent partial resection of a hyperfunctioning autotransplant and currently, 7 years after the original operation, is being weaned from cortisone. A fifth patient was weaned to a reduced dose of cortisone for 8.5 years, but the dose was recently increased. There is no evidence of Nelson's syndrome in any of these patients with clinical evidence of functioning autotransplants. We believe that bilateral adrenalectomy with autotransplantation still plays an important role in the long-term management of selected cases of Cushing's disease and that autotransplantation, when successful, results in few complications and allows long-term freedom from exogenous steroid medication.

Previous works from our laboratory and others have shown that there is a PRL-like immunoreactive protein with immunological, chromatographic, and biological characteristics identical to those of pituitary PRL, and this is widely distributed in the rat central nervous system. Since pituitary PRL is important in controlling hypothalamic LHRH release, we have hypothesized that hypothalamic PRL-like immunoreactive protein might serve a similar role, that of an endogenous neuromodulator influencing hypothalamic LHRH release. To this end, we have examined the effect of PRL antiserum and normal rabbit serum on the release of immunoreactive LHRH from rat hypothalamic fragments cultured in vitro. In the first experiment, LHRH release from hypothalami of intact rats, bathed in PRL antiserum (1:200 in Krebs-Ringer bicarbonate buffer), was significantly lower than that from hypothalami bathed in normal rabbit serum (1:200 in Krebs-Ringer bicarbonate buffer) for 90 min of incubation. It was, however, possible that the PRL, immunoneutralized in the first experiment, was material that represented contamination from pituitary PRL. Therefore, we repeated the experiment using hypothalami from animals that had been hypophysectomized 2 weeks before death. Again, PRL antibody significantly inhibited the release of LHRH compared with that by hypothalami incubated in normal rabbit serum. Since testosterone is important to LHRH synthesis, a third experiment was carried out using hypothalami from hypophysectomized male rats that had been implanted sc with testosterone-containing capsules 72 h before death. By 72 h serum testosterone levels had normalized. PRL antibody added to medium containing hypothalamic explants from these animals substantially inhibited in vitro LHRH release, a pattern essentially similar to that seen in intact and hypophysectomized animals without testosterone replacement. From these studies we have concluded that hypothalamic PRL is an important neuromodulator that promotes the release of LHRH from the hypothalamus. Testosterone, at least under the experimental conditions employed, appears not to be essential in this hypothalamic PRL-LHRH interaction.

The interpretation of aspiration cytologic smears that contain a predominance of follicular components often presents a dilemma to the clinician who is treating a patient who has a dominant thyroid nodule, especially when thyroid-stimulating hormone suppression does not produce any significant involution of the dominant nodule. We reviewed a consecutive series of 555 fine-needle aspiration cytologic examinations of dominant thyroid nodules. All specimens that contained colloid or follicular cells mixed with lymphocytes or Hürthle cells were excluded from this review. Additionally, nine aspirates contained degenerated follicular cells with insufficient material for cytologic diagnosis. The remaining 76 specimens contained a predominance of follicular cells: 27 specimens were interpreted as containing "normal" follicular cells, and the remaining 49 specimens were read as "atypical" follicular cells. Histopathologic examination of the resected specimens indicated a 60% incidence of neoplasia (30% carcinoma, 30% adenoma) in which the aspiration cytologic study was interpreted as "normal" follicular cells. On the other hand, a 63% incidence of neoplasia (27% carcinoma, 36% adenoma) occurred in which the cytologic study was read as "atypical." In conclusion, aspirates showing a predominance of follicular cells, whether "normal" or "atypical" indicate a 60% incidence of neoplasia in dominant thyroid nodules that do not decrease significantly in size with thyroid-stimulating hormone suppression.

Although parathyroid autotransplantation during the course of thyroidectomy was first described by Halsted in 1907, it is only during the past 20 years that this simple and effective method of preserving parathyroid function is being used by an increasing number of surgeons. Our group has autotransplanted normal parathyroids since 1965, whenever these glands could not be preserved in situ with adequate blood supply. With increasing experience, we find it much simpler to autotransplant parathyroid glands attached to the thyroid, than to dissect their precarious blood supply, hoping they will survive postoperative edema and fibrosis. Furthermore, it is our impression that in operations for thyroid carcinoma, attempts to preserve the blood supply to the parathyroids may compromise the completeness of the thyroidectomy or of the dissection of cervical nodes in the tracheoesophageal groove. In a review of our experience during the past four years (January 1, 1984 to December 31, 1988), 87 patients underwent total thyroidectomy. Parathyroid glands that could not be saved in situ were biopsied to confirm their identity by frozen section and autotransplanted in the ipsilateral sternocleidomastoid muscle. Among the 87 patients undergoing total thyroidectomy, 34 required no autotransplantation, whereas 52 had one to three glands autotransplanted, and one had four glands autotransplanted. Postoperatively, 23 patients (26 percent) developed hypocalcemia, whereas 18 required CaCO3 and five required vitamin D in addition. All patients (98%) except two had normal parathyroid function at four-month follow-up and thereafter, as judged by serum calcium, phosphorus and parathormone, when indicated.

The relationship between Hashimoto's thyroiditis and follicular cell carcinoma of the thyroid remains controversial. Hashimoto's thyroiditis is regarded by some as a premalignant lesion for which thyroidectomy is definitely indicated. In contrast, other investigators have found no increased evidence of thyroid carcinoma in patients with this disease. As a result, the management of thyroid nodules in patients with Hashimoto's thyroiditis remains highly individualized. A program for the management of patients with chronic Hashimoto's thyroiditis with co-existing neoplasia or primary hyperparathyroidism is outlined.

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.

Subtotal pancreatectomy specimens from two adults with hyperinsulinemic hypoglycemia and one adult with watery diarrhea syndrome were investigated. All three specimens were originally diagnosed as "nesidioblastosis"; none had a neoplasm, and all patients were cured of their endocrine dysfunction by the surgical procedure. Tissue samples were studied by light microscopy and light microscopic immunohistochemistry for serotonin, ACTH, bombesin, calcitonin, gastrin, glucagon, insulin, HPP, somatostatin, and VIP. The results were compared with those obtained from the parallel study of ten adult pancreata obtained at autopsy from patients without pancreatic disease or endocrine dysfunction. The total endocrine cell mass was not notably greater in the pancreata from patients with endocrine dysfunction than in the controls. Both groups had an estimated 95% of the endocrine cell population organized in islets while the remaining 5% was irregularly dispersed amidst the exocrine ducts and acini. Findings more conspicuous in patients with endocrine dysfunction but not absent in the controls included: large islets, islets with irregular contours and ragged edges, and large individual islet cells with abundant cytoplasm and bizarre nuclei. Immunoreactivity for insulin, glucagon, and somatostatin was demonstrated in all cases; the ratio among these hormones in the patients with endocrine dysfunction and in the controls was similar. In the patients with hyperinsulinemic hypoglycemia, step sections sequentially stained for insulin and somatostatin showed a close topographic relationship between these cell types. In the patient with the watery diarrhea syndrome, VIP immunoreactive cells were easily identified admixed with exocrine components; they were only rarely seen within islets. We suggest that the hyperinsulinemic hypoglycemia in these adults was not due to simple quantitative abnormalities in total endocrine cell mass nor to its maldistribution nor to lack of topographic proximity between insulin and somatostatin cells. We speculate that the syndrome may be based on still unknown derangements of insulin secretion, release, and/or its degradation. In the case of the watery diarrhea syndrome, the readily identifiable VIP immunoreactive cells represent the emergence of a functional expression regarded as ectopic for the endocrine cells of the pancreas. We conclude that nesidioblastosis per se cannot be viewed as the structural basis of these endocrine dysfunctions since many of its features were present in control pancreata lacking any such association.(ABSTRACT TRUNCATED AT 400 WORDS)

In a consecutive series of 118 total thyroidectomies during a period of 11 years, autotransplantation of one or more parathyroid glands was used in 64 patients. During the first nine years of this series, autotransplantation was used in only 25 per cent of the total thyroidectomies, with a 3 per cent incidence of permanent hypoparathyroidism. During the last two years, autotransplantation of the parathyroid was used in 89 per cent of 54 total thyroidectomies, with a zero incidence of hypoparathyroidism.

A case is presented of a fifty-six year old man with a thyroid hemangioma presenting as a neck mass with tracheal deviation and unilateral vocal cord paralysis. A standard thyroid scan yielded equivocal findings. The diagnosis was determined preoperatively by the use of a 99m-technetium angiogram that disclosed the vascular nature of the lesion. Subsequent arteriography demonstrated the main arterial supply of the mass to be from both inferior thyroid arteries. Operative removal of the mass was accomplished through a standard transverse cervical incision. Pathologic study revealed that the vascular tumor involved both the surrounding normal thyroid parenchyma and also a microfollicular adenoma. This case points out the value of utilizing all available diagnostic means in atypical cases of thyroid disease.

The development of hyperparathyroidism (HPT) is presented as well as various problems and possible solutions.

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.

Five unusual case studies are presented. Each case is followed by solutions proposed by three authorities and a concluding commentary by the editor.

Primary hyperparathyroidism masked by untreated hypothyroidism was first noted by Kissin and Bakst in 1947; since then there has been only a single case reported. As a result, it has been thought to be a rare complex of parathyroid disease. During the past 17 years we observed 17 patients who developed primary hyperparathyroidism after their treatment for hypothyroidism (secondary to Hashimoto's thyroiditis) with thyroxine had been well underway. The patients were all women whose ages ranged between 16 and 76 years. The clinical and biochemical manifestations of hyperparathyroidism were noted 2 months to 30 years after thyroxine therapy. All patients underwent standard subtotal parathyroidectomy. Fourteen patients had a single parathyroid adenoma and three had multiglandular adenomatous hyperplasia. It is of interest that all 17 patients were found to have Hashimoto's thyroiditis, based on antimicrosomal antibody titers or histopathologic criteria. Thus we present a series of patients who developed primary hyperparathyroidism in a background of Hashimoto's thyroiditis and hypothyroidism treated with thyroxine. We are intrigued by the association of hyperparathyroidism and Hashimoto's chronic thyroiditis. From this experience it seems appropriate to evaluate parathyroid function in patients with hypothyroidism secondary to Hashimoto's thyroiditis before the initiation of treatment with thyroxine and at intervals thereafter.

Forty-four patients with primary hyperparathyroidism were followed for 18 to 126 months after subtotal or total parathyroidectomy and parathyroid autotransplantation. Indications for autotransplantation included the devascularization of parathyroid glands during concomitant thyroid lobectomy or total thyroidectomy and the excision of the only remaining parathyroid tissue in patients with persistent hyperparathyroidism after previous unsuccessful parathyroidectomies. Before implantation, all parathyroid tissue was histologically evaluated by frozen-section light microscopy with hematoxylin and eosin stain. Fifteen patients had histologically normal implants; to date none of these patients have developed recurrent hyperparathyroidism. Twenty-nine patients had either adenomatous or hyperplastic parathyroid tissue used for implants; two of these patients developed graft-dependent recurrent hyperparathyroidism 4 and 7 years later. In both patients the grafts were preoperatively localized by thallium scanning and their resection restored eucalcemia. One hundred thirty-one patients from 11 series in the current literature had a cumulative incidence of 17.5% for presumed graft-dependent recurrence and a 9.2% incidence of graft excision followed by eucalcemia. In comparison, in the present series the incidence of graft-dependent recurrent hyperparathyroidism in patients with either adenomatous or hyperplastic implants stands at 6.9%. In contrast, in 15 patients with normal parathyroid tissue implants, the incidence was zero.

Two series of patients treated for primary hyperparathyroidism are reviewed for the incidence of associated pancreatitis. In an earlier series of 150 hyperparathyroid patients, six had documented pancreatitis as one of the primary clinical manifestations. Review of a more recent series failed to uncover a single case of pancreatitis in 26 patients with primary hyperparathyroidism. The incidence of pancreatitis associated with hyperparathyroidism appears to be steadily decreasing, possibly reflecting the earlier diagnosis of parathyroid disease, which is due to widespread screening testing methods currently available.

The recent controversy concerning the prognosis of Hürthle cell tumors instigated the review of our experience with 34 patients treated between 1972 and 1984. On the basis of strict histopathologic criteria, 14 patients with Hürthle cell hyperplasia, 10 with Hürthle cell adenoma, and 10 with Hürthle cell carcinoma were identified. There was a 40% incidence of bilateralism in Hürthle cell carcinoma, whereas we documented bilateral disease in only one of 10 patients with Hürthle cell adenoma. Lobectomies were performed in patients with tumors considered histopathologically benign and total thyroidectomy in patients with histologically malignant lesions as well as in most patients with a history of radiation exposure. Follow-up ranges from 4 months to 12 years (mean 3.1 years). To the present time there has been no evidence of recurrence and no deaths from Hürthle cell tumors. Consequently, in our experience, Hürthle cell tumors seem to behave in a rather benign manner. Therefore it seems that the appropriate treatment for Hürthle cell adenoma and nodular hyperplasia is a lobectomy. Total thyroidectomy is reserved for patients with Hürthle cell carcinoma primarily because of the high incidence of bilateralism.

Although thyroid disease in humans predominates in females, the prognosis of thyroid cancer in males is much less favorable. To further explore the role of male sex hormones, we utilized the experimental model of radiation-induced follicular cancer in the rat, studying the effects of castration on tumor development. Microscopic evidence of tumor formation was correlated with the biochemical parameters serum thyroxine (T4), thyrotropin (TSH), and thyrocalcitonin (TC) at 24 months. The incidence of follicular carcinomas in intact males ws 58%, compared to 28% in comparable females. Castration of males caused a reduction in the incidence to 22%. Mean circulating levels of TSH were markedly elevated in all three irradiated groups. Mean T4 levels were reduced significantly only in irradiated castrated animals. TC levels were reduced in all irradiated groups. We conclude that although elevated levels of TSH probably play a significant role in the development of radioactive iodine-triggered follicular thyroid neoplasms in the rat, male sex hormone may also play an important role beyond their known effect on basal and thyrotropin-releasing hormone-stimulated TSH.

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).

Of 351 patients treated for primary hyperparathyroidism from 1966 to 1981, 70 (20%) had grossly evident nodular thyroid disease at the time of subtotal parathyroidectomy. These patients have been reviewed to determine if prior radiation exposure may play a role in their coexistence and if combined subtotal parathyroidectomy and thyroidectomy are safe and efficacious. Thirty-three of the 70 patients (47%) had received prior radiation therapy for benign conditions of the head and neck. Nine of 15 patients with nonmedullary thyroid carcinoma had received previous irradiation. In addition to subtotal parathyroidectomy, 28 patients underwent total thyroidectomy, 14 underwent bilateral subtotal thyroidectomy, and 28 underwent unilateral lobectomy. There were no deaths and no permanent recurrent laryngeal nerve injury from combined subtotal parathyroidectomy and thyroidectomy. Two patients in whom parathyroid tissue was not autotransplanted required calcium and vitamin D supplementation. This study shows that (1) primary hyperparathyroidism and nodular thyroid disease occur simultaneously with sufficient frequency to warrant careful preoperative and intraoperative evaluation of both glands, (2) radiation probably does play a role in the pathogenesis of coexistent primary hyperparathyroidism and nodular thyroid disease, and (3) in experienced hands combined subtotal parathyroidectomy and thyroidectomy can be safely performed.

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.

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.

Parathyroid carcinoma is a rare cause of hyperparathyroidism. Cure results from successful en bloc resection. However, because of its rarity, the malignant nature may not be appreciated at the initial operative procedure and as a result, definitive resection may not be accomplished. However, even with extensive en bloc resections, local recurrences do occur and patients die of metabolic derangements associated with hypercalcemia. Thus in addition to operative intervention, palliative chemotherapy may be required to control the hypercalcemia. Radiotherapy has been unsuccessful. A single case of nonfunctioning parathyroid carcinoma responding to treatment with methotrexate, Adriamycin, cyclophosphamide, and CCNU has been reported. We report a case of recurrent functioning parathyroid carcinoma treated with dacarbazine (DTIC) in which biochemical and pathologic evidence of at least a partial response was seen. The patient, a 33-year-old woman, had undergone five previous neck explorations during a 26-month period for aggressive locally recurrent disease. Before DTIC therapy the intact parathyroid hormone (PTH) level was 1032 pg Eq/ml (normal 163 to 347 pg Eq/ml) and the serum calcium level was 16.8 mg/dl (normal 8.8 to 10.0 mg/dl). After a course of DTIC there was a marked improvement in her clinical status and biochemical parameters (intact PTH 545 pg Eq/ml; serum calcium 11.8 mg/dl). For 2 months her condition stabilized, with PTH levels between 700 and 760 pg Eq/ml and serum calcium levels between 10.2 and 16.0 mg/dl. With a slowly progressive rise in biochemical parameters a second course of DTIC was initiated and a marked drop in serum calcium levels (5.7 mg/dl) occurred, but PTH levels remained unchanged. A progressive course of septicemia, malnutrition, and disseminated intravascular clotting ultimately lead to her death 4 weeks later. At autopsy examination the tumor was confined to the neck. Grossly and microscopically there was extensive central as well as peripheral necrosis of the tumor, which was thought to be the result of the cytotoxic effect of DTIC. From this experience and because of the grim prognosis in patients with recurring parathyroid carcinoma, it may be that aggressive use of chemotherapy with DTIC early in the course of treatment should be considered.

There is a potential hazard of thyroid cancer after exposure to external irradiation for the treatment of adolescent acne vulgaris. We noted a 60% incidence of thyroid carcinoma among 20 patients with such a history, who were operated on for thyroid nodules during a five-year period. Eighty-three percent of the patients with carcinoma had either a follicular or a mixed papillary-follicular carcinoma; 17% had a papillary carcinoma; 33% had regional node metastases; none had evidence of distant metastases. The interval between radiation exposure and thyroidectomy ranged from nine to 41 years. This association of thyroid neoplasms and a prior history of radiation for acne vulgaris may be coincidental and therefore remains to be proved by retrospective surveys of large numbers of treated patients with appropriate controls.

During a period of 20 years (1965-1985), 206 consecutive patients were operated on for radiation-associated nodular thyroids. The ages ranged between 8 and 76 years (mean 38.7). there were 136 women and 70 men. The average duration between radiation exposure and operation was 27 years. The operations performed were total thyroidectomy (192) or, in patients who had undergone a previous lobectomy in another institution, another lobectomy (14). In addition, 25 patients required a neck dissection for nodal metastases and 27 underwent simultaneous subtotal parathyroidectomy for coexistent hyperparathyroidism. The pathologic findings were: 87 (42.2%) carcinoma (73 papillary, 13 follicular, 1 undifferentiated); 92 (44.7%) follicular adenomas; and 27 (13.1%) thyroiditis. To date, with an average follow-up of 6 years (0.5-31 years), only two patients have expired from recurrent disease. A third died of unrelated cause. A comparison of the first 100 patients (12 years) with the last 106 patients (8 years) demonstrated that the incidence of carcinoma has dropped from 48 to 37%, the incidence of lymph node metastases has decreased from 35 to 26%, and the incidence of bilaterality has fallen from 75 to 54%. On the basis of this series, it was concluded that total thyroidectomy is still indicated for radiation-associated nodular thyroids. However, if the trend of decreasing incidence, bilaterality, and metastatic disease persists, this approach may have to be reevaluated in the near future.

Hyperparathyroid crisis is a rare disease manifested by elevated serum calcium, weakness, nausea and vomiting, altered states of consciousness, and elevated circulating parathormone. This hypercalcemic state is noted for a frequently acute presentation and associated high mortality rate, approaching 60% in some series. Ten patients in parathyroid crisis were observed in a consecutive personal series of 325 cases of operatively proved hyperparthyroidism. All 10 patients were successfully treated. Each patient remained or lapsed into persistent coma despite extensive medical management and normalization of serum calcium in some instances. An emergency parathyroidectomy was performed in all cases. Reversal of the comatose state was noted in all patients within 24 hours, followed by gradual normalization of serum calcium. Serum calcium ranged from 15 to 19.6 mg/dl. The blood urea nitrogen level was elevated in six patients. A single adenoma was found in nine patients and multiglandular disease involving the neck and the mediastinum in one. All patients survived. The successful treatment of this disease demands prompt and accurate diagnosis coupled with vigorous medical therapy and emergency parathyroidectomy if the patient's status continues to deteriorate.

Subtotal parathyroidectomy was performed in a consecutive series of 292 patients with primary hyperparathyroidism. We evaluated the long-term postoperative results during a period of 16 years. Patients ranged in age from 14 to 83 years and included 176 women and 116 men. Of these, 16% had a history of exposure to radiation in childhood or adolescence, while thyroid disease requiring some form of thyroidectomy coexisted in 91 (31%) of the patients. Histologic information on three or more parathyroid glands was obtained in 73% of the cases. We considered 285 patients (97.6%) cured after their first operation. The remaining seven patients (2.4%) had persistent hyperparathyroidism. However, five were cured after a sternum-splitting mediastinal exploration and one after a second neck exploration. The seventh remains hypercalcemic despite a subsequent mediastinal exploration. Temporary postoperative hypoparathyroidism occurred in 10% of our cases and permanent hypoparathyroidism in 1%. There have been no instances of recurrent hyperparathyroidism.