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The diagnosis of primary hyperparathyroidism (1°HP) has become more complex, as fewer patients present with classic phenotype of concomitant elevation of calcium and parathyroid hormone (PTH). In addition, the distinction between normal versus abnormal patients is challenging, with an increasing number of patients with 1°HP, who have calcium and/or PTH values within the “reference” range. Patients with “inappropriately” elevated PTH values relative to their serum calcium are considered to have 1°HP. The study population consisted of 1753 patients with pathologically proven 1°HP and 74 healthy control patients. Nomograms were created by plotting PTH versus calcium of the two groups. The 95 % confidence zone of calcium and PTH for normal individuals was plotted and compared to patients with 1°HP. The comparison of control and disease groups showed a clear demarcation zone on the plots of calcium versus PTH. In the group of 1°HP, 70 % had classic 1°HP presentation with the concomitant elevation of both calcium (≥10.5 mg/dL) and PTH (≥65 pg/dL). 21 % had “normocalcemic” HP with calcium ≤10.5 mg/dL and PTH ≥65 pg/dL. 6 % had “normohormonal” HP with calcium ≥10.5 mg/dL and PTH ≤65 pg/dL. 3 % had both calcium and PTH within the reference range. 68.5 % of patients had single adenoma, 16 % double adenoma, and 15.5 % hyperplasia. This nomogram serves as a diagnostic tool to distinguish normal patients from those with 1°HP, particularly those with atypical presentations. This recognition would permit previously observed patients to benefit from curative surgery.

Current guidelines increasingly suggest the use of thyroid lobectomy for indeterminate (Bethesda 3 and 4) and high-risk (Bethesda 5 and 6) thyroid nodules; however, the clinical reality is often very different. The aim of this study was to determine the rate of completion thyroidectomy (CTx) for indeterminate and high-risk thyroid nodules which are pre-operatively classified as suitable for unilateral resection (lobe eligible) based on current guidelines. Seven hundred consecutive patients with thyroid nodules and FNA cytology over four years (2015–2018) were reviewed. Distribution of the dominant nodules by Bethesda was: non-diagnostic 3.9%, benign 28.1%, atypia of unknown significance 19.0%, follicular neoplasm 23.6%, suspicious for malignancy 6.1% and malignancy 19.3%. Of 298 indeterminate nodules, 68.8% (205/298) had relative but independent indications for a total thyroidectomy (TTx) and the remainder were candidates for lobectomy. For these lobe eligible patients, the overall risk of ultimately needing a TTx was 19.4% (18/93), comprising 4.3% (4/93) from intra-operative findings and 15.7% (14/89) from final pathology. Similarly, of 170 high-risk nodules, 63.5% (108/170) had upfront indications for a TTx and the remaining 62 nodules were lobe eligible. Of the patients taken to the operating room for a lobectomy, 21.0% (13/62) were upgraded to a TTx intra-operatively and 26.5% (13/49) post-operatively. The lobe success rate for indeterminate nodules was 25.2% and for high-risk nodules was 21.2%. The rate of CTx, or the proportion of patients needing a second operation was 15.7% (14/89) and 26.5% (13/49), respectively. In counselling a patient for surgery, the risk of needing a more radical initial procedure or second surgery needs to be accurately explained. There are three points of care that can influence operative strategy, pre-operatively by way of high-risk clinical factors, intra-operatively via anatomical findings and post-operatively in response to unrecognized pathological features. Additionally, the patient’s personal value judgment and level of risk aversion should be taken into consideration.

Elevation of parathyroid hormone (PTH) levels is commonly seen in patients with primary hyperparathyroidism (PHPT) who have undergone parathyroidectomy. This study evaluates differences in 2-week postoperative PTH levels in patients having focused-approach surgery versus four-gland exploration.Over 6 years, patients at Rhode Island Hospital (RIH) and the Cleveland Clinic (CCF) who had PHPT and underwent localization studies suggestive of single adenoma were analyzed. At RIH patients underwent focused-approach surgery, and at CCF routine four-gland exploration was performed. Postoperative calcium supplementation was routine at RIH and selective at CCF.There were 308 patients at RIH and 370 at CCF. They were similar in age (59.2 +/- 13.0 years at RIH and 60.4 +/- 12.9 years at CCF), and sex (76.9 and 80.0% female at RIH and CCF, respectively). The mean preoperative serum calcium measured 10.9 +/- 0.7 mg/dl at RIH and 11.1 +/- 0.7 mg/dl at CCF (P0.001). Preoperative PTH values were similar, measuring 143.8 +/- 104.8 pg/ml in the focused-approach group (RIH) and 157.6 +/- 150.3 pg/ml in the four-gland exploration group (CCF). Preoperative 25-hydroxyvitamin D (vitamin D-25) levels were 24.1 +/- 12.0 ng/ml at RIH and 27.4 +/- 10.6 ng/ml at CCF; and the prevalence of vitamin D-25 deficiency (level20 ng/ml) was 43.9% at RIH and 27% at CCF (P = 0.017). The proportion of patients whose intraoperative PTH value dropped byor=50% prior to completion of surgery was 95.0% at RIH and 95.5% at CCF. The total gland weight resected per patient was 942 mg at RIH versus 1,394 mg at CCF (P = 0.003). The 2-week postoperative serum PTH was65 pg/ml in 18.8% at RIH and in 38.7% at CCF (P0.001). The 2-week postoperative serum calcium values dropped to 9.2 +/- 0.6 mg/dl at RIH and to 9.5 +/- 0.8 mg/dl at CCF (P0.001). The incidence of multigland disease was 5.8% at RIH and 21.9% at CCF (Por= 0.001).Among patients with PHPT who underwent a localizing study indicating unilateral disease, a significant proportion had eucalcemic PTH elevation 2 weeks after parathyroidectomy. The elevation was more frequent in the four-gland exploration group and correlated most strongly with greater adenoma mass.

Secondary hyperparathyroidism (SHPT) and tertiary hyperparathyroidism (THPT) are disease entities in patients with chronic kidney disease that are caused by parathyroid hyperplasia. The role of preoperative localization studies in patients undergoing parathyroidectomy for these conditions remains poorly defined. To evaluate the utility of surgeon-performed neck ultrasound (US) as well as sestamibi scans in the localization of parathyroid glands in patients with SHPT/THPT. A retrospective analysis of patients with SHPT/THPT who underwent parathyroidectomy at a single institution. Results of preoperative localization studies were compared to intraoperative findings. One hundred and three patients underwent parathyroidectomy for SHPT/THPT. All patients underwent surgeon-performed neck US, while 92 (89 %) underwent sestamibi scans. US failed to localize any of the parathyroids in 4 patients (3.8 %), while sestamibi was negative in 11 (12 %). Forty-seven ectopic glands were identified in 38 patients in whom sestamibi was performed. In five patients (13 %), ectopic glands were identified by both modalities, by US only in 6 (16 %), by sestamibi only in 8 (21 %), and by neither study in 19 patients (50 %). US showed new thyroid nodules in 19 patients (18.4 %), leading to lobectomy or thyroidectomy at the time of parathyroidectomy in 16 patients (15.5 %). Pathology showed malignancy in 7 patients (6.8 %). US and MIBI offer little benefit in localizing ectopic glands and rarely change the conduct of a standard four-gland exploration. Although there was a benefit of US in the assessment of thyroid nodules, in only 8.7 % of patients was sestamibi of benefit in identifying ectopic glands.

Prophylactic and therapeutic neck dissections are used to control or eliminate local nodal disease in patients with thyroid cancer. The purpose of this study was to evaluate the results and complications of neck dissection. From 1992 to 1999 a series of 115 consecutive neck dissections were performed in 74 patients (32 men, 42 women; mean age 48 years) with thyroid cancer and nodal metastases. Operations included central compartment, lateral modified, and suprahyoid dissection with and without total or completion thyroidectomy. Sixty-four percent of the patients had papillary, 4% follicular, and 32% medullary thyroid cancer. Complications included transient hypocalcemia (23%) defined by a postoperative serum calcium level of

aparoscopic adrenalectomy is the standard for most surgical adrenal diseases. The aim of this study was to evaluate the safety and effectiveness of laparoscopic adrenalectomy for patients with pheochromocytoma. The medical records of 39 consecutive patients who underwent laparoscopic adrenalectomy for pheochromocytomas from 1994 to 2000 at the University of California-San Francisco were reviewed. Three groups of patients were identified. The first group comprised 17 patients with classic symptoms and signs of pheochromocytoma. The second group comprised 17 patients who had minimal symptoms and incidentally discovered pheochromocytoma (i.e., "incidentaloma"), almost half of whom inappropriately underwent fine-needle biopsies before diagnosis. The third group consisted of 5 patients who had acute hypertensive crises and required intensive preoperative preparation. The mean age of the 22 men and 17 women was 46 years (range 20-84 years), and the mean adrenal tumor size was 4.8 cm (range 2-12 cm). A total of 43 laparoscopic adrenalectomies were performed for 35 patients with unilateral tumors and 4 patients with bilateral tumors. The retroperitoneal approach was used in four patients and the lateral transabdominal approach in the remaining patients without conversion to an open operation. There were no intraoperative complications or mortality. The mean duration of hospitalization was 1.7 days. In conclusion, patients with pheochromocytoma have a wide spectrum of presentations, from minimal symptoms to hypertensive crises. When evaluating an incidentaloma, pheochromocytoma should be excluded by metabolic testing, not by needle biopsy. Laparoscopic adrenalectomy is the preferred surgical approach for patients with pheochromocytoma because it is safe and efficacious.

Because some papillary thyroid cancers continue to grow when thyroid-stimulating hormone (TSH) levels are suppressed, we questioned whether desensitization (i.e., a decreased cAMP response to repeat stimulation with TSH) occurs in normal and neoplastic thyroid tissue. If desensitization does occur, is it similar or different in these human thyroid cells? Normal and papillary thyroid cancer cells from the same patient were cultured as we have previously described. Normal and neoplastic thyroid tissues responded to TSH (0.01-10.0 mU/ml) by increasing cAMP production and growth in a dose-dependent manner. In normal cells there was an 11-fold mean increase in cAMP production at 4 hours, and all thyroid cultures responded. In neoplastic cells cAMP production increased from 1.5-fold to 3.0-fold with a mean 2.0-fold increase at 4 hours. In normal thyroid cells the cAMP response to a second TSH stimulus (desensitization) decreased up to 75% (range 25-75%), and desensitization occurred in all normal thyroid cell cultures. In neoplastic thyroid cells, however, the cAMP response to a second TSH stimulus decreased up to 17% (range 0-17%); and desensitization occurred in only two of the five neoplastic thyroid cell cultures. Thus when normal thyroid and neoplastic cells from the same patients were studied, greater desensitization occurred in the normal cells (75% vs. 17%). These studies document that there is greater desensitization in normal tissue than in neoplastic thyroid tissue, which may account for the increased growth of thyroid neoplasms in the presence of ever-changing low levels of TSH.

Hyperparathyroidism occurs sporadically, in association with multiple endocrine neoplasia (MEN) types I and II, or rarely as familial hyperparathyroidism (FHPT) without other manifestations. We analyzed our experience in 16 FHPT patients from 14 families treated between 1934 and 1991 and reviewed 51 other FHPT patients reported in the literature to determine the clinical course of these patients. Among our 16 patients, 7 (44%) had a serum calcium level/= 3.75 mmol/L, 5 (31%) presented with hypercalcemic crisis, 3 (19%) had osteitis fibrosa cystica, 5 (31%) had nephrolithiasis, 1 had pancreatitis, 12 (75%) had multiple abnormal parathyroid glands, 3 (19%) had supernumerary glands, and 7 (44%) required reoperation for persistent (n = 4) or recurrent (n = 3) hyperparathyroidism. Three patients (19%) also had papillary thyroid cancer, and 7 (44%) had other coexistent thyroid disorders. Among 51 patients with FHPT reported in the literature, 23 (45%) had serum calcium/= 3.75 mmol/L, and 23 (45%) had multiple abnormal parathyroid glands; 10 (20%) had recurrent hyperparathyroidism. FHPT without other endocrinopathies is a distinct entity. Patients with FHPT have multiple abnormal parathyroid glands and are prone to both recurrent and persistent hyperparathyroidism. They frequently present with profound hypercalcemia or hypercalcemic crisis, in contrast to patients with MEN-associated hyperparathyroidism or sporadic hyperparathyroidism.

Ultrasound (US) and sestamibi (MIBI) are traditionally considered positive or negative. The purpose of this study was to define and test a new scoring system for MIBI and US and to determine whether this can improve their accuracy for primary hyperparathyroidism. This is a prospective study of 200 consecutive patients with primary hyperparathyroidism who had a single uptake on MIBI scans before bilateral neck exploration at a tertiary academic center between 2007 and 2008. These patients also had surgeon-performed neck US in the office, which was scored as “typical” or “atypical” based on how characteristic the image resembled a parathyroid gland. The MIBI uptake was scored by the nuclear medicine specialist as “weak,” “moderate,” or “strong” compared with the signal intensity of the thyroid. US and MIBI scoring was done preoperatively and their findings were compared with operative data. Of 200 patients, 71 % had a single adenoma, 12 % had double adenomas, and 17 % had four-gland hyperplasia. A weak, moderate, and strong signal on MIBI had an accuracy of 23, 47, and 72 %, respectively, in demonstrating single-gland disease. An atypical versus typical US appearance was accurate in 55 and 74 % of the time, in identifying single-gland disease. An appraisal of US and MIBI positivity in relation to image characteristics affects the reliability of both studies. This information should be kept in mind when selecting patients for focal neck exploration.

Numerous investigations document that exposure to low dose external therapeutic radiation leads to the development of benign and malignant thyroid neoplasms. There is consideble controversy, however, concerning whether radioactive iodine (131I) causes thyroid cancer. The aim of this investigation was to examine our experience and that in the literature related to this problem. From 1982 to March 1993 seven of 373 patients (1.9%) with thyroid cancer who were treated by one surgeon had a history of treatment with radioactive iodine for Graves' disease and toxic nodular goiter. Sixty-five patients have previously been reported in the literature from 1957 to present. Our patients (five women, two men) ranged in age from 26 to 80 years (mean 57 years). The interval between the exposure to the internal radiation and development of cancer ranged from 3 to 29 years (mean 11.4 years), and the mean age at the time of 131I treatment was 45 years (18–76 years). The therapeutic dose of 131I was 5 to 100 mCi (mean 25.3 mCi) in our patients. Two of our patients received 131I twice. The age of patients reported in the literature at the time of 131I treatment ranged from 7 to 74 years (mean 48 years). The mean therapeutic dose of 131I was 20.6 mCi (1.25–180.0 mCi) and the latent period was documented for a mean 8.7 years (0.25–28.0 years) in these patients. Three of 29 patients in the literature received 131I twice. Fine-needle aspiration cytology of thyroid nodules was positive for cancer in six of our patients (86%). All patients were treated by total thyroidectomy, and three of them had a modified neck dissection. Six of our seven patients had invasive papillary thyroid carcinoma (stage III disease), and the seventh patient had extensive nodal metastasis and intrathyroidal invasion. Invasion into adjacent muscle and soft tissue were found in four patients, and two had tracheal invasion. Two patients had lymph node metastases. There were no postoperative complications. One patient (14%), however developed recurrent papillary and anaplastic thyroid cancer in his left neck and mediastinum 2 years after total thyroidectomy. He had extensive pulmonary metastases and malignant pleural effusions and died 23 days after a left modified radical neck dissection. In conclusion, radioactive iodine in doses to treat Graves' disease may increase the risk of developing thyroid cancer. These cancers are discovered at a later stage and appear to be aggressive.

We previously reported on the safety and efficacy of laparoscopic radiofrequency thermal ablation (RFA) for treating hepatic neuroendocrine metastases. The aim of this study is to report our 5-year RFA experience in the treatment of these challenging group of patients. Of the 222 patients with 803 liver primary and secondary tumors undergoing laparoscopic RFA between January 1996 and August 2001, a total of 34 patients with 234 tumors had neuroendocrine liver metastases. There were 25 men and 9 women with a mean +/- SEM age of 52 +/- 2 years who underwent 42 ablations. Primary tumor types included carcinoid tumor in 18 patients, medullary thyroid cancer in 7, secreting islet cell tumor in 5, and nonsecreting islet cell tumor in 4. There was no mortality, and the morbidity was 5%. The mean hospital stay was 1.1 days. Symptoms were ameliorated in 95%, with significant or complete symptom control in 80% of the patients for a mean of 10+ months (range 6-24 months). All patients were followed for a mean +/- SEM of 1.6 +/- 0.2 years (range 1.0-5.4 years). During this period new liver lesions developed in 28% of patients, new extrahepatic disease in 25%, and local liver recurrence in 13%; existing liver lesions progressed in 13%. Overall 41% of patients showed no progression of their cancer. Nine patients (27%) died. Mean +/- SEM survivals after diagnosis of primary disease, detection of liver metastases, and performance of RFA were 5.5 +/- 0.8 years, 3.0 +/- 0.3 years, and 1.6 +/- 0.2 years, respectively. Sixty-five percent of the patients demonstrated a partial or significant decrease in their tumor markers during follow-up. In conclusion, RFA provides excellent local tumor control with overnight hospitalization and low morbidity in the treatment of liver metastases from neuroendocrine tumors. It is a useful modality in the management of these challenging group of patients.

Neuroendocrine liver metastases are associated with slow clinical progression, prolonged patient survival, and symptoms of hormone oversecretion. Although surgical resection is the gold standard of treatment, most of the patients are not candidates for resection, and the 5-year survival of patients with neuroendocrine liver metastases is 11% to 40%. Cryotherapy, percutaneous alcohol injection, and radiofrequency thermal ablation are among the alternative regional treatment options available for these patients. The current role of these treatment options for neuroendocrine liver tumors are discussed in this review. Cryosurgery is the classic technique for local tumor destruction, mostly performed with open surgery. There has been limited experience with percutaneous alcohol injection for neuroendocrine liver metastasis. Radiofrequency thermal ablation is a relatively new modality that can be performed percutaneously or laparoscopically, and encouraging results have been obtained with it for treatment of neuroendocrine liver metastases.

Most people would agree that successful parathyroidectomy depends on two important variables: the surgeon's recognition and excision of the abnormal parathyroid gland(s) and the pathologist's confirmation that the removed tissue is parathyroid tissue. Frozen section is usually employed to confirm the identity of parathyroid tissue, but occasionally confirmation cannot be made without a permanent section, as with intrathyroidal glands. This study proposes a new method of expeditious and easy confirmation of parathyroid tissue utilizing the immunoassay for quick measurement of intraoperative parathyroid hormone (IOPTH). By directly aspirating the suspected adenoma, the assay becomes a rapid diagnostic tool that can be used as an alternative to frozen section. In cases where the surgeon is already planning to employ the assay, the elimination of frozen section is cost-effective. Intraoperative aspiration of histologically confirmed parathyroid adenomas was performed on 12 consecutive patients undergoing parathyroid surgery. Parathyroid glands were aspirated with a 22-gauge syringe after gland excision. Aspirates were placed in 1 to 3 ml of buffered saline. A similar process was performed on 12 thyroid controls. Specimens were centrifuged, aliquotted, and stored at -70 degrees C. The parathyroid hormone value was analyzed electively by rapid assay and the values recorded. For all parathyroid aspirates, the rapid assay value was > 1500 pg/ml, exceeding the uppermost limit of the diagnostic chart. Values for thyroid aspirates ranged from 58 to 85 pg/ml (mean 75.7 pg/ml). In all cases tissue confirmation was achieved with permanent section. Values were 100% sensitive and specific. Measurement of PTH from intraoperative aspiration of suspected parathyroid adenomas is clinically useful in patients for whom frozen section would routinely be employed. Values > 1500 pg/ml secure the tissue diagnosis. There is no additional cost in cases where IOPTH monitoring is already being utilized to confirm cure. The elimination of frozen section could be cost-effective and, for some institutions, actually decrease the operating time as the IOPTH assay takes only 15 minutes. PTH assay is an accurate diagnostic technique and to date is 100% sensitive and specific for differentiating between parathyroid tumors and thyroid nodules.

Desensitization is defined as a decreased functional response after continuous or repetitive stimulation of a receptor with its agonist. Thyrotropin (TSH) increases cAMP levels in normal and neoplastic thyroid tissue. The tumor promoter 12-O-tetradecanoyl-phorbol-13-acetate (TPA) activates protein kinase C (PKC). The aim was to determine whether TPA induces heterologous desensitization of the TSH-adenylate cyclase (AC) signal transduction system. Three human thyroid neoplasms in culture for 6 months or longer (one papillary carcinoma, one Hurthle cell carcinoma, one follicular adenoma) were incubated with TSH (10 mU/ml) and TPA (1.6 x 10(-8) M) separately and together for various time periods (from 10 minutes to 24 hours). The mixture was subsequently incubated for 30 minutes with TSH. TPA alone had no effect on cAMP levels, but co-incubation of TPA and TSH caused a significant reduction in cAMP response when compared to the cAMP response that resulted after stimulation with only TSH (p < 0.001). cAMP levels in response to TSH decreased by 31%, 44%, and 57% after preincubation with TSH for 10 minutes, 4 hours, and 24 hours, respectively (p < 0.01; ANOVA). Co-incubation of cells with TPA and staurosporine (10 ng/ml), a PKC inhibitor, prevented the effect of TPA on desensitization at 10 minutes and blunted the effect at 4 hours. This is the first demonstration in human neoplastic thyroid cells that TPA induced heterologous desensitization of the cAMP response to TSH. This TPA-induced effect appears to involve PKC activation, as it can be blocked by staurosporine.

Two-hundred and fifty patients undergoing initial exploration for primary hyperparathyroidism were analyzed for differences in clinical presentation, biochemical status, pathology, and outcome of surgery. In patients less than 60 years of age (younger patients, n = 119) the most common preoperative symptoms and signs were fatigue (40.3%), bone pain (33.6%), renal stones (31.0%), hypertension (27.7%), and psychiatric illness (27.7%). In patients greater than or equal to 60 years of age (older patients, n = 131) the most frequent symptoms and signs were hypertension (46.6%), fatigue (35.1%), bone pain (30.5%), muscle weakness (28.2%), and joint pain (22.9%). Renal stones were 2.6 times more common (p less than 0.001, chi 2) in younger patients and hypertension 1.7 times more common (p less than 0.05, chi 2) in older patients. There was no significant difference in the preoperative and postoperative laboratory values typically associated with primary hyperparathyroidism. Double adenomas were more common in older (9.2%) than in younger patients (2.5%, p less than 0.05, chi 2). Surgical cure was obtained in 98.8% of patients, and after parathyroidectomy 83% of the younger and 82% of the older patients experienced substantial relief of pre-operative symptoms. Specific questioning revealed most patients to be symptomatic and older patients appear to receive the same clinical and metabolic benefits from parathyroidectomy as younger patients.

Thyroid stimulating hormone (TSH) and epidermal growth factor (EGF) are growth factors for some thyroid cells in cultures. We have previously found more EGF receptors in neoplastic human thyroid tissues than in normal thyroid tissues. We have also found a higher TSH-stimulated adenylate cyclase (AC) activity in neoplastic human thyroid tissues than in normal thyroid tissues. To clarify the relationship between the effect of EGF and TSH on thyroid tissue, we measured the binding of EGF and TSH and the basal, TSH-stimulated and forskolin-stimulated adenylate cyclase activity in 49 normal, hyperplastic and neoplastic human thyroid tissues (5 normal, 2 Hashimoto thyroiditis, 5 Graves' disease, 14 multinodular goiters, 9 follicular adenomas, 5 follicular carcinomas, 8 papillary carcinomas, and 1 undifferentiated carcinoma). Specific binding of EGF and TSH were measured by radioreceptor assays using competitive inhibition of radio-labeled ligand by unlabeled ligand. Basal, maximally (300 mU/ml) TSH-stimulated, and maximally (100 mM) forskolin-stimulated adenylate cyclase activities were also measured in the same membrane particulate fractions from the thyroid tissues. We found: neoplastic thyroid tissues bind more labeled EGF than nonneoplastic thyroid tissues; follicular adenomas and carcinomas have higher EGF binding than other thyroid tissues; a weak but significant correlation between specific EGF binding and specific TSH binding, and between specific EGF binding and TSH-stimulated adenylate cyclase activity of the thyroid membrane preparations. These findings are consistent with the hypothesis that TSH stimulates an increase in thyroid EGF receptors by increasing intracellular cAMP.(ABSTRACT TRUNCATED AT 250 WORDS)

Prior studies in our laboratory have shown that human thyroid neoplasms have a greater adenylate cyclase activity in response to thyroid stimulating hormone (TSH) than does the adjacent histologically normal thyroid tissue. However, there is little information relating activity of the TSH receptor-adenylate cyclase system to the type of thyroid neoplasm. Thyroid tissue from 67 patients was divided by clinical and histological criteria into 6 categories: normal (59), benign tumors (20), stage 1 carcinoma—intrathyroidal involvement only (25), stage 2 carcinomaregional lymph node involvement (6), stage 3 and 4 carcinoma—tissue invasion or distant metastasis (11), and medullary carcinoma (3). Adenylate cyclase activity in an 8,000 x g thyroid membrane preparation was determined in the basal state and when maximally stimulated with 300 mU/ml TSH. The cyclase responsiveness was the ratio of TSH stimulated adenylate cyclase activity compared to basal adenylate cyclase activity. The cyclase responsiveness by category is: normal, 2.8±0.2 (mean ± SEM); benign, 17.9±2.4; stage 1 carcinoma, 9.2±1.9; stage 2 carcinoma, 4.0±1.0; stage 3 and 4 carcinoma, 1.6±0.4; and medullary carcinoma, 1.05±0.04 (for the neoplasms,p

Papillary and follicular thyroid neoplasms have been documented to have thyrotropin (TSH) receptors and an intact receptor-adenylate cyclase (AC) system. The AC response to TSH in most benign and malignant thyroid neoplasms is greater in the neoplasms than in the adjacent normal thyroid tissue. This increased AC response could be due to abnormal amounts of guanyl nucleotide regulatory (G) proteins, to an altered ratio of stimulating to inhibiting G proteins, or to the coupling of the G proteins—to either the receptor or to the catalytic unit of AC. To study why tumors have a greater AC response to TSH, we first extracted the G proteins from normal and neoplastic human thyroid tissue and placed them in membranes from cyclase minus S49 mouse lymphoma cells that lack a stimulating guanyl nucleotide regulatory protein (Gs). These studies demonstrated that there were comparable amounts of guanyl nucleotide regulatory protein in normal and neoplastic thyroid tissue. We next investigated whether there was an alteration in the ratio of inhibiting (Gi) to stimulating (Gs) guanyl nucleotide regulating proteins in thyroid neoplasms. Pertussis toxin (PT) (10 μg/ml) was used to study the activity of the inhibiting G protein since it stimulates AC activity by inhibiting the inhibitory regulatory protein by adenosine diphosphate ribosylating the alpha subunit of the Gi protein. Cholera toxin (CT) (10 ng/ml) was used because it selectively activates the stimulating G proteins. AC activity was determined by the conversion of [α-32P]ATP to cAMP in pmol/mg protein per 30 minutes. In 11 patients, PT-stimulated AC levels [8.55±1.7 SEM, (mean±standard deviation)] in normal tissues were higher than basal levels of AC (5.14±0.9,p< 0.01). However, there were no differences in basal and PT-stimulated levels in neoplastic tissues (6.43±1.0 and 6.87 ±1.8, respectively). This suggests that there is less Gi protein in the neoplasms since the AC response to PT was greater in normal tissues by 170%, but there was no significant stimulation in neoplastic tissues. In contrast, the AC response to CT (10 μg/ml that directly activates the stimulatory guanyl nucleotide regulatory proteins was greater in neoplastic thyroid tissue (174.3±30.1) than in normal thyroid tissue (78.5±16.3) from the same patients (p