Somatic mutation of the MEN1 gene in parathyroid tumours.

Primary hyperparathyroidism is a common disorder with an annual incidence of approximately 0.5 in 1,000 (ref. 1). In more than 95% of cases, the disease is caused by sporadic parathyroid adenoma or sporadic hyperplasia. Some cases are caused by inherited syndromes, such as multiple endocrine neoplasia type 1 (MEN1; ref. 2). In most cases, the molecular basis of parathyroid neoplasia is unknown. Parathyroid adenomas are usually monoclonal, suggesting that one important step in tumour development is a mutation in a progenitor cell. Approximately 30% of sporadic parathyroid tumours show loss of heterozygosity (LOH) for polymorphic markers on 11q13, the site of the MEN1 tumour suppressor gene. This raises the question of whether such sporadic parathyroid tumours are caused by sequential inactivation of both alleles of the MEN1 gene. We recently cloned the MEN1 gene and identified MEN1 germline mutations in fourteen of fifteen kindreds with familial MEN1 (ref. 10). We have studied parathyroid tumours not associated with MEN1 to determine whether somatic mutations in the MEN1 gene are present. Among 33 tumours we found somatic MEN1 gene mutation in 7, while the corresponding MEN1 germline sequence was normal in each patient. All tumours with MEN1 gene mutation showed LOH on 11q13, making the tumour cells hemi- or homozygous for the mutant allele. Thus, somatic MEN1 gene mutation for the mutant allele. Thus, somatic MEN1 gene mutation contributes to tumorigenesis in a substantial number of parathyroid tumours not associated with the MEN1 syndrome.

Inferior petrosal sinus sampling in healthy subjects reveals a unilateral corticotropin-releasing hormone-induced arginine vasopressin release associated with ipsilateral adrenocorticotropin secretion.

Arginine vasopressin (AVP) acts synergistically with corticotropin-releasing hormone (CRH) to stimulate ACTH release from the anterior pituitary. In a previous study of bilateral simultaneous inferior petrosal sinus (IPS) sampling in healthy human subjects, we observed lateralized ACTH secretion, suggesting lateralized secretion of an ACTH-regulating hypothalamic factor. To investigate this possibility, we measured ACTH, CRH, AVP, and oxytocin (OT) levels in the IPS and the peripheral circulation in nine normal volunteers, before and after 1 microgram/kg i.v. bolus ovine CRH (oCRH). At baseline, ACTH, AVP, and OT exhibited a significant (P < 0.05) two to threefold intersinus gradient (ISG), indicating the existence of a dominant petrosal sinus. Endogenous CRH was undetectable in all samples. Despite similar exogenous oCRH levels in both petrosal sinuses, oCRH caused a significant increase (P < 0.001) in the ACTH ISG (15.8 +/- 5.6, mean +/- SEM), suggesting increased responsiveness of one dominant side of the anterior pituitary. This was associated with an ipsilateral CRH-induced AVP release and a significant increase (P < 0.01) in the AVP ISG (8.6 +/- 2.3), suggesting lateralized AVP secretion by the hypothalamus. Furthermore, the increased AVP ISG after oCRH correlated strongly with the ACTH ISG (r = 0.92, P < 0.01). oCRH administration did not affect OT. These findings suggest that there is a dominant petrosal sinus in healthy volunteers that appears to reflect a dominant side of the adenohypophysis, characterized by increased functional activity and/or responsiveness of the pituitary corticotrophs. This may reflect lateralized hypothalamic and/or suprahypothalamic function resulting in CRH-responsive lateralized secretion of AVP from parvocellular and/or magnocellular axons in the median eminence and the posterior pituitary. Although the functional and teleologic significance of these findings remains to be investigated, our data suggest a novel mechanism for CRH-mediated ACTH release, namely CRH-induced release of AVP which then enhances CRH action on the corticotrophs. Furthermore, our data represent the first direct evidence for the concept of brain lateralization with respect to neuroendocrine secretion.

Reduced systemic drug exposure by combining intraarterial cis-diamminedichloroplatinum(II) with hemodialysis of regional venous drainage.

During cancer chemotherapy toxicity to normal tissues often limits the tolerable dose. To increase drug delivery to tumor while maintaining tolerable systemic exposure, regional treatments, such as intraarterial drug delivery, have been used. Despite intraarterial delivery, systemic toxicity often remains the dose-limiting sensitivity. If systemic drug exposure could be reduced after intraarterial infusion, the intraarterial dose could be increased, which should increase the therapeutic response. We compared the pharmacokinetic advantage after cisplatin infusion into the internal carotid artery to that obtained after infusing cisplatin into the internal carotid artery during extracorporeal removal of cisplatin from the jugular blood by hemodialysis. Four patients with malignant gliomas received intracarotid cisplatin, 100 mg/m2 over 60 min, every 4 weeks. During one treatment, while cisplatin was infused into the internal carotid artery, the jugular blood was dialyzed extracorporeally at 300 ml/min and returned to the inferior vena cava. Seventy to 96% of the free platinum that entered the dialyzer was removed. By aspirating blood from the jugular vein at 300 ml/min, 30-79% of the ipsilateral carotid blood was collected for extracorporeal circulation. Hemodialysis of the cerebral venous drainage during intracarotid infusion reduced the systemic exposure to cisplatin by 51-61% when compared to the exposure from internal carotid artery infusion without hemodialysis. The pharmacokinetic advantage (brain/body exposure ratio) was increased from 3 to 5/1 during internal carotid artery infusion alone to as much as 15/1 during treatment combining intracarotid infusion with hemodialysis of the jugular blood. Systemic toxicity now limits the dose of cisplatin that can be administered safely. Increased tumor exposure without increased systemic toxicity may be possible with the technique described and greater doses of cisplatin. Assuming no associated local toxicities, the results of the current study indicate that the dose of intracarotid cisplatin can be increased while maintaining tolerable systemic exposure.

Growth of newly diagnosed, untreated metastatic gastrinomas and predictors of growth patterns.

PURPOSE: The growth pattern of untreated metastatic neuroendocrine tumors is unknown. This uncertainty contributes to the disagreement regarding timing and could effect evaluation of the efficacy of antitumor treatment. The purpose of this study was to determine the growth rate of untreated hepatic metastatic gastrinoma and to identify its predictors. PATIENTS AND METHODS: Nineteen patients with histologically proven metastatic gastrinoma in the liver with Zollinger-Ellison syndrome were studied. Conventional imaging studies were performed initially and at 4- to 6-month intervals before any treatment. Metastases growth rates were calculated and correlated with laboratory and clinical parameters, as well as tumor extent on initial tumor assessment. RESULTS: Twenty-six percent of patients (five of 19) demonstrated no growth over a mean follow-up time of 29 months, 32% (six of 19) had slow growth (1% to 50% increase in volume per month) over a 19-month period, and 42% (eight of 19) had rapid growth (> 50% volume increase per month) over an 11-month period. In patients with rapid growth, 62% died; 0% of the no-growth or slow-growth group died. No clinical or laboratory parameter correlated with growth rate, except the rate increase in fasting serum gastrin and the presence of bilobar liver or bone metastases. The growth rate was highly predictive of death from tumor. CONCLUSION: The growth rate of metastatic gastrinoma varies markedly in different patients and 26% demonstrate no growth. The growth rate needs to considered in the determination of when and in whom antitumor therapy is initiated, as well as in the assessment of response to tumoricidal therapies.

Bone metastases in patients with gastrinomas: a prospective study of bone scanning, somatostatin receptor scanning, and magnetic resonance image in their detection, frequency, location, and effect of their detection on management.

PURPOSE: To determine whether bone scan, magnetic resonance imaging (MRI), or somatostatin receptor scintigraphy (SRS) is best for identifying bone metastases in patients with gastrinomas, as well as their frequency and location, whether their detection affects management, and what patient subgroups should be examined. MATERIALS AND METHODS: One hundred fifteen patients with gastrinoma were prospectively studied. Patients were examined yearly and those with liver metastases were reexamined every 3 months. Based on clinical history, histology, growth pattern, and development of new bone lesions, possible bone metastases were classified as to whether they were or were not bone metastases. Imaging results were correlated at different times in the disease course and with disease extent. RESULTS: Bone scan was positive in 52 patients, MRI in seven, and SRS in six. Eight patients (7%) were determined to have bone metastases and MRI was correctly positive in seven, SRS in six, and bone scan in five. SRS or MRI was positive in all patients with bone metastases. Bone scan had significantly lower specificity and sensitivity, and a higher rate (P < .02) of false-negative results than MRI or SRS. Bone metastases occurred in 31% of patients with liver metastases and 0% with only lymph node metastases. The initial bone metastases were in the spine or sacrum (75%) followed in descending order by the pelvis or sacroiliac joints (38%), scapula or shoulder, and ribs. In all cases, detection of bone metastases changed the management. CONCLUSION: SRS and MRI, because of high sensitivity and specificity, are recommended over bone scanning to screen for bone metastases in patients with gastrinomas. However, because bone metastases can occur initially outside the axial skeleton, SRS is the recommended initial localization method of choice. Bone metastases occur in 7% of all patients and 31% of patients with liver metastases, only occur in patients with liver metastases, are usually in the axial skeleton initially, and their detection changes management in all cases. Patients with pancreatic endocrine tumors with liver metastases should undergo SRS every 6 months to 1 year to detect bone metastases.

Prospective study of the clinical course, prognostic factors, causes of death, and survival in patients with long-standing Zollinger-Ellison syndrome.

PURPOSE: The long-term clinical course of unselected patients with gastrinomas as well as other functional pancreatic endocrine tumors (PETs) in whom the excess-hormone state is controlled is largely unknown. To address this issue, patients with gastrinomas were assessed. PATIENTS AND METHODS: Two hundred twelve patients with Zollinger-Ellison syndrome (ZES) were prospectively studied. All had controlled acid hypersecretion and were assessed yearly, with a mean follow-up period of 13.8+/-0.6 years (range, 0.1 to 31 years). Annual assessments of possible factors that might affect prognosis or treatment approaches were performed, such as those for tumor size and location; the presence, location, and extent of metastases; and the occurrence of ectopic Cushing's syndrome or another PET syndrome. Deaths were categorized as ZES-related or non-ZES-related and classified into different causes. RESULTS: Thirty-one percent of patients died, all of non-acid-related causes. One half died of a ZES-related cause; they differed from those who died of non-ZES deaths by having a large primary tumor, more frequently a pancreatic tumor; lymph node, liver, or bone metastases; ectopic Cushing's syndrome; or higher gastrin levels. The extent of liver metastases correlated with survival rate. The presence of liver metastases alone only moderately decreased survival time; however, the additional development of bone metastases or ectopic Cushing's syndrome markedly decreased survival rate. CONCLUSIONS: In ZES, gastrinoma growth is now the main single determinant of long-term survival, with one half of patients dying a gastrinoma-related death and none an acid-related death. Large primary tumors that are pancreatic in location, the development of liver metastases, (especially if associated with bone metastases or Cushing's syndrome), and the extent of liver metastases are all important prognostic factors. The identification of these factors allows the recognition of subgroups that can be used to tailor antitumor treatment approaches.

Prognostic value of initial fasting serum gastrin levels in patients with Zollinger-Ellison syndrome.

PURPOSE: To assess the value of the initial fasting serum gastrin (FSG) at presentation in patients with Zollinger-Ellison Syndrome (ZES) in predicting primary tumor characteristics and survival. PATIENTS AND METHODS: A total of 239 patients were treated for ZES between December 1981 and September 1998, with a mean follow-up of 9.1 +/- 0.6 years. At initial evaluation, 86 patients (36%) had mild (0 to 499 pg/mL), 61 (25.5%) had moderate (500 to 1,000 pg/mL), and 92 (38.5%) had severe (> 1,000 pg/mL) elevations in FSG. Primary tumor location and size, presence of lymph node or hepatic metastases, and survival were analyzed based on the level of initial FSG. RESULTS: In patients with sporadic ZES, but not in those with multiple endocrine neoplasia type 1 (MEN-1) and ZES, there was a significant relationship between the level of initial FSG and tumor size and location of primary tumor, frequency of lymph node and liver metastases, and survival. The median 5- and 10-year survival decreased with increasing initial FSG (P <.001) in patients with sporadic ZES; MEN-1 patients lived longer than sporadic ZES patients (P =.012), and survival in this group was not associated with the level of initial FSG. Multivariate analysis showed that factors independently associated with death from disease in patients with sporadic ZES were liver metastases (P =.0001), a pancreatic site (P =.0027), and primary tumor size (P =.011) but not initial FSG (P >.30). CONCLUSION: The severity of FSG at presentation is associated with size and site of tumor and the presence of hepatic metastases, factors that are significant independent predictors of outcome. The level of FSG at presentation may be useful in planning the nature and extent of the initial evaluation and management in patients with sporadic ZES.

Do glucocorticoids cause spinal epidural lipomatosis? When endocrinology and spinal surgery meet.

Here, we report pathogenetic aspects of spinal epidural lipomatosis (SEL) based on a literature review. SEL is a rare entity but can cause significant morbidity. Its symptoms can be identical to those of more common disorders such as vertebral and disc disease, and cord lesions (for example, transverse myelitis, multiple sclerosis and syringomyelia). Therefore, it often goes undiagnosed. In addition, SEL occurs in patients on glucocorticoid therapy, which can lead to myopathy, thereby mimicking the motor symptoms of SEL. Glucocorticoids seem to play a major role in the development of SEL, although idiopathic SEL has also been reported. The latter occurs almost exclusively in obese individuals who may have concurrent hypercortisolism. Once clinically suspected, SEL is best diagnosed by magnetic resonance imaging (MRI). Treatment of SEL is directed at reducing body weight in patients with idiopathic SEL, and at decreasing glucocorticoid excess in patients with endogenous or exogenous hypercortisolism. In severe cases, decompressive laminectomy might become necessary to alleviate the neurological symptoms caused by spinal cord compression.

Localization of parathyroid tumors in patients with asymptomatic hyperparathyroidism and no previous surgery.

A number of recently published series were reviewed evaluating noninvasive localizing studies (ultrasound, thallium-technetium subtraction scintigraphy, computed tomography, and magnetic resonance imaging) in patients with primary hyperparathyroidism and no previous surgery. The average true positive (%) and false positive (%) rates were (1) ultrasound, 66 and 12; (2) Th/Tc scanning 55 and 13; (3) computed tomography, 63 and inadequately documented; (4) magnetic resonance imaging, 75 and 18. The success rate of initial operation in this group of patients is over 90%. There is no evidence that preoperative localizing studies shorten operating time or prevent surgical failures. For these reasons, noninvasive localization studies are not indicated in patients with primary hyperparathyroidism before initial surgery.

Absence of intercavernous venous mixing: evidence supporting lateralization of pituitary microadenomas by venous sampling.

Preoperative lateralization of endocrine-active pituitary tumors may be possible by bilateral inferior petrosal sinus (IPS) sampling for hormone measurement. The reliability of this technique depends on unilateral drainage of blood from the adenoma within the pituitary gland, in its course from the gland to the ipsilateral cavernous sinus, and from the cavernous sinus to the junction of the IPS and the internal jugular vein. Anatomical studies demonstrate unilateral drainage of each hemihypophysis into the ipsilateral cavernous sinus. The degree of mixing of blood between the cavernous sinuses, via the intercavernous sinus, and between the IPSs, via the basilar plexus, is unknown. We determined the extent of mixing of blood flowing from the superior orbital vein to the junction of the IPS and the internal jugular vein in four rhesus monkeys. After catheterization of a superior orbital vein and both IPSs, 99Tc-colloidal sulfur was infused into the superior orbital vein while blood samples were taken simultaneously from both IPSs and a peripheral vein at 3-min intervals. Mean relative radioactivity was 100 +/- 14% (+/- SEM) in the ipsilateral IPS, 8 +/- 2% in the contralateral IPS, and 3 +/- 1% in a peripheral vein. Isotope reaching the ipsilateral IPS before recirculation from the periphery was 10- to 313-fold more concentrated than in the contralateral IPS. These findings suggest that mixture of blood between the cavernous sinuses and between the IPSs is insignificant and support the capability of preoperative lateralization of pituitary microadenomas by bilateral and simultaneous IPS sampling.

Primary pigmented nodular adrenocortical disease: reevaluation of a patient with carney complex 27 years after unilateral adrenalectomy.

A 45-yr-old man with primary pigmented nodular adrenocortical disease (PPNAD) is described. This patient underwent unilateral adrenalectomy for ACTH-independent Cushing's syndrome (CS) in 1969. Although his daily urinary free cortisol (UFC) excretion rate normalized, and the major clinical manifestations of CS subsided, loss of a circadian cortisol rhythm persisted after surgery. Twenty-seven years later, the patient presented again with short stature, severe osteopenia, skeletal deformities, thinning of the skin, and myopathy.

Thyrotropin-secreting pituitary tumors: diagnostic criteria, thyroid hormone sensitivity, and treatment outcome in 25 patients followed at the National Institutes of Health.

We report a large series of 25 patients with TSH-secreting tumors (23 macroadenomas) followed at the NIH. Hyperthyroid symptoms were severe in 14 patients, mild in 8, and absent in 3. Patients were divided into 2 groups according to whether their thyroid had been treated (n = 11) or not (n = 14). In untreated patients, the classical diagnostic criteria (unresponsive TRH test, high alpha-subunit, and high alpha-subunit/TSH ratio) were present, respectively, in 10, 8, and 12 cases (sensitivity, 71%, 75%, and 83%; specificity, 96%, 90%, and 65%). In treated patients, the respective sensitivities of the TRH test, alpha-subunit, and alpha-subunit/TSH ratio were 64%, 90%, and 90%, and their specificities were 100%, 82%, and 73%. Studies of thyroid hormone action revealed no evidence of acquired resistance to thyroid hormone in TSH-secreting tumors. Apparent cure was achieved in 35% of cases by surgery alone and in 22% more by combined therapies. Three deaths occurred, including 1 from metastatic thyrotroph carcinoma. Six patients had residual tumor, with symptoms of hyperthyroidism controlled with octreotide in 5. The size and invasiveness of the tumor, duration of symptoms, and intensity of hyperthyroidism were the main prognostic factors. Thus, early diagnosis and treatment are the keys to a good outcome.

The hypoplastic inferior petrosal sinus: a potential source of false-negative results in petrosal sampling for Cushing's disease.

Our purpose was to describe the hypoplastic or plexiform inferior petrosal sinus as a potential cause of false-negative sampling results in patients with Cushing's disease. Five hundred and one patients with surgically proven Cushing's disease and negative or equivocal magnetic resonance imaging scans of the pituitary gland underwent petrosal sinus sampling. Four patients (0.8%) with surgically proven Cushing's disease had false-negative results of petrosal sinus sampling. Retrograde inferior petrosal sinograms in these patients were reviewed to evaluate the anatomy of the inferior petrosal sinuses for abnormalities that could have contributed to this misdiagnosis. In addition, the retrograde inferior petrosal sinograms of 100 consecutive patients were reviewed to establish the frequency of asymmetric and/or hypoplastic inferior petrosal sinuses. All four patients with false-negative results of petrosal sampling demonstrated a hypoplastic or plexiform inferior petrosal sinus ipsilateral to an ACTH-secreting microadenoma. When the sampling catheter was in the hypoplastic petrosal sinus, retrograde sinograms from the contralateral side demonstrated anomalous drainage patterns on the side of the hypoplastic sinus. Because the negative results of petrosal sinus sampling false-suggested the presence of the ectopic ACTH syndrome, curative transsphenoidal surgery in these four patients was delayed up to 31 months. We conclude that the presence of a unilateral hypoplastic or plexiform inferior petrosal sinus can result in anomalous drainage from the pituitary gland that may lead to false-negative sampling results in patients with Cushing's disease.

A "pheo" lurks: novel approaches for locating occult pheochromocytoma.

Most, but not all, pheochromocytomas can be localized by computed tomography or magnetic resonance imaging. Here we introduce two novel approaches for localization of pheochromocytoma in a patient in whom conventional imaging modalities failed to show the tumor. First, we establish that measurements of plasma free metanephrines coupled with vena caval sampling are useful for localizing occult pheochromocytoma, particularly when elevations in plasma catecholamines are slight or intermittent. Second, we show that positron emission tomographic scanning using the imaging agent 6-[18F]fluorodopamine as a substrate for the norepinephrine transporter offers a highly effective method for tumor localization. These novel approaches may be of value in difficult cases, where biochemical and clinical evidence of pheochromocytoma is compelling, yet conventional imaging modalities fail to locate the tumor.

MRI-demonstrable regression of a pituitary mass in a case of primary hypothyroidism after a week of acute thyroid hormone therapy.

Although magnetic resonance imaging (MRI) characteristics of pituitary gland hyperplasia in primary hypothyroidism have been previously described, the time span necessary for the regression of the hyperplasia in response to acute thyroid hormone (TH) therapy has not been defined. A 26-yr-old woman underwent 131I ablation 11 yr before admission. Intermittent poor compliance to levothyroxine (LT4) therapy led to inappropriately high serum thyroid-stimulating hormone (TSH) for her triiodothyronine (T3) and thyroxine (T4) levels. The patient was investigated to rule out TSH-secreting pituitary adenoma or resistance to TH. On admission, the patient's clinical features and thyroid function tests, as well as thyrotropin-releasing hormone (TRH) and acute T3 suppression tests, were in favor of profound primary hypothyroidism. MRI revealed symmetrical enlargement of the pituitary gland with distinct morphological characteristics of a macroadenoma. The patient began high-dose TH therapy and was rescanned six days later. The follow-up scan revealed a dramatic shrinkage of the pituitary gland. Four weeks later, serum T4 and TSH were within the normal range, and repeat MRI scan of the pituitary at that time showed a normal gland. This case is the first to document dramatic shrinkage of pituitary hyperplasia in long-standing primary hypothyroidism within one week of acute TH therapy. MRI alone is unable to reliably differentiate between a TSH-secreting pituitary adenoma and hypothyroidism-induced pituitary hyperplasia. Dynamic endocrine testing as well as repeat pituitary MRI after a brief TH trial may provide a firm diagnosis in similar cases.

Predictive value of preoperative tests in discriminating bilateral adrenal hyperplasia from an aldosterone-producing adrenal adenoma.

In primary hyperaldosteronism, discriminating bilateral adrenal hyperplasia (BAH) from an aldosterone-producing adenoma (APA) is important because adrenalectomy, which is usually curative in APA, is seldom effective in BAH. We analyzed the results from our most recent 7-yr series to evaluate the predictive value of preoperative noninvasive tests compared with adrenal vein sampling (AVS). Forty-eight patients with hypertensive hyperaldosteronism underwent bedside testing, computed tomography (CT) imaging, and AVS. Those in whom the results of AVS indicated APA underwent adrenalectomy. Twelve (30%) and 14 (34%) of 41 patients with APA had paradoxical falls with ambulation in plasma aldosterone concentration (PAC) and 18-hydroxycorticosterone (18-OH-B), respectively. Twenty-nine (70%) and 26 (65%) APA patients had a rise in PAC and 18-OH-B, respectively, as did all 8 BAH patients. Significant identifiers of BAH were supine PAC values less than 15 ng/dL (P: = 0.04), an increase greater than 60% (P: = 0.02) in PAC with ambulation, and supine 18-OH-B values less than 60 ng/dL (P: = 0.04). CT imaging alone was not predictive for BAH or APA. In our population, patients with a positive bedside test result (e.g. a fall in PAC and/or 18-OH-B) and a unilateral adrenal nodule on CT (10 of 41 patients) could have proceeded directly to adrenalectomy for APA. However, a positive bedside test result with a negative CT or a negative bedside test result regardless of CT findings required AVS to confirm the diagnosis and site of disease.

The limited ability of inferior petrosal sinus sampling with corticotropin-releasing hormone to distinguish Cushing's disease from pseudo-Cushing states or normal physiology.

To determine whether petrosal sinus sampling is useful to distinguish patients with mild or intermittent Cushing's disease from normal subjects and individuals with pseudo-Cushing states, we performed bilateral inferior petrosal sinus sampling for ACTH before and after the administration of CRH in 7 eucortisolemic volunteers, 8 hypercortisolemic patients with pseudo-Cushing states, and 40 patients with ACTH-dependent Cushing's disease whose urinary free cortisol excretion was within the range found in patients with, pseudo-Cushing states (< 1000 nmol/day; < 360 micrograms/day). The ACTH level, the ratio of the inferior petrosal sinus ACTH to the peripheral venous ACTH concentration (the IPS:P ratio), and the greater ratio of right to left or left to right petrosal sinuses (the R:L ratio) were compared in patients with and without Cushing's disease. Maximal petrosal ACTH values were significantly elevated in patients with Cushing's disease compared to patients with pseudo-Cushing states before CRH administration (P < 0.001), but not after CRH. Maximal petrosal plasma ACTH values after the administration of CRH as high as 808 pmol/L (3670 pg/mL) and 469 pmol/L (2130 pg/mL) were found in patients with pseudo-Cushing states and in normal volunteers, respectively, whereas maximal petrosal ACTH levels as low as 10 pmol/L (46 pg/mL) were observed in patients with surgically proven Cushing's disease. Maximal and minimal IPS:P ratios were significantly greater in patients with Cushing's disease than in subjects without Cushing's disease before, but not after, CRH treatment. R:L ratios did not differ among groups either before or after CRH. All of the subjects without Cushing's disease showed large R:L gradients, consistent with the notion of one dominant petrosal sinus containing a greater percentage of pituitary effluent. The ACTH concentrations, IPS:P ratios, and R:L ratios exhibited great overlap between those with and without Cushing's disease, which resulted in a diagnostic accuracy of 81% at best for the diagnosis of Cushing's disease. We conclude that petrosal sinus sampling is of limited usefulness in distinguishing either normal individuals or patients with pseudo-Cushing states from those with mild Cushing's disease. This limited usefulness must be recognized when interpreting the results of petrosal sinus sampling in patients with mild or intermittent hypercortisolism who may have a pseudo-Cushing state. Because of these limitations, petrosal sinus sampling should be reserved for patients with clear clinical and biochemical evidence of Cushing's syndrome.

Selective venous sampling from the cavernous sinuses is not a more reliable technique than sampling from the inferior petrosal sinuses in Cushing's syndrome.

The purpose of this study was to compare ACTH levels in unstimulated samples obtained from the cavernous sinuses (CS) to unstimulated and CRH-stimulated samples obtained from the inferior petrosal sinuses (IPS) in 15 patients with surgically proven Cushing's disease. After unstimulated samples were obtained through 5-French catheters placed in both IPS, tracker catheters were introduced into both cavernous sinuses, and unstimulated samples were obtained within 5 min of the initial set. The Tracker catheters were removed, CRH was administered, and CRH-stimulated samples were obtained from the IPS. We compared the central to peripheral ACTH ratios in unstimulated samples from the cavernous sinuses to unstimulated and CRH-stimulated samples from the IPS as a basis for distinguishing pituitary from ectopic ACTH production. In addition, we compared the ability of the intercavernous and interpetrosal ACTH ratios to correctly predict the site of the microadenoma. Unstimulated levels of ACTH in the cavernous sinuses were generally higher than unstimulated levels of ACTH in the petrosal sinuses. However, 3 of 15 patients failed to show central to peripheral ACTH ratios greater than 2 in unstimulated samples from the cavernous sinuses and were thus falsely negative for the diagnosis of Cushing's disease (test sensitivity, 80%). By comparison, the test sensitivity for the petrosal sinus samples was 87% for the unstimulated samples and 100% for the CRH-stimulated samples. Lateralization was correct in 6 of 15 patients based on CS samples and in 9 of 15 patients based on IPS samples. Because of the 20% false negative rate, CS sampling without CRH stimulation is not recommended for the differential diagnosis of ACTH-dependent hypercortisolism.

Failure of bronchial lavage to detect elevated levels of adrenocorticotropin (ACTH) in patients with ACTH-producing bronchial carcinoids.

Saline lavage of the major bronchial segments was performed in five patients immediately preceding lobectomy to remove an ACTH-producing bronchial carcinoid. Lavage fluid from each bronchus was concentrated, and ACTH determinations were performed. Elevated concentrations of ACTH were not demonstrated in the aspirate from the bronchus containing the known tumor. Two additional patients with ectopic ACTH syndrome from an unknown primary source also underwent selective segmental bronchial lavage for ACTH determination. Neither patient demonstrated ACTH gradients in the lavage specimens. One was found to have an ACTH-producing bronchial carcinoid 18 months after negative lavage. Selective segmental bronchoscopic lavage with measurement of ACTH levels on the aspirate is not an effective technique for detecting ACTH-producing bronchial carcinoid tumor.

Thyroid gland abnormalities in patients with the syndrome of spotty skin pigmentation, myxomas, endocrine overactivity, and schwannomas (Carney complex)

Carney complex is a multiple neoplasia and lentiginosis syndrome that affects endocrine glands, including the pituitary, adrenals, and testes; thyroid gland involvement has not been unequivocally demonstrated. In the present study, the medical records of 12 families with Carney complex (53 affected patients) were reviewed for evidence of thyroid abnormality; 2 patients with thyroid carcinoma (1 papillary and 1 follicular; 3.8%) and 1 with follicular adenoma were identified in 3 unrelated kindreds. Six affected members of these kindreds were then screened for the presence of thyroid disease (familial cases). We also studied 5 patients with the complex who had no affected relatives (sporadic cases). These 11 patients consisted of 5 adults [mean age, 33.2 +/- 9.2 (+/- SD) yr] and 6 children and adolescents (mean age, 13.8 +/- 2.5 yr). All had normal results of physical and biochemical examination of the thyroid gland (total and free T4, T3, and TSH levels). Thyroid ultrasonography showed hypoechoic, cystic, solid, or mixed lesions in 3 of the 5 adults (60%) and 4 of the 6 children (67%). Two patients underwent fine needle aspiration biopsy, which identified follicular lesions. Thyroid gland abnormalities were documented in 5 siblings and 1 parent-child pair. We conclude that thyroid gland pathology is 1) common in patients with Carney complex; 2) includes a spectrum of abnormalities ranging from follicular hyperplasia and/or cystic changes to carcinoma; and 3) is inherited in an autosomal dominant manner, like the other manifestations of the syndrome, it is therefore, a candidate component of the syndrome. Ultrasonography is useful in the detection and clinical follow-up of these lesions.