Recurrent Cushing's disease after transsphenoidal surgery.

Thirty-four patients with proven Cushing's disease underwent transsphenoidal surgery between January 1976 and August 1988. Postoperatively, all the patients had biochemically proven remission. Seven patients who had recurrence of their disease (incidence, 20.6%) were evaluated clinically and biochemically and the results are presented. All of seven patients had surgically and pathologically proven pituitary adenomas. All of seven patients had postoperative adrenal insufficiency necessitating steroid replacement for a mean of 8 months. The time of recurrence varied widely and ranged from 29 to 62 months, with a mean of 40 months. We conclude that (1) the longer the period of follow-up, the higher the incidence of recurrence; (2) although the recurrence rate is low (20.6%), it is certainly appreciable; and (3) the time of recurrence can be delayed (62 months) and thus we recommend yearly follow-up with urinary free cortisol determinations.

Successful combination chemotherapy for metastatic parathyroid carcinoma.

A 54-year-old patient with metastatic parathyroid carcinoma and severe hypercalcemia refractory to conventional treatment was treated with chemotherapy consisting of fluorouracil, 500 mg/sq m intravenously (IV) daily for four days (24-hour infusion), cyclophosphamide, 500 mg/sq m IV daily for four days, and dacarbazine (imidazole carboxamide), 200 mg/sq m IV daily for four days. Complete objective and partial biochemical responses were noted, with the response duration being 5.0 + months. The toxic reaction was moderate and predominantly gastrointestinal.

Familial adrenocorticotropin-independent Cushing's syndrome with bilateral macronodular adrenal hyperplasia.

Familial Cushing's syndrome is rare, and when it occurs, it is usually associated with primary micronodular dysplasia. We report two cases, a mother and daughter, who each presented with clinical features of Cushing's syndrome at age 38 yr and were found to have ACTH-independent macronodular adrenal hyperplasia. In each case, bilateral adrenalectomy revealed the massively thickened adrenal cortex with nodules up to 1.3 cm in diameter and hyperplasia between nodules. Dynamic testing showed no suppression of free cortisol with high dose dexamethasone and no stimulation of 17-hydroxycorticosteroids with metyrapone. Two samples of serum obtained preoperatively from one patient that showed ACTH immunoreactivity of 4.6 and less than 2.2 pmol/L, respectively, each showed less than 2.2 pmol/L ACTH bioactivity. The lack of suppression with high dose dexamethasone, lack of stimulation with metyrapone, and low levels of ACTH immunoreactivity and bioactivity suggest that the bilateral hyperplasia was not dependent upon ACTH. These patients represent the first cases of ACTH-independent macronodular adrenal hyperplasia occurring in two generations of one family and illustrate the expanding clinical spectrum of Cushing's syndrome.

Octreotide as primary therapy for acromegaly.

The effects of octreotide (up to 5 yr) as primary treatment in 26 patients with acromegaly were compared with those in 81 patients with acromegaly who received octreotide as secondary or adjunctive therapy after previous surgery and/or pituitary radiation. These patients were part of a multicenter study that took place between 1989-1995. The study was divided into 3 phases beginning with a 1-month placebo-controlled treatment period followed by a 1-month washout period. In the second phase, patients were randomized to treatment with either 100 or 250 micrograms octreotide, sc, every 8 h for 6 months. Octreotide was then discontinued for 1 month and reinitiated at the lower dose for a total mean treatment duration of 39 months. The dose was titrated by each investigator to improve each patient's individual response, which included improvement in symptoms and signs of acromegaly as well as reduction of GH and insulin-like growth factor I (IGF-I) into the normal range. In the second phase of the study, in which patients were randomized to either 100 or 250 micrograms octreotide, three times daily, mean integrated GH and IGF-I concentrations after 3 and 6 months were equivalent in the primary and secondary treatment groups. During long term open label treatment, mean GH fell from 32.7 +/- 5.2 to 6.0 +/- 1.7 micrograms/L 2 h after octreotide injection in the primary therapy group and remained suppressed for a mean period of 24 months (range, 3-60 months). The mean final daily dose was 777 micrograms. In the patients receiving secondary treatment, mean GH fell from 30.2 +/- 7.6 to 5.6 +/- 1.1 micrograms/L after 3 months and remained suppressed for the remainder of the study (average dose, 635 micrograms daily). Mean IGF-I concentrations fell from 5.2 +/- 0.5 x 10(3) U/L (primary treatment group) and 4.7 +/- 0.4 x 10(3) U/L (secondary treatment group) to a mean of 2.2 +/- 0.3 x 10(3) U/L in both groups after 3 months of open label treatment and remained suppressed. IGF-I was reduced into the normal range during at least half of the study visits in 68% of the primary treatment group and in 62% of the secondary treatment group. Patients whose GH levels fell to at least 2 SD below the baseline mean GH were considered responders. There was no significant difference in the percentage of responders in the primary and secondary treatment groups (70% vs. 61%), nor was there a statistical difference in the mean GH concentrations between the groups. Symptoms of headache, increased perspiration, fatigue, and joint pain were reported at baseline by 46%, 73%, 69%, and 85%, respectively, of patients in the primary therapy group and improved during 3 yr of octreotide treatment in 50-100%. Similarly, these acromegaly-related symptoms were reported by 62%, 58%, 78%, and 60% of patients in the secondary therapy group, and improvement was noted in 62-88%. Pituitary magnetic resonance imaging scans were available in 13 of 26 patients in the primary treatment group before and after 6 months of octreotide treatment. Tumor shrinkage was observed in 6 of 13 patients, with reduction in tumor volume greater than 25% in only 3. Of 6 patients with documented tumor shrinkage, IGF-I was reduced into the normal range in 4 patients. Of the 7 remaining patients in whom tumor shrinkage was less than 10%, IGF-I was reduced into the normal range in 4 patients. Of the 7 remaining patients in whom tumor shrinkage was less than 10%, IGF-I was reduced into the normal range in 5 patients. The degree of tumor shrinkage did not correlate with the percent reduction in IGF-I or GH. In summary, octreotide was equally effective in 26 previously untreated acromegalic patients (primary treatment group) and 81 patients previously treated with either surgery or pituitary radiation (secondary treatment group). These observations call into question the current practice of surgical resection of all newly diagnosed GH-secreting pituitary adenomas regardless of the likelihood of cure. (AB

Erdheim-Chester disease. Case report and review of the literature.

Erdheim-Chester disease is a distinctive pathologic and radiographic entity characterized by bilateral, symmetric sclerosis of the metaphyseal regions of long bones and infiltration of foamy, lipid-laden histiocytes. Clinically, it ranges from an asymptomatic, focal process to a fatal, systemic disease. All previously reported cases of Erdheim-Chester disease are reviewed and a new case with diabetes insipidus, partial hypopituitarism, histiocytic skin lesions, and retro-orbital tumors is presented. An 11-year follow-up reveals progression from a benign, limited process to a progressive, systemic disease. Patients with Erdheim-Chester disease show markedly disparate clinical courses and some features similar to Hand-Schüller-Christian disease. They need careful monitoring and further attempts at treatment.

Immunologic studies in two patients with persistent lymphocytic thyroiditis, thyrotoxicosis, and low radioactive iodine uptake.

Two patients with persistent lymphocytic thyroiditis and thyrotoxicosis were studied. Both patients presented with severe hyperthyroidism of nine months' duration and had nontender, small thyroid glands. Uptake of radioactive iodine (131I) was consistently low. Serum thyroxine and triiodothyronine levels remained elevated without remission until thyroidectomy. The serum thyroglobulin level was normal, but testing for microsomal antibody gave weakly positive results in one case. Thyroglobulin and thyroid stimulatory antibodies were not found. The ratio of helper to suppressor T cells was elevated in one case. Neither patient showed response to propranolol, prednisone, or iodine. Light microscopic and immunohistologic studies showed severe lymphocytic thyroiditis with formation of secondary lymphoid follicles. Lymphocytes were predominately T cells (OKT11-positive), primarily helper/inducer T cells (OKT4-positive). Hyperplastic nodules contained high immunoreactive thyroglobulin and thyroxine levels. Aberrant thymus was seen within the thyroid. These studies suggest the possibility of intrathyroidal stimulation and hydrolysis of thyroglobulin within thyroid cells and also support the hypothesis that T and B cell immunoregulatory defects are important in the pathogenesis of this disease.

Adrenal carcinosarcoma presenting in a woman with clinical signs of virilization. A case report with immunohistochemical and ultrastructural findings.

An adrenal carcinosarcoma is reported in a 29-year-old female presenting with clinical signs of virilization. This is the first reported case of a functioning adrenal carcinosarcoma in the English language literature. The tumor measured 12.5 cm in greatest dimension, weighed 610 g, and consisted of large areas of typical adrenal cortical carcinoma that was, however, interspersed with multiple foci of sarcoma. Rhabdomyosarcomatous elements were identified and confirmed both immunohistochemically and ultrastructurally. After radical resection, the patient received adjuvant mitotane therapy but developed rapid local and metastatic recurrence. Systemic chemotherapy was unsuccessful, and the patient died 8 months after surgery.

Cushing's syndrome and pregnancy.

Women with active Cushing's syndrome rarely conceive. Only about 69 pregnancies have been reported in women with Cushing's syndrome, 60 of whom had maternal and fetal complications. Fourteen of the women have had therapy with unilateral adrenalectomy, bilateral adrenalectomy, pituitary surgery with selective adrenomectomy, or pituitary radiation.

Pleural effusion resulting from metastatic papillary carcinoma of the thyroid.

We present a patient with a symptomatic pleural effusion resulting from papillary carcinoma of the thyroid metastatic to the pleura. Distinctive features include clinically evident pleural metastasis and the presence of psammoma bodies in the pleural fluid, which are characteristic (albeit not pathognomonic) of papillary carcinoma of the thyroid.

Hyperparathyroidism after radioactive iodine therapy for Graves disease.

The association of external ionizing radiation to the head and neck and the subsequent development of hyperfunctioning parathyroid glands has been documented in recent years. This also has been demonstrated experimentally in animals. Despite the numbers of patients with Graves disease who have been treated with radioactive iodine, there are no reports in the literature of parathyroid surgery for hyperparathyroidism secondary to earlier treatment with radioactive iodine for Graves disease. This report describes the operative and pathologic findings in four patients with hyperparathyroidism. These patients had previously been treated with radioactive iodine for Graves disease. The pathologic findings at surgery included in three cases a single enlarged hyperplastic gland consistent with a parathyroid adenoma. One patient had hyperplasia of all four glands. The two largest glands and halves of the two remaining glands were removed. In a long-term follow-up of children and adolescents treated with radioactive iodine for Graves disease, Levy and Schumacher found calcium elevations in 10 of 159 patients. The increased incidence of hyperparathyroidism following radioactive iodine treatment for Graves disease in children and adolescents would seem several times higher than normal. Whether adults who have radioactive iodine treatment for Graves disease have a similar increase incidence is not known. Meanwhile it would seem reasonable to suggest that patients whose hyperthyroidism is treated with radioactive iodine should have their serum calcium levels determined at 5-year intervals.

Pituitary apoplexy: a complication of cardiac surgery.

Pituitary apoplexy occurred in 3 patients in the immediate postoperative period following cardiac operation with cardiopulmonary bypass. In this setting, this complication is extremely rare and not widely recognized. Precipitating factors may be related to the extracorporeal bypass apparatus, anticoagulation, low cerebral blood flow, and even anesthetic agents. Neurosurgical decompression can be safely performed in the early postoperative period following open-heart operations.

The natural history of untreated microprolactinomas.

The development of radioimmunoassay (RIA) for prolactin (PRL) and sensitive high-resolution computed tomography (HRCT) has resulted in documentation of large numbers of microprolactinomas (microPRL). To try to define the rate and prevalence of tumor growth, the authors performed serial HRCT scans in 38 untreated patients, an average of 31.7 months apart. In no patient, including two patients with exuberant rises in PRL, was there any evidence of subtle tumor growth. The authors conclude that the majority of patients with microPRL have a benign course, with tumor growth occurring, if at all, over a period of years.

Cushing's syndrome.

Cushing's syndrome remains one of the great diagnostic challenges to internists and endocrinologists. Urologists have the primary role in the treatment of many of the forms of Cushing's syndrome, especially adrenal tumors and micronodular hyperplasia. As we continue to gain experience with Cushing's disease treated with pituitary surgery and with etopic ACTH syndrome and the other forms of Cushing's syndrome, urologists are likely to become even more involved in the therapy of all types of Cushing's syndrome.

Pituitary enlargement and primary hypothyroidism: a report of two cases with sharply contrasting outcomes.

Primary hypothyroidism may be associated with pituitary enlargement. Two cases of pituitary enlargement with suprasellar extension associated with primary hypothyroidism are presented. In one patient, prompt regression of the pituitary enlargement occurred with replacement doses of L-thyroxine. In the second patient, there was progressive enlargement of the pituitary gland while the patient was on L-thyroxine therapy with documented normalization of serum levels of thyroid-stimulating hormone. We recommend repeat evaluation of all patients with pituitary enlargement that is thought to be secondary to primary hypothyroidism to document regression of pituitary size after L-thyroxine therapy.

Effect of 131 iodine therapy on the course of Graves' ophthalmopathy: a quantitative analysis of extraocular muscle volumes using orbital magnetic resonance imaging.

There remains uncertainty as to the effect of radioactive iodine (131I) therapy on the associated ophthalmopathy (GO). Twenty newly diagnosed patients with Graves' hyperthyroidism treated with 131I (median dose, 15.5 mCi) were followed with ophthalmologic evaluations (OE) and magnetic resonance imaging (MRI) at baseline, 2, and 6 months, and with OE alone at 3 years. For MRI, the superior, inferior, and medial rectus muscle volumes and total muscle volumes (TMV) were measured. Replacement levothyroxine was initiated as low thyroxine (T4) levels were noted. At baseline, 10 patients (50%) showed evidence of mild GO by OE and/or MRI. There was a significant difference in TMV between the 20 patients with Graves' hyperthyroidism and 10 controls (mean +/- standard error [SE]; 2,652 +/- 118 vs. 2,046 +/- 96 mm3; P = 0.002) and between the 10 patients with and 10 without GO (3,006 +/- 96 vs. 2,298 +/- 61 mm3; P = 0.001). TMV correlated with the Hertel score (r = 0.56, P = 0.01). TMV showed no significant change at 2 or 6 months posttreatment. The inferior rectus volume increased slightly at 2 months posttreatment (P = 0.03) but remained stable at 6 months. Furthermore, no significant changes occurred in Hertel scores or in clinical assessments up to 3 years posttreatment and none showed worsening or new development of GO. In conclusion, our results show no significant risk for radioiodine-induced initiation or progression of mild GO.

A carotid body and glomus jugulare paraganglioma secreting norepinephrine.

Extra-adrenal paragangliomas (PGOMAs) are rare and can occur anywhere along the sympathetic chain including the carotid body, glomus jugulare, vagal bodies, ganglium tympanicum, larynx, ciliary bodies, organs of Zuckerkandl, urinary bladder, and other locations. These are microscopically identical. The embryological origin is from neural crest cells. One to three percent are reported to be functioning, predominantly secreting norepinephrine. Diagnosis of a functioning PGOMA can be delayed, even when symptoms of catecholamine hypersecretion are present. Furthermore, diagnostic testing and surgery have a significant morbidity if the diagnosis is not considered in advance, as illustrated by the following cases. PGOMAs can be sporadic or familial with an autosomal dominant pattern with variable penetrance. They can be multicentric and associated with other endocrine gland tumors. Benign and malignant PGOMAs have been described, with malignancy being defined by lymph node metastasis. Few cases of functioning glomus jugulare and carotid body tumors have been reported in the medical literature.

Clinical significance of the association of the Von Hippel-Lindau disease with pheochromocytoma and pancreatic apudoma.

Von Hippel-Lindau disease (VHLD) is a rare disorder known to occur with pheochromocytoma. We report a case with this association and also with pancreatic apudoma. We believe that this is the fifth reported case of this triad, which represents an overlap in the multiple endocrine neoplasia (MEN) classification. Many recent reports of overlap of MEN syndromes challenge the validity of this classification. New understanding of the embryologic origin of cells of endocrine organs has led to the elucidation of the APUD (amine precursor uptake and decarboxylation)-neuroendocrine system. Integration of the APUD system may be important to understanding the pathogenesis of the MEN-like syndromes as well as their relationship to the neurocutaneous syndromes. Any endocrine tumor or neurocutaneous syndrome should be evaluated to exclude a spectrum of possible associations.