Primary pigmented nodular adrenocortical disease: diagnosis and management

A rare cause of Cushing's syndrome appearing to originate in the adrenal glands is primary pigmented nodular adrenocortical disease (PPNAD). It may be variably associated with a complex of other pathologic characteristics that include cardiac myxomas, cutaneous myxomas, and lentigines, mammary myxoid lesions, testicular tumors, pituitary adenomas, and neuroectodermal tumors. We have reviewed the clinical, biochemical, radiographic, operative, and pathologic details of seven patients with PPNAD who have been evaluated at Mayo Clinic. Biochemical testing supported autonomous adrenal hyperfunction. This was based on the failure of cortisol suppression by high-dose dexamethasone, failure of pituitary stimulation by metyrapone administration, either normal or suppressed basal adrenocorticotropic hormone (ACTH) levels, normal radiographic studies of the sella turcica, and normal abdominal and thoracic computerized tomography in search of an ectopic ACTH-producing tumor. Six patients underwent bilateral total adrenalectomy without postoperative complications. Nelson's syndrome has not occurred, but acute adrenocortical insufficiency may have contributed to the death of one patient. To recognize the possible diagnosis of PPNAD preoperatively is important to proceed directly with adrenalectomy, avoiding unnecessary pituitary surgery. Moreover, if PPNAD is part of the broader pathologic complex, the possible presence of cardiac myxomas that may be multiple, recurrent, in atypical locations, and familial must be borne in mind.     

Multiple recurrence of cardiac myxoma in a Carney complex patient 4 years after the first operation

Carney complex is a rare syndrome which includes cardiac myxoma, hyperactive endocrine neoplasm, spotty pigmented skin, and extracardiac myxomatous tumors. We report a case of a 26-year-old woman with Carney complex in whom recurrent multiple cardiac myxomas were resected 4 years after the first operation for left atrial (LA) myxoma. She had a history of left adrenalectomy in 1997 for Cushing syndrome due to primary pigmented nodular adrenocortical disease (PPNAD). In February 2001, she was diagnosed with Carney complex because of evidence of LA myxoma, her spotty pigmented skin lesions, her past history and family history of cardiac myxoma in her mother. Then, LA myxoma was successfully resected through the superior trans-septal approach and has been followed-up by ultrasound cardiography (UCG) every 6-month after discharge.In January 2005, UCG revealed 2 masses in the LA and the right ventricle outflow tract. The 2nd surgery was performed in February 2005. We found the 3rd myxoma during surgery, resembling a flat polyp in the LA just at the inflow of the right upper pulmonary vein. All 3 myxomas were successfully resected. Sixteen months after the 2nd operation, she has been doing well without any sign of recurrence of myxoma.     

The significance of multiple, recurrent, and "complex" cardiac myxomas

We reviewed the Mayo Clinic records of 56 patients who underwent operation for cardiac myxoma and 29 cases in which cardiac myxoma was found at autopsy. Five patients had a "complex" of unusual findings including multiple pigmented skin lesions (lentiginosis), myxoid fibroadenomas of the breast, skin myxomas, and primary pigmented nodular adrenocortical disease (a cause of Cushing's syndrome). Four of these five patients had multiple cardiac myxomas. Three of the four patients who underwent surgical excision of the cardiac myxomas had recurrent myxomas (the only recurrences in our series), and one of these patients had a second recurrence. The occurrence of multiple and recurrent myxomas in patients with the complex was significantly (p less than 0.001) higher than in our 80 patients with sporadic myxomas. The world literature was searched for cases of cardiac myxomas with the unusual associations of the complex, and also for familial, multiple, and recurrent myxomas. A group of patients were identified who had unusual biologic behavior including early development of myxomas, atypical myxoma locations, and a high risk for the development of recurrent myxomas. For these patients, we recommend a thorough search for multiple tumors at operation, close postoperative follow-up, and careful screening of family members.     

A case report of Cushing's syndrome due to adrenocortical nodular dysplasia, with remission period of 6 years after unilateral adrenalectomy

A 29 y.o. female had been associated with Cushing's syndrome, gradually, from 1977. She was advised to get further examination at our hospital on September 1980. A pre-operative diagnosis of Cushing's syndrome due to bilateral adrenocortical tumors was made and right adrenalectomy was performed on December 22, 1980, as the 1st of two stage operation. The right adrenal, 1.8 cm in diameter, had a pigmented nodule and multiple pigmented micronodules, which were diagnosed pathologically as primary adrenocortical nodular dysplasia. It was not necessary for this patient to maintain steroid therapy, but after 3 months she complained of the withdrawal syndrome and was administered dexamethasone. Since July, 1981, she had no symptom without adrenocortical steroid administration. In November 1986, she became cushingoid and on June 1, 1987, we performed left adrenalectomy on her. The appearance of the left adrenal was similar to the right. We have found no reports of the cases of adrenocortical nodular dysplasia such as delayed appearance of withdrawal syndrome after unilateral adrenalectomy. In this case, plasma ACTH had relatively poor correlation with cortisol. Her plasma ACTH was not always suppressed and sometimes within normal range. Her adrenals had not only autonomy but also pituitary dependency. It is concluded that in this case there may have been a pituitary-adrenal dual control.     

Tumors of the adrenal cortex and Cushing''s syndrome.

Fifty-nine patients with Cushing's syndrome, due to adrenocortical tumor, were studied and treated during the period 1953 through 1983 at Vanderbilt University Medical Center. Cushing's syndrome is caused by hypercortisolism that can be due to (1) medicinal use of steroids, (2) excess pituitary secretion of adrenocorticotropin (ACTH) (Cushing's disease), (3) adrenocortical tumor, benign or malignant, and (4) the ectopic ACTH syndrome. Clinical and endocrinologic features of Cushing's syndrome are described, and differential diagnosis of adrenocortical tumor by precise endocrinologic studies is detailed. Computerized axial tomographic (CAT) scan is currently the most accurate imaging modality for preoperative localization of tumors. Preoperative differential diagnosis between adrenocortical adenoma and carcinoma has become fairly accurate. Operative approaches in each category are described. Follow-up from 1 to 30 years has been completed for all patients, except for one who was lost after 7 years. Results of surgical treatment of adrenocortical adenomas are excellent, but the salvage from adrenocortical carcinomas is poor.     

Palatal Soft Tissue Myxoma in a Patient with Carney Complex

Carney complex (CNC) is a rare, autosomal dominant multiple neoplasia syndrome. Although cutaneous myxomas commonly occur in CNC patients, intraoral myxomas are extremely rare. We present a case of a palatal myxoma in a 21-year-old female patient with CNC, along with a review of the pertinent literature. She presented with a sessile nodule on the hard palate that microscopically showed a multilobulated and highly vascularized myxomatous tissue composed of loosely-arranged spindle, polygonal, and stellate cells, suggestive of myxoid neurofibroma. Six years after the oral lesion was removed, she presented with a growth hormone (GH)-producing pituitary adenoma, a cardiac myxoma, two cutaneous myxomas on the lower abdomen area, and one myxoma in the vaginal mucosa. Therefore, the final diagnosis of the palatal lesion was of a soft tissue myxoma related to CNC. The patient remains on close follow-up, with no recurrences of the palatal myxoma after 7 years.     

Heart-skin syndrome and cardiac myxoma: presentation of a case and clinical experience of 17 years.]

Between 1971 and 1988, cardiac myxoma was identified in 13 (0.003%) of 4000 patients who underwent open-heart surgery at the h?pital du Sacré-Coeur in Montreal. One patient with multiple right atrial tumours also had abnormal cutaneous pigmentation compatible with the recently identified syndrome of "Carney's complex." This syndrome has also been associated with endocrine abnormalities such as primary nodular adrenal hyperplasia, with or without Cushing's syndrome. The authors review the literature and compare the findings with their experience in the surgical treatment of cardiac myxomas.     

Cushing's disease caused by adrenocortical nodular hyperplasia--diagnosis and surgical treatment

Six cases of Cushing's disease, in which perplex diagnostic problem was encountered, were reported. In the endocrinological examination two cases were not suppressed by a high dose of dexamethasone (8 mg), and the other four cases showed complicated clinical findings due to adrenocortical nodular hyperplasia. Among those four cases with adrenocortical nodular hyperplasia two of them were of functionally autonomic and showed different attitude in responding endocrine assay. When the serum cortisol is not suppressed by a high dose of dexamethasone, differential diagnosis from other causes, such as Cushing's syndrome due to adrenocortical macronodular hyperplasia, becomes quite important for surgical treatment. Usually plasma ACTH in the case of Cushing's disease is slightly increased over the normal range and, on the other hand, it is lower than normal value in the case of Cushing's syndrome due to autonomic adrenocortical nodular hyperplasia because of negative feed back phenomenon. However, in some cases of Cushing's disease plasma ACTH is within normal range or even lower than normal level, and, furthermore, it is not extremely unusual to find a case of adrenocortical macronodular hyperplasia with slightly increased plasma ACTH level over normal range. Those cases offer particularly complex problem in making diagnosis and therapeutic indication. According to our clinical experiences with those six cases, selective venous sampling is found quite useful in differentiating Cushing's disease from other causes and ACTH value in selective venous sampling from inferior petrosal vein is remarkably increased in the cases due to pituitary ACTH secreting adenoma. Cushing's disease with adrenocortical nodular hyperplasia reduces the ACTH value in the sampling to the lower normal range as the adrenocortical nodular hyperplasia progresses.(ABSTRACT TRUNCATED AT 250 WORDS)     

Case of Carney complex complicated with pituitary adenoma and Rathke cleft cyst

Carney complex is a rare autosomal-dominant, familial tumor syndrome first described in the mid 80's. This syndrome is multiple neoplasia syndrome featuring cardiac, endocrine, cutaneous, and neural tumor, in addition to a variety of pigmented lesions of the skin and mucosa. We report the case of a 12-year-old female patient with Carney complex who manifested a high value of serum growth hormone (s-GH), cutaneous angiomyxomas and labial pigmented lesions. Magnetic resonance imaging (MRI) revealed a cystic pituitary tumor. We carried out removal of the pituitary tumor via the transsphenoidal approach. In addition to the pituitary adenoma, pathological examination revealed the presence of a Rathke cleft cyst. So far, approximately 500 cases of this disorder have been described, but there have been no cases similar to our case described here. Therefore, the present case seems to be the first case of Carney Complex complicated with pituitary adenoma and Rathke cleft cyst.     

Left ventricular mass in a patient with Carney's complex

IMPLICATIONS: Carney's complex is characterized by cardiac myxomas, adrenocortical disease, growth hormone-secreting adenomas, and other types of tumors. Its prevalence and incidence are unknown. The anesthesiologist must examine the patient or order tests to exclude cardiac tumors, signs of excess cortisol secretion, acromegaly, and possible peripheral nerve root involvement.     

Surgical management of Cushing''s syndrome with emphasis on adrenal autotransplantation

Cushing's syndrome may be caused by pituitary ACTH, ectopically produced ACTH, adrenocortical tumor or medication. Cushing's disease, due to excessive pituitary ACTH resulting in adrenocortical hyperplasia, remains a complex endocrine disorder for which no single treatment is wholly satisfactory. Twenty-two patients with surgically treated Cushing's syndrome are presented: Four with benign adrenocortical adenoma, two with adrenocortical carcinoma and 16 with adrenocortical hyperplasia. The four benign adenomas were excised with the one death due to respiratory failure and sepsis. Both patients with carcinoma and liver metastases died of their tumors. Of the 16 patients with adrenocortical hyperplasia and Cushing's disease, eight underwent subtotal adrenalectomy and thereafter eight had total intra-abdominal adrenalectomy with autotransplantation of adrenal tissue to the thigh. There was one operative death. Total adrenalectomy has now replaced subtotal resection in most clinics. All eight of the patients who had adrenal autotransplantation exhibited biopsy or functional evidence of some degree of graft survival. On patient stopped steroid replacement permanently and another developed recurrent Cushing's syndrome from the grafts. Of a total of 26 reported patients with adrenal autotransplants surveyed, 22 exhibited evidence of graft survival, 16 were able to discontinue steroid replacement therapy and three eventually developed recurrent Cushing's syndrome from the transplants. There is now strong evidence that most patients with Cushing's disease harbor a pituitary basophil ademona, and in the future the initial surgical attack may be directed to the pituitary rather than to the adrenals.     

Multiple pituitary adenomas in Cushing's disease

OBJECT: Clinically evident multiple pituitary adenomas rarely occur. The authors assess the incidence and clinical relevance of multiple adenomas in Cushing's disease. METHODS: A prospective clinical database of 660 pituitary surgeries was analyzed to assess the incidence of multiple pituitary adenomas in Cushing's disease. Relevant radiographic scans, medical records, and histopathological reports were reviewed. Thirteen patients with at least two separate histopathologically confirmed pituitary adenomas were identified. Prolactinomas (nine patients) were the most common incidental tumors. Other incidental tumors included secretors of growth hormone ([GH], one patient) and GH and prolactin (two patients), and a null-cell tumor (one patient). In two patients, early repeated surgery was performed because the initial operation failed to correct hypercortisolism, in one instance because the tumor excised at the initial surgery was a prolactinoma, not an adrenocorticotropic hormone-secreting tumor. One patient had three distinct tumors. CONCLUSIONS: Multiple pituitary adenomas are rare, but may complicate management of patients with pituitary disease.     

The role of adrenalectomy in Cushing's syndrome

Forty-four patients with Cushing's syndrome were treated by adrenalectomy between 1975 and 1989. Twenty patients had adrenal adenomas: 13 with obvious Cushing's syndrome and 7 whose disease was subclinical, detected after evaluation of an incidentally discovered adrenal mass (es). Twelve patients underwent bilateral adrenalectomies for Cushing's disease after failed transsphenoidal explorations and pituitary irradiation. Six patients had primary adrenal hyperplasia, five as manifestations of Carney's complex. Two others underwent bilateral adrenalectomies for ectopic adrenocorticotropic hormone from carcinoid tumors. Four patients had adrenocortical carcinoma treated with transabdominal adrenalectomy. Three are alive from 8 years to 5 months. There was one postoperative death (2.3%) caused by coagulopathy and multiple organ failure and three (7%) minor postoperative complications. Follow-up showed good to excellent results in 95% of patients. It is concluded that adrenalectomy provides prompt relief from the severe morbidity of Cushing's syndrome regardless of the cause. It is the treatment of choice for adrenal adenomas, carcinomas, primary hyperplasia, and selected patients with Cushing's disease.     

Coexistence of three distinct adrenal tumors in the same adrenal gland in a patient with primary aldosteronism and preclinical Cushing's syndrome

A 62-year-old woman was admitted to our hospital because of hypokalemia. Physical examination revealed no signs of excessive adrenocortical steroid production, as are found in Cushing's syndrome. Her plasma renin activity (PRA) was suppressed (0.10 ng/ml per h), and her serum aldosterone level was high (30.0 ng/dl). PRA was not increased after a renin-releasing test. Her plasma adrenocorticotropic hormone (ACTH) level was low (<5 pg/ml), but her serum cortisol level was normal (21.0 μg/dl). Administration of 8 mg dexamethasone did not suppress her plasma cortisol level. Finally, she was diagnosed with clinical primary aldosteronism associated with preclinical Cushing's syndrome. Magnetic resonance image revealed three sequential nodular masses (each 15 mm × 15 mm) in the right adrenal gland. A right adrenalectomy was performed by endoscopy. The three removed tumors appeared to have different characteristics. Microscopic examination revealed that the upper and lower tumors were adrenocortical adenomas, and the middle tumor was a black adenoma. Immunohistochemical staining for the enzymes involved in cortisol biosynthesis suggested that the upper tumor secreted aldosterone, whereas either or both of the two other tumors secreted cortisol. Surprisingly, at 33 years of age, she had been diagnosed with Cushing's syndrome, due to a cortisol-producing adrenocortical adenoma, and she had received a left adrenalectomy. Clinically and pathophysiologically, this was a very rare case.     

Laparoscopic Bilateral Partial Adrenalectomy for Adrenocortical Adenomas Causing Cushing's Syndrome: Report of a Case

Laparoscopic total adrenalectomy has become a standard technique for small adrenal tumors; however, bilateral adrenalectomy results in postoperative adrenal insufficiency, necessitating lifelong steroid replacement. To preserve adrenocortical function in a 41-year-old woman with bilateral adrenocortical adenoma (BAA) causing Cushing's syndrome, we performed laparoscopic bilateral partial adrenalectomy. We based our preoperative diagnosis of bilateral adrenocortical tumors causing Cushing's syndrome on the results of endocrinological investigations and imaging findings. Thus, we performed lateral transperitoneal laparoscopic bilateral partial adrenalectomy, preserving the adrenal glands, which were normal. Pathological examination of both tumors confirmed the diagnosis of adrenocortical adenoma. The patient had no postoperative complications, and her adrenocortical function was normal without steroid replacement at her 10-month follow-up. This report shows that Cushing's syndrome resulting from bilateral adenomas can be effectively treated by laparoscopic bilateral partial adrenalectomy as a minimally invasive, adrenocortical-preserving operation.     

Genetic background of adrenocortical tumor development

The increasing occurrence of incidentally discovered benign adrenocortical tumors has become a clinical dilemma because of the difficulties in differentiating them from their malignant counterpart. Adrenocortical tumors are associated with familial cancer syndromes such as the Beckwith-Wiedemann syndrome, the Li-Fraumeni syndrome, the Carney complex, multiple endocrine neoplasia type 1, congenital adrenal hyperplasia, and the McCune-Albright syndrome. Genetic events are known to take place on the chromosomal and gene level in sporadic adrenocortical tumors.     

Primary bilateral adrenocortical causes of Cushing's syndrome.

Nontumorous primary adrenal causes of Cushing's syndrome are exceedingly rare. Herein we review our results with seven patients in whom there is biochemical evidence of a primary (adrenocorticotropin independent) bilateral adrenal cause of endogenous hypercortisolism. Each patient had low plasma adrenocorticotropin levels. All patients had elevated 24-hour urinary free cortisol levels and 17-hydroxycorticosteroids that were not suppressed by high-dose dexamethasone. Plasma levels of adrenocorticotropin and cortisol were not elevated by ovine corticotropin-releasing factor. No patient had a gradient between petrosal and peripheral adrenocorticotropin levels. No pituitary tumors were detected by magnetic resonance imaging or computed tomography. Five of six patients who underwent iodocholesterol scanning showed bilateral adrenal activity. Computed tomographic and magnetic resonance imaging of the abdomen demonstrated bilateral small adrenal glands in three patients, an adrenal mass in one patient with Carney's complex, and massively enlarged glands in three patients. Each patient underwent bilateral adrenalectomy and was given glucocorticoid and mineralocorticoid replacement. Pathologic examination of four of these bilateral adrenal specimens revealed primary pigmented micronodular adrenocortical disease, with adrenal gland weights between 2.5 and 13.4 gm (mean 5.2 gm). However, the remaining three patients had primary adrenocorticotropin-independent bilateral macronodular adrenocortical disease with adrenal gland weights between 32 and 81 gm (mean 52 gm). Although each of the patients with primary pigmented micronodular adrenocortical disease was cured by bilateral adrenalectomy through a posterior approach, two of the three patients required an anterior approach. We conclude that Cushing's syndrome can arise through two distinct forms of primary bilateral adrenal cortical disease. Computed tomography is important in evaluation of these patients because the size of the adrenal glands influences the surgical approach.     

Male infertility as a component of Carney complex

Carney complex (CNC) is a multiple neoplasia syndrome characterised by endocrine tumours, spotty skin pigmentation, cardiac and other myxomas, psamommatous and pigmented schwannomas, large cell calcifying Sertoli cell tumours, and mammary ductal adenomas and other more rare lesions. CNC is inherited in an autosomal-dominant manner and has been mapped to at least two chromosomal loci. Patients who map to the CNC1 locus located on chromosome 17 carry inactivating mutations of the PRKAR1A gene that encodes the cAMP-dependent protein kinase regulatory subunit type 1-alpha (Kirschner et al., 2000). One gene responsible for type 2 (CNC2) is located on chromosome 2p16. Infertility in CNC can be caused by a number of factors; there is evidence that prkar1a deficiency in mice leads directly to infertility (Burton et al., 2006), but patients with CNC also have Sertoli cell tumours and a number of other reasons to affect fertility. We report on an infertile male with CNC and present evidence that male infertility should be considered as part of the phenotype of CNC.     

Selective removal of hypersecreting pituitary adenomas?

Summary The aim of this study of 101 pre- and postoperatively controlled hypersecreting pituitary adenomas (80 acromegalies, 15 Cushing's diseases, 6 Nelson's syndromes) was to establish in what cases a selective adenoma extirpation by the transnasal route is possible and advisable.In primary operations on acromegalics with small and medium size tumours 92% were postoperatively GH normal. Eighty five per cent of these had intact pituitary function. The results with larger tumours were worse (72%). During a control period of 1.5–5.5 years a renewed elevation of GH levels was observed in three cases, all in the first year, but never after clearly selective adenomectomy. These results, and the anterior lobe biopsies, which showed no GH cell hyperplasia, favour selective adenoma extirpation.In contrast to acromegaly, nodular ACTH cell hyperplasia in the anterior lobe was found in most cases of Cushing's disease, and therefore complete hypophysectomy was performed. The cortisol levels became either normal or, in most cases, lower than normal. A selective operation was performed on 6 Nelson tumours. The ACTH values became normal in about 50% of the patients but there was a tendency towards recurrence. Our experiences with Cushing's disease and Nelson's syndrome lead us to recommend total hypophysectomy.Supported by Deutsche Forschungsgemeinschaft, SFB 34.     

'Gangliocytomas' of the pituitary: a heterogeneous group of lesions with differing histogenesis

Hamartomatous or neoplastic ganglion cells in the sella turcica are an unusual cause of symptoms. They have been reported in association with a functioning or nonfunctioning pituitary adenoma, with pituitary cell hyperplasia, and occasionally as masses unassociated with an adenoma, again with variable endocrinologic findings. Fewer than 50 cases of intrasellar ganglion cell lesions have been reported in the literature, only six of them associated with Cushing's syndrome. We describe the clinicopathologic features of another eight patients, three of whom presented with acromegaly, four with apparently nonfunctioning adenohypophyseal masses, and one with Cushing's syndrome. On histology, six of them were found to have sparsely granulated growth hormone (GH)-producing adenomas with ganglion cell areas, one appeared to have a gangliocytoma not associated with an adenoma, whereas the eighth had a ganglion cell lesion in the posterior pituitary. The morphologic and immunohistochemical findings suggest that the ganglion cell component of seven of these tumors has resulted from neuronal differentiation in a GH-producing adenoma, despite the lack of demonstrable adenoma in one case. A true sellar "gangliocytoma" or hamartoma of ectopic hypothalamic-type neurons appears to be a rarer explanation for the presence of ganglion cells in a pituitary biopsy.