Primary Pigmented Nodular Adrenocortical Disease Research Articles

Surgical management of Cushing's syndrome

Patients with Cushing's syndrome (137 total) who underwent adrenalectomy from 1957 through 1999 were reviewed for survival and complications. Of the 137 patients, 83 had adrenocortical adenoma, 30 Cushing's disease, seven primary pigmented nodular adrenocortical disease (PPNAD), eight adrenocorticotropin (ACTH)-independent macronodular hyperplasia, five adrenocortical carcinoma, and four ectopic ACTH syndromes. Seventy-eight patients with adrenocortical adenoma are alive, and their survival rate was equal to the age-matched control population, when patients who died of postoperative complications were excluded. Of the patients with Cushing's disease, 20 are alive, and ten of 16 patients (63%) who were followed and evaluated, had skin pigmentation. Four of 16 patients (25%) developed Nelson's syndrome. Five PPNAD patients and six with ACTH-independent macronodular hyperplasia are alive. All five adrenocortical carcinoma patients and four with ectopic ACTH syndrome died within two years after operation. The prognosis for patients with adrenocortical adenoma after unilateral adrenalectomy is excellent, though it is important to avoid operative complications. The rapid disappearance of signs and symptoms of glucocorticoid excess after total adrenalectomy is assured, and the prognosis is satisfactory under careful glucocorticoid replacement, making total adrenalectomy an alternative treatment for Cushing's disease.

Paradoxical response to dexamethasone in the diagnosis of primary pigmented nodular adrenocortical disease.

Primary pigmented nodular adrenocortical disease causes the Cushing syndrome in children and young adults and is most frequently associated with the Carney complex. To evaluate diagnostic tests for primary pigmented nodular adrenocortical disease. Retrospective cohort study. Tertiary care center. 21 patients with primary pigmented nodular adrenocortical disease. The control groups consisted of 9 patients with macronodular adrenocortical disease and 15 patients with primary unilateral adrenocortical disease (single adenomas). Clinical characteristics, radiologic imaging, and a 6-day Liddle test with determination of urinary free cortisol and 17-hydroxycorticosteroid excretion. Adrenal imaging and other tests were of limited value for the diagnosis of primary pigmented nodular adrenocortical disease. The Liddle test, however, distinguished patients with this disorder from those with other primary adrenocortical lesions. An increase of 50% or more in urinary free cortisol levels on day 6 of the Liddle test identified 9 of 13 patients (69.2% [95% CI, 46.6% to 91.8%]) with primary pigmented nodular adrenocortical disease, excluded all patients with macronodular adrenocortical disease, and was present in only 3 of the 15 patients with single adrenocortical adenomas (20% [CI, 0% to 40.2%]). An increase in urinary free cortisol excretion of 100% or more on day 6 of the Liddle test identified only patients with primary pigmented nodular adrenocortical disease. Patients with primary pigmented nodular adrenocortical disease responded to dexamethasone with a paradoxical increase in glucocorticoid excretion during the Liddle test. This feature distinguishes such patients from those who have the Cushing syndrome caused by other primary adrenal disorders and may lead to timely detection of the Carney complex (a potentially fatal disorder) in asymptomatic patients.

Synaptophysin immunoreactivity in primary pigmented nodular adrenocortical disease: neuroendocrine properties of tumors associated with Carney complex.

Carney complex (CNC) is characterized by lentiginosis and myxomatosis together with a variety of endocrine, neural crest-derived, and other tumors, including primary pigmented nodular adrenocortical disease (PPNAD). PPNAD is characterized by lipofuscin-containing, autonomously functioning, cortisol-producing nodules surrounded by mostly atrophic adrenocortical and normal adrenomedullary tissue. The nature and origin of the tumors, including the myxomas and PPNAD, are unclear. In this study, seven paraffin-embedded PPNAD tumors, one skin myxoma, and two cell lines (one myxoma and one PPNAD) established from patients with CNC were stained with antisera for synaptophysin (SYN), neuron-specific enolase, chromogranin A, tyrosine hydroxylase, and the neural cell adhesion molecule (NCAM). In addition, one PPNAD specimen and one myxoma were analyzed by electron microscopy. The results showed that chromogranin A and tyrosine hydroxylase stained adrenomedullary tissue, but not the PPNAD nodules or the extranodular adrenal cortex. SYN, neuron-specific enolase, and NCAM also stained the medulla. PPNAD nodules and the PPNAD cell line, but not the extranodular adrenal cortex, stained intensely for SYN. The myxoma cell line, but not normal fibroblasts, stained for SYN and NCAM. Ultrastructural analysis of a PPNAD tumor and a skin myxoma revealed a well developed rough endoplasmic reticulum, prominent mitochondria, and vesicle-like structures dispersed throughout the cytoplasm. We conclude that immunostaining for SYN, a marker protein for neuroendocrine cells, clearly distinguishes PPNAD nodules from surrounding adrenocortical tissue and can be helpful in the detection of small nodules in apparently unaffected cortex. The cells of a cutaneous myxoma were also stained positive by two of the three neuroendocrine markers. Finally, both PPNAD and myxoma cells demonstrated ultrastructural features suggestive of neuroendocrine properties. These results support the previously suggested hypothesis that the genetic mechanism leading to CNC involves genes with a neuroendocrine role.

Synaptophysin Immunoreactivity in Primary Pigmented Nodular Adrenocortical Disease: Neuroendocrine Properties of Tumors Associated with Carney Complex

Synaptophysin Immunoreactivity in Primary Pigmented Nodular Adrenocortical Disease: Neuroendocrine Properties of Tumors Associated with Carney Complex

Corticotropin-independent macronodular adrenal hyperplasia: a clinicopathologic correlation.

To investigate the clinical presentation, laboratory findings, and pathologic characteristics of patients with corticotropin (ACTH)-independent macronodular adrenal hyperplasia. Retrospective review. Academic medical center. All patients with bilateral adrenocortical nodules associated with ACTH-independent hypercortisolism without clinicopathologic features of primary pigmented nodular adrenocortical disease with atrophic internodular adrenal cortex. Compare and contrast our findings with those previously reported; assess response to adrenalectomy. Nine patients met the criteria for corticotropin-independent macronodular adrenal hyperplasia. All patients had biochemical evidence of Cushing syndrome, although repetitive testing was frequently required. As a result, the diagnosis was delayed from 1 to 20 years. In all patients, both the low- and high-dose dexamethasone suppression tests failed to suppress cortisol secretion. No patient had elevated ACTH levels, and following curative bilateral adrenalectomy, no patient subsequently developed Nelson syndrome, with follow-up ranging from 1 to 8.5 years. Unique histologic features were identified in all cases. Amalgamating this series with other clinical reports plus basic research information, corticotropin-independent macronodular adrenal hyperplasia must be considered a separate and legitimate cause of Cushing syndrome.

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(Cline Endocrinol Metab 82: 1274–1278, 1997).

Cytogenetic and microsatellite alterations in tumors from patients with the syndrome of myxomas, spotty skin pigmentation, and endocrine overactivity (Carney complex).

Carney complex (CC) is a familial multiple neoplasia and lentiginosis syndrome, transmitted in an autosomal dominant manner. It is the only familial form of cardiac and skin myxomas known and includes endocrine neoplasms causing Cushing's syndrome [primary pigmented nodular adrenocortical disease (PPNAD)] and acromegaly (GH-producing adenoma). The molecular defect leading to CC remains unknown, but was recently mapped to chromosome 2p16 by linkage analysis. This region has exhibited cytogenetic aberrations in atrial myxomas from patients with CC and harbors the hMSH2 and hMSH6 genes, which are involved in the preservation of microsatellite length stability of replicating human cells. In the present study, we examined 15 tumor and normal tissue specimens from 13 patients with CC [GH-producing adenoma (n = 1), adrenal tumors (PPNAD, n = 8), thyroid cancer (n = 1), normal adrenal gland (n = 1)] and 4 cultured cell lines [heart myxoma (n = 3) and eyelid myxoma (n = 1)]. Chromosome analysis was obtained by standard cytogenetic techniques. One of the myxoma cell lines and 3 PPNAD specimens contained multiple telomeric associations (tas). The normal adrenocortical tissue from a patient with PPNAD contained no apparent chromosomal anomalies, whereas the neighboring PPNAD tissue demonstrated tas. DNA was extracted from peripheral blood, tumor cell lines, and frozen or paraffin-embedded tissues and subjected to PCR amplification with primers from 64 microsatellite locations covering chromosomes 1 and 3-22 and 14 loci covering chromosome 2. The alterations detected were loss and gain of heterozygosity (LOH and GOH; 49% and 26%, respectively), deletions of both alleles (DEL; 10%), and microsatellite length instability (15%). GOH and LOH were the most frequent changes, with telomeric markers significantly over-represented (P < 0.05). Chromosomes 6, 11, 22, 10, and 19 demonstrated mostly LOH, GOH, or DEL in over 40% of the informative loci tested (73%, 59%, 47%, 46%, and 44%, respectively), whereas markers on chromosome 2 showed only microsatellite length instability (10%). The degree of genomic instability and its type were independent of tumor type (P > 0.1). We conclude that tumors and tumor cell lines from patients with CC demonstrate significant genomic, but not microsatellite length, instability. Thus, the CC gene(s) on chromosome 2p16 is different from the hMSH2 and hMSH6 genes and has dominant, rather than recessive, tumorigenic function. This gene(s) appears to be involved in the regulation of genomic stability of dividing cells, in particular the structure of telomeres in replicating chromosomes and/or the function of the mitotic apparatus.

Adrenalectomy for treatment of Cushing syndrome: results in 122 patients and long-term follow-up studies.

Patients with Cushing syndrome (n = 122) who underwent adrenalectomy from 1957 through 1993 were reviewed for survival and complications. Of the 122 patients, 70 had adrenocortical adenoma, 30 Cushing's disease, 6 primary pigmented nodular adrenocortical disease (PPNAD), 7 other types of primary nodular hyperplasia, 5 adrenocortical carcinoma, and 4 ectopic ACTH syndrome. Sixty-five patients with adrenocortical adenoma are alive, and the survival rate was equal to the age-matched control population, when patients who died of the postoperative complication were excluded. Of the patients with Cushing's disease, 20 are alive; and 10 of 16 patients (63%) who were followed-up and evaluated had skin pigmentation. Four of sixteen patients (25%) developed Nelson's syndrome. Four PPNAD patients and five with other types of nodular hyperplasia are alive. Most of these patients underwent bilateral total adrenalectomy, but some patients remitted after unilateral adrenalectomy. All of five adrenocortical carcinoma patients and four with ectopic ACTH syndrome died within 2 years after operation. The prognosis for patients with adrenocortical adenoma after unilateral adrenalectomy is excellent, though it is important to avoid operative complications. The rapid cure of signs and symptoms of glucocorticoid excess after total adrenalectomy is ensured, and prognosis is satisfactory under careful glucocorticoid replacement, making total adrenalectomy an alternative treatment for Cushing's disease.

Adrenocorticotropic Hormone-Independent Adrenal Hyperplasia

Cushing's syndrome with bilateral adrenal hyperplasia usually is caused by chronic adrenocorticotropic hormone (ACTH) stimulation of the adrenal cortex. Until recently, the existence of ACTH-independent bilateral adrenal hyperplasia has not been firmly established. Evidence that such disorders do exist has accumulated, and in some instances, the mechanism is understood. Bilateral adrenalectomy is most often the appropriate therapy. Activation of the adrenocortical adenylate cyclase system by ACTH-independent mechanisms will cause ACTH-independent Cushing's syndrome with bilateral adrenal hyperplasia. Increased cAMP activates downstream signaling and subsequently cell division and Cortisol production. In food-dependent Cushing's syndrome there is functional evidence for ectopic gastric-inhibitory peptide receptor expression in the adrenal cortex. Food ingestion stimulates gastric-inhibitory peptide release and activates the adrenal adenylate cyclase system. ACTH-independent Cushing's syndrome with bilateral hyperplasia may be the initial presentation of the McCune-Albright syndrome. A R201C or R201H substitution in the alpha subunit of Gs constitutively activates adenylate cyclase. In other variants of ACTH-independent adrenal hyperplasia, the mechanisms are less defined. Primary pigmented nodular adrenocortical disease may occur sporadically or in a familial form, and activating adrenal antibodies have been postulated in its etiology. ACTH-independent bilateral macronodular adrenal hyperplasia is characterized by marked adrenal gland enlargement with multiple large nodules. Its etiology is unknown.

Bilateral testicular large-cell calcifying Sertoli cell tumor and recurrent cardiac myxoma in a patient with Carney’s complex

Large-cell calcifying Sertoli cell tumors are exceedingly rare testicular tumors which can be distinguished from pure Sertoli cell tumors by distinctive microscopic features and multifocal and bilateral calcifications [1]. We describe the characteristic sonographic appearance of the tumor with pathologic correlation. This tumor also constitutes one of the conditions of Carney's complex [2], which includes cardiac and skin myxomas, myxoid mammary fibroadenomas, spotty skin pigmentation, primary pigmented nodular adrenocortical disease, pituitary adenoma and unusual testicular tumors, especially large-cell calcifying Sertoli cell tumor. We report the case of a 10-year-old boy with four of the above conditions. Recognition of this complex is important as cardiac myxomas can lead to lethal complications. Because of a tendency for familial occurrence, family members should be screened carefully [3].

Carney complex: The complex of myxomas, spotty pigmentation, endocrine overactivity, and schwannomas

The complex of myxomas, spotty pigmentation, endocrine overactivity, and schwannomas (the Carney complex) is a multisystem tumorous disorder that is transmitted as a mendelian autosomal dominant trait. Approximately 150 affected patients are known worldwide. The myxomas, which tend to be multiple in the involved organ, affect the heart, skin and breast. Typical sites for the skin myxomas are the eyelids, external ear canal, and nipples. The lesions commonly recur after excision. The spotty skin pigmentation includes lentigines and blue nevi, but ephelides and junctional and compound nevi also occur. The lentigines are widespread and typically involve the centrofacial area, including the vermilion border of the lips, and the conjunctiva, especially the lacrimal caruncle and the conjunctival semilunar fold. One or more intraoral pigmented spots are seen occasionally. The blue nevi occur on the face, trunk, and limbs, but not the hands and feet. Endocrine overactivity includes Cushing's syndrome (caused by primary pigmented nodular adrenocortical disease), acromegaly (caused by growth hormone-producing pituitary adenoma), and sexual precocity (caused by large-cell calcifying Sertoli cell tumor). The schwannomas are a special histological type, featuring psammoma bodies and melanin. Most commonly, they affect the upper gastrointestinal tract and sympathetic nerve chains, but a few have occurred in the skin. The most serious component of the Carney complex is cardiac myxoma. Patients suspected of having the syndrome (and their primary relatives) should be examined for this neoplasm.

Cushing's syndrome due to primary pigmented nodular adrenocortical disease--a case report reviews of the literature.

Primary pigmented nodular adrenocortical disease (PPNAD) is a rare cause of Cushing’s syndrome in infants, children and young adults. It is characterized by non-adrenocorticotropic hormone-dependent hypersecretion of cortisol by multiple, pigmented nodules of hyperplastic adrenocortical cells. Biochemically, PPNAD is characterized by elevated levels of plasma and urinary cortisol that are not suppressed by high doses of dexamethasone (8mg/d for 2 days). Pathologically, the adrenal glands contain multiple dark brown or black nodules and the intervening cortical tissue is atrophic. Recognition of this diagnosis, although rare, is important, as bilateral adrenalectomy is the treatment of choice.We experienced a case of Cushing’s syndrome due to primary pigmented nodular adrenocortical disease and report it with reviews of the literature.

Endocrine pathological analysis of primary pigmented nodular adrenocortical disease

We have studied eleven cases of the adrenal with primary pigmented nodular adrenocortical disease (PPNAD) by immunohistochemistry of all steroidogenic enzymes involved in cortisol biosynthesis, by in situ hybridization of P450C17 in seven cases in order to localize the sites of steroidogenesis and by chromosome suppression in situ hybridization of genomic DNA in five cases in order to determine possible genetic abnormalities of the disorder. Immunoreactivity of all the enzymes examined was intense in almost all the cells in adrenocortical nodules while internodular adrenal cortex, including the cases without cortical atrophy, was negative for the enzymes with the exception of 3 beta HSD. In situ hybridization studies of P450C17 yielded results consistent with those of immunohistochemistry. These results may be consistent with autonomous cortisol production by the nodular cells and indicate that almost all of the cells in the cortical nodules produce cortisol, which can explain the presence of hypercortisolism despite small sizes of adrenals in PPNAD. Chromosome suppression in situ hybridization analysis demonstrated possible genetic defects in chromosome 16 in this disorder.

Carney's Complex with Primary Pigmented Nodular Adrenocortical Disease and Spotty Pigmentations.

Carney's complex is composed of myxoma, spotty pigmentation and endocrine overactivity. A 27-year-old male was diagnosed to have Carney's complex on the basis of intense spotty pigmentations on his face, soles and palms, and bilateral adrenal nodular hyperplasia on computed tomography scanning (CT) and magnetic resonance imaging (MRI). Total bilateral adrenectomy was done; histological findings were compatible with primary pigmented adrenocortical disease (PPNAD). Recently, his sister and one of his brothers were suspected to have Carney's complex with PPNAD. We report the first familial case of Carney's complex with PPNAD and spotty pigmentations in Japan.

Coexisting acromegaly and a unilateral cortisol-producing adrenal adenoma: a possible variant of multiple endocrine neoplasia type I.

An unusual case of coexisting acromegaly and Cushing's syndrome is reported in a 34-yr-old female. There was no biochemical or morphological evidence to suggest the presence of other endocrinopathies. She did not have any family history to suggest a hereditary tendency to endocrine disorders. Her acromegaly and Cushing's syndrome were proven to be due to a pituitary somatotroph adenoma and a cortisol-producing adenoma in the right adrenocortex, respectively. Surgical removal of both tumors led to a marked biochemical improvement of the two endocrinopathies. To account for the simultaneous occurrence of the two endocrine tumors, at least two endocrine syndromes may be considered. One of them is Carney's complex. However, Cushing's syndrome in this complex is unexceptionally due to primary pigmented nodular adrenocortical disease, differing from the adrenal pathology of our patient. In addition, a lack in this case of any other characteristic suggestive of this syndrome appears to speak against this possibility. A second possibility is multiple endocrine neoplasia type 1. The absence of a parathyroid or pancreatic islet cell tumor does not strongly support this possibility, but adrenocortical lesions are not rare in this syndrome although they are only rarely functional. However, existence of similar case reports, although very few, in the literature leaves the possibility that she represents another rare variant of sporadic multiple endocrine neoplasia type I syndrome.

Primary Pigmented Nodular Adrenocortical Disease and Its Associated Conditions

Primary pigmented nodular adrenocortical disease, a rare pituitary-independent, adrenal-dependent cause of the Cushing syndrome, is characterized by: (1) hypercortisolism resistant to suppression by dexamethasone or stimulation by metyrapone or corticotropin-releasing hormone; (2) variable findings

Cushing's syndrome due to primary pigmented nodular adrenocortical disease with cardiac myxomas and mucocutaneous lentigines.

A young Japanese female demonstrated unusual features of Cushing's syndrome, cardiac myxomas and mucocutaneous lentigines. At the age of 12 years she presented with growth failure and obesity. The dexamethasone suppression test, the metyrapone test and low corticotropin concentrations indicated a primary adrenal disorder. At surgery, the adrenal glands were not enlarged (the right, 4.0 g; the left; 4.5 g) but had numerous small dark brown nodules. The pathological findings showed multiple small black cortical nodules containing large cells with eosinophilic cytoplasm and lipofuscin, and internodular cortical atrophy. These abnormalities were consistent with primary pigmented nodular adrenocortical disease. At age 22 years she complained of fatigue and palpitations associated with mid-chest pain. Four cardiac myxomas, suspected from the echocardiogram, were surgically removed. Because Cushing's syndrome and cardiac myxomas are life-threatening conditions, an awareness of the complex is important.

Adrenal disease.An advance of diagnosis and treatment.2.New concept of recently noticed disease state.2. Primary pigmented nodular adrenocortical disease and hyporenemic hypoaldosteronism.

Primary pigmented nodular adrenocortical disease (PPNAD)は副腎に原発する遺伝疾患で,副腎病変は過形成ではなく異形成であり,臨床的にはCushing症候群を呈する.病理組織学的ならびに臨床的にいくつかの特徴があり,心粘液腫などを合併する. hyporenemic hypoaldosteronism (HH)は糖尿病などで腎障害を生じ,プロレニンから活性型レニンへの転換が悪いためにアルドステロンの分泌が低下する病態である.臨床的には60歳以上の高齢者に多く高カリウム血症, Adams-Stokes発作を伴うA-Vブロックを起こす.最近副腎球状層におけるアルドステロン産生低下も指摘されている.

Primary Pigmented Nodular Adrenocortical Disease

Primary pigmented nodular adrenocortical disease (PPNAD) is a rare cause of Cushing's syndrome, which is adrenocorticotropic hormone-independent and involves both adrenal glands. The characteristic pathological features include multiple pigmented cortical nodules and atrophy of the internodular cortex. The adrenal size ranges from small to normal or slightly enlarged. Review of the gross, light microscopic, and ultrastructural features of eight cases seen at the National Institutes of Health revealed several very unusual findings. We observed the following in our patients: macronodules up to 3.0 cm; microscopic foci of necrosis; mitoses; cortical hyperplasia rather than internodular atrophy; focal confluence of nodules giving a diffuse pattern of cortical involvement, and a focal trabecular growth pattern. The nodules were composed primarily of eosinophilic, lipid-poor cells similar to those of the zona reticularis. However, lipid-rich cells similar to those of the zona fasciculata were also demonstrated in the nodules by both light and electron microscopy. This suggests that the adrenal cortical nodules of PPNAD may be derived from not only the zona reticularis, but also the zona fasciculata.

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.