Extrapituitary parasellar microadenoma in Cushing's disease.

Negative sellar exploration (despite the results of endocrine evaluation indicating Cushing's disease), the high incidence of failure of total hypophysectomy, and remission of Cushing's syndrome after unsuccessful hypophysectomy and sellar irradiation suggest that the etiology of refractory Cushing's disease, in some patients, lies near the sella but not in the pituitary gland. We present 5 patients, out of 626 who received surgery for Cushing's disease, in whom an ACTH-secreting extrapituitary parasellar adenoma was identified: 2 after unsuccessful total hypophysectomy for the treatment of refractory Cushing's disease, 2 after unsuccessful hemihypophysectomy (the first, 2 yr before treatment at the NIH for Nelson's syndrome; and the second, with recurrent Cushing's disease 5 yr after negative transsphenoidal exploration), and 1 with a preoperative diagnosis of an intraclival microadenoma, which was cured by resection of the tumor. In all cases, an extrapituitary parasellar microadenoma was confirmed unequivocally as the cause of the disease, by negative pathology of the resected pituitary gland (patients 1, 2, 3, and 5), and/or the remission of the disease after selective resection of the extrasellar adenoma (patients 3, 4, and 5). Three of 5 patients had a partial empty sella. These patients support the thesis that ACTH-secreting tumors can arise exclusively from remnants of Rathke's pouch, rather than from the adenohypophysis (anterior lobe or pars tuberalis of the pituitary gland) and can be a cause of Cushing's disease. In the sixth presented case, an extrapituitary tumor was suspected at surgery after negative pituitary exploration, but serial sections of the hemihypophysectomy specimen revealed a microscopic focus of tumor at the margin of the resected gland. This case demonstrates the importance of negative pituitary histology to establish the presence of an extrapituitary parasellar tumor as an exclusive source of ACTH, and it supports the value of clinical outcome to establish the diagnosis with selective adenomectomy of an extrapituitary parasellar tumor. In patients with negative pituitary magnetic resonance imaging, especially in the presence of a partial empty sella, the diagnostic and surgical approach in Cushing's disease should consider the identification and resection of extrapituitary parasellar adenoma, which can avoid total hypophysectomy, as was possible in 3 of our 5 patients.     

ACTH-producing pituitary adenomas in Addison's disease: two cases treated by transsphenoidal microsurgery

In 2 women with known Addison's disease, progressive hyperpigmentation reappeared years after an initial remission under conventional substitution therapy with cortisone. Excessively elevated plasma ACTH concentrations and radiological evidence of sella turcica deformation led to the diagnosis of ACTH-producing adenomas and prompted their removal by transsphenoidal microsurgery. In one patient, a large Crooke's cell adenoma with extensive extrasellar expansion had caused severe and irreversible bilateral defects of the visual fields and unilateral optic atrophy. Surgical removal of the tumour and radiotherapy brought about a permanent disappearance of the hyperpigmentation, but eventually led to secondary hypothyroidism. In the second patients, the selective removal of a small intrasellar eosinophilic adenoma consisting of ACTH-producing cells did not alleviate the hyperpigmentation and did not lower the plasma ACTH concentration. However, hyperpigmentation regressed markedly within a year of treatment with a higher dose of cortisone. The rarity of similar cases in the literature seems to indicate that insufficient feedback suppression of ACTH-producing cells in treated Addison's disease does not by itself induce the development of a pituitary adenoma, but might promote the growth of an independently and coincidentally occurring microadenoma, which would have caused Cushing's disease in a person with intact adrenal glands.     

Spontaneous Remission of Cushing’s Disease after Disappearance of a Microadenoma Attached to the Pituitary Stalk

Cushing's disease caused by a microadenoma located near the pituitary stalk is infrequent and spontaneous remission caused by necrosis of a corticotropinoma in such location has not been reported. A 42-year-old woman with ACTH-dependent Cushing's syndrome presented on magnetic resonance imaging (MRI) a 3-mm microadenoma attached to the pituitary stalk. Treatment with ketoconazole normalized urinary free cortisol (UFC) from 433.0 to 66.0 microg/day, although it failed to reduce elevated serum androgen levels (DHEAS 4770 ng/ml). After one year, treatment was stopped and UFC rose again to 936.0 microg/day but one month later the patient presented acute headache and signs of steroid withdrawal syndrome. Endocrine evaluation showed glucocorticoid and androgen deficiency (UFC 5.0 microg/day; DHEAS < 300 ng/ml); control MRI revealed disappearance of the microadenoma. Cushingoid signs subsided and steroid replacement was initiated, proving still necessary over two years after the episode. Infarction or hemorrhage of a corticotrope adenoma could be a probable underlying mechanism although its precipitating factor is unclear. Ketoconazole withdrawal, through abrupt increase in cortisol production and/or the interruption of a hypothetical inhibitory action on cell replication followed by tumor growth and compromise of vascular supply, may be considered as possible triggering factors. To the best of our knowledge, this is the first report of spontaneous remission of Cushing's disease caused by presumed infarction of a microadenoma, unusually located in the superior rim of the pituitary, attached to the stalk.     

Cushing's disease in a patient with steroid 21-hydroxylase deficiency

Cushing's disease rarely appears as a consequence of hereditary disease. However, familial diseases with diminished glucocorticoid feedback are associated with secondary hypercorticotropinism and have been shown to give rise to pituitary adenomas. We here describe the rare case of a 30-year old female patient with congenital adrenal hyperplasia who also showed clinical signs and a typical history of hypercortisolism that was specified as Cushing's disease. After removal of a pituitary microadenoma, serum-cortisol levels fell below normal and the symptoms improved. However, after four years the menstrual cycle was irregular again and ACTH levels were in the upper range of normal. A corticotropin challenge showed a minor cortisol response but a marked increase in 17-hydroxyprogesterone serum concentrations. Genetic analysis revealed a homozygous mutation in exon 7 of the CYP21A2 gene (CTG>TTG, p.V281L). We conclude that a marked ACTH drive was able to override insufficient 21-hydroxylation and even to cause hypercortisolism. Although we describe a rare case, the impairment of the glucocorticoid feedback system in the context of congenital adrenal hyperplasia and other diseases may contribute to the development of secondary hypercorticotropinism as well as corticotropin producing adenomas.     

Recurrence after a surgically induced remission.

In December 1976, an 18-year-old woman had symptoms typical of Cushing's syndrome. Laboratory evaluations and roentgenograms documented pituitary-dependent Cushing's disease in a patient with a pituitary microadenoma. In May 1977, she underwent transsphenoidal pituitary exploration. A 2-mm pituitary microadenoma was removed. The patient improved, and laboratory evaluation documented remission of the disease. In June 1978, she again complained of symptoms compatible with Cushing's disease. Laboratory evaluation confirmed a pituitary-dependent hypercortisonism. This case report marks the first recurrence of Cushing's disease in a patient previously cured by transsphenoidal resection of a pituitary tumor.     

Radiation therapy for Cushing's disease: a review

Because patients with Cushing's disease have an increased morbidity and an age-corrected mortality, treatment is generally started as soon as possible. The goal of treatment in these patients is to induce remission. Although a variety of treatments are available, pituitary radiation is a good option for aggressive Cushing's disease that fails to respond to surgery, disease that invades the cavernous sinus, and disease that relapses following an initial remission. Conventional radiation therapy, stereotactic radiosurgery, fractionated stereotactic radiation therapy, and brachytherapy with Yttrium-90 (Y 90) and Gold-198 (Au 198) have been used successfully to treat ACTH-secreting pituitary adenomas in specialized centers. Conventional radiation therapy is the most frequently used method of radiation therapy for Cushing's disease. Stereotactic radiosurgery may be used as an alternative in patients with adenomas that are smaller than 30 mm and located at least 3 to 5 mm from the optic chiasm. Fractionated stereotactic radiation therapy is an alternative to radiosurgery while interstitial pituitary irradiation is an alternative to surgical resection in invasive tumors. Hypopituitarism is the most common side effect of pituitary irradiation. This article will review the role of radiation in the primary and secondary treatment in patients with Cushing's disease caused by pituitary adenomas.     

Successful treatment of Cushing��s disease caused by ectopic intracavernous microadenoma

Adrenocorticotropic hormone (ACTH)-secreting pituitary adenomas are sometimes difficult to visualize, even with high-quality magnetic resonance imaging, due to their small size and variable location. Sampling the cavernous or inferior petrosal sinus is helpful for confirming the central origin of a tumor, but ectopic corticotroph adenomas in the paraseller region also typically exhibit a high central/peripheral plasma ACTH ratio. We experienced an extremely rare case of Cushing??s disease caused by an ACTH-secreting microadenoma located entirely inside the left cavernous sinus attached to the medial wall (ectopic pituitary adenoma) that was not visible by preoperative MRI. In this case, the microadenoma was completely removed and an endocrinologic cure was achieved. This case reveals that in addition to meticulous sectioning of the pituitary gland, bilateral periglandular inspection with visualization of the medial wall of the cavernous sinus and of the diaphragm should always be performed to detect ectopic parasellar microadenomas when no adenoma is visible by preoperative MRI.     

Cushing's disease

Cushing's disease is a form of Cushing's syndrome, persistent inappropriate hypercortisolism, that results from pituitary ACTH hypersecretion. It currently accounts for 70 per cent of adult cases of Cushing's syndrome and affects mainly women of childbearing age. The pathology, cause, and clinical and laboratory features of the disease are discussed. The initial step in diagnosis is documentation of endogenous hypercortisolism, which is followed by identification of the cause. Selective transsphenoidal resection of ACTH-producing pituitary adenomas is the initial treatment of choice. The roles of radiotherapy and medical therapy are discussed.     

Mutation analysis of leukemia inhibitory factor-receptor (LIF-R) in ACTH-secreting pituitary adenomas.

Numerous cytokines and particularly leukemia inhibitory factor (LIF) are involved in the differentiation, proliferation, and secretory function of ACTH-producing pituitary cells. LIF and its receptor LIF-R are abundantly expressed in normal pituitaries and in ACTH producing adenomas. The present study was performed to evaluate the possible role of LIF-R in the pathogenesis of ACTH-secreting pituitary adenomas. To test the hypothesis that a possible mutation of LIF-R might be involved in pathogenesis of Cushing's disease we analyzed ACTH-producing pituitary adenomas as well as inactive pituitary adenomas by RT-PCR and direct cycle sequencing. No mutations have been found in the adenomas investigated. We thus conclude that mutations in LIF-R are an unlikely cause for the development of Cushing's disease.     

Primary adrenocortical nodular dysplasia, a distinct subtype of Cushing's syndrome. Case report and review of the literature

Non-iatrogenic Cushing's syndrome has been associated primarily with three entities: pituitary-dependent processes due to pituitary adenomas or microadenomas causing adrenal hyperplasia; pituitary-independent primary adrenal causes, predominantly unilateral adenomas, rarely multiple adenomas or adrenal carcinoma; ectopic sources of adrenocorticotropic hormone (ACTH) production. Although non-neoplastic bilateral adrenal disease generally has been ascribed to extra-adrenal stimulation, a rare cause of Cushing's syndrome that involves bilateral adrenal nodule formation independent of pituitary stimulation has been identified. Nodular adrenal diseases represent a confusion of terms in the literature, but one subgroup of Cushing's syndrome has most frequently--and, perhaps, most appropriately--been designated primary adrenocortical nodular dysplasia. A case of this unusual entity is presented, and previous case reports pertaining to this confusing area of adrenal hyperfunction are reviewed. The characteristic manifestations that separate this diagnosis from other types of nodular adrenal disease are also discussed. Recognition of this diagnosis, although rare, is important, as bilateral adrenalectomy in the treatment of choice.     

Cushing's disease in childhood.

Cushing's disease is rare in childhood. There is an equal sex incidence, and it accounts for approximately 75% of pediatric causes of Cushing's syndrome. Predominant features are weight gain, growth failure, virilization, and headache. Following confirmation of the presence of inappropriate hypercortisolemia, the accurate differential diagnosis to establish the pituitary as the source of excessive ACTH secretion involves demonstration of > 50% suppression of circulating cortisol during high-dose dexamathasone administration and exaggeration of the cortisol response to corticotropin-releasing hormone (CRH). Imaging of the pituitary reveals a microadenoma in only a minority of cases, but inferior petrosal sinus sampling for ACTH can be of value in confirming the pituitary location of the tumor and possibly its lateralization. Primary therapy is transsphenoidal surgery, which can be supported by direct pituitary irradiation if hypercortisolemia persists. In experienced hands, the therapeutic outcome is good.     

Repeated Remissions of Cushing's Disease Due to Recurrent Infarctions of an ACTH-Producing Pituitary Macroadenoma

Infarction of prolactin-secreting or growth hormone-secreting pituitary adenomas is not unusual. However, Infarction of ACTH-secreting adenomas has rarely been reported. Cyclical course of Cushing's syndrome alternating with adrenal insufficiency due to recurrent infarction of an ACTH-secreting pituitary adenoma has not been reported. We report here a 20-year-old lady who presented with florid signs of Cushing's syndrome but was found to have adrenal insufficiency on biochemical evaluation. Magnetic resonance imaging (MRI) of the pituitary gland showed that she had infarction of an ACTH-secreting macroadenoma. Over the next 6 years, her disease ran a cyclical course characterized by periods of hypercortisolism alternating with adrenal insufficiency due to repeated episodes of infarctions of the ACTH-secreting pituitary macroadenoma with corresponding changes in the pituitary adenoma on serial MRIs. The case alerts clinicians to this possibility when a patient presents with clinical picture of Cushing's syndrome but has adrenal insufficiency on biochemical testing. It also suggests that silent or subclinical infarction of pituitary adenomas is not uncommon and is probably under diagnosed.     

Subclinical Cushing's disease: presentation of three cases and critical review

Unlike subclinical Cushing's disease, adrenal subclinical Cushing's syndrome is widely recognized. It is defined as an autonomous cortisol hyperproduction of mild intensity not causing specific clinical signs, but detectable biochemically as derangements of the hypothalamic-pituitary-adrenal axis function. Although Cushing's disease accounts for the majority of hypercortisolism states, subclinical Cushing's disease has been rarely reported. Three cases of subclinical Cushing's disease due to pituitary corticotrophic macroadenomas, confirmed by immunohistochemistry, are presented in order to underscore its recognition by clinical endocrinologists and to emphasize a diagnostic evaluation of hypercortisolism in all cases of pituitary adenomas.     

Clonal composition of pituitary adenomas in patients with Cushing's disease: determination by X-chromosome inactivation analysis.

The synthesis and secretion of anterior pituitary hormones are subjected to a variety of positive and negative feedback mechanisms. Aberrancies of these highly regulated phenomena may lead to hyperplasia involving multiple cells of the anterior lobe. Alternatively, a rare genetic mutation in a single cell may precede its clonal expansion. Which of these mechanisms is operative in the development of corticotroph adenomas is not known. To examine this question, we studied the clonal composition of ACTH-producing pituitary adenomas from female patients with Cushing's disease by using X-chromosome inactivation analysis. Nine of 27 patients examined were heterozygous at 1 of the 2 X-chromosome-linked polymorphic loci, hypoxanthine-phosphoribosyl-transferase and phosphoglycerate-kinase. The methylation patterns of the hypoxanthine-phosphoribosyl-transferase and phosphoglycerate-kinase genes, distinguishing between the active and inactive alleles, were analyzed in DNA extracted from the central part of the tumor and compared with those of autologous lymphocyte DNA. Six tumors (4 microadenomas and 2 macroadenomas) showed a single active allele of the X-chromosome-linked genes and were monoclonal in nature. The other 3 pituitary adenomas (1 microadenoma and 2 macroadenomas, 1 from a patient with Nelson's syndrome) revealed a polyclonal pattern of X-chromosome inactivation. Our data demonstrate that corticotroph adenomas of the pituitary may arise from a single cell or from more than one cell. Whether fundamentally different endocrine mechanisms underlie the two processes remains to be seen.     

Cure of Cushing's disease by transsphenoidal removal of a microadenoma from a pituitary gland despite a radiographically normal sella turcica.

A 37-year-old woman had symptoms of Cushing's disease for two years. Galactorrhea was present. The diagnosis was confirmed by finding intermittently elevated urinary 17-hydroxysteroids, absent circadian rhythm, and elevated plasma ACTH. Plasma prolactin was slightly elevated. Films of the sella turcica were normal. A 9 mm basophilic microadenoma was removed by the transphenoidal approach. Immunocytochemical and electron-microscopic studies showed that the tumor was composed exclusively of ACTH secreting cells. Endocrine re-evaluation one year later revealed normal adrenal function. Serum prolactin had returned to normal. This case provides further evidence that Cushing's disease can be caused by a pituitary microadenoma insufficient in size to deform the sella.     

SELECTIVE BILATERAL AND SIMULTANEOUS CATHETERIZATION OF THE INFERIOR PETROSAL SINUS: CRF STIMULATES PROLACTIN SECRETION FROM ACTH-PRODUCING MICROADENOMAS IN CUSHING''S DISEASE

Bilateral, selective and simultaneous catheterization of the inferior petrosal sinus with measurements of ACTH after stimulation with ovine corticotrophin-releasing factor (CRF) is now frequently used to establish the differential diagnosis in patients with Cushing's disease and to determine the side of the microadenoma in the pituitary. To investigate whether CRF has any effect on other pituitary hormones, we also determined prolactin (PRL) concentrations in the samples obtained during this procedure. Fourteen patients under evaluation for Cushing's syndrome and one patient with a hormonally inactive pituitary tumour were catheterized. Baseline PRL levels in the peripheral veins were within the normal range before and after CRF in all patients (3.7-16.0 ng/ml). In 10 patients ACTH- and PRL concentrations lateralized to one side of the pituitary and could both be stimulated by CRF. The gradient of PRL between inferior petrosal sinus and periphery ranged from 7 to 147 ng/ml after CRF. There was no correlation between ACTH and prolactin increase in response to CRF. In three patients with no ACTH-gradient but a positive response to CRF, no tumours could be found during transsphenoidal surgery; they had no PRL-gradient and showed no PRL response to CRF. One patient with the ectopic ACTH syndrome had no ACTH- and no PRL response to CRF. The patient with the inactive pituitary tumour showed a normal ACTH-, but no PRL response to CRF. These data demonstrate for the first time that in normo-prolactinaemic patients with Cushing's disease, in contrast to patients bearing no microadenoma, PRL is secreted in response to CRF.(ABSTRACT TRUNCATED AT 250 WORDS)     

Reduction of a pancreatic tumor after total removal of an ACTH secreting pituitary tumor: differential diagnosis of Cushing's syndrome

Endocrinologic tests sometimes fail to distinguish adrenocorticotropic hormone (ACTH)-secreting pituitary adenoma from ectopic ACTH-secreting tumor. The authors experienced a case of Cushing's disease associated with a pancreatic tumor. Venous sampling contributed to the final diagnosis of Cushing's disease in this complex case, while endocrinologic tests showed paradoxical results. A 54-year-old woman presented with Cushing's syndrome and pancreatic tumor. Magnetic resonance imaging (MRI) failed to reveal a pituitary tumor, but a gadolinium-enhanced tumor with cystic components was seen in the pancreatic tail. Results of conventional endocrinologic tests suggested ectopic ACTH syndrome, but venous sampling including cavernous sinus sampling indicated an ACTH-secreting pituitary adenoma. Transsphenoidal surgery revealed a pituitary microadenoma, and total removal of the tumor was achieved. Postoperative abdominal MRI revealed that the pancreatic tumor diminished gradually without treatment. Selective cavernous sinus sampling was useful for distinguishing ACTH-secreting pituitary adenoma from ectopic ACTH syndrome in this complex case. This was a rare case in which the pancreatic tumor diminished after total removal of the ACTH-secreting pituitary adenoma.     

Imaging in Cushing's syndrome

Once the diagnosis of Cushing's syndrome (CS) has been established, the main step is to differentiate between ACTH dependent and independent disease. In adults, 80% of CS is due to ACTH-dependent causes and 20% due to adrenal causes. ACTH-secreting neoplasms cause ACTH-dependent CS. These are usually anterior pituitary microadenomas, which result in the classic Cushing's disease. Non-pituitary ectopic sources of ACTH, such as a small-cell lung carcinoma or carcinoid tumours, are the source of the remainder of ACTH-dependent disease. In the majority of patients presenting with clinical and biochemical evidence of CS, modern non-invasive imaging can accurately and efficiently provide the cause and the nature of the underlying pathology. Imaging is essential for determining the source of ACTH in ectopic ACTH production, locating the pituitary tumours and distinguishing adrenal adenomas, carcinomas and hyperplasias. In our chapter we review the adrenal appearances in ACTH-dependent and ACTH-independent CS. We also include a discussion on the use of MRI and CT for the detection and management of pituitary ACTH secreting adenomas. CT of the chest, abdomen and pelvis with intravenous injection of contrast medium is the most sensitive imaging modality for the identification of the ectopic ACTH source and detecting adrenal pathology. MRI is used for characterising adrenal adenomas, problem solving in difficult cases and for detecting ACTH-secreting pituitary adenomas.     

Silent corticotroph adenomas

Silent corticotroph pituitary adenomas (SCA) are defined as pituitary adenomas showing positive staining for adrenocorticotrophic hormone in immunohistochemical studies, but not associated with perioperative clinical or laboratory features of hypercortisolaemia. They account for 1.1-6% of surgically removed pituitary adenomas. Currently, two distinct pathologic subtypes of SCA are recognised. Their pathogenesis remains unclear. They present with local mass effects (headache, visual deterioration, cranial nerve palsies, endocrine dysfunction). The lack of manifestations of cortisol excess has not been conclusively explained. In surgical series, most tumours are macroadenomas with suprasellar extension present in 87-100% of the cases; this is in contrast to Cushing's disease, which is mostly attributed to microadenomas. Surgery remains the main therapeutic approach. Attempts to identify predictors of recurrence have not been successful. Management and follow-up protocols should be planned taking into account their potential aggressive behaviour, particularly upon recurrence. The development of florid pituitary Cushing's syndrome and local recurrence followed by metastatic disease (occasionally outside the central nervous system) have been rarely reported.     

Double Pituitary Lesions in Three Patients with Cushing's Disease

Double pituitary adenomas are rare in surgical specimens and the most common clinical feature in reported patients has been acromegaly. We report 3 cases of double pituitary lesions in patients who presented with Cushing's disease. In a 22-year-old man (case 1) with delayed puberty and low testosterone levels, mild hyperprolactinemia was diagnosed and treated with dopamine agonist therapy that reduced the prolactin (PRL) levels to normal. Over a 1-year period Cushing's disease developed gradually and was confirmed with classical endocrine testing. In a 27-year-old woman (case 2) who initially presented with severe depression and morbid obesity there was a gradual onset of Cushing's disease; initially she had minimally elevated serum PRL. In a 33-year-old woman (case 3) there was a 2-year history of Cushing's disease characterized by hirsutism, hypertension and weight gain; serum PRL was normal. Magnetic resonance imaging in all 3 patients revealed a microadenoma that was successfully removed by transsphenoidal pituitary surgery. Histology and immunocytochemistry in case 1 and case 3 revealed a corticotroph cell adenoma and a PRL cell adenoma in separate areas of the pituitary. In case 3 the PRL cell adenoma was silent but in case 1 the PRL cell adenoma may have been the cause of the mild hyperprolactinemia. In case 2 nodular corticotroph hyperplasia was the cause of Cushing's disease and a silent PRL cell adenoma was also identified.We conclude from these cases and a literature review that double pituitary lesions may occur in patients with Cushing's disease. The corticotroph part of the double lesion may consist of a corticotroph cell adenoma or, as reported in this study, of corticotroph nodular hyperplasia. The counterpart of the double lesion may consist either of a silent PRL cell adenoma or a functional PRL cell adenoma causing hyperprolactinemia.