Ultrastructural pathology of the adrenal gland in Cushing's syndrome

The ultrastructural pathology of the adrenal glands was studied in fifteen cases of Cushing's syndrome. Some specific features correlated with the pathological aspects of adrenals were found. In the hyperplastic adrenal cortex the cytoplasms contained a rich smooth endoplasmic reticulum and many mitochondria. Increased lipid-pigment complexes were found especially in the compact cells. In adenomas, the clear cells showed large lipid vacuoles; the compact cells presented anisomorphous mitochondria, a well developed smooth endoplasmic reticulum and many pigment bodies. The nuclei of adenomatous cells were irregular, with deep invaginations. In adrenal carcinomas, the pleomorphism of nuclei, nucleoli, mitochondria, and smooth endoplasmic reticulum was more obvious. Absolutely reliable characteristics proving malignancy at ultrastructural level do not, however, exist. The steroidogenic activity of both hyperplastic and tumoral adrenal glands can be assessed using the agranular endoplasmic reticulum and the mitochondria as functional parameters.     

The use of the corticotropin-releasing hormone test to monitor the recovery of patients with Cushing's disease or Cushing's syndrome due to an adrenal adenoma after adenomectomy

Six patients with Cushing's disease and three with Cushing's syndrome due to an adrenal adenoma were monitored after their adenomectomy with the corticotropin-releasing hormone test to evaluate the progress of recovery of their pituitary adrenal function. Before surgery the patients with Cushing's disease showed either high, normal or low responses of plasma ACTH and cortisol to 100 micrograms synthetic ovine corticotropin-releasing hormone (CRH) administered intravenously, whereas all three patients with Cushing's syndrome due to an adrenal adenoma showed no response of plasma ACTH or cortisol to CRH. One or two months after surgery, the patients who had Cushing's disease had low levels of basal plasma ACTH and cortisol and their responses to CRH were extremely low. However, the same patients were tested later, it was found that their responses to CRH gradually increased and reached normal ranges approximately within one year after tumor removal, which coincided with the overall improvement in their clinical signs and symptoms due to adrenal insufficiency. In contrast, the recovery of the pituitary adrenal function in patients who had Cushing's syndrome due to an adrenal adenoma was not complete even one year after surgery. Thus the corticotropin-releasing factor test is a useful criteria to evaluate the recovery of the pituitary adrenal function in these patients after surgery, since the responses of plasma ACTH and cortisol to the administered CRH are parallel with the improvements in clinical signs and symptoms due to adrenal insufficiency in patients with Cushing's disease.     

Hyperparathyroidism associated with Cushing's syndrome due to an adrenal cortical adenoma

Two patients with the rare association of Cushing's syndrome and primary hyperparathyroidism are reported. Initially, both patients suffered from Cushing's syndrome due to adrenal cortical adenomas with typical features and laboratory findings. Five years after treatment of the Cushing's syndrome by removal of the tumor, asymptomatic mild hypercalcemia was incidentally noticed in both patients, which suggested the occurrence of primary hyperparathyroidism. An enlarged parathyroid gland was removed surgically in both cases and was histologically shown to be a parathyroid adenoma. The levels of serum calcium returned to normal after parathyroidectomy. Papillary adenocarcinoma of the thyroid in one patient and adenomatous goiter in the other were also incidentally detected at operation. These findings suggest that Cushing's syndrome resulting from an adrenal cortical adenoma may be another presentation of multiple endocrine neoplasia type I.     

Preclinical Cushing's syndrome resulting from black adrenal adenoma. A case report

A 59-year-old Japanese woman, admitted for the treatment of diabetes mellitus and hypertension, was incidentally discovered to have a solid mass of 1.4 cm in diameter by CT scan with the attenuation value of 38 Hounsfield units, relatively higher for ordinary adrenal adenomas. Magnetic resonance imaging revealed no reduction of signal intensity on opposite-phase image on T1-weighted sequence. Adrenal scintigraphy imaging with 131I-adosterol did not show any uptake of the isotope in the area corresponding to both adrenals. Although she had no characteristic feature of overt Cushing's syndrome, her serum cortisol level was not suppressed after an overnight dexamethasone administration. She was diagnosed as having preclinical Cushing's syndrome. Left adrenalectomy was performed, revealing the well-circumscribed black tumor, mainly consisted of compact cell, in which cytoplasm was filled with numerous granules pigmented with dark to golden brown colors on hematoxylin-eosin staining. These findings suggested that her incidentaloma was a black adrenal adenoma. Production of steroid hormones was confirmed by immunohistochemical analysis of steroidogenic enzymes and by measurement of the tissue contents of hormones, whose levels were comparable with those in adenomas of overt Cushing's syndrome. This is the first case report of preclinical Cushing's syndrome resulting from black adrenal adenoma.     

Advances in the management of paediatric Cushing's disease

Cushing's disease (CD) is rare in the paediatric age range, but may present a difficult therapeutic challenge. Most paediatric endocrinologists have limited experience managing children or adolescents with CD and thus benefit from close consultation with adult colleagues. Prior to definitive treatment, a diagnostic protocol for investigation is required which broadly follows the model for adult patients. Treatment strategies for CD are described and critically appraised. The management of paediatric CD patients after cure also presents challenges for optimizing growth, bone health, reproduction and body composition from childhood into and during adult life.     

External irradiation of the hypophysis for Cushing's disease

During the past 12 years 17 patients with Cushing''s disease (bilateral adrenal hyperplasia secondary to excessive pituitary adrenocorticotrophic hormone) have been treated initially with external pituitary irradiation. Of the 15 patients who have had adequate follow-up, nine showed complete biochemical remission, and one showed biochemical improvement. There were no complications. It is therefore recommended that the first mode of therapy for all patients with Cushing''s disease should be pituitary irradiation if the patient''s clinical condition permits.     

Metyrapone in long-term management of Cushing's disease.

Metyrapone was used in the long-term management of 13 patients with pituitary-dependent bilateral adrenal hyperplasia (Cushing''s disease). The total length of treatment ranged from two to 66 months, with a mean of 21 months. The clinical features of the disease rapidly improved on metyrapone and this improvement was maintained. Although plasma ACTH concentrations rose in all patients, the increase was insufficient to overcome the adrenal blockade induced by the drug. Eight of the 13 patients had additional external pituitary irradiation as definitive treatment of their disease and one underwent a transfrontal hypophysectomy. Radiotherapy cured one patient, and after three years metyrapone was withdrawn. Slight hirsuties was noted in four of the seven women who received the drug for six months or more. A fifth woman had more severe hirsuties and this led to bilateral adrenalectomy. Other than hirsuties, side effects were few and the routine use of metyrapone is recommended as an adjunct to more definitive treatment in all patients who present with Cushing''s syndrome, irrespective of aetiology.     

An ultrastructural study of the adrenal cortex in Cushing's syndrome without and with hyperaldosteronism]

This paper reports ultrastructural comparision of the adrenal gland zones of a rare case of a combination from Cushing's syndrome and hyperaldosteronism with a pure Cushing's syndrom and with a normal human adrenal gland. Whilst between the zona glomerulosa of the normal adrenal gland and of the Cushing's syndrom there are no differences, the morphological state of the glomerulosa cells of the Cushing's syndrom in combination with hyperaldosteronism is interpreted as an inhibition of the activity of these cells. In the cells of the hyperplastic zona fasciculata of Cushing's syndrom in combination with hyperaldosteronism, there are no electronmicroscopical characteristics, who are morphological equivalent of the production of aldosterone. The abundant quantity of steroid producing organells in these cells point to a high function. The cells of the adenoma of Cushing's syndrom contain abundant vacuols of lipids, in which presumable are stored steroid hormones.     

Coexistence of 21-hydroxylase and 11 beta-hydroxylase deficiency in adrenal incidentalomas and in subclinical Cushing's syndrome

OBJECTIVE: The prevalence of steroid secretion abnormalities was studied by evaluating the 17-hydroxyprogesterone (17-OHP) and 11-deoxycortisol (S) responses to adrenocorticotropic hormone (ACTH) stimulation in 48 patients with 'nonfunctioning' incidentalomas and in 10 patients with 'subclinical' Cushing's syndrome. METHODS: In all patients the cortisol, 17-OHP, and S levels were measured after ACTH test. Eight patients were reinvestigated after surgery. RESULTS: In patients with nonfunctioning lesions, the ACTH test induced 17-OHP and S peaks higher than in normals (p < 0.005). In 10 cases an augmented rise of 17-OHP and S was observed. In patients with subclinical Cushing's syndrome, the 17-OHP peak after ACTH was greater than in patients with nonfunctioning lesions and in normals (p < 0.005); the S peak was also higher than in controls (p < 0.005). In 7 of 8 operated patients, the exaggerated 17-OHP peak was normalized. CONCLUSIONS: A combined impairment of different enzyme activities is frequently present in adrenal incidentalomas; the alteration of enzymatic pathways can also coexist with the presence of partial cortisol autonomy.     

Recurrent gain-of-function USP8 mutations in Cushing's disease

Cushing''s disease, also known as adrenocorticotropic hormone (ACTH)-secreting pituitary adenomas (PAs) that cause excess cortisol production, accounts for up to 85% of corticotrophin-dependent Cushing''s syndrome cases. However, the genetic alterations in this disease are unclear. Here, we performed whole-exome sequencing of DNA derived from 12 ACTH-secreting PAs and matched blood samples, which revealed three types of somatic mutations in a candidate gene, USP8 (encoding ubiquitin-specific protease 8), exclusively in exon 14 in 8 of 12 ACTH-secreting PAs. We further evaluated somatic USP8 mutations in additional 258 PAs by Sanger sequencing. Targeted sequencing further identified a total of 17 types of USP8 variants in 67 of 108 ACTH-secreting PAs (62.04%). However, none of these mutations was detected in other types of PAs (n = 150). These mutations aggregate within the 14-3-3 binding motif of USP8 and disrupt the interaction between USP8 and 14-3-3 protein, resulting in an elevated capacity to protect EGFR from lysosomal degradation. Accordingly, PAs with mutated USP8 display a higher incidence of EGFR expression, elevated EGFR protein abundance and mRNA expression levels of POMC, which encodes the precursor of ACTH. PAs with mutated USP8 are significantly smaller in size and have higher ACTH production than wild-type PAs. In surgically resected primary USP8-mutated tumor cells, USP8 knockdown or blocking EGFR effectively attenuates ACTH secretion. Taken together, somatic gain-of-function USP8 mutations are common and contribute to ACTH overproduction in Cushing''s disease. Inhibition of USP8 or EGFR is promising for treating USP8-mutated corticotrophin adenoma. Our study highlights the potentially functional mutated gene in Cushing''s disease and provides insights into the therapeutics of this disease.     

Cushing's syndrome due to unilateral adrenal nodular hyperplasia with incomplete inhibition of the contralateral gland

A 57-year-old woman was demonstrated to be affected by adrenocorticotropic hormone (ACTH)-independent Cushing's syndrome. Computed-axial tomography of the abdomen demonstrated an expansion of the left adrenal. In apparent contrast with these findings, adrenal scintigraphy demonstrated radiocholesterol uptake also by the right gland. At surgery, the left adrenal was found to be hard and enlarged and was excised, while the right gland was found of normal appearance and left in place. Histologic examination of the excised gland demonstrated nodular hyperplasia. Early after surgery, plasma cortisol returned to normal values with a normal circadian rhythm and complete inhibition by low dose dexamethasone; the response of plasma cortisol to ACTH was normal. The patient represents a rare case of unilateral adrenal nodular hyperplasia. Radiocholesterol uptake by the contralateral gland and early recovery from adrenal atrophy after surgery are exceptional findings and suggest incomplete inhibition of endogenous ACTH.