Pathology of Adrenocorticotropic Hormone Excess B Y K ALMAN K OVACS ,M D , AND F ATEME S ALEHI

Adrenocorticotropic hormone (ACTH) excess may give rise to severe clinical symp- toms and marked laboratory alterations that, if not properly treated, can lead to irre- versible organ damage and patient death. This issue of Endocrinology Rounds presents an overview of the causes and pathology of ACTH hypersecretion, which is generally associ- ated with Cushing's disease. The most common morphologic abnormality associated with this disorder is a basophilic microadenoma of the pituitary gland, accompanied by Crooke's hyaline change in the cytoplasm of nontumourous corticotrophs. Tumour cells exhibit cytoplasmic PAS positivity and are immunoreactive for ACTH and related proopio- melanocortin (POMC)-derived peptides. Other tumour variants include chromophobic macroadenomas and Crooke's cell adenomas. Corticotroph carcinomas are rare and gen- erally diagnosed only when cerebrospinal and/or systemic metastases are documented. Patients with Nelson's syndrome usually have rapidly growing, invasive, aggressive corti- cotroph adenomas. Cushing's disease may rarely be the result of a nodular or diffuse corti- cotroph hyperplasia. ACTH oversecretion may also be caused by ectopic ACTH and/or corticotropin-releasing hormone (CRH) production by various tumours, as well as small cell carcinomas of the lung. Other tumours (eg, various carcinoids, medullary carcinomas of the thyroid, pheochromocytomas, or neoplasms of the pancreatic islets) may also cause the ectopic ACTH/CRH syndrome. A "silent" corticotroph adenoma is caused by an ACTH-synthesizing pituitary neoplasm that is not associated with ACTH secretion; these patients have no clinical and laboratory evidence of Cushing's disease although their tumours are often aggressive macroadenomas prone to hemorrhage, necrosis, and recur- rence. In this case, the discrepancy between the presence of immunoreactive ACTH in the cytoplasm of tumour cells and the lack of ACTH excess (and absence of hypercorticism) is unresolved. In spite of numerous studies, Cushing's disease is still an enigma and further research is required to resolve the cause, prognosis, and therapy of this intriguing disease. Cushing's disease Increased secretion of ACTH stimulates production and release of corticosteroids by the adrenocortical cells, resulting in various degrees of hypercorticism. Clinical symptoms include truncal obesity, hypertrichosis, abdominal striae, elevated blood pressure, backaches, osteoporosis, fatigue, and weakness. The disease was first described by Cushing in 1932. He recognized that the clinical findings were often associated with a basophilic pituitary adenoma and called the syndrome "pituitary basophilism;" however, the syndrome was subsequently renamed "Cushing's disease," giving credit to its discoverer. There is a female preponderance; approximately 75% of cases occur in women. Corticotroph adenomas