Cushing's disease-from Minnie G to key issues in the early 21st century.

Oct 7, 2019, marks the 80th anniversary of the death of Harvey Cushing, the father of modern neurosurgery. Here we give a historical perspective from Cushing's original description of the clinical syndrome that now bears his name through to the modern day. We highlight some of the key milestones that allowed improved understanding and management of this extraordinarily challenging condition, and identify some of the key issues that still exist in the 21st century.

Harvey Cushing: Cushing's disease.

In 1932 Harvey Cushing published an article entitled 'Basophil adenomas of the pituitary and their clinical manifestations'. These are rare tumours of the anterior pituitary gland, at the base of the brain, with striking manifestations, which include adiposity of the face and trunk, but not the limbs, weakness, fatigue, abdominal striae, facial hair, high blood pressure and raised blood sugar. Although I spent two years in an army neurosurgical unit, I never saw a case. More frequently, the same clinical picture is produced by a benign adenoma of the suprarenal cortex, but today by far the commonest cause of this condition is seen in the patient receiving high dosage of cortisone, when we talk about the person exhibiting 'Cushingoid features'. Most readers of this journal will have seen such cases.

The history of pituitary surgery for Cushing disease.

Although he never performed a pituitary operation for the disease, Harvey Cushing was the first to describe and treat patients with Cushing disease (CD). Other surgeons at the time were reluctant to operate on the pituitary due to the normal sella on skull radiographs in CD and the unclear etiology of the disorder. To better define and understand factors influencing the history of pituitary surgery for CD, the authors analyzed historical texts related to CD biology, diagnosis, and treatment. Cushing's monograph on basophilic pituitary adenomas and cortisol excess appeared in 1932. One year later in 1933, Alfred Pattison performed the first successful pituitary operation for CD by implanting radon seeds in the sella. Resection of a pituitary adenoma for CD was attempted 1 month later in 1933 by Howard Naffziger, resulting in only transient improvement that corresponded to the lack of tumor in the resected tissue. Soon thereafter, Susman in 1935 and Costello in 1936 described pituitary basophilic adenomas at autopsy in patients without premorbid endocrinopathy. They concluded that the adrenal gland was the cause of CD, which resulted in a 3-decade abandonment of pituitary surgery for CD. Jules Hardy in 1963 used the operating microscope to perform the first selective removal of an adrenocorticotropic hormone (ACTH)-secreting microadenoma, which established a pituitary cause and defined the modern treatment of CD. Subsequent reports by Hardy, Laws, and Wilson resulted in widespread acceptance of pituitary surgery for CD. Initial reluctance to operate on the pituitary for CD was multifaceted and included general uncertainty surrounding the etiology of Cushing syndrome as well as a lack of early surgical success, both due to the small size of ACTH-secreting adenomas. Selective removal of ACTH-secreting adenomas identified the source of CD and ended the delay in acceptance of pituitary surgery for CD.