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.