Nelson syndrome is progressive pituitary corticotroph tumor enlargement after bilateral adrenalectomy is performed for the treatment of pituitary-dependent Cushing syndrome. Although the treatment of choice for a corticotroph adenoma is selective adenectomy at the time of transsphenoidal surgery (see Plate 1-22), bilateral laparoscopic adrenalectomy is indicated when pituitary surgery is not successful. When bilateral adrenalectomy cures hypercortisolism, there is less negative feedback on the corticotroph tumor cells with physiologic glucocorticoid replacement, and the adenoma may grow. Nelson syndrome occurs in a minority of patients who follow the treatment sequence of failed transsphenoidal surgery and bilateral adrenalectomy. Most corticotroph microadenomas do not enlarge over time in this setting. However, when pituitary-dependent Cushing syndrome is caused by a corticotroph macroadenoma (10 mm in largest diameter), the risk of tumor enlargement after bilateral adrenalectomy is high.
The clinical features of Nelson syndrome are skin hyperpigmentation related to the markedly increased blood levels of pro-opiomelanocortin and corticotropin (adrenocorticotropic hormone [ACTH]) and symptoms related to mass effects of an enlarging pituitary tumor (e.g., visual ﬁeld defects, oculomotor nerve palsies, hypopituitarism, and headaches). As in Addison disease (see Plate 3-22), generalized hyperpigmentation is caused by ACTH-driven increased melanin production in the epidermal melanocytes. The extensor surfaces (e.g., knees, knuckles, elbows) and other friction areas (e.g., belt line, bra straps) tend to be even more hyper- pigmented. Other sites of prominent hyperpigmentation include the inner surface of the lips, buccal mucosa, gums, hard palate, recent surgical scars, areolae, freckles, and palmar creases (the latter may be a normal ﬁnding in darker-skinned individuals). The ﬁngernails may show linear bands of darkening arising from the nail beds. Suspected Nelson syndrome can be conﬁrmed by magnetic resonance imaging (MRI) of the sella that demonstrates an enlarging sellar mass. In addition, blood ACTH concentrations are markedly increased in this setting (e.g., 1000 pg/mL; reference range, 10–60 pg/mL).
Patients with pituitary-dependent Cushing syndrome who are treated with bilateral adrenalectomy should be monitored annually with pituitary MRI for approximately 10 years. Tumor-directed radiation therapy should be considered if tumor growth is documented on serial MRI. If feasible, gamma knife radiosurgery is the treatment of choice for Nelson corticotroph tumors. However, unlike most pituitary adenomas, these neoplasms may demonstrate aggressive growth despite radiotherapy. Extensive cavernous sinus involvement may result in multiple cranial nerve palsies. No effective pharmacologic options are available to treat this locally aggressive neoplasm. Temozolomide is being investigated as a potential treatment option for aggressive pituitary tumors or carcinoma.
Despite the concern about potential development of Nelson syndrome, clinicians should never hesitate to cure Cushing syndrome with bilateral laparoscopic adrenalectomy when transsphenoidal surgery has not been curative. Untreated Cushing syndrome can be fatal, but Nelson syndrome is usually manageable.