NELSON SYNDROME

Definition

• Nelson syndrome: Progressive pituitary corticotroph tumor enlargement after bilateral adrenalectomy has been performed for the treatment of pituitary-dependent Cushing syndrome.

PATHOPHYSIOLOGY

1. Sequence of Events
   • Failed Transsphenoidal Surgery: When selective adenectomy does not successfully treat a corticotroph adenoma, bilateral laparoscopic adrenalectomy becomes indicated to control hypercortisolism.
   • Loss of Negative Feedback: Once the adrenal glands are removed and only physiologic glucocorticoid replacement is given, there is less negative feedback on any remaining corticotroph tumor cells, allowing the adenoma to potentially grow.
2. Frequency
   • Nelson syndrome occurs in a minority of patients who undergo the treatment sequence of failed pituitary surgery followed by bilateral adrenalectomy.
   • Most corticotroph microadenomas do not enlarge over time in this setting, but corticotroph macroadenomas (>10 mm) carry a high risk of enlargement post-adrenalectomy.

CLINICAL FEATURES

1. Skin Hyperpigmentation
   • Caused by markedly increased levels of pro-opiomelanocortin (POMC) and ACTH.
   • Similar mechanism as in Addison disease, leading to generalized hyperpigmentation.
   • Areas commonly affected include:
     • Extensor surfaces (knees, knuckles, elbows)
     • Friction areas (belt line, bra straps)
     • Inner surface of lips, buccal mucosa, gums, hard palate
     • Recent surgical scars, areolae, freckles, palmar creases
     • Fingernails may show linear bands of darkening.
2. Mass Effect Symptoms
   • Enlargement of the residual or recurrent pituitary tumor can lead to:
     • Visual field defects
     • Oculomotor nerve palsies
     • Hypopituitarism
     • Headaches

DIAGNOSIS

1. Imaging Studies
   • MRI of the Sella: Demonstrates an enlarging sellar mass if Nelson syndrome is suspected.
2. Laboratory Findings
   • Markedly Elevated ACTH (e.g., >1000 pg/mL; reference range, 10–60 pg/mL).

MONITORING AND MANAGEMENT

1. Follow-up After Bilateral Adrenalectomy
   • Patients with pituitary-dependent Cushing syndrome treated by bilateral adrenalectomy should undergo annual pituitary MRI for ~10 years to detect any tumor growth.
2. Tumor-Directed Radiation Therapy
   • If Tumor Growth Is Documented: Radiation therapy to the sella is considered.
   • Gamma Knife Radiosurgery is the treatment of choice if feasible.
   • However, Nelson corticotroph tumors can demonstrate aggressive growth despite radiotherapy, often with extensive cavernous sinus involvement and multiple cranial nerve palsies.
3. Pharmacologic Options
   • No Effective Standard Pharmacotherapy for these locally aggressive neoplasms.
   • Temozolomide is under investigation for aggressive pituitary tumors or carcinoma.
4. Clinical Priority
   • Despite concerns about potential Nelson syndrome, clinicians should not hesitate to cure Cushing syndrome with bilateral laparoscopic adrenalectomy when transsphenoidal surgery fails.
   • Untreated Cushing syndrome can be fatal, whereas Nelson syndrome is usually manageable.
5. Thromboembolic Risk
   • As with any patient with active or prior Cushing syndrome, prophylactic measures against deep venous thrombosis are important, especially perioperatively.