A. Cushing Disease with Elevated Acth Levels

About 68% of cases are due to Cushing "disease," caused by a benign ACTH-secreting pituitary adenoma that is typically smaller than 5 mm and usually located in the anterior pituitary (94%); however, about 6% of such adenomas are ectopic in locations such as the cavernous sinus, sphenoid sinus, ethmoid sinus, or posterior pituitary. Cushing disease is at least three times more frequent in women than men, and the median age is 41 years at diagnosis.

About 7% of cases are due to nonpituitary ACTH-secreting neuroendocrine neoplasms that produce ectopic ACTH. Ectopic locations include the lungs (55%), pancreas (9%), mediastinum-thymus (8%), adrenal (6%), GI tract (5%), thyroid (4%), and other sites (13%). About 15% of cases are due to ACTH from a source that cannot be initially located.

B. Cushing Disease with Normal or Low Acth

About 25% of cases are due to excessive autonomous secretion of cortisol by the adrenals. Cortisol secretion is independent of ACTH, and plasma ACTH levels are usually low or low-normal. Most such cases are due to a unilateral adrenal tumor. Benign adrenal adenomas are generally small and produce mostly cortisol; adrenocortical carcinomas are usually large when discovered and can produce excessive cortisol as well as androgens but may be nonsecretory. ACTH-independent macronodular adrenal hyperplasia can also produce hypercortisolism due to the adrenal cortex cells' abnormal stimulation by hormones such as catecholamines, arginine vasopressin, serotonin, hCG/LH, or gastric inhibitory polypeptide; in the latter case, hypercortisolism may be intermittent and food-dependent, and plasma ACTH levels may not be completely suppressed. Bilateral primary pigmented adrenal macronodular adrenocortical disease is a rare cause of Cushing syndrome in children and young adults. Bilateral primary pigmented adrenal macronodular adrenocortical disease may be an isolated condition or part of the Carney complex, an autosomal dominant condition with additional features consisting of myxomas of the heart and skin with spotty skin pigmentation and facial freckles.

A. Symptoms and Signs

The manifestations of Cushing syndrome vary considerably. Early in the course of the disease, patients frequently describe nonspecific symptoms, such as fatigue or reduced endurance but may have few, if any, of the physical stigmata described below. On average, patients with Cushing syndrome have seen four clinicians with a delay in diagnosis of 5 years before the diagnosis is made. Most patients eventually develop weight gain with central obesity and a plethoric "moon face," "buffalo hump," supraclavicular fat pads, protuberant abdomen, and thin extremities. Muscle atrophy causes weakness, with difficulty standing up from a seated position or climbing stairs. Patients may also experience backache, headache, hypertension, osteoporosis, avascular necrosis of bone, acne, hirsutism, superficial skin infections (eFigure 28-19. Typical Findings in Cushing Syndrome), and oligomenorrhea or amenorrhea in women or erectile dysfunction and diminished libido in men. Patients may have thirst and polyuria (with or without glycosuria), renal calculi, glaucoma, purple striae (eFigure 28-20. Axillary Pigmented Striae of Cushing Syndrome Preoperatively) (especially around the thighs, breasts, and abdomen, and easy bruising. Unusual bacterial or fungal infections are common. Wound healing is impaired. Mental symptoms may range from diminished ability to concentrate to depression and increased lability of mood. Anxiety may sometimes be accompanied by psychosis. Hyperglycemia with diabetes mellitus is common. Patients are susceptible to opportunistic infections. Hyperpigmentation is common with ectopic ACTH-secreting neoplasms that tend to produce very high plasma ACTH levels; hyperpigmentation is uncommon with pituitary Cushing disease.

Adrenal carcinomas usually have gross metastases by the time of diagnosis. Microscopic metastases are not visible by scanning but can be inferred from the presence of detectable cortisol levels following removal of the primary adrenal tumor in patients with a cortisol-secreting carcinoma and Cushing syndrome. The ENSAT staging system is used: stage 1 is a localized tumor 5 cm or smaller; stage 2, a localized tumor larger than 5 cm; stage 3, tumor with local metastases; and stage 4, tumor with distant metastases.

B. Laboratory Findings

Glucose tolerance is impaired as a result of insulin resistance. Polyuria is present as a result of increased free water clearance; diabetes mellitus with glycosuria may worsen it. Patients with Cushing syndrome often have leukocytosis with granulocytosis (AGC greater than 8000 cells/mcL) and relative lymphocytopenia (RLC less than 24%). Hypokalemia may be present, particularly in cases of ectopic ACTH secretion.

C. Imaging

In ACTH-independent Cushing syndrome, CT of the adrenals usually detects a mass lesion, which is most often an adrenal adenoma. Adrenocortical carcinomas can usually be distinguished from benign adrenal adenomas since they are generally larger (average 11 cm) and many have metastases that are visible on preoperative scans. Adrenal carcinoma is suspected in the following circumstances: (1) diameter of 4 cm or more (average 11 cm diameter); (2) nodule growth; or (3) atypical imaging: density on noncontrast CT greater than 10 Hounsfield units (HU) or CT contrast washout 60% or more or relative contrast washout 40% or more at 15 minutes after intravenous administration.

In ACTH-dependent Cushing syndrome, MRI of the pituitary gland demonstrates a pituitary lesion in about 85% of cases; lesions tend to be small (median 9.1 mm). Very small lesions (less than 5 mm) are not diagnostic. Premature cerebral atrophy is often noted. When the pituitary MRI is normal or shows a tiny (less than 5 mm) irregularity that may be incidental, selective catheterization of the inferior petrosal sinus veins draining the pituitary is performed. ACTH levels in the inferior petrosal sinus that are more than twice the simultaneous peripheral venous ACTH levels are indicative of pituitary Cushing disease. Inferior petrosal sinus sampling is also done during ovine CRH (oCRH or Acthrel) administration, which ordinarily causes the ACTH levels in the inferior petrosal sinus to be over three times the peripheral ACTH level when the pituitary gland is the source of ACTH.

When inferior petrosal sinus ACTH concentrations are not above the requisite levels, a search for an ectopic source of ACTH is undertaken. Location of ectopic sources of ACTH begins with CT scanning of the chest and abdomen, with special attention to the lungs (for carcinoid or small cell carcinomas), the thymus, the pancreas, and the adrenals. In patients with ACTH-dependent Cushing syndrome, chest masses should not be assumed to be the source of ACTH, since opportunistic infections are common. It is prudent to biopsy a chest mass to confirm the pathologic diagnosis prior to resection.

For Cushing syndrome due to ectopic ACTH, CT scanning fails to detect the source of ACTH in about 34% of cases. In such cases, the most sensitive (82%) scanning technique is whole-body imaging with ⁶⁸ Ga-somatostatin receptor-PET/CT (⁶⁸ Ga-DOTATOTATE-PET/CT). The next most sensitive (58%) scanning technique is whole-body imaging with ¹⁸ F-DOPA-PET/CT.

A. Surgical Therapy

Pituitary Cushing disease is best treated with transsphenoidal selective resection of the pituitary adenoma, even when the pituitary MRI is normal or inconclusive. With an experienced pituitary neurosurgeon, remission rates range from 80% to 90%. Postoperative hyponatremia occurs frequently; serum sodium should be monitored often for the first 2 weeks postoperatively. The patient should be screened for secondary hypothyroidism with a serum free T₄ within 1-2 weeks after surgery. After successful pituitary surgery, the rest of the pituitary usually returns to normal function; however, the pituitary corticotrophs remain suppressed and require 6-36 months to recover normal function. Therefore, patients receive empiric replacement-dose hydrocortisone postoperatively. Postoperative secondary adrenal insufficiency is a mark of successful pituitary surgery; screening may include a morning serum cortisol 8 hours following the prior evening dose of hydrocortisone. The cosyntropin test becomes abnormal by 2 weeks following successful pituitary surgery. Patients with secondary adrenal insufficiency and their families require patient education about the condition and must continue corticosteroid replacement until a cosyntropin stimulation test is normal. A pituitary MRI is obtained about 3 months postoperatively and repeated as indicated for clinical evidence of recurrent Cushing disease.

Cushing disease may persist after pituitary surgery, particularly when there has been cavernous sinus involvement. After apparent successful pituitary surgery, Cushing disease recurs in 16% after a mean of 38 months. Patients must have repeated evaluations for recurrent Cushing disease for years postoperatively. For patients with persistent or recurrent Cushing disease, repeat transsphenoidal pituitary surgery may be warranted if the recurrent tumor is visible and deemed resectable. Otherwise, bilateral laparoscopic adrenalectomy is usually the best treatment option, particularly for patients with very severe disease, since it renders an immediate remission in a condition with significant morbidity and mortality. Residual or recurrent ACTH-secreting pituitary tumors may also be treated with stereotactic radiosurgery, which normalizes urine free cortisol in 70% of patients within a mean of 17 months, compared with a 23% remission rate with conventional radiation therapy. Pituitary radiosurgery can also be used to treat Nelson syndrome.

Ectopic ACTH-secreting tumors should be surgically resected. If the tumor cannot be localized or is metastatic, laparoscopic bilateral adrenalectomy is usually recommended. Medical treatment with an oral combination of mitotane (3-5 g/24 hours), ketoconazole (0.4-1.2 g/24 hours), and metyrapone (3-4.5 g/24 hours) often suppresses the hypercortisolism.

B. Medical Therapy

For patients with Cushing syndrome who decline surgery or for whom surgery has been unsuccessful, medical therapy may be considered: Osilodrostat orally twice daily can normalize urine free cortisol and improve the manifestations of hypercortisolism. It reduces cortisol synthesis by blocking the adrenal enzyme 11b-hydroxylase. Adverse effects include adrenal insufficiency, a prolonged cardiac QT interval, hypertension, hirsutism, and acne. Ketoconazole inhibits adrenal steroidogenesis and is another treatment option when given in doses of about 200 mg orally every 6 hours; however, it is marginally effective and can cause liver toxicity. Metyrapone can suppress hypercortisolism; required median oral daily doses are 1250-1500 mg/day in divided doses. It may be combined with other therapies. Metyrapone also may be used for patients with secretory adrenocortical carcinoma whose hypercortisolism is not fully controlled with mitotane. Mitotane is approved for use with adrenocortical carcinoma and reduces cortisol secretion over several weeks. It accelerates hydrocortisone clearance, so glucocorticoid replacement is usually required at double usual doses. Etomidate is an intravenous anesthetic agent that blocks adrenal steroidogenesis. It can be given in sub-anesthetic doses to control severe hypercortisolism in severely ill patients with Cushing syndrome.

Mineralocorticoid hypertension can be treated with spironolactone, eplerenone, finerenone, or dihydropyridine calcium channel blockers. Women with hyperandrogenism may be treated with flutamide. Cabergoline, 0.5-3.5 mg orally twice weekly, reduced hypercortisolemia in 40% of patients with Cushing disease in one small study. Pasireotide, a multireceptor-targeting somatostatin analog, is a treatment option for refractory ACTH-secreting pituitary tumors causing Cushing disease or Nelson syndrome.

Metastatic ACTH-producing tumors that are visible with Octreoscan or ⁶⁸ Ga-DOTATATE-PET imaging have somatostatin receptors. Such tumors may respond to therapy with somatostatin analogs; pasireotide LAR (60 mg intramuscularly every 28 days) or octreotide LAR (30-40 mg intramuscularly every 28 days) slows progression of the malignancy and reduces ACTH secretion in up to half such patients. Potassium-sparing diuretics are often helpful. Radionuclide therapy with several cycles of ¹⁷⁷ Lu-DOTATATE has produced remissions in some patients.

Patients who are successfully surgically treated for Cushing syndrome typically develop "cortisol withdrawal syndrome," even when given replacement corticosteroids for adrenal insufficiency. Manifestations can include hypotension, nausea, fatigue, arthralgias, myalgias, pruritus, and flaking skin. Increasing the hydrocortisone replacement to 30 mg orally twice daily can improve these symptoms; the dosage is then reduced slowly as tolerated.

Benign adrenal adenomas may be resected laparoscopically if they are smaller than 6 cm; cure is achieved in most patients. However, most patients experience prolonged secondary adrenal insufficiency. Patients with bilateral adrenal macronodular hyperplasia usually require bilateral adrenalectomies and an evaluation for Carney complex that can be confirmed with a genetic evaluation for activating mutations in the gene PRKAR1A or genetic changes at chromosome 2p16. Such patients require regular screening for testicular and thyroid tumors and frequent echocardiogram screening for atrial myxomas.

Adrenocortical carcinomas are resected surgically. If the adrenocortical carcinoma was functional, postoperative secondary adrenal insufficiency is a good prognostic sign, with an increased chance that the tumor was completely resected without metastases; however, detectable postoperative cortisol levels predict metastases, even if no metastases are detectable on scans.

Patients with secretory adrenocortical carcinomas are usually treated with mitotane postoperatively, particularly if metastases are visible or cortisol is detectable postoperatively. Patients with nonsecretory metastatic adrenocortical carcinomas have also responded to mitotane. Mitotane is typically given for 2-5 years postoperatively. It is given orally with meals, beginning with 0.5 g twice daily, increasing to 1 g twice daily within 2 weeks, with subsequent increased doses every 2-3 weeks to reach serum levels of 14-20 mcg/mL. Only half the patients are able to reach these levels due to side effects. Mitotane side effects include CNS depression, lethargy, hypercholesterolemia, hypocalcemia, hepatotoxicity, leukopenia, hypertension, nausea, and rash. Mitotane also induces the hepatic enzyme CYP3A4, which accelerates the metabolism of sunitinib, cortisol, calcium channel blockers, benzodiazepines, some statins, some opioids, and some macrolide antibiotics. Mitotane can cause hypogonadism, can suppress TSH and cause hypothyroidism, and can cause primary adrenal insufficiency. Replacement hydrocortisone or prednisone should be started when mitotane doses reach 2 g daily. The replacement dose of oral hydrocortisone starts at 15 mg in the morning and 10 mg in the afternoon but must often be doubled or tripled because mitotane increases cortisol metabolism and cortisol-binding globulin levels; the latter can artifactually raise serum cortisol levels. Combined chemotherapy with etoposide, doxorubicin, cisplatin, and mitotane (EDP-M) appears to be the most effective regimen for recurrent or metastatic adrenocortical carcinoma.