The adrenal glands are paired retroperitoneal organs superomedial to the kidneys at the level of the 12th rib. They are surrounded by loosely attached fat posteriorly to diaphragmatic muscle. This fat can obscure the visualization and identification of adrenal tumors. Left-sided adrenal tumors lie adjacent to and can invade the spleen, pancreas tail, liver, kidney, or renal hilum. If not careful, it is possible to mistake the tail of the pancreas for the left adrenal gland given the similar texture and size. Right-sided adrenal tumors lie adjacent to and can invade the liver or inferior vena cava (IVC).

The arterial supply to the adrenals originates from the inferior phrenic arteries, aorta, and renal arteries. Despite being quite variable, the majority of the arterial supply approaches from the medial and inferior borders of the adrenals with few substantial arteries from the superior, posterior, or lateral sides. The adrenal arteries are generally small and amenable to electrocautery or vessel sealing devices.

Generally, the venous drainage from the right adrenal was thought to consist of a single, large, short vein draining into the IVC. On the left, drainage was thought to proceed to the left renal vein or inferior phrenic vein via a longer, single vein. These anatomic descriptions were based largely on cadaveric studies on non-diseased adrenal glands. In the 1940s, Anson and Caudwell identified only a single venous variant in nearly 900 adrenals examined.¹ However, others have found significant heterogeneity in venous anatomy during operative intervention for adrenal pathology. Scholten et al. found 13% variance in venous anatomy in 546 consecutive adrenalectomies—no main adrenal vein, a single main vein with multiple small veins, double adrenal veins, and drainage sites including the IVC, hepatic vein, or inferior phrenic vein. The incidence of variant anatomy was more likely on the right side, with larger tumors, and with pheochromocytomas. Further, variant anatomy is associated with higher rates of transfusions due to operative complications.²

Each gland is divided into an outer cortex and an inner medulla, which are histologically and functionally distinct layers derived from separate embryologic origin. The cortex originates from mesodermal cells that form into cords of endocrine cells. In the adult, the cortex is composed of three zones. From outermost to innermost, they are: (1) zona glomerulosa, which regulates electrolyte homeostasis via production of aldosterone in response to the renin-angiotensin system, potassium concentration, and atrial natriuretic peptide, (2) zona fasciculata, which produces cortisol to promote gluconeogenesis and delivery of glucose to tissues, and (3) zona reticularis, which develops after roughly age 5 and produces the androgens dehydroepiandrosterone (DHEA) and dehydroepiandrosterone sulfate (DHEAS) in response to adrenocorticotrophic hormone (ACTH) stimulation.³

The medulla is derived from neural crest cells, called chromaffin cells, which migrate and become imbedded into the inner portion of the gland. They develop into modified postganglionic sympathetic neurons that secrete up to 80% of the epinephrine and 20% of the norepinephrine in circulation in response to centrally mediated sympathetic cholinergic stimuli during stress. Cortisol produced in the cortex is shuttled past the medullary chromaffin cells, which increases production of phenylethanolamine-N-methyltransferase (PNMT), which converts norepinephrine to epinephrine.³

The following sections detail specific conditions along with the evaluation and treatment approaches for adrenal disease. This is summarized in Table 81-1

Diseases of the Cortex

ADENOMA

Cortisol Producing—Cushing Syndrome

Adrenal adenomas that produce cortisol can be incidentally discovered during abdominal imaging or when the patient develops the signs and symptoms of Cushing syndrome. In the early 1930s, Harvey Cushing was among the first to describe the clinical entity of hypercortisolism, which is characterized by truncal obesity, round face, fragile skin, depression, and abdominal striae. These tumors autonomously secrete cortisol without the usual dependence on ACTH and can increase the risk of cardiovascular complications and mortality. Preoperative testing includes overnight dexamethasone suppression test, 24-hour urine collection for free cortisol, and salivary cortisol measurement.^4,5 To perform the overnight dexamethasone test, give 1 mg of dexamethasone at 11 pm and then check serum cortisol at 8 am, which should suppress under 5 μg/dL.⁶ Some clinicians will increase the dose of dexamethasone to 2 or 3 mg, perform a 48-hour suppression test, or decrease the threshold of an abnormal am serum cortisol level to 1.8 μg/dL in order to reduce the false negative rate.^7,8 Table 78-2 shows common methods for testing.

Adrenalectomy in this population has been associated with normalization of blood pressure, dyslipidemia, glucose metabolism, body mass index, and improved quality of life.⁹ Bilateral adrenalectomy is indicated for severe ACTH-independent and ACTH-dependent Cushing syndrome that cannot be medically controlled.^10,11

Because adrenocortical carcinomas (ACCs) also frequently secrete cortisol, a careful preoperative evaluation should be performed to look for signs of malignancy, such as radiographic evidence of local invasion, regional lymphadenopathy, distant metastases, and rapid growth. Small tumor size and well-defined borders are features commonly found in benign, cortisol-producing adenomas. Furthermore, adenomas tend to be homogenous, lack necrosis, and have radiodensities lower than 10 Hounsfield units.⁴ For newly discovered adrenal masses, the risk of ACC is significantly higher in tumors that are larger than 6 cm. When previous studies are available, comparison should be used to determine tumor growth, since ACCs tend to grow at a much higher rate than benign adenomas.

The obesity resulting from Cushing syndrome can present an additional technical challenge for laparoscopy. Furthermore, tissues tend to be weak such that port sites at the skin typically dilate during the procedure, resulting in gas leakage during the operation. Therefore, it is ideal to make the port site incisions as small as technically possible to avoid gas leakage during peritoneal insufflation.

Postoperatively, adrenal function may be suppressed in the contralateral gland, and patients should be given a prophylactic hydrocortisone taper to avoid potential postoperative adrenal insufficiency, which can be life threatening. The steroid taper can progress according to patient symptoms and can be monitored with serum cortisol and morning ACTH levels as well as an ACTH stimulation test. Clinicians should closely monitor for the signs of Addisonian crisis, which include hemodynamic instability, abdominal discomfort, fatigue, and electrolyte imbalance. Mineralocorticoid replacement with a fludrocortisone taper may also be required. Lastly, patients with mild or subclinical Cushing syndrome may not require a steroid taper. Some groups will check a serum cortisol level the morning after surgery; if levels exceed a threshold (eg, 8 μg/dL), patients can be followed closely for signs and symptoms of Addisonian crisis without a steroid taper.

Aldosterone Producing—Conn Syndrome

Aldosteronomas are cortical adrenal tumors that autonomously secrete aldosterone. Hyperaldosteronism was first described by Jerome Conn in 1955 and is characterized by hypertension and hypokalemia.¹² These symptoms should be controlled preoperatively with an aldosterone antagonist and potassium supplements. Biochemical confirmation of autonomous hypersecretion of aldosterone should be confirmed prior to adrenalectomy. Primary preoperative testing includes measurement of the plasma aldosterone and renin concentration where an aldosterone to renin ratio greater than 20 ng/dL or an aldosterone level greater than 15 ng/dL is indicative of disease.^4,13 Confirmatory testing is best achieved by salt loading with normal saline solution and measurement of plasma aldosterone (Table 78-2).¹⁴ Aldosterone antagonists should be held prior to testing for at least a few weeks. While there are several forms of primary hyperaldosteronism, surgery is indicated only in the setting of unilateral adrenal adenoma or hyperplasia. There is a general lack of randomized controlled trials comparing medical and surgical management of aldosteronomas in terms of managing hypertension and albuminuria. Surgery appears to be associated with need for fewer antihypertensives, less cost (due to decreased need for intense follow-up), and overall increased quality of life.¹⁵

Since benign, nonfunctional adrenal tumors are common relative to the incidence of Conn syndrome, selective venous sampling should be used to confirm laterality of disease in patients who are older than 40 years. Although many surgeons believe that computerized tomography (CT) or magnetic resonance imaging (MRI) is sufficient when unilateral disease is identified in younger patients, it is our practice to perform selective venous sampling for all patients who are considered candidates for adrenalectomy.¹⁶ This is supported by a recent study that found that 50% of patients within a primary hyperaldosteronoma cohort would have been inappropriately managed based on preoperative CT findings alone.¹⁷

Postoperatively, normalization of aldosterone levels confirms surgical cure and is typically associated with correction of hypokalemia. Infrequently, hyperkalemia can result from chronic suppression of the contralateral adrenal gland. With complete resection of the aldosteronoma, nearly all patients have normal serum potassium levels and hypertension is improved in most. Approximately half of patients can stop all hypertensive medications after adrenalectomy, and the remainder require less medication. Thus, antihypertensive medications should be held for the first day after surgery to determine if the patient has persistent hypertension. When hypertension persists after curative adrenalectomy, it is usually due to underlying essential hypertension.

ADRENOCORTICAL CARCINOMA

ACC is a rare (1-2 cases per million individuals) and aggressive tumor derived from the adrenal cortex. Women are affected more frequently than men, and left-sided tumors are more common than right. The side predominance may be related to the proximity of right-sided tumors to the IVC, thus precluding surgery and national registration. Early age at diagnosis, a family history of cancer, and parallel primary tumors in a proband should raise suspicion of an inherited cancer syndrome such as Beckwith–Wiedemann, Li–Fraumeni, Carney, multiple endocrine neoplasia 1, or Lynch syndrome.^18,19

At presentation, most tumors are large, and as many as 60% in adults autonomously hypersecrete cortisol or sex steroids. Preoperative findings consistent with ACC, and thus important for planning, are large size, irregular borders, and extension into surrounding structures. ACC tends to be vascular, greater than 10 Hounsfield units, and associated with necrosis on CT imaging.⁴ Sturgeon et al. found that tumors greater than 4 cm in size and those that were greater than 8 cm had a 10% and 47% likelihood of malignancy, respectively.²⁰ Other methods such as PET-CT, mass spectrometry analysis of urinary steroid profiling, and ¹²³I imaging have shown utility in the diagnosis of ACC.¹⁸

The overall 5-year survival is roughly 30%. For tumors less than 5 cm and without lymph node involvement, median survival may be as high as 10 years.¹⁸ Metastatic disease holds a grim prognosis and is predominately dealt with medically. We recommend surgical intervention if (1) complete resection of the primary tumor is feasible in the absence of metastases, (2) when resection or ablation of oligometastases is feasible, or (3) when the patient may benefit from the palliative debulking of a functional tumor.¹⁹

The cornerstone of systemic medical therapy is mitotane, which specifically targets the adrenal gland. However, mitotane is adrenolytic and it rarely results in a complete response. Other agents such as cisplatin and streptozosin are often used in concert.^19,21 Although there was no effect on overall survival, the FIRM-ACT trial showed that use of etoposide, doxorubicin, and cisplatin in combination with mitotane, as opposed to streptozosin, was associated with increased progression-free survival and tumor response rate.²¹

Complete surgical resection is the only curative treatment for ACC. Classically, a formal lymph node dissection has not been carried out, but recent data suggest a prognostic benefit to lymph node dissection, a decreased risk of local recurrence, and a decrease in disease-related death when lymph node dissection is performed.¹⁸

Local invasion typically precludes complete extirpation. Thus, often a large incision is necessary for adequate exposure, complete resection of invaded structures, and vascular control. All structures with evidence of invasion require resection. In a study of 133 patients who underwent open anterior resection of their ACC, 55 had an extended operation consisting of removal of the kidney (27), kidney plus other (19), or other organ (9) at their index operation. Initial recurrence at 28 months occurred most often locally, followed by distant metastasis, nodal disease, and peritoneal carcinomatosis. Median disease-free survival was 13 months, and overall median life expectancy was 43 months.²²

Patients with borderline resectable disease—as defined by imaging suggestive of resectable metastasis or local invasion requiring multiorgan or vascular resection—may benefit from neoadjuvant chemotherapy followed by complete surgical resection.²³ When counseling patients about their options, it is important to balance the morbidity that is often inherent in complete surgical resection and organ preservation that is potentially afforded by early use of chemotherapy.

Those with high risk of recurrence—as defined by large tumor size, positive margins, and tumor capsule rupture—are candidates for adjuvant chemotherapy and radiation. Postoperative follow-up includes regular imaging and biomarker analysis.

There have been multiple studies aimed at characterization of ACC tumor biology in hopes of defining molecular targets for therapy, disease prediction, and prognostication. Techniques such as next-generation sequencing and RNA interference are changing how we look at tumor biology and the information we can provide our patients. For example, while not yet clinically used, tumor microRNA analysis appears to provide important prognostic and diagnostic value in terms of disease progression, recurrence, and survival.²⁴ As we become more sophisticated in our characterization, we stand to improve our clinical fidelity and decision making.

Miscellaneous

Simple cystic lesions are usually incidental, and surgery is not indicated unless there is a solid component to the cyst wall. Complex cysts with evidence of local invasion should undergo open resection. Large cysts that cause symptoms or that carry a high risk of spontaneous rupture can be excised by laparoscopic nodulectomy or subjected to fenestration of the cyst wall into the peritoneal cavity.

Myelolipomas are also typically discovered in an incidental manner. Their appearance can cause confusion with liposarcoma, a situation easily resolved with needle biopsy showing typical bone marrow elements. Patients with these benign adrenal lesions are often referred to surgery because of compressive symptoms

Diseases of the Medulla

PHEOCHROMOCYTOMA

Pheochromocytomas are rare neuroendocrine tumors that are derived from chromaffin cells and usually arise from the adrenal medulla. Although most pheochromocytomas are sporadic and unilateral, genetic syndromes such as multiple endocrine neoplasia 2a/2b and von Hippel–Lindau increase the risk of bilateral disease. They can produce catecholamines such as epinephrine, norepinephrine, and dopamine that can cause the classic clinical symptomatology of this disease: episodic headaches, palpitations, and diaphoresis. Rarely, pheochromocytomas are nonfunctional.

The Endocrine Society recently published practice guidelines for the evaluation and management of pheochromocytoma/paraganglioma.²⁵ The biochemical diagnosis can be made with either fractionated urine catecholamines (24-hour collection) or serum metanephrines (Table 78-2).²⁶ Due to the high level of false positive results, plasma metanephrine testing should be completed in patients with a high pretest probability.²⁷ Furthermore, at least a fourfold elevation of these biochemical tests should be expected from symptomatic pheochromocytoma. Surgeons should be aware that many medications could influence these biochemical tests, which include, but are not limited to, acetaminophen, β-blockers, vasodilators, α-blockers, stimulants, antipsychotics, antidepressants, and calcium channel blockers. Equivocal results should prompt repeat testing after holding these medications. Marginal elevations in biochemical tests are unlikely to driven by pheochromocytoma. Clinical context is important for diagnosis, since pheochromocytoma can be excluded with confidence when testing results are normal in a hypertensive and symptomatic patient.²⁵ Borderline serum metanephrine elevations less than fourfold warrant repeat testing after 30 minutes of supine rest.

CT imaging is similar to that for ACC—tumors tend to be large, heterogeneous, solitary, hypervascular, and greater than 10 Hounsfield units.⁴ Pheochromocytomas typically have a characteristic intensity on T2-weighted MRI. This is an ideal imaging modality for patients with surgical clips that cause artifacts on CT, in patients with an allergy to iodinated contrast agents, and in patients who cannot receive ionizing radiation. Meta-iodobenzylguanidine (MIBG) enables scintigraphic functional imaging of the whole body, which is useful when familial, extradrenal, or metastatic disease is suspected. Rarely, MIBG can be useful in the final diagnosis of equivocal cases. MIBG scanning is not as sensitive as FDG-PET CT for finding extra-adrenal tumors and metastatic disease. In patients with metastatic pheochromocytoma, I123-MIBG scanning can also be useful to determine whether future high-dose I131-MIBG can be a treatment option.²⁸

Preoperative preparation with α-blockade (eg, phenoxybenzamine, doxazosin) and salt loading should be undertaken. Ideally, this can be done in the outpatient setting. The α-blocker is titrated up to the maximal tolerated dose, which is typically limited by orthostatic hypotension. Salt loading, either by ingestion of salty foods or by saline infusion, can help to reduce orthostasis and enable higher doses of α-blocker. In addition, β-blockade can be added to the regimen if the patient has persistent tachyarrhythmias. Although the optimal preparation time before pheochromocytoma resection is controversial, we generally α-block and salt-load patients for 1 to 2 weeks before elective adrenalectomy and operate only after orthostatic hypotension is achieved.

Delicate tissue handling and avoidance of tumor compression should be emphasized to minimize catecholamine release. Because tumor manipulation and adrenal vein clipping can result in significant hemodynamic changes, coordination and communication between the adrenal surgeon and anesthesiologist are critical to the success of this operation. It has been generally proposed that in the resection of pheochromocytomas ligation of the adrenal vein should precede the rest of the dissection to limit hemodynamic instability. However, delayed ligation of the vein has been shown to result in a similar rate of intraoperative hypertension and concentration of plasma catecholamines when compared with early ligation.^29,30 Further, some authors caution that adrenal vein ligation increases intratumor venous pressure, which can increase bleeding.²⁹ In our practice we have found that grasping the tumor side of the divided adrenal vein to be quite helpful. Regardless of the decision on timing of ligation, communication between the surgical and anesthesia teams is imperative because hypotension often accompanies vein ligation.

Paraganglioma

Paragangliomas are neuroendocrine tumors histologically similar to pheochromocytomas but that occur in extra-adrenal sites throughout the pelvis, abdomen, chest, neck, and head. Most of these tumors are sporadic, although some are associated with hereditary paraganglioma syndromes. They typically present as a painless mass or with the symptomatology of a pheochromocytoma resulting from catecholamine production. There are a several case reports of successful laparoscopic resection of these tumors, but the decision to pursue laparoscopy again is determined by location and size of the paraganglioma.^31-33