Browse the corpus

Adrenal cortical hyperplasia refers to the abnormal enlargement of the adrenal glands' cortex, which is responsible for producing essential hormones such as cortisol, mineralocorticoids, and sex hormones. This condition often arises from enzyme dysfunctions that disrupt these hormone pathways, potentially leading to life-threatening complications. While radiological findings may reveal growths or nodules, differentiating functional from non-functional lesions poses a diagnostic challenge. The increasing discovery of adrenal incidentalomas highlights the need for clinicians to refine their diagnostic approach, given that most of these lesions are benign, but a small percentage may be linked to serious conditions, including adrenocortical carcinoma. Proper diagnosis requires collaboration between clinical evaluation and advanced imaging techniques, with input from endocrinologists and radiologists. Participants in this course learn to evaluate and manage adrenal cortical hyperplasia by integrating current diagnostic strategies and treatment approaches. The course emphasizes the importance of interprofessional collaboration, where primary care clinicians, endocrinologists, radiologists, and surgeons work together to improve diagnostic accuracy and treatment outcomes. By fostering coordination between specialties, healthcare teams can better differentiate benign from malignant lesions and optimize patient care through timely interventions, ultimately enhancing patient safety and reducing the risks of misdiagnosis. Objectives: Recognize adrenal lesions through advanced imaging techniques and distinguish between incidentalomas and potentially functional or malignant nodules. Implement systematic screening protocols for patients with risk factors such as age, diabetes, hypertension, and obesity to detect adrenal lesions promptly. Apply evidence-based diagnostic approaches, including hormonal assays and imaging modalities, to accurately assess the functionality of adrenal lesions and guide appropriate management. Coordinate follow-up care and long-term monitoringfor patients with adrenal lesions with an interprofessional healthcare team, fostering a proactive approach to address any changes in lesion characteristics or patient symptoms. Access free multiple choice questions on this topic.

The adrenal glands are paired retroperitoneal structures located superior to the kidneys. Adrenal glands are divided into 2 physiologically separated segments: the cortex and the medulla. The cortex has 3 distinct layers: the zona glomerulosa, which secretes mineralocorticoids; the zona fasciculata, which secretes glucocorticoids; and the zona reticularis, which secretes androgens. The adrenal medulla secretes epinephrine and norepinephrine in response to dopamine, which is secreted during stress reactions.[1] Cortical hyperplasia is the enlargement of the adrenal cortex, usually due to functional or, more commonly, nonfunctional nodules.[1] Adrenal tumors are very common and often discovered incidentally on imaging for unrelated issues. Present in up to 4% of the general population, the incidence increases with age, in those with diabetes, hypertension, or who are obese. Increased detection of cortical enlargement is also due to imaging technology advances and increased frequency of imaging studies. For example, in the United States and Canada, between 2000 and 2016, the number of magnetic resonance imaging and computed tomography studies performed doubled and, in some cases, even tripled. Incidentally found lesions are often called "incidentalomas" due to the benign nature of most lesions. However, there are some exceptions, notably functional adrenal lesions (usually secreting cortisol) comprising fewer than 10% of the total lesions and adrenocortical carcinoma comprising fewer than 2% of all cases—but with metastatic potential. In addition, the adrenal gland is highly vascularized, despite its small size, and therefore is at risk for metastatic disease. The most common primary malignancies metastatic to the adrenal gland are lung (about 35%), gastrointestinal, kidney, and breast. Bilateral nodules are more common with metastatic disease than other etiologies, so this finding should raise concern for metastatic disease.[2]

Various etiologies of adrenal cortical hyperplasia are described and are typically classified into adrenocorticotropic hormone (ACTH)-dependent and ACTH-independent causes. Moreover, many other disorders masquerade with the signs and symptoms of adrenal cortical hyperplasia. While the most common etiology of Cushing syndrome is the exogenous administration of corticosteroids, endogenous etiologies are commonly encountered. Cushing disease and Cushing syndrome are named after Dr Harvey Cushing, a neurosurgeon who first described Cushing disease, in which the basophil cells of the pituitary are overstimulated. This accounts for most endogenous Cushing syndrome cases. Although the discrete threshold of pituitary adenoma has not been identified yet, a tumor size larger than 6 millimeters is highly indicative of Cushing disease as the cause of Cushing syndrome.[3] Ectopic ACTH secretion, mostly due to paraneoplastic causes, is the second-most common cause of ACTH-dependent cortical hyperplasia.[4][5] ACTH-independent hypercortisolism, or adrenal-originating Cushing syndrome, may occur due to conditions including primary pigmented nodular adrenal disease (PPNAD) or ACTH-independent macronodular adrenal hyperplasia. PPNAD is categorized as with or without association with Carney complex. ACTH-independent macronodular adrenal hyperplasia presents in the late 40s, is more common in men, and is characterized by extremely enlarged adrenal glands—up to 20 to 25 times normal.[6][7] Carney Complex and Adrenal Hypercorticoplasia Carney complex (CNC) is a rare genetic mutation caused by inactivating mutations of PRKAR1A (CNC1) localized on the long arm of chromosome 17. PRKAR1A codes for the type 1A regulatory protein kinase A (PKA) subunit. The mutation(s) is inherited in an autosomal dominant pattern, but up to 30% of cases are de novo mutations.[8] Of note, CNC has previously also been called NAME (nevi, atrial myxoma, ephelides) and LAMB (lentigines, atrial myxoma, blue nevi) syndrome.[9] Please see StatPearls' companion reference "Carney Complex" for further information.[10]

Carney complex (CNC) is a rare genetic mutation caused by inactivating mutations of PRKAR1A (CNC1) localized on the long arm of chromosome 17. PRKAR1A codes for the type 1A regulatory protein kinase A (PKA) subunit. The mutation(s) is inherited in an autosomal dominant pattern, but up to 30% of cases are de novo mutations.[8] Of note, CNC has previously also been called NAME (nevi, atrial myxoma, ephelides) and LAMB (lentigines, atrial myxoma, blue nevi) syndrome.[9] Please see StatPearls' companion reference "Carney Complex" for further information.[10] The clinical presentation of CNC is variable even within families, and diagnosis is often delayed, sometimes by decades, due to a lack of knowledge regarding this rare condition. Currently, about 750 cases have been described worldwide, but many more undiagnosed cases likely exist. The constellation of symptoms includes 4 major criteria: Spotty skin pigmentation: Pigmented lentigines and blue nevi on the face, neck, and trunk, including the lips, conjunctivae, and sclera. Abnormal skin pigmentation may be present at birth, but lentigines develop during puberty. Endocrine tumors: PPNAD is the most common endocrine finding in CNC. Less common findings include growth hormone-secreting pituitary adenomas, thyroid adenomas, and thyroid carcinomas. Myxomas: These include cardiac myxomas (most importantly), breast myxomatosis, osteochondromyxomas, and cutaneous and mucosal myxomas. Nonendocrine tumors: These include psammomatous melanotic schwannomas, ovarian cysts, testicular large-cell calcifying Sertoli cells, and breast ductal adenomas.[11] Definitive diagnosis of CNC requires 2 or more of these manifestations. Diagnosis may also be made if one of the above major criteria is present and a first-degree relative has CNC or an inactivating mutation of PRKAR1A. About 80% of patients with PPNAD show a variant in the PRKAR1A gene. Cardiac myxomas and psammomatous schwannomas are the most common causes of mortality.[11]

Results from many studies have shown an incidence of adrenal nodules of up to 10% in the older population.[12] Benign adrenal adenomas are rarely seen in patients younger than 30, so if noted, these nodules require further evaluation. Lesions smaller than 1 cm and less than 10 Hounsfield units on computed tomography scans are generally considered benign and do not necessarily require further workup.[13] Macronodular adrenal hyperplasia is a very rare disorder and occurs in less than 1% of patients with endogenous Cushing syndrome. The prevalence of endogenous Cushing syndrome is approximately 1 in 26,000 people. MAH most commonly affects people in their 40s to 50s with no known sex predilection.[14] Patients with PPNAD present before age 30 years and, in half of cases, before age 15 years.[9][15] Patients' sex and pubertal status change the development of Cushing syndrome in PPNAD: after adolescence, PPNAD affects women more than men; by the age of 40, more than 70% of women with PRKAR1A mutation develop PPNAD, compared to 45% of men.[16]

ACTH-independent causes of Cushing syndrome account for about 15% to 20% of cases and are related to primary hormone production by the adrenal gland. Unilateral adrenal causes are adenomas and carcinomas; bilateral causes are PPNAD and macronodular adrenal hyperplasia. With ACTH-independent sources, the serum ACTH level is expected to be low. ACTH-dependent causes include pituitary production of ACTH (Cushing disease) and ectopic ACTH production, usually by a neoplastic process. About 80% to 85% of excess ACTH production is due to pituitary adenomas or, very rarely, carcinomas. The most common neoplastic cause of ectopic ACTH is lung cancer, especially bronchial carcinoid tumors and small cell lung cancer. Other ectopic ACTH sources include neuroendocrine tumors involving the thymus, bowel, pancreas, thyroid, or pheochromocytoma. In up to 20% of cases of ectopic ACTH, the source is never discovered. Adrenal nodularity is more common with ectopic than with pituitary ACTH.[17] Congenital adrenal hyperplasia is an autosomal recessive disorder with gene mutations for enzymes that produce glucocorticoids, mineralocorticoids, or sex hormones. The negative feedback inhibition of ACTH by the pituitary is consequently interrupted, leading to hyperplasia of the adrenal cortex and increased production of steroid precursors in the pathway, most of which are converted to androgens. Up to 95% of cases are caused by deficiency of the 21-hydroxylase enzyme. Please see StatPearls' companion reference, "Congenital Adrenal Hyperplasia," for further information. Primary aldosteronism is thought to occur in 5% to 20% of patients who are hypertensive, but it is often overlooked. About half of these cases are due to an aldosterone-producing adenoma.[18] Aldosterone is the primary hormone produced by the zona glomerulosa in response to angiotensin II, potassium, and, to a lesser extent, ACTH. ACTH increases aldosterone through stimulation of the early steps in the steroidogenesis pathway, contributing to increased aldosterone. After binding to nuclear mineralocorticoid receptors, aldosterone increases the reabsorption of sodium and excretion of both potassium and hydrogen ions in kidney tubules.[19] In primary aldosteronism, the adrenal glands can appear normal, enlarged, or nodular.[18]

Primary aldosteronism is thought to occur in 5% to 20% of patients who are hypertensive, but it is often overlooked. About half of these cases are due to an aldosterone-producing adenoma.[18] Aldosterone is the primary hormone produced by the zona glomerulosa in response to angiotensin II, potassium, and, to a lesser extent, ACTH. ACTH increases aldosterone through stimulation of the early steps in the steroidogenesis pathway, contributing to increased aldosterone. After binding to nuclear mineralocorticoid receptors, aldosterone increases the reabsorption of sodium and excretion of both potassium and hydrogen ions in kidney tubules.[19] In primary aldosteronism, the adrenal glands can appear normal, enlarged, or nodular.[18] Macronodular adrenal hyperplasia, associated with an elevated level of cortisol with a decreased level of plasma ACTH, occurs via several mechanisms, including: One mechanism is an extraordinarily increased expression of aberrant G-protein-coupled receptors located throughout the membranes of specific cells capable of producing estrogen via specific corresponding ligands.[20][21] Another mechanism is the indirect function of the abnormally enlarged adrenal tissue is via a paracrine effect.[22] Specific mutations with several variable types, including germline and somatic mutations are evident in approximately 50% of those affected with bilateral macronodular adrenal hyperplasia.[23]

With ACTH-independent cortical nodular hyperplasia, the glands are massively enlarged, mimicking a neoplasm. In the later stages, cortical nodules sometimes show a transformation from diffuse hyperplasia; these nodules are yellow and vary in size from 0.2 to larger than 4.0 cm. The nodules are composed of fasciculata-type clear cells, reticularis-type cells, or a mixture of both cell types. Distinct nodules with zona glomerulosa hyperplasia and intervening cortical atrophy are observed in children with McCune-Albright syndrome.[24][25] In PPNAD (sometimes referred to as “micronodular adrenal disease”), the glands are usually normal-sized, although they can be small or slightly enlarged. Multiple pigmented cortical nodules are commonly seen amidst an atrophic cortex.[26][27] The nodules may abut the corticomedullary junction, extend beyond the periadrenal fat, or involve cortical full thickness. Pigmentation is due to intracytoplasmic lipofuscin. The nodules are composed of uniform eosinophilic cells with some balloon cells similar to the normal zona reticularis. The cells are strongly positive for synaptophysin but negative for chromogranin.[28] Occasional additional pathologic findings include microscopic foci of necrosis, mitotic figures, and a trabecular growth pattern.[29]

A comprehensive organ system and generalized physical examination for visceral or central obesity, increased blood pressure, purple skin striae, non-generalized muscle atrophy, and skin discoloration should be undertaken. Signs and symptoms of elevated plasma and urinary cortisol, including significant weight gain, abnormal menstruation cycles, and hirsutism, should be noted. Other signs of hypercortisolism include decreased bone mineral density, accumulated fat depositions in the posterior neck, and fertility disturbances; these should raise suspicion for adrenal cortical hyperplasia. In the presence of the mentioned signs and symptoms accompanied by a positive history of exogenous corticosteroid administration, further diagnostic investigation is unnecessary. In the absence of exogenous steroids, a variety of imaging and laboratory examinations, including brain magnetic resonance imaging (MRI) and chest and abdominopelvic computed tomography (CT) scans, should be obtained to clarify the possible underlying cause of Cushing disease.[4]

Patients affected with adrenal cortical hyperplasia may present with clinical and laboratory evidence of an increased level of aldosterone, including elevated blood pressure, decreased level of serum potassium, and abnormal arterial blood gas demonstrating metabolic alkalosis.[30][31] An elevated level of cortisol can be documented utilizing several specific laboratory examinations, including the measurement of unbound cortisol in 24-hour collected urine, evaluating the dexamethasone suppression test, and the assessment of nocturnal salivary cortisol.[32] Urine Cortisol Test: 24 Hour This measures the amount of urine cortisol produced over an entire day. Levels higher than 50 to 100 micrograms per day in an adult suggest hypercortisolism. Although most patients with Cushing syndrome have elevated levels of cortisol, it is becoming increasingly evident that many patients with mild cases of Cushing syndrome may also have normal levels of cortisol, requiring several 24-hour urine collections to confirm a diagnosis.[32] Dexamethasone Suppression Test This measures the adrenal glands' response to ACTH and has been widely utilized for 4 decades. This test involves taking a small dose of a cortisol-like drug, dexamethasone (1 mg), at 11 PM, then having blood drawn to screen for cortisol the following morning. In patients without Cushing syndrome, the morning level of cortisol is typically very low after dexamethasone administration, which should suppress ACTH and cortisol production. Normal patients will suppress their cortisol to a very low level (1.8 mg/dL), whereas those with ACTH-dependent Cushing syndrome will not. Using this strict criterion, this test should provide an estimated 95% to 97% diagnostic accuracy rate. However, some patients with a mild case of Cushing disease may suppress their cortisol to low levels, making it difficult to use this test in mild cases.[32] A brief summary of this test is that with a normal pituitary-adrenal axis, low-dose dexamethasone will suppress ACTH, leading to low ACTH and cortisol. With Cushing disease, ACTH and cortisol levels are high. Test results are as follows: The low-dose test does not suppress morning cortisol levels. The high-dose test does suppress morning cortisol levels, indicating a pituitary source of ACTH.

A brief summary of this test is that with a normal pituitary-adrenal axis, low-dose dexamethasone will suppress ACTH, leading to low ACTH and cortisol. With Cushing disease, ACTH and cortisol levels are high. Test results are as follows: The low-dose test does not suppress morning cortisol levels. The high-dose test does suppress morning cortisol levels, indicating a pituitary source of ACTH. With ectopic ACTH production, neither dexamethasone dose is suppressive, leading to high ACTH and cortisol. With an adrenal source, cortisol will be high and ACTH low. Late-night Salivary Cortisol Test This test checks for elevated cortisol levels in the saliva between 11 pm and midnight. Cortisol secretion is usually very low late at night, but in patients with Cushing syndrome, the level will always be elevated. Saliva collection requires special sampling tubes; however, this is an easy test for patients to perform and can be done multiple times. Normal levels of the late-night salivary cortisol virtually exclude the diagnosis of Cushing syndrome. The normal salivary cortisol level between 10 pm and 1 am is less than 0.09 mcg/dL.[33] The collection of saliva for cortisol assay using mass spectrometry/chromatography needs to follow a specific protocol, such as 0.5 mL saliva (minimum volume 0.2 mL) collected at least 60 minutes after brushing the teeth or liquid/solid food intake and 10 minutes after rinsing the mouth with water to avoid contamination of the saliva by interfering substances. The patient is then instructed to place the salivary kit swab in the mouth,  where it should remain for 2 minutes without chewing. If an extremely small amount of saliva is produced, the patient is asked to leave the swab in the mouth for longer. This sample must be refrigerated immediately and transported on an ice pack. The specimen stability at standard room temperature is 72 hours but longer when refrigerated (21 days) or frozen (6 months).[33]

This test checks for elevated cortisol levels in the saliva between 11 pm and midnight. Cortisol secretion is usually very low late at night, but in patients with Cushing syndrome, the level will always be elevated. Saliva collection requires special sampling tubes; however, this is an easy test for patients to perform and can be done multiple times. Normal levels of the late-night salivary cortisol virtually exclude the diagnosis of Cushing syndrome. The normal salivary cortisol level between 10 pm and 1 am is less than 0.09 mcg/dL.[33] The collection of saliva for cortisol assay using mass spectrometry/chromatography needs to follow a specific protocol, such as 0.5 mL saliva (minimum volume 0.2 mL) collected at least 60 minutes after brushing the teeth or liquid/solid food intake and 10 minutes after rinsing the mouth with water to avoid contamination of the saliva by interfering substances. The patient is then instructed to place the salivary kit swab in the mouth,  where it should remain for 2 minutes without chewing. If an extremely small amount of saliva is produced, the patient is asked to leave the swab in the mouth for longer. This sample must be refrigerated immediately and transported on an ice pack. The specimen stability at standard room temperature is 72 hours but longer when refrigerated (21 days) or frozen (6 months).[33] When the impression is Cushing syndrome with the laboratory evidence of an increased cortisol level has been established, the exclusion of exogenous hypercortisolism should be prioritized.[34] Following the exclusion of exogenous hypercortisolism, the stepwise diagnosis approach demands differentiation of the major causes into those that are ACTH-dependent and ACTH-independent. Plasma ACTH levels should be evaluated to categorize the mentioned groups. Afterward, corticotropin-releasing hormone assessment is recommended if there is any uncertainty in diagnosis.[35]

When the impression is Cushing syndrome with the laboratory evidence of an increased cortisol level has been established, the exclusion of exogenous hypercortisolism should be prioritized.[34] Following the exclusion of exogenous hypercortisolism, the stepwise diagnosis approach demands differentiation of the major causes into those that are ACTH-dependent and ACTH-independent. Plasma ACTH levels should be evaluated to categorize the mentioned groups. Afterward, corticotropin-releasing hormone assessment is recommended if there is any uncertainty in diagnosis.[35] Further confirmatory tests, including serum aldosterone and metanephrines, are highly recommended for patients who are undiagnosed after the previously mentioned studies. In most of the patients with Cushing syndrome, the etiology is ACTH hypersecretion.[36] Early on, obtaining a brain MRI and abdominal CT scan is recommended for ACTH-dependent and ACTH-independent cases, respectively.[37] The patient’s age has a significant impact on obtaining the diagnosis. Congenital adrenal hyperplasia, primarily diagnosed during childhood, is among ACTH-dependent types of adrenal hyperplasia. A variety of enzymatic defects are responsible; however, the most common defect responsible for congenital adrenal hyperplasia is the 21-hydroxylase deficiency. Therefore, screening for serum concentrations of 17-hydroxyprogesterone is among the screening tests that are routinely performed in the United States.[38][39] Imaging of Adrenal Nodules As mentioned earlier, the incidence of higher-resolution imaging has been increasing over the last decade; therefore, the prevalence of incidentalomas has also increased. The prevalence of adrenal incidentaloma is higher in older patients (10%), obesity, diabetes, and hypertension.[38][40] Bilateral masses: Bilateral adrenal masses can be seen with metastatic disease, congenital adrenal hyperplasia, cortical adenomas, lymphoma, infection (eg, tuberculosis, fungal), hemorrhage, ACTH-dependent Cushing syndrome, pheochromocytoma, primary aldosteronism, amyloidosis, infiltrative disease of the adrenal glands, macronodular adrenal hyperplasia. In one study of 208 adrenal incidentaloma patients, the results showed that 9% proved to have adrenal metastases, and 53% had bilateral disease.[41]

Bilateral masses: Bilateral adrenal masses can be seen with metastatic disease, congenital adrenal hyperplasia, cortical adenomas, lymphoma, infection (eg, tuberculosis, fungal), hemorrhage, ACTH-dependent Cushing syndrome, pheochromocytoma, primary aldosteronism, amyloidosis, infiltrative disease of the adrenal glands, macronodular adrenal hyperplasia. In one study of 208 adrenal incidentaloma patients, the results showed that 9% proved to have adrenal metastases, and 53% had bilateral disease.[41] CT scan features of nodules: The adrenal glands are often bilaterally smooth and enlarged. Nodularity is thought to result from long-term ACTH stimulation and is present in up to 40% of patients with ACTH-dependent etiologies.[17] A homogeneous adrenal mass smaller than 4 cm with a smooth border and an attenuation value of less than 10 Hounsfield units (HU) on unenhanced CT is very likely to be a benign cortical adenoma. Imaging characteristics suggesting adrenal carcinoma or metastases include irregular shape, inhomogeneous density, high unenhanced CT attenuation values of more than 20 HU, larger than 4 cm, and tumor calcification. All patients with adrenal incidentalomas should be evaluated for the possibility of subclinical hormonal hyperfunction or hypofunction. In some patients with bilateral disease, one adrenal mass proves to be a nonfunctioning cortical adenoma, while the contralateral adrenal mass is hormone-secreting.[42] MRI scans: Although CT is the recommended primary adrenal imaging procedure in most cases, MRI has advantages in certain clinical situations. Conventional spin-echo MRI is the most frequently used technique. Using low- or mid-field strength magnets, T1- and T2-weighted imaging can distinguish benign adenomas from malignancy and pheochromocytoma. MR with chemical shift imaging (CSI) accurately distinguishes adrenal adenomas from non-adenomas based on their elevated amounts of intracytoplasmic fat. Results from a large meta-analysis showed that CSI demonstrated a sensitivity of 94% and a specificity of 95%.[43]

MRI scans: Although CT is the recommended primary adrenal imaging procedure in most cases, MRI has advantages in certain clinical situations. Conventional spin-echo MRI is the most frequently used technique. Using low- or mid-field strength magnets, T1- and T2-weighted imaging can distinguish benign adenomas from malignancy and pheochromocytoma. MR with chemical shift imaging (CSI) accurately distinguishes adrenal adenomas from non-adenomas based on their elevated amounts of intracytoplasmic fat. Results from a large meta-analysis showed that CSI demonstrated a sensitivity of 94% and a specificity of 95%.[43] In addition, an MRI of the head is used to image the pituitary in Cushing disease. Surprisingly, the pituitary gland can appear normal in over 50% of cases of proven Cushing disease. In this situation, bilateral inferior petrosal sampling with corticotropin-releasing hormone stimulation can be useful. However, it should be noted that pituitary adenomas may be found incidentally in up to 10% of the population. A pituitary tumor larger than 6 mm is highly suggestive of Cushing disease.[17] Ultrasound and fluoroscopy (genitography) are most commonly used in the fetal period and children. Ultrasound is the imaging method of choice for babies and children as it lacks radiation and can usually be performed easily; this is commonly used to diagnose congenital adrenal hyperplasia.[17]

The treatment plan for pituitary adenomas primarily consists of trans-sphenoidal surgery using a microsurgical approach, which might cause up to 90%, and less than 70% absolute resolution in micro and macroadenomas, respectively.[44][45] A less common surgical approach in the treatment of Cushing disease is utilizing endoscopic tumor resection, which has been shown to improve outcomes.[46] The treatment plan for ectopic ACTH depends on the functional status of the patient. In those affected with clinically symptomatic Cushing syndrome and acceptable functional status, surgical resection of the inciting tumor is highly recommended, while medical treatment in those with poor functional status is preferred. Moreover, medical treatment might be prioritized in cases demanding emergent treatment of hypercortisolism and an unknown primary tumor. On the other hand, the treatment plan for those with intractable hypercortisolism and inoperable Cushing syndrome due to ectopic ACTH hypersecretion, bilateral surgical resection of the adrenal glands, and long-term hormone replacement is preferred.[47] ACTH-independent hypercortisolism might occur due to several reasons, including adrenal adenomas, primary pigmented nodular adrenal disease, or macronodular adrenal hyperplasia.[6] PPNAD is generally benign and is categorized into those with or without association with the Carney complex. The treatment plan for both conditions with curative purpose is bilateral surgical resection of adrenal glands.[6][48] The treatment for macronodular adrenal hyperplasia is similar to PPNAD, which consists of bilateral surgical removal of adrenal glands and lifelong glucocorticoid replacement.[6][7] Patients with unilateral adrenal hyperplasia who meet the following criteria should be scheduled for surgical resection: Imaging criteria suspicious for malignancy Nodules larger than 4 to 6 cm or other concerning radiology characteristics Clinical evidence of functional adrenal mass, including manifestations attributed to cortisol, aldosterone, or catecholamine hypersecretion [30][49][50][51] Although there is debate about treating those patients with mild hypercortisolism, there is a consensus on utilizing the dexamethasone suppression test to identify those benefiting from intervention.

Clinical evidence of functional adrenal mass, including manifestations attributed to cortisol, aldosterone, or catecholamine hypersecretion [30][49][50][51] Although there is debate about treating those patients with mild hypercortisolism, there is a consensus on utilizing the dexamethasone suppression test to identify those benefiting from intervention. With bilateral symmetrical hyperplasia, along with an elevated level of urinary cortisol more than 3 to 4 times above normal, bilateral adrenalectomy may be recommended.[52] Furthermore, those with less than 3 times elevation in urinary cortisol and bilateral macronodular adrenal hyperplasia may experience complete remission, but a significant 23% rate of recurrence must be taken into account.[53][54] Planning to resect only 1 of the adrenal glands remains controversial; some recommend the removal of the larger gland or the one with higher radioactive agent uptake, while others recommend making decisions based on more invasive assessments, including the results of adrenal venous sampling. Careful follow-up to exclude post-procedural adrenal insufficiency is crucial as it may occur in up to 40% of patients.[55] Those patients affected with bilateral adrenal cortical hyperplasia due to hyperadrenalism might be considered for non-surgical treatment with mineralocorticoids antagonists; however, if the cause of adrenal cortical hyperplasia is an adrenal cause, surgical management with bilateral surgical removal of adrenal glands and lifelong substitution of both glucocorticoid and mineralocorticoid should be considered.[56]

Pheochromocytoma is rare but the second most common tumor identified in adrenalectomy specimens and 7% of primary adrenal tumors.[57] The classic triad of symptoms—episodic headaches, sweating, and tachycardia—is seen in about 30% of the cases.[58] Histologic presentation overlaps with normal adrenal medulla. Adrenocortical carcinoma is a rare, very aggressive tumor with an estimated prevalence of between 0.5 and 12 per million.[59] The architecture is less ordered than in adenomas. Necrosis, increased mitosis, local invasion, and distant metastasis are common. Other differential diagnoses include metastases, lymphoma, myelolipoma, amyloidosis, and infections such as tuberculosis, histoplasmosis, and blastomycosis.

Predicting the prognosis of the standard surgical approach of the adrenal cortical hyperplasia depends on a variety of factors. However, medical responsiveness to specific potassium-sparing diuretics, like spironolactone, might be reliable and suggestive of a good prognosis. On the other hand, chronic elevation of blood pressure, along with multiple organ failure, predicts a poor prognosis.[60] The overall survival of Cushing syndrome of all causes has significantly improved over the last 70 years. Vascular compromise of the cardiac and nervous systems, along with infectious-related morbidities, were all found to be strong negative predictors of general outcomes and escalate the standard mortality ratio.[32]

Traditional surgical treatment of adrenal cortical hyperplasia harbors several complications, with the most common being bleeding, occurring during or after the surgical process in more than 1 out of 5 patients. Moreover, other surgery-related complications are incisional hernia and wound complications. Most predictably, medical complications related to surgical adrenalectomy include the effect of systemic elimination of cortisol. Among laparoscopic-related complications, infectious and thromboembolic morbidities are more common in devastating events.[61] In other words, surgical complications associated with adrenalectomy can be categorized based on the affected organ systems to include renal, cardiac, and pulmonary complications.[62]

Patients should be educated about the etiology and manifestations of their disease. When appropriate, genetic counseling may be advisable, such as in the case of Carney complex. Definite curative treatment of bilateral surgical resection of both glands requires lifelong hormone replacement. Compliance with this medication and the effects of insufficient replacement or overreplacement should be thoroughly reviewed with patients.

Primary care clinicians are often the first to encounter patients with clinical symptoms of excess hormone production. The precise diagnosis of adrenal cortical nodular hyperplasia is often obtained through laboratory and imaging tests requested by endocrinologists. After diagnosis, the patient might need to be referred to general or endocrine surgeons to schedule the appropriate operation. The pathologist should precisely examine the specimen to confirm the diagnosis and exclude other possible differential diagnoses. As ablative procedures impose a lifelong demand for glucocorticoid and mineralocorticoid replacement, the patient should be followed by an interprofessional team, including surgeons, endocrinologists, and pharmacists. During surgery, the anesthesiologist should be prepared for the most lethal and possible complications. Nurses frequently check the vital signs to preclude the possible devastating and irreversible consequences of bleeding and thromboembolic events, which is crucial in the postoperative period. Social workers help coordinate post-treatment care and home health services. A strategic approach is equally crucial, involving evidence-based strategies to optimize treatment plans and minimize adverse effects. Ethical considerations must guide decision-making, ensuring informed consent and respecting patient autonomy in treatment choices. Each healthcare professional must be aware of their responsibilities and contribute their unique expertise to the patient's care plan, fostering a multidisciplinary approach. Effective interprofessional communication is paramount, allowing seamless information exchange and collaborative decision-making among the team members. Care coordination plays a pivotal role in ensuring that the patient's journey from diagnosis to treatment and follow-up is well-managed, minimizing errors and enhancing patient safety. By embracing these principles of skill, strategy, ethics, responsibilities, interprofessional communication, and care coordination, healthcare professionals can deliver patient-centered care, ultimately improving patient outcomes and enhancing team performance when managing adrenal cortical nodular hyperplasia.