A comprehensive organ-system and generalized physical examination, considering visceral or central obesity, increased blood pressure, purple skin striae, non-generalized muscle atrophy, and skin discoloration, should be undertaken to evaluate adrenal cortical hyperplasia. Every sign and symptom of elevated level of plasma and urinary cortisol, including significant weight gain, abnormal menstruation cycles, hirsutism, should be considered. 

Several other evidence of the indirect effect of hypercortisolisms including diminished bone mineral density, accumulated fat depositions in specific areas, posterior aspect of the neck and proximal to the clavicle, and fertility disturbances should raise suspicion to the adrenal cortical hyperplasia. In the presence of the mentioned signs and symptoms accompanying with a positive history of exogenous corticosteroid administration, there is a lack of demand for further diagnostic investigations. On the other hand, a variety of imaging and laboratory examinations, including brain MRI, chest and abdominal pelvic CT scan should be obtained to clarify the possible underlying cause of Cushing disease.[2]

Few patients affected with adrenal cortical hyperplasia might present with clinical and laboratory evidence of an increased level of aldosterone, including elevated blood pressure, decreased level of potassium, and disturbed arterial blood gas demonstrating metabolic alkalosis.[21] The elevated level of cortisol is well documented utilizing several specific laboratory examinations, including the measurement of unbounded cortisol in 24-hour collected urine, evaluating low dose dexamethasone suppression test, and assessment of nocturnal salivary cortisol.[22] When the impression is Cushing syndrome (CS), and the laboratory evidence of an increased level of cortisol has been established, the exclusion of exogenous hypercortisolism should be prioritized.[23] Following exclusion of exogenous hypercortisolism, the stepwise diagnosis approach demands differentiation of a couple of major causalities; Those which are dependent on ACTH secretion and those which are not dependant on ACTH secretion. To categorize the mentioned groups, plasma ACTH levels should be evaluated. Afterward, in case of any uncertainty in diagnosis, corticotropin-releasing hormone (CRH) assessment is recommended.[24] 

Further confirmatory tests, including serum aldosterone, and metanephrines, are highly recommended for those who are undiagnosed despite previously mentioned studies. In the majority of patients affected with Cushing syndrome, including pituitary adenoma, and ACTH hypersecretion due to ectopic causalities; hypercortisolism is dependent on ACTH hypersecretion.[25] From the very early steps of evaluation, obtaining brain MRI and abdominal CT scan is recommended for ACTH-dependent and ACTH-independent, respectively.[26] To obtain the diagnosis, the patient’s age has a significant impact. Congenital adrenal hyperplasia, mostly 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 CAH is the 21-hydroxylase deficiency. Therefore, screen testing for serum concentrations of 17-hydroxyprogesterone is among the screening tests that are routinely performed in the United States.[27][28]

Cushing disease, or hypophysial corticotropin producing adenoma, accounts for the vast majority of Cushing syndrome causalities. Although the discrete threshold of pituitary adenoma has not been identified yet, tumor size of equal or greater than 6 millimeters is highly indicative of Cushing disease as the causality of Cushing syndrome.[3] 

The treatment plan for pituitary adenomas mostly consists of transsphenoidal surgery by utilizing a microsurgical approach, which might cause up to 90%, and less than 70% absolute resolution in micro and macroadenomas, respectively.[29][30] The less common surgical approach in the treatment of Cushing's disease is utilizing endoscopic tumor resection, which has greatly improved the outcomes recently.[31]

Ectopic ACTH, mostly due to paraneoplastic causalities, accounts for the second-most common cause of ACTH-dependent cortical hyperplasia. The three most common cause of the mentioned etiology of Cushing syndrome includes lung, bronchial carcinoid tumor, and small cell lung cancer.[2][4]

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 demanding emergent control of the elevated level of cortisol, and 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, and long term hormone replacement is preferred.[32]

 ACTH-independent hypercortisolism or adrenal originated Cushing syndrome might occur due to a couple of causalities, including primary pigmented nodular adrenal disease (PPNAD) or ACTH-independent macronodular adrenal hyperplasia (AIMAH).[5] The former one is a benign situation and is categorized to 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.[5][33] The later one presents in the late 40s, mostly in male patients, and is characterized by extremely, almost 20 to 25 times heavier adrenal glands. The treatment plan is similar to the former one, which consists of bilateral surgical removal of adrenal glands and lifelong glucocorticoid replacement.[5][6]

• Adrenal cortical adenoma is usually unilateral and solitary, although bilateral adenomas have also been reported. They are often unencapsulated. The cut surface is yellow with brown foci.[34]
• Pheochromocytoma is a rare, second most common tumor identified in adrenalectomy specimens and 7% of primary adrenal tumors.[35] The classic triad symptoms of episodic headaches, sweating, and tachycardia are seen in about 30%.[36] Histologic presentation overlaps with normal adrenal medulla.
• Adrenocortical carcinoma is a rare but very aggressive tumor with an estimated prevalence of between 0.5 and 12 per million.[37] The architecture is less ordered than in adenomas. Necrosis, increased mitosis, local invasion, and distant metastasis are common.
• The other differentials include congenital adrenal hyperplasia, metastases, lymphoma, myelolipoma, amyloidosis, and infections involving adrenals such as tuberculosis, histoplasmosis, and blastomycosis.

Those patients with unilateral adrenal insufficiency who meet the following criteria should be scheduled for surgical resection: (1) Suspicious malignancy regarding imaging criteria, (2) Those with greater than 4 to 6 cm size, and (3) clinical evidence of functional adrenal mass, including every manifestation attributed to cortisol, aldosterone, or catecholamines hypersecretion.[38][39][40][41] Although there is a debate in discrete defining hypercortisolism due to cortisol hypersecretion, to cover the optimal management of those patients with mild hypercortisolism, there is a consensus in utilizing dexamethasone suppression test to identify those demanding interventions.

 In bilateral symmetrical hyperplasia along with an elevated level of urinary cortisol for greater than 3 to 4 times above normal, bilateral adrenalectomy might be recommended.[42] Furthermore, those with lower than three times elevation in urinary cortisol, and bilateral macronodular adrenal hyperplasia may experience relatively complete remission, but a significant 23% rate of recurrence is threatening.[43][44] Planning to resect which one of the adrenal glands remains controversial, while some recommend removal of the larger gland or the one with higher radioactive agents uptake, others highly recommend making decisions based on more invasive assessments, including the results of adrenal venous sampling. Careful follow up to exclude the post-procedural adrenal insufficiency is crucial as it might happen in up to 40%.[45]

Those patients affected with bilateral adrenal cortical hyperplasia due to hyperadrenalism might be considered for non-surgical treatment with mineralocorticoids antagonists, however, if the causality of adrenal cortical hyperplasia is supposed to be outstanding hypercortisolism, surgical management with bilateral surgical removal of adrenal glands and lifelong substitution of both glucocorticoid and mineralocorticoid should be considered.[46] 

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 diuretic, spironolactone might be a reliable one, suggestive of good prognosis. On the contrary, chronic elevation of blood pressure, along with multiple organ failure, predicts the poor prognosis. Multiple organ failure, by definition, attributes to evidence of end-organ damage in at least a couple of vital organs.[47]

The overall survival of Cushing syndrome of all causes has significantly changed over the last 70 years from slightly more than 4.5 years in the early 1950s. Vascular compromise in the cardiac and nervous system, along with infectious related morbidities, were all found to be strong negative predictors on general outcomes and escalate the standard mortality ratio.[22]

Traditional surgical treatment of adrenal cortical hyperplasia harbor several complications, with the most common one has been found to be any type of bleeding, occurring during or after the surgical process in more than one out of five patients. Moreover, a couple of more surgery-related complications are incisional hernia and wound complications. Most predictable medical complication related to surgical adrenalectomy includes the metabolic effect of systemic elimination of cortisol. Among laparoscopic-related complications, infectious and thromboembolic morbidities are more common in devastating events.[48] In other words, surgical complications associated with adrenalectomy can be categorized based on the affected organ systems to include renal, cardiac, and pulmonary complications.[49]

Adrenal cortical hyperplasia is among the differential diagnosis of the adrenal incidentaloma. Following the exclusion of the exogenous corticosteroid intake, the stepwise laboratory and imaging investigations are highly recommended. Nodular adrenal cortical hyperplasia occurs in a couple of subtypes, including primary pigmented nodular adrenal disease (PPNAD) or ACTH-independent macronodular adrenal hyperplasia (AIMAH), which both are common in terms of a low level of ACTH, and elevated level of cortisol. Abdominal imaging, including CTscan and MRI, might elucidate characteristic findings relevant to the diagnosis. Definite curative treatment could be assumed via bilateral surgical resection of both glands and lifelong hormone replacement. 

The precise diagnosis of adrenal cortical nodular hyperplasia might be obtained through laboratory and imaging tests requested by endocrinologists. After exclusion of the differential diagnoses, the patient might be referred to general and/or laparoscopic surgeons to schedule for the punctual surgical management. As ablative procedure imposes the lifelong demand for glucocorticoid and mineralocorticoid replacement, the patient should be followed up by an interprofessional team, including surgeons and endocrinologists. During surgery, the anesthesiologist should be aware of the most post impression of adrenal cortical hyperplasia and be prepared for the most lethal and possible complications. Regarding the postoperative complications, the registered nurse is supposed to frequently check the vital signs, to preclude the possible devastating and irreversible consequences of bleeding and thromboembolic events. In suspicious occasions of bleeding and thromboembolic events, following timely management via fluid replacement and emergent anticoagulant initiation, respectively, is preferred. The pathologist should precisely examine the specimen to confirm the diagnosis and exclude other possible differential diagnoses.