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Adrenal Cortical Nodular Hyperplasia

Editor: Mehran Taherian Updated: 7/18/2023 11:47:36 AM


The adrenal glands are retroperitoneal structures, bilaterally located superior to the kidneys. They are highly vascularized organs. Adrenal glands have a couple of anatomically and physiologically separated segments, including cortex and medulla. The former one has three distinguished layers; glomerulosa, fasciculata, and reticularis, responsible for secreting aldosterone, cortisol, and androgens, respectively. They consequently regulate homeostasis. The second segment, medulla, mainly secretes epinephrine and norepinephrine, which are hormones essential during stress episodes.[1] Cortical hyperplasia is a benign enlargement of the gland. Normal adrenal gland size differs between two sides. The maximal normal width in the right and left adrenal glands are 0.61 and 0.79 cm, respectively.[1]


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A variety of etiologies for adrenal cortical hyperplasia has been described including ACTH-dependent and ACTH-independent causes, and also congenital adrenal hyperplasia. Moreover, a wide range of disorders may masquerade the signs and symptoms of adrenal cortical hyperplasia.

Cushing syndrome: Most commonly caused by abnormal corticosteroid intake. If an obvious history of glucocorticoid administration along with a variety of symptoms including visceral obesity, buffalo hump, moon face appearance, generalized abdominal and limb striae, and decreased bone mineral density exists, obtaining extra diagnostic tests would be unnecessary.[2] 

 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 cause of Cushing syndrome.[3] 

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

 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 into those with or without association with the Carney complex. The latter one presents in the late 40s, mostly in male patients, and is characterized by extremely heavier adrenal glands, (almost 20 to 25 times).[5][6]


Macronodular Adrenal Hyperplasia (MAH) 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.[7] Patients with PPNAD present before age 30 years and in half of the cases before 15 years old.[8][9] Patients' sex and puberty state change the development of Cushing syndrome in PPNAD: after adolescence, PPNAD affects females more than males; by the age of 40, more than 70% of females with PRKAR1A mutation develop PPNAD, compared with 45% of males.[10]


Background pathophysiology mechanism of macronodular adrenal hyperplasia, which is generally described as the state of elevated level of cortisol, along with the decreased level of plasma adrenocorticotrophin (ACTH) has been implicated with several possible mechanisms including:

  1. Extraordinary increased expression of aberrant G-protein-coupled receptors which are located through the membranes of specific cells that are capable of producing estrogen via specific corresponding ligands.[11][12] 
  2. The indirect function of the abnormally enlarged adrenal tissue via the paracrine effect.[13] 
  3. Specific mutations with a couple of variable types, including germline and somatic ones that are evident in approximately 50% of those affected with bilateral macronodular adrenal hyperplasia (BMAH).[14]


In most of the cases, nodular cortical hyperplasia is ACTH-independent. The glands are massively enlarged, mimicking a neoplasm. The cortical nodules in the late-stage sometimes show a transformation from diffuse hyperplasia; these nodules are yellow and vary in size from 0.2 to over 4.0 cm. The nodules compose 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.[15][16]

In PPNAD (sometimes referred to as “micronodular adrenal disease”), the glands are usually of normal size, although they can be small or slightly enlarged. Multiple pigmented cortical nodules are present with commonly seen intervening atrophic cortex.[17][18] 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 compose 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.[19] Occasional additional pathologic findings include microscopic foci of necrosis, mitotic figures, and a trabecular pattern of growth.[20]

History and Physical

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, like the posterior aspect of the neck and proximal to the clavicle, and fertility disturbances should raise suspicion for the adrenal cortical hyperplasia. In the presence of the mentioned signs and symptoms accompanied 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 the effect of low dose dexamethasone suppression test, and the assessment of nocturnal salivary cortisol.[22] When the impression is Cushing syndrome (CS) with 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, the 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]

Treatment / Management

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] (B2)

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](B2)

Ectopic ACTH, mostly due to paraneoplastic causalities, accounts for the second-most common cause of ACTH-dependent cortical hyperplasia. The three most common types of the mentioned etiology of Cushing syndrome includes lung, bronchial carcinoid tumor, and small cell lung cancer.[2][4](B3)

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 of the adrenal glands, 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 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.[5][33] The latter 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](B2)

Differential Diagnosis

  • 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 is seen in about 30% of the cases.[36] 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.[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.

Treatment Planning

Those patients with unilateral adrenal hyperplasia 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 intervention.

 In bilateral symmetrical hyperplasia along with an elevated level of urinary cortisol of 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 only one of the adrenal glands remains controversial; some recommend removal of the larger gland or the one with higher radioactive agents uptake, while others 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 diuretics, like spironolactone might be a reliable one and suggestive of good prognosis. On the contrary, chronic elevation of blood pressure, along with multiple organ failure, predicts a 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 harbors several complications, with the most common one being 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]

Deterrence and Patient Education

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 are both 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. 

Enhancing Healthcare Team Outcomes

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 need to be referred to general and/or laparoscopic surgeons to schedule the appropriate operation. 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 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, timely management with 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.



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