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Adrenal Cortical Nodular Hyperplasia
Introduction
The adrenal glands are paired retroperitoneal structures located above the kidneys. Adrenal glands are divided into two physiologically separated segments: the cortex and the medulla. The cortex has three distinct layers: the zona glomerulosa, which secretes aldosterone; the zona fasciculata, which secretes cortisol; 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 enlargement of the adrenal glands, usually due to functional or, more commonly, non-functional 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, diabetes, hypertension, and obesity. Increased detection is also due to imaging technology advances and increased frequency of imaging studies. For example, in the US and Canada, between 2000 and 2016, magnetic resonance imaging (MRI), and computerized tomography (CT scans) performed doubled, and in some cases even tripled in number. These 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 the potential for metastases. 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 for this are lung (about 35%), gastrointestinal, kidney, and breast. Bilateral nodules are more common with metastatic disease than other etiologies, so this should raise concern for metastatic disease.[2]
Etiology
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Etiology
A variety of etiologies for adrenal cortical hyperplasia has been described, including adrenocorticotropic hormone (ACTH)-dependent and ACTH-independent causes, such as congenital adrenal hyperplasia. Moreover, many other disorders masquerade with the signs and symptoms of adrenal cortical hyperplasia.
Cushing Disease and Cushing Syndrome
Named after Dr. Harvey Cushing, a neurosurgeon who first discovered Cushing disease, in which the basophil cells of the pituitary are overstimulated, the hypophysial corticotropin-producing adenoma accounts for the vast majority of 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, mostly due to paraneoplastic causes, is the second-most common cause of ACTH-dependent cortical hyperplasia. The three most common types of malignancy include lung, bronchial carcinoid, and small cell lung cancers.[4][5]
ACTH-independent hypercortisolism or adrenal-originated Cushing syndrome may occur due to conditions including primary pigmented nodular adrenal disease (PPNAD) or ACTH-independent macronodular adrenal hyperplasia. PPNAD is categorized into those with or without association with the Carney complex. ACTH-independent macronodular adrenal hyperplasia presents in the late 40s, mostly in male patients, and is characterized by extremely enlarged adrenal glands, up to 20 to 25 times normal.[6][7]
Carney Complex and Adrenal Hypercorticoplasia
The Carney complex (CNC) is a rare genetic mutation caused by inactivating mutationsof PRKAR1A (CNC1) localized on the long (q) arm of Chromosome 17. PRKAR1A codes for the type 1A regulatory protein kinase A (PKA) subunit. It 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 our companion StatPearls article "Carney Complex" for further information.[10]
Clinical presentation 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 are known worldwide, but many more undiagnosed cases likely exist. The constellation of symptoms includes 4 major criteria:[11]
- 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: Primary Pigmented Nodular Adrenocortical Disease (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 (most importantly) myxomas, 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.
Definitive diagnosis of CNC requires two 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]
Epidemiology
Many studies show an incidence of adrenal nodules of up to 10% in the elderly population.[12] Benign adrenal adenomas are rarely seen in patients younger than 30, so if noted, these nodules require further workup. Lesions smaller than 1 cm and less than 10 Hounsefield units on CT scan are generally considered benign and do not necessarily require further workup.[13]
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.[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 females more than males; by the age of 40, more than 70% of females with PRKAR1A mutation develop PPNAD, compared with 45% of males.[16]
Pathophysiology
The background pathophysiology mechanism of macronodular adrenal hyperplasia, which is generally described as the state of elevated level of cortisol, along with a decreased level of plasma ACTH has been implicated in several possible mechanisms including:
- Extraordinarily increased expression of aberrant G-protein-coupled receptors, located throughout the membranes of specific cells capable of producing estrogen via specific corresponding ligands.[17][18]
- The indirect function of the abnormally enlarged adrenal tissue is via a paracrine effect.[19]
- Specific mutations with several variable types, including germline and somatic mutations that are evident in approximately 50% of those affected with bilateral macronodular adrenal hyperplasia (BMAH).[20]
Histopathology
In most cases, nodular cortical hyperplasia is ACTH-independent. 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.[21][22]
In PPNAD (sometimes referred to as “micronodular adrenal disease”), the glands are usually normally-sized, although they can be small or slightly enlarged. Multiple pigmented cortical nodules are commonly seen amidst an atrophic cortex.[23][24] 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.[25] Occasional additional pathologic findings include microscopic foci of necrosis, mitotic figures, and a trabecular growth pattern.[26]
History and Physical
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 including 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 with a positive history of exogenous corticosteroid administration, further diagnostic investigation is not necessary. On the other hand, a variety of imaging and laboratory examinations, including brain MRI,and chest and abdominal pelvic CT scan should be obtained to clarify the possible underlying cause of Cushing disease.[4]
Evaluation
[27]Rarely, 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 potassium, and abnormal arterial blood gas demonstrating metabolic alkalosis.[28] The elevated level of cortisol is well documented utilizing several specific laboratory examinations, including the measurement of unbound cortisol in 24-hour collected urine, evaluating the effect of low dose dexamethasone suppression test, and the assessment of nocturnal salivary cortisol.[29]
Twenty-four-hour Urine Cortisol Test
Measures the amount of urine cortisol produced over an entire day. Levels higher than 50 to 100 micrograms per day in an adult suggest the presence of Cushing syndrome. Although the majority of patients with Cushing syndrome have elevated levels of cortisol, it is becoming increasingly evident that many patients with a mild case of Cushing syndrome may also have normal levels of cortisol, resulting in several 24-hour urine collections to confirm a diagnosis.[29]
The low-dose Dexamethasone Suppression Test
Measures the adrenal glands' response to ACTH and has been widely utilized for four decades. It 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’s syndrome, the morning level of cortisol is typically very low, indicating that the evening dose of dexamethasone suppressed ACTH secretion. In patients with Cushing’s syndrome, the morning cortisol level will be high. Normal patients will suppress their cortisol to a very low level (1.8 mg/dL), whereas those suffering from Cushing’s syndrome will not. Using this strict criterion, this test should provide an estimated 95-97 percent diagnostic accuracy rate. However, some patients with a mild case of Cushing’s syndrome can suppress their cortisol to low levels, making it difficult to diagnose utilizing this test fully.[29]
The late-night Salivary Cortisol Test
Checks for elevated cortisol levels in the saliva between 11 p.m. 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's syndrome. The normal salivary cortisol level between 10 pm and 1 am is ≤0.09 mcg/dL. [30] The collection of saliva for cortisol assay using mass spectometry/chromatography needs to follow a specific protocol, such as 0.5 mL saliva (minimum volume 0.2 mL) collected at the earliest 60 minutes after brushing teeth, a meal (liquid/solid food intake) or oral intake of medication 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 as the specimen stability at standard room temperature is for 72 hours but longer when refrigerated (21 days) or frozen(6 months). [30]
When the impression is Cushing syndrome (CS) with the laboratory evidence of an increased cortisol level has been established, the exclusion of exogenous hypercortisolism should be prioritized.[31] Following the exclusion of exogenous hypercortisolism, the stepwise diagnosis approach demands differentiation of several major causes; those which are ACTH-dependent and those which are ACTH-independent. Plasma ACTH levels should be evaluated to categorize the mentioned groups. Afterward, corticotropin-releasing hormone (CRH) assessment is recommended if there is any uncertainty in diagnosis.[32]
Further confirmatory tests, including serum aldosterone and metanephrines, are highly recommended for undiagnosed patients despite previously mentioned studies. In the majority of patients affected with Cushing syndrome, including pituitary adenoma, and ectopic ACTH hypersecretion, the hypercortisolism is dependent on ACTH hypersecretion.[33] Early on, obtaining brain MRI and abdominal CT scans are recommended for ACTH-dependent and ACTH-independent, respectively.[34] The patient’s age has a significant impact on obtaining the diagnosis. 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, screening for serum concentrations of 17-hydroxyprogesterone is among the screening tests that are routinely performed in the United States.[35][36]
Imaging of Adrenal Nodules
As mentioned earlier, the incidence of higher resolution imaging has been increasing over 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[35][37].
Bilateral masses— Bilateral adrenal masses can be seen with metastatic disease, congenital adrenal hyperplasia, cortical adenomas, lymphoma, infection (eg, tuberculosis, fungal), hemorrhage, corticotropin (ACTH)-dependent Cushing syndrome, pheochromocytoma, primary aldosteronism, amyloidosis, infiltrative disease of the adrenal glands, and primary bilateral macronodular adrenal hyperplasia (PBMAH). In one study of 208 adrenal incidentaloma patients, 9% proved to have adrenal metastases; and 53% had bilateral disease [38]
CT scan features of adrenal nodules: A homogeneous adrenal mass of less than 4 cm in diameter with a smooth border and an attenuation value less than 10 Hounsfield unit (HU) on unenhanced CT is very likely to be a benign cortical adenoma. The imaging characteristics that suggest adrenal carcinoma or metastases include irregular shape, inhomogeneous density, high unenhanced CT attenuation values of more than 20 HU, diameter 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).[39]
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. In a meta-analysis of 1280 lesions (859 adenomas), CSI demonstrated a sensitivity of 94 percent (95% CI 88-97 percent) and a specificity of 95 percent (95% CI 89-97 percent).[40]
As imaging serves a strong role in diagnosing and treating adrenal conditions, CT has been the primary modality for adrenal imaging owing to reproducibility, temporal and spatial resolution, and broad access. MRI can be used to further evaluate indeterminate CT findings or serve as an adjunct tool without the use of ionizing radiation. Ultrasound and fluoroscopy (genitography) are most commonly used in the fetal period, as well as in children to evaluate congenital adrenal hyperplasia
Treatment / Management
Cushing disease, or hypophysial corticotropin-producing adenoma, accounts for the vast majority of Cushing syndrome cases. Although the discrete threshold of pituitary adenoma has not been identified yet, a tumor size greater than 6 millimeters is highly indicative of Cushing disease as the cause 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.[41][42] The less common surgical approach in the treatment of Cushing's disease is utilizing endoscopic tumor resection, which has greatly improved the outcomes recently.[43](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 disease include lung, bronchial carcinoid tumor, and small cell lung cancer.[4][5](B3)
The treatment plan for ectopic ACTH depends on the functional status of the patient. In those affected with clinically symptomatic Cushing's 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.[44]
ACTH-independent hypercortisolism might occur due to several reasons, including primary pigmented nodular adrenal disease (PPNAD) or ACTH-independent macronodular adrenal hyperplasia (AIMAH).[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][45] The AIMAH presents in the late 40s, mostly in male patients.. The treatment plan is similar to PPNAD, which consists of bilateral surgical removal of adrenal glands and lifelong glucocorticoid replacement.[6][7](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.[46]
- Pheochromocytoma is rare but the second most common tumor identified in adrenalectomy specimens and 7% of primary adrenal tumors.[47] The classic triad of symptoms—episodic headaches, sweating, and tachycardia—is seen in about 30% of the cases.[48] 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.[49] The architecture is less ordered than in adenomas. Necrosis, increased mitosis, local invasion, and distant metastasis are common.
- 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, or other concerning radiology characteristics (3) Clinical evidence of functional adrenal mass, including manifestations attributed to cortisol, aldosterone, or catecholamine hypersecretion.[27][50][51][52] 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 the 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.[53] Furthermore, those with less 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 concerning.[54][55] Planning to resect only one of the adrenal glands remains controversial; some recommend 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%.[56]
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 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.[57]
Prognosis
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 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 several vital organs.[58]
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.[29]
Complications
Traditional surgical treatment of adrenal cortical hyperplasia harbors several complications, with the most common eing any type of bleeding, occurring during or after the surgical process in more than one out of five patients. Moreover, other surgery-related complications are incisional hernia and wound complications. Most predictably, medical complications related to surgical adrenalectomy includes the effect of systemic elimination of cortisol. Among laparoscopic-related complications, infectious and thromboembolic morbidities are more common in devastating events.[59] In other words, surgical complications associated with adrenalectomy can be categorized based on the affected organ systems to include renal, cardiac, and pulmonary complications.[60]
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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