• Sign Up

Use coupon code EXTENDEDHOLIDAY2020 at checkout for 20% off

Adrenal Cortical Nodular Hyperplasia


Adrenal Cortical Nodular Hyperplasia

Article Author:
Saran Lotfollahzadeh
Article Editor:
Mehran Taherian
Updated:
12/1/2020 9:51:13 AM
For CME on this topic:
Adrenal Cortical Nodular Hyperplasia CME
PubMed Link:
Adrenal Cortical Nodular Hyperplasia

Introduction

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 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. Even the maximal width of adrenal glands differs among two sides as 0.28 and 0.33 cm in the right and left adrenal, respectively.[1]

Etiology

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

Cushing syndrome: Mostly 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 causality 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 cause of the mentioned etiology of Cushing syndrome includes 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 to those with or without association with the Carney complex. The later one presents in the late 40s, mostly in male patients, and is characterized by extremely heavier adrenal glands, (almost 20 to 25 times heavier).[5][6]

Epidemiology

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.[8][9] Patients' sex and puberty 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]

Pathophysiology

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

Histopathology

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, 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]

Evaluation

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]

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] 

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]

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 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.

Treatment Planning

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] 

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 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]

Complications

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]

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 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. 

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 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.


References

[1] Vincent JM,Morrison ID,Armstrong P,Reznek RH, The size of normal adrenal glands on computed tomography. Clinical radiology. 1994 Jul     [PubMed PMID: 8088036]
[2] Lila AR,Sarathi V,Jagtap VS,Bandgar T,Menon P,Shah NS, Cushing's syndrome: Stepwise approach to diagnosis. Indian journal of endocrinology and metabolism. 2011 Oct     [PubMed PMID: 22145134]
[3] Ejaz S,Vassilopoulou-Sellin R,Busaidy NL,Hu MI,Waguespack SG,Jimenez C,Ying AK,Cabanillas M,Abbara M,Habra MA, Cushing syndrome secondary to ectopic adrenocorticotropic hormone secretion: the University of Texas MD Anderson Cancer Center Experience. Cancer. 2011 Oct 1     [PubMed PMID: 21412758]
[4] Chaudhary V,Bano S, Imaging of the pituitary: Recent advances. Indian journal of endocrinology and metabolism. 2011 Sep     [PubMed PMID: 22029027]
[5] Manipadam MT,Abraham R,Sen S,Simon A, Primary pigmented nodular adrenocortical disease. Journal of Indian Association of Pediatric Surgeons. 2011 Oct     [PubMed PMID: 22121318]
[6] New MI,Wilson RC, Steroid disorders in children: congenital adrenal hyperplasia and apparent mineralocorticoid excess. Proceedings of the National Academy of Sciences of the United States of America. 1999 Oct 26     [PubMed PMID: 10536001]
[7] De Venanzi A,Alencar GA,Bourdeau I,Fragoso MC,Lacroix A, Primary bilateral macronodular adrenal hyperplasia. Current opinion in endocrinology, diabetes, and obesity. 2014 Jun     [PubMed PMID: 24739311]
[8] Young WF Jr,Carney JA,Musa BU,Wulffraat NM,Lens JW,Drexhage HA, Familial Cushing's syndrome due to primary pigmented nodular adrenocortical disease. Reinvestigation 50 years later. The New England journal of medicine. 1989 Dec 14     [PubMed PMID: 2586567]
[9] Zhou J,Zhang M,Bai X,Cui S,Pang C,Lu L,Pang H,Guo X,Wang Y,Xing B, Demographic Characteristics, Etiology, and Comorbidities of Patients with Cushing's Syndrome: A 10-Year Retrospective Study at a Large General Hospital in China. International journal of endocrinology. 2019     [PubMed PMID: 30915114]
[10] Bertherat J,Horvath A,Groussin L,Grabar S,Boikos S,Cazabat L,Libe R,René-Corail F,Stergiopoulos S,Bourdeau I,Bei T,Clauser E,Calender A,Kirschner LS,Bertagna X,Carney JA,Stratakis CA, Mutations in regulatory subunit type 1A of cyclic adenosine 5'-monophosphate-dependent protein kinase (PRKAR1A): phenotype analysis in 353 patients and 80 different genotypes. The Journal of clinical endocrinology and metabolism. 2009 Jun     [PubMed PMID: 19293268]
[11] Bourdeau I,D'Amour P,Hamet P,Boutin JM,Lacroix A, Aberrant membrane hormone receptors in incidentally discovered bilateral macronodular adrenal hyperplasia with subclinical Cushing's syndrome. The Journal of clinical endocrinology and metabolism. 2001 Nov     [PubMed PMID: 11701732]
[12] Vassiliadi DA,Ntali G,Stratigou T,Adali M,Tsagarakis S, Aberrant cortisol responses to physiological stimuli in patients presenting with bilateral adrenal incidentalomas. Endocrine. 2011 Dec     [PubMed PMID: 21598069]
[13] Louiset E,Duparc C,Young J,Renouf S,Tetsi Nomigni M,Boutelet I,Libé R,Bram Z,Groussin L,Caron P,Tabarin A,Grunenberger F,Christin-Maitre S,Bertagna X,Kuhn JM,Anouar Y,Bertherat J,Lefebvre H, Intraadrenal corticotropin in bilateral macronodular adrenal hyperplasia. The New England journal of medicine. 2013 Nov 28     [PubMed PMID: 24283225]
[14] Assié G,Libé R,Espiard S,Rizk-Rabin M,Guimier A,Luscap W,Barreau O,Lefèvre L,Sibony M,Guignat L,Rodriguez S,Perlemoine K,René-Corail F,Letourneur F,Trabulsi B,Poussier A,Chabbert-Buffet N,Borson-Chazot F,Groussin L,Bertagna X,Stratakis CA,Ragazzon B,Bertherat J, ARMC5 mutations in macronodular adrenal hyperplasia with Cushing's syndrome. The New England journal of medicine. 2013 Nov 28     [PubMed PMID: 24283224]
[15] Carney JA,Young WF,Stratakis CA, Primary bimorphic adrenocortical disease: cause of hypercortisolism in McCune-Albright syndrome. The American journal of surgical pathology. 2011 Sep     [PubMed PMID: 21836496]
[16]     [PubMed PMID: 8008746]
[17]     [PubMed PMID: 4085982]
[18]     [PubMed PMID: 6329005]
[19]     [PubMed PMID: 1542635]
[20]     [PubMed PMID: 2679153]
[21]     [PubMed PMID: 22499224]
[22]     [PubMed PMID: 18334580]
[23]     [PubMed PMID: 25639322]
[24]     [PubMed PMID: 11932295]
[25]     [PubMed PMID: 28639924]
[26]     [PubMed PMID: 25372578]
[27]     [PubMed PMID: 20823466]
[28]     [PubMed PMID: 16950973]
[29]     [PubMed PMID: 18413427]
[30] Hammer GD,Tyrrell JB,Lamborn KR,Applebury CB,Hannegan ET,Bell S,Rahl R,Lu A,Wilson CB, Transsphenoidal microsurgery for Cushing's disease: initial outcome and long-term results. The Journal of clinical endocrinology and metabolism. 2004 Dec     [PubMed PMID: 15579802]
[31] Starke RM,Reames DL,Chen CJ,Laws ER,Jane JA Jr, Endoscopic transsphenoidal surgery for cushing disease: techniques, outcomes, and predictors of remission. Neurosurgery. 2013 Feb     [PubMed PMID: 23149974]
[32] Wannachalee T,Turcu AF,Auchus RJ, Mifepristone in the treatment of the ectopic adrenocorticotropic hormone syndrome. Clinical endocrinology. 2018 Nov     [PubMed PMID: 30019523]
[33]     [PubMed PMID: 10966714]
[34] McNicol AM, Lesions of the adrenal cortex. Archives of pathology & laboratory medicine. 2008 Aug     [PubMed PMID: 18684025]
[35] Kulis T,Knezevic N,Pekez M,Kastelan D,Grkovic M,Kastelan Z, Laparoscopic adrenalectomy: lessons learned from 306 cases. Journal of laparoendoscopic & advanced surgical techniques. Part A. 2012 Jan-Feb     [PubMed PMID: 22166088]
[36] Baguet JP,Hammer L,Mazzuco TL,Chabre O,Mallion JM,Sturm N,Chaffanjon P, Circumstances of discovery of phaeochromocytoma: a retrospective study of 41 consecutive patients. European journal of endocrinology. 2004 May     [PubMed PMID: 15132724]
[37]     [PubMed PMID: 12614096]
[38]     [PubMed PMID: 21471169]
[39]     [PubMed PMID: 17287480]
[40]     [PubMed PMID: 19022420]
[41]     [PubMed PMID: 14768652]
[42]     [PubMed PMID: 25971648]
[43]     [PubMed PMID: 25727927]
[44]     [PubMed PMID: 23592061]
[45]     [PubMed PMID: 26330465]
[46]     [PubMed PMID: 26297495]
[47]     [PubMed PMID: 8634926]
[48]     [PubMed PMID: 16980207]
[49]     [PubMed PMID: 8063073]