Rare benign adrenal lesions
Prerna Dogra,1 Anders Sundin,2 C. Christofer Juhlin, 3,4 Jan Calissendorff,5,6 Henrik Falhammar,5,6 and Irina Bancos İD *
1Division of Endocrinology, Diabetes, Metabolism and Nutrition, Mayo Clinic, Rochester, MN 55905, United States
2Department of Surgical Sciences, Radiology & Molecular Imaging, Uppsala University Hospital, Uppsala, SE-751 85 Uppsala, Sweden
3Department of Pathology and Cancer Diagnostics, Karolinska University Hospital, Stockholm, Sweden
4Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden
5Department of Endocrinology, Karolinska University Hospital, Stockholm, Sweden
6Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden
*Corresponding author: Division of Endocrinology, Diabetes, Metabolism and Nutrition, Mayo Clinic, Rochester, MN 55905, USA. Email: Bancos.Irina@mayo.edu
Abstract
While most benign lesions of the adrenal glands represent either an adrenocortical adenoma or a myelolipoma, the advent and frequent use of high-resolution radiological investigations have led to relatively increased incidental discovery of rare adrenal lesions, specifically benign adrenal cysts, adrenal ganglioneuromas, adrenal schwannomas, adrenal hemorrhage, and adrenal calcifications. Radiological characteristics of the different rare benign adrenal lesions could vary from distinct to indeterminate. Though typically nonfunctional, these rare lesions require evaluation for adrenal hormone excess, as they may phenotypically appear similar to pheochromocytoma or adrenocortical carcinoma and could sometimes be associated with or conceal an underlying functional adrenal tumor. In this review, we discuss the various rare benign adrenal lesions, emphasizing a practical perspective.
Keywords: adrenal cyst, ganglioneuroma, schwannoma, hemorrhage, calcification
Significance
Better quality and frequent use of radiological investigations in the last few decades has resulted in the increased discovery of rare benign adrenal lesions such as benign adrenal cysts, adrenal ganglioneuromas, adrenal schwannomas, adrenal hemor- rhage, and adrenal calcifications. This review provides insight into the epidemiology, clinical presentation, diagnostic evalu- ation, and management of these rare benign adrenal lesions with a practical perspective.
Introduction
Paralleling the availability of high-resolution radiological inves- tigations, increased identification and a better understanding of the adrenal (gland) lesions have occurred over the last two dec- ades.1 Nowadays, most adrenal lesions are discovered inciden- tally, with an estimated prevalence of 7% in those undergoing cross-sectional abdominal imaging for alternate reasons.2,3 Though adrenal lesions can occur at any age, they are more com- mon in older age groups, with peak incidence in the fifth-sixth decades of life.2-4 Based on epidemiological data, the vast major- ity of adrenal lesions represent a benign etiology and only 5%-8% are malignant.3,5 Irrespective of the benign or malig- nant nature, these lesions can be associated with adrenal hor- mone excess (cortisol, aldosterone, catecholamine, and rarely androgen), though up to 50%-85% are hormonally inactive.
Benign adrenal lesions include adrenocortical adenomas (80%-85%), myelolipomas (4%-6%), and rare lesions (<5%) such as benign adrenal cysts, ganglioneuromas, schwannomas, hemorrhage, calcifications, and other rare le- sions.3,5 Unlike lipid-rich adrenocortical adenomas and
myelolipomas, with recognizable imaging characteristics and a well-delineated approach to management,6-8 little is known about other, much more rare lesions. The focus of this article is to review the epidemiology, clinical presentation, diagnosis, and management of rare benign adrenal lesions.
Benign adrenal cysts and pseudocysts
Clinical presentation
Benign adrenal cysts account for ~1%-2% of all adrenal masses,3,5 and can occur at any age, with the peak age of diag- nosis during the fifth decade of life and a 1.2-1.5 times female predominance.9-13 Most cysts are currently found incidentally on imaging performed for unrelated reasons12,14 and in up to 10%-20% of patients, symptoms of mass effect (abdominal or back discomfort, nausea, loss of appetite) lead to discov- ery.15,16 Rare reports of spontaneous or traumatic cyst rup- ture17,18 arterial hypertension resulting from renal artery compression,19 or presentation with hemorrhagic shock20 have been described in literature.
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Diagnostic evaluation
Imaging characteristics
Benign adrenal cysts are predominantly unilateral lesions, without a side predilection, and 3%-8% bilateral.15 Most are round or oval-shaped homogenous lesions with well- defined borders (Figures 1A, B and 2A). However, 15%-20% may have lobulated or heterogeneous appear- ance.15 Calcifications is a common finding, seen in up to 60%-70% of cysts, predominantly in a peripheral pattern and, less commonly, septal, or intra-cystic.15 Benign adrenal cysts are typically large lesions with a median size of 5.8 cm (range, 0.5-20 cm), and a tendency to enlarge slowly over time (~2 mm/year), but some cysts may remain stable or even decrease in size. 15,16
On abdominal ultrasonography, benign adrenal cysts ap- pear as well-defined anechoic and sometime hypoechoic le- sions.16 In the largest series of benign adrenal cysts, a median non-contrast attenuation of 19 HU on computed tom- ography (CT) was reported, but ranged widely between 0 and 83 HU.15 Characteristically, benign adrenal cysts do not dem- onstrate vascular enhancement following intravenous con- trast administration (Figures 1A, B and 2A), however, in some cysts, a thin enhancing rim (<3 mm) of the surrounding normal adrenal gland can be seen.15,16 A benign cyst can arise following an adrenal bleeding, with incomplete resolution of the hematoma, and alternatively, hemorrhage may also ap- pear in an existing adrenal cyst. The high attenuation is there- fore most probably attributable to hemorrhage or intra-cystic debris, commonly associated with these lesions. Conversely, corresponding to the various stages of hema- toma, the non-contrast attenuation of benign adrenal cysts
can change over time. The occasionally high attenuation on non-contrast CT consequently prevents their radiological characterization as cysts. In the rare instances when the pa- tients undergo surgery, the diagnosis is histopathological, but for the vast majority the likely diagnosis of an adrenal cyst is based on the absence of contrast-enhancement or un- changed size and appearance on subsequent imaging. On magnetic resonance imaging (MRI), benign adrenal cysts are typically hypointense on T1- and hyperintense on T2-weighted sequences (Figure 1C and D), and do not en- hance following intravenous administration of extracellular gadolinium contrast media.16
In terms of clinically significant differential diagnoses to ad- renal cysts, different primary tumors of the adrenal gland as well as metastases to the adrenal may occasionally present with a partially cystic phenotype and must be taken into con- sideration when evaluating these lesions (Figure 2B-E).21 These entities include adrenocortical tumors and pheochro- mocytomas with regressive features, adrenal hemangioma, lymphangioma, and metastatic renal cell carcinoma, to name a few.21,22
Hormonal evaluation
Benign adrenal cysts are typically nonfunctional lesions.11,12,23 However, since benign adrenal cysts can arise following hemor- rhage or infarction into an adrenal adenoma, there may be some adrenal neoplastic tissue with a degree of functionality.15 Furthermore, other cystic lesions of the adrenal gland, such as cystic pheochromocytoma and adrenocortical carcinoma, could rarely mimic benign adrenal cysts on imaging (Figure 2B-E).22 Thus, all non-typical cystic lesions of the adrenal gland should
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undergo a thorough hormonal evaluation for cortisol, aldoster- one, and catecholamine excess.
Histopathology
Based on Abeshouse/Foster24,25 and the latest WHO classifi- cation,21 adrenal cysts can be histologically categorized into four subtypes based upon evaluation of the cyst wall. Though indicative of distinct etiologies and pathogenic mech- anisms21; the various histological subtypes are generally radiologically indistinguishable.15
1. Pseudocysts or “hemorrhagic cysts”: The cyst wall is composed of dense fibrous connective tissue and lacks an endothelial or epithelial lining, and the cyst itself is built-up by fibrino-hemorrhagic content (Figure 3A and B). Pseudocysts result from spontaneous resolution of hemorrhage within the normal adrenal gland but may occasionally present in adrenal tumors with cystic degeneration, and careful macroscopic evaluation and sampling of the cyst wall is therefore recommended.21
Pseudocysts usually do not require immunohistochemical profiling.
2. Endothelial cysts (also referred to as vascular cysts or “simple cysts”) are distinguished by multiloculated cysts with a capsular structure lined by a monolayer of endo- thelial cells (Figure 3C). The cells are highlighted by im- munohistochemical positivity for CD31, and further evaluation using EGR and D2-40 will differentiate be- tween endothelial or lymphatic endothelium, however this distinction seems to lack clinical significance.21
3. Epithelial/mesothelial cysts or “true cysts”: The cyst wall consists of a monolayer of flat to cuboidal epithelial lining positive for mesothelial markers such as calretinin, WT1, and mesothelin (Figure 3D).
4. Parasitic cysts: Almost always echinococcal in origin. However, few cases of leishmaniasis have been reported. These generally are thick-walled cysts with the parasite in the wall and daughter cysts, and a PAS stain may aid in the identification of parasitic membranes.21
Different studies note either endothelial or pseudocysts as the prevalent histological subtype, epithelial cysts as rare
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CD31
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and parasitic cysts as extremely rare. 9,15,25,26 It should be mentioned that the histological distinction between endothe- lial cysts and adrenal neoplasia with a vascular appearance (hemangioma/lymphangioma) is challenging. Although of limited clinical importance given the benign nature of these en- tities, it could potentially lead to variations in the incidence of endothelial cysts in different regions.
Management and prognosis
Historically, significant proportion of patients with adrenal cysts was treated surgically. However, in a recent series of
92 consecutive patients with benign adrenal cysts, 50% were managed conservatively, and despite the large cyst size and tendency to enlarge, no adverse outcomes occurred during a median follow-up of 54 months (range, 0-292).15 In the same study, most patients who were managed surgically underwent adrenalectomy via laparoscopic approach without any major complications or cyst recurrence during follow- up.15 Though cyst aspiration can be performed, based on lim- ited data, the risk of reaccumulation is relatively high.26
Considering the uncomplicated clinical course of benign ad- renal cysts, most patients can be managed conservatively, and sur- gical management should be reserved for patients with symptoms
of mass effect, or if cysts demonstrate imaging characteristics (het- erogeneity, solid component or thick enhancing rim) or abnormal hormonal evaluation concerning for another etiology.15,21,
Adrenal ganglioneuroma
Ganglioneuromas are benign tumors of sympathoadrenal lin- eage arising from the neural crest. They represent the most ma- ture form of peripheral neuroblastic tumors followed by nodular ganglioneuroblastoma, intermixed ganglioneuroblas- toma, and neuroblastomas (in decreasing order of differenti- ation).27 They can develop independently or following either spontaneous or treatment-induced transformation of ganglio- neuroblastoma and neuroblastoma.28,29 Though ganglioneur- omas can arise anywhere in the body, the most common site of involvement is retroperitoneal, and about 30% are located in the adrenal glands.
Adrenal ganglioneuromas are rare and represent 0.2%-1.6% of all adrenal tumors in population-based studies3,5 and 1.9%-3.5% in surgical cohorts of patients treated with adrena- lectomy.33,34 They frequently occur as isolated tumors, but in 20%-45%, may present as composite tumors associated with a secondary component.31,35,36 The secondary component is commonly a pheochromocytoma, and a prevalence as high as 45% was found in one study.36 Other less prevalent histologic components such as neuroblastoma, ganglioneuroblastoma and malignant nerve sheath tumor, have also been reported in the literature.35,37
Clinical presentation
Adrenal ganglioneuromas can occur in the pediatric and adult population with a peak incidence during the third to fifth dec- ades of life.34,36,38 Different studies note up to 1.5 times higher incidence in females.34,36,38 In most patients, adrenal ganglio- neuromas are discovered incidentally on imaging, but 10%-30% can present with symptoms of tumor mass effect and rarely, due to symptoms related to hormone ex- cess.33,36,38,39 Most adrenal ganglioneuromas are sporadic in origin but syndromic presentation with neurofibromatosis, multiple endocrine neoplasia type 2A and 2B, and Turner syn- drome can also be found. 40-42
Diagnostic evaluation
Imaging characteristics
Adrenal ganglioneuromas are predominantly unilateral le- sions (>98%) with almost equal right and left side distribu- tion,36,38 and an average tumor size of 5.5-6.5 cm (range, 1.0-20 cm).33,34,36,39 Adrenal ganglioneuromas are either round or lobulated in shape, have well-defined margins, and are usually noncystic.36,38 They are homogeneous appearing masses in 60%-70%36 and comprise calcifications in 30%-60% of lesions. The mean non-contrast CT attenuation is 30-35 HU (range, 20-40 HU)34-36,38,39 and demonstrate over time progressive tumor enhancement following intraven- ous contrast medium administration (Figure 4A-C).39 On MRI, adrenal ganglioneuromas are typically hypo- or isoin- tense on T1-, and heterogeneously hyperintense on T2-weighted images (Figure 4D and E).35,38,39 Reports on functional imaging are sparse and variable, with one study noting 123I-metaiodbenzylguanidine (MIBG) positivity on MIBG scintigraphy in 27% of adrenal ganglioneuromas, whereas 42% were 18F-fluorodeoxyglucose (FDG) positive
on positron emission tomography (PET), with a median stand- ardized uptake value (SUV) of 3.7 (range 2-6.3).38
Hormonal evaluation
Adrenal ganglioneuromas are typically nonfunctional, unless associated with pheochromocytomas. In a multicenter COMETE network study of 104 adrenal ganglioneuromas that excluded composite tumors, no biochemical abnormality was described in 91% of patients with hormonal evaluation and in the remainder 9%, hormonal work-up was either discrepant or indeterminate.38 While, in another study of 45 patients that included 20 composite ganglioneuroma- pheochromocytomas, 95% of composite tumors had a posi- tive biochemical test for catecholamine excess. 36
Histopathology
Microscopically, ganglioneuromas are composed of ganglion cells embedded in a Schwannian stroma, and nerve fibres. 43 Ganglion cells are usually mature, and Schwann cells are de- void of nuclear atypia. Necrosis and an increased mitotic in- dex are not seen. The Schwann cells are identified by S100 positivity adjoined by GFAP negativity. Rarely, ganglioneuro- mas arise in composite with a pheochromocytoma compo- nent, in these instances the neuroendocrine component is visualized by immunohistochemical expression of chromogra- nin A and GATA3. Synaptophysin is not a reliable distinguish- ing marker in this context, as both ganglion cells and Schwann cells exhibit synaptophysin immunoreactivity.
Management and prognosis
In a recent systematic review of 421 patients with adrenal gan- glioneuromas diagnosed between 1980 and 2019, 90% under- went adrenalectomy (laparoscopic in 58%; open laparotomy in 41%) and 10% had adrenal biopsies performed.36 Establishing a preoperative diagnosis of adrenal ganglioneur- oma is challenging due to non-specific clinical presentation and lack of pathognomonic radiological or hormonal findings, making it difficult to differentiate it from other adrenal tu- mors. In addition to the concern for seeding and inadvertent catecholamine crisis in the setting of a pheochromocytoma, adrenal biopsy carries the risk of missing a composite ganglioneuroma-pheochromocytoma or ganglioneuromas- neuroblastoma tumor, the latter of which would ultimately direct management. Thus, in the current era, most adrenal ganglioneuromas are managed via surgical resection, and an accurate diagnosis established on surgical histopathology of the entire specimen. The overall prognosis following sur- gery is excellent and in various studies with different dur- ation of follow-up (5.5-114 months), no cases of recurrence or mortality related to adrenal ganglioneuromas have been reported.32,36
Adrenal schwannoma
Schwannomas (or neurilemmomas) are benign mesenchymal tumors that arise from the Schwann cells of the peripheral ner- vous system. Though schwannomas can occur in any part of the body, the head & neck and flexor surface of extremities are the most typical sites involved. Retroperitoneal schwanno- mas are uncommon, accounting for less than 5% of all schwannomas, and rarely involve the adrenal glands.
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Adrenal schwannomas represent 0.2%-0.5% of adrenal tu- mors3,44 and arise from the Schwann cells of the phrenic nerve, the vagus nerve, or the sympathetic trunk that innervate the ad- renal glands, and can be found within the adrenal glands (pri- mary adrenal schwannoma) or in the juxta-adrenal area (juxta-adrenal schwannoma). Adrenal schwannomas are benign tumors that rarely undergo malignant transformation, the latter described in two cases of juxta-adrenal schwannomas. 45,46
Clinical presentation
Adrenal schwannomas typically occur in adults with a peak in- cidence in the fifth decade of life and are seen 1.7 times more frequently in women.47 Only two cases of pediatric adrenal schwannoma have been reported in the literature.48,49 In most patients, adrenal schwannomas are asymptomatic and discovered incidentally on imaging obtained for unrelated rea- sons.50,51 Potentially related to the large tumor size, up to 30% of patients can manifest non-specific pain in the abdo- men, back, or flank pain symptoms.47 Adrenal schwannomas are sporadic in presentation, and unlike schwannomas in oth- er locations, rare syndromic association with neurofibroma- tosis type 2, familial schwannomatosis, or Carney complex has not yet been reported.52
Diagnostic evaluation
Imaging characteristics
Adrenal schwannomas are predominantly unilateral tumors with no side predilection.47 These are well-encapsulated, round, or oval-shaped tumors with an average size between 5.7-8.1 cm (range, 1.0-15 cm) in different studies. 44,51,53,54 Adrenal schwannomas are hypovascular and generally solid tumors with a homogenous texture, but heterogeneous ap- pearance has been described in up to 40% of cases, because
of cystic or hemorrhagic degeneration (Figure 2F).47,55 Less commonly, they can appear as entirely cystic. Occasionally, calcifications can appear in punctate, coarse, or curvilinear form along the tumor wall. On abdominal ultrasonography, adrenal schwannomas usually appear as hypoechoic masses, but a mixed echo due to secondary degenerative changes can be seen.44,56 On color-flow doppler, adrenal schwannomas display minimal to no vascularity. On non-contrast CT, ad- renal schwannomas exhibit a mean attenuation of 30 HU (range 18-43 HU) and show increasing enhancement over time after intravenous contrast medium administration (Figure 5A-C).44,53,54 On MRI, they appear hypointense on T1- and heterogeneously hyperintense on T2-weighted images (Figure 5D and E).53-55 Adrenal schwannomas are lipid-poor, and therefore, there is no signal drop in the out-of-phase MRI sequence.55 Reports on FDG-PET characteristics of adrenal schwannomas per se are scarce, but despite their benign nature they demonstrate widely varying FDG-uptake, SUVmax 1.5-17.3.57
Hormonal evaluation
Adrenal schwannomas are nonfunctional tumors. 47 Nevertheless, a complete hormonal evaluation is advised due to challenges with establishing a non-histological diagnosis and imaging characteris- tics that could mimic a malignant tumor and pheochromocytoma.
Histopathology
Like schwannomas elsewhere, adrenal schwannomas show hyper- cellular areas composed of spindle-shaped Schwann cells (Antoni A areas) sometimes with nuclear palisading (Verocay bodies) alter- nating with loosely textured hypocellular areas (Antoni B areas).52 Schwannomas can be microscopically classified into conventional, cellular, ancient, plexiform, epithelioid, microscopic/cellular, and melanotic variants.52 In adrenal schwannomas, the majority are
conventional or cellular subtypes and less than 10% belong to oth- er subtypes.47 On immunostaining, schwannomas show strong and diffuse reactivity for S-100 protein.58
Management and prognosis
Due to non-specific clinical and radiological features, it is dif- ficult to establish a definitive diagnosis of adrenal schwanno- mas in the absence of histopathology. Most patients with adrenal schwannomas are managed with adrenalectomy, lap- aroscopically, or via open laparotomy depending on patient and tumor characteristics.47 In a recent systematic review of primary adrenal schwannomas, no recurrence or distant me- tastasis were reported in the 85 patients during a mean 45 month (range 5-115 months) follow-up.47
Adrenal hemorrhage
Adrenal hemorrhage (or apoplexy) refers to bleeding into the adrenal gland and, when unrecognized, can have a potentially devastating outcome. The true incidence of this condition re- mains unclear with old autopsy studies reporting 0.14%-1.8% adrenal hemorrhages.59,60 Unlike earlier days when adrenal hemorrhage was a histopathologic diagnosis on autopsy, the condition is nowadays generally diagnosed on cross-sectional imaging.61
Each adrenal gland is supplied by three suprarenal arteries, via numerous small branches that form a rich vascular plexus upon entering the adrenal cortex.62 This highly vascular plexus drains into relatively fewer venous channels located at the corticomedullary junction, and supplies the medullary sinusoids, which eventually drain into a single central adrenal vein, thus, creating a “vascular dam”.63 Additionally, the ec- centric arrangement of muscular bundles in the central adrenal vein results in a turbulent flow. Acute physiological stress stimulates corticotropin release and catecholamine secretion. Corticotropin enhances the adrenal gland’s blood flow and cortisol production, making it edematous and susceptible to hemorrhagic necrosis.64 The increased catecholamine secre- tion, especially in the central adrenal vein exposed to the high- est concentration, results in vasoconstriction and platelet aggregation, causing obstruction and increased venous back- pressure.65 This complex interplay of the unique vasculature and physiological stress response makes the adrenal glands particularly vulnerable to thrombosis and hemorrhage.
Clinical presentation
Adrenal hemorrhage is a heterogeneous condition that can oc- cur in a wide variety of clinical settings, and across various age groups and may be unilateral or bilateral. An adrenal hemor- rhage can be traumatic or nontraumatic (or pathologic), and data from autopsy and clinical series suggest traumatic etiology is more likely in young and pathologic in the elderly.66,67 Based on an unpublished Mayo Clinic series data of 450 consecutive patients, adrenal hemorrhage mainly occurred during the sixth-eighth decades of life with 1.8 times higher predisposition in males and predominant unilateral presentation (~ 90%).
Traumatic adrenal hemorrhage
Adrenal gland injury from trauma is uncommon, with a re- ported incidence between 0.22% and 1.7% and severe ab- dominal trauma associated with higher frequency.67-69 In >90% of patients, traumatic adrenal injuries are unilateral,
associated with polytrauma, and rarely require intervention (<3%).67-69 In a national database series of 7791 patients with adrenal gland injuries, the need for adrenalectomy in 80 (1%) patients were associated with penetrating trauma or concurrent injury to the spleen or intestine.68 None of the pa- tients with an isolated adrenal injury died or required interven- tion. Compared to unilateral injury, bilateral adrenal injury is associated with higher severity, morbidity, and mortality.70 The injury severity score was higher in trauma patients with adrenal hemorrhage than in those without.67
Non-traumatic (or pathologic) adrenal hemorrhage
Adrenal hemorrhage can happen in various clinical settings, including spontaneous occurrence in an underlying adrenal neoplasm. Though cited as a rare event, the exact incidence of adrenal mass with hemorrhage has not been reported in the literature. In a systematic review of 133 patients, mean age 50 years (range 17-77), with adrenal hemorrhage and underlying neoplasm, the majority of events occurred unilat- erally (94%), associated with pheochromocytoma (48%) fol- lowed by metastasis (14%), and 86% were treated with adrenalectomy or transarterial embolization.71 On the other hand, in a retrospective single-center study of 141 adult pa- tients, that excluded those with underlying adrenal neoplasm, hemorrhage most commonly occurred in the setting of sepsis or severe non-traumatic stress (40%), followed by incidental discovery on imaging performed for other reasons (20%)72 Other less common clinical scenarios included the presence of antiphospholipid syndrome or lupus anticoagulant (14%), spontaneous in the absence of trauma or anticoagulant therapy (12%), postoperative complication of non-adrenal surgeries (10%), and anticoagulant therapy (2%).72 Bilateral adrenal hemorrhage (or Waterhouse-Friderichsen syndrome) occurred in nearly half of the patients in this series, predominantly in the setting of antiphospholipid syndrome or lupus anticoagulant (100%), postoperative complication (93%), sepsis or severe non-traumatic stress (64%), and less commonly in association with anticoagulant therapy (33%), spontaneous in the absence of trauma or anticoagulant therapy (12.5%) or incidentally dis- covered (7%).72 Based on a hospital-based case-control study on bilateral adrenal hemorrhage, thrombocytopenia, heparin exposure of >3 days, and sepsis confers the highest risk, where- as hypotension or use of thrombolytic, coumadin, and antipla- telet therapy, had no association.73 Rarely, right-sided adrenal hemorrhage can happen following orthotopic liver transplant- ation as the procedure entails litigation and division of the right adrenal vein, which could cause adrenal infarction and hemor- rhage.74 Through the recent pandemic, reports of adrenal hemorrhage with predominant bilateral involvement as a com- plication of COVID-19 infection and vaccination have been re- ported worldwide.75-77
Neonatal adrenal hemorrhage is a rare event in preterm and term neonates, with a reported incidence of 1.6%. Common predisposing risk factors include disseminated intravascular coagulation secondary to sepsis, perinatal hypoxia, acidemia, or macrosomia.78-80 Limited data show this is predominantly a unilateral event, with one study showing equal laterality7 and others noting preferential right-side gland involve- ment.78,80,81 In most neonates, adrenal hemorrhage is self- limited and rarely results in adrenal insufficiency.
Adrenal hemorrhage is a frequently overlooked diagnosis due to nonspecific clinical presentation. Patients can be
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asymptomatic or present with flank or abdominal pain, fever, confusion, hypotension, thrombocytopenia, a sharp drop in hemoglobin, prolonged prothrombin or activated thrombo- plastin time, and rarely, hyponatremia and hyperkalemia.72,82 The most common manifestation in neonates is unexplained jaundice, and some may have a palpable flank mass or, rarely, scrotal ecchymosis due to tracking of blood via patent proces- sus vaginalis or along the retroperitoneum. 80,81 In most scen- arios, adrenal hemorrhage is a consequence rather than the primary inciting event, with a presentation that is easily as- cribed to coexisting medical condition. Nonetheless, early diagnosis and timely treatment can alter the clinical course, warranting the need for high index of clinical suspicion in the right setting.
Diagnostic evaluation
Imaging characteristics
Imaging is essential to confirm the diagnosis and evaluate for the presence of an underlying mass. The imaging appearance of adrenal hemorrhage is diverse, demonstrating characteristic evolutionary features over time (Figure 6A-F). The size can vary from focal to massive, occupying the entire adrenal gland and extending retroperitoneally.60 It can appear either as solid or mixed solid-cystic mass, with well-defined or irregular mar- gins that can take various forms (adreniform, round or oval, infiltrative).83
(a) Ultrasound: Ultrasound is preferred in neonates due to small body size with a relatively sizeable adrenal gland and lack of retroperitoneal fat, making it easy to visual- ize pathology in the adrenal area. However, in older chil- dren and adults, ultrasound of this area can be technically challenging. In acute stages, the hematoma shows heterogeneous echogenicity. As the clotting pro- cess occurs, the hematoma may appear diffusely hypere- choic. Over time with clot lysis, the mass demonstrates a central hypoechoic area, and subsequently evolves into
an anechoic cyst. Doppler imaging can help confirm the avascular nature of the hematoma.
(b) CT: Due to universal availability and quick turnaround time, CT is considered the imaging modality of choice in most patients. Before the hemorrhagic event, the ad- renal glands could appear diffusely thickened and with periadrenal fat stranding, due to increased hydrostatic pressure within the gland.84 On non-contrast CT, a hy- peracute bleed shows an attenuation of 30-45 HU, similar to that of the circulating blood. A few hours later, the at- tenuation on non-contrast CT increases to 70-80 HU, re- flecting increasing hemoglobin concentration. With time, the attenuation decreases in a centripetal fashion as clot lysis occurs. Subsequently, the hematoma evolves into a low-density fluid collection (30 HU) with a pseudocapsule (pseudocyst) that may remain stable, decrease in size or resolve completely (Figure 6A-F).85 Months or years later, calcifications can develop in the old hemorrhagic bed or in the pseudocapsule. Contrast-enhanced CT performed during active bleeding may show contrast medium extravasation, but within the hemorrhage there is a lack of contrast-enhancement.85 Rarely, hematomas may develop to mimic adrenocortical adenomas, showing at- tenuation <10 HU on non-contrast CT, and contrast-enhancement because of internal fibrosis.86
(c) MRI: MRI can be helpful in non-emergency setting to better determine the age of the hematoma, and evaluate an underlying lesion, not evident on CT. In the hyper- acute phase, the hemorrhage appears isointense on the T1- and hypointense on the T2-weighted sequence, due to intracellular oxyhemoglobin. In the acute phase (<2 days), as oxyhemoglobin breaks down to deoxyhemo- globin, the hemorrhage appears hypointense on T1- and T2-weighted sequences. In the subacute phase (3 to 14 days), as deoxyhemoglobin oxidizes to methemo- globin, the hematoma appears hyperintense on both T1- and T-weighted sequences. In the chronic stage (>14 days onset), as the hematoma evolves into a cyst, the center appears isointense on T1 and hyperintense
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on T2 sequences, and due to hemosiderin, the rim ap- pears hypointense on T1- and T2-weighted sequen- ces.87,88 Occasional calcifications in an adrenal hematoma can be difficult to recognize on MRI.
(d) Functional Imaging: FDG-PET/CT has a limited role in diagnosing adrenal hemorrhage but can help identify an underlying malignant neoplasm with 90%-97% sen- sitivity and 91% specificity.89,90 False-positive results could occur in the setting of a hormonally active aden- oma or hyperplasia. False-negative results have been re- ported in small (<1 cm) malignant lesions, significant hemorrhagic necrosis or neuroendocrine tumors metas- tasis with low metabolic activity.
Hormonal evaluation
Adrenal insufficiency resulting from adrenal hemorrhage hap- pens when more than 90% of the adrenal cortex is destroyed in both adrenals. Clinical and hormonal evaluation for pri- mary adrenal insufficiency with baseline elevated cortico- tropin and low cortisol concentrations is usually sufficient to make the diagnosis. However, as clinical presentation can be non-specific and overlap with other comorbidities, a high in- dex of suspicion is occasionally needed to diagnose bilateral adrenal hemorrhage and subsequent primary adrenal insufficiency.
Management
Adrenal hemorrhage is usually a self-limiting process followed by spontaneous resolution of the hematoma, with or without adrenal gland atrophy. Thus, in most scenarios, conservative
Box 1. Rare benign adrenal lesions.
· Represent <5% of all benign lesions of the adrenal glands.
. Most are discovered incidentally on imaging and, less commonly, due to symptoms of mass effect or acute abdominal/back pain.
. They are typically nonfunctional unless associated with another hormonally active tumor (eg, composite adrenal ganglioneuroma-pheochromocytoma or ad- renal hemorrhage associated with an underlying functional adrenal neoplasm).
· Predominantly unilateral, the imaging phenotype spans from unique (eg, benign adrenal cyst, calcifi- cation, or hemorrhage) to less distinct (eg, adrenal ganglioneuroma or schwannoma).
· Diagnosis is established based on typical radio- logical characteristics (eg, benign adrenal cyst, ad- renal calcification, or hemorrhage) or surgical histopathology (eg, adrenal ganglioneuroma or schwannoma).
· Management (conservative versus surgical) de- pends on the possibility of establishing a definitive preoperative diagnosis.
| Benign Adrenal Cyst | Adrenal Ganglioneuroma | Adrenal Schwannoma | Adrenal Hemorrhage | Adrenal Calcificationa | |
|---|---|---|---|---|---|
| Prevalence | ≤1% | 0.2%-1.6% | 0.2%-0.48% | 0.1%-1.8% | ≤1% |
| Age at diagnosis | 40-50 years | 30-50 years | 40-50 years | 50-70 yearsª | 50-70 years |
| Gender predisposition | 1.2-1.5 times higher in women | 1.0-1.5 times higher in women | 1.7 times higher in women | 1.8 times higher in mena | Equal |
| Mode of | Incidental 90% | Incidental 70%-90% | Incidental 70% | Incidental 42%ª | Incidental 87% |
| discovery | Mass effect 10% | Mass effect 10%-30% Hormone excess rarely | Mass effect 30% | Abdominal/back pain 28% Trauma 23% Sepsis 8% | Cancer staging 12% |
| Adrenal insufficiency 2% | |||||
| Size | Median 5.8 cm (range 0.5-20) | Mean 5.5-6.5 cm (range 1.0-20) | Mean 5.7-8.1 cm (range 1.0-15) | — | — |
| Laterality | Unilateral >97% | Unilateral > 98% | Predominantly unilateral | Unilateral >80%ª | Unilateral >90% |
| Unenhanced CT | Median 19 HU | Mean 30-35 HU | Mean 30 HU | Hyperacute - mean 30-45 HU | ≥100 HU |
| attenuation | (range 0-83) | (range 20-40) | (range 18-43) | Acute - mean 70-80 HU | |
| Subacute to chronic - mean 30 HU | |||||
| Contrast enhancement | Non-enhancing | Progressive enhancement | Progressive enhancement | Non-enhancing | Non-enhancing |
| MRI-weighted images | T1 hypointense T2 hyperintense | T1 hypo- or isointense | T1 hypointense | Hyperacute - T1 isointense, T2 hypointense Acute - T1 and T2 hypointense Subacute - T1 isointense, T2 hyperintense Chronic - T1 isointense, T2 hyperintense | — |
| T2 heterogeneously hyperintense | T2 heterogeneously hyperintense | ||||
| Calcification | 60%-70% | 30%-60% | 5%-10% | In chronic stages, exact prevalence is unknown | — |
| Adrenal hormone excess | Absent | Absent unless composite tumor with pheochromocytoma (20%-45%) | Absent | Absent, unless associated with functional adrenal neoplasm | Absent, unless associated with a functional adrenal neoplasm |
| Adrenal insufficiency | Absent | Absent | Absent | May be present in bilateral adrenal hemorrhage | May be present when bilateral calcification is a |
| Differential diagnosis | Other cystic lesions of the adrenal gland (eg, pheochromocytoma, adrenocortical cancer) | Lipid-poor adenoma, pheochromocytoma, malignancy | Lipid-poor adenoma, pheochromocytoma, malignancy | Underlying adrenal neoplasm, trauma, sepsis, coagulopathy, anticoagulant therapy, postoperative complication | sequela of infiltrative process, such as hemorrhage or infection Differential diagnosis is broad, and may be complicated by the underlying adrenal mass |
| Establishing diagnosis | Typical radiological features or surgical histopathology | Surgical histopathology. Adrenal biopsy is not preferred due to the risk of missing composite tumors. | Surgical histopathology | Typical radiological features with evolutionary changes noted on serial imaging. Rarely, surgical histopathology. | when present Typical radiological features. |
| Management | Mostly conservative. Adrenalectomy in selected patients with mass effect, atypical appearing cysts or abnormal hormonal evaluation. | Conservative management if etiology is clear. Most are treated with adrenalectomy due to indeterminate imaging features. | Conservative management if etiology is clear. Most are treated with adrenalectomy due to indeterminate imaging features. | Mostly conservative and directed towards underlying precipitating factor. Rarely, endovascular or surgical intervention is needed in the setting of hemodynamic instability. If associated with adrenal neoplasm, additional management depends on the underlying etiology of the neoplasm. | No intervention. Management is directed towards underlying pathology. |
Abbreviations: CT - Computed Tomography, HU - Hounsfield Unit, MRI - Magnetic Resonance Imaging. aUnpublished data from Mayo Clinic.
European Journal of Endocrinology, 2023, Vol. 188, No. 4
management is sufficient. However, rarely in the setting of un- controlled hemorrhage or hemodynamic instability that is re- fractory to supportive measures such as blood transfusions, endovascular intervention, or exploratory laparotomy should be considered. Follow-up interval imaging after a few months should be obtained to evaluate for an underlying adrenal mass, especially when not apparent on the initial imaging. Importantly, patients with bilateral adrenal hemorrhage oc- curring simultaneously or sequentially should be monitored closely for primary adrenal insufficiency as well as adrenal cri- sis and managed accordingly.91
Adrenal calcification
Literature on adrenal calcification is even more sparse. In a re- cent study from China that included 5057 patients who under- went adrenal surgery over a seven-year period, adrenal calcification was found in 1.5%.92 The presence of adrenal calcification is not diagnostic of a specific etiology and can be seen in both benign and malignant adrenal lesions. Based on data from an unpublished Mayo Clinic series of 540 con- secutive patients with radiologically discovered adrenal calci- fications, <20% were associated with an adrenal malignancy including pheochromocytoma. In most scenarios, adrenal cal- cification represents an old hemorrhagic or necrotic process within an adrenal tumor, or in the gland itself. Rare cases of granulomatous infection such as tuberculosis or histoplasmo- sis can also present with adrenal calcification.93,94 Radiologically, adrenal calcifications appear as bright white spots (Figure 7A-D) and characterized by non-contrast CT at- tenuation ≥100 HU and lack of contrast enhancement. They can occur in various forms (punctate, coarse, curvilinear), and in different locations (peripheral, septal, central) when as- sociated with an underlying adrenal mass or cyst (Figure 7A-D). Management in adrenal calcification should be directed towards the underlying pathology, and it is unlike- ly for surgical intervention to be required for the calcification itself.
Other rare lesions
Though most infiltrative adrenal diseases are malignant (me- tastasis, lymphoma, sarcoma),3 rarely, inflammatory (sarcoid- osis, histiocytosis) or infectious (tuberculosis, fungal) diseases could infiltrate the adrenal gland.95 Literature on these benign infiltrative adrenal pathologies is limited,95-97 and geographic- al location is likely to impact prevalence. Radiologically, infiltrative pathologies present with nonspecific adrenal en- largement of one or both adrenal glands.95 Diagnostic evalu- ation is based on clinical suspicion, other systemic manifestations, ancillary laboratory and radiological informa- tion, and/or percutaneous adrenal biopsy. The underlying pathology guides treatment. As benign infiltrative adrenal le- sions are frequently bilateral, evaluation for primary adrenal insufficiency is important at baseline, and during follow-up treatment.
Conclusions
Rare benign adrenal lesions comprise <5% of all benign le- sions of the adrenal glands and are typically nonfunctional, predominantly unilateral lesions with imaging characteristics either specific to the underlying etiology or indeterminate. Management (surgical or conservative) depends on whether
a preoperative diagnosis can be definitively established based on imaging characteristics (Box 1, Table 1).
Funding
Magnus Bergvall Foundation grant 2021-04226 (HF). This re- search was partly supported by the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) and National Institute of Aging (NIA) of the National Institute of Health (NIH) USA under award K23DK121888, R03DK132121, and R03AG71934 (to I.B). The views ex- pressed are those of the author(s) and not necessarily those of the National Institutes of Health USA.
Disclosure statement
Irina Bancos is on the editorial board of EJE. She was not in- volved in the review or editorial process for this paper, on which she is listed as an author.
Conflicts of interest: H.F., J.C., C.C.J., A.S., P.D. have noth- ing to disclose. I.B. reports consulting (fee to institution) from HRA Pharma, Recordati, Corcept, Sparrow, Neurocrine, Diurnal, Adrenas, Spruce, outside this work. I.B. reports fund- ing for investigator-initiated award from Recordati (outside this work).
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