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Seminars in Pediatric Surgery
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kune 37 / Number 2 / April 2018
SEMINARS IN PEDIATRIC SURGERY
The Perioperative Experience
Adrenocortical tumors in children
Zachary J. Kastenberg*, Eric R. Scaife
Division of Pediatric Surgery, Department of Surgery, University of Utah School of Medicine, 100N Mario Cappecchi Dr., Suite #3800, Salt Lake City, UT, United States
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ARTICLE INFO
Keywords: Adrenal cortex Adrenocortical neoplasm Carcinoma
ABSTRACT
Adrenocortical neoplasms are rare in childhood. Unlike their adult counterparts, they are often hormon- ally active and malignant. Despite being uncommon, adrenocortical neoplasms in children have signifi- cant associated morbidity and require complete surgical resection for effective management. Furthermore, the clinical overlap between adrenocortical neoplasms, adrenal medullary neoplasms, and functional dis- orders of the adrenal cortex requires that the practicing pediatric surgeon have a solid working knowl- edge of the presentation, diagnostic workup, and management of these anatomically related yet disparate pathologies.
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Introduction
The adrenal gland, while a single organ in the gross anatom- ical sense, represents two distinct embryologic regions, which in turn may be thought of as four clinically relevant histologic sub- divisions. The three interdependent layers of the adrenal cortex - the granulosa, fasiculata, and reticularis - are of mesodermal origin and produce mineralocorticoids, corticosteroids, and sex steroids, respectively. The adrenal medulla, the center of the gland, is of ec- todermal origin and is responsible for catecholamine production, thereby serving as a major regulator of the systemic sympathetic response.
Pathology of the adrenal gland often presents a diagnostic puz- zle given clinical overlap between adrenal cortical neoplasms and non-neoplastic masses, medullary neoplasms, and purely func- tional endocrine disorders. Complex endocrine pathways with in- tercommunication between central and peripheral systems allows for a variety of presenting symptoms resulting from purely func- tional, purely anatomic, or mixed functional-anatomic pathology.
For the pediatric surgeon there is often variability in the stage of diagnostic workup at which one becomes involved. If consulted on a child with physical manifestations of an endocrinopathy, it is important to understand both the purely functional and mixed functional-anatomic (functional adrenal neoplasms) disorders. On the other hand, when asked to consult on a child with a recently identified adrenal mass it is essential to understand the spectrum of potential pathologic entities, often with chemical evaluation per- formed retroactively.
In this chapter, we discuss the basic manifestations of adrenal cortical dysfunction and the associated pediatric surgical patholo- gies. We offer two potential foundational frameworks on which to build the reader’s knowledge: A modified Venn diagram in- corporating the purely functional, purely anatomic, and mixed functional-anatomic pathology to be referenced when confronted first with the functional endocrinopathy (Fig. 1); and a flow di- agram to be used as a construct when first confronted with the suprarenal mass (Fig. 2). It is worth bearing in mind that adreno- cortical neoplasms are quite rare in the pediatric population repre- senting approximately 25-50 new diagnoses per year in the United States.1-3 The majority of these tumors will be functional adreno- cortical carcinomas.
Adrenal dysfunction
Adrenal cortical dysfunction may result from aberrations in the endocrine pathways that lead to mineralocorticoid, corticosteroid, or sex steroid production (e.g. congenital adrenal hyperplasia) or from tumors that either lead to excess secretion of cortical hor- mones (e.g. adrenocortical carcinoma or aldosteronoma) or de- struction of normal cortex and, thus, adrenal insufficiency (e.g. bi- lateral adrenal hemorrhage). This section provides an overview of the functional disorders of the adrenal cortex and offers a concep- tual framework for understanding the patient presenting with the clinical sequelae of an adrenocortical endocrinopathy.
Mineralocorticoids - hyperaldosteronism
Hyperaldosteronism presents with the classic signs of hyperten- sion and hypokalemia. The initial workup is directed at confirm- ing excess aldosterone secretion. In addition to testing plasma and
* Corresponding author.
E-mail address: zachary.kastenberg@hsc.utah.edu (Z.J. Kastenberg).
Neuroblastoma
Extra-adrenal neuroblastoma
Adrenal Dysfunction
Bilateral adrenal hyperplasia (Hyperaldosteronism)
Suprarenal neuroblastoma +/- catecholamine secretion
ACTH-dependent Cushing syndrome, pituitary or ectopic (Hypercortisolemia)
Adrenal Medullary Tumors
Pheochromocytoma (Paraganglioma if extra-adrenal) +/- catecholamine secretion
ACTH-independent Cushing syndrome, primary pigmented nodular adrenocortical disease (Hypercortisolemia)
Adrenocortical neoplasms (Adenoma/Carcinoma)
Adrenocortical Tumors/Masses
Congenital adrenal hyperplasia (Virilization/Feminization)
Non-functional adenoma Adrenal hemorrhage Adrenal abscess
Post-hemorrhagic/infectious Addison disease (Adrenal insufficiency)
*ACC, adrenocortical carcinoma
Fig. 1. Spectrum of pediatric adrenal pathology.
Adrenal Tumors
Medullary
Cortical
Benign
Suprarenal Neuroblastoma
Abscess
Pheochromocytoma
Aldosteronoma
Malignant
Hemorrhage
Adenoma
ACC
*ACC, adrenocortical carcinoma
Clinical/Pathologic Overlap
urine aldosterone levels, plasma renin levels are evaluated to con- firm primary (decreased renin) versus secondary (elevated renin) hyperaldosteronism. Primary hyperaldosteronism is due to either an aldosterone secreting adenoma - an aldosteronoma - or bilat- eral adrenocortical hyperplasia.4 Causes of secondary hyperaldos- teronism include massive ascites, left ventricular failure and renal artery stenosis.
If no tumor is identified on cross-sectional imaging, bilateral adrenocortical hyperplasia is the presumptive diagnosis. In cases of diagnostic uncertainty, nuclear scintigraphy or adrenal venous
sampling may be of use in determining unilateral versus bilateral disease.5 The treatment for bilateral adrenal hyperplasia is long- term corticosteroid administration, which suppresses excess aldos- terone secretion and has been generally considered less morbid than bilateral adrenalectomy. The treatment of aldosteronoma is unilateral adrenalectomy, which is curative. It is worth noting that aldosteronoma, a benign tumor, is extremely rare in the pediatric population (See section on aldosteronoma below).
There are a number of syndromes that occasionally present diagnostic confusion given their physiologic overlap with hyper-
aldosteronism. While a complete description of these syndromes is beyond the scope of this review and outside the scope of practice of the contemporary pediatric surgeon, there are a few key points worth remembering. Bartter syndrome is a disorder of the renal tubules that leads to salt wasting and ultimately a hy- pokalemic, hypochloremic, metabolic alkalosis.6 Pseudo-Bartter syn- drome is similar in chemical presentation, but has no associated re- nal tubular pathology and can be associated with cystic fibrosis.7,8
Corticosteroids - hypercortisolemia and adrenal insufficiency
Harvey Williams Cushing, a mentee of William Halsted and the Pulitzer Prize-winning scholar Sir William Osler, is widely known as the first neurosurgeon in North America and is credited with describing the disease that now bears his name.9,10 Cushing dis- ease results when a pituitary adenoma secretes excessive adreno- corticotropic hormone (ACTH) leading to stimulation of the adrenal cortex and, thus, hypercortisolemia.11
Cushing syndrome encompasses a broader set of pathologies, all with the end result of hypercortisolemia.12 Pituitary adenoma secreting ACTH, ectopic ACTH secretion from other malignancies, ACTH independent hypercortisolemia (adrenocortical tumor or hy- perplasia), or excessive exogenous corticosteroid administration may all cause the sequelae of Cushing syndrome. The characteris- tic findings include rounded facies, acne, development of a buffalo hump, central weight gain, abdominal striae, and easy bruising.
The endocrine workup for Cushing syndrome is often com- pleted prior to the involvement of the pediatric surgeon, how- ever, the general progression of diagnostic tests is worth review. Again, a detailed description is beyond the scope of this article, but may be found elsewhere for the interested reader.13 When Cush- ing syndrome is suspected, the initial goal is to confirm hyper- cortisolemia by means of either a 24-hour urinary cortisol level, a nighttime salivary cortisol, or nighttime plasma cortisol. After con- firming an elevated cortisol, a low-dose dexamethasone test may be used to confirm pathologic hypercortisolemia. Next, the ACTH level is quantified with an elevated ACTH signifying an ACTH- dependent Cushing syndrome (i.e. pituitary or ectopic secretion of ACTH) while a low ACTH indicates an ACTH-independent cause (i.e. adrenal tumor or hyperplasia). ACTH-dependent Cushing syndrome prompts a high-dose dexamethasone suppression test. Pituitary tu- mors will typically respond to high-dose dexamethasone admin- istration with suppressed ACTH secretion, while ACTH secretion due to ectopic production will remain elevated. ACTH-independent Cushing syndrome is then further evaluated with cross-sectional imaging of the abdomen.
For the pediatric surgeon confronted with a child manifest- ing signs of hypercortisolemia, the primary goal is to identify, if present, an adrenocortical tumor. Typically, a contrast-enhanced computed tomography scan is performed. If a tumor of the adrenal gland is discovered in the setting of hypercortisolemia, the most common diagnosis in the pediatric population is adrenocorti- cal carcinoma (See section on Adrenocortical Neoplasms - The Adenoma-Carcinoma Spectrum below). The majority of these tumors will also present with concurrent signs of virilization.
Another potential cause of ACTH-independent Cushing syn- drome is primary pigmented nodular adrenocortical disease (PP- NAD). This is a bilateral, diffuse pathology of the adrenal cortex that has been associated with Carney complex.14 It often has no imaging correlate, but is classically identified by the beaded ap- pearance of the adrenal cortex on cross-sectional imaging. Treat- ment in persistent cases may requires bilateral adrenalectomy.15
Addison disease is the eponymous representation of adrenocor- tical insufficiency as opposed to the hypercortisolemia of Cush- ing syndrome. Addison disease presents with the sequelae of in- adequate corticosteroid production and, often times, inadequate
mineralocorticoid secretion as well.16 Clinically this presents as lethargy or fatigue, chronic pain, and hyperpigmentation from the melanocytic effects of hypersecretion of ACTH in response to chronic hypocortisolemia. Addisonian crisis describes acute adrenal insufficiency leading to hypotension, abdominal pain, fevers, and hyperkalemia and can be fatal if left untreated. For the pediatric surgeon it is important to recognize the clinical presentation of Ad- dison disease and Addisonian crisis as congenital adrenal hyperpla- sia, bilateral adrenal hemorrhage, cessation of exogeneous steroid administration, or elective adrenalectomy, may present with or precipitate adrenal insufficiency.17
Sex steroids - virilization/feminization
There is considerable conceptual overlap between disorders of sexual development, certain sex cord stromal ovarian tumors, and adrenocortical dysfunction resulting in sex steroid secreting tu- mors. Generally speaking, a neonate with an internal or external reproductive structure anomaly is considered to have a disorder of sexual development, the most common etiology being congen- ital adrenal hyperplasia secondary to 21-hydroxylase deficiency.18 On the other hand, an infant, adolescent, or teenager with signs of precocious puberty, virilization, or feminization raises concern for either a sex cord stromal ovarian tumor or an adrenocortical tumor. These patients should undergo a formal endocrine workup and cross-sectional imaging of the abdomen and pelvis.
Adrenocortical tumors and masses
The proper evaluation of a neonate, infant, or child with a suprarenal mass requires one to entertain a complete differential diagnosis including adrenocortical neoplasms, adrenal medullary neoplasms (please see Chapter on Pheochromocytoma and para- ganglioma in children), and non-neoplastic pathologies. The most common suprarenal mass in a neonate is adrenal hemorrhage. The most common suprarenal neoplasm in the neonate and infant is neuroblastoma. Adrenocortical neoplasms are rare, but most of- ten present as hormonally functional, malignant tumors. There is a bimodal distribution with most occurring in children younger than five years of age or older than 10 years of age, with those in the latter group having a worse prognosis.19 These general rules provide guidance when evaluating a pediatric patient with a suprarenal mass.
In adult patients the majority of adrenal neoplasms are iden- tified incidentally. They are small, non-functional adenomas, gen- erally considered to be of no clinical significance. Current adult guidelines support observation of non-functional adrenal adeno- mas less than four centimeters in maximal diameter.20 In adults there is a very distinct difference in biologic behavior between the rare adrenocortical carcinoma and the much more common, non- functional adenoma.
In children, however, this boundary - that between benign and malignant - is much less clear. The majority of adrenocortical tu- mors are functional and occur along a spectrum of aggressiveness as opposed to a binary cutoff between benign and malignant. As such, the clinical decision-making algorithm for the pediatric pa- tient with a suprarenal mass requires the clinician to differentiate between neoplastic and non-neoplastic disease (i.e. adrenal hem- orrhage or abscess) while also considering the clinical clues that enable delineation of adrenocortical versus adrenal medullary tu- mors. This section provides detailed descriptions of the adrenocor- tical tumors and masses encountered in children.
Adrenocortical neoplasms - the adenoma-carcinoma spectrum
Greater than 85% of adrenocortical neoplasms - adenoma or carcinoma - in children are hormonally active with the majority being classified as malignant adrenocortical carcinoma.21 In the United States there are roughly 25-30 cases of adrenocortical carci- noma diagnosed annually.22 These tumors most often present with symptoms of virilization alone, virilization with Cushing syndrome, or less frequently virilization with hyperaldosteronism.21,23 Non- functional tumors, those causing Cushing syndrome alone, or those causing hyperaldosteronism alone are much less common.
While many adrenocortical neoplasms occur sporadically, there are important associations to bear in mind. In 1967 Fraumeni and Miller described a series of 62 patients with adrenocortical neo- plasms in which they identified a number of comorbid patholo- gies including hemihypertophy and cutaneous lesions.24 This re- port foreshadowed the description of multiple cancer predisposi- tion syndromes associated with adrenocortical neoplasms includ- ing Beckwith-Weideman syndrome (11p15 locus mutations: hemi- hypertrophy, embryonal tumors, childhood adrenocortical neo- plasms), Li-Fraumeni syndrome (TP53 mutations: pre-menopausal breast cancer, soft tissue sarcoma, osteosarcoma, central ner- vous system tumors, childhood adrenocortical neoplasms), Car- ney complex (PRKAR1A mutations: lentiginosis; cardiac and/or cu- taneous myxomas; ACTH-independent Cushing syndrome, most commonly secondary to PPNAD; and less commonly, childhood adrenocortical neoplasms) and multiple endocrine neoplasia type 1 (MEN1 mutations; parathyroid adenomas, neuroendocrine tu- mors of the pancreas, pituitary adenomas, infrequent adrenocor- tical neoplasms).25-28 Roughly 50% of patients with adrenocortical neoplasms harbor germline mutations in the TP53 tumor suppres- sion gene.25,29
This finding is of particular interest to the subset of children with adrenocortical neoplasms in Brazil, where it has been pos- tulated that the lasting impact of the population founder effect (i.e. decreased genetic diversity resulting from a relatively small ancestral population) led to an unusually high density of carri- ers of the germline p.R337H mutation in the TP53 tumor suppres- sor gene.30,31 In Southeastern Brazil there are approximately three to four cases of adrenocortical neoplasms per one million chil- dren, representing an 18-fold increase in incidence compared to other parts of the world. Greater than 90% of these children harbor the p.R337H mutation. Current literature supports the notion that family members of children with the p.R337H mutation should be tested given a 21% cumulative cancer risk in carriers of the p.R337H mutation by the age of 45 (most often breast and gastric cancer) compared to just a 2% cumulative risk in non-carriers.30
The preoperative workup for a patient with an adrenocortical neoplasm involves clinical and laboratory evaluation of the hor- monal aberrations described in the preceding section. Cross sec- tional imaging is important to evaluate for both the local extent of disease and for metastatic disease. Tumor thrombus in the renal vein or inferior vena cava has been suggested to be an indication for neoadjuvant chemotherapy, though the chemotherapy-resistant nature of these neoplasms highlights the importance of a thought- ful, case-by-case approach.31
Sporadic, inherited, or syndromic, the most important aspect of the management of adrenocortical neoplasms is complete sur- gical resection. In the case of localized disease this implies uni- lateral adrenalectomy. Larger tumors with substantial risk of R1 resection (cancer cells present at the resection margin) or tumor rupture should be approached by laparotomy.32,33 The laparoscopic approach is reasonable for small tumors confined to the adrenal gland for which R0 resection (no cancer cells present at the resec- tion margin) can confidently be achieved.34 In this scenario the di- agnosis of adrenocortical carcinoma is often unknown at the time
of resection. Locally advanced disease often requires multivisceral resection. In cases of diaphragmatic extension or involvement of the posterior sector of the liver, a thoracoabdominal incision may be advantageous.
The most common sites of metastases for adrenocortical car- cinoma are the liver, lungs and lymph nodes. Metastatic disease should be resected whenever possible to offer the possibility of long-term survival. The specific utility of pulmonary metastectomy has been described for adrenocortical carcinoma,35 though similar to many other pediatric malignancies, no consensus on the appro- priateness of thoracoscopy versus thoracotomy has been reached. Whether performing staged operations of combined resection of the primary tumor and metastectomy requires, again, case-by-case consideration.
Following resection, histopathologic evaluation provides infor- mation regarding tumor biology. In 1984 Lawrence Weiss described a set of nine histopathologic features to aid in differentiating be- tween benign and malignant adrenocortical neoplasms in adults. In this oft-cited report, Weiss reviewed 43 adrenocortical neoplasms treated at the Peter Bent Brigham and Brigham and Women’s Hos- pitals between 1959 and 1980. The patient ages ranged from 20 to 70 years. The histopathologic features evaluated included: Nu- clear grade, mitotic rate, atypical mitoses, cytoplasm clarity, tumor architecture, tumor necrosis, and invasion of venous, sinusoidal, and capsular structures.36 While this system performed well in the adult population,36,37 it was not as accurate when applied to chil- dren.38
In 2003 Wieneke et al. put forth a set of macro- and micro- scopic factors specifically for differentiating between benign and malignant adrenocortical neoplasms in children. They evaluated 83 tumors from patients less than 20 years of age collected by the En- docrine Registry of the Armed Forces Institute of Pathology span- ning the years 1965 to 1997. Using advanced modeling, nine fac- tors were chosen that subdivide tumors into three categories - be- nign, indeterminate, and malignant. The criteria include: mitotic rate, atypical mitoses, tumor necrosis, venous invasion, capsular in- vasion, as well as the macroscopic findings of tumor weight greater than 400 g, tumor size greater than 10.5 cm, invasion into the vena cava, and extension into the surrounding soft tissue or or- gans.19 The presence of less than three of these criteria (benign categorization) correctly identified 55% of benign-behaving tumors, the presence of 3 criteria (indeterminate categorization) included 22% of the total patient sample of whom 4% had tumors that ulti- mately behaved in a malignant fashion, and the presence of greater than 3 criteria (malignant categorization) correctly identified 78% of malignant-behaving tumors.
While multiple single institution studies have validated the util- ity of the Wieneke criteria in a retrospective fashion,38-41 there re- mains room for improvement. Recent efforts to improve upon our ability to differentiate between benign and malignant neoplasms have focused on the molecular tumor biology.39,41,42 In a study conducted by Das et al., the evaluation of 17 adrenocortical neo- plasms associated both abnormal expression of P53 and a high Ki- 67 index with malignant tumor behavior. 39 While in a joint effort between St. Jude and the Children’s Oncology Group, the presence of MHC class II, a surrogate for the presence of tumor-infiltrating immune cells within the adrenocortical neoplasm, was associated with benign tumor behavior and higher rates of progression-free survival.42
The preceding few paragraphs are, essentially, a pedantic at- tempt to convey the fact that the ongoing conversation between what constitutes a benign versus a malignant childhood adreno- cortical neoplasm is more a debate of academic interest than of pragmatic import. In a contemporary study evaluating 111 chil- dren with documented adrenocortical neoplasms from the National Cancer Data Base, the factors associated with decreased 1- and 3-
year survival were older age at diagnosis, larger tumors, locally ad- vanced disease, metastatic disease, and positive surgical margins.43 Parallel conclusions were drawn from the modern Brazilian expe- rience.44 While there are certainly many nuances to the biological underpinnings of these tumors, adrenocortical neoplasms remain a surgical disease for which timely diagnosis and adequate surgical resection remain paramount.
In the case of incomplete surgical resection (R1 or R2 resection) or grossly metastatic disease, the issue of adjuvant therapy must be considered. Given the rarity of this disease in children there are few guidelines to follow. The two specific issues to be considered are that of when traditional adjuvant chemotherapy should be rec- ommended and under what circumstances should the adrenolytic agent, mitotane, be administered. In a retrospective analysis of data collected by the German GPOH-MET 97 trial, the use of traditional adjuvant chemotherapy, with no specific regimen defined, was rec- ommended for cases of incompletely resected tumors or tumor spillage. The use of mitotane was also associated with improved outcomes.32
To date, the only prospective study evaluating adjuvant strategies was undertaken by the Children’s Oncology Group (ARAR0032), which closed for enrollment in 2013. Though official publications remain forthcoming, the final study report was posted online in 2016. The stated conclusions were as follows: tumors confined to the adrenal gland that are 5 cm or less (Stage I disease) are treated effectively with surgery alone; tumors confined to the adrenal gland that are greater than 5 cm (Stage II disease) have a high rate of recurrence and consideration should be given to mi- totane or mitotane with traditional chemotherapy; tumors that are locally advanced, metastatic to lymph nodes, or present with dis- tant metastases (Stages III and IV) disease should receive surgery and chemotherapy - though the most effective chemotherapy reg- imen remains to be determined. Notably, there was a 10.5% dis- continuation rate for toxicities related to mitotane and a 31.6% dis- continuation rate for toxicities related to the employed regimen of cisplatin, doxorubicin, and etoposide. The study section considered this cisplatin-based regimen infeasible due to such a high rate of associated morbidity.45
In contemporary series, patients with small tumors and no metastases do well, while those with large, locally aggressive tu- mors or those with distant metastases fare poorly. One-year sur- vival for those with localized disease is greater than 70% compared to approximately 40% one-year survival when distant metastases are present at diagnosis. Further analysis of just those with local- ized disease reveals one-year survival of nearly 90% when the dis- ease is confined to the adrenal gland compared to 30-40% one- year survival when the tumor is locally advanced.43 Three-year overall survival reported in the Children’s Oncology Group study was 92% for those with tumors confined to the adrenal gland and 5 cm or less (Stage 1 disease) compared to just 13% for those with metastatic disease at presentation (Stage IV disease).45
Aldosteronoma
As described in the preceding section, adrenal neoplasms in the pediatric population are generally thought to occur along a spec- trum of benign to malignant pathology, with the majority of the tumors being functional. This not infrequently implies a combina- tion of hormone secretion from the three layers of the adrenal cor- tex. There are, however, case reports of pediatric adrenal adenomas that are small (typically less than 2 cm), fatty yellow, well encap- sulated tumors surrounded by normal adrenal tissue that secrete only aldosterone - aldosteronomas. There are roughly 25-30 such cases reported in the literature suggesting that this distinct, gener- ally adult pathology, does in fact occur in children.46
This is more than a simple issue of semantics. Aldosteronoma, the tumor originally described by Jerome W. Conn in 1955, leads to the constellation of hypertension and hypokalemia due to exces- sive aldosterone secretion with suppressed plasma renin levels.47 This should be considered a pathology separate from the adrenal neoplasms described in the preceding section that will sometimes secrete aldosterone in conjunction with other adrenocortical hor- mones. True aldosteronomas are benign, generally solitary and uni- lateral, and the resulting Conn syndrome is cured with laparo- scopic adrenalectomy.
When presented with the pediatric patient with hyperaldos- teronism confirmed to be primary in nature (i.e. low plasma renin levels), one must differentiate bilateral adrenal hyperplasia, the most likely etiology, from aldosteronoma. Cross sectional imaging with magnetic resonance or computed tomography is the diagnos- tic study of choice, with some reports of nuclear scintigraphy being helpful in difficult cases.5 If an adrenal tumor is identified, Conn syndrome secondary to aldosteronoma is the assumed diagnosis and laparoscopic adrenalectomy is the next step in management. If no tumor is identified, a trial of corticosteroid-induced aldos- terone suppression is attempted as bilateral adrenal hyperplasia generally responds to corticosteroid administration. In the setting of refractory disease, bilateral adrenal vein sampling may be per- formed.48 If asymmetric aldosterone secretion is confirmed, unilat- eral adrenalectomy is performed. Only in severe cases of refractory hyperaldosteronism due to bilateral adrenal hyperplasia is bilateral adrenalectomy considered.
Following resection of an aldosteronoma, hypokalemia and hypertension generally promptly resolve. Recurrence or metachronous disease has not, to our knowledge, been described. There are reports, however, of cases involving delayed diagnosis or prolonged exposure to elevated aldosterone levels in which patients develop nephrocalcinosis and refractory hypertension due to chronic kidney disease or intractably elevated peripheral vascular resistance.49
Adrenal hemorrhage
An adrenal mass in a neonate most likely represents an adrenal hemorrhage, a neuroblastoma, or less frequently an adrenal ab- scess or subdiaphragmatic extralobar pulmonary sequestration. The incidence of adrenal hemorrhage has presumably increased in re- cent years, most likely secondary to the increased use of diagnostic imaging techniques such as ultrasound and computed tomography. It is now recognized as the most common cause of adrenal mass in the neonate. Adrenal hemorrhage occurs in roughly 2 per 1000 live births and is associated with birth trauma, perinatal hypox- emia, and inherited or acquired bleeding diatheses.50
Neonatal adrenal hemorrhage most characteristically presents as prolonged anemia, indirect hyperbilirubinemia, or occasionally a scrotal hematoma.51,52 Physical exam will reveal an upper abdomi- nal or flank mass. Ultrasound confirms the diagnosis. A fluid-filled, cystic mass often quite impressive in size, will be identified in the suprarenal space.
Generally, the clinical scenario will suggest the diagno- sis of adrenal hemorrhage as opposed to cystic neuroblas- toma. To this end, however, plasma or urine metanephrines and normetanephrines should be obtained during the diagnostic workup. Intervention other than transfusion and correction of co- agulopathy is typically unnecessary for adrenal hemorrhage. In the case of diagnostic uncertainty serial abdominal ultrasonography will show slow reabsorption of an adrenal hematoma while one would expect a large cystic neuroblastoma or adrenocortical neo- plasm to persist.53
Unilateral adrenal hemorrhage should resolve without long- term clinical sequelae. Importantly, bilateral adrenal hemorrhage is
a rare entity that may lead to persistent adrenal insufficiency. In a single institution series describing cases of primary adrenal insuffi- ciency, bilateral adrenal hemorrhage was implicated as the under- lying etiology in two out of 42 children over an 11-year period.54
Adrenal abscess
Adrenal abscesses generally present in the neonatal period, but have been described in infants and in later childhood. There are approximately 50 case reports of adrenal abscesses in the pedi- atric literature with the true incidence remaining unknown.55 The pathophysiology has been described as either bacterial seeding of the healthy adrenal gland or suprainfection of an existing adrenal hematoma.56 Common organisms implicated included staphylococ- cus and enteric gram-negative organisms in neonates and my- cobacterium tuberculosis in children and adolescents - generally in endemic regions.57-59
The most common presentation is lethargy, failure to thrive, fevers, flank mass, and leukocytosis within the first few months of life. Similar to the presentation of adrenal hemorrhage, there is most commonly a history of birth trauma or hypoxia. The workup includes standard chemistries and complete blood count to evalu- ate for signs of adrenal insufficiency (hypoglycemia, hyponatremia, hyperkalemia) and systemic inflammation. Abdominal ultrasound often reveals a cystic suprarenal mass with semisolid components. Serum or urine metanepherines and normetanephrines should be evaluated to rule out a functional suprarenal neuroblastoma. Other diagnostic possibilities include adrenocortical neoplasm, Wilms tu- mor, or other less common renal tumors. Depending on the quality of the ultrasound and the reassurance of the laboratory workup, the decision for further cross-sectional imaging can be made.
In the absence of imaging characteristics or laboratory findings suggestive of neoplasm, the surgical principles related to source control apply. The literature contains descriptions of needle aspira- tion, percutaneous drainage, open drainage, and formal adrenalec- tomy - all of which have been successful in conjunction with in- travenous antibiotics.57,60 It seems prudent to attempt less invasive measures starting with antibiotics in conjunction with aspiration or percutaneous drainage, while reserving adrenalectomy for cases in which these methods fail to achieve source control or for cases of diagnostic uncertainty.
Prompt resolution of the suprarenal mass is typically observed with case reports describing near complete resolution (generally following drainage with 14 days of antibiotics) on follow up ultra- sound without signs of chronic adrenal insufficiency. Notably, re- gions of the world in which mycobacterium tuberculosis remains prevalent have relatively high rates of adrenal insufficiency sec- ondary to chronic mycobacterial infections of the adrenal gland. Of historical interest, Addison’s initial description in 1855, of the dis- ease that now bears his name was made after observing the de- velopment of adrenal insufficiency in a series of patients suffering from mycobacterial infections.61,62
Summary
Adrenocortical neoplasms in children require a management paradigm that is quite different from that applied to the adult population. In adults, adrenocortical carcinoma is a distinct patho- logical entity when compared to the much more common, non- functional adenoma that is often management non-operatively. In children, however, the term adrenocortical neoplasm is used to represent the pathologic spectrum of tumors that span from the completely benign to the aggressively malignant, with overt metastatic disease being the only definitive indication of a malig- nant lesion prior to resection. In the absence of clinical signs sup- porting the diagnosis of a non-neoplastic lesion such as adrenal
hemorrhage or abscess, malignancy must be assumed and, thus, surgical resection is the foundation of the management strategy.
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