Author's Accepted Manuscript
Rare Adrenal Tumours in Children Radu Mihai MD PhD FRCS
PII: DOI: Reference:
www.elsevier.com/locate/sempedS1055-8586(14)00006-7 surg http://dx.doi.org/10.1053/j.sempedsurg.2014.03.004 YSPSU50470
To appear in:
Seminars in Pediatric Surgery
Cite this article as: Radu Mihai MD PhD FRCS, Rare Adrenal Tumours in Children, Seminars in Pediatric Surgery, http://dx.doi.org/10.1053/j.sempedsurg.2014.03.004 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting galley proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
#3 Rare Adrenal Tumours in Children
Radu Mihai, MD PhD FRCS Consultant Endocrine Surgeon Address
Churchill Cancer Centre Old Road, Headington Oxford OX3 7LE United Kingdom
Telephone
+44 1865 223555
Fax
+44 1865 223589
Email:
[email protected]
ABSTRACT Apart from neuroblastomas, adrenal tumours are exceedingly rare in children and young adults. In this age group, the vast majority of patients present with clinical signs associated with excess hormone production. The most common tumour to arise from the adrenal cortex is an adrenocortical carcinoma (ACC). Similar to the situation in adults, this tumour is frequently diagnosed at a late stage and carries a very poor prognosis. ACCs require extensive/aggressive local resection followed by Mitotane chemotherapy. A multidisciplinary approach is essential and these children should be referred to units with previous experience in managing ACC. International registries are an invaluable source for evidence-based care and such collaborations should be further developed in the future. Phaeochromocytomas are derived from the adrenal medulla and present with symptoms caused by high secretion of catecholamines. At least a third of these children will be found to carry genetic mutations, most commonly the RET gene (MEN2 syndrome) or the VHL gene. Open radical adrenalectomy should be offered to children with adrenocortical cancers. For all other cases, laparoscopic adrenalectomy is the treatment of choice.
It is possible that the
retroperitoneoscopic approach will gain increasing favour. The role of robotic adrenalectomy remains controversial.
KEY WORDS
Adrenal, adrenalectomy, laparoscopic, phaeochromocytoma, adrenocortical cancer
1
Introduction Tumours of the adrenal gland, other than neuroblastomas, are extremely rare in children. Consequently, adrenal surgery is seldom indicated in children and young adults, and the experience of the majority of individual surgeons remains very limited. For example, the national audit maintained by the British Association of Endocrine Surgeons (BAETS) has logged only 33 adrenalectomies in patients under 21 years of age out of a total of 1359 such operations performed by BAETS members (http://www.baets.org.uk/wp-content/uploads/2013/05/4th-National-Audit.pdf). This paper discusses the common indications and technical aspects of adrenal surgery in children by reviewing papers published in the last 10 years in the English literature. All information is based on non-randomised cohort studies from centres with large practice, as well as a few individual casereports that illustrate these conditions. This paper does not address any issues related to neuroblastomas.
Etiology of adrenal tumours in children
The adrenal gland has two distinct parts: the cortex and the medulla. Each part has a different embryological origin, each produces different hormones, and each is the origin of different types of tumours. The cortex arises from the mesoderm and starts to develop in the fourth week of gestation as a proliferation of coelomic mesothelium into the underlying mesenchyme between the root of the dorsal mesogastrium (the root of the mesentery) and the urogenital ridge (the mesonephros and the developing gonad). This close proximity explains why ectopic adrenal tissue has been described to be located below the kidneys and associated with the testes or ovaries. In the initial phase, the adrenogonadal primordium (AGP) is first distinguished and expresses the essential transcription factor SF1 (steroidogenic factor 1). In the second phase (8th week gestation in humans), the AGP separates into two distinct structures, the adrenal and the gonadal primordial. This second phase is followed by migration of neural crest cells through the fetal cortex to establish the medulla. The embryogenesis of the adrenal medullary cells starts in the second month of gestation. Before this, during the fourth week of embryonic life, the neural plate develops and then infolds to form the neural tube. A portion of the neuroectoderm adjacent to the tube separates and remains between the neural
2
tube and the definitive ectoderm as the neural crest. Cells derived from the neural crest (sympathogonia, primitive spinal ganglia) migrate ventrally from the apex of the neural tube to the dorsal aorta (where they aggregate and differentiate into neuroblasts to form sympathetic neurons) or to the adrenal primordia (where they differentiate into phaeochromoblasts to form chromaffin cells).
At the end of gestation, the adrenal gland is organized into distinct zones: glomerulosa, transitory (that appears between weeks 22-24, the future zona fasciculata) and dominant fetal zone. Immediately after birth, the fetal zone undergoes rapid involution. Moreover, the zona reticularis starts to develop at the age of 4-6 or even 8 years, while structure typical to adults stabilizes at the age of 10-20 years. The fascicular and reticular zones of the adult cortex proliferate from the glomerular zone after birth and are fully differentiated by about the 12th year. It appears therefore, that the adrenal gland in children is in a process of continuous transformation. In this context, tumours that develop in children are either sporadic or, more commonly, appear in the context of genetic syndromes associated with a risk of adrenal tumours.
The most well known
associations are the development of phaeochromocytomas in Multiple Endocrine Neoplasia Type 2 (MEN2) and in von-Hippel-Lindau (VHL) syndromes, and the appearance of adrenocortical carcinoma (ACC) as a hallmark cancer in families with Li Fraumeni syndrome resulting from mutations in the TP53 gene.
Adrenocortical cancer
Incidence
Adrenocortical carcinomas (ACCs) are very rare tumours, with an incidence of 1-1.5 per million population per year. Data published by the International Association of Cancer Registries showed that there is a peak of incidence in childhood and one in the 5th decade of life. The situation differs in Brazil where a disproportionately large number of children are diagnosed with ACC due to p53 mutations.
3
Clinical presentation
Most children present with clinical signs. In a series of 20 children operated in a single center at a mean age of 7 years (range, 2.5 to 13 years), endocrine dysfunction was noted in 83% of the patients, with virilization being the most common presentation, followed by Cushing's syndrome. Fourteen patients presented with a palpable abdominal mass and three patients presented with distant metastases. The mean time from initial symptoms to diagnosis was 8 months. The majority (80%) had regional or metastatic disease by the time of presentation (1). Similar findings from another series of 23 children with a mean age of 9 years reported tumor hormone production in 74% of patients and advanced stage for disease in 66% (2). These findings were confirmed in a multicentre registry of 254 patients, of whom the majority (84.2%) had virilization, while Cushing's syndrome without virilization was uncommon (5.5%) (3). The high percentage of children with functioning tumors suggests that earlier detection is possible if there is increased awareness of this possible diagnosis amongst clinicians who assess these children at the onset of their symptoms (2).
Diagnosis
In some patients the diagnosis is suggested by the clinical presentation if signs of virilisation are observed in a girl or rapid onset of ‘early puberty’ occurs in a young child. In the absence of signs of metastatic disease, the radiological suspicion of malignancy is generally based on the size of the tumour. For adults the risk of an adrenal tumour representing a ACC increases from 4 cm (risk 10 cm (risk close to 100%). Likely these dimensions have to be interpreted based on the age of the child. Further signs suggestive of malignancy include a high Hounsfield unit on unenhanced scans (>10 HU) and rapid washout of the contrast. There are no studies aassessing the role of PET scanning in children with adrenal tumours but in adults the technique to commonly used to assess for metastatic disease, Furthermore, the SUV ration between liver and adrenal tumour is used in some centres as a sign of malignancy. There is no role of biopsy of the adrenal gland as the cytological diagnosis of ACC is unreliable and the procedure can increase the risk of contamination of normal anatomical planes. The histological diagnosis is based on assessing how many of the nine characteristics summarized on the Weiss score are present (nuclear grade, mitoses/50 high-power fields, atypical mitoses, clear cells, diffuse architecture, confluent necrosis, venous invasion, sinusoidal invasion, capsular
4
infiltration). Tumours with a score of 6 are malignant and a score of 3-6 are indeterminate.
Surgical treatment
In all reported series radical surgery is considered necessary in order to ensure complete excision hence in addition to adenalectomy, ipsilateral nephrectomy and/or right hepatic lobectomy plus nephrectomy should be considered (1). The aim of such aggressive approach is to limit the risk of local recurrence.
Postoperative treatment
Adjuvant chemotherapy consisting of mitotane or mitotane plus cisplatin and etoposide is commenced postoperatively. Systemic chemotherapy and mitotane therapy are both important therapeutic options in the treatment of advanced pediatric ACC patients. Neoadjuvant therapy should be considered for patients with primarily incomplete resectable or inoperable tumors, and tumor spillage is an indication for adjuvant chemo- and mitotane therapy. In the GPOH-MET-97 study over half of children had chemotherapy (neoadjuvant, adjuvant, and salvage) and mitotane therapy. Duration of mitotane treatment longer than 6 months and mitotane levels greater than 14 mg/l were found to be associated with significantly better survival (4).
Prognosis
The prognosis for these tumours is poor with an overall 5-year survival of less than 30%. In this context it remains distressing to know that the vast majority of patients are treated in units with minimal previous experience. The expectation is that all pediatric ACC patients should be treated in pediatric oncological centers according to a consistent protocol in a highly interdisciplinary setting (including surgeons experienced in radical adrenalectomy), but the rarity of the disease makes it difficult to monitor adherence to such guidelines worldwide. Nevertheless, in Germany this approach has been followed since 1997, with all pediatric ACC patients being treated according to the non-
5
randomized, single arm study - GPOH-MET-97. Data regarding 60 patients with ACC (age 0.24-18 years, with a M:F gender ratio of 1:2) treated according to the GPOH-MET-97 protocol, showed that among all patients, event-free survival and overall survival were 43% and 65%, respectively (4) Children with a tumor volume of >300 mL (n=25) showed an increased rate of operative complications and a poorer overall survival rate. A total of 14 patients showed metastatic spread, particularly to the lungs and lymph nodes. R2 resection only was achievable in 5 patients, and surgery was not feasible in 3 patients. Interestingly, preoperative biopsy and/or experienced tumor rupture were associated with poorer overall-survival rate, reinforcing the view that biopsy should not be used in the diagnosis workup of adrenal masses suspected as ACC (5). An International Pediatric Adrenocortical Tumor Registry was also created and provided a descriptive analysis of 254 patients treated between 1990-2001 (3). Tumors were completely resected in 83% of patients and at a median follow-up of 30 months, 157 patients (62%) survived without evidence of disease and 97 patients (38%) had died. The 5-year event-free survival estimate was 54% (95% CI, 48% to 60%). In a multivariate analysis, disease stage, presenting signs of endocrine dysfunction, and age were independently associated with prognosis (3).
Primary hyperaldosteronism
Incidence
Unilateral aldosterone-secreting adenomas (Conn’s syndrome) are seldom encountered in children. At the present time, there is increased interest in assessing adult hypertensive patients for Conn's, because allegedly up 10% of them may have primary hyperaldosteronism. If the proposed changes in the protocols for investigating adults with hypertension, this should also be extended to children found to be hypertensive.
At the present time, however, there has been no published series of
adrenalectomies for primary hyperaldosteronism in children and all information is derived from case reports of hypertensive children with/without hypokalaemia.
6
Diagnosis
The diagnosis of primary hyperaldosteronism relies on demonstrating increased aldosterone, low renin levels, and a raised aldosterone/renin ratio in a child diagnosed with hypertension. For example, a 15year-old girl complained of headache lasting for approximately 1.5 years, which was diagnosed as severe hypertension. Primary aldosteronism was diagnosed on the basis of hypokalemia and alkalosis accompanied by plasma renin activity of 3.9 ng/mL/h and an aldosterone level of 1007 pg/mL (normal: 40-480). Left adrenalectomy was performed because a 10x12x12 mm adenoma was detected on abdominal magnetic resonance imaging. Her 24-h ambulatory blood pressure values of the patient were normal at 10 months after the operation, the treatment was stopped, and she remained normotensive when followed up for 15 months without any treatment (6). This sequence of events mirrors the situation in many adults. There are however, many patients in whom cross-sectional radiology cannot demonstrate the laterality of the adrenal adenoma, as most of them are < 1 cm in diameter.
These patients undergo selective adrenal venous sampling with measurement of
aldosterone/cortisol ratio in each adrenal vein and in the peripheral blood. Though this test is widely employed in diagnostic pathways of adults with primary hyperaldosteronism, there are no case series demonstrating the use of this technique in children.
Treatment
Laparoscopic adrenalectomy is the treatment of choice for patients with unilateral disease. Those with bilateral disease are primarily treated medically with Spironolactone and potassium supplements
Congenital adrenal hyperplasia
The most common form of congenital adrenal hyperplasia is due to a deficiency of 21-hydroxylase (21OHD) activity and is caused by a mutation in the CYP21 gene. By genotyping patients, new and important information can be gained, including the presence or absence of 21OHD in borderline cases, determining the severity of disease and identifying heterozygote carriers. The adrenal
7
management of patients with 21OHD involves administering sufficient glucocorticoids to suppress excess adrenal androgen secretion, but not such high doses that bone growth and mineralization are impaired. New management strategies have been proposed and include administering only substitution doses of corticosteroids and counteracting side-effects by administering an anti-androgen and aromatase inhibitor. Adrenalectomy has also been proposed but plays a minor role, but further evaluation of this approach is necessary (7). No series have been published on this, and therefore the only information available is derived from individual case-reports.
Phaeochromocytoma
Phaeochromocytomas (PHAEOs) are catecholamine-secreting adrenal tumours derived from the adrenal medulla. When they occur in extradrenal locations they are called paragangliomas (PGGLs).
Clinical presentation
As blood pressure is not routinely measured in childhood, PHAEOs are challenging to diagnose in children and the diagnosis is frequently significantly delayed. Children may present with episodes of intense headaches, but more subtle signs such as paroxysmal tachycardia are not easy to elicit from the history in children. Sweating and abdominal pain are other predominant signs of PHAEOs. The situation differs for children who are members of families with known genetic syndromes associated with high risk of developing a PHAEO and in whom the diagnosis is then often based on biochemical screening in all children carrying the mutation.
Diagnosis
Biochemical diagnosis is based on measuring the concentration of 24-hour urinary metanephrines. In small children (when 24 hour urine collection is much harder) and in children with a high risk of having such tumours (i.e. members of MEN-2 families involved in regular biochemical screening), the diagnosis is based on measuring the plasma concentration of metanephrines. Once biochemical diagnosis is secured, localisation of the tumour is based on cross-sectional imaging with abdominal MRI or CT scanning.
8
Genetic screening
Due to the rarity of PHAEOs in young patients, current guidelines recommend that all patients diagnosed with this condtion should undergo genetic screening, even if they are not members of recognized families with a syndromic mutation.
Spectrum of disease
In three large series including a total of 49 children with PHAEO, the incidence of bilateral disease (overall 10%) and malignant disease (overall 10%) varied significantly between series (see Table 1).
Treatment
All patients undergo adrenergic blockade preoperatively in an attempt to prevent uncontrolled rise in blood pressure during tumor manipulation. Phenoxybenzamine is traditionally used in most centers, but some clinicians prefer ‘newer’ alpha-beta blockers (e.g. Doxazosin) while others prefer calcium channel blockers. Surgery is undertaken once adrenergic blockade is firmly established, usually after 4-6 weeks of medication. The preferred approach is laparoscopic adrenalectomy (vide infra). In all the reported series (see Table 1), the majority, but not all, patients were cured of their disease after adrenalectomy. For example, in one series, at the last follow up, 10 out of 12 patients (83 %) were disease free, while two with recurrent disease were still awaiting surgery (9). In contrast, all children diagnosed with malignant PHAEO died of their disease (8) (10).
Management of Familial PHAEOs
In MEN2, management guidelines recommend continuous biochemical screening for PHAEO and/or primary hyperparathyroidism. This implicit assumption of linear tumor development is difficult to reconcile with current thinking that cells accrue somatic mutations stochastically, yielding a bellshaped distribution. Recent data from a German referral centre suggests that biochemical screening should be adjusted based on carrier age and ATA class. The authors analysed 474 carriers of ATA
9
class D (37 patients), C (170 patients), B (112 patients), and A (155 patients) mutations. PHAEOs developed in 84 carriers (18%), of whom half had bilateral disease. Bell-shaped age distribution curves were obtained for unilateral and bilateral phaeochromocytoma (ATA class D, C, and B). Owing to the rarity of events, the bell shape of the distribution curve was faint but consistent with a random distribution
for
ATA
class
A
mutations
(unilateral
phaeochromocytoma
and
primary
hyperparathyroidism). With decreasing penetrance, the bell-shaped distribution curve, becoming narrower and flatter, shifted to the right toward higher age groups (11). This analysis therefore, provides the basis of guidelines for biochemical screening adjusted to the type of mutation in each family. Children with von Hippel-Lindau syndrome (VHL) are at an increased risk for developing bilateral PHAEOs during their life-time but are more likely to present with unilateral disease. The largest published series consisted of 10 pediatric patients who underwent 18 successful partial adrenalectomies (4 open, 14 laparoscopic). The median tumor size removed was 2.6 cm (range, 1.26.5 cm). Over a median follow-up of 7.2 years (range, 2.6-15.8 years), additional tumors in the ipsilateral adrenal gland were found in two patients (12).
Surgical Technique
Laparoscopic Adrenalectomy
After Michel Gagner reported the first laparoscopic adrenalectomy in adults in the early 1990s, the technique has been adopted around the world, and at the present time it has become the 'goldstandard' for the surgical approach for removing benign adrenal tumours. Reporting on the laparoscopic technique for adrenal disease in children and adolescents has been limited, but several authors have published significant personal experience (Table 2), and the procedure has been reviewed recently (13). However, the
main indication for adrenalectomy in all these series was
neuroblastoma, in addition to the small number of cases of PHAEO.
Retroperitoneoscopic adrenalectomy (RPA)
10
This technique has the advantage of avoiding intra-abdominal organ retraction. The technique is slowly being adopted by a number of adult endocrine surgeons because is expected to create less morbidity, less post-operative pain, and the potential for one day admissions. The downside is the small space available for the operating field in adults, a limitation that is even more of a problem in children. The experience in children is restricted to a small number of case reports. For example, one report presented two children, aged 8 and 14-years with incidental right adrenal masses (a 7-cm ganglioneuroma and a 5-cm pheochromocytoma) resected using an anterior approach to RPA. In the authors’ experience, the technique was feasible even in children with a smaller retroperitoneal space and a large adrenal mass (17). One group reviewed 10 cases of RPA, with only two intra-operative complications: one opening of the diaphragm and one intra-operative bleed, but tumour resection was complete in all cases, with no conversions to open surgery and no postoperative complications (18).
Robot-assisted adrenalectomy
Currently the daVinci Surgical System is increasingly being used for a variety of surgical procedures and some enthusiasts have adopted the technique in paediatric surgery. In a retrospective review of 144 robot-assisted pediatric surgical procedures performed in one institution there was only one adrenalectomy
performed
while
the
most
common
indication
being
fundoplications
and
cholecystectomies (19). For adrenalectomy in adults the technique remains rather controversial as the increased costs and duration are not off-set by any benefits. It remains therefore unlikely that a randomized study will be organized to evaluate the benefits, if any, and the long-term outcomes of robotic adrenalectomy in children or adults.
References
1.
Ciftci AO, Senocak ME, Tanyel FC, Buyukpamukcu N. Adrenocortical tumors in children. J
Pediatr Surg. 2001;36(4):549-54. 2.
Hanna AM, Pham TH, Askegard-Giesmann JR, Grams JM, Iqbal CW, Stavlo P, et al.
Outcome of adrenocortical tumors in children. J Pediatr Surg. 2008;43(5):843-9.
11
3.
Michalkiewicz E, Sandrini R, Figueiredo B, Miranda EC, Caran E, Oliveira-Filho AG, et al.
Clinical and outcome characteristics of children with adrenocortical tumors: a report from the International Pediatric Adrenocortical Tumor Registry. J Clin Oncol. 2004;22(5):838-45. 4.
Redlich A, Boxberger N, Strugala D, Fruhwald MC, Leuschner I, Kropf S, et al. Systemic
treatment of adrenocortical carcinoma in children: data from the German GPOH-MET 97 trial. Klinische Padiatrie. 2012;224(6):366-71. 5.
Hubertus J, Boxberger N, Redlich A, von Schweinitz D, Vorwerk P. Surgical aspects in the
treatment of adrenocortical carcinomas in children: data of the GPOH-MET 97 trial. Klinische Padiatrie. 2012;224(3):143-7. 6.
Onder A, Kendirci HN, Bas VN, Agladioglu SY, Cetinkaya S, Aycan Z. A pediatric Conn
syndrome case. Journal of pediatric endocrinology & metabolism : JPEM. 2012;25(1-2):203-6. 7.
Ritzen EM, Lajic S, Wedell A. How can molecular biology contribute to the management of
congenital adrenal hyperplasia? Horm Res. 2000;53 Suppl 1:34-7. 8.
Bissada NK, Safwat AS, Seyam RM, Al Sobhi S, Hanash KA, Jackson RJ, et al.
Pheochromocytoma in children and adolescents: a clinical spectrum. J Pediatr Surg. 2008;43(3):5403. 9.
Gupta A, Agarwala S, Tandon N, Srinivas M, Bajpai M, Gupta DK, et al. Pheochromocytoma
Management, Outcomes and the Role of Cortical Preservation. Indian J Pediatr. 2013. 10.
Ciftci AO, Tanyel FC, Senocak ME, Buyukpamukcu N. Pheochromocytoma in children. J
Pediatr Surg. 2001;36(3):447-52. 11.
Machens A, Lorenz K, Dralle H. Peak incidence of pheochromocytoma and primary
hyperparathyroidism in multiple endocrine neoplasia 2: need for age-adjusted biochemical screening. J Clin Endocrinol Metabol. 2013;98(2):E336-45. 12.
Volkin D, Yerram N, Ahmed F, Lankford D, Baccala A, Gupta GN, et al. Partial adrenalectomy
minimizes the need for long-term hormone replacement in pediatric patients with pheochromocytoma and von Hippel-Lindau syndrome. J Pediatr Surg . 2012;47(11):2077-82. 13.
Heloury Y, Muthucumaru M, Panabokke G, Cheng W, Kimber C, Leclair MD. Minimally
invasive adrenalectomy in children. J Pediatr Surg. 2012;47(2):415-21. 14.
Lopes RI, Denes FT, Bissoli J, Mendonca BB, Srougi M. Laparoscopic adrenalectomy in
children. J Pediatr Urol. 2012;8(4):379-85. 15.
Sukumar S, Jadhav S, Nair B, Bhat SH, Kumar GP, Mathew G. Laparoscopic adrenal surgery
in children: Lessons from a single centre experience. J Minim Access Surg. 2011;7(2):141-4.
12
16.
St Peter SD, Valusek PA, Hill S, Wulkan ML, Shah SS, Martinez Ferro M, et al. Laparoscopic
adrenalectomy in children: a multicenter experience. J Laparoendosc Surg. 2011;21(7):647-9. 17.
Eassa W, El-Sherbiny M, Jednak R, Capolicchio JP. The anterior approach to
retroperitoneoscopic adrenalectomy in children: technique. J Pediatr Urol. 2012;8(1):35-9. 18.
Steyaert H, Juricic M, Hendrice C, Lembo MA, Al Mohaidly M, Guitard J, et al.
Retroperitoneoscopic approach to the adrenal glands and retroperitoneal tumours in children: where do we stand? Eur J Pediatr Surg. 2003;13(2):112-5. 19.
Alqahtani A, Albassam A, Zamakhshary M, Shoukri M, Altokhais T, Aljazairi A, et al. Robot-
assisted pediatric surgery: how far can we go? World J Surg. 2010;34(5):975-8.
13
Table 1. Clinical series of paediatric patients with phaeochromocytomas
Reference
Number
Adrenal
Extra-adrenal
Bilateral
Malignant
Sporadic
Familial
of Cases (8)
21
17
4
-
2
17
4
(9)
12
11
1
5
-
12
-
(10)
16
16
-
6
3
14
2
Total
49
44
5
11
5
43
6
Table 2. Reported Series of Laparoscopic Adrenalectomies in Children.
Reference
Number
Mean
Bilateral
of Cases
Age
Tumors
Tumor Size
Conversi
Hospital
Length of
on to
Stay (Days)
Follow-up
Open
(Months)
Surgery (14)
19
(15)
10
(16)*
140
4
9.6
-
3 5
20-65 mm
2-7 cm
0
3.5 (range
81 (range 2-
2-15)
144)
0
3-10
24-87
13
-
18
*Retrospective review of laparoscopic adrenalectomy at 12 institutions over the past 10 years
14
Rare Adrenal Tumours in Children Radu Mihai MD PhD FRCS
PII: DOI: Reference:
www.elsevier.com/locate/sempedS1055-8586(14)00006-7 surg http://dx.doi.org/10.1053/j.sempedsurg.2014.03.004 YSPSU50470
To appear in:
Seminars in Pediatric Surgery
Cite this article as: Radu Mihai MD PhD FRCS, Rare Adrenal Tumours in Children, Seminars in Pediatric Surgery, http://dx.doi.org/10.1053/j.sempedsurg.2014.03.004 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting galley proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
#3 Rare Adrenal Tumours in Children
Radu Mihai, MD PhD FRCS Consultant Endocrine Surgeon Address
Churchill Cancer Centre Old Road, Headington Oxford OX3 7LE United Kingdom
Telephone
+44 1865 223555
Fax
+44 1865 223589
Email:
[email protected]
ABSTRACT Apart from neuroblastomas, adrenal tumours are exceedingly rare in children and young adults. In this age group, the vast majority of patients present with clinical signs associated with excess hormone production. The most common tumour to arise from the adrenal cortex is an adrenocortical carcinoma (ACC). Similar to the situation in adults, this tumour is frequently diagnosed at a late stage and carries a very poor prognosis. ACCs require extensive/aggressive local resection followed by Mitotane chemotherapy. A multidisciplinary approach is essential and these children should be referred to units with previous experience in managing ACC. International registries are an invaluable source for evidence-based care and such collaborations should be further developed in the future. Phaeochromocytomas are derived from the adrenal medulla and present with symptoms caused by high secretion of catecholamines. At least a third of these children will be found to carry genetic mutations, most commonly the RET gene (MEN2 syndrome) or the VHL gene. Open radical adrenalectomy should be offered to children with adrenocortical cancers. For all other cases, laparoscopic adrenalectomy is the treatment of choice.
It is possible that the
retroperitoneoscopic approach will gain increasing favour. The role of robotic adrenalectomy remains controversial.
KEY WORDS
Adrenal, adrenalectomy, laparoscopic, phaeochromocytoma, adrenocortical cancer
1
Introduction Tumours of the adrenal gland, other than neuroblastomas, are extremely rare in children. Consequently, adrenal surgery is seldom indicated in children and young adults, and the experience of the majority of individual surgeons remains very limited. For example, the national audit maintained by the British Association of Endocrine Surgeons (BAETS) has logged only 33 adrenalectomies in patients under 21 years of age out of a total of 1359 such operations performed by BAETS members (http://www.baets.org.uk/wp-content/uploads/2013/05/4th-National-Audit.pdf). This paper discusses the common indications and technical aspects of adrenal surgery in children by reviewing papers published in the last 10 years in the English literature. All information is based on non-randomised cohort studies from centres with large practice, as well as a few individual casereports that illustrate these conditions. This paper does not address any issues related to neuroblastomas.
Etiology of adrenal tumours in children
The adrenal gland has two distinct parts: the cortex and the medulla. Each part has a different embryological origin, each produces different hormones, and each is the origin of different types of tumours. The cortex arises from the mesoderm and starts to develop in the fourth week of gestation as a proliferation of coelomic mesothelium into the underlying mesenchyme between the root of the dorsal mesogastrium (the root of the mesentery) and the urogenital ridge (the mesonephros and the developing gonad). This close proximity explains why ectopic adrenal tissue has been described to be located below the kidneys and associated with the testes or ovaries. In the initial phase, the adrenogonadal primordium (AGP) is first distinguished and expresses the essential transcription factor SF1 (steroidogenic factor 1). In the second phase (8th week gestation in humans), the AGP separates into two distinct structures, the adrenal and the gonadal primordial. This second phase is followed by migration of neural crest cells through the fetal cortex to establish the medulla. The embryogenesis of the adrenal medullary cells starts in the second month of gestation. Before this, during the fourth week of embryonic life, the neural plate develops and then infolds to form the neural tube. A portion of the neuroectoderm adjacent to the tube separates and remains between the neural
2
tube and the definitive ectoderm as the neural crest. Cells derived from the neural crest (sympathogonia, primitive spinal ganglia) migrate ventrally from the apex of the neural tube to the dorsal aorta (where they aggregate and differentiate into neuroblasts to form sympathetic neurons) or to the adrenal primordia (where they differentiate into phaeochromoblasts to form chromaffin cells).
At the end of gestation, the adrenal gland is organized into distinct zones: glomerulosa, transitory (that appears between weeks 22-24, the future zona fasciculata) and dominant fetal zone. Immediately after birth, the fetal zone undergoes rapid involution. Moreover, the zona reticularis starts to develop at the age of 4-6 or even 8 years, while structure typical to adults stabilizes at the age of 10-20 years. The fascicular and reticular zones of the adult cortex proliferate from the glomerular zone after birth and are fully differentiated by about the 12th year. It appears therefore, that the adrenal gland in children is in a process of continuous transformation. In this context, tumours that develop in children are either sporadic or, more commonly, appear in the context of genetic syndromes associated with a risk of adrenal tumours.
The most well known
associations are the development of phaeochromocytomas in Multiple Endocrine Neoplasia Type 2 (MEN2) and in von-Hippel-Lindau (VHL) syndromes, and the appearance of adrenocortical carcinoma (ACC) as a hallmark cancer in families with Li Fraumeni syndrome resulting from mutations in the TP53 gene.
Adrenocortical cancer
Incidence
Adrenocortical carcinomas (ACCs) are very rare tumours, with an incidence of 1-1.5 per million population per year. Data published by the International Association of Cancer Registries showed that there is a peak of incidence in childhood and one in the 5th decade of life. The situation differs in Brazil where a disproportionately large number of children are diagnosed with ACC due to p53 mutations.
3
Clinical presentation
Most children present with clinical signs. In a series of 20 children operated in a single center at a mean age of 7 years (range, 2.5 to 13 years), endocrine dysfunction was noted in 83% of the patients, with virilization being the most common presentation, followed by Cushing's syndrome. Fourteen patients presented with a palpable abdominal mass and three patients presented with distant metastases. The mean time from initial symptoms to diagnosis was 8 months. The majority (80%) had regional or metastatic disease by the time of presentation (1). Similar findings from another series of 23 children with a mean age of 9 years reported tumor hormone production in 74% of patients and advanced stage for disease in 66% (2). These findings were confirmed in a multicentre registry of 254 patients, of whom the majority (84.2%) had virilization, while Cushing's syndrome without virilization was uncommon (5.5%) (3). The high percentage of children with functioning tumors suggests that earlier detection is possible if there is increased awareness of this possible diagnosis amongst clinicians who assess these children at the onset of their symptoms (2).
Diagnosis
In some patients the diagnosis is suggested by the clinical presentation if signs of virilisation are observed in a girl or rapid onset of ‘early puberty’ occurs in a young child. In the absence of signs of metastatic disease, the radiological suspicion of malignancy is generally based on the size of the tumour. For adults the risk of an adrenal tumour representing a ACC increases from 4 cm (risk 10 cm (risk close to 100%). Likely these dimensions have to be interpreted based on the age of the child. Further signs suggestive of malignancy include a high Hounsfield unit on unenhanced scans (>10 HU) and rapid washout of the contrast. There are no studies aassessing the role of PET scanning in children with adrenal tumours but in adults the technique to commonly used to assess for metastatic disease, Furthermore, the SUV ration between liver and adrenal tumour is used in some centres as a sign of malignancy. There is no role of biopsy of the adrenal gland as the cytological diagnosis of ACC is unreliable and the procedure can increase the risk of contamination of normal anatomical planes. The histological diagnosis is based on assessing how many of the nine characteristics summarized on the Weiss score are present (nuclear grade, mitoses/50 high-power fields, atypical mitoses, clear cells, diffuse architecture, confluent necrosis, venous invasion, sinusoidal invasion, capsular
4
infiltration). Tumours with a score of 6 are malignant and a score of 3-6 are indeterminate.
Surgical treatment
In all reported series radical surgery is considered necessary in order to ensure complete excision hence in addition to adenalectomy, ipsilateral nephrectomy and/or right hepatic lobectomy plus nephrectomy should be considered (1). The aim of such aggressive approach is to limit the risk of local recurrence.
Postoperative treatment
Adjuvant chemotherapy consisting of mitotane or mitotane plus cisplatin and etoposide is commenced postoperatively. Systemic chemotherapy and mitotane therapy are both important therapeutic options in the treatment of advanced pediatric ACC patients. Neoadjuvant therapy should be considered for patients with primarily incomplete resectable or inoperable tumors, and tumor spillage is an indication for adjuvant chemo- and mitotane therapy. In the GPOH-MET-97 study over half of children had chemotherapy (neoadjuvant, adjuvant, and salvage) and mitotane therapy. Duration of mitotane treatment longer than 6 months and mitotane levels greater than 14 mg/l were found to be associated with significantly better survival (4).
Prognosis
The prognosis for these tumours is poor with an overall 5-year survival of less than 30%. In this context it remains distressing to know that the vast majority of patients are treated in units with minimal previous experience. The expectation is that all pediatric ACC patients should be treated in pediatric oncological centers according to a consistent protocol in a highly interdisciplinary setting (including surgeons experienced in radical adrenalectomy), but the rarity of the disease makes it difficult to monitor adherence to such guidelines worldwide. Nevertheless, in Germany this approach has been followed since 1997, with all pediatric ACC patients being treated according to the non-
5
randomized, single arm study - GPOH-MET-97. Data regarding 60 patients with ACC (age 0.24-18 years, with a M:F gender ratio of 1:2) treated according to the GPOH-MET-97 protocol, showed that among all patients, event-free survival and overall survival were 43% and 65%, respectively (4) Children with a tumor volume of >300 mL (n=25) showed an increased rate of operative complications and a poorer overall survival rate. A total of 14 patients showed metastatic spread, particularly to the lungs and lymph nodes. R2 resection only was achievable in 5 patients, and surgery was not feasible in 3 patients. Interestingly, preoperative biopsy and/or experienced tumor rupture were associated with poorer overall-survival rate, reinforcing the view that biopsy should not be used in the diagnosis workup of adrenal masses suspected as ACC (5). An International Pediatric Adrenocortical Tumor Registry was also created and provided a descriptive analysis of 254 patients treated between 1990-2001 (3). Tumors were completely resected in 83% of patients and at a median follow-up of 30 months, 157 patients (62%) survived without evidence of disease and 97 patients (38%) had died. The 5-year event-free survival estimate was 54% (95% CI, 48% to 60%). In a multivariate analysis, disease stage, presenting signs of endocrine dysfunction, and age were independently associated with prognosis (3).
Primary hyperaldosteronism
Incidence
Unilateral aldosterone-secreting adenomas (Conn’s syndrome) are seldom encountered in children. At the present time, there is increased interest in assessing adult hypertensive patients for Conn's, because allegedly up 10% of them may have primary hyperaldosteronism. If the proposed changes in the protocols for investigating adults with hypertension, this should also be extended to children found to be hypertensive.
At the present time, however, there has been no published series of
adrenalectomies for primary hyperaldosteronism in children and all information is derived from case reports of hypertensive children with/without hypokalaemia.
6
Diagnosis
The diagnosis of primary hyperaldosteronism relies on demonstrating increased aldosterone, low renin levels, and a raised aldosterone/renin ratio in a child diagnosed with hypertension. For example, a 15year-old girl complained of headache lasting for approximately 1.5 years, which was diagnosed as severe hypertension. Primary aldosteronism was diagnosed on the basis of hypokalemia and alkalosis accompanied by plasma renin activity of 3.9 ng/mL/h and an aldosterone level of 1007 pg/mL (normal: 40-480). Left adrenalectomy was performed because a 10x12x12 mm adenoma was detected on abdominal magnetic resonance imaging. Her 24-h ambulatory blood pressure values of the patient were normal at 10 months after the operation, the treatment was stopped, and she remained normotensive when followed up for 15 months without any treatment (6). This sequence of events mirrors the situation in many adults. There are however, many patients in whom cross-sectional radiology cannot demonstrate the laterality of the adrenal adenoma, as most of them are < 1 cm in diameter.
These patients undergo selective adrenal venous sampling with measurement of
aldosterone/cortisol ratio in each adrenal vein and in the peripheral blood. Though this test is widely employed in diagnostic pathways of adults with primary hyperaldosteronism, there are no case series demonstrating the use of this technique in children.
Treatment
Laparoscopic adrenalectomy is the treatment of choice for patients with unilateral disease. Those with bilateral disease are primarily treated medically with Spironolactone and potassium supplements
Congenital adrenal hyperplasia
The most common form of congenital adrenal hyperplasia is due to a deficiency of 21-hydroxylase (21OHD) activity and is caused by a mutation in the CYP21 gene. By genotyping patients, new and important information can be gained, including the presence or absence of 21OHD in borderline cases, determining the severity of disease and identifying heterozygote carriers. The adrenal
7
management of patients with 21OHD involves administering sufficient glucocorticoids to suppress excess adrenal androgen secretion, but not such high doses that bone growth and mineralization are impaired. New management strategies have been proposed and include administering only substitution doses of corticosteroids and counteracting side-effects by administering an anti-androgen and aromatase inhibitor. Adrenalectomy has also been proposed but plays a minor role, but further evaluation of this approach is necessary (7). No series have been published on this, and therefore the only information available is derived from individual case-reports.
Phaeochromocytoma
Phaeochromocytomas (PHAEOs) are catecholamine-secreting adrenal tumours derived from the adrenal medulla. When they occur in extradrenal locations they are called paragangliomas (PGGLs).
Clinical presentation
As blood pressure is not routinely measured in childhood, PHAEOs are challenging to diagnose in children and the diagnosis is frequently significantly delayed. Children may present with episodes of intense headaches, but more subtle signs such as paroxysmal tachycardia are not easy to elicit from the history in children. Sweating and abdominal pain are other predominant signs of PHAEOs. The situation differs for children who are members of families with known genetic syndromes associated with high risk of developing a PHAEO and in whom the diagnosis is then often based on biochemical screening in all children carrying the mutation.
Diagnosis
Biochemical diagnosis is based on measuring the concentration of 24-hour urinary metanephrines. In small children (when 24 hour urine collection is much harder) and in children with a high risk of having such tumours (i.e. members of MEN-2 families involved in regular biochemical screening), the diagnosis is based on measuring the plasma concentration of metanephrines. Once biochemical diagnosis is secured, localisation of the tumour is based on cross-sectional imaging with abdominal MRI or CT scanning.
8
Genetic screening
Due to the rarity of PHAEOs in young patients, current guidelines recommend that all patients diagnosed with this condtion should undergo genetic screening, even if they are not members of recognized families with a syndromic mutation.
Spectrum of disease
In three large series including a total of 49 children with PHAEO, the incidence of bilateral disease (overall 10%) and malignant disease (overall 10%) varied significantly between series (see Table 1).
Treatment
All patients undergo adrenergic blockade preoperatively in an attempt to prevent uncontrolled rise in blood pressure during tumor manipulation. Phenoxybenzamine is traditionally used in most centers, but some clinicians prefer ‘newer’ alpha-beta blockers (e.g. Doxazosin) while others prefer calcium channel blockers. Surgery is undertaken once adrenergic blockade is firmly established, usually after 4-6 weeks of medication. The preferred approach is laparoscopic adrenalectomy (vide infra). In all the reported series (see Table 1), the majority, but not all, patients were cured of their disease after adrenalectomy. For example, in one series, at the last follow up, 10 out of 12 patients (83 %) were disease free, while two with recurrent disease were still awaiting surgery (9). In contrast, all children diagnosed with malignant PHAEO died of their disease (8) (10).
Management of Familial PHAEOs
In MEN2, management guidelines recommend continuous biochemical screening for PHAEO and/or primary hyperparathyroidism. This implicit assumption of linear tumor development is difficult to reconcile with current thinking that cells accrue somatic mutations stochastically, yielding a bellshaped distribution. Recent data from a German referral centre suggests that biochemical screening should be adjusted based on carrier age and ATA class. The authors analysed 474 carriers of ATA
9
class D (37 patients), C (170 patients), B (112 patients), and A (155 patients) mutations. PHAEOs developed in 84 carriers (18%), of whom half had bilateral disease. Bell-shaped age distribution curves were obtained for unilateral and bilateral phaeochromocytoma (ATA class D, C, and B). Owing to the rarity of events, the bell shape of the distribution curve was faint but consistent with a random distribution
for
ATA
class
A
mutations
(unilateral
phaeochromocytoma
and
primary
hyperparathyroidism). With decreasing penetrance, the bell-shaped distribution curve, becoming narrower and flatter, shifted to the right toward higher age groups (11). This analysis therefore, provides the basis of guidelines for biochemical screening adjusted to the type of mutation in each family. Children with von Hippel-Lindau syndrome (VHL) are at an increased risk for developing bilateral PHAEOs during their life-time but are more likely to present with unilateral disease. The largest published series consisted of 10 pediatric patients who underwent 18 successful partial adrenalectomies (4 open, 14 laparoscopic). The median tumor size removed was 2.6 cm (range, 1.26.5 cm). Over a median follow-up of 7.2 years (range, 2.6-15.8 years), additional tumors in the ipsilateral adrenal gland were found in two patients (12).
Surgical Technique
Laparoscopic Adrenalectomy
After Michel Gagner reported the first laparoscopic adrenalectomy in adults in the early 1990s, the technique has been adopted around the world, and at the present time it has become the 'goldstandard' for the surgical approach for removing benign adrenal tumours. Reporting on the laparoscopic technique for adrenal disease in children and adolescents has been limited, but several authors have published significant personal experience (Table 2), and the procedure has been reviewed recently (13). However, the
main indication for adrenalectomy in all these series was
neuroblastoma, in addition to the small number of cases of PHAEO.
Retroperitoneoscopic adrenalectomy (RPA)
10
This technique has the advantage of avoiding intra-abdominal organ retraction. The technique is slowly being adopted by a number of adult endocrine surgeons because is expected to create less morbidity, less post-operative pain, and the potential for one day admissions. The downside is the small space available for the operating field in adults, a limitation that is even more of a problem in children. The experience in children is restricted to a small number of case reports. For example, one report presented two children, aged 8 and 14-years with incidental right adrenal masses (a 7-cm ganglioneuroma and a 5-cm pheochromocytoma) resected using an anterior approach to RPA. In the authors’ experience, the technique was feasible even in children with a smaller retroperitoneal space and a large adrenal mass (17). One group reviewed 10 cases of RPA, with only two intra-operative complications: one opening of the diaphragm and one intra-operative bleed, but tumour resection was complete in all cases, with no conversions to open surgery and no postoperative complications (18).
Robot-assisted adrenalectomy
Currently the daVinci Surgical System is increasingly being used for a variety of surgical procedures and some enthusiasts have adopted the technique in paediatric surgery. In a retrospective review of 144 robot-assisted pediatric surgical procedures performed in one institution there was only one adrenalectomy
performed
while
the
most
common
indication
being
fundoplications
and
cholecystectomies (19). For adrenalectomy in adults the technique remains rather controversial as the increased costs and duration are not off-set by any benefits. It remains therefore unlikely that a randomized study will be organized to evaluate the benefits, if any, and the long-term outcomes of robotic adrenalectomy in children or adults.
References
1.
Ciftci AO, Senocak ME, Tanyel FC, Buyukpamukcu N. Adrenocortical tumors in children. J
Pediatr Surg. 2001;36(4):549-54. 2.
Hanna AM, Pham TH, Askegard-Giesmann JR, Grams JM, Iqbal CW, Stavlo P, et al.
Outcome of adrenocortical tumors in children. J Pediatr Surg. 2008;43(5):843-9.
11
3.
Michalkiewicz E, Sandrini R, Figueiredo B, Miranda EC, Caran E, Oliveira-Filho AG, et al.
Clinical and outcome characteristics of children with adrenocortical tumors: a report from the International Pediatric Adrenocortical Tumor Registry. J Clin Oncol. 2004;22(5):838-45. 4.
Redlich A, Boxberger N, Strugala D, Fruhwald MC, Leuschner I, Kropf S, et al. Systemic
treatment of adrenocortical carcinoma in children: data from the German GPOH-MET 97 trial. Klinische Padiatrie. 2012;224(6):366-71. 5.
Hubertus J, Boxberger N, Redlich A, von Schweinitz D, Vorwerk P. Surgical aspects in the
treatment of adrenocortical carcinomas in children: data of the GPOH-MET 97 trial. Klinische Padiatrie. 2012;224(3):143-7. 6.
Onder A, Kendirci HN, Bas VN, Agladioglu SY, Cetinkaya S, Aycan Z. A pediatric Conn
syndrome case. Journal of pediatric endocrinology & metabolism : JPEM. 2012;25(1-2):203-6. 7.
Ritzen EM, Lajic S, Wedell A. How can molecular biology contribute to the management of
congenital adrenal hyperplasia? Horm Res. 2000;53 Suppl 1:34-7. 8.
Bissada NK, Safwat AS, Seyam RM, Al Sobhi S, Hanash KA, Jackson RJ, et al.
Pheochromocytoma in children and adolescents: a clinical spectrum. J Pediatr Surg. 2008;43(3):5403. 9.
Gupta A, Agarwala S, Tandon N, Srinivas M, Bajpai M, Gupta DK, et al. Pheochromocytoma
Management, Outcomes and the Role of Cortical Preservation. Indian J Pediatr. 2013. 10.
Ciftci AO, Tanyel FC, Senocak ME, Buyukpamukcu N. Pheochromocytoma in children. J
Pediatr Surg. 2001;36(3):447-52. 11.
Machens A, Lorenz K, Dralle H. Peak incidence of pheochromocytoma and primary
hyperparathyroidism in multiple endocrine neoplasia 2: need for age-adjusted biochemical screening. J Clin Endocrinol Metabol. 2013;98(2):E336-45. 12.
Volkin D, Yerram N, Ahmed F, Lankford D, Baccala A, Gupta GN, et al. Partial adrenalectomy
minimizes the need for long-term hormone replacement in pediatric patients with pheochromocytoma and von Hippel-Lindau syndrome. J Pediatr Surg . 2012;47(11):2077-82. 13.
Heloury Y, Muthucumaru M, Panabokke G, Cheng W, Kimber C, Leclair MD. Minimally
invasive adrenalectomy in children. J Pediatr Surg. 2012;47(2):415-21. 14.
Lopes RI, Denes FT, Bissoli J, Mendonca BB, Srougi M. Laparoscopic adrenalectomy in
children. J Pediatr Urol. 2012;8(4):379-85. 15.
Sukumar S, Jadhav S, Nair B, Bhat SH, Kumar GP, Mathew G. Laparoscopic adrenal surgery
in children: Lessons from a single centre experience. J Minim Access Surg. 2011;7(2):141-4.
12
16.
St Peter SD, Valusek PA, Hill S, Wulkan ML, Shah SS, Martinez Ferro M, et al. Laparoscopic
adrenalectomy in children: a multicenter experience. J Laparoendosc Surg. 2011;21(7):647-9. 17.
Eassa W, El-Sherbiny M, Jednak R, Capolicchio JP. The anterior approach to
retroperitoneoscopic adrenalectomy in children: technique. J Pediatr Urol. 2012;8(1):35-9. 18.
Steyaert H, Juricic M, Hendrice C, Lembo MA, Al Mohaidly M, Guitard J, et al.
Retroperitoneoscopic approach to the adrenal glands and retroperitoneal tumours in children: where do we stand? Eur J Pediatr Surg. 2003;13(2):112-5. 19.
Alqahtani A, Albassam A, Zamakhshary M, Shoukri M, Altokhais T, Aljazairi A, et al. Robot-
assisted pediatric surgery: how far can we go? World J Surg. 2010;34(5):975-8.
13
Table 1. Clinical series of paediatric patients with phaeochromocytomas
Reference
Number
Adrenal
Extra-adrenal
Bilateral
Malignant
Sporadic
Familial
of Cases (8)
21
17
4
-
2
17
4
(9)
12
11
1
5
-
12
-
(10)
16
16
-
6
3
14
2
Total
49
44
5
11
5
43
6
Table 2. Reported Series of Laparoscopic Adrenalectomies in Children.
Reference
Number
Mean
Bilateral
of Cases
Age
Tumors
Tumor Size
Conversi
Hospital
Length of
on to
Stay (Days)
Follow-up
Open
(Months)
Surgery (14)
19
(15)
10
(16)*
140
4
9.6
-
3 5
20-65 mm
2-7 cm
0
3.5 (range
81 (range 2-
2-15)
144)
0
3-10
24-87
13
-
18
*Retrospective review of laparoscopic adrenalectomy at 12 institutions over the past 10 years
14
