ELSEVIER
Surgery
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SURGERY
NOWEMBER 2018
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A nationwide study evaluating indications and outcomes for adrenalectomy in children in the Netherlands
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Allon van Uitert, MDª,*, Marc H.W. Wijnen, MD, PhDb, Dominique C. Simons, MDb, Charlotte L. Vietor, MDC, Tessa M. van Ginhoven, MD, PhDC, Ronald R. de Krijger, MD, PhDd,e, Menno R. Vriens, MD, PhDf, Els J. Nieveen van Dijkum, MD, PhD&, Jan H. Koetje, MD, PhDh, Schelto Kruijff, MD, PhDh,ij, Michiel F. Schreuder, MD, PhDk, Henri J.L.M. Timmers, MD, PhD’, Johan F. Langenhuijsen, MD, PhDª
a Department of Urology, Radboud University Medical Center, Nijmegen, the Netherlands - Dutch Adrenal Network
b Department of Pediatric Surgery, Princess Máxima Center for Pediatric Oncology, Utrecht, the Netherlands
” Department of Surgical Oncology and Gastrointestinal Surgery, Erasmus MC Cancer Institute, Rotterdam, the Netherlands - Dutch Adrenal Network
d Department of Pathology, Princess Máxima Center for Pediatric Oncology, Utrecht, the Netherlands
e Department of Pathology, University Medical Center Utrecht, Utrecht, the Netherlands - Dutch Adrenal Network Department of Surgery, University Medical Center Utrecht, Utrecht, the Netherlands - Dutch Adrenal Network
% Department of Surgery, Amsterdam University Medical Center, Amsterdam, the Netherlands - Dutch Adrenal Network
h Department of Surgical Oncology, University Medical Center Groningen, Groningen, the Netherlands - Dutch Adrenal Network
Department of Nuclear Medicine and Molecular Imaging, University Medical Center Groningen, Groningen, the Netherlands - Dutch Adrenal Network
j Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden
k Department of Pediatric Nephrology, Radboudumc Amalia Children’s Hospital, Nijmegen, the Netherlands - Dutch Adrenal Network
Department of Internal Medicine, Radboud University Medical Center, Nijmegen, the Netherlands - Dutch Adrenal Network
ARTICLE INFO
Article history: Accepted 1 July 2025 Available online 14 August 2025
ABSTRACT
Background: Adrenal tumors are rare in children, with neuroblastoma being most common. Surgery is the preferred treatment option, using either an open or minimally invasive approach. In this study we evaluated the incidence, spread, and perioperative outcomes of adrenalectomies in children in the Netherlands. Methods: Patients treated between 2011 and 2022 were reviewed in this nationwide study across 5 academic hospitals and the national pediatric oncology center. Patient characteristics, perioperative data, and follow-up data were collected.
Results: The epidemiologic data of 187 patients and the clinical data of 137 patients were included. Annually, 18-20 adrenalectomies in children are performed, mostly for neuroblastoma (64%), pheo- chromocytoma (18%), and adrenocortical carcinoma (6%). Open adrenalectomy was performed in 88 patients (64%), transperitoneal laparoscopic adrenalectomy in 39 patients (29%), and posterior retro- peritoneoscopic adrenalectomy in 10 patients (7%). There was a significant difference in duration of surgery between these approaches (median 171 minutes [interquartile range, 120-213], 105 minutes [interquartile range, 85-148], and 67 minutes [interquartile range, 53-101], respectively, P < . 001). Minimally invasive adrenalectomy was used more frequently in older patients with presumed benign disease. Perioperative complications occurred in 25 patients (18%), and 36 patients (26%) had a post- operative complication, of which 3 were major. Disease recurrence was observed in 32% of patients. Conclusion: Adrenalectomies in children are rare in the Netherlands, especially for non-neuroblastoma tumors, and most surgeons perform less than 1 procedure per year. Open adrenalectomy is usually per- formed for suspected malignant tumors, whereas minimally invasive approaches are used more selectively.
@ 2025 The Author(s). Published by Elsevier Inc. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
* Corresponding author: Allon van Uitert, MD, Department of Urology, Radboud University Medical Center, Geert Grooteplein Zuid 10, Nijmegen 6525 GA, the Netherlands.
E-mail address: allon.vanuitert@radboudumc.nl (A. van Uitert).
Introduction
Adrenal tumors are rare in children. They may be found inci- dentally or can be identified during evaluation of a child presenting with endocrine, metabolic, or neurologic symptoms, or with a
https://doi.org/10.1016/j.surg.2025.109592
palpable abdominal mass. These tumors can originate from either the adrenal medulla or cortex, may be hormonally active or not, and can be either benign or malignant.1 Medullary tumors include neuroblastoma, ganglioneuroblastoma, ganglioneuroma, and pheochromocytoma. Neuroblastoma is the most common extra- cranial solid tumor, affecting 1 in 7,000 children.1 Forty percent arise in the adrenal gland, often presenting as a large intra- abdominal mass, with metastases at diagnosis in 70% of cases.2 Image-defined risk factors (IDRFs) help stage the disease and pre- dict surgical risk on the basis of preoperative imaging.3 Ganglio- neuroblastoma is a mixed tumor of which less than 50% of tumor volume is neuroblastoma upon pathologic evaluation. Ganglioneuroma is a benign tumor.4 Pheochromocytoma is a catecholamine-secreting tumor, with an estimated incidence in childhood of 0.2-0.3 cases per million, and all pheochromocytomas are considered malignant according to the 2022 World Health Or- ganization classification of neuroendocrine tumors.5 The age of presentation in children is approximately 10 years of age and pa- tients present with symptomatic catecholamine hypersecretion, tumor mass effects (eg, pain), or during family screening for a he- reditary syndrome (eg, von Hippel-Lindau disease, multiple endo- crine neoplasia 2A and 2B, familial paraganglioma syndromes).6,7 Apart from congenital adrenal hyperplasia, cortical tumors are very rare, with an estimated incidence of 0.3 cases per million in the pediatric population.1 These tumors include benign cortical ade- noma and malignant adrenocortical carcinoma. They can present with specific endocrinologic syndromes, such as hypercortisolism, primary aldosteronism, hyperandrogenism, or hyperestrogenism.8
In all aforementioned tumor types, surgery is the preferred treatment option; however, for neuroblastomas, it is performed after induction chemotherapy, and for adrenocortical carcinoma it is dependent of preoperative staging.9 The adrenal gland can be removed using an open approach or a minimally invasive tech- nique, such as the transperitoneal laparoscopic adrenalectomy (TLA), posterior retroperitoneoscopic adrenalectomy (PRA), or robot-assisted. In adults, minimally invasive adrenalectomy (MIA) has proven to be effective for adrenal gland removal, with superior perioperative outcomes compared with open surgery.10 There have been several publications describing MIA in the pediatric popula- tion, both for TLA and PRA.11-15 However, the dispersion of MIA in children remains low.16 This could be the result of small patients’ sizes combined with large, malignant tumors, making MIA less feasible.17 On the basis of a systematic review by Gurria et al,18 minimally invasive resection by an experienced surgeon was considered safe for carefully selected small abdominal neuroblas- tomas (<4-6 cm) that were IDRF-negative, provided that oncologic principles are followed. In the Netherlands, treatment for pediatric solid tumors is centralized in the Princess Máxima Center for pe- diatric oncology since November 2014, and as of 2018 all pediatric oncologic care is provided there. In a retrospective study by Van der Steeg et al,19 results of surgical treatment of neuroblastoma since the start of the centralization were presented and compared to a historical cohort. However, there are no national data available about the incidence, spread, and outcomes of all adrenalectomies in children. Our primary goal was to evaluate the incidence, spread, and outcomes of adrenalectomy in children in the Netherlands.
Methods
We performed a retrospective nationwide study, collecting pa- tient data from all hospitals where adrenalectomies in children are performed; 5 academic hospitals (Amsterdam University Medical Center, Erasmus Medical Center, University Medical Center Gro- ningen, University Medical Center Utrecht, and Radboud University Medical Center) and the national pediatric oncology center
(Princess Máxima Center for pediatric oncology) in the Netherlands. The data from all children (<18 years) who underwent an adrenalectomy between 2011 and 2022 were anonymously collected in an online Castor database (CastorEDC, Amsterdam, the Netherlands). Only patients with localized adrenal tumors or with limited local lymphadenopathy were included, which was chosen for in the interest of comparability of data, because patients with extensive intra-abdominal or metastatic disease at the time of surgery require a different scale of surgical treatment. Since November 2014, all patients with neuroblastoma underwent sur- gery in the Princess Máxima Center for pediatric oncology. There is some overlap between the clinical data in this study and the pub- lished study by Van der Steeg et al.19 The completeness of the epidemiologic data was compared with histological national data using the Dutch Nationwide Pathology Database (Palga, reference number 2023-39).20 A study protocol was written and subse- quently approved by the Medical Ethics Committee East- Netherlands (METC Oost-Nederland, CMO-number: 2022-13580), which wavied the need for informed consent.
Preoperative data
Baseline patient characteristics included age, sex, height and weight, diagnosis, hormonal activity, comorbidity, and presence of germline pathogenic variants or hereditary syndromes. Further- more, data were collected regarding preoperative medication use and radiologic examinations. In case of neuroblastoma, vascular infiltration and the presence of IDRFs were scored. In patients with malignant disease and infiltrative growth, the presence of lymph- adenopathy, metastases, and use of neoadjuvant chemotherapy/ immunotherapy were scored.
Perioperative data and follow-up
Alpha-blockade was scored in patients with a pheochromocy- toma. Data concerning surgical technique, side, blood loss, duration of surgery, conversion to open surgery, total compared with partial (cortical-sparing) adrenalectomy, perioperative complications, and length of hospital stay were collected. Postoperative complications were scored using the Clavien-Dindo system.21 Histologic di- agnoses were collected, as well as data on surgical margins, number of resected lymph nodes and whether these nodes were positive for malignancy. The need for hormonal replacement treatment, adjuvant chemotherapy, radiotherapy and/or surgery was recorded, as well as recurrence of disease, duration of follow- up, and mortality.
Statistical analysis
Statistical analysis was performed using SPSS 29.0 for Windows (SPSS Inc, Chicago, IL). Continuous outcomes are displayed as me- dian (interquartile range [IQR]). Statistical analysis was performed using nonparametric tests, x2 test, and multivariable binary logistic regression.
Results
Epidemiology
For the study period, the epidemiologic data of 187 patients were collected. Clinical data from 50 patients with neuroblastoma treated in the Princess Máxima Center for pediatric oncology be- tween 2015 and 2017 could not be included in this study because these were obtained from patients who underwent surgery after the official opening in 2018. Therefore, the clinical data of 137
| All patients (n = 137) | |
|---|---|
| Distribution between centers | |
| 1 (2011-2022) | 12 (9%) |
| 2 (2011-2022) | 13 (9%) |
| 3 (2011-2022) | 18 (13%) |
| 4 (2011-2022) | 8 (6%) |
| 5 (2011-2022) | 6 (4%) |
| 6 (2018-2022) | 80 (58%) |
| Age during surgery, yr | 4 (4-11) |
| Sex, male | 71 (52%) |
| Preoperative diagnosis | |
| Neuroblastoma | 87 (64%) |
| Pheochromocytoma | 24 (18%) |
| Adrenocortical carcinoma | 8 (6%) |
| Nonfunctional adenoma | 6 (4%) |
| Cushing syndrome | 3 (2%) |
| Primary aldosteronism | 3 (2%) |
| Other | 6 (4%) |
| Tumor size, mm | 48 (31-68) |
| Hereditary syndromes | 71 (52%) |
| MYCN-amplification | 20 (15%) |
| 1p-deletion/1p-gain | 9 (7%) |
| VHL | 7 (5%) |
| SDH-A/SDH-B | 6 (4%) |
| Li-Fraumeni | 3 (2%) |
| MEN-2A | 2 (1%) |
| NF-1 | 2 (1%) |
| Other | 22 (16%) |
| Preoperative imaging | |
| Ultrasound | 55 (40%) |
| CT scan | 29 (21%) |
| MRI | 119 (87%) |
| PET scan/PET-CT | 83 (61%) |
Categorical variables are presented as n (%); continuous variables are presented as median (interquartile range).
BMI, body mass index; CT, computed tomography; MEN-2A, multiple endocrine neoplasia, type 2A; MRI, magnetic resonance imaging; NF-1, neurofibromatosis, type 1; PET, positron emission tomography; SDH, succinate dehydrogenase; VHL, von Hippel Lindau.
* Centers are anonymized for privacy reasons.
patients were analyzed. Baseline characteristics are shown in Table I. After comparing the study database with the national histologic database, we deemed that the number of adrenalec- tomies for the period 2014-2022 was comparable in both data- bases (162 vs 177, respectively). This resulted in an estimated incidence of 18-20 adrenalectomies per year in a total population of 3.3 million children. An overview of the spread of patients between the different hospitals is provided in Figure 1. This il- lustrates the process of centralization that occurred from November 2014 onwards. Most patients underwent surgery for a suspected neuroblastoma (87 patients [64%]), followed by pheo- chromocytoma (24 patients [18%]), adrenocortical carcinoma (8 patients [6%]), nonfunctional adenoma (6 patients [4%]), Cushing syndrome (3 patients [2%]), primary aldosteronism (3 patients [2%]), and other diagnoses (6 patients [4%]). In 52% of patients there were pathogenic germline variants or hereditary syndromes. In this study, 40% of all patients received preoperative imaging using an ultrasound, 21% received a computed tomography scan, 87% magnetic resonance imaging, and 61% a positron emission tomography scan. In most cases histology confirmed the preop- erative diagnosis; however, in 2 cases with suspected adrenocor- tical carcinoma the tumor proved to be a benign adenoma, and in 2 cases of suspected pheochromocytoma the tumor was a ganglioneuroma.
Surgical techniques and outcomes
Unilateral adrenalectomy was performed in 131 patients, 6 pa- tients underwent bilateral adrenalectomy (Table II). Open adre- nalectomy was performed in 88 patients (64%), TLA was performed in 39 patients (29%), and PRA in 10 patients (7%). Median age for open surgery was 3 years (IQR, 2-5 years), for TLA 10 years (IQR, 2-14 years), and for PRA 16 years (IQR, 12-17 years, P < . 001) (Table III). There was a significant difference in duration of surgery between open surgery, TLA, and PRA (median 171 [IQR, 120-213] minutes, 105 minutes [IQR, 85-148], and 67 minutes [IQR, 53-101], respectively, P < . 001). When preoperative suspicion of malignancy was present, open surgery was performed in 83% of patients, compared with 23% of patients with suspected benign disease. Over the years, there was no increase in the use of MIA compared with open adrenalectomy (Figure 2). Surgeries were performed either by an endocrine surgeon, pediatric surgeon, urologist, or with a combined team. Perioperative complications occurred in 25 pa- tients (18%), of which bleeding (11 patients) and partial renal ischemia (7 patients) were most common. These complications occurred during surgery for neuroblastoma in 21 patients (24%), for adrenocortical carcinoma in 3 patients (50%), and for pheochro- mocytoma in 1 patient (5%). In 36 patients (26%) a postoperative complication occurred, of which 3 were Clavien-Dindo 3 or 4: one case each of hemodynamic insufficiency due to postoperative sepsis, intestinal intussusception that required a relaparotomy, and gastroparesis for which a duodenal feeding tube was placed using gastroduodenoscopy. Positive surgical margins were found in 83 patients (61%), mostly after neuroblastoma surgery; however, this is in accordance with the debulking nature of neuroblastoma sur- gery (Table IV). The median duration of follow-up was 65 months (IQR, 39-81 months).
Neuroblastoma
Eighty-six percent of patients with a neuroblastoma received neoadjuvant chemotherapy, with different regimens depending on pretreatment risk classification, following different research pro- tocols. For patients with neuroblastoma, the median age at time of surgery was 3 years (IQR, 1-5), the median tumor size was 53 mm (IQR, 37-72), and 73 patients (85%) underwent open surgery (Table V). The presence of pathogenic germline variants signifi- cantly increased the presence of IDRFs (P = . 04), but there was no significant correlation with the presence of metastases, surgical approach, complications, positive lymph nodes, adjuvant chemo- or radiotherapy, or disease recurrence.
In 13 patients TLA was performed, of which 2 patients had 1 IDRF, and 1 patient had 2 IDRFs. Median tumor size was signifi- cantly lower in TLA when compared with open surgery (28 mm [IQR, 20-36] vs 57 mm [IQR, 42-72], P = . 002). Positive surgical margins were found in 76 patients (88%), both after open and laparoscopic surgery. Fifty-six patients (65%) received both adju- vant chemotherapy and radiotherapy, 17 patients (20%) only adju- vant chemotherapy, and 3 patients (3%) only adjuvant radiotherapy. Thirty-four patients (40%) had recurrence of disease after surgery (either local recurrence or metastatic disease) despite adjuvant therapy, with a median time to recurrence of 8 months (IQR, 3-14). After binary logistic regression, the presence of metastases on preoperative imaging was the only significant predictor for disease recurrence (P = . 02). Thirty-two patients (37%) died during follow- up, of whom 30 patients died due to disease progression and 2 patients due to infection, after a median follow-up of 14 months
Spread between hospitals
30
Hospitals
1
2
3
4
5
6
Number of patients
20
10
0
2011
2012
2013
2014
2015
2016
2017
2018
2019
2020
2021
2022
Year of surgery
| All patients (n = 137) | Unilateral adrenalectomy (n = 131) | Bilateral adrenalectomy (n = 6) | |
|---|---|---|---|
| Surgical techniques | |||
| Open | 88 (64%) | 86 (66%) | 2 (33%) |
| Transperitoneal laparoscopy | 39 (29%) | 36 (28%) | 3 (50%) |
| Retroperitoneoscopy | 10 (7%) | 19 (7%) | 1 (17%) |
| Side of adrenalectomy (left/right) | n.a. | 73 (56%)/58 (44%) | n.a. |
| Duration of surgery, min | 144 (95-189) | 142 (94-187) | 157 (116-272) |
| Blood loss, mL | 40 (5-100) | 40 (4-100) | 38 (5-213) |
| Conversion to open surgery | 3 (6%) | 3 (7%) | 0 (0%) |
| Perioperative complications | 25 (18%) | 25 (19%) | 0 (0%) |
| Partial adrenalectomy | 7 (5%) | 6 (5%) | 1 (17%) |
| Lymph node dissection | 41 (30%) | 41 (31%) | 0 (0%) |
| Duration of admission, d | 7 (5-8) | 6 (5-8) | 8 (7-35) |
| Postoperative complications | 36 (26%) | 36 (27%) | 0 (0%) |
| Clavien-Dindo 1 | 12 (9%) | 12 (9%) | |
| Clavien-Dindo 2 | 21 (15%) | 21 (15%) | |
| Clavien-Dindo 3 | 2 (2%) | 2 (2%) | |
| Clavien-Dindo 4 | 1 (1%) | 1 (1%) |
Categorical variables are presented as n (%); continuous variables are presented as median (interquartile range).
(IQR, 10-29). After multivariable logistic regression analysis, dis- ease recurrence was the strongest predictor of mortality (P < . 001).
Pheochromocytoma
The median age of patients with a pheochromocytoma was 15 years (IQR, 12-16). Fourteen patients (64%) had a genetic pre- disposition, of whom 7 patients had Von Hippel-Lindau disease, 5 patients had succinate dehydrogenase deficiency, and 2 patients had multiple endocrine neoplasia, type 2A syndrome. All patients received preoperative alpha-blockade using doxazosin or phenox- ybenzamine, and 5 patients received additional beta-blockade
using propranolol or metoprolol. In 13 patients (59%) TLA was performed, in 6 patients (27%) PRA was performed, and 3 patients underwent an open adrenalectomy, probably as the result of larger tumor size, although this was not statistically significant (median, 71 mm [IQR, 52-102] vs 37 mm [IQR, 19-45] for MIA, P = . 09). Positive surgical margins were found in 4 patients (18%), all of whom underwent TLA. Of the patients with a positive surgical margin, 3 of 4 patients (75%) had recurrent disease, compared with 4 of 20 patients (20%) without positive surgical margins, after a median of 22 months (IQR, 11-49). Five patients received addi- tional surgery: 1 patient for a local recurrence after partial adre- nalectomy, 2 patients for a local recurrence after total
| Open transperitoneal (n = 88) | Laparoscopic transperitoneal (n = 39) | Laparoscopic retroperitoneal (n = 10) | |
|---|---|---|---|
| Sex, male | 46 (52%) | 19 (49%) | 6 (60%) |
| Age during surgery, yr | 3 (2-5) | 10 (2-14) | 16 (12-17) |
| Body mass index, kg/m2 | 16.5 (15.4-18.2) | 18.4 (16.6-21.3) | 20.1 (15.7-20.8) |
| Preoperative diagnosis | |||
| Neuroblastoma | 73 (83) | 14 (36) | 0 (0) |
| Pheochromocytoma | 4 (5) | 14 (36) | 6 (60) |
| Adrenocortical carcinoma | 5 (6) | 2 (5) | 0 (0) |
| Adenoma | 3 (3) | 1 (3) | 2 (20) |
| Cushing syndrome | 0 (0) | 3 (8) | 0 (0) |
| Primary aldosteronism | 0 (0) | 1 (3) | 2 (20) |
| Other | 3 (3) | 4 (10) | 0 (0) |
| Side of adrenalectomy (left/right/bilateral) | 51 (58)/35 (40)/2 (2) | 19 (49)/17 (44)/3 (8) | 3 (30)/6 (60)/1 (10) |
| Tumor size, mm | 58 (42-73) | 29 (19-45) | 38 (19-48) |
| Duration of surgery, min | 171 (120-213) | 105 (85-148) | 67 (53-101) |
| Blood loss, mL | 75 (20-140) | 5 (0-20) | 5 (0-5) |
| Duration of admission, d | 7 (6-9) | 5 (4-7) | 5 (4-8) |
| Postoperative complications | 34 (39) | 2 (5) | 1 (10) |
| Clavien-Dindo 1 | 10 (11) | 1 (3) | 1 (10) |
| Clavien-Dindo 2 | 20 (23) | 1 (3) | 0 (0) |
| Clavien-Dindo 3-4 | 3 (3) | 0 (0) | 0 (0) |
Categorical variables are presented as n (%); continuous variables are presented as median (interquartile range).
Surgical techniques
25
Surgical approach
☐ Open transabdominal
☒ Transabdominal laparoscopic
☐ Posterior retroperitoneoscopic
20
Number of patients
15
10
5
0
2011
2012
2013
2014
2015
2016
2018
2019
2020
2021
2022
Year of surgery
adrenalectomy, and 2 patients for a second primary paraganglioma. No patients died during the median duration of follow-up of 72 months (IQR, 57-123).
Adrenocortical carcinoma
The median age of patients with an adrenocortical carcinoma was 3 years (IQR, 3-14 years). In 4 patients (67%) there was a functional tumor, and 2 patients (33%) had metastatic disease at presentation for which they received neoadjuvant chemotherapy.22 Open adrenalectomy was performed in 5 patients (83%), and TLA was performed in 1 patient (17%). In 1 patient there was a positive surgical margin after open adrenalectomy, this patient had
recurrence of disease after 12 months, despite adjuvant chemo- therapy. Two patients died during follow-up after 25 and 29 months, respectively, both due to disease progression.
Discussion
In this nationwide study, we investigated adrenal surgery in children over the last 10 years in the Netherlands. The main indi- cation for surgery was neuroblastoma, accounting for 64% of all patients, followed by pheochromocytoma in 18% of the patients. Surgeries were performed in 5 academic hospitals and the pediatric oncology center, with an incidence of 18-20 patients per year in a total population of 3.3 million children in the Netherlands, with
| All patients (n = 137) | |
|---|---|
| Histologic diagnosis | |
| Neuroblastoma | 86 (63%) |
| Pheochromocytoma | 22 (16%) |
| Adenoma | 8 (6%) |
| Adrenocortical carcinoma | 6 (4%) |
| Ganglioneuroma | 5 (4%) |
| Primary aldosteronism | 3 (2%) |
| Cushing syndrome | 3 (2%) |
| Other | 4 (3%) |
| Positive surgical margins | 83 (61%) |
| Positive lymph nodes | 26 (63%) |
| Hormonal substitution therapy | 21 (15%) |
| Adjuvant chemotherapy | 74 (54%) |
| Adjuvant radiotherapy | 57 (42%) |
| Disease recurrence | 44 (32%) |
| Time to recurrence, mo | 9 (4-18) |
| Adjuvant surgery | 10 (7%) |
| Duration of follow-up, mo | 65 (39-81) |
| Mortality | 36 (27%) |
| Time until death, mo | 15 (10-28) |
Categorical variables are presented as n (%); continuous variables are presented as median (interquartile range).
approximately 170,000 births per year. Because of nationwide centralization of pediatric oncological care, all adrenalectomies for neuroblastoma were performed in 1 center from November 2014 onwards. In the other hospitals, the incidence of adrenalectomy was approximately 1 child per year. In comparison, a large registry- based, retrospective nationwide cohort study by Uttinger et al,17 in which the incidence of adrenalectomy in patients <21 years was examined in Germany, found that most hospitals (78%) performed an average of just 0.2 cases per year, whereas only 22% of hospitals carried out more than 1 adrenalectomy annually. In the study by Van der Steeg et al,19 the effect of centralization of neuroblastoma care was investigated, which showed significant differences regarding blood loss, vascular complications and duration of sur- gery, as well as lower grades of short-term complications, favoring the post-centralization cohort. Furthermore, benefits of centrali- zation are seen not only by centralizing to specific hospitals, but also within these hospitals, as high-volume surgeons have better outcomes. 23,24
Positive surgical margins were found in 88% of patients with a neuroblastoma, 18% with a pheochromocytoma, and 17% with an adrenocortical carcinoma. However, the objective of neuroblas- toma surgery is generally not a margin-free complete resection but debulking of the tumor (>90-95% of visible tumor mass), especially
| Neuroblastoma (n = 86) | Pheochromocytoma (n =22) | Adrenocortical carcinoma (n = 6) | |
|---|---|---|---|
| Sex, male | 52 (61%) | 12 (55%) | 1 (17%) |
| Genetic predisposition | 47 (55%) | 14 (64%) | 1 (17%) |
| Age during surgery, yr | 3 (1-5) | 15 (12-16) | 3 (0-14) |
| BMI, kg/m2 | 16.5 (15.4-18.0) | 18.6 (15.8-20.4) | 19.3 (17.9-25.6) |
| Tumor size, mm | 53 (37-72) | 44 (24-48) | 62 (24-110) |
| Functional tumor | 65 (76%) | 22 (100%) | 4 (67%) |
| Vascular infiltration | 3 (4%) | 0 (0%) | n.a. |
| Image-defined risk factors | n.a. | n.a. | |
| 0 | 34 (40%) | ||
| 1 | 21 (24%) | ||
| 2 | 15 (17%) | ||
| 3 | 10 (12%) | ||
| 4-6 | 6 (7%) | ||
| Infiltrating growth on imaging | 27 (31%) | 1 (5%) | 1 (17%) |
| Metastases on imaging | 63 (73%) | 1 (5%) | 2 (33%) |
| Neoadjuvant chemotherapy | 74 (86%) | 1 (5%) | 2 (33%) |
| Surgical technique | |||
| Open transperitoneal | 73 (85%) | 3 (14%) | 5 (83%) |
| Laparoscopic transperitoneal | 13 (15%) | 13 (59%) | 1 (17%) |
| Laparoscopic retroperitoneal | 0 (0%) | 6 (27%) | 0 (0%) |
| Duration of surgery, min | 165 (117-210) | 97 (84-148) | 171 (61-198) |
| Blood loss, mL | 50 (10-119) | 10 (1-100) | 75 (0-450) |
| Partial adrenalectomy | 1 (1%) | 4 (18%) | 0 (0%) |
| Duration of admission, d | 7 (6-8) | 7 (5-9) | 6 (5-8) |
| Postoperative complications | 28 (33%) | 4 (18%) | 2 (33%) |
| Clavien-Dindo 1 | 7 (8%) | 4 (18%) | 0 (0%) |
| Clavien-Dindo 2 | 18 (21%) | 0 (0%) | 2 (33%) |
| Clavien-Dindo 3-4 | 3 (3%) | 0 (0%) | 0 (0%) |
| Positive surgical margins | 76 (88%) | 4 (18%) | 1 (17%) |
| Positive lymph-nodes | 25 (29%) | 0 (0%) | 0 (0%) |
| Hormonal substitution therapy | 4 (5%) | 4 (18%) | 2 (33%) |
| Adjuvant chemotherapy | 70 (81%) | 0 (0%) | 3 (50%) |
| Adjuvant radiotherapy | 56 (65%) | 0 (0%) | 0 (0%) |
| Disease recurrence | 34 (40%) | 7 (32%) | 2 (33%) |
| Adjuvant surgery | 4 (5%) | 5 (23%) | 1 (17%) |
| Duration of follow up, mo | 41 (16-68) | 72 (57-123) | 46 (28-69) |
| Mortality | |||
| Disease progression | 30 (35%) | 0 (0%) | 2 (33%) |
| Infection | 2 (2%) | 0 (0%) | 0 (0%) |
| Time until death, mo | 14 (10-29) | n.a. | 25 and 29 |
Categorical variables are presented as n (%); continuous variables are presented as median (IQR).
in high-risk neuroblastoma.25 In these patients, there remains a debate about the degree of aggressiveness in surgical resection and its impact on outcomes.26 Surgery is typically performed after neoadjuvant chemotherapy, which was given in 86% of patients with neuroblastoma in our study. The aim of neoadjuvant therapy is to reduce metastatic disease, to improve patient’s condition for surgery, to decrease tumor size for better resectability, and to decrease infiltration or encasement of nearby organs, nerves, or blood vessels. Nevertheless, surgery remains a crucial part of treating the primary tumor and for gaining local control. However, it is also important to prevent surgical complications that could hinder the administration of postoperative multimodal ther- apy.25,27 Furthermore, for overall prognosis, other factors should be considered, such as MYCN-amplification status or segmental chromosomal deletions/gains.28,29 These adverse genetic factors were present in 33% of patients with neuroblastoma in this study and were significantly correlated with the presence of IDRFs. Despite neoadjuvant, surgical and adjuvant treatment, the mor- tality rate for neuroblastoma was 37%, which is comparable to the outcomes of other nationwide registries.30,31
Although most patients with a neuroblastoma underwent open surgery, 14 patients (16%) were treated with TLA. Of these patients, 11 patients had no IDRFs, 2 patients had 1 IDRF, and 1 patient had 2 IDRFs, and tumor size was significantly smaller. There is increasing evidence that, when performed by experts, TLA has favorable out- comes regarding blood loss and complication rates in patients with neuroblastoma without IDRFs on preoperative imaging, while achieving similar oncological outcomes compared to open sur- gery.15,32,33 The robot-assisted approach has been described for patients with 0-1 IDRFs as well, but available evidence is limited.34
In this study a comparison between different surgical tech- niques is difficult due to the large number of surgeons, heteroge- neous adrenal pathologies and patients. Over the last 10 years, the incidence of MIA did not increase in the study population. Patients who received TLA were older than those who underwent open adrenalectomy and had presumed benign disease in 59% of cases. For patients who received PRA, all had presumed benign disease. The conversion rate from TLA to open surgery was low, supporting the feasibility of this approach after adequate patient selection. However, it is crucial to adhere to oncological principles during surgical resection and to consider a strategic conversion if chal- lenges arise. There were no conversions during PRA. In the litera- ture TLA was proven feasible and safe both for benign tumors and for localized malignant disease.12,35,36 Walz et al11 showed good results in their large series investigating PRA and TLA for pediatric pheochromocytomas and paragangliomas, with low morbidity and short duration of admission. Especially in bilateral cases PRA has an advantage compared with TLA, since the patient does not need to be repositioned. To achieve an optimal retroperitoneal space, minimizing lumbar lordosis is key. Since the degree of lumbar lordosis is much lower in children, PRA can be performed using a modified jack-knife position, placing the child prone on a standard operating table with limited flexing of the hip.37 Expanding this technique to appropriately selected children in centers with expertise in this approach could further improve surgical outcomes.
There are several limitations to this study. First of all, clinical data from 2015 to 2017 were incomplete since clinical data of 50 patients could not be included, possibly skewing the results. Sec- ond, since this is a multicenter study, heterogeneity exists regarding diagnostics, neoadjuvant treatment, surgical treatment and follow up, which makes a comparison between different pa- tient groups challenging. Furthermore, especially for patients with neuroblastoma, treatment protocols have evolved over time and several patients were treated in study protocols. Third, only adrenal
neuroblastomas with limited local lymphadenopathy were included, and patients with extensive intra-abdominal or meta- static disease at the time of surgery were excluded. This may have resulted in a selection bias since the selection was performed on a case-by-case basis without strict definitions. Last, postsurgical quality of life scores could not be obtained because this was a retrospective study.
In conclusion, this study provides a nationwide overview of adrenalectomies in children over the last 10 years in the Netherlands, with an estimated incidence of 18-20 adrenalec- tomies per year. Most patients present with a neuroblastoma, and they are usually treated with an open adrenalectomy. For suspected malignancy, MIA was performed only in selected cases, whereas in patients with presumed benign disease and in older patients MIA was performed more often. Since November 2014 there was a clear centralization of patients with neuroblastoma toward the pediatric oncology center. However, since surgeons in most referral hospitals perform approximately 1 adrenalectomy in a child per year, centralization of nononcologic adrenal tumors could be beneficial. Since patients with benign, hormonally active tumors are typically older and are therefore anatomically more similar to adults, it could be hypothesized that they may benefit from undergoing surgery in selected high-volume adrenal centers, leveraging endocrinologic, anesthesiologic, and surgical expertise from adult adrenal care. However, this would need to be prospectively investigated. This approach could also promote further multidisciplinary collabora- tion within and across different centers.
Funding/Support
The authors received no funding for this work.
Conflict of Interest/Disclosures
The authors have no relevant financial disclosures.
CRediT authorship contribution statement
Allon van Uitert: Writing - review & editing, Writing - original draft, Visualization, Validation, Software, Resources, Project administration, Methodology, Investigation, Formal analysis, Data curation, Conceptualization. Marc H.W. Wijnen: Writing - review & editing, Supervision, Methodology, Investigation, Data curation, Conceptualization. Dominique C. Simons: Writing - review & editing, Methodology, Investigation, Data curation, Conceptualiza- tion. Charlotte L. Vietor: Writing - review & editing, Methodology, Investigation, Data curation, Conceptualization. Tessa M. van Ginhoven: Writing - review & editing, Methodology, Investigation, Data curation, Conceptualization. Ronald R. de Krijger: Writing - review & editing, Supervision, Methodology, Investigation, Data curation, Conceptualization. Menno R. Vriens: Writing - review & editing, Methodology, Investigation, Data curation, Conceptualiza- tion. Els J. Nieveen van Dijkum: Writing - review & editing, Methodology, Investigation, Data curation, Conceptualization. Jan H. Koetje: Writing - review & editing, Methodology, Investi- gation, Data curation, Conceptualization. Schelto Kruijff: Writing - review & editing, Methodology, Investigation, Data curation, Conceptualization. Michiel F. Schreuder: Writing - review & editing, Methodology, Investigation, Data curation, Conceptualiza- tion. Henri J.L.M. Timmers: Writing - review & editing, Supervi- sion, Methodology, Investigation, Data curation, Conceptualization. Johan F. Langenhuijsen: Writing - review & editing, Writing - original draft, Validation, Supervision, Project administration, Methodology, Investigation, Formal analysis, Data curation, Conceptualization.
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