Safety and Feasibility of Laparoscopic Resection of Neuroblastoma Without Image-Defined Risk Factors Performed by Pediatric Surgical Trainees: A Multicenter Comparison Study

Abstract

Introduction:

Laparoscopic resection has gradually been adopted for neuroblastoma patients; however, some authors reported that, due to its technically demanding procedures, this operation should be performed only by highly experienced surgeons. The aim of this study was to evaluate the safety and feasibility of laparoscopic resection of abdominal neuroblastoma by pediatric surgical trainees.

Subjects and Methods:

In this multicenter, retrospective study, including 18 children with abdominal neuroblastoma indicated for 19 laparoscopic resections (1 with bilateral neuroblastomas) from 1999 to 2018, the clinical data were retrospectively reviewed and compared between trainee and attending surgeons.

Results:

None of the cases had image-defined risk factors (IDRFs) at surgery. All patients successfully underwent complete laparoscopic resection without blood transfusion, open conversion, or intraoperative or postoperative complications. Of the 19 cases, 6 were performed by pediatric surgical trainees under the guidance of attending surgeons, and 13 were performed by attending surgeons. With comparable tumor, largest diameter, operative time, and bleeding amount were not significantly different between the two groups. In the trainee surgeon group, one local recurrence occurred at a secondary resection site in the bilateral neuroblastoma patient with Stage L2.

Conclusions:

Laparoscopic resection of neuroblastoma could be safe and feasible when limited to absent IDRFs at surgery by pediatric surgical trainees under the guidance of experienced attending surgeons, as well as by attending surgeons.

Introduction

Abdominal neuroblastoma is one of the most frequent solid malignant tumors in children that is usually treated by a combination of surgery, chemotherapy, and radiation therapy. Since surgical resection has an important role in local control and prompt transition to subsequent treatments,^1,2 surgical complications should be minimized. Since laparoscopic surgery is generally associated with rapid recovery and less invasiveness than laparotomy,³ laparoscopic resection for abdominal neuroblastoma has gradually become a standard procedure. There have been some reports regarding its indications, but they remain controversial.^1,3–6

Most articles regarding laparoscopic resection of neuroblastoma suggested that the operation should be performed only by highly experienced surgeons due to its technically demanding skills.^7,8 Since 2009, image-defined risk factors (IDRFs) were introduced to predict the surgical risks of localized neuroblastoma by the International Neuroblastoma Risk Group (INRG) Taskforce.^9,10 It has been reported that neuroblastoma without IDRFs was associated with a significantly lower risk of surgical complications.^2,6 Since the absent-IDRF neuroblastoma has no encasement of vessels, tumor dissection from the surrounding tissues can be performed by standard laparoscopic procedures. Therefore, we assumed that laparoscopic resection of neuroblastomas without IDRFs could be safely performed not only by highly experienced surgeons, but also by pediatric surgical trainees under the guidance of attending surgeons, because they had completed training in adult surgery and had thereby acquired basic laparoscopic skills.

The aim of this study was to evaluate the safety and feasibility of laparoscopic total resection for abdominal neuroblastoma without IDRFs performed by pediatric surgical trainees under the guidance of experienced attending surgeons.

Patients and Methods

This was a retrospective study at Osaka University Graduate School of Medicine, Osaka Women's and Children's Hospital, Osaka City General Hospital, Kindai University Nara Hospital, and Hyogo College of Medicine. This study complied with the Declaration of Helsinki, and the Institutional Review Board (IRB) at each participating hospital approved the study protocol (IRB number of Osaka University Hospital was 18500).

Between January 1999 and December 2018, 18 children were planned for laparoscopic total resections of abdominal neuroblastomas. The use of the laparoscopic approach was determined by the attending surgeons in each hospital, taking into account the availability of staff expertise for pediatric laparoscopic surgery. They chose the cases in which it was judged that complete resection of the tumor was possible laparoscopically. Tumors without IDRFs, except for contact with renal vessels at surgery, seemed to be selected. Laparoscopic resection of neuroblastoma was carried out using three or four ports. The preoperative clinical data and intraoperative and postoperative results of these patients were retrospectively reviewed.

Preoperative clinical data included tumor location, tumor size, INRG Staging System, presence of IDRFs at surgery, and history of laparotomy. Tumor size was evaluated based on the largest diameter assessed on the latest preoperative computed tomography. The IDRFs were defined according to the original Monclair report published in 2009.⁹ According to a new guideline for assessing IDRFs published in 2011,¹¹ tumor contact with renal vessels is considered IDRF present.

Our previous study demonstrated that the new guideline increased the ratio of IDRF-present patients from 31% to 71% among total of 107 patients with localized neuroblastoma.² A considerable number of patients with Stage L2 disease had undergone chemotherapy after application of the new guideline due to tumor contact with renal vessels, who could have safely been cured by surgery alone. Therefore, in the current clinical study of neuroblastomas conducted by the Japan Neuroblastoma Study Group, the previous IDRFs defined in 2009 were used, and thereby, tumor contact with renal vessels was considered to be IDRF absent in the present study.

Intraoperative and postoperative outcomes included operative time, intraoperative bleeding amount, need for blood transfusion, postoperative complications, and oncologic outcomes (relapse and mortality).

To evaluate the difference in surgical outcomes due to the experience of the surgeons, the neuroblastoma cases were divided into two groups: the trainee surgeon group and the attending surgeon group. Our training system for pediatric surgeons includes 2 years of adult general surgery training followed by two postgraduate years for fostering general clinical skills. After the general surgery training, over 3 years of pediatric surgical training are then required to obtain board certification by the Japanese Society of Pediatric Surgeons. In addition, our education and training system policy requires that they usually enroll in 4-year doctoral course for basic research during the training period. Therefore, a minimum of 12 years of training is required in our pediatric surgery training program.

The trainee surgeon group was defined as including the cases that underwent surgery by a pediatric surgical trainee who had not yet obtained board certification as a specialist in pediatric surgery by the Japanese Society of Pediatric Surgeons (postgraduate year ≤12). Meanwhile, the attending surgeon group was defined as including those cases that underwent surgery by a surgeon who had already obtained such certification (postgraduate year >12). Recently, young pediatric surgeons have been assigned as operators of laparoscopic resection of neuroblastoma in our center's policy. The clinical factors and surgical outcomes of these two groups were then compared.

Continuous data are expressed as medians with range values. Between-group comparisons were analyzed using Fisher's exact test, the Mann–Whitney U-test, or Welch's t-test, as appropriate. All analyses were performed with GraphPad Prism 8 (GraphPad Software, Inc., San Diego, CA). P < .05 was considered significant.

Results

During the 20-year study period, a total of 192 cases of total tumor resection were performed for abdominal neuroblastoma at our hospitals. Of these 192 cases, 19 resection cases (9.9%) were performed laparoscopically for 18 patients (8 males, 10 females). One patient with mosaic partial trisomy 2p developed synchronous bilateral neuroblastomas and thus underwent laparoscopic resection of the left tumor at the age of 19 months, followed by reduction of right tumor volume. Since the right-sided tumor showed gradual growth, it was resected laparoscopically at the age of 52 months.

Of the 19 cases, 6 were performed by pediatric surgical trainees under the guidance of attending surgeons, and 13 were performed by attending surgeons. All 6 cases in the trainee surgeon group belonged to a single high-volume center. In our recent policy, young pediatric surgeons have been assigned as operators of laparoscopic pediatric surgery in the high-volume center. The number of the trainees was 6 (each trainee operated one NB case), and that of the attending surgeons was 11. The number of postgraduate years was significantly lower in trainee surgeons than in attending surgeons [6 (4–12) versus 18 (14–28) years, P < .0001].

The clinical characteristics of the patients are shown in Table 1. Three patients had a history of laparotomy, including two tumor biopsies and one laparoscopic resection of a contralateral neuroblastoma in a bilateral case. Neoadjuvant chemotherapy was performed in five cases (two in L2 cases, one in an MS case, and two in M cases). Two IDRF-positive cases were effectively treated with neoadjuvant chemotherapy and turned out to be IDRF negative. None of the cases was IDRF positive at surgery. The median largest tumor diameter was 35 mm (range 10–55 mm).

Table 1.

Patients' Characteristics: Overall and by Surgeon Group

	Total cases (n = 19)	Trainee surgeon group (n = 6)	Attending surgeon group (n = 13)	P
Age at surgery (months)	20 (8–183)	28 (8–52)	20 (9–183)	.85
Height at surgery (cm)	78.0 (64.7–150.0)	84.3 (64.7–96.8)	78.0 (66.0–150.0)	.91
Weight at surgery (kg)	10.8 (6.4–27.0)	11.0 (7.3–14.1)	10.8 (6.4–27.0)	.95
History of laparotomy	3 (15.8%)	1 (16.7%) (laparoscopic tumor resection)	2 (15.4%) (tumor biopsies)	>.99
INRG Staging System	L1: 14, L2: 2, MS: 1, M: 2	L1: 5, L2: 1	L1: 9, L2: 1, MS: 1, M: 2	—
Neoadjuvant chemotherapy	5 (26.3%)	1 (16.7%)	4 (30.8%)	>.99
Presence of IDRFs at surgery	0	0	0	—
Tumor largest diameter (mm)	35 (10–55)	40 (20–50)	31 (10–55)	.39
Primary tumor site	Lt. adr. gl.: 11, Rt. adr. gl.: 7, Para-aortic sympathetic ganglia: 1	Lt. adr. gl.: 1, Rt. adr. gl.: 4, Para-aortic sympathetic ganglia: 1	Lt. adr. gl.: 10, Rt. adr. gl.: 3	—

Data are expressed as medians with ranges or as n (%).

adr.gl., adrenal gland; IDRF, image-defined risk factor; INRG, International Neuroblastoma Risk Group; Lt, left; Rt, right.

All patients successfully underwent complete laparoscopic resection without open conversion, both by trainee surgeons and by attending surgeons. The surgical outcomes of the patients are shown in Table 2. The median operative time was 196 (range 102–350) minutes. The median bleeding amount was 0.4 (range 0–16.4) mL/kg body weight, and none of the patients required blood transfusion. No intraoperative or postoperative complications were observed. In the median follow-up period of 37 (3–176) months, there was one local recurrence. A bilateral neuroblastoma patient with Stage L2 developed local recurrence 18 months after secondary resection for a contralateral tumor. Although one patient (Stage M) died due to tumor progression, the others were alive with disease-free status.

Table 2.

Surgical Outcomes: Overall and by Surgeon Group

	Total cases (n = 19)	Trainee surgeon group (n = 6)	Attending surgeon group (n = 13)	P
Operative time (minutes)	196 (102–350)	187 (132–265)	201 (102–350)	.89
Bleeding amount (mL/kg BW)	0.4 (0–16.4)	0.9 (0–8.1)	0.3 (0–16.4)	.48
Required blood transfusion	0	0	0	—
Intraoperative complications	0	0	0	—
Open conversion	0	0	0	—
Postoperative complications	0	0	0	—
Local recurrence	1 (5.3%)	1 (16.7%)	0	.32
Metastatic recurrence	1 (5.3%)	0	1 (7.7%)	>.99
Follow-up period (months)	37 (3–176)	31 (3–59)	47 (5–176)	.19

Data are expressed as medians with ranges or as n (%).

BW, body weight.

Comparisons of the patients' characteristics and surgical outcomes between the trainee and attending surgeon groups are shown in Tables 1 and 2, respectively. There were no significant differences between the trainee surgeon group and the attending surgeon group in age at surgery [28 (8–52) versus 20 (9–183) months], present history of laparotomy (one laparoscopic tumor resection versus two tumor biopsies), neoadjuvant chemotherapy (one versus four cases), and largest diameter of the tumor [40 (20–50) versus 31 (10–55) mm], respectively. Blood transfusions and intraoperative and postoperative complications were not observed in both groups. There were no significant differences in operative time and intraoperative bleeding amount between the two groups. One local recurrence was observed in the trainee surgeon group, and one metastatic recurrence was observed in the attending surgeon group.

Discussion

Laparoscopic resection of abdominal neuroblastomas has been reported to be associated with less bleeding, decreased time to start postoperative feeding and postoperative chemotherapy, and shorter hospital stay, in addition to cosmetic advantages compared with open laparotomy.^1,3,12 However, despite the frequent success of the operation, most series consist of a heterogeneous group of retrospective cases in a small cohort due to lack of patient accrual.^{1,3,6–8,12,13} The present study patients were enrolled from five institutes. All 19 cases had no IDRFs at surgery with tumor size ≤55 mm in its largest diameter. Laparoscopic complete resection of neuroblastoma was successfully performed in all cases without blood transfusion, intraoperative and postoperative complications, or open conversion.

To the best of our knowledge, this is the first study to investigate the feasibility of laparoscopic resection of neuroblastoma by pediatric surgical trainees. From the present result that the median postgraduate year of trainee surgeons was 6, they were considered to have little or no experience doing advanced laparoscopic procedures. Although board certification as a specialist in pediatric surgery does not guarantee skill in pediatric endoscopic surgery, the present study showed that perioperative outcomes were not significantly different between the trainee surgeon group and the attending surgeon group with almost the same patient background characteristics. Therefore, laparoscopic resection of neuroblastoma without IDRFs at surgery could be feasible by pediatric surgical trainees under the guidance of experienced attending surgeons, as well as by attending surgeons.

The tumor size limit for laparoscopic excision is unclear, and some reports have supported the indication of laparoscopic excision for tumors <4–6 cm.^3–5 In the present study, all patients safely underwent laparoscopic resection with tumor size limited to within 55 mm in its largest diameter. The present results were consistent with those previous reports; however, for assessment of the indication by tumor size, further study, including analysis of long-term outcomes, may be required.

One of the advantages of laparoscopy is decreasing the amount of bleeding. Under the magnification of laparoscopy, the dissection could be performed and the site of vascular injury identified more precisely than at open laparotomy. In the present study, intraoperative bleeding was well controlled in most cases, and no patients required blood transfusion.

In the present study, all cases had no IDRFs at surgery. There are some reports that the indication for laparoscopic resection of abdominal neuroblastomas might be absent IDRFs.^1,6,10 The present results support their findings. Tanaka et al.⁶ demonstrated that four of the five IDRF-positive cases developed postoperative complications, including partial renal infarction or open conversion. However, the idea of IDRFs has not yet spread sufficiently, because some recent studies regarding the safety and efficacy of laparoscopic resection of neuroblastoma did not mention the presence or absence of IDRFs.^7,13,14 The present results are expected to contribute to the widespread use of IDRFs as indications for laparoscopic resection of abdominal neuroblastoma.

Two of the present cases had IDRFs at diagnosis, and neoadjuvant chemotherapy decreased their IDRFs. They safely underwent laparoscopic resection without intraoperative and postoperative complications. However, Yoneda et al. reported that Stage L2 tumors (IDRF present at diagnosis) may have a potential risk for surgery even after reduction of IDRFs by neoadjuvant chemotherapy.¹⁵ Therefore, further study is needed to confirm the safety of laparoscopic resection of neuroblastomas without IDRFs at surgery after neoadjuvant chemotherapy.

Local recurrence occurred in a bilateral neuroblastoma patient with trisomy 2p. After a secondary operation for contralateral tumor following neoadjuvant chemotherapy, he developed recurrence at the secondary resection site despite complete resection. Pederiva et al. reported that bilateral neuroblastomas are extremely rare, and whether this represented double synchronic primaries or contralateral metastases of a unilateral tumor was unknown.¹⁶ Therefore, the main factors related to local recurrence in the present study could not be identified.

Neoadjuvant chemotherapy was performed in one case of the trainee surgeon group and four cases of the attending surgeon group. Despite no significant difference, whether the neoadjuvant chemotherapy was related to operative difficulties was evaluated. In the present results, the operative time was 189 minutes in the trainee surgeon group case and 104, 108, 111, and 260 minutes in the attending surgeon group cases. The bleeding amount was 0.4 mL/kg body weight in the trainee surgeon group case and 0, 0.1, 0.3, and 5.5 mL/kg body weight in the attending surgeon group cases. Therefore, although they were few cases, neoadjuvant chemotherapy might not have affected the degree of operative difficulties and the surgical outcomes in the two groups of surgeons in this study.

In the field of adult surgery, some reports also suggested that laparoscopic gastrointestinal surgery could be safely performed by trainee surgeons, as well as by experienced surgeons.^17–19 As the reason for these results, the laparoscopic view can provide more accurate identification of anatomical structures and dissection planes.¹⁷ Additionally, several useful tools were available, including the dry box for practice and operative videos for learning.^18,19 In the Japanese training program for pediatric surgeons, almost 2 years of surgical training in general surgery are required before pediatric surgery training. Basic laparoscopic skills have been reported to be acquired through experience with laparoscopic cholecystectomy.^19–21

Recently, laparoscopic cholecystectomy, laparoscopic inguinal hernia repair, and laparoscopic colectomy have become general procedures in Japan.^19,22 Therefore, we considered that nearly all pediatric surgical trainees already had sufficient basic laparoscopic skills, including how to use laparoscopic instruments, create effective operation fields, and dissection with hand/eye coordination in a two-dimensional view.¹⁸ Since one can share the operative field with other surgeons during laparoscopy, we consider that pediatric surgical trainees under the guidance of attending surgeons can also safely perform laparoscopic resection of neuroblastomas without IDRFs.

There were some limitations in this study. First, this was a retrospective case series. There have been some retrospective studies comparing laparoscopic and open surgeries for abdominal neuroblastomas.^1,2,7,13 The most important limitation of these studies is selection bias due to their single-center nature. Of the above studies, the backgrounds of the two groups were different in terms of tumor size.^7,13 Moreover, since most laparoscopic surgeries were performed in recent years with relatively shorter follow-up periods, treatment outcomes cannot be validated precisely. The present study was a feasibility study that can add knowledge to previous studies regarding the safety and efficacy of laparoscopic resection of neuroblastoma and its indications. Second, despite the fact that this study involved five institutions, the number of patients was still small. Further investigations, including long-term outcomes in larger populations are needed.

In summary, we consider that laparoscopic resection of abdominal neuroblastomas without IDRFs at surgery could be safely performed even by pediatric surgical trainees, with previous experience in minimally invasive general surgery, under the guidance of experienced attending surgeons, as well as by attending surgeons.

Footnotes

Disclosure Statement

No competing financial interests exist.

Funding Information

There were no funding sources.

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