Pediatric oncologic endosurgery.

Despite increasing popularity of minimal-invasive techniques in the pediatric population, their use in diagnosis and management of pediatric malignancy is still debated. Moreover, there is limited evidence to clarify this controversy due to low incidence of each individual type of pediatric tumor, huge diversity of the disease entity, heterogeneity of surgical technique, and lack of well-designed studies on pediatric oncologic minimal-invasive surgery. However, a rapid development of medical instruments and technologies accelerated the current trend toward less invasive surgery, including oncologic endosurgery. The aim of this article is to review current literatures about the application of the minimal-invasive approach for pediatric tumors and to give an overview of the current status, indications, individual techniques, and future perspectives.

Introduction

Holcomb et al1 first introduced minimal-invasive surgery (MIS) for pediatric tumors in 1995 as an alternative to the open approach. The initial indications were tumor biopsy, assessment of resectability, staging, and evaluation of metastasis. Over the following 2 decades, MIS emerged as an alternative for most of these indications in adults2. In children, however, there has been slow corresponding acceptance.

In 1996, the Pediatric Oncology Group received funding from the National Cancer Institute to conduct prospective randomized controlled studies to evaluate the roll of MIS in children with cancer. Unfortunately, these studies were closed prematurely in 1998. Using the accrued data, Ehrlich et al3 evaluated the factors that led to study failure, and postulated the following main reasons: (1) inadequate communication between oncologists and surgeons, (2) lack of surgical expertise with endoscopic procedures, and (3) preconceived surgeon bias toward each surgical approach.

Unfortunately, even after undergoing this symbolic trial and error, no randomized controlled trials or controlled clinical trials evaluating endoscopic surgery in the treatment of solid tumors in children have been conducted since4. The main obstacles remain the limited number of patients regarding each tumor type, as well as the substantial heterogeneity in tumor biology. Another technical aspect is the relatively small working space of pediatric patients compared with adults, which therefore limits oncologic MIS to pediatric surgeons with advanced endosurgical skills.

Still, the acceptance of MIS for pediatric solid tumors seems to be increasing5. Although most published studies are case reports, case series, cohort-control, or small case-control trials, it seems that pediatric cancer patients may benefit from certain advantages of MIS in terms of faster recovery, less pain, better cosmetic result, and earlier adjuvant treatment6.

Early reports suggested several potential limitations of pediatric oncologic MIS, such as tumor recurrence, trocar site metastasis, inadequate resection, tumor growth, and dissemination after CO2 insufflation7. Another concern was the difficulty to adhere to oncologic principle in pediatric endoscopic surgery due to loss of tactile sensation, possible tumor spillage, and difficulty of safe specimen removal specimens through small incisions8. Auxiliary techniques such as computed tomography (CT)-guided wire marking techniques may overcome these issues9.

This article includes an overview of the status, indications, individual techniques, and a future prospective of endoscopic surgery for pediatric solid tumors based on the review of currently published literature.

Current status of pediatric oncologic endosurgery

Biopsy and staging

Most tumors in children require biopsy before initiating multimodal management. The ability of endoscopy to visualize almost the entire abdominal and thoracic cavity is one of the most powerful advantages of this technique. It not only enables tissue confirmation, but also supplies information about the size, location, and anatomy of the tumor. The diagnostic accuracy of MIS has been reported ranging from 85% up to 100%. Cribbs et al10 summarized several large series of laparoscopic procedures in children with abdominal masses, resulting in a 99% positive yield. For thoracoscopy, the success rate was 98%, with a combined conversion rate of only 12%.

MIS can be also used as an adjunctive tool to CT, magnetic resonance imaging, ultrasound, or positron emission tomography scanning to evaluate the extent of disease. Despite significant improvements in tumor imaging, there is frequently a discrepancy between preoperative and intraoperative staging5. Endosurgery allows direct visualization of the tumor, exact evaluation of invasion into adjacent organs, as well as a thorough inspection of the peritoneal or pleural surface for implants. In adults, laparoscopy has actually been shown to avoid unnecessary laparotomy in up to 67% of patients11. During staging, metastatic deposits not detected by previous radiologic evaluation can be identified, and targeted biopsy is possible. Metzelder et al5 reported a total of 41 laparoscopic and 35 thoracoscopic biopsy and staging procedures in children, yielding a combined diagnostic accuracy of 98%.

Tumor resection

Recently, pediatric endosurgery has been more commonly used for curative intentions. Laparoscopic adrenalectomy is the most common procedure, with a conversion rate of only 10%10. The International Pediatric Endosurgery Group issued guidelines in 2010 for laparoscopic adrenalectomy, based on level III evidence, and confirmed feasibility without an absolute contraindication12.

Laparoscopic nephrectomy has been reported for Wilms tumor after chemotherapy13. The authors reported that 8 tumors were completely removed, including appropriate lymph node sampling, without significant complications. In addition, endosurgical resection of thoracic neuroblastoma14, primary liver cancers15, and ovarian tumors16 all have been reported in children.

Some authors attempted pediatric MIS in complex disease states such as the resection of neuroblastomas with vascular encasement11,13,17. Retroperitoneoscopy has been used for lymph node sampling, diagnostic biopsy, and complete resection of the tumor in recent series as well18.

Metastasis

After a primary resection and chemotherapy, imaging techniques frequently provide only limited information on tumor recurrence or metastasis. MIS is an option for the determination and characterization of metastatic lesions, and may help define a treatment plan. This approach is particularly suitable for pulmonary lesions. In fact, technical advances in imaging have led to an increased detection of small lung nodules of uncertain histologic nature. The development of localization techniques has enabled the resection of even small lung nodules by thoracoscopy19, decreasing the need for a potentially morbid, open thoracotomy. Localizing techniques include placing a CT-guided wire into the lesion, or tatooing the lesions on the pulmonary surface using the patient’s own blood or methylene blue20.

A particular clinical challenge is the resection of pulmonary osteosarcoma metastases, as these are characteristically firm and detectable by direct palpation. Thoracoscopic instruments diminish tactile feedback, so that thoracoscopy cannot be currently recommended for the search and resection of pulmonary osteosarcoma metastasis21.

Other supportive treatment and complications

Pediatric endosurgery can be performed for tumor complications, including cholecystectomy for cholecystitis, splenectomy for splenic involvement, oophorectomy for metastasis, Nissen fundoplication for gastroesophageal reflux, enterolysis for adhesive bowel obstruction, and feeding tube placement for tumor-associated cachexia22. Insertion of peritoneal catheters for intra-abdominal administration of cytoreductive agents have also been reported laparoscopically10. When the commonly used central veins are thrombosed or have been ligated, central venous catheters can be placed by MIS directly into the right atrium or via hepatic veins into the inferior vena cava21.

Infectious complications are common in children receiving intense multimodal therapy. MIS can be used to identify their source by obtaining samples of fluid or tissue22. Endosurgical procedures also have been used to treat complications due to leukemic infiltration of organs, and intussusception from intraluminal bowel malignancies. Laparoscopy has also been used to create enteroenterostomies to treat chronic obstruction due to infiltrative malignancy.

Abdominal approach

Neuroblastoma and neurogenic tumors

Neuroblastoma (Fig. ) is the most common abdominal solid tumor in children, arising from the adrenal gland in 40%23. Iwakana et al24 suggested that earlier time to postoperative feeding can be accomplished after laparoscopic resection. Leclair et al17 published a multicenter study of 45 cases of abdominal neuroblastoma. The median diameter of the tumors was 37 mm. Four procedures were converted to open surgery, and 2 major complications occurred. A recent retrospective study of 79 patients showed that laparoscopic resection of adrenal neuroblastoma can be performed with equivalent risks compared with open surgery25. The authors suggested selection criteria for laparoscopic tumor resection, including size smaller than 5 cm, and absence of vascular encasement. These studies show feasibility and good oncologic outcome of MIS in selected small, encapsulated low/intermediate risk tumors, while the roll of endosurgical procedures for complicated tumors has yet to be defined26.

Endoscopic view of laparoscopic resection of neuroblastoma in the left adrenal gland. In this depiction, the tumor has been circumferentially mobilized and the adrenal vein is being ligated using a bipolar sealing device.

Ganglioneuroma is a benign form of peripheral neurogenic tumor, often diagnosed incidentally in children. It may show invasiveness, leading to a high incidence of postoperative complications27,28. However, if it is well-capsulated, tumors can generally be resected endosurgically without complications23.

Pheochromocytoma

In children, 40% of cases of pheochromocytoma are associated with genetic mutations29. In pediatric patients, there is an increased risk of bilaterality and recurrence30. Complete surgical resection is the most important prognostic factor, and minimal-invasive procedure have been successfully utilized31. In patients with bilateral disease, laparoscopic partial adrenalectomy can be performed with good success32. Nau et al33 reported that laparoscopic pheochromocytoma resection showed similar outcomes compared with other adrenal entities, despite higher conversion rate. As in open surgery, careful intraoperative hemodynamic monitoring is mandatory. Also, the vein should always be ligated before any major manipulation because of the dangers of systemic catecholamine release.

Adrenocortical tumors (ACTs)

ACTs are rare in children, and generally have poor prognosis. Complete excision is the cornerstone of management because chemotherapy and radiotherapy are ineffective29. As these tumors are usually large and their capsules are friable, rupture and spillage frequently occurs. Few pediatric cases operated by endosurgery for small tumors (<55 mm) have been reported34. However, because of the overall aggressive nature, and the fact that upfront complete (R0) resection is the only chance of survival, the authors generally recommend against using MIS for preoperatively identified ACTs.

Nephroblastoma

Nephroblastoma is the most common genitourinary malignancy of children. It is also an example of successful multimodal treatment, with an overall cure rate of over 90%35. Despite good data, some controversies remain, including contralateral kidney exploration, indications for partial nephrectomy, and exclusive surgical treatment for some patients with low-risk diseases36. As there is clear evidence that tumor spill during surgery increases the risk of local recurrence37, laparoscopic resection of large nephroblastomas is considered challenging. To date, there is insufficient evidence to make general recommendations on MIS for nephroblastoma38. Endosurgical nephrectomy may offer a shorter length of stay, decreased use of narcotics, and lower intraoperative blood loss39. However, large tumors are associated with a higher risk of intraoperative spillage40. Conversely, in the European studies, preoperative chemotherapy is administered in all patients, followed by operative resection41. Neoadjuvant chemotherapy usually leads to relevant tumor shrinkage, possibly decreasing the risk of tumor rupture13, facilitating an MIS approach in some cases8. Large tumors may be difficult to handle, and carry a higher risk of tumor rupture42. The tumor should therefore always be placed in a retrieval bag. Morcellation is not recommended due to the risk of tumor rupture and rendering an accurate pathologic analysis impossible43.

Hepatic tumors

MIS for hepatic tumors in children is currently considered experimental. Several series reported nonanatomic liver resection using endosurgical techniques in tumors such as fibrous nodular hyperplasia44, mesenchymal harmatoma45, and hemangioblastoma. In small and selective locations (anterolateral segments) of hepatoblastoma, endosurgical resection has been reported in few patients46.

Ovarian tumors

Ovarian tumors lend themselves to endosurgical resection47. Laparoscopic resection of cystic ovarian neoplasms has been widely reported, most commonly in teratoma16. Mature teratomas are particularly suited for this approach (Fig. ), but potential malignancy makes it more controversial48. Some authors recommend laparotomy for tumors larger than 7.5 cm because complete tumor resection is the key factor for good prognosis42. However, MIS has been effectively used for staging and inspection of the peritoneal cavity and liver surface. Laparoscopic oophorosalpingectomy is certainly an option for malignant tumors confined to the ovary (Fig. ).

When mature features are clearly visible on preoperative imaging, an ovary-spearing resection of an ovarian teratoma (A) can be performed. The tube is preserved and the capsule is carefully opened (B). A plane can usually be developed between the teratoma (below the electrocautery hook) and healthy ovarian tissue, above (C).

The surgeon is preparing for oophorosalpingectomy of a germ cell tumor using the endoscopic bipolar sealing device.

Sacrococcygeal teratoma

Sacrococcygeal tumors in neonates most commonly present as large external tumors, but some are partially or entirely intrapelvic (Altman classification). For all types, the authors recommend a combined laparoscopic abdominal and subsequent open perineal approach. Laparoscopic ligation of the median sacral artery (Fig. ) before perineal resection proactively decreases the risk of life-threatening bleeding49. The authors have acquired extensive favorable experience with this hybrid technique.

Endoscopic view of ligation of middle sacral artery in a neonate with sacrococcygeal teratoma.

Thoracic indications

Thoracic neurogenic tumors

Thoracoscopic resection of neuroblastoma, ganglioneuroblastoma, and ganglioneuromas has evolved over time, with a considerable decrease in complication rates50. Compared with conventional open surgery, thoracoscopic neuroblastoma resection is associated with shorter length of stay, lower blood loss, and lower chest tube requirement51. Postoperative pain seems to be improved, as does the potential risk of tumor dissemination52. A shorter recovery time after MIS may allow for earlier commencement of adjunctive therapy53.

Germ cell tumors

Approximately 4% of all germ cell tumors are located within the chest54. Complete surgical resection is the most important factor for long-term survival. Frequently, these tumors infiltrate the surrounding tissues. Therefore, one should be cautious to use thoracoscopy when planning complete surgical resection.

Others

Besides the entities discussed, the mediastinum is a common location for intrathoracic masses in children. Primary pulmonary malignancies are less frequent than metastatic lesions. Surgical removal of lung metastasis improves survival in osteosarcoma and nephroblastoma, although it is less defined for other entities55. In cases where the therapeutic goal is not the complete removal of all lung lesions (evaluation of dignity of incidentally diagnosed nodules, for example), the endosurgical approach is preferred56.

Technical tips and tricks

The first suggestion for successful pediatric oncologic MIS is optimal exposure. Trocars should be carefully placed to allow adequate visualization and ergonomic handling. Transabdominal stay sutures to retract surrounding tissue and organs can enhance exposure. Finally, the patient should be firmly secured to the table so that the table can be shifted for gravity to aid in organ retraction.

Single-lung ventilation should be considered in older, relatively healthy patients when complex thoracoscopic interventions are planned. Single-lung ventilation can be achieved by using special double-lumen endotracheal tubes, by selective mainstem bronchus intubation, or by using a bronchial blocker in the ipsilateral side.

While we generally try to use the lowest pressures and flows possible during laparoscopy or thoracoscopy, temporarily increasing the pressure in the abdomen or thorax to gain working space during particularly critical phases can be beneficial.

Tumors should always be extracted in a tear-resistant endoscopic retrieval bag, and the corresponding incision must be made large enough to easily accommodate the tumor. Excessive manipulation of the specimen may break the bag and lead to inadvertent tumor spillage.

Although some authors claim that tumor size does not play a major role in choosing an endosurgical approach, large tumors are usually difficult to handle. We, therefore, advocate for careful case selection depending on surgical experience. In this context, Duarte et al13 suggested that MIS may be considered if the tumor’s dimensions are ≤10% of the child’s height.

Finally, if in doubt, conversion to a small thoracotomy or laparotomy to introduce a finger for haptic feedback can be helpful.

Future prospective

Single-incision surgery

Single-incision pediatric endosurgery (Fig. ) has been validated for many general pediatric procedures, but rarely for tumors57,58. Significant challenges include higher cost, a steep learning curve, lack of triangulation, and close instrument proximity, which is even more pronounced in smaller children59. Most series using single-incision surgery include mixed oncologic and nononcologic cases. Single-incision endosurgery has been reported for unilateral benign adrenal tumors60, metanephric adenoma58, granulosa cell tumors61, mature teratoma, and cystadenoma57. An advantage of single-incision pediatric endosurgery is a relatively large (15 to 20 mm) incision through which the tumor can be removed easier than through standard laparoscopic 3-, 5-, or 10-mm port incisions.

View of single-incision surgery performing left adrenalectomy for neuroblastoma.

Robotic surgery

Robotic surgery is well established in adults with prostatic, renal, and rectal cancers. Currently there are some limitations in adopting this technique in children. There are few case series reported for robotic-assisted tumor resection in pediatric solid tumors. Robotic surgery has been reported in the resection of pediatric brain tumors62, as well as mediastinal and abdominopelvic masses63. Mediastinal tumors have been proposed as the ideal indication of robotic surgery63. Before robotic surgery can be universally adopted in the treatment of pediatric neoplasia, further miniaturization of the instruments is necessary, and benefits should first be documented for benign disease in clinical studies.

Navigation and in situ diagnosis

Endoscopic navigation is an intriguing tool to improve identification of tumors or metastases. Preoperative identification of the target lesion with image-guided needle localization has been reported as described above for the lung. However, this requires a preoperative intervention, which may not be tolerated as well by children.

Recently, fluorescence laparoscopy has been introduced as a tool for the in vivo diagnosis and photodynamic therapy of childhood rhabdomyosarcoma64. This technique entails intraoperative intravenous injection of a fluorescent substance that lights up during laparoscopy using illumination at a particular wave length. In select cases, this may enable the more precise identification of the tumor margins based on the fluorescence, and may facilitate complete resection of the tumor.

Hayashi et al65 proposed a surgical navigation system based on CT-derived patient anatomy superimposed on the laparoscopic view in real time during surgery in adults. This surgical navigation system is based on virtual laparoscopy. In the future, it may overcome some limitations of MIS.

Multiphoton microscopy is a real time technique that allows imaging of tissue without time-consuming tissue labeling or staining66. It can visualize malignant cells in vivo through the tumors’ capsule (Fig. ). Therefore, it has a certain potential for future intraoperative diagnosis by providing immediate feedback to the surgeon on resection margins and anatomic-pathologic features. The authors are currently evaluating the use of multiphoton microscopy in the management of pediatric solid tumors.

Images of multiphoton microscopy for hepatocellular carcinoma through the tumor capsule. Collagen fibers are visible in red (second harmonic generation), cellular components in green (autofluorescence).

Conclusions

Currently, no clear evidence exists to universally support pediatric oncologic endosurgery in all cases. However, with more emerging studies and more robust data, minimal-invasive techniques have a definitive potential to replace some of the standard open procedures in the future. Minimal-invasive oncologic surgery seems to be associated with faster recovery times, less pain, better cosmesis, and earlier commencement of adjunctive therapies. Therefore, families and practitioners often prefer minimal-invasive to open surgery whenever feasible. The treatment of cancer is a complex, multimodal endeavor, in which many aspects come into play. Endosurgical procedures for pediatric oncology should be applied under the premise of careful patient selection, thoughtful decision making, and strictly respecting universal oncologic principles.