The role of surgery in the treatment of neuroblastoma metastases at rare sites

The department of Pediatric Surgery and Pediatric Urology at the University Children’s Hospital in Tuebingen, Germany, is a national surgical reference center for different extracranial solid tumor entities in children, including neuroblastoma. All patients in this study were operated on by the senior author (JF). We retrospectively analyzed all patients who underwent surgery for neuroblastoma at our department between March 2002 and October 2022. Staging was performed in accordance with INRS and INSS criteria (Shimada et al. 1999; Monclair et al. 2009). Risk stratification was based on the national guideline by the German Society for Pediatric Oncology and Hematology (Simon 2019). The decision for surgical treatment of neuroblastoma metastases was made on an interdisciplinary basis in the German national MDT, and individual circumstances were considered. Written informed consent for surgical treatment was obtained from the patient’s parents. Patient data, therapy, indication for surgery, intraoperative and pathology findings, and outcome data were analyzed retrospectively. Data were acquired and processed according to the latest version of the “World Medical Association Declaration of Helsinki–Ethical Principles for Medical Research Involving Human Subjects”. The study was approved by the local ethical committee (project number 013/2022BO2).

A 26-month-old boy with neuroblastoma stage IV (intermediate-risk group, negative MYCN amplification, negative 1p deletion) was referred to our department. MIBG scintigraphy showed a mIBG-positive primary tumor in the left adrenal region, a skin metastasis on the right-frontal skull and a penile metastasis adjacent to the glans with a size of 4.2 cm/1.7 inch (Fig. 1) and infiltration of the corpus spongiosum and the urethra. After initial diagnosis, he was treated with 2 cycles of N4 chemotherapy according to the NB2016 registry protocol (Berthold 2004). After chemotherapy, the primary tumor was no longer detectable. The patient was referred to the author’s center for surgical management of the growing penile metastasis. Due to the high probability of side effects such as erectile dysfunction and scarring of the penile tissue after local irradiation of the penis, the national MDT recommended surgical therapy of the penile neuroblastoma metastasis. As a secondary finding, we saw a condition of coronal hypospadias with a megalourethra.

Surgery was performed under general endotracheal anesthesia. A transurethral balloon catheter was inserted under sterile conditions. The transition region was incised from glans to penile shaft, and a degloving of the penile skin from the shaft was performed. Step by step, the corpus spongiosum was separated from the corpora cavernosa. The corpus spongiosum was found to be infiltrated by the metastasis on a length of 2 cm. The corpus spongiosum and urethra were mobilized, and the intact urethra was pulled up to the tip. Subsequently, the neurovascular bundle was dissected using quadruple magnifying glasses, and finally, the metastasis was resected from the glans with a resection margin of 2–3 mm. Furthermore, the metastasis was removed from the corpus spongiosum so that the penis was divided into 3 essential parts according to the Mitchell technique: the glans with the neurovascular bundle, the corpus spongiosum, and the corpora cavernosa (Mitchell and Bagli 1996). A complete resection of the metastasis could be performed, and the corpora cavernosa were sutured to the glans. Non-absorbable sutures were used for this step, and the urethra was brought to the tip of the glans. Extensive reconstruction of the glans with opposing mattress sutures was performed. Excess penile shaft skin was resected, and the remaining skin reconstructed. After the surgery, the penis was found to be well perfused. Dressing was applied in the same way as after surgical hypospadias repair: a film dressing was applied as the first layer and a gauze bandage was wrapped around the penis shaft as the second layer.

The postoperative course was uneventful. After 10 days, the transurethral catheter was removed, and we saw repeated spontaneous voiding and no clinical irregularities. The patient was discharged the following day with dry wound conditions and in good general condition. At follow-up 18 months after surgery, the patient was alive without signs of tumor relapse, was voiding regularly without problems and had regular erections according to the parents.

A 6-year-old boy with evidence of a second relapse of a neuroblastoma stadium 4 (high-risk group, negative MYCN amplification, negative 1p deletion; initial diagnosis: October 2016, first relapse: August 2017, second relapse: March 2019) was referred to the department of Pediatric Oncology and Hematology for stem cell transplantation. At diagnosis, the patient had a mIBG-positive tumor manifestation originating from the left adrenal gland with multiple mIBG-positive bone metastases and a suspicious lymph node in the right axilla with a diameter of 0.14 cm/0.55 inch (Fig. 2). The primary treatment consisted of chemotherapy according to Children’s Oncology Group protocol, tumor resection, autologous bone marrow transplantation, and radiotherapy (Pinto et al. 2015, Irwin et al. 2021). A relapse of the tumor was detected during routine follow-up examination, and mIBG therapy with 2 additional cycles of chemotherapy was administered. A few weeks later, a second relapse was detected. The following treatment included 1 cycle of chemotherapy with ifosfamide, carboplatin and etoposide, a second regimen of mIBG therapy, haploidentical stem cell transplantation, local radiation (the right elbow and right axilla were irradiated with a dose of 40 Gy in 20 fractions and the right proximal femur, as well as the cranial bone were irradiated with a dose of 36 Gy in 18 fractions), and immunotherapy with dinutuximab. After therapy of the second relapse, the metastasis of the right ulna and the lymph node in the right axilla were still visible on imaging and appeared to be vital. The patient’s main objectives were discussed in the local MDT, and it was decided to resect both metastases as part of the multimodal therapy.

Under general endotracheal anesthesia, a tourniquet was applied around the right upper arm. The surgical removal was performed together with a pediatric neurosurgeon. An opposing l-shaped incision was made in the area of the ulnar metastasis, which was followed by nerve visualization and preparation of the muscle insertions. After transection of the muscle attachment at the ulnar process, the metastasis was visible and could then be separated from the radial and ulnar arteries. A gross total resection with removal of approximately 98% of the tumor mass was performed using a sharp spoon and raspatory instrument. The bone structures proximal and distal to the metastasis were visualized, and the integrity of the elbow joint was assessed. It was decided to use bone cement and osteostimulative bone substitute with silicate substitution (Actifuse^®, Baxter Inc., Deerfield, IL/USA) to fill the bone defect. In addition, a fibrin sealant patch (TachoSil^®, Takeda Pharmaceutical Company Limited, Tokyo/Japan) was applied. Then, the muscle attachments were reconstructed, the ulnar nerve repositioned, and the wound closed layer by layer with insertion of a drain. After resection of the ulnar metastasis, the axillary lymph node metastasis was resected. At the end of the surgery, an upper arm cast was attached, and the patient was transferred to the pediatric surgical ward. Before discharge, the cast was changed to an elbow orthosis (Epico ROM^®, Medi GmbH & Co. KG, Bayreuth/Germany), with which immobilization of the elbow joint at an angle of 100° was established. At follow-up, the freedom of mobility of the left elbow joint could rapidly be improved until after six weeks the range of motion was only limited at maximum flexion and supination. At this time, imaging was performed using mIBG scintigraphy. No more mIBG-positive tumor sites or metastases could be detected. At follow-up 2.5 years after surgical treatment of the metastases, no signs of tumor relapse were noted, and according to the family, the patient is doing well.

A 6-year-old girl was referred to our department with a neuroblastoma stadium 4 (high-risk group, MYCN amplification, negative 1p deletion) originating from the right adrenal gland (and the right sympathetic trunk) with encasement of the large abdominal vessels and infiltration of the diaphragm. The patient had metastatic disease to intra-abdominal and left cervical lymph nodes, the pancreatic tail with a diameter of 1.1 cm/0.43-inch, the liver, to various bones, and in the bone marrow (Fig. 3). After initial diagnosis, the patient was treated with 5 N5/N6 chemotherapy cycles according to the GPOH registry protocol (Berthold 2004). The patient was referred to the author’s department for resection of the primary tumor of the right adrenal gland and the liver and pancreas metastases. The national MDT’s decision to resect the metastases was made because the metastases had shown growth and high viability in the MRI, based on advanced diagnostic imaging value and diffusion weighted imaging as well as image-defined risk factors (Monclair et al. 2009, 2015). In addition, non-surgical therapy had shown no effect. A transverse upper abdominal laparotomy was realized, and a complex gross total resection was performed with release of all encased vessels without organ injuries. The excision of the metastases of the pancreatic tail and the liver was realized by pancreatic tail resection and right hemihepatectomy without any complications. Intraoperatively, the remaining organ mass of the liver was estimated to be 55%, and the pancreas still had approximately 60% of its original volume. During the postoperative course, there was no evidence of pancreatic or bile leakage as well as no clinical or laboratory signs of endocrine or exocrine pancreatic insufficiency. The patient died 6.5 months after surgery due to local tumor relapse and rapid tumor progression under palliative treatment in a hospital near her home.