ABSTRACT
Aim
Malignant chest wall tumors are rare in children. We aimed to study the management of the Ewing family of tumors (EFT) in the chest walls of children.
Materials and Methods
The files of patients diagnosed with primitive neuro-ectodermal tumor and Ewing sarcoma of the chest wall in the prior 2 decades were retrospectively reviewed.
Results
A total of 15 children with a median age of 10 (8-14) years were included. Their symptoms were palpable mass (n=6), chest pain (n=4), B symptoms (n=2), cough (n=2) and abdominal pain. Their history revealed delayed diagnoses in 1/3 of the patients due to a misinterpretation of the symptoms. All children except for one had tru-cut biopsy and upfront chemotherapy. The median greatest diameter of mass at diagnosis was 100 (67-148) mm and 51 (39-100) mm at preoperative imaging after chemotherapy. Pleural effusion (n=8), costal destruction (n=9), extension to neural foramina (n=3), pulmonary or diaphragmatic nodule (n=5) and distant bone metastasis (n=4) were present at diagnosis in some cases. More than one surgery was performed in 9 (60%) of the children in order to remove the primary tumor and metastases. Costal excision (n=11), diaphragmatic resection (n=6) and chest wall reconstruction with graft material were performed on 8 patients. All cases had radiotherapy postoperatively. Mortality occurred in 9 (60%) patients due to local recurrences or metastases. Only 3 children reached 5-year survival and were considered to be cured. The remaining 3 patients completed their first line oncologic treatments and were under surveillance without treatment.
Conclusion
The EFT in the chest wall are aggressive tumors with poor prognosis despite multimodality treatment. Surgeons dealing with these patients should be familiar with complex chest wall reconstruction techniques.
Introduction
Chest wall tumors are rare in childhood, comprising only 2% of all childhood malignancies. Most of them are soft tissue sarcomas or tumors arising from bony or cartilaginous tissues of the chest wall (1). Peripheral primitive neuro-ectodermal tumor (PNET) and Ewing sarcoma are very similar tumors in terms of their histology, biology and clinical presentation and they are collectively known as the Ewing family of tumors (EFT) (2). Most of the tumors arising from the chest wall in childhood belong to this family of tumors. They show aggressive and infiltrative behavior but are also chemo- and radio-sensitive (3). Treatment is multidisciplinary, which is similar to most of the pediatric solid tumors. Neoadjuvant chemotherapy followed by surgery and radiotherapy is the standard treatment approach. Recurrences and metastasis are common in these patients and they are managed by second line treatments and palliative interventions. The huge diameters and infiltrative growth patterns of these tumors demand extensive resections and reconstructive surgical applications. In this study, we aimed to present our experiences with this rare tumor of childhood from a pediatric surgical oncology standpoint.
Materials and Methods
This study covered patients admitted to a pediatric surgery clinic during the previous 2 decades with a diagnosis of PNET and Ewing sarcoma. The patient list was derived from the institutional tumor registry of the hospital electronic database. The selected patient files were reviewed retrospectively for age, gender, presenting symptoms, computed tomography reports, surgical details and pathology results. All cases in this cohort were evaluated, treated and followed by a team of physicians from the pediatric surgery, radiology, pathology and oncology departments which are dedicated to the care of pediatric oncology and oncologic surgery patients. The management algorithm is as follows: tru-cut biopsy followed by 6 cycles of induction chemotherapy, surgical excision and adjuvant chemotherapy and radiotherapy. The patients in this study were treated according to the European Ewing regimen, specifically Arm A, which consists of VIDE (vincristine, ifosfamide, doxorubicin, and etoposide) induction therapy followed by VAC (vincristine, actinomycin D, and cyclophosphamide) consolidation therapy.
This study was approved by the Hacettepe University Non-interventional Clinical Research Ethics Board (approval no.: 2022/22-10, date: 27.12.2022).
Statistical Analysis
The statistical analyses were performed with SPSS software (version 22.0). Two-tailed p-values <0.05 were considered statistically significant. Continuous variables are presented as median (interquartile range-IQR) because of their non-normal distribution.
Results
A total of 15 children (10 female, 5 male) were diagnosed with PNET/Ewing sarcoma of the chest wall during the study period. The median age of the patients was 10 (8-14) years. The presenting symptoms were palpable mass in 6 cases, chest pain in 4, B symptoms in 2, cough in 2 and abdominal pain in one patient. History revealed delayed diagnosis in 1/3 of the patients due to misinterpretations of the symptoms. At the time of diagnosis, 12 patients had positron emission tomography computed tomography which showed long bone metastasis in 3, lymph node metastasis in one and bone marrow infiltration in another patient. Fluorodeoxyglucose uptake limited to the primary tumor was the case in 7 patients. Median greatest diameter of mass at diagnosis was 100 (67-148) mm and 51 (39-100) mm at preoperative imaging after chemotherapy. The mass was located posteriorly in 8, laterally in 6 and anteriorly in one patient (Table I). Imaging studies revealed costal destruction in 9 cases (Figure 1), pleural effusion in 8, pulmonary or diaphragmatic involvement in 5 and extension to neural foramina in 3 patients. All of the children except one had tru-cut biopsy at the time of diagnosis and received upfront chemotherapy. More than one surgery was performed on 9 (60%) children in order to remove the primary tumor, its metastases or recurrences. Costal resection was carried out in 11 patients and the median number of resected ribs was 3 (1-3). The chest wall was reconstructed with ePTFE graft material in 8 out of the 11 patients who had more than one costal excision. To ensure en bloc resection, pulmonary tissue adjacent to the tumor was resected in 8 cases and diaphragmatic resection was performed in 6 cases. In all cases, gross total resection without macroscopic residue was achieved. The postoperative period was uneventful and the median hospital stay was 7 (6-10) days. Pathologic examination of the resected tumor showed diffuse histologic changes secondary to treatment in 11 patients and >95% necrosis in 5 individuals. Surgical margins were positive in 10 patients. FISH study was positive for Ewing sarcoma breakpoint region 1 (EWSR1) translocation in 10 out of 11 patients.
All cases received radiotherapy and chemotherapy in the postoperative period. The mortality rate was 60%. The cause of death was distant metastasis in 5, local recurrences in 3 and secondary leukemia in one patient. Only 3 children reached 5-year survival and were considered to be cured. The remaining 3 patients completed their treatment and were under close surveillance. There were no long-term complications such as scoliosis or posture abnormality in those patients who survived the disease.
Discussion
Malignant tumors arising from the chest wall are very rare in childhood and Ewing sarcoma/PNET is the most common diagnosis in these patients. They arise from bony structures, muscles or connective tissue but tend to grow in an infiltrative pattern affecting various tissues. The main surgical aim should be total resection without macroscopic residue as in all cases of sarcomas (1). Due to these features, surgery involves the resection of different tissues and the reconstruction of a functioning chest wall. Experience is limited in this patient group since they constitute only 2% of childhood malignancies (4). We reviewed our experiences in the management of EFT arising from the chest wall in children.
EFT at the time of diagnosis are usually huge in diameter with costal, pleural, muscular, adjacent pulmonary or diaphragmatic invasion and extension to spinal foramen. Surgical resection should be deferred until after the induction chemotherapy (5). Treatment-induced size reduction may allow for less extensive resection and a higher rate of negative margins. A fifty percent reduction in the greatest diameter was achieved with neoadjuvant chemotherapy in our patients. This finding was compatible with previous data (2, 4). In addition, chemotherapy should be employed upfront to treat occult metastatic foci and circulating tumor cells (3).
Surgical resection and the reconstruction of the chest wall is a formidable challenge in children. Their growing body size and long life expectancy distinguish children from adults. There are various materials which can be employed to cover defects in the chest wall when we resect components of the chest wall neighboring a tumor. There are synthetic, biologic and metallic prosthetic materials which are used to cover defects in the chest wall and each have different properties (4-6). In cases of malignant tumor resection, the graft material should be compatible with radiotherapy, suitable for re-entrance for surgery since these tumors tend to recur and possess some amount of flexibility in order to adapt to a growing thoracic wall (5-7). We prefer ePTFE mesh in our practice. It integrates well into the thoracic wall showing minimal tissue reaction. Also, all patients had radiotherapy on the surgical field in the postoperative period. Scoliosis is a well-known long-term complication in patients with chest wall resection (8). Due to the low life expectancy and complete cure rates in our group, we could not deduce any statistically significant information regarding this issue.
The risk of local recurrence and distant metastasis remains high in the EFT despite advances in all aspects of oncologic treatments. Histologic response to neoadjuvant chemotherapy is an indicator of prognosis in these patients. Good histologic response is defined by the degree of necrosis and >95% is generally acceptable (3). We observed this amount of necrosis in only 1/3 of our patients and assumed that it was one of the major contributors to the high mortality rate in our cohort. Another issue is to achieve negative surgical margins in sarcoma patients (3). Even though aggressive surgical resection involving the full thickness of the chest wall, pulmonary and diaphragmatic resections, the surgical margins were positive microscopically in the majority of our patients which implies a high possibility of local recurrence. The posteriorly location of the tumor and a tumor diameter >10 cm at diagnosis are associated with poor prognosis (1, 9). More than half of our patients had posteriorly located tumors and >10 cm diameter at the time of diagnosis. The largest study regarding the outcome in Ewing sarcoma and PNET including 3,575 patients derived from the SEER database revealed a 5-year survival rate of slightly above 50%. However, this cohort included cases of all anatomic locations, not just exclusive to the chest wall (2).
Study Limitations
Main limitation of our study was its small sample size. Multi-centric studies should be designed in order to recruit more patients in such rare tumors of children.
Conclusion
The EFT located in the chest wall are rare tumors in childhood with infiltrative growth patterns. Although they respond well to chemotherapy and radiotherapy, their clinical behavior is usually aggressive. With neoadjuvant chemotherapy, tumors shrink in most cases. Surgical management involves extensive resection of the chest wall components, lung and/or diaphragm and the reconstruction of the defect with graft material. Despite total resection, negative surgical margins are seldom reached. Local recurrences and metastasis are associated with poor prognosis. Multicenter studies should be planned in order to better understand the nature of this rare patient group.