Neuroblastoma is the most common extracranial solid tumor diagnosed in children. This inaugural version of the NCCN Guidelines for Neuroblastoma provides recommendations for the diagnosis, risk classification, and treatment of neuroblastoma. The information in these guidelines was developed by the NCCN Neuroblastoma Panel, a multidisciplinary group of representatives with expertise in neuroblastoma, consisting of pediatric oncologists, radiologists, pathologists, surgeons, and radiation oncologists from NCCN Member Institutions. The evidence-based and consensus recommendations contained in the NCCN Guidelines are intended to guide clinicians in selecting the most appropriate treatments for their patients with this clinically heterogeneous disease.

Neuroblastoma is the most common extracranial solid tumor diagnosed in children. This inaugural version of the NCCN Guidelines for Neuroblastoma provides recommendations for the diagnosis, risk classification, and treatment of neuroblastoma. The information in these guidelines was developed by the NCCN Neuroblastoma Panel, a multidisciplinary group of representatives with expertise in neuroblastoma, consisting of pediatric oncologists, radiologists, pathologists, surgeons, and radiation oncologists from NCCN Member Institutions. The evidence-based and consensus recommendations contained in the NCCN Guidelines are intended to guide clinicians in selecting the most appropriate treatments for their patients with this clinically heterogeneous disease.

Background: Management of small lymph nodes or lesions in dense nodal basins found on Positron Emission Tomography (PET) scans can be challenging to identify, access and locate intraoperatively. Herein we describe the first reported case series utilizing pre-operative CT-guided radionuclide-tagged macro-aggregated albumin (TC 99m MAA) for localization and resection of extra-pulmonary PET-avid lymph nodes in pediatric cancer patients. Methods: Pediatric cancer patients (<21 years) who underwent pre-operative TC 99m MAA localization of suspicious lymph nodes were identified and retrospectively reviewed.Results: Ten procedures were performed on 10 children at our institution from 2017 to 2021. Median age was 14 [13, 18]; 70% were male. Primary tumor type was variable. Lymph nodes were in various nodal basins including the axilla, groin, neck, popliteal fossa, retroperitoneum, and mediastinum. Three patients underwent resection of both pulmonary and extra-pulmonary lesions during the same procedure. Median node size was 15 mm (range: 10 mm-23 cm). In 60.0% of patients the localized lymph nodes of concern were non-palpable at the time of operation. In 90% of the patient, biopsy findings changed the course of disease management.Conclusion: Pre-operative labeling with TC 99m MAA is a safe and effective technique to facilitate the localization, biopsy, and resection of suspicious lymph nodes found on PET scans in pediatric cancer patients that are located in dense nodal basins. This technique enables accurate resection of small, concerning lymph nodes that might otherwise be difficult to operatively identify and excise; the resultant information can affect the staging and further treatment of these patients. Level of evidence: IV.& COPY; 2022 Elsevier Inc. All rights reserved.

PURPOSE Monoclonal antibodies directed against insulin-like growth factor-1 receptor (IGF-1R) have shown activity in patients with relapsed Ewing sarcoma. The primary objective of Children's Oncology Group trial AEWS1221 was to determine if the addition of the IGF-1R monoclonal antibody ganitumab to interval-compressed chemotherapy improves event-free survival (EFS) in patients with newly diagnosed metastatic Ewing sarcoma. METHODS Patients were randomly assigned 1:1 at enrollment to standard arm (interval-compressed vincristine/doxorubicin/cyclophosphamide alternating once every 2 weeks with ifosfamide/etoposide = VDC/IE) or to experimental arm (VDC/IE with ganitumab at cycle starts and as monotherapy once every 3 weeks for 6 months after conventional therapy). A planned sample size of 300 patients was projected to provide 81% power to detect an EFS hazard ratio of 0.67 or smaller for the experimental arm compared with the standard arm with a one-sided α of .025. RESULTS Two hundred ninety-eight eligible patients enrolled (148 in standard arm; 150 in experimental arm). The 3-year EFS estimates were 37.4% (95% CI, 29.3 to 45.5) for the standard arm and 39.1% (95% CI, 31.3 to 46.7) for the experimental arm (stratified EFS-event hazard ratio for experimental arm 1.00; 95% CI, 0.76 to 1.33; 1-sided, P = .50). The 3-year overall survival estimates were 59.5% (95% CI, 50.8 to 67.3) for the standard arm and 56.7% (95% CI, 48.3 to 64.2) for the experimental arm. More cases of pneumonitis after radiation involving thoracic fields and nominally higher rates of febrile neutropenia and ALT elevation were reported on the experimental arm. CONCLUSION Ganitumab added to interval-compressed chemotherapy did not significantly reduce the risk of EFS event in patients with newly diagnosed metastatic Ewing sarcoma, with outcomes similar to prior trials without IGF-1R inhibition or interval compression. The addition of ganitumab may be associated with increased toxicity.

BACKGROUND:To determine outcomes of children with rhabdomyosarcoma (RMS) with isolated lung metastases. METHODS:Data were analyzed for 428 patients with metastatic RMS treated on COG protocols. Categorical variables were compared using Chi-square or Fisher's exact tests. Event-free survival (EFS) and overall survival (OS) were estimated using Kaplan-Meier method and compared using the log-rank test. RESULTS:Compared with patients with other metastatic sites (n = 373), patients with lung-only metastases (n = 55) were more likely to be <10 years of age, have embryonal histology (embryonal rhabdomyosarcoma), have N0 disease, and less likely to have primary extremity tumors. Lung-only patients had significantly better survival outcomes than patients with all other sites of metastatic disease (p < .0001) with 5-year EFS of 48.1 versus 18.8% and 5-year OS of 64.1 versus 26.9%. Patients with lung-only metastases, and those with a single extrapulmonary site of metastasis, had better survival compared with patients with two or more sites of metastatic disease (p < .0001). In patients with ERMS and lung-only metastases, there was no significant difference in survival between patients ≥10 years and 1-9 years (5-year EFS: 58.3 vs. 68.2%, 5-year OS: 66.7 vs. 67.7%). CONCLUSIONS:With aggressive treatment, patients with ERMS and lung-only metastatic disease have superior EFS and OS compared with patients with other sites of metastatic disease, even when older than 10 years of age. Consideration should be given to including patients ≥10 years with ERMS and lung-only metastases in the same group as those <10 years in future risk stratification algorithms.

The Children's Oncology Group (COG) uses Clinical Group (CG) and modified Tumor Node Metastasis (TNM) stage to classify rhabdomyosarcoma (RMS). CG is based on surgicopathologic findings and is determined after the completion of initial surgical procedure(s) but prior to chemotherapy and/or radiation therapy. The modified TNM stage is based on clinical and radiographic findings and is assigned prior to any treatment. These systems have evolved over several decades. We review the history, evolution, and rationale behind the current CG and modified TNM classification systems used by COG for RMS. Data from the seven most recently completed and reported frontline COG trials (D9602, D9802, D9803, ARST0331, ARST0431, ARST0531, ARST08P1) were analyzed, and confirm that CG and modified TNM stage remain relevant and useful for predicting prognosis in RMS. We propose updates based on recent data and discuss factors warranting future study to further optimize these classification systems.

PURPOSE:Fertility is a quality of life outcome adversely affected by cancer therapy. Many childhood cancer patients, however, are not offered options to preserve their fertility. Providers acknowledge difficulty discussing impaired fertility to patients due to lack of knowledge of available options. Our objective was to review the impact of a pediatric multidisciplinary fertility preservation program on providers' fertility preservation counseling and discussion of options. METHODS:A retrospective medical chart review was conducted for pediatric cancer patients prior to and following program establishment. Fertility preservation discussions, consults, and incidence were noted. Following filtering and stratification, 198 and 237 patients were seen prior to and following program establishment, respectively. RESULTS:Following program establishment, provider-patient discussions of impaired fertility (p = 0.007), fertility preservation consults (p = 0.01), and incidence of fertility preservation procedures (p < 0.001) increased among patients. Furthermore, the number of patients who received fertility preservation consults after receiving gonadotoxic treatment decreased (p < 0.001). This trend was particularly noted in pre-pubertal and female patients, for whom fertility preservation options are limited without an established program. CONCLUSION:The establishment of a formal program greatly improved access to fertility preservation consults and procedures in children with cancer.

Study ObjectivesTo describe the structure of a pediatric fertility preservation (FP) program and to share safety and patient satisfaction data.DesignThe FP program operates under prospective research protocols approved by the Mayo Clinic Institutional Review Board (IRB).SettingThe FP program is a multidisciplinary effort between pediatric gynecology, reproductive endocrinology, pediatric urology, pediatric surgery, and laboratory medicine.ParticipantsThe FP program enrolls patients between 0-17 years of age who have been diagnosed with a fertility-threatening condition and/or are scheduled to undergo gonadotoxic treatment.InterventionsFP is offered in the form of ovarian tissue cryopreservation (OTC) and testicular (TTC) tissue cryopreservation.Main Outcome MeasuresThe outcome measures are the safety of the procedure and results of patient surveys conducted by phone using a standard list of questions to assess attitudes towards FP.ResultsTo date, we have enrolled 38 OTC and 37 TTC patients. The median age (range) of OTC and TTC patients was 11 years (0.83-17 years) and 10 years (0.92-17 years) at the time of enrollment, respectively. Childhood cancers currently represent 88% of the fertility-threatening diagnoses. Meanwhile, patients with non-malignant conditions include those with gender dysphoria, aplastic anemia, and Turner's syndrome. To date, no serious adverse events (SAEs) have been reported following surgery. According to n = 34 one-year follow-ups, 100% of parents felt that FP was a good decision.ConclusionConsistent with the literature, our data suggests FP is safe and improves the quality of care provided to pediatric patients for their fertility-threatening diagnoses and/or treatments.Trial RegistrationNCT02872532, NCT02646384.

Study Objective Rhabdomyosarcomas (RMSs) of the female genital tract (FGT) have been recently shown to be associated with germline pathogenic variation in DICER1, which can underlie a tumor predisposition disorder. We sought to determine the incidence of a pathogenic variation in DICER1 in a cohort of RMSs of the FGT, as well as to evaluate the clinicopathological features and outcomes of the patients. Design, Setting, Participants, Interventions, and Main Outcome Measures We retrospectively reviewed medical records of the patients diagnosed with RMS of the FGT between 1990 and 2019. Molecular genetic sequencing of the tumor to detect an RNase IIIb domain hot spot mutation in DICER1 samples was performed in 7 patients. Individuals with a missense mutation in the tumor were also screened for a loss of function germline mutation in DICER1. Results Of 210 cases of pediatric RMS, 11 arose from the FGT. Molecular genetic sequencing of the tumor samples revealed a somatic missense mutation in the RNase IIIb domain of DICER1 in a total of 3 patients, 2 patients with embryonal RMS of the cervix/uterus, and 1 patient with ovarian embryonal RMS. As a result of genetic testing for the loss of function germline mutation in DICER1, a heterozygous pathogenic variant was also found in 2 of these patients. Conclusion Despite the limited number of patients, our findings suggest that it is important to be aware of the possible association between RMS of FGT and pathogenic germline DICER1 variants because the detection of this mutation in a patient or relatives can provide the opportunity for surveillance of related conditions that might improve long-term outcomes and survival.

Hereditary thrombotic thrombocytopenic purpura is an ultra-rare disorder caused by biallelic mutations in the ADAMTS13 gene. Because it can be difficult to diagnose, plasma ADAMTS13 activity assessment should be considered in patients with thrombocytopenia, anemia, and schistocytes on peripheral blood smear. We present the diagnostic evaluation of a patient with hereditary thrombotic thrombocytopenic purpura. Genetic testing revealed one known pathogenic mutation and one novel mutation of ADAMTS13 classified as likely pathogenic on the basis of parental genetic testing and in silico analyses. We further discuss off-label use of prophylactic plasma-derived Factor VIII (Koate-DVI) and the benefit of rare disease registries.

Paratesticular rhabdomyosarcoma (PT-RMS) carries a favorable prognosis, but questions persist regarding optimal management. Our goal was to determine the importance of primary tumor resection and surgical assessment of retroperitoneal lymph nodes during staging in patients with PT-RMS. We analyzed patients with localized PT-RMS enrolled onto one of four Children's Oncology Group studies (D9602, ARST0331, D9803 or ARST0531). Surgical resection of the primary tumor prior to chemotherapy and radiotherapy was encouraged when possible with retroperitoneal lymph node dissection (RPLND) recommended for patients >= 10 years of age. Among 279 patients (median 8.1 years old), most tumors were resected with negative margins (78.5%) and most patients did not have radiographic enlargement of regional lymph nodes (90.3%). In patients older than 10 years, imaging alone will miss over 51.5% of nodal disease. Five-year event-free survival (EFS) was 92.0% (95% CI 88.4%-95.6%). Sampling >= 7 to 12 retroperitoneal lymph nodes appeared optimal for detecting positive nodes; while there was a trend toward improved EFS among those undergoing template RPLND, this was not statistically significant (P= .068). Age (P= .28), N-stage (P= .39), T-stage (P= .11) and pathologic node involvement (P= .53) were not associated with overall survival. However, older age and larger tumor size had an additive impact on EFS (P= .027) though not overall survival (P= .13). In conclusion, outcomes for patients with PT-RMS are excellent. Reliance on imaging to detect nodal involvement will miss pathologic node involvement and may result in undertreatment. Surgical nodal staging requires at least 7 to 12 nodes to accurately identify patients with regional nodal disease.

The first large multi-institutional trial in children and adolescents less than 21 years of age with rhabdomyosarcoma (RMS) and undifferentiated soft-tissue sarcoma (UDS) was planned by members of the Children’s Cancer Study Group A (CCSGA) in North America, under the leadership of Denman Hammond, MD, Group Chairman, and led by Ruth M. Heyn, MD. This study included pediatric oncologists in the United States and Canada and was composed of physicians specializing in surgery, pathology, radiation oncology, hematology/oncology, and statisticians. The rationale and results were published in two successive articles. The first part of the study, opened in 1967, was to answer this randomized question: would the addition of chemotherapy with dactinomycin (actinomycin D, denoted by A) and vincristine (VA) to surgery (S) and radiation therapy (RT) for patients with newly diagnosed RMS and UDS who had undergone complete removal of localized disease result in a more favorable outcome, compared to those who underwent only local therapy without VA chemotherapy? Finding a statistically significant improvement in disease-free survival with the addition of VA led to the conclusion that all young patients with RMS and UDS should receive chemotherapy for 1 year along with local treatments (Heyn et al. 1974). The second part of the study, later amended to include oral cyclophosphamide (C, collectively called VAC), opened in 1970 for patients with localized disease, grossly removed, with pathologically demonstrable microscopic residual tumor, patients with localized disease and grossly visible tumor after biopsy or subtotal resection, and those with distant metastases at diagnosis. The results were 3-year survival rates of 70.8%, 43.2%, and 27.2%, respectively (Heyn et al. 1977). The addition of C to VA did not result in a significantly improved survival rate compared to patients with the same amounts of residual disease in the first study (Heyn et al. 1974).

10538 Background: Rhabdomyosarcoma (RMS) of the female genital tract is rare, accounting for 3.5% of cases of rhabdomyosarcomas. Germline DICER1 mutations are associated with predisposition to pleuropulmonary blastoma and other tumors including sarcomas. Recently DICER1-associated RMS of the uterus/ovary has ben reported.. The aim of this study is to evaluate demographic characteristics, molecular pathogenesis, treatment and long term outcome of female genital tract rhabdomyosarcoma. Methods: Files of children with RMS of the female genital tract diagnosed at the Istanbul University, Oncology Institute during 1990-2019 were reviewed. Molecular genetic sequencing was performed by polymerase chain reaction amplification of genomic DNA extracted from the formalin-fixed, paraffin embedded tumors, followed by Sanger sequencing. Genetic testing for DICER1 variants of the proband and family members was performed if DICER1 mutation was detected in the tumor of the proband. Results: Of 210 RMS cases, 11 arose from the female genital tract. The median age at diagnosis was 52 months (10 months-15 years). Primary sites were vaginal (n = 5), uterus (n = 4), and ovary(n = 2). Presenting symptoms included vaginal mass (n = 6), vaginal bleeding (n = 5), and abdominal pain (n = 3). Four had group 1, five group 3, two group 2 disease and all received chemotherapy (vincristine, actinomycinD + cyclophosphamide).Three received radiotherapy; three underwent hysterectomy. DICER1 mutation was detected in tumor tissue in three patients:[ c.5113G > A (p.E1705K); c.5428G > T (p.D1810Y); c.1870C > T (p.Arg624Ter)] Genetic testing revealed germline DICER1 pathogenic variation in two patients and their family members, one of whom had cystic nephroma in infancy and history of Wilms tumor in an uncle. They were referred for surveillance for the DICER1 related diseases. A patient with metachronous bilateral ovarian RMS died. Two are married, one has children. The 5 year survival for RMS of the female genital tract was 85.7 % at a median follow-up of 34 (4-298) months. Conclusions: Rhabdomyosarcoma of the female genital tract is associated with a favorable prognosis, however some individuals undergo aggressive local therapies. Individuals with RMS of the female genital tract should be tested for DICER1 pathogenic variation. The detection of a DICER1 mutation in an individual or family members is important to facilitate surveillance for related tumors, so that they may be detected at the earliest possible stage, potentially increasing survival and decreasing risks of late effects.

Soft tissue sarcoma comprises 7.4% of childhood soft tissue malignancies with rhabdomyosarcoma (RMS) being the most common soft tissue sarcoma in children. RMS can arise in virtually any site in the body. Presenting symptoms depend on the site of origin of the tumor and can range from urinary obstruction or constipation in patients with pelvic or bladder/prostate tumors to proptosis in patients with orbital RMS, sinusitis symptoms in patients with parameningeal/sinus tumors, or a painless mass in extremity tumors. In North America there are about 350 new cases of RMS in children annually, with a similar number of new cases in Europe. The staging system for rhabdomyosarcoma has already been discussed in Chap. 5 and will not be repeated here. Risk stratification has evolved over the past several decades. Meza and colleagues analyzed patient and disease characteristics of patients with nonmetastatic RMS treated on the third and fourth Intergroup Rhabdomyosarcoma Studies and identified the prognostic significance of histology (alveolar (ARMS) and embryonal RMS (ERMS)), stage, group, and primary site (Meza et al. 2006) and resulted in stratification of patients into two low risk, one intermediate risk, and one high risk group for North American studies from 1997 to 2004. In Europe ongoing protocols use IRS Group, histology, patient age, primary tumor site, and size and nodal involvement to assign patients into four groups: low risk, standard risk, high risk, and very high risk. A multivariate analysis of risk factors in 788 patients with metastatic RMS treated in nine studies in Europe and North America from 1984 to 2000 identified age under 1 year or older than 10, unfavorable site of primary tumor, presence of three or more sites of metastatic disease, and presence of bone or bone marrow involvement as being correlated with inferior event-free survival (EFS) (Oberlin et al. 2008).Risk group assignment for therapy differs between European and North American trials, so comparison of outcomes for clinical trials needs to take this into consideration. For example, in the European trials, positive lymph nodes in patients with unfavorable histology and Group III tumors result in assignment of patients to very high-risk therapy, whereas they are treated as intermediate risk on Children’s Oncology Group (COG) trials. Many other COG “intermediate-risk” patients on the “D” series of studies were considered in European Pediatric Soft Tissue Sarcoma Group (EpSSG) or Cooperative Weichteilsarkom Studie (CWS) to be “high risk” (Sultan and Ferrari 2010).

Epithelial marker expression and/or epithelial differentiation, as well as "anomalous" expression of keratins, are features of some soft tissue tumors. Recently, we have encountered an unusual mesenchymal tumor composed of bland, distinctly eosinophilic, keratin-positive epithelial cells, which were almost entirely obscured by xanthogranulomatous inflammation. Six cases were identified (5 F, 1 M; 16–62 years (median 21 years)) arising in soft tissue (n = 4) and bone (n = 2) and ranging in size from 2 to 7 cm. The tumors were generally circumscribed, with a fibrous capsule containing lymphoid aggregates, and consisted in large part of a sheet-like proliferation of foamy histiocytes, Touton-type and osteoclast-type giant cells, and chronic inflammatory cells. Closer inspection, however, disclosed a distinct population of uniform, cytologically bland mononuclear cells with brightly eosinophilic cytoplasm arranged singly and in small nests and cords. Overt squamous and/or glandular differentiation was absent. By immunohistochemistry, these cells were diffusely positive with the OSCAR and AE1/AE3 keratin antibodies, and focally positive for high-molecular weight keratins; endothelial and myoid markers were negative and SMARCB1 was retained. RNA-seq identified a PLEKHM1 variant of undetermined significance in one case, likely related to this patient's underlying osteopetrosis. Follow-up to date has been benign. In summary, we have identified a novel tumor of soft tissue and bone with a predilection for young females, provisionally termed "xanthogranulomatous epithelial tumor". These unusual lesions do not appear to arise from adnexa, or represent known keratin-positive soft tissue tumors, and the origin of their constituent epithelial cells is obscure. The natural history of this distinctive lesion appears indolent, although study of additional cases and longer term follow-up are needed.

Staging of soft tissue sarcoma, Ewing sarcoma, and osteosarcoma involves MRI of the primary tumor, computed tomography of the chest, and, in the case of Ewing Sarcoma and rhabdomyosarcoma, evaluation of the bone marrow. FDG PET imaging, when available, is replacing technetium bone scanning for evaluation of metastatic disease in sarcomas and is being investigated to determine response to treatment and prognosis. Staging and risk assignment for rhabdomyosarcoma (RMS) have undergone significant evolution since the original description of the clinical group assignment and modified TNM system. The next generation of RMS studies in the Children’s Oncology Group will use fusion status instead of histologic determination for treatment assignment. For selected low-risk patients, some staging studies can be omitted. There remain some differences in risk and treatment assignment between the European Pediatric Soft Tissue Sarcoma Group and the Children’s Oncology Group.

BACKGROUND Vertebra plana in children is a diagnostic dilemma for orthopaedic surgeons. This radiographic finding sometimes has been said to be pathognomonic for eosinophilic granuloma (Langerhans cell histiocytosis); however, vertebra plana may also be caused by a range of other conditions. We sought to determine whether vertebra plana can be associated with malignancies other than eosinophilic granuloma. QUESTIONS/PURPOSES (1) To report the underlying diagnoses for children with vertebra plana and determine how frequently these patients were found to have eosinophilic granuloma as opposed to an underlying malignant process, (2) to evaluate the occurrence of nondiagnostic results on biopsy, and (3) to determine whether the presenting characteristics of spinal lesions were associated with the ultimate clinical diagnosis. METHODS As part of a retrospective review, our institutional electronic medical record was searched for all patients younger than 18 years between 1976 and 2017 whose clinical record included the term vertebra plana. Patients with trauma were excluded. Twenty-seven patients met the inclusion criteria (mean [range] age 9 years [0 to 18]; 12 girls). To address our first research purpose about the underlying diagnoses of patients with vertebra plana, we reviewed the final clinical diagnosis. To address our second research purpose about the utility of biopsy, we reviewed which patients underwent a biopsy and whether it had been diagnostic. To address our third research purpose about the radiographic criteria, we classified the radiographs and compared this to the clinical diagnosis. Vertebral collapse was described as less than 50% collapse, 50% to 100% collapse, symmetrical, and asymmetrical. The location of each lesion was noted. RESULTS Twelve of 27 patients had a diagnosis of eosinophilic granuloma. Six of 27 had other neoplastic etiologies, including acute lymphoblastic leukemia, primary germ cell tumor, giant cell tumor, rhabdomyosarcoma and teratoma. Seventeen of 27 patients underwent biopsy to confirm the diagnosis; six biopsies were consistent with eosinophilic granuloma, six for other etiologies, and five were nondiagnostic. With the limited patient numbers available, there was no difference in the frequency of less than 50% loss of height or 50% to 100%, or symmetric and asymmetric loss of height, and location of the lesion among patients with eosinophilic granuloma and those with other diagnoses. CONCLUSIONS Eosinophilic granuloma or Langerhans cell histiocytosis is a common cause of vertebra plana, but other causes must be considered in children presenting with this radiographic finding. Six of 27 of patients presenting to our center with vertebra plana had an underlying neoplasm other than eosinophilic granuloma. With the limited patient numbers available, pain, spinal location, and the degree and symmetry of collapse were not associated with a diagnosis of eosinophilic granuloma in this series. Thus, patients presenting with vertebral plana and back pain need a comprehensive work-up and potentially tissue biopsy to determine diagnosis and appropriate treatment. LEVEL OF EVIDENCE Level IV, diagnostic study.