Equivocal end-of-therapy imaging findings do not predict a higher risk of local relapse after definitive radiotherapy in pediatric Ewing sarcoma and rhabdomyosarcoma.

BACKGROUND: Posttherapy imaging studies can provide reassurance or induce anxiety regarding risk of recurrence for patients and their families. In some cases, it is difficult to determine if imaging findings represent posttreatment changes or residual disease. Equivocal radiographic findings can occur due to therapy-related inflammation or residual, inactive soft tissue masses, but it is unknown if such findings indicate an increased likelihood of local recurrence. The aim of this study was to assess the value of initial posttherapy scans for predicting local relapse in patients with Ewing sarcoma (EWS) or rhabdomyosarcoma (RMS) who received radiotherapy (RT) for local control. These findings are critical to inform clinicians' surveillance recommendations and ability to accurately counsel patients and their families. PROCEDURE: The primary endpoint was time to local progression (LP). Patients were classified as having posttherapy scans that were "positive" (residual disease within the RT field), "negative" (no evidence of residual disease within the RT field), or "equivocal" (no determination could be made). The value of initial posttreatment scans for predicting LP was assessed using positive predictive value (PPV) and negative predictive value (NPV). RESULTS: Negative imaging findings (n = 51) had an NPV of 88%, and positive imaging findings (n = 1) had a PPV of 100%. When equivocal findings (n = 16) were categorized with negative results (i.e., positive vs. equivocal/negative), the NPV was 90%. When equivocal findings were categorized with positive results (equivocal/positive vs. negative), the PPV was 12%. CONCLUSION: Equivocal findings within the RT field on end-of-therapy imaging studies indicate no higher risk of local recurrence than negative findings. These results may contribute to appropriate surveillance schedules and accurate counseling of patients with RMS and EWS who have received RT for local control.

Extrarenal, Soft Tissue Malignant Rhabdoid Tumor Arising in the Mons Pubis.

Extrarenal, extracranial malignant rhabdoid tumors (MRT) are uncommon malignancies with poor prognoses that may be diagnostically challenging. Reports of soft tissue MRTs in children are rare. For this reason, there are no standard treatment protocols. Historically, an aggressive multimodal approach has been taken. Here, we present a case of metastatic superficial pelvic MRT in a 16-year-old girl who remains disease-free after aggressive multi-modal therapy.

Aggressive Multimodality Therapy for a Urachal Rhabdomyosarcoma.

Urachal rhabdomyosarcoma is a rare entity with a remarkably poor prognosis. Here we report on a 2-year-old male who presented with abdominal pain, fatigue, and urinary frequency. Imaging and subsequent surgical pathology confirmed urachal primary embryonal rhabdomyosarcoma. Our patient underwent upfront surgical resection with adjuvant chemoradiation per Children's Oncology Group protocol D9803. He is doing well 15 months after diagnosis.

Brachytherapy in children, adolescents, and young adults: An underutilized modality in the United States?

BACKGROUND: Brachytherapy (BT) delivers highly conformal radiation and spares surrounding tissues, which may limit late effects in pediatric, adolescent, and young adult (AYA) patients. We aimed to characterize trends in BT use for this population in the United States, focusing on patients with rhabdomyosarcoma (RMS). METHODS: The National Cancer Database was queried to identify patients ≤ 21 who were treated for solid tumor malignancies in the United States from 2004 to 2016. We obtained disease, treatment, and outcome data for patients treated with BT, in particular for RMS. RESULTS: 99 506 pediatric and AYA patients met study inclusion. Of these, 22 586 (23%) received radiation therapy (external beam radiation therapy [EBRT] and/or BT) and 240 (0.2%) received BT. Among patients treated with BT, 139 (58%) underwent surgery and 58 (24%) received EBRT. A total of 3836 patients were treated for RMS during this period. Of these, 2531 (66%) received any radiation and 37 (1%) received BT (EBRT + BT in 3, BT in 34). Of patients treated with BT for RMS, 28 (76%) underwent surgery + BT. Survival data were available for 31 patients treated with BT for RMS. With a median follow-up of 63 months, overall survival was 100% for patients with RMS of a favorable site treated with BT. CONCLUSIONS: BT is rarely used to treat pediatric and AYA patients in the United States. Patients treated with BT for RMS experienced favorable survival, suggesting that this approach may not compromise oncologic outcomes and warrants further study as a therapeutic option in pediatric and AYA patients, specifically in RMS.

Circulating Plasma Tumor DNA Is Superior to Plasma Tumor RNA Detection in Ewing Sarcoma Patients: ptDNA and ptRNA in Ewing Sarcoma.

The detection of tumor-specific nucleic acids from blood increasingly is being used as a method of liquid biopsy and minimal residual disease detection. However, achieving high sensitivity and high specificity remains a challenge. Here, we perform a direct comparison of two droplet digital PCR (ddPCR)-based detection methods, circulating plasma tumor RNA and circulating plasma tumor DNA (ptDNA), in blood samples from newly diagnosed Ewing sarcoma patients. First, we developed three specific ddPCR-based assays to detect EWS-FLI1 or EWS-ERG fusion transcripts, which naturally showed superior sensitivity to DNA detection on in vitro control samples. Next, we identified the patient-specific EWS-FLI1 or EWS-ERG breakpoint from five patient tumor samples and designed ddPCR-based, patient-specific ptDNA assays for each patient. These patient-specific assays show that although plasma tumor RNA can be detected in select newly diagnosed patients, positive results are low and statistically unreliable compared with ptDNA assays, which reproducibly detect robust positive results across most patients. Furthermore, the unique disease biology of Ewing sarcoma enabled us to show that most cell-free RNA is not tumor-derived, although cell-free-DNA burden is affected strongly by tumor-derived DNA burden. Here, we conclude that, even with optimized highly sensitive and specific assays, tumor DNA detection is superior to RNA detection in Ewing sarcoma patients.

Pediatric Metastatic Cardiac Angiosarcoma Successfully Treated With Multimodal Therapy: Case Report and Review of Literature.

Cardiac angiosarcoma (AS) is an extremely rare, malignant vascular tumor with <10 cases reported in the pediatric literature. Prognosis is dismal with overall survival often <1 year from initial diagnosis. In this report, we present the case of a 10-year-old boy with metastatic cardiac AS who is currently alive and is the longest pediatric survivor of metastatic cardiac AS reported in the literature. This is the only published pediatric case to successfully use a combination of surgical resection, conventional chemotherapy, radiation and targeted therapies including bevacizumab and pazopanib for metastatic cardiac AS.

Pediatric ovarian Sertoli-Leydig cell tumors with heterologous rhabdomyosarcoma elements: Clinical case series and review of the literature.

Sertoli-Leydig cell tumors (SLCTs) are rare ovarian neoplasms in pediatric patients. More exceedingly rare are SLCTs that also contain heterologous rhabdomyosarcoma (RMS) elements. For these patients, there is no standardized treatment. We report four cases of pediatric SLCT with heterologous RMS elements that were successfully treated with surgical resection and adjuvant chemotherapy. All four patients are alive and remain in remission.

Castleman disease in pediatrics: Insights on presentation, treatment, and outcomes from a two-site retrospective cohort study.

BACKGROUND: Castleman disease (CD) is an uncommon lymphoproliferative disorder that is rare in pediatric populations; the literature describing this population is sparse. We sought to describe pediatric CD, including unicentric CD (UCD) and human herpes virus-8 (HHV8)-negative multicentric CD (MCD), in a multi-institutional cohort. METHODS: We retrospectively reviewed 24 patients, aged 0 to 26 years at diagnosis, who were diagnosed with CD between January 1, 2005, and May 16, 2017, at two tertiary children's hospitals. Demographic and clinical data were collected. RESULTS: Most patients (75%, 18/24) presented with UCD. All patients with MCD were HHV8-negative. The most common histopathologic variant was hyaline vascular (75%, 18/24). Plasma cell variant occurred in 33% (2/6 [95% confidence intervals (CI), 4-78%]) of patients with HHV8-negative MCD and 17% (3/18 [95% CI, 4-41%]) of patients with UCD. Systemic symptoms were present in 4 of 6 of patients with HHV8-negative MCD and 8 of 18 of patients with UCD. Anemia and laboratory inflammation occurred in both UCD and MCD patients, with nonsignificantly higher rates of anemia and elevated C-reactive protein in MCD patients. All but two UCD patients underwent gross total resection as definitive therapy. Among HHV8-negative MCD patients, a combination of resection, chemotherapy, and immunotherapy was used. No UCD patients and three of six HHV8-negative MCD patients experienced disease progression/relapse prior to lasting remission. There were no deaths. CONCLUSION: Pediatric patients with CD most commonly have unicentric, hyaline vascular variant disease. Pediatric patients with both UCD and MCD commonly have systemic inflammation and, despite risk of progression/relapse in MCD patients, ultimately have excellent survival.

Central Nervous System Involvement of Rhabdomyosarcoma: A Single Institution Experience.

The incidence of central nervous system (CNS) involvement in patients with rhabdomyosarcoma (RMS) is low, and the outcome is dismal. We present a single institution analysis of CNS involvement of pediatric RMS. In 59 patients, the prevalence of CNS involvement was 11.9% (7 patients), higher than prior reports. Of the 6 deaths from disease, all had rapid progression, with a median survival of 14 days. The higher incidence could be secondary to treatment modifications or more sensitive detection. These findings are useful for decisions at the time of CNS involvement and could lead to modifications for future RMS clinical trials.

Pulmonary toxicity in paediatric patients with relapsed or refractory Hodgkin lymphoma receiving brentuximab vedotin.

Brentuximab vedotin (Bv) is becoming increasingly important in the treatment of Hodgkin lymphoma (HL), with improved outcomes and an overall favourable toxicity profile. However, Bv is associated with severe pulmonary toxicity when combined with bleomycin, suggesting that additive toxicity may be an important consideration. Furthermore, little has been published on tolerability in paediatric patients. We retrospectively evaluated the occurrence of pulmonary toxicity of Bv in 19 paediatric and young adult patients with relapsed or refractory HL. Patient characteristics, baseline health status, treatment regimens including cumulative doses of Bv, bleomycin, gemcitabine, radiation and carmustine, and the occurrence of pulmonary toxicity were collected. Seven (36·8%) of the 19 patients were treated with Bv. The odds of pulmonary toxicity were 4·0-fold higher (95% confidence interval 0·55-29·18) in patients exposed to Bv compared to unexposed patients in univariate analysis (P = 0·17). Similar results were found in multivariable analysis. Pulmonary toxicity occurred frequently in our cohort and was more common in patients who received Bv than in patients who did not receive Bv, although this was not statistically significant. Because patients with HL are exposed to a myriad of therapies with potential for pulmonary toxicity, continuing to evaluate the risk associated with Bv is critical.

Timing of Radiation Therapy in Pediatric Wilms Tumor: A Report From the National Cancer Database.

PURPOSE: To determine, using the National Cancer Database (NCDB), the impact of the surgery to radiation therapy interval (SRI) on survival in contemporary patients with Wilms tumor (WT). METHODS AND MATERIALS: The NCDB was queried for patients aged ≤25 years diagnosed from 2004 to 2013 with unilateral WT who underwent definitive surgery and radiation therapy. The SRI was calculated for each patient. A stratified analysis was performed based on presence of metastasis using logistic regression to calculate risk factors for prolonged SRI, with a focus on the recommended SRI according to recent Children's Oncology Group trials (by day 14) and National Wilms Tumor Study-5 (by day 9). Cox regression was performed to assess the association of SRI with overall survival. RESULTS: A total of 1488 patients were included; 32.1% had metastasis at diagnosis. Among both metastatic and nonmetastatic groups, older patients were more likely to have prolonged SRI. For those without metastasis, SRI > 14 days was associated with increased risk of mortality (hazard ratio 2.13, P = .013). Analyzing SRI as a continuous variable also demonstrated an increased risk of death with longer SRI (hazard ratio 1.04 per day, P = .006) in this group. In contrast, among patients with metastasis, no significant association between SRI and mortality was found. CONCLUSION: Early initiation of radiation therapy remains a critical component of multimodal treatment for patients with nonmetastatic WT. For nonmetastatic patients, SRI ≤ 14 days correlates with improved overall survival. However, no such association was noted for patients with metastases. These results may inform the development of future WT trials.

Metastatic angiosarcoma arising in malignant peripheral nerve sheath tumor in a young patient with neurofibromatosis type 1.

Neurofibromatosis type 1 (NF1) is a cancer predisposition syndrome with an incidence of approximately one in 3,000 and a lifetime risk of malignancy estimated at 8-13%. Here, we report the case of a patient with NF1 who developed synchronous malignant peripheral nerve sheath tumors, one with a focus of angiosarcoma. He succumbed to metastatic angiosarcoma despite local resection and adjuvant chemotherapy. This case highlights the need for monitoring for malignancy in NF1 patients, the risks of sampling error during tumor biopsy, and the clinical decision - making involved in choosing a therapeutic plan for a patient with multiple simultaneous malignancies.

Patterns of care and survival outcomes for adolescent and young adult patients with testicular seminoma in the United States: A National Cancer Database analysis.

INTRODUCTION: Testicular germ cell tumors (GCTs) are the most common solid tumor among adolescent and young adult (AYA) males. AYA patients with GCTs most typically have non-seminoma compared with seminoma, and accordingly there are fewer data reported on the AYA experience with testicular seminoma. OBJECTIVE: To evaluate national trends in postoperative treatment and overall survival (OS) outcomes in testicular seminoma by age group, specifically comparing AYAs with older adults. STUDY DESIGN: The National Cancer Data Base (NCDB) was queried for patients with testicular seminoma diagnosed between 2004 and 2012, who underwent orchiectomy followed by observation or adjuvant therapy (chemotherapy, radiation (RT), or both). Patients were grouped by age: AYA (15-39 years), adults between 40 and 55 years, and adults >55 years. Overall survival (OS) was presented using Kaplan-Meier curves and groups compared via a log-rank test. Univariate (UVA) and multivariate (MVA) analyses were performed using Cox proportional hazards regression models. Binary multiple logistic regression identified differences in variables by age category. RESULTS: Of the total 22,361 patients the majority were AYAs (12,880, 57.6%), followed by adults 40-55 years (8,022, 35.9%), and >55 years (1,459, 6.5%). Unadjusted 5-year OS was significantly better for AYAs versus adults 40-55 years and >55 years (98.0%, 96.4%, 87.7%; p < 0.001), as was 10-year OS (96.1%, 91.8%, 71.3% respectively; p < 0.001). The Table shows that on a MVA, OS was significantly better for AYAs versus adults 40-55 years and adults >55 years. AYA patients were also more commonly treated at centers with greater clinical volume. Additionally, AYA patients were less likely to present with metastatic disease. Accordingly, AYA patients were less likely to undergo retroperitoneal lymph node dissection (OR 0.81; p = 0.001) and were less often managed with adjuvant therapy including chemotherapy (OR 0.91; p = 0.027), RT (OR 0.93; p = 0.025), or both (OR 0.68; p = 0.020). DISCUSSION: AYA patients with testicular seminoma present with earlier stage disease and in the clinical Stage I setting are more often are managed with active surveillance following orchiectomy when compared with older adults in this population-based analysis. Among AYA patients, OS was modestly better when compared with adults 40-55 years and significantly better when compared with adults >55 years. CONCLUSION: Our objective to describe the patterns of care and survival outcomes for AYA patients with testicular seminoma in the USA was met by reviewing this large national dataset. These results may inform future guidelines for management of AYA seminoma.

Reliability of intraoperative frozen section for the diagnosis of renal tumors suspicious for malignancy in children and adolescents.

BACKGROUND: The ability of intraoperative frozen section (IFS) to reliably diagnose renal tumors in children and adolescents is largely unknown. The objective of our study is to evaluate the ability of IFS to establish a histologic diagnosis for renal tumors in this population. METHODS: We reviewed our experience with patients who underwent IFS at the time of surgery for a renal tumor suspicious for malignancy from 2005 to 2015. The IFS was compared to the final pathology (FP). Data on concordance and reliability were analyzed. RESULTS: One hundred thirty patients underwent surgical interventions for a renal tumor suspicious for malignancy, and 32 (25%) patients underwent IFS. Median turnaround time for IFS was 20 min (range 13-44). The histologic IFS diagnosis correlated with FP in 26 (81.2%) cases was discrepant in three (9.4%) cases, and IFS was deferred to FP in three (9.4%) cases (kappa 0.71, 95% confidence interval [CI]: 0.52-0.899, P < 0.001). The IFS correctly distinguished between Wilms tumor and non-Wilms tumor in 30 (94%) cases (kappa 0.874, 95% CI: 0.705-1, P < 0.001). A total of 17 of 19 (89.5%) Wilms tumors were correctly diagnosed by IFS, yielding a sensitivity of 0.89 (95% CI: 0.67-0.99) and a specificity of 1 (95% CI: 0.75-1). CONCLUSION: IFS is a reliable tool to establish a histologic diagnosis and to differentiate between Wilms and non-Wilms tumors in children and adolescents with renal tumors. The use of IFS should be encouraged in cases in which obtaining a diagnosis will provide guidance for important "real-time" medical decision making, specifically additional adjunctive surgical procedures.

Pathologic Risk Factors for Metastatic Disease in Postpubertal Patients With Clinical Stage I Testicular Stromal Tumors.

OBJECTIVE: To systematically review the existing literature to analyze the impact of previously identified pathologic risk factors on harboring occult metastatic disease (OMD) in patients with Clinical Stage I testicular stromal tumors (TSTs). MATERIALS AND METHODS: A literature search using PubMed was conducted using the following terms: "testicular stromal tumors," "testicular Leydig cell tumors," "testicular Sertoli tumors," "testicular interstitial tumors," "testicular granulosa tumor," and "testicular sex cord tumors." For analysis, we included only studies with data on available recurrence, survival, and time-to-event. We hypothesized that patients with ≥2 risk factors would experience lower 5-year OMD-free survival (OMDFS) than those with <2 risk factors. RESULTS: Two hundred ninety-two patients from 47 publications were included with a median age at diagnosis of 35 years (range 12-76). Five-year OMDFS and overall survival in patients with Stage I TSTs were 91.2% and 93.2%, respectively. When comparing those who harbored OMD to those who did not, we observed an increased risk of OMD for each additional risk factor (P < .001). Five-year OMDFS was 98.1% for those with <2 risk factors vs 44.9% for those with ≥2 risk factors (P < .001). CONCLUSION: The existing literature on pathologic risk factors for OMD in this population is insufficient to make broad clinical recommendations. However, these factors appear to risk-stratify patients and may be useful for future research investigating adjuvant therapy in higher-risk patients. This review indicates that such a stratification system has a rational basis.

Survival outcomes of adolescent and adult patients with non-seminomatous testicular germ-cell tumors: A population-based study.

BACKGROUND: In adolescents, approximately 90% of testicular germ cell tumors (T-GCTs) are non-seminomas (NS T-GCTs). Few studies have evaluated the impact of age, specifically in adolescence, on outcomes of NS T-GCTs. OBJECTIVE: The purpose of this study was to review all patients diagnosed with NS T-GCTs in the Surveillance, Epidemiology, and End Results (SEER) database to evaluate the association between age (adolescents vs. adults) and survival outcomes. METHOD: The SEER database was queried for individuals ≥13 years old diagnosed with NS T-GCTs from 1995 to 2012. Patients were categorized into adolescent (13-19 years) and adult (≥20 years) cohorts. A Cox proportional hazards model was used for multivariate analysis (MVA). RESULTS: A total of 13,963 patients (1496 adolescents, 12,467 adults) was included. Median follow-up was 71 months (range 1-215). Five-year overall survival (OS) for adolescent and adult patients was 94% and 92%, respectively (p = 0.007); 5-year cancer-specific survival (CSS) was 95% and 94%, respectively (p = 0.139). Under MVA, adolescent patients had improved OS (HR 0.61; 95% CI 0.50-0.75; p < 0.001) and CSS (HR 0.65; 95% CI 0.51-0.82; p < 0.001), when compared with adults (Table). In a logistic regression analysis adjusting for demographics, adolescent patients were more likely to present with regional or distant metastatic disease (OR 1.16; 95% CI 1.01-1.35; p = 0.039), undergo an orchiectomy (OR 2.44; 95% CI 1.50-4.00; p < 0.001) or tumor excision (OR 2.43; 95% CI 1.57-3.77; p < 0.001), and receive other adjuvant surgery (OR 5.87; 95% CI 2.25-15.30; p < 0.001). CONCLUSIONS: To our knowledge, this is the largest population-based comparative analysis in NS T-GCTs comparing outcomes between these two age groups. Adolescent patients with NS T-GCTs had slightly improved survival compared with adults, despite presenting with more advanced disease. While adolescent patients present at more advanced stage, they achieve excellent survival outcomes possibly at the cost of a greater therapeutic burden.

Cardiac Mortality in Children and Adolescents with Hodgkin's Lymphoma: A Surveillance, Epidemiology and End Results Analysis.

PURPOSE: The purpose of this study was to evaluate the risk of cardiac death in pediatric Hodgkin's lymphoma (HL) survivors and identify high-risk groups that may need additional surveillance. METHODS: The Surveillance, Epidemiology and End Results program database was queried to analyze the rates of radiation therapy (RT) use and cardiac-specific mortality (CSM) in HL patients, aged 0-21 years, treated from 1973 to 2007. Primary endpoint was cardiac mortality. RESULTS: A total of 6552 patients were included. Median follow-up was 12 years (range, 0-40). Median age at diagnosis was 17 years (range, 0-21). The majority were white (85.5%), from western states (41.2%), had nodular sclerosis HL (73.2%), presented with stage I or II disease (51.5%), and received RT (56.1%). Death from cardiac disease occurred in 114 patients (9.2% of all deaths). CSM for the entire cohort at 10-, 20-, and 30-year time points was 0.3%, 1.6%, and 5.0%, respectively. Median age at the time of cardiac death was 39 years (range, 18-58 years). Under multivariate analysis (MVA), adolescent patients (ages 13-21) had higher rates of CSM (hazard ratio [HR], 3.05; p = 0.005). Female gender (HR, 0.43; p < 0.001), patients treated from 1998 to 2007 (HR, 0.19; p = 0.018), and those with lymphocyte-rich histology (HR, 0.14; p = 0.047) had significantly lower rates of CSM. Use of RT was not associated with CSM under MVA (HR, 1.18, p = 0.452). CONCLUSION: The cumulative incidence of CSM in this population analysis of pediatric HL was 9.2%, with a steady decline over the past several decades. Adolescent patients at diagnosis and males were more likely to die of cardiac-related causes.

Pathologic Risk Factors in Pediatric and Adolescent Patients With Clinical Stage I Testicular Stromal Tumors.

BACKGROUND: Testicular stromal tumors (TSTs) are rare. In adult men with TSTs, various pathologic risk factors have been identified in patients with clinically localized disease that increase the risk of occult metastatic disease (OMD). We systematically reviewed existing literature to analyze the impact of these risk factors on OMD in prepubertal (0 to 12 y) and postpubertal (13 to 21 y) patients. METHODS: A literature search was conducted using the combination of terms: "testicular stromal tumors," "testicular leydig cell tumors," "testicular sertoli tumors," "testicular interstitial tumors," "testicular granulosa tumor," and "testicular sex cord tumors." Studies of patients 0 to 21 years with clinical stage I TSTs were included. RESULTS: A total of 100 patients from 31 publications were included with a median age at diagnosis of 5.7 years (range, 1.2 mo to 21 y). Seventy-nine patients were 12 years and below (median 7.2 mo) and 21 patients were 13 to 21 years (median 16 y). No patients in either group were identified to have OMD at retroperitoneal lymph node dissection or during follow-up surveillance (median follow-up 45.6 y; range, 4 to 360 mo). 99% of those 12 years and below versus 95% of those above 12 years had 0 to 1 pathologic risk factors, and 1% versus 5% had 2+ pathologic risk factors (P=0.38). CONCLUSIONS: Clinical stage I TSTs in adolescent, postpubertal patients appear to behave in a benign manner with few pathologic risk factors, similar to prepubertal patients. Given the low risk of relapse in this population, low-impact surveillance strategies are paramount. Prospective study of these patients is needed, and entry into a tumor registry such as the International Ovarian and Testicular Stromal Tumor Registry is important to learning more about this rare disease.