Comparison of overall and patterns of care in patients with a malignant ovarian germ cell tumor by age in the United States: a National Cancer Database (2004-2016) analysis.

BACKGROUND: Women aged ≥40 years diagnosed with a malignant ovarian germ cell tumor are more likely to have poor outcomes than their younger counterparts (aged 15-39 years). OBJECTIVE: We used the National Cancer Database (NCDB) to evaluate patterns of care and overall survival for individuals diagnosed with one of the four most common histologic subtypes of malignant ovarian germ cell tumor by age group. METHODS: We identified women aged 15-90 diagnosed with ovarian germ cell tumors in the NCDB (2004-2016). Logistic regression was used to compare patterns of care, demographic, and disease characteristics by age group. Cox proportional hazards regression was used to evaluate associations between a range of demographic, clinical, and treatment characteristics with overall survival. RESULTS: A total of n=2998 patients who were diagnosed with one of the four most common histologic subtypes (immature teratoma, dysgerminoma, yolk sac tumor, and mixed germ cell) of ovarian germ cell tumor were included in the analysis. Patients aged ≥40 years diagnosed with ovarian germ cell tumors were more likely to have co-morbidities, a bilateral tumor, higher stage of disease, receive chemotherapy only, and have a residual tumor after resection as compared with patients aged <40 years. Moreover, women aged ≥40 years had the highest risk of death (reference: 15-24 year olds; HR=5.37, 95% CI 3.76 to 7.66) after adjustment for demographic characteristics, tumor histology, and treatment received. In stratified analyses, women aged ≥40 years had significantly worse overall survival at each disease stage and histologic subtype. CONCLUSION: Findings suggest that women aged ≥40 years who are diagnosed with ovarian germ cell tumors have worse overall survival than those aged <40, independent of stage, disease characteristics, and treatment. Our study highlights the need for future research to better understand reasons for poorer outcomes in women aged ≥40 years.

Diagnostic Conundrum of a Sertoli Cell Tumor in a 2-Year-Old Girl with Peripheral Precocious Puberty and a Café-au-Lait Macule: A Case Report.

INTRODUCTION: Ovarian Sertoli cell tumors represent a subset of sex cord stromal tumors and are exceedingly rare in prepubertal children. Here, we report a girl with vaginal bleeding due to a Sertoli cell tumor who was originally thought to have McCune-Albright syndrome (MAS). CASE PRESENTATION: A previously healthy girl presented at age 2 years 6 months with breast development and vaginal bleeding. On exam, she had Tanner 4 breasts, Tanner 1 pubic hair, estrogenized vaginal mucosa, and a café-au-lait macule. Laboratory studies revealed an elevated estradiol with suppressed gonadotropins and negative tumor markers. Her bone age was advanced by more than 3 years. Pelvic ultrasound (US) revealed an enlarged uterus and a slightly larger left compared to right ovary. She was started on tamoxifen for presumed MAS. A repeat pelvic US 1 month later showed a heterogenous mass in the left ovary which was subsequently resected. Pathology revealed a Sertoli cell tumor, lipid-rich variant. Germline sequencing revealed a pathogenic STK11 variant, diagnostic for Peutz-Jeghers syndrome (PJS). CONCLUSION: The findings in our patient were strikingly similar to those encountered in MAS. To our knowledge, our patient is the youngest ever reported to present with precocious puberty due to a Sertoli cell tumor in the setting of PJS.

Outcomes in ovarian Sertoli-Leydig cell tumor: A report from the International Pleuropulmonary Blastoma/DICER1 and Ovarian and Testicular Stromal Tumor Registries.

OBJECTIVE: Sertoli-Leydig cell tumors (SLCTs) are rare sex cord-stromal tumors, representing <0.5% of all ovarian tumors. We sought to describe prognostic factors, treatment and outcomes for individuals with ovarian SLCT. METHODS: Individuals with SLCT were enrolled in the International Pleuropulmonary Blastoma/DICER1 Registry and/or the International Ovarian and Testicular Stromal Tumor Registry. Medical records were systematically abstracted, and pathology was centrally reviewed when available. RESULTS: In total, 191 participants with ovarian SLCT enrolled, with most (92%, 175/191) presenting with FIGO stage I disease. Germline DICER1 results were available for 156 patients; of these 58% had a pathogenic or likely pathogenic germline variant. Somatic (tumor) DICER1 testing showed RNase IIIb hotspot variants in 97% (88/91) of intermediately and poorly differentiated tumors. Adjuvant chemotherapy was administered in 40% (77/191) of cases, and among these, nearly all patients received platinum-based regimens (95%, 73/77), and 30% (23/77) received regimens that included an alkylating agent. Three-year recurrence-free survival for patients with stage IA tumors was 93.6% (95% CI: 88.2-99.3%) compared to 67.1% (95% CI: 55.2-81.6%) for all stage IC and 60.6% (95% CI: 40.3-91.0%) for stage II-IV (p < .001) tumors. Among patients with FIGO stage I tumors, those with mesenchymal heterologous elements treated with surgery alone were at higher risk for recurrence (HR: 74.18, 95% CI: 17.99-305.85). CONCLUSION: Most individuals with SLCT fare well, though specific risk factors such as mesenchymal heterologous elements are associated with poor prognosis. We also highlight the role of DICER1 surveillance in early detection of SLCT, facilitating stage IA resection.

Consensus and controversy in the management of paediatric and adult patients with ovarian immature teratoma: the Malignant Germ Cell International Consortium perspective.

Ovarian immature teratoma (IT) is a rare neoplasm comprising ∼3% of ovarian cancers, occurring primarily in young females. Management presents several challenges, including those with elevated serum alpha-fetoprotein, potential confusion regarding pathology interpretation, and paucity of data to support decision-making. MaGIC (https://magicconsortium.com/) is an interdisciplinary international consortium of GCT experts from multiple subspecialties, with members receiving frequent queries regarding IT patient management. With evidence from published literature where available, we summarise consensus management of such patients. Given lack of published data, controversy in certain areas remains. The most obvious variance in practice is between paediatric and adult teams, despite very similar outcomes. Paediatric teams typically employ a surgery-only approach, whereas in adult practice, all patients, except those with stage IA, grade 1 (low-grade) tumours, still generally receive adjuvant chemotherapy. Given the rarity of ovarian IT and lack of published data, discussion with GCT experts and/or national advisory panels is recommended.

Critical elements of pediatrics sacrococcygeal germ cell tumor surgery.

Sacrococcygeal teratoma is the most common extragonadal germ cell tumor in the pediatric population, and accounts for approximately 70% of all teratomas in childhood.1,2 They present in two distinct phases, with most cases seen in neonates with large predominately exophytic tumors, often detected in utero on prenatal sonography or at birth. A smaller cohort presents in older infants and children with primarily hidden tumors in the pelvis which have a much higher rate of malignancy. The primary surgical objective is complete tumor resection without compromise to critical structures or function. Herein we outline the critical elements of tumor resection and management of sacrococcygeal germ cell tumors with a focus on the technical aspects of this tumor across a range of presentations.

Critical elements in the operative management of pediatric malignant ovarian germ cell tumors.

Performance of the appropriate operation is highly important to ensure that any patient with a suspected ovarian germ cell tumor receives optimal therapy that prioritizes cure while simultaneoulsy minimizing risk of short and long-term toxicities of treatment. The following critical elements of any operative procedure performed for a suspected pediatric or adolescent ovarian germ cell tumor are reviewed: 1. Complete resection of the tumor via ipsilateral oophorectomy while avoiding tumor rupture and spillage, and 2. Performance of complete intraperitoneal staging at the time of initial tumor resection.

Critical elements of pediatric testicular germ cell tumors surgery.

Children, adolescents and young adults with testicular germ cell tumors require appropriate surgical care to insure excellent outcomes. This article presents the most critical elements, and their basis in evidence, for surgery in this population. Specifically, the importance of inguinal radical orchiectomy for malignant tumors, partial orchiectomy for prepubertal tumors and normal serum tumor markers, and the appropriate use of post-chemotherapy retroperitoneal lymph node dissection in those with residual retroperitoneal masses.

Characterizing Lymphovascular Invasion in Pediatric and Adolescent Malignant Ovarian Nongerminomatous Germ Cell Tumors: A Report from the Children's Oncology Group.

BACKGROUND: Lymphovascular invasion (LVI) has been identified as a poor prognostic factor for a variety of tumors; however, its significance in malignant ovarian germ cell tumors (MOGCT) in pediatric and adolescent patients is not well described. We aim to clarify the significance of LVI in the subset of patients with nongerminomatous MOGCT. METHODS: Records of patients 0-20 years of age with MOGCT enrolled on Children's Oncology Group study AGCT0132 were reviewed. Patients with documented presence or absence of LVI in either institutional or central review pathology reports were included. RESULTS: Of 130 patients with MOGCTs, 83 patients had of the presence or absence of LVI documented in their pathology report. 42/83 patients (50.6%) were found to have LVI present. The estimated odds of having LVI was higher in patients with stage II and III disease, 11 years and older and with the presence of choriocarcinoma. Event-free survival (EFS) and overall survival (OS) remained high in patients with LVI. Approximately 50% of patients with a documented LVI status in either institutional pathology report or central review were found to have LVI. CONCLUSIONS: The presence of LVI was higher in tumors with adverse risk factors including higher stage and age greater than 11 years. While LVI was not associated with EFS or OS in the intermediate risk group, further work is necessary to determine the effect of LVI on long-term disease-free survival. We, therefore, recommend routinely incorporating LVI status into institutional pathology reports for pediatric and adolescent patients with MOGCT. LEVEL OF EVIDENCE: III.

Integrated genomic analysis reveals aberrations in WNT signaling in germ cell tumors of childhood and adolescence.

Germ cell tumors (GCTs) are neoplasms of the testis, ovary and extragonadal sites that occur in infants, children, adolescents and adults. Post-pubertal (type II) malignant GCTs may present as seminoma, non-seminoma or mixed histologies. In contrast, pre-pubertal (type I) GCTs are limited to (benign) teratoma and (malignant) yolk sac tumor (YST). Epidemiologic and molecular data have shown that pre- and post-pubertal GCTs arise by distinct mechanisms. Dedicated studies of the genomic landscape of type I and II GCT in children and adolescents are lacking. Here we present an integrated genomic analysis of extracranial GCTs across the age spectrum from 0-24 years. Activation of the WNT pathway by somatic mutation, copy-number alteration, and differential promoter methylation is a prominent feature of GCTs in children, adolescents and young adults, and is associated with poor clinical outcomes. Significantly, we find that small molecule WNT inhibitors can suppress GCT cells both in vitro and in vivo. These results highlight the importance of WNT pathway signaling in GCTs across all ages and provide a foundation for future efforts to develop targeted therapies for these cancers.

Urinary excretion of low-osmolar contrast media during small-bowel follow-through studies in infants is not definitive evidence of bowel perforation.

BACKGROUND: Presence of contrast agent in the urinary system in infants after small-bowel follow-through study with low-osmolar contrast media has been described as a sign of bowel perforation. OBJECTIVE: To evaluate how often the presence of contrast agent in the bladder after small-bowel follow-through is a reliable sign of bowel perforation or necrosis. MATERIALS AND METHODS: From the radiology information system, we retrieved imaging reports of infants evaluated with small-bowel follow-through and findings of contrast agent in the bladder. We retrieved demographic and clinical information from the medical records. Presence of bladder contrast medium was considered true-positive evidence of bowel perforation or necrosis if confirmed by pneumoperitoneum, extraluminal contrast agent, surgery or pathology within 3 days of the small-bowel follow-through. False-positives for bowel perforation or necrosis were based on surgical findings or clinical follow-up. RESULTS: Of the 207 infants who had small-bowel follow-through, 18 infants (12 boys; mean age 50 days, range 14 days to 8.5 months) had contrast medium in the bladder after the small-bowel follow-through. Fifteen of the 18 (83.3%) had a history of prematurity and 11 had prior abdominal surgery. Four of the 18 (22.2%) had bowel perforation or necrosis at surgery or pathology performed more than 3 days after the small-bowel follow-through and were considered indeterminate and excluded. Eight of the remaining 14 infants (57.1%) had bowel perforation or necrosis based on surgical evidence of perforation or pathology confirmation of necrosis (n=6), pneumoperitoneum (n=1) or contrast agent leakage from enterocutaneous fistula (n=1). Six of the 14 (42.9%) were false-positives, without evidence of bowel perforation or necrosis based on clinical follow-up (n=4) or surgery (n=2). CONCLUSION: Demonstration of urinary contrast agent post small-bowel follow-through with low-osmolar contrast medium in newborns/infants with complex medical problems is not a definitive indication of bowel perforation or necrosis. More than one-third of our patients with contrast medium in the bladder did not have bowel perforation or necrosis.

Addressing the diagnostic and therapeutic dilemmas of ovarian immature teratoma: Report from a clinicopathologic consensus conference.

Ovarian immature teratoma is a rare subtype of germ cell tumour that can be pure or associated with non-teratomatous germ cell tumour elements and is graded based on extent of the immature neuroectodermal component. Immature teratoma (IT) can also be associated with somatic differentiation in the form of sarcoma, carcinoma, or extensive immature neuroectodermal elements and may produce low levels of serum alpha-fetoprotein. Variable interpretation of these issues underlies diagnostic and management dilemmas, resulting in substantial practice differences between paediatric and adult women with IT. The Malignant Germ Cell International Consortium (MaGIC) convened oncologists, surgeons, and pathologists to address the following crucial clinicopathologic issues related to IT: (1) grading of IT, (2) definition and significance of 'microscopic' yolk sac tumour, (3) transformation to a somatic malignancy, and (4) interpretation of serum tumour biomarkers. This review highlights the discussion, conclusions, and suggested next steps from this clinicopathologic conference.

Clinicopathologic predictors of outcomes in children with stage I testicular germ cell tumors: A pooled post hoc analysis of trials from the Children's Oncology Group.

BACKGROUND: Patients with clinical stage I (CS I: cN0M0) testicular germ cell tumors (TGCT) exhibit favorable oncologic outcomes. While prognostic features can help inform treatment in adults with CS I TGCT, we lack reliable means to predict relapse among pediatric and adolescent patients. OBJECTIVE: We sought to identify predictors of relapse in children with CS I TGCT. STUDY DESIGN: We performed a pooled post hoc analysis on pediatric and adolescent AJCC CS I TGCT patients enrolled in 3 prospective trials: INT-0097 (phase II), INT-0106 (phase III), and AGCT0132 (phase III). Pathology was centrally reviewed. Patient demographics, pT stage, serum tumor markers, margin status, histology, relapse, and survival were compiled. Cox regression analyses were used to identify predictors of events, defined as relapse, secondary malignant neoplasm, or death. RESULTS: 106 patients were identified with outcomes data available. Most patients were pT1-2 stage. Among patients with evaluable histopathology, yolk sac tumor elements were present in all patients and lymphovascular invasion in 51% of patients. Over a median follow-up of 56 months, no patients died, and 25 patients (24%) experienced an event (median event-free survival not reached). Independent predictors of events on multivariable analysis included age ≥12 years at diagnosis (HR 8.87, p < 0.001) and higher pT stage (pT2 HR 7.31, p = 0.0017; pT3 HR 13.5, p = 0.0043). DISCUSSION: Although our study population reflects the largest pooled prospective cohort of CS I pediatric and adolescent TGCT to our knowledge, the relatively low event rate limits our multivariable analysis, and longer follow-up duration would help further characterize the natural history of these patients. Centralized pathologic review was also unable to be performed for several patients. CONCLUSION: Pediatric and adolescent CS I TGCT patients exhibit remarkable 5-year survival. Using combined data from multiple prospective trials, our study identifies clinicopathologic features that predict relapse and inform personalized treatment for these patients by potentially guiding surveillance versus adjuvant treatment strategies.

Management of Germ Cell Tumors in Pediatric Patients.

Germ cell tumors arise from primordial germ cells. Most develop in the gonads or along midline structures of the body. Genetic aberrations leading to disruption in the molecular signaling responsible for primordial germ cell migration early in development may provide rationale for why germ cell tumors originate in extragonadal locations. Establishing best practices for treating pediatric germ cell tumors remains an area of active investigation. Recent advances focused on limiting toxicities of therapy, identifying new therapies for relapsed and refractory tumors, defining best practices for surgical staging and resection, and developing novel methods to monitor for disease relapse.

Imaging Appearance of Nongerminoma Pediatric Ovarian Germ Cell Tumors Does Not Discriminate Benign from Malignant Histology.

STUDY OBJECTIVE: Pediatric ovarian neoplasms with imaging appearance suggestive of teratoma are often presumed to have low risk of malignancy. We assessed the pre-operative imaging appearance of pediatric malignant ovarian germ cell tumors (MOGCT) and the presence of associated teratoma in a series of MOGCT. DESIGN: Retrospective review of clinical and pathology data. SETTING: Multicenter trial for extracranial malignant germ cell tumors in young female individuals by the Children's Oncology Group (COG study AGCT0132) that included yolk sac tumor, embryonal carcinoma and choriocarcinoma. PARTICIPANTS: Female individuals 0-20 years of age at enrollment with ovarian primary nonseminomatous malignant germ cell tumors. INTERVENTIONS: Review of data forms, including prospectively collected surgical checklist documenting imaging characteristics of the tumor, and review of pathology reports. MAIN OUTCOME MEASURES: Description of imaging appearance and frequency of mixed histology with benign teratoma elements. RESULTS: A total of 138 female individuals (11 months to 20 years of age) had primary ovarian tumors. Imaging appearance and pathology information were available for 133 patients. Among the 133 patients, tumor appearance was solid (10.5%), solid with calcification (3.0%), mixed cystic and solid (58.7%), mixed cystic and solid with calcification (24.8%), and unknown (3.0%). In all, 54% had elements of teratoma in addition to malignant histology. CONCLUSION: Mixed cystic and solid appearance with or without calcification was seen in 83.5% of pediatric ovarian malignant germ cell tumors. Associated benign teratoma was common. The presence of a mixed cystic and solid appearance on preoperative imaging should not dissuade the surgeon from obtaining preoperative serum markers and undertaking complete surgical staging.

Outcomes of adolescent males with extracranial metastatic germ cell tumors: A report from the Malignant Germ Cell Tumor International Consortium.

BACKGROUND: Adolescents with extracranial metastatic germ cell tumors (GCTs) are often treated with regimens developed for children, but their clinical characteristics more closely resemble those of young adult patients. This study was designed to determine event-free survival (EFS) for adolescents with GCTs and compared them with children and young adults. METHODS: An individual patient database of 11 GCT trials was assembled: 8 conducted by pediatric cooperative groups and 3 conducted by an adult group. Male patients aged 0 to 30 years with metastatic, nonseminomatous, malignant GCTs of the testis, retroperitoneum, or mediastinum who were treated with platinum-based chemotherapy were included. The age groups were categorized as children (0 to <11 years), adolescents (11 to <18 years), and young adults (18 to ≤30 years). The study compared EFS and adjusted for risk group by using Cox proportional hazards analysis. RESULTS: From a total of 2024 individual records, 593 patients met the inclusion criteria: 90 were children, 109 were adolescents, and 394 were young adults. The 5-year EFS rate was lower for adolescents (72%; 95% confidence interval [CI], 62%-79%) than children (90%; 95% CI, 81%-95%; P = .003) or young adults (88%; 95% CI, 84%-91%; P = .0002). The International Germ Cell Cancer Collaborative Group risk group was associated with EFS in the adolescent age group (P = .0020). After adjustments for risk group, the difference in EFS between adolescents and children remained significant (hazard ratio, 0.30; P = .001). CONCLUSIONS: EFS for adolescent patients with metastatic GCTs was similar to that for young adults but significantly worse than for that children. This finding highlights the importance of coordinating initiatives across clinical trial organizations to improve outcomes for adolescents and young adults. LAY SUMMARY: Adolescent males with metastatic germ cell tumors (GCTs) are frequently treated with regimens developed for children. In this study, a large data set of male patients with metastatic GCTs across different age groups has been built to understand the outcomes of adolescent patients in comparison with children and young adults. The results suggest that adolescent males with metastatic GCTs have worse results than children and are more similar to young adults with GCTs. Therefore, the treatment of adolescents with GCTs should resemble therapeutic approaches for young adults.

Traumatic abdominal wall hernias in children: A case for early exploration.

PURPOSE: Traumatic abdominal wall hernia (TAWH) is a rare consequence of blunt abdominal trauma (BAT). We examined a series of patients suffering TAWH to evaluate its frequency, rate of associated concurrent intraabdominal injuries (CAI) and correlation with CT, management and outcomes. METHODS: A Level 1 pediatric trauma center trauma registry was queried for children less than 18 years old suffering TAWH from BAT between 2009 and 2019. RESULTS: 9370 patients were admitted after BAT. TAWH was observed in 11 children, at incidence 0.1%. Eight children (73%) were male, at mean age 10 years, and mean ISS of 16. Six cases (55%) were because of MVC, three (27%) impaled by a handlebar or pole, and two (18%) dragged under large machinery. Seven (64%) had a CAI requiring operative or interventional management. Patients with CAI were similar to those without other injury, with 20% and 50% CT scan sensitivity and specificity for detection of associated injury, respectively. Five patients had immediate hernia repair with laparotomy for repair of intraabdominal injury, three had delayed repair, two have asymptomatic unrepaired TAWH, and one resolved spontaneously. CONCLUSIONS: Children with TAWH have high rates of CAI requiring operative repair. CT scans have low sensitivity and specificity for detecting associated injuries. A high suspicion of injury and low threshold for exploration must be maintained in TAWH cases. LEVEL OF EVIDENCE: IV.

Retroperitoneal and Pelvic Lymph Nodes in Children: What Is Normal?

OBJECTIVE. The purpose of this study was to evaluate size criteria for retroperitoneal and pelvic lymph nodes in healthy children. MATERIALS AND METHODS. We identified all trauma patients younger than 18 years old without underlying disease and with CT scans without abnormalities in the abdomen and pelvis during 2014-2015. Two pediatric radiologists reviewed the studies independently and recorded the number of retroperitoneal and pelvic lymph nodes with a long diameter 5 mm or greater and the size (two perpendicular diameters) of the largest lymph node in five anatomic locations. Discrepant results were reviewed in consensus. The relationship of short diameter to age and interobserver variability was evaluated. RESULTS. A total of 166 patients (86 boys) with a mean age of 7.2 years old (range, 0.1-18.0 years old) were identified. More than 95% of lymph nodes in the retroperitoneum and pelvis had a short diameter measuring at most 7 and 8 mm, respectively, by consensus. The size of the largest short diameter of lymph nodes did not vary with age. More than four lymph nodes were identified in any anatomic location in only three patients, by only one of the radiologists. Agreement for lymph nodes with largest diameter of 5 mm or greater between radiologists ranged from 70.5% to 97.6% for the five anatomic locations with poor interobserver agreement (κ, 0.2-0.3). CONCLUSION. The size and number of retroperitoneal and pelvic lymph nodes in children are less than in adults. A short diameter threshold of 7 mm (retroperitoneal) and 8 mm (pelvic) and more than four lymph nodes with long diameter of 5 mm or greater in one location may define disease.

Umbilical access in laparoscopic surgery in infants less than 3 months of age: A survey of the American Pediatric Surgical Association.

PURPOSE: Laparoscopy is commonplace in pediatric surgery. Abdominal access via the umbilicus may present a unique challenge in neonates and young infants predisposing them to complications. We hypothesized that these complications may occur more than described in the literature. METHODS: Members of the American Pediatric Surgical Association (APSA) were anonymously surveyed in February of 2018 via REDCap™ regarding technique of umbilical access in infants less than 3 months of age and complications experienced during umbilical access. Approval was obtained from the IRB and the APSA Outcomes and Evidence-based Practice Committee. RESULTS: The response rate was 31.3% (329/1050). 62.3% of respondents performed 21 or greater neonatal laparoscopic procedures annually. 34 of 322 respondents reported a direct complication from umbilical access for laparoscopy in this age group (10.6%). Surgeons described 37 specific cases with complications related to umbilical access, with laparoscopic pyloromyotomy making up 47.2% (17/36). CO2 embolism was the most common complication; 15.4% of surgeons reported not knowing about the possibility of CO2 embolism. 41% of surgeons confirm intraabdominal placement of the umbilical trocar prior to insufflation. There was no association between any complication and where the umbilical trocar was placed (above/below/through umbilicus) or placement technique in patients with no umbilical cord stump. There may be an association between complication and where the umbilicus is entered in patients with an umbilical cord stump still in place (p = 0.013). CONCLUSIONS: Umbilical access for laparoscopy in neonates and infants less than 3 months of age can present a unique challenge and result in significant complications. All techniques and methods had complications. Surgeons should be aware of these risks and be prepared to manage them emergently if they arise. LEVEL OF EVIDENCE: V, expert opinion.