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.

Current surgical approach: Extracranial malignant germ cell tumors.

Germ cell tumors (GCT) are a complex, heterogeneous collection of tumors that may present in either gonadal or extragonadal sites. They consist of a variety of benign and malignant histologies that can occur at several locations throughout the body. An important component of treatment is surgical resection, and while the key components of resection are site specific, the universal goals of GCT resection include the complete resection of tumor without violating the tumor capsule, while preserving function of surrounding organs, minimizing morbidity, and assessing for regional spread.

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.

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.

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.

α-Fetoprotein as a predictor of outcome for children with germ cell tumors: A report from the Malignant Germ Cell International Consortium.

BACKGROUND: There are several studies describing the correlation between unsatisfactory tumor marker decline and a poor prognosis for adult patients treated for germ cell tumors. In pediatric patients, the data are limited. Therefore, this study retrospectively analyzed data from Children's Oncology Group (COG) protocol AGCT0132 to determine whether a relationship exists between α-fetoprotein (AFP) decline and outcome. METHODS: One hundred thirty-one patients with germ cell tumors who were enrolled in COG protocol AGCT0132 were eligible for this analysis of AFP decline. The serum AFP half-life was calculated from levels collected postoperatively as a baseline and after the start of chemotherapy. AFP decline was defined as automatically satisfactory (AFP normalized within the first 2 AFP measures after the start of chemotherapy), calculated satisfactory (AFP half-life ≤7 days after the start of chemotherapy), and unsatisfactory. RESULTS: The 3-year cumulative incidence of relapse was 11% (95% confidence interval [CI], 6.0%-18%) for patients with a satisfactory decline and 38% (95% CI, 13%-64%) for patients with an unsatisfactory decline (P = .006). In stratified analyses, this effect was limited to patients who were 11 years of age or older and had standard risk 2 (SR2) disease (P = .004 and P = .007, respectively). Three-year overall survival (OS) for patients with a satisfactory decline versus an unsatisfactory decline was not statistically significant. CONCLUSIONS: This study is the first to show an association between AFP decline and the cumulative incidence of relapse in pediatric patients treated for germ cell tumors. Recognition of patients at high risk for relapse may allow for early intensification of therapy, which could affect future clinical trial design.

Is carboplatin-based chemotherapy as effective as cisplatin-based chemotherapy in the treatment of advanced-stage dysgerminoma in children, adolescents and young adults?

OBJECTIVE: Dysgerminoma is the most common malignant ovarian germ cell tumor (GCT) with peak incidence during adolescence and young adulthood. Current standard of care for patients with disease that has spread outside of the ovary (advanced-stage) utilizes platin-based chemotherapy regimens. The study objective was to compare clinical outcomes between platin-based (carboplatin versus cisplatin) strategies across all age groups (children < 11 years (y), adolescents = 11-25 y and young adult women > 25 y) for advanced-stage dysgerminoma. METHODS: The Malignant Germ Cell Tumor International Consortium (MaGIC) pooled data from six GCT trials (3 = pediatric, 3 = adult) conducted internationally by pediatric and gynecologic oncology clinical trial organizations (CTOs) between 1983 and 2009. Newly diagnosed patients, with advanced-stage (FIGO IC-IV) dysgerminoma, who received either carboplatin- or cisplatin-based chemotherapy were eligible for analysis. RESULTS: 126 eligible patients were identified; 56 patients (38 = pediatric, 18 = adult) received carboplatin-based and 70 patients (50 = pediatric, 20 = adult) received cisplatin-based chemotherapy. Mean age was 20 y (range = 6-46 y). The median follow-up was 10.3 y (range = 0.17-21.7 y). The five-year event-free survival (EFS5) and overall survival (OS5) was 0.94 (95%CI, 0.88-0.97) and 0.96 (95%CI, 0.91-0.99) respectively. Survival outcomes were comparable between carboplatin-(EFS5 = 0.96 (95%CI, 0.85-0.99), OS5 = 0.96 (95%CI, 0.85-0.99)) and cisplatin-(EFS5 = 0.93 (95%CI, 0.83-0.97), OS5 = 0.96 (95%CI, 0.87-0.99)) based regimens. Across three age groups, comparison of the EFS5 (<11 y = 0.1, 11-25 y = 0.91 (95%CI, 0.82-0.96), >25 y = 0.97 (95%CI, 0.81-0.99)) and OS5 (<11 y = 0.1, 11-25 y = 0.95 (95%CI, 0.87-0.99), >25 y = 0.97 (95%CI, 0.81-0.99)) did not demonstrate any statistically significant differences in outcomes. CONCLUSIONS: Patients diagnosed with dysgerminoma have an excellent OS, across all ages, even in the context of metastatic disease. Data from three large CTOs supports the investigation of carboplatin-based regimens in the frontline treatment of all patients with advanced-stage dysgerminoma to minimize treatment-related toxicities.

Gonadal dysgenesis is associated with worse outcomes in patients with ovarian nondysgerminomatous tumors: A report of the Children's Oncology Group AGCT 0132 study.

PURPOSE: In this report, we characterize the timing and behavior of malignant ovarian germ cell tumors (GCTs) in pediatric patients with dysgenetic gonads compared to those with normal gonadal development. PATIENTS AND METHODS: Patients from the Children's Oncology Group AGCT0132 with malignant ovarian GCTs were included. Within this population, we sought to identify patients with gonadoblastoma, streak ovaries, or other evidence of gonadal dysgenesis (GD). Patients with malignant GCTs containing one or more of the following histologies-yolk sac tumor, embryonal carcinoma, or choriocarcinoma-were included. Patients were compared with respect to event-free survival (EFS) and overall survival (OS). RESULTS: Nine patients with GD, including seven with gonadoblastoma (mean age, 9.3 years), were compared to 100 non-GD patients (mean age, 12.1 years). The estimated 3-year EFS for patients with GD was 66.7% (95% CI 28.2-87.8%) and for non-GD patients was 88.8% (95% CI 80.2-93.8%). The estimated 3-year OS for patients with GD was 87.5% (95% CI 38.7-98.1%) and for non-GD patients was 97.6% (95% CI of 90.6-99.4%). CONCLUSION: Patients presenting with nongerminomatous malignant ovarian GCTs in the context of GD have a higher rate of events and death than counterparts with normal gonads. These findings emphasize the importance of noting a contralateral streak ovary or gonadoblastoma at histology for any ovarian GCT and support the recommendation for early bilateral gonadectomy in patients known to have GD with Y chromosome material. In contrast to those with pure dysgerminoma, these patients may represent a high-risk group that requires a more aggressive chemotherapy regimen.

Paediatric extracranial germ-cell tumours.

Management of paediatric extracranial germ-cell tumours carries a unique set of challenges. Germ-cell tumours are a heterogeneous group of neoplasms that present across a wide age range and vary in site, histology, and clinical behaviour. Patients with germ-cell tumours are managed by a diverse array of specialists. Thus, staging, risk stratification, and treatment approaches for germ-cell tumours have evolved disparately along several trajectories. Paediatric germ-cell tumours differ from the adolescent and adult disease in many ways, leading to complexities in applying age-appropriate, evidence-based care. Suboptimal outcomes remain for several groups of patients, including adolescents, and patients with extragonadal tumours, high tumour markers at diagnosis, or platinum-resistant disease. Survivors have significant long-term toxicities. The challenge moving forward will be to translate new insights from molecular studies and collaborative clinical data into improved patient outcomes. Future trials will be characterised by improved risk-stratification systems, biomarkers for response and toxic effects, rational reduction of therapy for low-risk patients and novel approaches for poor-risk patients, and improved international collaboration across paediatric and adult cooperative research groups.

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.

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.

Bronchogenic/foregut cyst of the ileal mesentery in a child mimicking ovarian mass.

Intraabdominal bronchogenic cysts, a type of foregut cyst, are very rare. We report a case in a 12-year-old female who presented with severe abdominal pain and, in radiology workup, a cystic lesion that mimicked ovarian mass.

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.

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.

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.

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.

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.

Bleeding risk for surgical dialysis procedures in children with hemolytic uremic syndrome.

Children with hemolytic uremic syndrome (HUS) frequently develop acute kidney injury (AKI) requiring renal replacement therapy (RRT). Peritoneal dialysis (PD) is commonly used. Despite high rates of thrombocytopenia, there is concern that platelet transfusions may worsen HUS by exacerbating microthrombi formation. We evaluated bleeding risk for PD catheter placement with or without central venous catheter (CVC) placement in children with HUS. Records from 1998 to 2007 were searched. Data regarding patient demographics, PD catheter placement, CVC placement, occurrence of procedure-associated bleeding, and time from insertion to removal of PD catheter were collected. Patients were stratified according to those who received and those who did not receive platelet transfusions. Seventy-three patients were identified. Twenty-two (30%) patients received platelet transfusion while 51 (70%) did not. Mean preoperative platelet counts were 37,600+/-21,900/mm(3) in patients receiving transfusions and 64,800 +/- 38,800/mm(3) in patients not receiving transfusions. Sixty-seven children (92%) also underwent CVC placement. There were no bleeding complications related to these procedures in either group. No differences in time to removal of the PD catheter were detected. Although caution and sound clinical judgment must be exercised, our findings suggest that PD catheter and CVC placement can be accomplished safely in most children with HUS, without need for platelet transfusion in spite of the associated thrombocytopenia.

Cardiac arrest after induction of anesthesia in a 2-month-old infant with undiagnosed Williams syndrome.

A 2-month-old male infant presented for elective repair of inguinal hernias. His preoperative medical history and physical examination were unremarkable. During induction of anesthesia, the infant sustained an adverse cardiac event. The event was characterized by tachycardia, hypotension, and massive ST-segment elevation. Despite vigorous resuscitation, spontaneous hemodynamic stability could not be achieved and extracorporeal membrane oxygenation was required. A transthoracic echocardiogram revealed severe hypoplasia of the ascending aorta. As effective cardiac function did not recover and there was evidence of diffuse ischemic brain injury, life support was withdrawn. Genetic testing performed postoperatively was definitive for Williams syndrome.