Lymph node metastases are more frequent in paediatric appendiceal NET ≥1.5 cm but without impact on outcome - Data from the German MET studies.

BACKGROUND: Paediatric appendiceal neuroendocrine tumours (appNET) are very rare tumours, mostly detected incidentally by histopathological evaluation after appendectomy. Treatment recommendations are based on adult data considering high-risk NET as defined by European Neuroendocrine Tumour Society (ENETS) guidelines for completion right-sided hemicolectomy (RHC). Recent data suggest that less aggressive therapy may be justified. PROCEDURE: Analysis of children and adolescents with appNET prospectively registered with the German Malignant Endocrine Tumour (MET) studies between 1997 and 2022. RESULTS: By December 2022, 662 patients (64.7% females, 35.3% male) had been reported. Median age was 13.3 years [4.5-17.9], median duration of follow-up 2.2 years [0-10.9]. No distant metastases were reported. Tumour size was <1 cm in 63.5%, 1-2 cm in 33.2%, and >2 cm in 3.2% of patients. WHO grade 1 and 2 tumours were diagnosed in 76.9% and 23.1% of patients, respectively. Lymphovascular invasion and lymph node metastases were associated with tumour size ≥1.5 cm. 27.0% of patients presented with high-risk NET according to ENETS criteria. Of those, only 55.9% underwent secondary oncological right hemicolectomy. Neither distant metastases, nor recurrences or disease-related deaths occurred in patients with appendectomy only as well as in patients with completion RHC. Overall and event-free survival were both 100%. CONCLUSIONS: Internationally harmonized consensus recommendations on treatment of children and adolescents with appendiceal NET are urgently needed to avoid completion RHC in high-risk patients.

Puzzling phenomenon: adult-onset cancer predisposition and pediatric cancer.

Pathogenic variants (PVs) in DNA repair-linked adult-onset cancer predisposition genes, including double heterozygosity, are increasingly identified in pediatric patients with cancer. Their role in childhood cancer, however, remains poorly understood. Integrating comprehensive tumor analysis is integral for understanding the contribution of such PVs in cancer development and personalized cancer care.

International consensus on mitotane treatment in pediatric patients with adrenal cortical tumors: indications, therapy, and management of adverse effects.

OBJECTIVE: Mitotane is an important cornerstone in the treatment of pediatric adrenal cortical tumors (pACC), but experience with the drug in the pediatric age group is still limited and current practice is not guided by robust evidence. Therefore, we have compiled international consensus statements from pACC experts on mitotane indications, therapy, and management of adverse effects. METHODS: A Delphi method with 3 rounds of questionnaires within the pACC expert consortium of the international network groups European Network for the Study of Adrenal Tumors pediatric working group (ENSAT-PACT) and International Consortium of pediatric adrenocortical tumors (ICPACT) was used to create 21 final consensus statements. RESULTS: We divided the statements into 4 groups: environment, indications, therapy, and adverse effects. We reached a clear consensus for mitotane treatment for advanced pACC with stages III and IV and with incomplete resection/tumor spillage. For stage II patients, mitotane is not generally indicated. The timing of initiating mitotane therapy depends on the clinical condition of the patient and the setting of the planned therapy. We recommend a starting dose of 50 mg/kg/d (1500 mg/m²/d) which can be increased up to 4000 mg/m2/d. Blood levels should range between 14 and 20 mg/L. Duration of mitotane treatment depends on the clinical risk profile and tolerability. Mitotane treatment causes adrenal insufficiency in virtually all patients requiring glucocorticoid replacement shortly after beginning. As the spectrum of adverse effects of mitotane is wide-ranging and can be life-threatening, frequent clinical and neurological examinations (every 2-4 weeks), along with evaluation and assessment of laboratory values, are required. CONCLUSIONS: The Delphi method enabled us to propose an expert consensus statement, which may guide clinicians, further adapted by local norms and the individual patient setting. In order to generate evidence, well-constructed studies should be the focus of future efforts.

The endocrine phenotype induced by paediatric adrenocortical tumours is age- and sex-dependent.

CONTEXT: Adrenocortical carcinomas are very rare malignancies in childhood associated with poor outcome in advanced disease. Most adrenocortical tumours (ACT) are functional causing signs and symptoms of adrenal hormone excess. In most studies, endocrine manifestations were reported 4-6 months prior to diagnosis. OBJECTIVE: We seeked to extend our knowledge on endocrine manifestations with regard to age and sex to facilitate early diagnosis. DESIGN/SETTINGS/PATIENTS: We retrospectively analysed features of adrenal hormone excess in children and adolescents with ACT registered with the GPOH-MET studies between 1997 and 2022. Stage of puberty was defined as `prepubertal` in females <8 years of age and males <9 years. RESULTS: By December 2022, 155 patients (110 female, 45 male) with data on endocrine manifestations had been reported. Median age at ACT diagnosis was 4.2 years [0.1-17.8], median interval from first symptoms 4.2 months [0-90.7]. In 63 females of prepubertal age pubarche (68.3%), clitoral hypertrophy (49.2%), and weight gain (31.7%) were most frequently reported, in 47 pubertal female excessive pubic hair (46.8%), acne (36.2%), and hypertension (36.2%). Leading symptoms in 34 males of prepubertal age were pubarche (55.9%), penile growth (47.1%), and acne (32.4%) and in 11 pubertal males, weight gain (45.5%), hypertension (36.4%), excessive pubic hair (27.3%), and cushingoid appearance (27.3%). In pubertal patients, symptoms of androgen excess were mainly unrecognized as part of pubertal development while symptoms of Cushing's syndrome were more frequently apparent. CONCLUSIONS: The endocrine phenotype induced by paediatric ACT is age- and sex-dependent.

Individualized targeted treatment in a case of a rare TFG::ROS1 fusion positive inflammatory myofibroblastic tumor (IMT).

BACKGROUND: Inflammatory myofibroblastic tumor (IMTs) are rare mesenchymal neoplasms with slow growth. Resection is considered as therapeutic standard, with chemotherapy being insufficiently effective in advanced disease. ALK translocations are present in 50% of cases, ROS1 fusions (YWHAE::ROS1, TFG::ROS1) are extremely rare. Here, we present a case with TFG::ROS1 fusion and highlight the significance of molecular tumor boards (MTBs) in clinical precision oncology for post-last-line therapy. CASE PRESENTATION: A 32-year-old woman presented with IMT diagnosed at age 27 for biopsy and treatment evaluation. Previous treatments included multiple resections and systemic therapy with vinblastine, cyclophosphamide, and methotrexate. A computed tomography scan showed extensive tumor infiltration of the psoas muscles and the posterior abdomen. Next generation sequencing revealed an actionable ROS1 fusion (TFG::ROS1) with breakpoints at exon 4/35 including the kinase domain and activating the RAS-pathway. TFG, the Trk-fused gene, exerts functions such as intracellular trafficking and exhibits high sequence homology between species. Based on single reports about efficacy of ROS1-targeting in ROS1 translocation positive IMTs the patient was started on crizotinib, an ATP-competitive small molecule c-MET, ALK and ROS1-inhibitor. With a follow-up of more than 9 months, the patient continues to show a profound response with major tumor regression, improved quality of life and no evidence for severe adverse events. CONCLUSION: This case underscores the importance of the availability of modern molecular diagnostics and interdisciplinarity in precision oncology to identify rare, disease-defining genotypes that make an otherwise difficult-to-treat disease targetable.

Locally Advanced Adrenocortical Carcinoma in Children and Adolescents-Enigmatic and Challenging Cases.

BACKGROUND: Locally advanced tumors account for approximately 50% of children and adolescents with adrenocortical carcinoma (ACC), and of these, up to 50% relapse. We explored the five-item microscopic score and the pS-GRAS score for guiding management. METHODS: Data from children and adolescents with COG stage II and III ACC registered in the MET studies were included. The five-item and pS-GRAS score were retrospectively calculated. RESULTS: By December 2021, 55 patients with stage II and III (stage II n = 18, stage III n = 37) had been reported. Median age was 4.3 years [0.1-17.8], median duration of follow-up 6.0 years [0-16.7]. 3-year event-free survival (EFS) rate was 76.5% and 49.8% (p = 0.088), respectively. In stage II tumors, neither the five-item score (p = 0.872) nor pS-GRAS grouping (p = 0.218) had any effect as prognostic factors. In stage III patients, EFS was impaired in tumors with unfavorable histology according to the five-item score (100% vs. 30.8%, p = 0.018). No difference was observed for pS-GRAS groups (p = 0.798). CONCLUSIONS: In patients with COG stage III, but not stage II, the five-item score affected EFS. Further studies are needed to identify patients at risk in COG stage II.

Bronchial carcinoid tumors in children and adolescents - A report and management considerations from the German MET studies.

OBJECTIVES: Bronchial carcinoid tumors (BC) are exceptionally rare in childhood, with an incidence of <0.2/1,000,000 per year. Typical low-grade BCs are distinguished from atypical, intermediate-grade BCs. Little is known about BCs in pediatric patients and management guidelines are missing. In this study, we explored characteristics and outcome of pediatric patients with BC prospectively registered with the Malignant Endocrine Tumor studies. MATERIAL AND METHODS: We performed a retrospective multicenter study in children, adolescents, and young adults (aged 0-20 years) with BC reported to the German MET registry between January 1997 and December 2022. Data were last updated on 28 of February 2023. RESULTS: Thirty-two patients were diagnosed at a median age of 15.0 years (range, 9.8-19.2). Atypical BCs (23.3%) were less frequent than typical, but more common than in adulthood. Lymph node metastases were present in 14.3% of cases (atypical BC: 28.6%, typical BC: 10.5%), distant metastases in one (3.1%) patient with atypical BC. 92.6% of patients were in complete remission after surgical resection (median follow-up: 2.7 years). The patient with metastatic spread and one patient with atypical BC and multiple recurrences were on treatment at last follow-up. 5-year event-free survival of typical BC was 100% and 83.3% in atypical BC. CONCLUSIONS: Completely resected localized BCs in pediatric patients have a favorable outcome also with lung tissue sparing surgery. Atypical BC with risk of metastatic spread and recurrence occurred more frequently compared to adults. Interdisciplinary management and collaborative efforts are needed to improve our understanding and the management of pediatric BC.

Psychosocial Well-Being of Siblings of Pediatric Patients in Palliative Home Care.

CONTEXT: Despite the proposed high burden of siblings of children and adolescents with life-limiting conditions receiving pediatric palliative care (PPC) at home, little is known about their psychosocial well-being. METHODS: In this prospective, cross-sectional trial siblings of patients of a large pediatric palliative home care team were asked to answer the KINDL survey of health-related quality of life, the strengths and difficulties questionnaire (SDQ) to assess problems and resources of children and adolescents as well as the LARES questionnaire, a potential tool for early screening of distress in siblings of chronically ill children. The results of the KINDL total and subdomains as well of the SDQ-subdomains were compared to recent German normative data using multiple t-tests. RESULTS: In total, 44 siblings (28 female; age 7-18 years, mean 11.8 ± 3.03) of 29 families participated in this study. The subgroup which matches the age range of current normative data of 11-17 years old siblings (n = 25) reported a significant lower total quality of life as measured by KINDL in comparison to normative data. Subscale analyses revealed a significant lower physical and psychological well-being and self-esteem. Siblings of PPC patients yielded significant higher scores in the subdomain prosocial behavior compared to normative data as measured by the SDQ. CONCLUSIONS: Siblings of children receiving PPC in a home care setting are at risk for a relevant impairment of their health-related quality of life. Future studies should address the potential for possible interventions specific for this population-at-risk.

Beyond germline genetic testing - heterozygous pathogenic variants in PMS2 in two children with Osteosarcoma and Ependymoma.

BACKGROUND: Lynch syndrome (LS) is not considered part of childhood cancer predisposition syndromes. CASE PRESENTATION: Analysis of a pediatric osteosarcoma (OS) displayed hypermutation (16.8), alternative lengthening of telomeres (ALT), loss of PMS2 expression in tumor tissue (retained in non-neoplastic cells), PMS2 loss of heterozygosity (LOH), and high-degree of microsatellite instability (MSI) tested by PCR. A heterozygous duplication c.1076dup p.(Leu359Phefs*6) in exon 10 of NM_000535.6:PMS2 was detected by SNV analysis in peripheral blood, confirming diagnosis of LS in the patient. The tumor molecular features suggest LS-associated development of OS. In a second case, whole-genome sequencing identified a heterozygous SNV c.1 A > T p.? in exon 1 of PMS2 in tumor and germline material of a girl with ependymoma. Tumor analysis displayed evidence for ALT and low mutational burden (0.6), PMS2 expression was retained, MSI was low. Multiplex ligation-dependent probe amplification identified no additional PMS2 variant and germline MSI testing did not reveal increased gMSI ratios in the patient´s lymphocytes. Thus, CMMRD was most closely excluded and our data do not suggest that ependymoma was related to LS in the child. CONCLUSIONS: Our data suggest that the LS cancer spectrum may include childhood cancer. The importance of LS in pediatric cancers necessitates prospective data collection. Comprehensive molecular workup of tumor samples is necessary to explore the causal role of germline genetic variants.

Comprehensive neurological evaluation of a cohort of patients with neurofibromatosis type 1 from a single institution.

Neurofibromatosis type 1 (NF1) is a phenotypically heterogenous multisystem cancer predisposition syndrome manifesting in childhood and adolescents. Central nervous system (CNS) manifestations include structural, neurodevelopmental, and neoplastic disease. We aimed to (1) characterize the spectrum of CNS manifestations of NF1 in a paediatric population, (2) explore radiological features in the CNS by image analyses, and (3) correlate genotype with phenotypic expression for those with a genetic diagnosis. We performed a database search in the hospital information system covering the period between January 2017 and December 2020. We evaluated the phenotype by retrospective chart review and imaging analysis. 59 patients were diagnosed with NF1 [median age 10.6 years (range, 1.1-22.6); 31 female] at last follow-up, pathogenic NF1 variants were identified in 26/29. 49/59 patients presented with neurological manifestations including 28 with structural and neurodevelopmental findings, 16 with neurodevelopmental, and 5 with structural findings only. Focal areas of signal intensity (FASI) were identified in 29/39, cerebrovascular anomalies in 4/39. Neurodevelopmental delay was reported in 27/59 patients, learning difficulties in 19/59. Optic pathway gliomas (OPG) were diagnosed in 18/59 patients, 13/59 had low-grade gliomas outside the visual pathways. 12 patients received chemotherapy. Beside the established NF1 microdeletion, neither genotype nor FASI were associated with the neurological phenotype. NF1 was associated with a spectrum of CNS manifestations in at least 83.0% of patients. Regular neuropsychological assessment complementing frequent clinical and ophthalmologic testing for OPG is necessary in the care of each child with NF1.

EBV-driven lymphoid neoplasms associated with pediatric ALL maintenance therapy.

The development of a second malignancy after the diagnosis of childhood acute lymphoblastic leukemia (ALL) is a rare event. Certain second malignancies have been linked with specific elements of leukemia therapy, yet the etiology of most second neoplasms remains obscure and their optimal management strategies are unclear. This is a first comprehensive report of non-Hodgkin lymphomas (NHLs) following pediatric ALL therapy, excluding stem-cell transplantation. We analyzed data of patients who developed NHL following ALL diagnosis and were enrolled in 12 collaborative pediatric ALL trials between 1980-2018. Eighty-five patients developed NHL, with mature B-cell lymphoproliferations as the dominant subtype (56 of 85 cases). Forty-six of these 56 cases (82%) occurred during or within 6 months of maintenance therapy. The majority exhibited histopathological characteristics associated with immunodeficiency (65%), predominantly evidence of Epstein-Barr virus-driven lymphoproliferation. We investigated 66 cases of post-ALL immunodeficiency-associated lymphoid neoplasms, 52 from our study and 14 additional cases from a literature search. With a median follow-up of 4.9 years, the 5-year overall survival for the 66 patients with immunodeficiency-associated lymphoid neoplasms was 67.4% (95% confidence interval [CI], 56-81). Five-year cumulative risks of lymphoid neoplasm- and leukemia-related mortality were 20% (95% CI, 10.2-30) and 12.4% (95% CI, 2.7-22), respectively. Concurrent hemophagocytic lymphohistiocytosis was associated with increased mortality (hazard ratio, 7.32; 95% CI, 1.62-32.98; P = .01). A large proportion of post-ALL lymphoid neoplasms are associated with an immunodeficient state, likely precipitated by ALL maintenance therapy. Awareness of this underrecognized entity and pertinent diagnostic tests are crucial for early diagnosis and optimal therapy.

[Osteonecrosis-severe side effect of treatment for acute lymphoblastic leukemia]. / Osteonekrosen ­ gravierende Therapiefolge bei akuter lymphoblastischer Leukämie.

Osteonecrosis occurs as an acute and long-term serious side effect in children, adolescents, and adults with acute lymphoblastic leukemia. It is associated with severe pain and reduced mobility, ultimately leading to joint destruction and significant long-term morbidity. The cumulative incidence ranges from 11 to 20% in adolescents and young adults. In symptomatic patients, multiple joints are frequently affected, which in turns poses a risk factor for the development of severe osteonecrosis. The genesis of leukemia-associated osteonecrosis is multifactorial. Risk factors include the use of corticosteroids and asparaginase. These exert their effects on the blood supply to the bone through hypercholesterolemia, hypertriglyceridemia, and hypertension. Bacteriemia, genetic susceptibility, and stem cell transplantation pose additional risk factors. The treatment of osteonecrosis is challenging and not evidence based. Preventive measurements have as yet mainly been tested in preclinical models.

Key factors for effective mitotane therapy in children with adrenocortical carcinoma.

Adjuvant treatment with mitotane and chemotherapy is recommended for paediatric advanced and metastatic adrenocortical carcinoma (ACC). Yet, questions on the indication, dosage, and length of therapy are unanswered. Data from the German Paediatric Oncology Haematology-Malignant Endocrine Tumour studies were analysed retrospectively for patients receiving mitotane during first- and/or second-line therapy. Forty-three patients were identified (median age: 7.5 years (range: 0.2-17.8); 29 female) with median follow-up of 2.2 years (range: 0.04-12.71). Three-year overall (OS) and progression-free survival (PFS) were 44.9% and 28.5%, respectively. Eleven of 43 patients received mitotane as neoadjuvant treatment, and 4/11 tumours reached partial remission (PR). Twenty-seven of 43 patients received mitotane combined with chemotherapy in an adjuvant setting resulting in PR of measurable target lesions in 5/13 patients. Metastatic disease (hazard ratio (HR): 3.2; 95% CI: 1.2-18.6; P = 0.018), duration of mitotane treatment <9 months (HR: 5.6; 95% CI: 1.9-16.9; P = 0.002), and not achieving drug target range (TR) (HR: 28.5; 95% CI: 5.4-150.3; P < 0.001) significantly impacted as negative prognostic factors upon PFS and OS (metastatic disease: HR: 4.9; 95% CI: 1.6-15.5; P = 0.006; duration of mitotane treatment: HR: 7.0: 95% CI 1.9-26.0; P = 0.004; TR not reached: HR: 13.5; 95% CI 3.6-50.3; P < 0.001). Cox regression determined the risk of event decreasing by 10.4% for each month of mitotane treatment (P = 0.015). Re-treatment with mitotane after first-line treatment proved ineffective. The duration of mitotane treatment and reaching mitotane TR significantly impacted survival. Improving the efficacy of mitotane, including appropriate indications, needs to be evaluated in prospective randomized trials.

Adrenocortical Tumors and Pheochromocytoma/Paraganglioma Initially Mistaken as Neuroblastoma-Experiences From the GPOH-MET Registry.

In children and adolescents, neuroblastoma (NBL), pheochromocytoma (PCC), and adrenocortical tumors (ACT) can arise from the adrenal gland. It may be difficult to distinguish between these three entities including associated extra-adrenal tumors (paraganglioma, PGL). Precise discrimination, however, is of crucial importance for management. Biopsy in ACT or PCC is potentially harmful and should be avoided whenever possible. We herein report data on 10 children and adolescents with ACT and five with PCC/PGL, previously mistaken as NBL. Two patients with adrenocortical carcinoma died due to disease progression. Two (2/9, missing data in one patient) patients with a final diagnosis of ACT clearly presented with obvious clinical signs and symptoms of steroid hormone excess, while seven patients did not. Blood analyses indicated increased levels of steroid hormones in one additional patient; however, urinary steroid metabolome analysis was not performed in any patient. Two (2/10) patients underwent tumor biopsy, and in two others tumor rupture occurred intraoperatively. In 6/10 patients, ACT diagnosis was only established by a reference pediatric pathology laboratory. Four (4/5) patients with a final diagnosis of PCC/PGL presented with clinical signs and symptoms of catecholamine excess. Urine tests indicated possible catecholamine excess in two patients, while no testing was carried out in three patients. Measurements of plasma metanephrines were not performed in any patient. None of the five patients with PCC/PGL received adrenergic blockers before surgery. In four patients, PCC/PGL diagnosis was established by a local pathologist, and in one patient diagnosis was revised to PGL by a pediatric reference pathologist. Genetic testing, performed in three out of five patients with PCC/PGL, indicated pathogenic variants of PCC/PGL susceptibility genes. The differential diagnosis of adrenal neoplasias and associated extra-adrenal tumors in children and adolescents may be challenging, necessitating interdisciplinary and multidisciplinary efforts. In ambiguous and/or hormonally inactive cases through comprehensive biochemical testing, microscopical complete tumor resection by an experienced surgeon is vital to preventing poor outcome in children and adolescents with ACT and/or PCC/PGL. Finally, specimens need to be assessed by an experienced pediatric pathologist to establish diagnosis.

Neurofibromatosis type 1: A comparison of the 1997 NIH and the 2021 revised diagnostic criteria in 75 children and adolescents.

PURPOSE: Examining a cohort of patients suspicious of neurofibromatosis type 1 (NF1) we compared the revised diagnostic criteria with the previous National Institutes of Health (NIH) diagnostic criteria. We asked whether the refinement improved distinguishing between NF1, Legius syndrome, and constitutional mismatch repair deficiency (CMMRD). METHODS: A database search in the hospital information system of the University Children's Hospital Augsburg between 2017 and 2020 ascertained patients with International Classification of Diseases-10 code Q85.0; their clinical phenotype was evaluated by retrospective chart review. RESULTS: A total of 75 patients were identified (median age 11.0 years [range 1.1-22.6 years]; 35 female). At first suspicion of NF1, 44 patients met the NIH criteria and 56 met the revised diagnostic criteria. In total, 12 patients were diagnosed with NF1 after performing molecular genetic testing. In 31 patients, only pigmentary findings were present, whereas nonpigmentary NF1 manifestations presented with time in 9 patients. In 1 patient a heterozygous variant of uncertain significance was identified in SPRED1. Requirements for CMMRD testing were fulfilled in another patient. A total of 3 patients presented with segmental clinical findings. Three additional patients did not meet the NIH criteria, 1 of them presented with 1 additional feature of CMMRD without fulfilling requirements for testing. CONCLUSION: In our pediatric cohort, the revised diagnostic criteria discovered more patients with proven NF1 than the NIH criteria.

Radiotherapy for pediatric adrenocortical carcinoma - Review of the literature.

Background and purpose: Pediatric adrenocortical carcinoma (pACC) is a rare disease with poor prognosis. Publications on radiotherapy (RT) are scarce. This review summarizes the current data on RT for pACC and possibly provides first evidence to justify its use in this setting. Materials and methods: We searched the PubMed and Embase database for manuscripts regarding RT for pACC. Results: We included 17 manuscripts reporting on 76 patients treated with RT, after screening 2961 references and 269 full articles. In addition, we added data of 4 unreported pACC patients treated by co-authors. All reports based on retrospective data. Median age at first diagnosis was 11.1 years (70% female); 78% of patients presented with hormonal activity. RT was mostly performed for curative intent (78%). 88% of RT were administered during primary therapy. The site of RT was predominantly the local tumor bed (76%). Doses of RT ranged from 15 to 62 Gy (median 50 Gy). Information on target volumes or fractionation were lacking. Median follow-up was 6,9 years and 64% of the patients died of disease, with 33% alive without disease. In 16 of 48 patients with available follow-up data after adjuvant RT (33%) no recurrence was reported and in 3 of 9 patients palliative RT seemed to induce some benefit for the patient. Conclusions: Our first systematic review on RT for pACC provides too few data for any general recommendation, but adjuvant RT in patients with high risk might be considered. International collaborative studies are urgently needed to establish better evidence on the role of RT in this rare malignancy.

Incidences and characteristics of primary lung malignancies in childhood in Germany: An analysis of population-based data from German cancer registries.

BACKGROUND: Primary lung malignancies are a heterogeneous group of cancers that occur very rarely in childhood. Due to limited knowledge of their epidemiologic and clinical features, these tumors present a challenge to the treating physicians. This study aimed to increase the knowledge about the occurrence of primary lung malignancies in childhood in Germany. MATERIALS AND METHODS: Pseudonymized data of cases recorded at the German Center for Cancer Registry Data (ZfKD) between 1990 and 2017 were retrieved. Primary lung malignancies were identified using the ICD- and ICD-O classification. Numbers were compared to those reported to the German Childhood Cancer Registry (GCCR). Crude incidence rates were calculated using the ZfKD database. RESULTS: A total of 168 patients diagnosed with primary lung malignancies in the age below 19 years were identified from the ZfKD. The median age at diagnosis was 13 years. The most common tumor entities were lung carcinoids (n = 49), lung carcinoma (n = 36), and pleuropulmonary blastoma (n = 14). An unexpected accumulation of lung cancer cases was noted in the first year of life without a clearly specified histopathological diagnosis. A substantial discrepancy in the numbers of primary lung malignancies between ZfKD and GCCR was found. CONCLUSIONS: We present population-based data on the occurrence of primary childhood lung malignancies in Germany, which were more frequent than previously anticipated but likely remained underreported. For better understanding and optimal treatment of these entities, cancer registration needs to be improved through mandatory reporting to the GCCR and regular data sharing between GCCR, population-based and clinical cancer registries.

Age, American Thyroid Association Risk Group, and Response to Therapy Are Prognostic Factors in Children With Differentiated Thyroid Cancer.

CONTEXT: Against the background of increasing incidence, pediatric differentiated thyroid carcinoma (DTC) frequently presents with advanced disease and high recurrence rates while prognosis remains excellent. BACKGROUND: We investigated the use of a pediatric classification and an adult response to therapy risk stratification for pediatric DTC patients and their implications for adaptation of treatment and follow-up. METHODS: Data from patients aged <18 years with a diagnosis of primary DTC, registered with the German Pediatric Oncology Hematology-Malignant Endocrine Tumor registry since 1995, were analyzed. For risk prediction, patients were retrospectively assigned to the American Thyroid Association (ATA) risk groups and evaluated for response to therapy. RESULTS: By October 2019, 354 patients with DTC had been reported (median age at diagnosis 13.7 years, range 3.6-17.9) with lymph node and distant metastases in 74.3% and 24.5%. Mean follow-up was 4.1 years (range 0-20.6). Ten-year overall and event-free survival (EFS) rates were 98.9% and 78.1%. EFS was impaired for patients with lymph node and distant metastases (P < .001), positive postoperative thyroglobulin (P = .006), incomplete resection (P = .002), sequential surgeries to achieve total thyroidectomy (P = .042), invasion of capsule (P < .001) and lymph vessels (P = .005), infiltration of surrounding soft tissues (P < .001), tumor multifocality (P < .001), ATA intermediate- and high-risk group (P < .001), and age <10 years (P < .001). Multivariate analysis revealed age <10 years at diagnosis, ATA high-risk level, and poor response to therapy as significant negative prognostic factors for EFS. CONCLUSION: Age, ATA risk group, and response to therapy emerged as significant prognostic factors for EFS in pediatric patients with DTC, requiring risk-adapted individualized therapy and follow-up.

The need for tumor surveillance of children and adolescents with cancer predisposition syndromes: a retrospective cohort study in a tertiary-care children's hospital.

Expert recommendations for the management of tumor surveillance in children with a variety of cancer predisposition syndromes (CPS) are available. We aimed (1) at identifying and characterizing children who are affected by a CPS and (2) at comparing current practice and consensus recommendations of the American Association for Cancer Research workshop in 2016. We performed a database search in the hospital information system of the University Children's Hospital for CPS in children, adolescents, and young adults and complemented this by review of electronic patients' charts. Between January 1, 2017, and December 3, 2019, 272 patients with 41 different CPS entities were identified in 20 departments (144 [52.9%] male, 128 [47.1%] female, median age 9.1 years, range, 0.4-27.8). Three (1.1%) patients died of non-malignancy-associated complications of the CPS; 49 (18.0%) patients were diagnosed with malignancy and received regular follow-up. For 209 (95.0%) of the remaining 220 patients, surveillance recommendations were available: 30/220 (13.6%) patients received CPS consultations according to existing consensus recommendations, 22/220 (10.0%) institutional surveillance approaches were not complying with recommendations, 84/220 (38.2%) patients were seen for other reasons, and 84/220 (38.2%) were not routinely cared for. Adherence to recommendations differed extensively among CPS entities. CONCLUSION: The spectrum of CPS patients at our tertiary-care children's hospital is manifold. For most patients, awareness of cancer risk has to be enhanced and current practice needs to be adapted to consensus recommendations. Offering specialized CPS consultations and establishing education programs for patients, relatives, and physicians may increase adherence to recommendations. WHAT IS KNOWN: • A wide spectrum of rare syndromes manifesting in childhood is associated with an increased cancer risk. • For many of these syndromes, expert recommendations for management and tumor surveillance are available, although based on limited evidence. WHAT IS NEW: • Evaluating current practice, our data attest significant shortcomings in tumor surveillance of children and adolescents with CPS even in a tertiary-care children's hospital. • We clearly advocate a systematic and consistent integration of tumor surveillance into daily practice.

Outcome for Pediatric Adreno-Cortical Tumors Is Best Predicted by the COG Stage and Five-Item Microscopic Score-Report from the German MET Studies.

Background: Adrenocortical tumors (ACTs) encompassing the adrenocortical adenoma (ACA), carcinoma (ACC), and tumors of undetermined malignant potential (ACx) are rare endocrine neoplasms with a poor prognosis. We report on pediatric ACT patients registered with the Malignant Endocrine Tumor studies and explore the EXPeRT recommendations for management. Patients: Data from the ACT patients (<18 years) were analyzed. For the risk prediction, the patients were retrospectively assigned to the COG stages and the five-item score. Results: By December 2021, 161 patients with ACT (ACA n = 51, ACx n = 19, and ACC n = 91) had been reported (the median age at the diagnosis was 4.3 years with a range of 0.1−17.8), with lymph node and distant metastases in 10.7% and 18.9% of the patients with ACC/ACx. The mean follow-up was 4.5 years (with a range of 0−16.7). The three-year overall (OS) and event-free survival (EFS) rates were 65.5% and 50.6%. In the univariate analyses, the OS was impaired for patients aged ≥ 4 years (p = 0.001) with the initial biopsy (p = 0.016), tumor spillage (p = 0.028), incomplete tumor resection (p < 0.001), unfavorable histology (p = 0.047), and COG stages III/IV (p = 0.002). Multivariate analysis revealed COG stages III/IV and an unfavorable five-item score as independent negative prognostic factors for the EFS and OS. Conclusions: Age defines the clinical presentation and prognosis in pediatric ACTs. The outcome is best predicted by the COG stage and five-item score.