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 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

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

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

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

Refractory and relapsed paediatric ACC in the MET studies – a challenging situation necessitating novel diagnostic and therapeutic concepts

Background Paediatric adrenocortical carcinomas (ACC) are highly aggressive malignancies with a dismal prognosis in advanced and metastatic disease. Little is known about outcome of patients with refractory and relapsed (r/r) disease. Procedure National retrospective multicentre study including r/r ACC diagnosed in patients aged <18 years registered in the MET studies between January 1997 and December 2021 Results A total of 16 patients (5 male; median age 12.9 years) with refractory disease were included. Median time to progression was 0.6 years [0.0-1.3]. Site of progression was locoregional (n=1), distant (n=3), and combined (n=12). 3-year overall (OS) and progression-free (PFS) survival were both 0%. Thirty patients with relapse (11 male; median age 7.3 years) were identified. Median time to relapse was 0.7 years [0.1-3.2]. Site of relapse was locoregional (n=8), distant (n=15), and combined (n=7). At last follow-up, 20 patients had died of disease or complications or were alive with disease, 10 patients were in second complete remission (median follow-up: 6.8 years [0-10.5]). 3-year OS and PFS following relapse were 39.1% and 31.9%. Survival was superior in patients with distant relapse (59.6%) compared to locoregional (28.6%) and combined (14.3%) (p=0.028) and in patients with complete surgical resection of all sites of recurrence (70.0%) compared to incomplete (21.4%) and no surgery (0%) (p=0.003). Conclusions For patients nonresponsive to first-line therapy or who experience relapse, prognosis is dismal and options are scarce. Site of relapse and resectability define prognosis. Novel therapeutic concepts are needed to improve the outcome of paediatric patients with r/r ACC

Fertility education for adolescent cancer patients: Gaps in current clinical practice in Europe

Objective: As adolescent cancer patients may suffer from infertility following treatment, fertility counselling is essential. Our aim was to explore the current situation in four European countries in terms of (I) education about the risk for infertility, (II) counselling on fertility preservation, (III) patients' knowledge on fertility, (IV) sufficiency of information and (V) uptake of cryopreservation. Methods: In total, 113 patients (13–20 years) at 11 study centres completed a self-report questionnaire three and six months after cancer diagnosis. Multivariate logistic regression was used to estimate odds ratios (OR) with 95% confidence intervals (CI). Results: As many as 80.2% of participants reported having received education about the risk for infertility prior to treatment, 73.2% recalled counselling on fertility preservation. Only 52.3% stated they felt sufficiently informed to make a decision. Inability to recall counselling on fertility preservation (OR = 0.03, CI: 0.00–0.47) and female gender (OR = 0.11, CI: 0.03–0.48) was associated with lower use of cryopreservation, whereas older age was associated with higher use. Conclusion: Fertility counselling was available to a relatively high proportion of patients, and it did influence the utilisation of cryopreservation. However, many patients did not feel sufficiently informed. Further improvement is needed to enable adolescent cancer patients to make an informed decision on fertility preservation

Osteonecrosis in adults with acute lymphoblastic leukemia: an unmet clinical need

Osteonecrosis is a serious complication of antileukemic therapy associated with severe pain and reduced mobility, ultimately leading to joint destruction and significant long-term morbidity. The 5-year cumulative incidence of osteonecrosis ranges from 11% to 20% in adolescents and young adults to 3% to 8% in patients aged 30 years and older. Most symptomatic patients have multiple joints affected, which in turn poses a risk factor for developing severe osteonecrosis. Osteonecrosis has a multifactorial genesis. Treatment-associated risk factors for developing osteonecrosis depend on the therapeutic context including the use of glucocorticosteroids and the simultaneous and/or intensified use of asparaginase (ASP) which may, among others, exert its effect on blood supply to the bone through hypertriglyceridemia, hypercholesterolemia, and hypertension. Allogeneic hematopoietic stem cell transplantation, bloodstream infections, and genetic factors may additionally impact the risk of osteonecrosis. In this article, the authors used the best available evidence in the literature to develop management recommendations for the use in the context of steroid and asparaginase containing regimens. These considerations may be helpful for similar treatment approaches

Osteonecrosis in children with acute lymphoblastic leukemia

The morbidity and toxicity associated with current intensive treatment protocols for acute lymphoblastic leukemia in childhood become even more important as the vast majority of children can be cured and become long-term survivors. Osteonecrosis is one of the most common therapy-related and debilitating side effects of anti-leukemic treatment and can adversely affect long-term quality of life. Incidence and risk factors vary substantially between study groups and therapeutic regimens. We therefore analyzed 22 clinical trials of childhood acute lymphoblastic leukemia in terms of osteonecrosis incidence and risk factors. Adolescent age is the most significant risk factor, with patients >10 years old at the highest risk. Uncritical modification or even significant reduction of glucocorticoid dosage cannot be recommended at this stage. A novel and innovative approach to reduce osteonecrosis-associated morbidity might be systematic early screening for osteonecrosis by serial magnetic resonance images. However, discriminating patients at risk of functional impairment and debilitating progressive joint disease from asymptomatic patients still remains challenging