Objective: Pheochromocytomas and paragangliomas (PPGLs) are rare neuroendocrine tumors that are associated with cancer predisposition syndromes in up to 80% of affected children. PPGLs can be divided into molecularly defined groups with comparable pathogenesis and biology: (1) pseudohypoxic, (2) kinase signaling, and (3) Wntaltered. Methods:We report the data of children and adolescents diagnosed with PPGL who have been registered with the German GPOH-MET registry since 1997.Results: By December 2019, a total of 88 patients with PPGL were reported.Pheochromocytoma occurred in 56%, paraganglioma in 35%, and synchronous PPGLs in 9.1%. A total of 16% of patients presented with lymph node (5.7%) and distant metastases (10%). Median follow-up was 4.2 years (range 0-17.1). Overall and disease-free survival (DFS) were 98.6% and 54.0%, respectively. Local relapses, metastases, and subsequent PPGLs occurred in 11%, 4.5%, and 15% of patients. Germline mutations were detected in 83% of patients (51% in VHL, 21% in SDHB, 7.8% in SDHD, and one patient each in RET and NF1). One patient was diagnosed with Pacak-Zhuang syndrome. A total of 96% of patients presented with PPGL of the pseudohypoxic subgroup (34% TCA cycle-related, 66% VHL/EPAS1-related). In multivariate analyses, extent of tumor resection was a significant prognostic factor for DFS. Conclusions:Most pediatric PPGLs belong to the pseudohypoxia subgroup, which is associated with a high risk of subsequent PPGL events and metastatic disease. Comprehensive molecular profiling of children and adolescents with newly diagnosedPPGLs will open new avenues for personalized diagnosis, treatment, and surveillance.

The development of a second malignancy after 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 (NHL) following pediatric ALL therapy, excluding stem-cell transplantation. We analyzed data of patients enrolled in 12 collaborative pediatric ALL trials between 1980-2018, who developed NHL following ALL diagnosis. Eighty-five patients developed NHL, with mature B-cell lymphoproliferations as the dominant subtype (56/85). Forty-six of these 56 cases (82%) occurred during or within six months of maintenance therapy. The majority (65%) exhibited histopathological characteristics associated with immunodeficiency, predominantly evidence of Epstein-Barr virus (EBV)-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, five-year overall survival for the 66 patients with immunodeficiency-associated lymphoid neoplasms was 67.4% (95% 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 (HR, 7.32; 95% CI, 1.62 to 32.98; p=0.01). 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.

Adjuvant treatment with mitotane and chemotherapy is recommended for paediatric advanced and metastatic adrenocortical carcinoma (ACC). Yet, questions on 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. In total, 43 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). 3-years overall (OS) and progression-free survival (PFS) were 44.9% and 28.5%. Eleven/43 patients received mitotane as neoadjuvant treatment, 4/11 tumours reached partial remission (PR). Twenty-seven/43 patients received mitotane combined with chemotherapy in an adjuvant setting resulting in PR of measurable target lesions in 5/13 patients. Metastatic disease [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 upon survival. Improving the efficacy of mitotane, including appropriate indications, needs to be evaluated in prospective randomized trials.

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