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Long-term prognosis of patients with pediatric pheochromocytoma
Birke Bausch1, Ulrich Wellner, Dirk Bausch
12nd Department of Medicine, University of Freiburg, Freiburg, Germany Department of Surgery, University Hospital Schleswig-Holstein, Campus Luebeck, Luebeck, Germany Department of Medicine, Familial Cancer Clinic and Oncoendocrinology, University of Padova, Padova, Italy Center for Endocrinological Investigations (CEDIE), Hospital de Ninos R. Gutierrez, Buenos Aires, Argentina Department of Surgery, Center of Minimally Invasive Surgery, Kliniken Essen-Mitte, Essen, Germany Department of Hypertension, Institute of Cardiology, Warsaw, Poland Department of Endocrinology, University of Lorraine, Nancy, France Division of Pediatric Surgery, Department of Pediatrics, University Hospital of Padova, Padova, Italy Pediatric Oncology, Division of Hematology and Oncology, Department of Pediatrics, University Hospital of Padova, Padova, Italy Department of Endocrinology, University Medical Center, University of Duisburg and Essen, Essen, Germany Department of Pediatrics, Hospital Great Ormond Street, London, UK 2nd Department of Internal Medicine, Semmelweis University, Budapest, Hungary Institute of Otorhinolaryngology, NAMS of Ukraine, Kiev, Ukraine Department of Endocrinology, University of Riga, Riga, Latvia Department of Endocrinology, La Timone Hospital, Aix-Marseille University, Marseille, France Department of Nuclear Medicine, University Hospital Timone, Marseilles, France Section for Preventive Medicine, Department of Nephrology and General Medicine, University of Freiburg, Freiburg, Germany Department of Visceral Surgery, University of Freiburg, Freiburg, Germany Department of Pediatrics, University of Freiburg, Freiburg, Germany Department of Pathology, University Medical Center, University of Duisburg and Essen, Essen, Germany Genomic Medicine Institute, Lerner Research Institute and Taussig Cancer Institute, Cleveland Clinic, Cleveland, Ohio, USA.
Abstract:
A third of patients with paraganglial tumors, pheochromocytoma, and paraganglioma, carry germline mutations in one of the susceptibility genes, RET, VHL, NF1, SDHAF2, SDHA, SDHB, SDHC, SDHD, TMEM127, and MAX. Despite increasing importance, data for long-term prognosis are scarce in pediatric presentations. The European-American-Pheochromocytoma-Paraganglioma-Registry, with a total of 2001 patients with confirmed paraganglial tumors, was the platform for this study. Molecular genetic and phenotypic classification and assessment of gene-specific long-term outcome with second and/or malignant paraganglial tumors and life expectancy were performed in patients diagnosed at <18 years. Of 177 eligible registrants, 80% had mutations, 49% VHL, 15% SDHB, 10% SDHD, 4% NF1, and one patient each in RET, SDHA, and SDHC. A second primary paraganglial tumor developed in 38% with increasing frequency over time, reaching 50% at 30 years after initial diagnosis. Their prevalence was associated with hereditary disease (P=0.001), particularly in VHL and SDHD mutation carriers (VHL vs others, P=0.001 and SDHD vs others, P=0.042). A total of 16 (9%) patients with hereditary disease had malignant tumors, ten at initial diagnosis and another six during follow-up. The highest prevalence was associated with SDHB (SDHB vs others, P<0.001). Eight patients died (5%), all of whom had germline mutations. Mean life expectancy was 62 years with hereditary disease. Hereditary disease and the underlying germline mutation define the long-term prognosis of pediatric patients in terms of prevalence and time of second primaries, malignant transformation, and survival. Based on these data, gene-adjusted, specific surveillance guidelines can help effective preventive medicine.
Insights
Pediatric paraganglioma patients with germline mutations face higher risks of secondary tumors and malignancy. Gene-specific surveillance is crucial for managing long-term outcomes and improving life expectancy in these hereditary conditions.
Area of Science:
- Endocrinology and Oncology
- Genetics and Molecular Biology
- Pediatric Medicine
Background:
- A significant proportion of paraganglioma and pheochromocytoma cases are linked to inherited genetic mutations.
- Long-term prognostic data for pediatric paraganglioma patients are limited, hindering effective management strategies.
- Understanding the impact of germline mutations on tumor behavior and patient survival is critical for this population.
Purpose of the Study:
- To assess the long-term outcomes, including second primary tumors, malignant transformation, and survival, in pediatric patients with paraganglioma.
- To investigate the association between specific germline mutations and the risk of developing secondary or malignant tumors.
- To establish gene-specific surveillance guidelines for improved preventive medicine in hereditary paraganglioma.
Main Methods:
- Analysis of data from the European-American-Pheochromocytoma-Paraganglioma-Registry, including 177 pediatric patients (<18 years) with confirmed paraganglioma.
- Molecular genetic and phenotypic classification of tumors.
- Assessment of gene-specific outcomes: development of second primary tumors, malignant transformation, and life expectancy.
Main Results:
- Eighty percent of eligible pediatric patients had germline mutations, with VHL (49%), SDHB (15%), and SDHD (10%) being the most common.
- A second primary paraganglioma developed in 38% of patients, with increased frequency over time, particularly in VHL and SDHD mutation carriers.
- Malignant tumors occurred in 9% of hereditary cases, most frequently associated with SDHB mutations. Five percent of patients died, all with germline mutations.
Conclusions:
- Hereditary disease and specific germline mutations significantly influence the long-term prognosis of pediatric paraganglioma patients.
- Gene-adjusted surveillance is essential for effective preventive medicine, addressing risks of secondary tumors, malignancy, and survival.
- The study highlights the need for tailored management based on genetic profiles to improve outcomes in pediatric paraganglioma.
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