Metastatic pheochromocytoma/paraganglioma related to primary tumor development in childhood or adolescence: significant link to SDHB mutations - PubMed (original) (raw)

. 2011 Nov 1;29(31):4137-42.

doi: 10.1200/JCO.2011.34.6353. Epub 2011 Oct 3.

Tamara Prodanov, Vitaly Kantorovich, Tito Fojo, Jacqueline K Hewitt, Margaret Zacharin, Robert Wesley, Maya Lodish, Margarita Raygada, Anne-Paule Gimenez-Roqueplo, Shana McCormack, Graeme Eisenhofer, Dragana Milosevic, Electron Kebebew, Constantine A Stratakis, Karel Pacak

Affiliations

Kathryn S King et al. J Clin Oncol. 2011.

Abstract

Purpose: To present data on the high rate of SDHB mutations in patients with metastatic pheochromocytoma/paraganglioma whose initial tumor presentation began in childhood or adolescence.

Patients and methods: From 2000 to 2010, 263 patients with pheochromocytoma/paraganglioma were evaluated through the National Institutes of Health (NIH), Bethesda, MD. Of the 263 patients, 125 patients were found to have metastatic disease; of these 125 patients, 32 patients presented with a tumor before 20 years of age. An additional 17 patients presented with a tumor before 20 years of age but demonstrated no development of metastatic disease. Genetic testing for mutations in the VHL, MEN, and SDHB/C/D genes was performed on patients without previously identified genetic mutations.

Results: Of the 32 patients who presented with metastatic disease and had their primary tumor in childhood or adolescence, sequence analysis of germline DNA showed SDHB mutations in 23 patients (71.9%), SDHD mutations in three patients (9.4%), VHL mutations in two patients (6.3%), and an absence of a known mutation in four patients (12.5%). The majority of these 32 patients (78.1%) presented with primary tumors in an extra-adrenal location.

Conclusion: The majority of patients with metastatic pheochromocytoma/paraganglioma who presented with a primary tumor in childhood/adolescence had primary extra-adrenal tumors and harbored SDHB mutations. Except for primary tumors located in the head and neck where SDHD genetic testing is advised, we recommend that patients who present with metastatic pheochromocytoma/paraganglioma with primary tumor development in childhood or adolescence undergo SDHB genetic testing before they undergo testing for other gene mutations, unless clinical presentation or family history suggests a different mutation.

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Conflict of interest statement

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

Figures

Fig 1.

Fig 1.

Flow chart of study patient population. Statistical analysis that compared percentages of pediatric/adolescent patients in the metastatic versus nonmetastatic groups (26.7% and 12.7%, respectively) showed statistical significance (P = .006) in the metastatic group. Similarly, statistical analysis that compared the rate of SDHB mutations among pediatric/adolescent patients with metastatic disease with the pediatric/adolescent patients without metastatic disease demonstrated statistical significance (P = .002) in the metastatic group. (*) Statistically higher compared with the nonmetastatic tumor group. MEN2, multiple endocrine neoplasia type 2; NF1, neurofibromatosis type 1; SDHB, succinate dehydrogenase subunit B; SDHD, succinate dehydrogenase subunit D; Sporadic, no mutation identified; VHL, von Hippel-Lindau.

Fig 2.

Fig 2.

Kaplan-Meier survival curve and 95% confidence band: Metastases-free survival for all patients (N = 49). The two main characteristics of this estimated survival curve were (1) an early set of failures within 2 years (the 2-year estimate was 79.2%, which indicated that approximately 20% of patients would develop metastatic disease within 2 years of diagnosis) and (2) a slow but steady decrease in the curve from 2 to 30 years, with a 30-year estimate of 4.5%. Small tic marks indicate follow-up times for patients who did not develop metastases.

Fig 3.

Fig 3.

Comparison of metastases-free survival between succinate dehydrogenase subunit B (SDHB) patients (n = 27) and non-SDHB patients (n = 22). Although both groups showed an early set of failures (within 2 years) followed by a steady stream of patients who developed metastases over the next two to three decades, SDHB patients fared substantially worse (P = .005). Small tic marks indicate follow-up times for patients who did not develop metastases.

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