The size and location of the primary tumor were significant clinical risk factors for metastasis and decreased overall survival duration. These findings delineate the follow-up and treatment for these tumors.

Although PHEO/PGL are rarely diagnosed during childhood, the pediatric provider should be able to recognize and screen for such tumors, particularly in the context of a known genetic predisposition. Optimal care of these children includes a multidisciplinary team approach at centers experienced in the evaluation and treatment of these uncommon yet fascinating endocrine neoplasms.

Pheochromocytomas (PHs) and sympathetic paragangliomas (SPGs) are rare neuroendocrine tumors. Approximately 17 % of these tumors are malignant, but because no molecular or histologic markers for malignancy exist, patients are often diagnosed with malignant PHs or SPGs after unresectable disease has formed. Patients with progressive metastatic tumors and overwhelming symptoms are currently treated with systemic chemotherapy and radiopharmaceutical agents such as metaiodobenzylguanidine. These therapies lead to partial radiographic response, disease stabilization, and symptomatic improvement in approximately 40 % of patients, and systemic chemotherapy is associated with a modest improvement in overall survival duration. However, over the past decade, substantial progress has been made in clinical, biochemical, and radiographic diagnosis of PHs and SPGs. Approximately 50 % of patients with malignant PHs and SPGs have been found to carry hereditary germline mutations in the succinate dehydrogenase subunit B gene (SDHB), and anti-angiogenic agents such as sunitinib have been found to potentially play a role in the treatment of malignant disease, especially in patients with SDHB mutations. In some patients, treatment with sunitinib has been associated with partial radiographic response, disease stabilization, decreased fluorodeoxyglucose uptake on positron emission tomography, and improved blood pressure control. These findings have led to the development of prospective clinical trials of new targeted therapies for metastatic disease. Here, we provide an updated review of the clinical and genetic predictors of malignant disease, radiographic diagnosis of malignant disease, and information from the most relevant studies of systemic therapies, as well as proposed treatment guidelines for patients with metastatic or potentially malignant PHs and SPGs.

Background The purpose of this study was to evaluate the clinical benefits of systemic chemotherapy for patients with metastatic pheochromocytomas or sympathetic paragangliomas by assessing reduction in tumor size, blood pressure, and improvement in overall survival. Methods We retrospectively reviewed the medical records of patients with metastatic pheochromocytomas-sympathetic paragangliomas who had received chemotherapy at The University of Texas MD Anderson Cancer Center Results Clinical benefit and overall survival (OS) were assessed. Of fifty-four patients treated with chemotherapy, fifty-two were evaluable for response. Seventeen (33%) experienced a response, defined as decreased or normalized blood pressure/decreased number and dosage of antihypertensive medications and/or reduced tumor size after the first chemotherapy regimen. The median OS time was 6.4 years (95 confidence interval (CI): 5.2–16.4) for responders and 3.7 (95% CI: 3.0–7.5) years for non-responders. Of patients who had synchronous metastatic disease, a positive response at 1 year after the start of chemotherapy was associated with a trend toward a longer overall survival (log-rank test, P-value =0.095). In a multivariate Cox proportional hazards model, the effect of response to chemotherapy on overall survival was significant (hazard ratio=0.22, 95% confidence interval: 0.05–1.0; P-value = 0.05). All responders had been treated with dacarbazine and cyclophosphamide. Vincristine was included for 14 responders and doxorubicin was included for 12 responders. We could not identify clinical factors that predicted response to chemotherapy. Conclusion Chemotherapy may decrease tumor size and facilitate blood pressure control in about 33% of patients with metastatic pheochromocytoma-sympathetic paraganglioma. These patients exhibit a longer survival.

The clinical phenotype of BAP1 hereditary cancer predisposition syndrome (MIM 614327) includes uveal melanoma (UM), cutaneous melanoma (CM), renal cell carcinoma (RCC), and mesothelioma. However, the frequency of the syndrome in patients with UM and the association with other cancers are still not clear. In this study, we screened 46 previously untested, unrelated UM patients with high risk for hereditary cancer for germline mutation in BAP1. We also studied four additional patients with a personal or family history suggestive of BAP1 hereditary cancer syndrome. We identified three patients with germline pathogenic mutations (c.2050 C>T, pGln684*; c.1182C>G, p.Tyr394*, and c.1882_1885delTCAC, p. Ser628Profs*8) in BAP1. Two of these three patients presented with UM and the third with a metastatic adenocarcinoma likely from a hepatic cholangiocarcinoma. Reported family histories included UM, mesothelioma, RCC, CM, and several other internal malignancies. The results of this study confirm the association between germline BAP1 mutation and predisposition to UM, mesothelioma, CM and RCC. However, other cancers, such as cholangiocarcinoma and breast carcinoma may be part of the phenotype of this hereditary cancer predisposition syndrome. In addition, the results support the existence of other candidate genes in addition to BAP1 contributing to hereditary predisposition to UM.