Metastatic Pheochromocytoma and Paraganglioma: Focus on Therapeutics

Abstract

Metastatic pheochromocytomas and paragangliomas are rare and challenging tumors. The tumor burden, combined with excessive catecholamine production, predispose to a broad spectrum of complications that range from spinal cord compression to any organ damage, all of which may lead to decreased quality of life and overall survival. Current therapies include surgery, systemic chemotherapy and radiopharmaceutical agents. Surgery is often a preferred therapy because it may cure or allow a long-term remission in patients with locoregional or isolated resectable distant metastases. Additionally, surgery can palliate symptoms related to tumor burden or catecholamine excess. However, in patients for whom surgery is not an option, systemic chemotherapy and radiopharmaceutical agents are preferred options. Systemic chemotherapy and radiopharmaceutical agents such as 131I-Metaiodobenzylguanidine (131I-MIBG) may cause partial responses or stabilization of disease with better blood pressure control and symptomatic and performance status improvement. However, as these therapies are only palliative, patients' quality of life and personal preferences should always be considered. The recognition of molecular pathways involved in the pheochromocytoma and paraganglioma tumorigenesis has driven the development of new therapeutic options. Agents such as tyrosine kinase, MAPK, PI3K, or hypoxia inducible factor inhibitors, alone or in combination, may represent novel therapeutic strategies that could be evaluated in prospective clinical trials. Transcriptional profiling and the development of personalized cancer medicine will help to pave the way for more specific therapeutic approaches and combinations.

Treatment and outcome of metastatic paraganglioma of the spine

“…Also, for the progressive spinal MPG, 3 cases receiving revision surgery showed the increase of Ki-67 index which may indicate the positive association between the Ki-67 and the possibility of metastasis. In our cohort, 13 primary PG specimens were bigger than 5 cm in maximum diameter which accorded with reports that bigger than 5 cm was more likely to transfer to malignancy and metastasis [7,10].…”

“…1 accounting for 66.7% of all our cases. Metastasis could be presented at the time of diagnosis of the PG or years later [7,14] and the mean duration from surgical resection of the primary tumor to spinal metastasis was 8.2 (0.5-15) years. As a result, long-term follow-up was recommended for patients who had the PG treatment history, especially retroperitoneal ones.…”

“…It is a slow-growing tumor that often presents as a painless mass in the fifth or sixth decade of life [4], and often recurs after incomplete surgical resection. Although regarded as benign in nature, PG possesses metastatic possibility which is a marker of malignant transformation [5,6] as there are no molecular or cellular markers existing for determining whether PG is malignant [7][8][9]. Metastatic PGs (MPG) are among the solid tumors that most frequently spread to the skeleton, with spine being the most frequently affected site [10].…”

Consensus Statement on next-generation-sequencing-based diagnostic testing of hereditary phaeochromocytomas and paragangliomas

“…Detection of a PPGL-related somatic mutation in the tumour of a germ line 'negative PPGL' suggests sporadic disease, and, consequently, averts the need for screening the patient's relatives. Moreover, identification of a somatic mutation provides insights into tumour biology, and might guide targeted therapies, especially in patients with metastatic disease (when treatment options are limited) [56][57][58][59] . The Study Group recommends that the analysis of somatic mutations in PPGLs be carried out whenever possible.…”

Trp53 inactivation leads to earlier phaeochromocytoma formation in pten knockout mice

“…Radiotherapy with 131 I-MIBG is an option if patients have a good uptake of 123 I-MIBG in active metastases. In addition, systemic chemotherapy has also been used to treat metastatic disease; however, the number of patients in these studies was too less to draw evidence-based conclusions (Adjalle et al 2009, Plouin et al 2012. A recent study on two mouse PCC cell lines showed that a combination of drugs that specifically block mTORC1/2, PI3K, ERK1/2, AKT, VEGF and EGF receptor functions can have a significant effect on the growth of these tumour cells.…”