Since the last ISP in 2011, basic and clinical pheochromocytoma (PHEO) and paraganglioma (PGL) research has made important progress in the pathogenesis, genetics, diagnosis, localization, and treatment of these tumors.
New genes, TMEM127, MAX, HIF2A, H-RAS, FH, and PHD1 have been discovered, although all are found much less frequently (altogether in about 10% of these tumors) than other previously described PHEO/PGL susceptibility genes (e.g. MEN2, NF1, VHL, SDHB/D).
The HIF signaling pathway became one of the most paramount ones to represent a common pathway connecting hereditary PHEOs/PGLs in terms of their tumorigenesis and perhaps their treatment targets in the near future.
Additionally and uniquely, other tumor types have been associated with PHEO/PGL susceptibility genes, including some pituitary tumors with the presence of succinate dehydrogenase subunit B/D (SDHB/D) mutations and somatostatinomas with the presence of HIF2A mutations.
While 19 PHEO/PGL susceptibility genes are currently known, more are expected to be discovered, especially in metastatic PHEO/PGL with unknown genetic backgrounds, as well as somatic mutations in sporadic tumors.
Next generation sequencing, international collaborations and studies (e.g. TCGA study), and other initiatives and approaches will undoubtedly speed up such discoveries.
In addition to improved genetic diagnoses, the clinical diagnosis of PHEO/PGL has been enriched by the implementation of methoxytyramine in the biochemical diagnosis of these tumors, especially those with SDHx mutations.
Methoxytyramine, a novel biomarker became an important diagnostic tool in the assessment of metastatic PHEOs/PGL and those with SDHx mutations.
Very recently, metabolomic profiles were also introduced for the diagnostic evaluation of these tumors.
High succinate-to-fumarate or succinate-to-glutamate ratios were found to be characteristic for SDHx tumors.
Although metabolomics are not meant to replace genetic or other testing methods for these tumors, in the near future, especially when blood samples are used, they may be useful for monitoring tumor responses, resistance to chemotherapy or radiotherapy, and acute changes in the activity of these tumors, including predicting their more aggressive or metastatic spread.
The use of functional imaging, particularly positron emission tomography compounds, in the localization of these tumors has also been expanded and further supported by several new studies.
[18F]-fluorodopa PET was found to be the best available imaging modality for head and neck PGLs, [18F]-fluorodeoxyglucose PET has been recommended as the first imaging modality for metastatic PHEO/PGL.
New studies using DOTA analogs (67Ga-DOTATOC/DOTANOC/DOTATATE) have been performed, and it is highly expected that these analogs quickly replaceing Octreoscan and becoming paramount in the diagnosis of these tumors, especially if metastatic.
Comparison with other anatomical and functional imaging modalities is expected to be available soon, as well as the first results using DOTA analogs in the treatment of metastatic PHEO/PGL.
The search for additional new treatments for PHEO/PGL continues to be hindered by the lack of suitable animal models and human cell lines, although one sporadic PHEO-derived human cell line has been introduced.
New therapeutic options for metastatic PHEO/PGL are still in their infancy, although several new studies are either in progress or planned.
Promising new treatment avenues may include compounds stabilizing HIF- or topoisomerase or receptor tyrosine kinase inhibitors.
Finally, “Diagnosis and treatment of pheochromocytoma and paraganglioma: An Endocrine Society Clinical Practice Guideline” has been launched this year.
Acknowledgements
This research was supported by the Intramural Research Program of the NICHD/NIH.
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