Abstract and Introduction
Context Pheochromocytomas (PCCs) are tumors that are derived from the chromaffin cells of the adrenal medulla. Extra-adrenal PCCs called paragangliomas (PGLs) are derived from the sympathetic and parasympathetic chain ganglia. PCCs secrete catecholamines, which cause hypertension and have adverse cardiovascular consequences as a result of catecholamine excess. PGLs may or may not produce catecholamines depending on their genetic type and anatomical location. The most worrisome aspect of these tumors is their ability to become aggressive and metastasize; there are no known cures for metastasized PGLs.
Methods Original articles and reviews indexed in PubMed were identified by querying with specific PCC/PGL- and Krebs cycle pathway–related terms. Additional references were selected through the in-depth analysis of the relevant publications.
Results We primarily discuss Krebs cycle mutations that can be instrumental in helping investigators identify key biological pathways and molecules that may serve as biomarkers of or treatment targets for PCC/PGL.
Conclusion The mainstay of treatment of patients with PCC/PGLs is surgical. However, the tide may be turning with the discovery of new genes associated with PCC/PGLs that may shed light on oncometabolites used by these tumors.
In 1886, the year that Robert Louis Stevenson published his novel Strange Case of Dr. Jekyll and Mr. Hyde, the first case of pheochromocytoma (PCC) was documented in Germany and described an 18-year-old woman with hypertensive crisis due to bilateral adrenal tumors. A quarter century later, the German pathologist Ludwig Pick noted a color change after adding chromium salts to adrenal medullary tumors. He coined the term pheochromocytoma from the Greek "phaios" (dark), "chroma" (color), and "cytoma" (tumor). Over the years, PCC and paraganglioma (PGL) tumors have revealed, like the main character in Stevenson's novel, their "split personality" in presentation and behavior, as well as in different genetic origins.
The clues as to what has been hiding behind the changes come from Dr. Otto Warburg's insightful observation that tumorogenic cells use glucose at higher levels compared with normal cells. Warburg went on to propose that this difference in metabolism is the fundamental cause of cancer. A better understanding of glucose metabolism came through the discovery of the tricarboxylic acid (TCA) cycle, or Krebs cycle, by Warburg's mentee, Dr. Hans Krebs. By 1937, the TCA cycle was thoroughly described and provided the foundation of our understanding of cell metabolism. However, the connection between deficient Krebs cycle and cancer only became uncovered in the 21st century, when mutations were found in the succinate dehydrogenase subunits (SDHx) complex in hereditary PCC/PGLs. This discovery became the first documented case that directly linked defective mitochondrial protein with cancer predisposition.
J Clin Endocrinol Metab. 2018;103(5):1779-1789. © 2018 Endocrine Society