The Historical Evolution of Neuroendocrine Tumor Disease

As has been well-stated, “those who forget the lessons of history are destined to repeat it.” Thus, the past must be regarded as a prologue. This is certainly true for neuroendocrine (NE) disease, where much has been gained and lost in the mists of history, misunderstandings, and misinterpretations. The road has been long and winding, and the errors, oversights, and omissions substantial as in all discovery paths, yet, in aggregate, much progress has been made, albeit sometimes too slowly. This overview is dedicated to those who laid the path, those who imagined the future, and the innumerable scientists, physicians, and patients who have contributed to unraveling the conundrum, wrapped in an enigma and shrouded by the paradox that is neuroendocrine tumor disease. It has been almost 150 years since Heidenhain, Kulchitsky, and Ciaccio identified chromaffin cells and initiated the cellular basis for understanding the endocrine system. Feyrter provided a unifying concept of a diffuse neuroendocrine network, while Pavlov, Starling, and Bayliss enunciated its functional and regulatory basis. Gosset and Masson identified the neoplastic potential of the cells, and Oberndorfer recognized the prototypical tumors in his seminal pathological description of carcinoid disease. Thereafter, the peptides and amines based on the syndromic aspects of neuroendocrine disease were identified for individual tumors of the pancreas, small bowel, and lungs. Pearse, Bloom, and Polak delineated, defined, and sought to unify what appeared to be a Gordian knot. Berson developed a radioimmunoassay (RIA) and facilitated diagnostic measurements of insulin, serotonin, and other implicated bioactive agents. Vale and Schally’s identification of the somatostatin receptor (SSTR) system led to the development of symptom-controlling agents and provided the basis for Krenning to develop isotope-based tumor visualization (OctreoScan) and then therapeutic applications for yttrium and lutetium (peptide receptor radionuclide therapy (PRRT)). The advance of therapy has been less roseate in its outcome—more scorched earth than intrepid advance. Surgical resection was pioneered by Graham and reached its apogee (sic) with the application of the Whipple technique. The introduction of “specific” therapeutic agents exemplified by everolimus that seemed promising has remained disappointing and toxic, and no effective targeted agents, apart from PRRT, have been identified to date. Overall, enthusiasm has been substantial but dividend yield somewhat limited. Recent advances in molecular identification of tumors by Scarpa, identification of the molecular circulosome of neuroendocrine neoplasia by Modlin and Kidd, and identification of key oncogenic dependencies by Califano have provided novel advances that may initiate the next chapter in the history of neuroendocrine tumor disease. What is past must be remembered so that what is future may be respected as the lessons of yesteryear become the compass of tomorrow.