Manish C. Champaneria

A Three-Decade Analysis of 3,911 Small Intestinal Neuroendocrine Tumors: The Rapid Pace of No Progress

OBJECTIVES:Small intestinal neuroendocrine tumors (SI-NETs) are the most common gastrointestinal neuroendocrine tumor, but their natural history and outcome remain poorly defined, which hinders both the prediction of disease progression and appropriate therapeutic options. We examined patterns, incidence, prognosis, and outcomes of these tumors over a 30-yr period.METHODS:Data were extracted from the NCIs SEER registry (1973–2002). Incidence rates, distribution, and 5-yr survival rates were analyzed and adjusted (U.S. decennial census data).RESULTS:Of the 18,641 NETs, 3,911 (21.0%) were SI-NETs, of which 1,953 (49.6%) were ileal. Since 1973, both SI-NET and its ileal variant have increased annually by 3.8% and 2.1%, respectively. Ileal tumors, as a percentage of SI tumors, have increased from 52% to 63.6%. The age-adjusted incidence of ileal, small intestinal, and digestive system NETs has increased 225%, 460%, and 720% over 30 yr. Ileal tumors have specifically increased in prevalence in white (274%) and black (500%) men and women (213% and 286%, respectively); an overall increase of fourfold in blacks and 2.4-fold in whites. Although 83.3% of SI-NETs were staged, 83.7% were histologically ungraded. Five-year survival rates for SI-NETs were 62.6 ± 1% (all stages), 73.8% (localized), 72% (regional), and 43.2% (distant). These have not significantly altered since 1973 (P = 0.11).CONCLUSIONS:SI-NETs have increased, particularly in men and in the black population, which may be due to in vivo changes, increased clinical and pathological awareness, or increased detection of tumors. SI-NETs are malignant, diagnosed late, and survival rates have remained unchanged over 30 yr.

Small bowel carcinoid (enterochromaffin cell) neoplasia exhibits transforming growth factor-β1-mediated regulatory abnormalities including up-regulation of C-myc and MTA1

Although it is known that small intestinal carcinoids are derived from enterochromaffin (EC) cells, these cells remain poorly characterized and little is known of the growth regulatory mechanisms of these neuroendocrine cells. Down‐regulation or loss of the transforming growth factor‐β1 (TGFβ1) cytostatic program and activation of TGFβ‐mediated transcriptional networks is associated with uncontrolled growth and metastasis in other neural tumors, glioblastomas. Whether this phenomenon is common to small intestinal carcinoid tumors was investigated.

Evolution of the Diffuse Neuroendocrine System – Clear Cells and Cloudy Origins

As early as the 2nd century, Galen proposed that ‘vital spirits’ in the blood regulated human bodily functions. However, the concept of hormonal activity required a further 18 centuries to develop and relied upon the identification of ‘ductless glands’, Schwann’s cell and the recognition by Bayliss and Starling of chemical messengers. Bernard’s introduction of ‘internal secretion’ and its role in homeostasis laid a physiological basis for the development of endocrinology. Kocher and Addison recognized the consequences of ablation of glands by disease or surgery and identified their necessary role in life. Detailed descriptions of the endocrine cells of the gut and pancreas and their putative function were provided by Heidenhain, Langerhans, Laguesse and Sharpey-Schäfer. Despite the dominant 19th century concept of nervism (Pavlov), in 1902, Starling and Bayliss using Hardy’s term ‘hormonos’ described secretin and in so doing, established the gut as an endocrine organ. Thus, nervism was supplanted by hormonal regulation of function and thereafter numerous bioactive gut peptides and amines were identified. At virtually the same time (1892), Ramón y Cajal of Madrid reported the existence of a group of specialized intestinal cells that he referred to as ‘interstitial cells’. Cajal postulated that they might function as an interface between the neural system and the smooth muscles of the gut. Some 22 years later, Keith suggested that their function might be analogous to the electroconductive system of the heart and proposed their role as components of an intestinal pacemaker system. This prescient hypothesis was subsequently confirmed in 1982 by Thuneberg and a decade later Maede identified c-Kit as a critical molecular regulator in the development and function of the interstitial cells of Cajal and further confirmed the commonality of neural and endocrine cells. The additional characterization of the endocrine regulatory system of the GI tract was implemented when Feyrter (1938) using Masson’s staining techniques, identified ‘helle Zellen’ within the pancreatic ductal system and the intestinal epithelium and proposed the concept of a diffuse neuroendocrine system. Pearse subsequently grouped the various cells belonging to that system under the rubric of a unifying APUD series. Currently, the gut neuroendocrine system is viewed as a syncytium of neural and endocrine cells sharing a common cell lineage whose phenotypic regulation is as yet unclear. Their key role in the regulation of gastrointestinal function is, however, indubitable.

Friedrich Feyrter: A Precise Intellect in a Diffuse System

Prior to the contributions of Friedrich Feyrter (1895–1973), the regulation of gastrointestinal function was an ill-understood field that was polarized by a combination of the inability of clinical scientists to perceive the relationship between the cellular elements of ‘nervism’ and the newly recognized chemical messenger system. Feyrter, an Austrian pathologist of luminescent intellect and possessed of rigorous analytic capacity, recognized the interface of the divergent elements (neural and endocrine) and established the concept of the diffuse neuroendocrine system. His pathological descriptions of the specialized neuroendocrine cells producing biologically active substances and regulating homeostasis by a network functioning via endocrine, paracrine, and neuracrine mechanisms laid the basis for contemporary understanding of gut function. In 1938, Feyrter identified Helle Zellen (clear cells) of the pancreas and gastrointestinal tract, which was later incorporated into the amine precursor uptake decarboxylation concept of endocrine cells by A.G.E. Pearse (1916–2003). Feyrter proposed a diffuse network as a functional regulatory system as opposed to the then current doctrine of ‘organ’ regulation in his 1938 manuscript Über diffuse endokrine epitheliale Organe. In addition to this seminal contribution, the prodigious intellect of Feyrter produced an array of novel observations including benign and malignant tumors of the skin, gastrointestinal tract, and eyes, carcinoid tumors and the carcinoid syndrome, the genesis of the nevus, the transformation of lipids and disorders of cellular metabolism. Sadly, the contributions of Feyrter were obscured in the catastrophe of wartime Germany and his accomplishments little recognized. We describe the life and times of this gifted scientist, teacher, and pathologist, often referred to as the ‘Father of Neuroendocrinology’.