Kevin D. Lye

A 50-year analysis of 562 Gastric carcinoids: Small tumor or larger problem?

OBJECTIVES:Interest in gastric carcinoid tumors has amplified considerably given the biological establishment of their relationship to gastrin and advances in the elucidation of the pathobiology of such lesions. The recognized propensity of acid-suppressing agents such as the proton pump inhibitor class of drugs to increase plasma gastrin levels has been proposed as a causal relationship in the apparent increase in the identification of such lesions although the increased prevalence of endoscopy and the enhanced awareness of pathologists have also been considered as contributory factors. We sought to examine if there has been an increase in gastric carcinoid incidence time correlative with these parameters.METHODS:Carcinoid tumor cases from the End Results Group (1950–1969) and the Third National Cancer Survey (TNCS) (1969–1971) databases were combined with the most recent release of the National Cancer Institutes Surveillance, Epidemiology, and End Results (SEER) registry (1973–1999); these three datasets revealed 13,715 carcinoid cases, of which 562 were gastric in origin. Age-adjusted analyses as well as population-based gender and race correction ratios were completed in conjunction with United States decennial census data. To allow a finer granularity in incidence trends, the SEER database was divided into early (1973–1991) and late (1991–1999) subsets.RESULTS:Since 1950, the percentage of gastric carcinoids among all gastric malignancies has increased from 0.3% to 1.77%. Since 1969, the proportion of gastric carcinoids among all enteric carcinoid lesions has increased from 2.4% to 8.7%. Age-adjusted incidence rates among male, female, black, and white population subsets have all increased since the TNCS time period, with the greatest increase (800%) noted in white females. The male:female ratio has fallen from 0.90 to 0.54. The occurrence of synchronous or metachronous noncarcinoid tumors with gastric carcinoid tumors has decreased by 26% during the course of SEER data collection. The 5-yr survival rate for gastric carcinoids overall has risen from 51% to 63% during the same time period.CONCLUSIONS:Gastric carcinoids have increased in incidence over the last 50 yr. Differential increases in predominance across gender and race subdivisions may reflect genetic-based propensities (or protection) for gastric carcinoid tumors among certain ethnic populations. Increased endoscopic surveillance and associated sophisticated pathological evaluation of gastric biopsies undoubtedly are responsible for some of the observed increase in the incidence of gastric carcinoid tumors. These data allow no specific role to be assigned to the effects of acid-suppressive medications. Nevertheless the role of such agents cannot be discounted at this time since the time frame of the increased incidence is somewhat comparable to the introduction of these agents as is the known biological effect of gastrin on ECL cell proliferation.

Carcinoid tumors of the stomach.

Interest in gastric carcinoid tumors has in recent time amplified considerably as the understanding of both their biological background and clinical significance has developed. The increase in identification associated with the widespread availability of upper gastrointestinal endoscopy has facilitated diagnosis. In addition concern related to the consequences of long-standing hypergastrinemia generated by the use of potent acid-suppressive medications has augmented both clinical and scientific focus on gastric neuro endocrine issues. The elucidation of the regulatory mechanisms of the progenitor cell (ECL cell) of the gastric carcinoid tumor, the refinement of a pathological grading system for ECL cell proliferation, and the availability of specific immunohistologic identification techniques have further amplified the characterization of this lesion. Although the putative malignant potential of gastric carcinoids may ultimately be of only modest concern in a background of hypergastrinemia its relationship to gastric adenocarcinoma is still enigmatic and worthy of further consideration. This review will describe the molecular interrelationship between low-acid states, gastrin, and ECL cell proliferation and will discuss the pathological classification of the distinct types of gastric carcinoid tumors. In addition, the clinical rationale of current diagnostic and therapeutic strategies will be examined, providing a logical basis for the formulation of appropriate management strategies for patient care.

Gastroesophageal reflux disease: then and now.

Although Galen first described esophagitis almost 2000 years ago, its relation to acid was only recognized in the 19th century by Rokitansky. Considerably more interest in the symptoms and complications of esophagitis has been evident over the last century, as gastroesophageal reflux disease displaced peptic ulceration and became the principal acid-related disease of our times. Of particular interest has been the recognition of the clinical significance of the previously overlooked extraesophageal manifestations of the disease such as laryngitis, asthma, and sleep disturbance. The evolution of highly effective medical therapy has over the last decade drastically reduced the need for surgical intervention for control of symptoms except under select conditions, especially volume-related reflux and children with refractory symptoms. The proton pump inhibitor class of drugs is indisputably the most effective overall form of management, while individual proton pump inhibitors appear to be equivalent in their efficacy. Issues that remain to be resolved include the management of nonerosive gastroesophageal reflux disease, the long-term dependence of many patients on acid-suppressing medication, and the recognition of atypical manifestations and rare but serious complications of gastroesophageal reflux disease. In this respect, Barretts esophagus still presents a major biologic and management conundrum for the physicians and scientists alike.

Molecular strategies and 111in-labelled somatostatin analogues in defining the management of neuroendocrine tumour disease: a new paradigm for surgical management

This manuscript provides a gene-chip examination of gastric ECL cell proliferation in an animal model of neuroendocrine tumour disease. Data that were used to identify molecular targets were then utilised to develop novel therapeutic strategies as appropriate adjuncts to surgery in human disease. Alterations in growth-mediated cell signaling (the AP-1 pathway) and in the cell cycle were identified in ECL cell tumours in the animal model and confirmed in human tumour tissue. The growth-inhibitory somatostatin receptor subtype 2 was identified as a potential clinical target. An investigation of patients with neuroendocrine tumours treated using SSTR2 targeted radiotherapy [111In]pentetreotide producing encouraging preliminary results. Fifty-six per cent of patients with evaluable hormone markers demonstrated stable levels or a significant decrease in one or more measured markers. This data demonstrate that gene pathways recognised to be altered in an animal model of a human disease can be used to identify therapeutic agents. This approach was successfully used to discover novel strategies that can be both effective and appropriate adjuncts to surgery for patients with neuroendocrine tumour disease.

Historical perspectives on the treatment of gastroesophageal reflux disease

The current vogue in the historical evolution of the management of the problem of reflux is represented by augmentation procedures for the lower esophageal sphincter. Rather than employ a transperitoneal approach, these are directed at the sphincter by the transesophageal route and include stitching, collagen injection and radio-frequency-induced fibrosis. It is however probable that these techniques will suffer all the drawbacks of any mechanical intervention but somewhat decrease the morbidity of open, albeit minimally invasive surgery. Similarly, a specific pharmacotherapeutic probe targeting the lower esophageal sphincter, while long fantasized, remains to be identified.