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R H Riddell

Publications and source records attributed to R H Riddell.

At least 37 records · Page 2Linked to original sources
PubMed1999

Morphologic criteria applicable to biopsy specimens for effective distinction of inflammatory bowel disease from other forms of colitis and of Crohn's disease from ulcerative colitis.

BACKGROUND: Inflammatory bowel disease (IBD)--and Crohn's disease (CD) and ulcerative colitis (UC) in particular--could be more reliably diagnosed by using biopsy criteria incorporating the colorectal distribution of specific histologic features. The aim of this study was to elucidate criteria distinguishing IBD from other forms of colitis (non-IBD), and CD from UC on the basis of multiple colorectal biopsies. METHODS: We examined multiple biopsy specimens (mean, 6.1) from 299 consecutive Japanese subjects with active colitis and performed multiple logistic regression analyses on 70 histologic features, from which 2 equations were constructed for the probabilities (P(IBD) and P(CD)) of a) IBD (versus non-IBD), and b) CD (versus UC), respectively, being present. On the basis of a receiver-operating characteristic curve, we determined four cut-off values for P(IBD) and constructed the criteria, consisting of the five categories 'definite IBD', 'probable IBD', 'unknown', 'probable non-IBD', and 'definite non-IBD'. The criteria for CD versus UC were constructed in a similar manner. Their validities were evaluated using 132 Canadian subjects. RESULTS: The statistically significant histologic features were as follows: for IBD, crypt architectural abnormalities, basal plasmacytosis with severe chronic inflammation, and distal Paneth cell metaplasia; for CD, segmental crypt architectural abnormalities and mucin depletion, mucin preservation at the active sites, and focal chronic inflammation without crypt atrophy. In the categories of probable IBD and probable non-IBD, both sensitivities and specificities exceeded 97%. Probable CD and probable UC showed high specificities of more than 97%, and their sensitivities were 94% and 89%, respectively. Kappa statistics showed these criteria to be sufficiently reproducible. CONCLUSIONS: Specific histological features together with their distribution can reliably diagnose IBD, distinguish CD from UC, and provide an estimate of the probability of the underlying disease being present.

Adult↗
PubMed1999

Interstitial cells of Cajal as precursors of gastrointestinal stromal tumors.

Interstitial cells of Cajal (ICC) are implicated in the regulation of gut peristalsis and are immunostained by antibodies against Kit (CD117), a tyrosine kinase receptor. Most gastrointestinal mesenchymal tumors (GIMTs) are of uncertain histogenesis, although many are CD34-positive. CD34 was found to colocalize with vimentin (Vim) and the Kit-positive networks of cells within and around neural plexi, indicating that ICC can be Vim- and CD34-positive. ICCs appear to be the only Kit+CD34+Vim+ cell in the gut. Formalin-fixed, paraffin-embedded tissues from 43 GIMTs were immunostained for Kit, CD34, Vim, PGP 9.5 (PGP, a neural marker), muscle-specific actin (MSA), and other markers including desmin (Des). Eight tumors were myoid (MSA+Des+Vim-Kit-CD34-), and one was a schwannoma (PGP+S100+Vim+Kit-CD34-), but 34 tumors were of uncertain histogenesis (gastrointestinal stromal tumors, GIST), exhibiting neither a complete myoid nor a schwannian immunophenotype. All 34 were Vim+, and 33/34 were either Kit (n = 30) or CD34 (n = 23) immunoreactive. Of these 34 GIST, 24 were negative for all myoid and neural markers, 6 were PGP+S100-, and 4 were MSA+Des-. The Kit+CD34+Vim+ immunophenotype of GIST suggests that they originate from, or have differentiated into, ICC-like cells; the term ICC tumor (ICCT) is suggested. Kit is a more sensitive marker than CD34 for ICCT, but both are required in tumor identification. All clinically malignant GISTs were pathologically malignant (size, mitoses) but also showed loss of either CD34 or Kit. "Blind" examination of electron micrographs in 10 tumors showed them to be heterogeneous. Some had features seen in normal ICC, but cells could not be positively identified as being adult ICC. GIMT may therefore be classifiable into those with pure myoid, schwannian (or neural) differentiation, but the majority are of ICC origin or show ICC differentiation immunophenotypically (ICCT).

Biomarkers, Tumor↗
PubMed1999

Evaluation of gastric biopsies for neoplasia: differences between Japanese and Western pathologists.

Cited variations in the evaluation of gastric endoscopic biopsies for neoplasms between pathologists in Japan and those in the United States and Europe (the West) may have stemmed from several causes. The five-tiered group classification of the Japanese Research Society for Gastric Cancer (JRSGC) for interpretation of biopsies is not used in the West. Some differences may also exist in the morphologic criteria to reach a diagnosis of dysplasia or carcinoma. The goals of this study were to test the Western and Japanese classifications of gastric dysplasia and adenocarcinoma and to assess the differences between four Japanese and seven Western pathologists. One hundred biopsies, 20 from each of the five categories of the JRSGC scheme as determined by one observer, were collected. The Japanese observers used the JRSGC system, expressed in Roman numerals, whereas Western pathologists used a five- or six-tiered scheme expressed in diagnostic terms. Pairwise agreement was evaluated using k statistics within both groups. Consensus diagnosis on each biopsy was accepted as the opinion of the majority. The sensitivity and specificity of each reviewer for a certain diagnosis were also assessed. The intragroup agreements were moderate for both the Japanese (mean k = 0.663) and the Westerners (mean k = 0.652). The pairwise agreements between Japanese and Western observers were low (mean k = 0.542). Overall, the sensitivity was low for all Japanese observers for the diagnosis of dysplasia (38.7% vs 92.5%), and the sensitivity for the diagnosis of adenocarcinoma was high in both groups but higher among the Japanese observers (93.9% and 85.2%, respectively). Overall, the Japanese-Western interobserver agreement was moderate. The JRSCG scheme did not translate into higher interobserver agreement among Japanese observers. The sensitivity for the diagnosis of gastric adenocarcinoma was high for both groups, but the specificity was low among the Japanese. The cause seemed to be centered around the diagnosis of dysplasia in the Western system, which was a lesion frequently interpreted as carcinoma in Japan because of the different definitions of carcinoma in each system. Such a discrepancy might be important because it may explain some of the differences in the prevalence and prognosis of early gastric cancer between Japan and the West. An international effort is needed to harmonize morphologic criteria and analyze whether therapeutic consequences may stem from such discrepancies.

Biopsy↗
PubMed1999

Pathobiology of Helicobacter pylori infection in children.

In the pediatric population, the associations of Helicobacter pylori with gastritis, gastric ulcer, duodenitis and duodenal ulcer, and with duodenal gastric surface metaplasia and disorders of the D cell- G cell axis resulting in hypergastrinemia, are well established and in many ways resemble their counterparts in adults. Eradication of H pylori invariably results in the reversal of these diseases with time. There are also suggestions that gastric surface metaplasia is more extensive in children with H pylori, and may be the site of duodenal H pylori infection and associated duodenal erosions or ulcers. There is no consensus as to whether H pylori in children is more or less severe than in adults. In one pediatric cohort, H pylori was associated with increased intensity of inflammation, while other studies suggest that acute inflammation may be less intense in children overall but that chronic inflammation may be increased in intensity, including lymphoid hyperplasia, which in turn may correlate with endoscopic nodularity. Lymphoid hyperplasia and nodular gastritis appear to be more frequent in children than in adults and usually regress following H pylori eradication. However, in children, other diseases or morphological abnormalities, including some loss of glands (atrophy), occasionally intestinal metaplasia, lymphoproliferative diseases including low grade mucosal-associated lymphoid tissue lymphoma, lymphocytic gastritis and hypertrophic gastritis/Menetrier's disease, are much less frequently associated with H pylori than in adults. Other associations are rarely seen in children, primarily because the time required for these to develop takes the individual to adulthood; for example, while intestinal metaplasia occurs in the pediatric population, the complications of adenoma/dysplasia and carcinoma are rare. In adults, inflammatory and hyperplastic polyps, atrophic gastritis and pernicious anemia, and in some patients granulomas (granulomatous gastritis), may also be associated with H pylori infection. Greater awareness of the spectrum of diseases associated with H pylori may well lead to their increased recognition in the pediatric population. Some diseases, particularly Crohn's disease, but also human immunodeficiency virus infection, have a negative association with H pylori that appears not to be simply a result of the excess antibiotic therapy that these patients receive. These variations in association and reactions to H pylori, some of which are age-related, may allow the different host responses to H pylori that occur in humans to be examined.

Adult↗
PubMed1998

Differences in the diagnostic criteria used by Japanese and Western pathologists to diagnose colorectal carcinoma.

BACKGROUND: In view of the many studies of early stage colorectal carcinoma from Japan, it is essential to know whether the criteria for the histologic diagnosis of colorectal carcinoma are similar in Japan and Western countries. METHODS: Eight expert pathologists from Japan (4), North America (2), and Europe (2) individually reviewed microscope slides of 20 colorectal lesions from Japanese patients who had undergone endoscopic mucosal resection or surgery because early stage carcinoma and/or adenoma was suspected. The pathologists indicated the pathologic findings on which they based each diagnosis. RESULTS: For 11 slides that showed adenoma according to the Western pathologists with low grade dysplasia according to at least half of them, the Japanese diagnosed definite carcinoma with or without adenoma in 4 cases and adenoma in 5, and in 2 cases they were equally divided between a diagnosis of adenoma and carcinoma. For five slides showing adenoma with high grade dysplasia according to the Western pathologists, the Japanese diagnosed definite carcinoma with adenoma in three cases and adenoma in one, and in one case they were equally divided between a diagnosis of adenoma and carcinoma. For one case in which the Western pathologists were equally divided between a diagnosis of carcinoma and adenoma with high grade dysplasia, all the Japanese pathologists diagnosed definite carcinoma with or without adenoma. Three slides showed definite carcinoma with or without adenoma, according to both the Western and the Japanese pathologists. The presence of invasion was the most important diagnostic criterion of colorectal carcinoma for the Western pathologists, whereas for the Japanese the nuclear features and glandular structures were more important. CONCLUSIONS: In Japan, colorectal carcinoma is diagnosed on the basis of nuclear and structural criteria, even in cases considered by Western pathologists to be noninvasive lesions with low grade dysplasia. This diagnostic practice may contribute to the relatively high incidence of early stage colorectal carcinoma reported in Japan as compared with Western countries.

Adenoma↗
PubMed1998

Problems arising from eastern and western classification systems for gastrointestinal dysplasia and carcinoma: are they resolvable?

It has become increasingly apparent that the Japanese and Western systems of classifying dysplasia and carcinoma in the gastrointestinal tract are not the same. The implication of these differences is that in an article in a Western journal on gastrointestinal 'cancer' originating from Japan, it is often impossible to repeat the study to confirm or refute it, because of these differences in definitions. Although there is no reason why it should not be just as much of a problem if Western research is published in Japanese journals, this is currently not a major problem. The terminological differences do not mean that one is right and one wrong; they are simply different. We had an opportunity to look at these differences in detail in a series of 100 gastric biopsies. In this review, we outline these differences and indicate the similarities, differences and problems between these two systems. 'Carcinoma' is diagnosed in Japan by virtue of its structural and cytological features, but by invasion in the Western system. Adenoma does not mean a dysplastic lesion in the Japanese system (although it can) but in most cases is similar to low-grade dysplasia irrespective of the macroscopic/endoscopic appearances (hence flat and depressed adenomas in the Japanese system); however, most examples of high-grade dysplasia in the Western system, as well as some low-grade dysplasia, becomes 'cancer' in the Japanese system. Conversely, both have conceptual areas that are useful in the other's systems. Because we were ultimately able to use each other's systems, we were able to show where these systems come together and diverge. These provide hope that a common classification encompassing both systems that allows communication between both systems is feasible.

Europe↗
PubMed1998

Histology of the stomach and duodenum in Crohn's disease.

Crohn's disease (CD) not uncommonly affects the stomach and duodenum, but its histologic appearance is not well described beyond the identification of granulomas. We retrospectively identified 209 upper gastrointestinal biopsy samples from 80 sets of biopsies from 49 patients with CD. Age- and sex-matched control biopsies were selected from recent cases of Helicobacter pylori gastritis (73 biopsy samples from 34 patients), from patients with a known history of nonsteroidal antiinflammatory drug use (18 biopsy samples from 12 patients), and from three patients with ulcerative colitis. Architectural and inflammatory changes were evaluated and compared. Over three fourths of the patients with CD had abnormal biopsy results. Fifty-six percent of patients with CD had acute inflammation, but only 10% of the patients were infected with H pylori. Focal acute inflammation was a characteristic of H pylori-negative CD (stomach, 31%; duodenum, 40%), which was much less common in the non-CD group (stomach, 2%; duodenum, 8%). Surface intraepithelial neutrophils of the duodenum were more common in H pylori-negative patients with CD (25%) than in those who did not have CD (4%), and deep acute inflammation of the duodenum was more likely in H pylori-negative patients with CD (19% vs. 0%). Granulomas were found in only 9% of the CD group. Focal acute inflammation of the gastroduodenum, especially in a background of noninflamed mucosa, is strong evidence for CD in the appropriate clinical context, but the stomach and duodenum must be properly sampled and carefully examined for any evidence of H pylori.

Adolescent↗
PubMed1998

Terminal ileal imaging with ileoscopy versus small-bowel meal with pneumocolon.

Disease of the terminal ileum can be diagnosed by ileocolonoscopy or barium radiography. We compared the diagnostic accuracy in the terminal ileum of ileocolonoscopy and small-bowel meal with pneumocolon. Consecutive patients during an 18-month period who had both ileocolonoscopy and small bowel meal with pneumocolon were identified and their colonoscopy reports, radiographs, and ileal biopsies reviewed blindly by paired gastroenterologists, radiologists, and pathologists, respectively. A gold-standard diagnosis was determined for each patient by consensus. Of 48 study subjects, 14 (29.2%) had Crohn's disease, 5 (10.4%) had lymphoid nodular hyperplasia, and 29 (60.4%) were normal. The sensitivity for a diagnosis of Crohn's ileitis was 92.9% for ileocolonoscopy and 100% for small-bowel meal, while their specificities were 100% and 97.1% respectively. The gold standard diagnosis confirmed ileocolonoscopic findings in 45 patients (93.8%) and radiographic findings in 42 patients (87.5%). Agreement between ileocolonoscopy and small bowel meal occurred in 39 cases (81.2%). By combining histology with ileocolonoscopy, the sensitivity and specificity could be increased to 100% for all diagnoses. Ileocolonoscopy and small-bowel meal with pneumocolon are complementary techniques for imaging the terminal ileum. A prospective comparative trial is now needed to more objectively assess their accuracy, cost effectiveness, and adverse effects.

Adolescent↗
PubMed1997

Differences in diagnostic criteria for gastric carcinoma between Japanese and western pathologists.

BACKGROUND: There have been many studies on gastric carcinoma in populations with contrasting cancer risks. We aimed to find out whether the criteria for the histological diagnosis of early gastric carcinoma were comparable in Western countries and Japan. METHODS: Eight pathologists from Japan, North America, and Europe individually reviewed 35 microscope slides: 17 gastric biopsy samples and 18 endoscopic mucosal resections taken from 17 Japanese patients with lesions ranging from early gastric cancer to adenoma, dysplasia, and reactive atypia. The pathologists were given a list of pathological criteria and a form on which they were asked to indicate the criteria on which they based each diagnosis. FINDINGS: For seven slides most Western pathologists diagnosed low-grade adenoma/dysplasia, whereas the Japanese diagnosed definite carcinoma in four slides, suspected carcinoma in one, and adenoma in only two. Of 12 slides with high-grade adenoma/dysplasia according to most Western pathologists the Japanese gave the diagnosis of definite carcinoma in 11 and suspected in one. Of six slides showing high-grade adenoma/dysplasia with suspected carcinoma according to most Western pathologists the Japanese diagnosed definite carcinoma in all. There were no major differences in the diagnoses of three slides showing reactive epithelium and seven slides with clearly invasive carcinoma. When the opinion of the majority of the pathologists was taken as the final diagnosis there was agreement between Western and japanese in 11 of the 35 slides (kappa coefficient 0.15 [95% CI 0.01-0.29]). Presence of invasion was the most important diagnostic criterion for most Western pathologists whereas for the Japanese nuclear features and glandular structures were more important. INTERPRETATION: In Japan, gastric carcinoma is diagnosed on nuclear and structural criteria even when invasion is absent according to the Western viewpoint. This diagnostic practice results in almost no discrepancy between the diagnosis of a superficial biopsy sample and that of the final resection specimen. This may also contribute to the relatively high incidence and good prognosis of gastric carcinoma in Japan when compared with Western countries.

Adenoma↗
PubMed1996

Omeprazole produces parietal cell hypertrophy and hyperplasia in humans.

While there is evidence that omeprazole may induce changes in parietal cells, the effect of acid suppression on parietal cells in humans is poorly documented. This study was undertaken to evaluate the effects of omeprazole in human parietal cells over time. The light microscopic morphology of parietal cells in gastric biopsies from 17 patients on omeprazole were compared with those from 13 patients on ranitidine and 20 patients on no acid-lowering medication. Light microscopic and ultrastructural morphology of parietal cells was also evaluated in an additional 14 patients before and after omeprazole administration. Objective measurements of parietal cell height, mass and number were analyzed using analyses of variance. Electron microscopy was used to evaluate parietal cell enlargement. Twenty-five of 31 biopsies from patients on omeprazole, 1 of 13 from patients on ranitidine, and 0 of 20 from patients on neither drug showed parietal cell enlargement. Parietal cell height, mass, and number were increased in omeprazole-treated patients compared with ranitidine-treated patients and those on neither drug, and with the group also evaluated prior to beginning omeprazole treatment. Parietal cell height and mass were increased in patients on omeprazole longer than 12 months compared with biopsies from patients on the drug for less than 12 months. Resin-embedded sections and electron microscopy showed enlarged parietal cells with prominence of cytoplasmic tubulovesicles with sparse secretory canaliculi. Parietal cell hypertrophy and hyperplasia develops in patients on chronic omeprazole therapy; this can be recognized on routine examination of histologic sections. These morphologic changes increase with duration of therapy.

Adolescent↗
PubMed1996

The biopsy diagnosis of gastroesophageal reflux disease, "carditis," and Barrett's esophagus, and sequelae of therapy.

Histologic changes indicative of gastroesophageal reflux disease (GERD) are found on both sides of the squamocolumnar junction (Z-line). In the gastric cardia, inflammation is found as part of GERD in the absence of Helicobacter pylori or other causes of gastritis (carditis). The squamous mucosa is the location most likely to show inflammatory changes, such as neutrophils or eosinophils, close to the Z-line, whereas traditional reactive changes in the squamous mucosa are found only in biopsies taken at least 3 cm above the Z-line. Endoscopic criteria for GERD have a morphologic counterpart in capillary congestion and hemorrhage into the papillae, which have largely been ignored by pathologists as secondary to biopsy trauma. A biopsy protocol that maximizes the chances of detecting changes of GERD is suggested. The traditional definition of Barrett's esophagus as requiring 3 cm of glandular mucosa extending into the esophagus is no longer tenable. However, even the concept of short-segment Barrett's esophagus, in which less than 3 cm of intestinalized mucosa is present, often as tongues, is being challenged because random biopsies immediately distal to the Z-line may also show intestinal metaplasia when Barrett's esophagus is unsuspected endoscopically. Moreover, it is difficult or impossible to determine whether these changes indicate the earliest lesion of Barrett's esophagus or intestinal metaplasia in native cardiac mucosa. It is suggested that Barrett's esophagus be redefined as intestinal metaplasia in the lower esophagus. It is presently unclear whether patients with such minimal Barrett's epithelium are at increased risk for adenocarcinoma or require surveillance. Successful therapy for GERD results in healing of disease in squamous mucosa and may result in regression of Barrett's epithelium. In the stomach it may be associated with temporary regression of H. pylori and associated inflammation, migration of H. pylori into the oxyntic mucosa, hypertrophy and hyperplasia of parietal cells, and a variant of fundic gland polyps. Some patients may be at risk for accelerated atrophic gastritis if inflammation is present before therapy.

Adult↗
PubMed1996

Early detection of neoplasia of the esophagus and gastroesophageal junction.

Recommendations for preventing adenocarcinoma: The standard definition of Barrett's epithelium should be the presence of intestinalized mucosa in the lower esophagus. Patients in this category should be considered for inclusion in a screening program for the detection of dysplasia or carcinoma. Those who are a poor operative risk should not be screened if the detection of an end-point such as high-grade dysplasia or intramucosal carcinoma will still not lead to resection. In some centers, however, alternative experimental methods of mucosal ablation may be available. The endpoint for screening is invasive or intramucosal carcinoma (or--in centers with a very low operative mortality--high-grade dysplasia). These should lead to consideration of surgery or, in specialized centers and as part of controlled studies, newer alternative modes of epithelial ablation. Intermediate markers, e.g., use of aneuploidy, gene markers, or their products, are at present experimental. Screening should be carried out annually or, possibly, biennially. This screening should utilize a standard protocol with an endoscope capable of obtaining large-particle biopsies. Four quadrant biopsies should be taken about every 2 cm, beginning 2 cm above the proximal limit of the gastric rugae, continuing until unequivocally in squamous mucosa, and following any tongues of glandular epithelium. Recommendations for prevention of squamous carcinoma: In high-risk populations, esophageal cytology, possibly supplemented by tests for blood in the stomach, appear most useful. Repeated screening may be necessary to detect early invasive or preinvasive (dysplastic) tumors. Although preliminary results from dietary intervention studies have yet to show a statistically significant decrease, if trends continue these will reach significance and may be the best overall method of cancer prevention. Measures to reduce smoking and drinking are to be encouraged, but their effectiveness is questionable. For patients who are positive on screening, endoscopy (possibly with Lugol's iodine) may provide the best indication of harboring underlying carcinoma or dysplasia. Endoscopic resection will play an increasing role in treatment. With the exception of tylosis, most other predisposing conditions are unlikely to be cost effective.

Adenocarcinoma↗
PubMed1996

Premalignant and early malignant lesions in the gastrointestinal tract: definitions, terminology, and problems.

The definition of a "premalignant" lesion is discussed, together with its relationship to dysplastic change. The definition and description of dysplasia are given. Systems for grading dysplasia are set out, and the clinical implications of these changes are discussed. Although the "dysplasia terminology" in current use remains the gold standard for clinical practice, a series of more recent developments, including the discovery of flat and depressed adenomas, the possibility of de novo carcinoma throughout the gastrointestinal tract, as well as advances in molecular biology, raise the question of whether this terminology will be adequate in future. Other terminologies exist that provide an alternative viewpoint, but none is satisfactory.

Gastrointestinal Neoplasms↗
PubMed1995

Pathophysiological effects of long-term acid suppression in man.

A critical evaluation has been made of the available evidence in man of the effects of prolonged low acid states on the structure and function of the stomach. Various human models have been examined. 1. Ageing does not affect acid output from the normal male stomach, and there may be an increase in women. With progressive atrophy of the corpus mucosa, which is more frequent and rapid in patients with gastric ulcer, there is an associated loss of secretory function. Chronic gastritis and atrophy are the most important age-related changes, which in many cultures are hypothesized to develop via a prior Helicobacter pylori-related gastritis. However, H. pylori colonization of the mucosa decreases with increasing grades of gastric atrophy probably because intestinal metaplasia provides a hostile environment. Atrophy and intestinal metaplasia are associated with precancerous lesions and gastric cancer. Apparent hyperplasia of the gastric argyrophil endocrine cells is a common and spontaneous phenomenon in patients with atrophic gastritis, which in part may be related to the preferential loss of nonendocrine cells. 2. Pernicious anemia is associated with a complete lack of acid production, marked hypergastrinemia, and endocrine cell hyperplasia in the majority of patients. ECL-cell carcinoids and gastric cancer occur with a prevalence of 3-7%, and endoscopic surveillance in routine clinical practice is not warranted. 3. Gastric ECL-cell carcinoids are rare events that have been described in association with two diseases in man, pernicious anemia and Zollinger-Ellison syndrome as part of multiple endocrine neoplasia syndrome type I, and usually relate to marked hypergastrinemia and the presence of chronic atrophic gastritis with gastric antibodies or a genetic defect rather than the presence or absence of acid. Regression or disappearance of ECL-cell carcinoids, either spontaneously or after removal of the gastrin drive, has been recorded. Lymph node, and rarely hepatic, metastases are documented but death in these cases has been anecdotal. 4. Therapy with H2 antagonists may result in up to a twofold rise in serum gastrin levels but in man no endocrine cell hyperplasia has been recorded. However, the data for H2 antagonists on these aspects are very limited. There is no drug-related risk of gastric or esophageal cancer, although the incidence of the latter may be raised. Long-term treatment with omeprazole is associated with a two- to fourfold increase in gastrin levels over baseline values in one third of patients and apparent endocrine cell hyperplasia in 7% of cases overall.(ABSTRACT TRUNCATED AT 400 WORDS)

Aging↗