Effects of vitamin/mineral supplementation on the prevalence of histological dysplasia and early cancer of the esophagus and stomach: results from the General Population Trial in Linxian, China.

A randomized nutrition intervention trial was conducted among 29,584 adult residents of Linxian, China, to examine the effects of vitamin/mineral supplementation on the occurrence of esophageal/gastric cardia cancer in this high-risk population. A fractional factorial study design allowed evaluations of four different combinations of nutrients: (A) retinol and zinc; (B) riboflavin and niacin; (C) vitamin C and molybdenum; and (D) beta-carotene, vitamin E, and selenium. During the 5.25-year intervention, significant reductions in total mortality, total cancer mortality, and stomach cancer mortality occurred among those receiving beta-carotene, vitamin E, and selenium. At the end of intervention, an endoscopic survey was carried out in a sample of subjects to see if the nutritional supplements had affected the prevalence of clinically silent precancerous lesions and early invasive cancers of the esophagus or stomach. Endoscopy was performed on 391 individuals from two study villages. The prevalences of esophageal and gastric dysplasia and cancer were compared by nutrient factor. Cancer or dysplasia was diagnosed in 15% of the participants. No statistically significant reductions in the prevalence of esophageal or gastric dysplasia or cancer were seen for any of the four vitamin/mineral combinations. The greatest reduction in risk (odds ratio, 0.38; P = 0.09) was seen for the effect of retinol and zinc on the prevalence of gastric cancer. Although no significant protective effects were seen in this endoscopic survey, there was a suggestion that supplementation with retinol and zinc may protect against the development of gastric neoplasia in this high-risk population. Additional studies with larger numbers of endpoints will be needed to further evaluate this possibility.

Effects of vitamin/mineral supplementation on the prevalence of histological dysplasia and early cancer of the esophagus and stomach: results from the Dysplasia Trial in Linxian, China.

Linxian, China has some of the highest rates of esophageal/gastric cardia cancer in the world, and epidemiological evidence suggests that chronically low intake of micronutrients may contribute to these high cancer rates. To examine whether supplementation with multiple vitamins and minerals can affect the occurrence of esophageal/gastric cardia cancer in this population, a two-arm randomized nutrition intervention trial was conducted among 3318 Linxian residents with cytological evidence of esophageal dysplasia. During the 6-year intervention, esophageal/gastric cardia cancer mortality was 8% lower among those receiving the active supplements. After 30 and 72 months of intervention, endoscopic surveys were carried out to see if the nutritional supplements had affected the prevalence of clinically silent precancerous lesions and early invasive cancers of the esophagus and stomach. In the first survey, in 1987, 833 subjects were endoscoped; in the second survey, in 1991, 396 subjects were examined. The histological diagnoses from each survey were compared by treatment group. Cancer or dysplasia was diagnosed in 28% of the subjects endoscoped in 1987 and 24% of those examined in 1991. The odds ratio for subjects in the treatment group (versus those in the placebo group) having esophageal or gastric dysplasia or cancer was 0.84 (95% confidence interval, 0.61-1.15) in 1987 and 0.86 (0.54-1.38) in 1991. Although modest protective effects on worst overall diagnosis were seen in the supplemented group in both surveys, none of the results was statistically significant, and the findings must be considered inconclusive.(ABSTRACT TRUNCATED AT 250 WORDS)

Studies of esophageal balloon cytology in Linxian, China.

Esophageal cancer is the second leading cause of cancer death in China. Esophageal cancer has a very poor prognosis, principally because most tumors are asymptomatic until they are unresectable. Esophageal balloon cytology is an early detection method developed by Chinese scientists to identify resectable early cancers and precursor lesions. Previous studies have reported high sensitivities for detecting esophageal cancer in symptomatic patients. The current report describes several studies evaluating this diagnostic technique in asymptomatic individuals. A comparison of Chinese and U. S. cytological diagnoses of the same esophageal samples showed that the Chinese categories of precancerous neoplasia were more inclusive than the corresponding U. S. categories. Comparisons of both Chinese and U. S. cytological diagnoses with concurrent histological findings showed low (14-36%) sensitivities for the cytological detection of biopsy-proven cancers. Prospective follow-up studies of several screened cohorts showed a consistent progression of risk for developing esophageal cancer with increasing severity of initial cytological diagnosis. These preliminary studies suggest that esophageal balloon cytology is a useful technique that can benefit from additional research to improve its optimal performance.

Amanita poisoning: treatment and the role of liver transplantation.

Fatal mushroom poisoning has long been recognized as a major health problem in western Europe and more recently in the United States. The majority of deaths are attributable to the genus Amanita. Amanita phalloides (death cap) has been found with increasing frequency across the United States and presents a significant health hazard in this country to those who pick and consume wild mushrooms. This article discusses the pharmacologic basis and clinical manifestations of Amanita intoxication. It outlines the rationale of various treatment modalities and, from these, summarizes a protocol that the authors believe will be useful to the clinician. In addition, two patients are presented who underwent successful orthotopic liver transplantation for fulminant hepatic failure secondary to Amanita poisoning. The role of liver transplantation both acutely and as treatment for chronic active hepatitis secondary to severe intoxication is discussed.

Carcinoid tumors and the mixed (composite) glandular-endocrine cell carcinomas.

Carcinoid tumors display a wider histologic spectrum than was previously thought. Some tumors may show atypical features such as glandular profiles, a spindle cell pattern, squamous or osteoid metaplasia, or pleomorphism. In rare cases they may be poorly differentiated and resemble undifferentiated carcinoma or lymphoma. As is well known, some carcinoids are associated with well-defined syndromes, such as the carcinoid or the Zollinger-Ellison syndrome, due to the secretion of amines or peptides. Immunohistochemical analysis of these tumors, however, has shown that whereas one amine or peptide may predominate, most are multihormonal. These findings are also seen with the clinically silent tumors such as the foregut and hindgut carcinoids. Furthermore, the immunohistochemically demonstrated amines and peptides in the primary tumor do not necessarily correspond to those normally found in the overlying endocrine cells. An increasing number of tumors have recently been described which contain an admixture of neoplastic endocrine and nonendocrine epithelial cells. Thus, the classification of gut mucosal tumors into carcinomas and endocrine tumors has had to be modified to include those tumors which have been designated as mixed or composite tumors. These have been further subdivided into several distinctive histologic types. Some of these tumors, such as the microglandular-goblet cell carcinomas, have a distinctive clinical behavior, whereas others, such as the adenoendocrine cell carcinomas, appear to behave in a manner similar to adenocarcinoma. Additionally, there is another tumor type, namely the amphicrine tumor, which differs from the mixed tumors in that endocrine and epithelial cell constituents are present within the same cell.

Massive hepatomegaly in adult polycystic liver disease.

In adult polycystic liver disease, the liver gradually enlarges as it is replaced by cysts. The disease rarely produces symptoms or complications. Liver cysts are thought to arise from aberrant embryonic intrahepatic bile ducts (Von Meyenburg's complexes). We present a case of adult polycystic liver disease with Von Meyenburg's complexes and unusually severe hepatomegaly (7.7 kg, 22,080 cm3). The autopsy prevalence of adult polycystic liver disease at UCLA Medical Center is 0.13%; 93% of these cases had polycystic kidney disease. Adult polycystic kidney disease had associated liver cysts in 45% of cases.

Immunoperoxidase and immunofluorescence in lymph node biopsies: a comparative study.

A comparison study was made of staining for immunoglobulin by immunofluorescence and immunoperoxidase in 23 lymph node biopsies. Cryostat sections were stained for immunoglobulins using a direct technique while paraffin-embedded sections were stained for immunoglobulins using the peroxidase-antiperoxidase (PAP) technique. Of 23 cases studied, including seven reactive hyperplasias and 16 lymphoid cancers, there was agreement between the two techniques in 18 cases. Nine of 14 non-Hodgkin's lymphomas showed agreement of results. All reactive hyperplasias showed complete agreement and had a distinctive pattern by both immunofluorescence and immunoperoxidase. Fixation, reagent specificity, and sensitivity of the methods may account for some of the discrepancies noted. Immunoperoxidase staining may be a useful diagnostic aid, particularly when immunofluorescent staining is not possible.

Diffuse colitis cystica profunda. Report of a case.

A 20-year-old man had a 2-year history of ulcerative colitis with multiple exacerbations and failure of medical management. In addition to evidence of ulcerative colitis involving the descending colon and rectum, the remainder of the total proctocolectomy specimen demonstrated prominent, circumferential, polypoid elevations of mucosa and epithelial-lined, submucosal mucous cysts diagnostic of colitis cystica profunda. The involvement of the ascending and transverse colon was diffuse. Colitis cystica profunda is an uncommon condition, usually localized to the rectum and which can be misdiagnosed both clinically and pathologically as invasive carcinoma. Diffuse involvement of the proximal colon as noted in this case, is exceedingly rare.

Lymphoid hyperplasia of the gastrointestinal tract. A study of 26 cases and review of the literature.

Based on a study of 26 cases and a review of the literature, lymphoid hyperplasia of the gastrointestinal tract can be categorized into four clinicopathologic groups: focal lymphoid hyperplasia of the stomach, focal lymphoid hyperplasia of the small intestine, focal lymphoid hyperplasia of the rectum, and nodular lymphoid hyperplasia of the gastrointestinal tract. The focal lesions are single, variably circumscribed, and produce thickening of the wall of the affected part of the viscus. While a substantial number of the gastric lesions are associated with chronic peptic ulcers, ulceration is absent or insignificant in focal lesions located in the intestine. The extent of the infiltrate may range from involvement of the mucosa and submucosa only to infiltration of the full thickness of the wall. Nodular lymphoid hyperplasia of the gastrointestinal tract produces multiple discrete mucosal nodules in a variable segment of the small intestine, large intestine, or both. Gastric involvement is rare. The lymphoid infiltrate is confined to the lamina propria and superficial submucosa. Nodular lymphoid hyperplasia is most commonly encountered incidentally during radiologic examination or at autopsy, but it also occurs in association with hypogammaglobulinemia, especially late-onset acquired hypogammaglobulinemia. Lymphoid hyperplasia of the gastrointestinal tract can be distinguished from malignant lymphoma by the polymorphic nature of the infiltrate, the absence of significant cytologic atypia, and the presence of reactive follicles within the lesion.

Disease recurrence following liver transplantation.

Recurrence of disease following liver transplantation is emerging as a major area of concern. We retrospectively investigated for evidence of recurrent hepatitis B, hepatitis non-A, non-B (NANB), primary biliary cirrhosis (PBC) and malignancy in 106 transplant patients. Recurrence of hepatitis B was diagnosed in 11 of 14 (79%) patients who survived longer than 2 months posttransplant. The first histologic evidence of recurrence occurred at 4 to 64 weeks posttransplant (mean, 22.2 weeks). In two patients, progression to cirrhosis was documented histologically. Recurrence was diagnosed in three patients transplanted for fulminant hepatic necrosis due to hepatitis B. Administration of hepatitis B vaccine and hepatitis B immunoglobulin was ineffective in preventing recurrence. Recurrence of hepatitis NANB was diagnosed in only two of 23 patients transplanted for hepatitis NANB cirrhosis. Evidence of posttransplant hepatitis was also detected in one of 10 patients transplanted for fulminant hepatitic failure presumably caused by hepatitis NANB. Recurrence of PBC was not diagnosed in any of 15 patients, but the length of follow-up was too limited in most patients to allow definite conclusions to be made. Posttransplant antimitochondrial antibodies titers remained elevated in nine of 11 patients tested. Six of 13 patients transplanted for hepatocellular carcinoma (46%) developed recurrent tumor, and five died. The role of preoperative and postoperative chemotherapy is currently undefined.

Disseminated bombesin-producing carcinoid tumor of pulmonary origin.

A case of a bombesin-producing carcinoid tumor of the lung is reported. Morphologically, the tumor was a typical argentaffinic carcinoid which contained bombesin as demonstrated by diffuse granular cytoplasmic staining using the immunoperoxidase method. Electron microscopy revealed dense-core granules measuring 100-150 nm, consistent with bombesin-containing endocrine cells. In man, bombesin-producing endocrine cells are found predominantly in the bronchopulmonary tree and scattered throughout the intestinal tract. The majority of previously reported bombesin-producing tumors have arisen, as in this case, in the lung; thus the demonstration of bombesin-like immunoreactivity in a widely metastatic tumor should direct the search for a primary lesion to the lung. Bombesin is known to have gastrin-releasing hormone activity. The presence of a gastric ulcer in the present patient raised the possibility of a bombesin-mediated Zollinger-Ellison-like syndrome, an association not previously described.

Malignant islet cell tumor with rhabdomyosarcomatous differentiation.

We present a widely metastatic islet cell tumor of the pancreas with focal areas resembling rhabdomyosarcoma. To our knowledge, this is the first reported case of islet cell/carcinoid tumor exhibiting such differentiation. Desmin was localized to the rhabdoid areas by immunohistochemistry. Cross striations were not seen by light microscopy, but Z-lines and thick filaments were seen on electron microscopy.

Clinical and pathologic overlap in nonsteroidal anti-inflammatory drug-related small bowel diaphragm disease and the neuromuscular and vascular hamartoma of the small bowel.

Diaphragm disease (DD) is a radiographically subtle cause of small bowel obstruction and is part of the spectrum of diseases associated with nonsteroidal anti-inflammatory drug injury. The neuromuscular and vascular hamartoma (NMVH) is a nonepithelial hamartomatous, submucosally based proliferation of mature submucosal elements capable of causing small bowel obstruction. The authors report two patients in whom the clinical setting and gross pathology are that of DD, but the histologic characterization is identical to that described for NMVH. It is probable that in some patients the two diseases overlap so that some patients readily fit the criteria for both entities.

Histopathology of bacillary angiomatosis of lymph node.

Bacillary angiomatosis, a recently characterized pseudoneoplastic vascular proliferation caused by a bacterium identical or related to the cat-scratch disease bacillus, usually presents as cutaneous lesions. We report the histologic findings of this disease involving the lymph nodes of two immunocompromised patients. The lymph nodes showed patchy involvement by coalescent nodules of proliferated blood vessels lined by plump endothelial cells with pale cytoplasm. There were foci exhibiting mild to moderate nuclear atypia. Although neutrophil infiltration was prominent in one case, it was minimal in the other. The interstitium was formed by pink-staining material in hematoxylin-eosin-stained sections, and this proved to be aggregated bacilli on Warthin-Starry stain. Recognition of this potentially fatal disease is important because it is curable with antibiotics.

Chronic active hepatitis of hepatitis B and non-A, non-B etiology.

Sixty-six consecutive liver biopsies demonstrating chronic hepatitis (CAH) were stained for the presence of HBsAg using the three-step peroxidaseantiperoxidase technique. Only cases of CAH thought to be attributable to either hepatitis B or non-A, non-B hepatitis were included in this series. Twenty-three of 30 biopsies taken from 24 patients with HBsAg-positive serum stained positively. None of the HBsAg sero-negative cases stained postively. Hepatocytes staining positively for HBsAg were generally few in number and randomly distributed within the liver lobules. Three cases of membranous staining were noted. After grading both the degree of inflammatory activity and the amount of HBsAg staining, we found that a statistically significant inverse relationship exists. The biopsies of six of the GBsAg sero-positive patients who had received steroid therapy for their liver disease did not stain differently from the biopsies of the remaining 18 HGsAg sero-positive patients. Stains for HBsAg may help in distinguishing acute hepatitis B (HB) superimposed on preexisting liver disease from hepatitis B-CAH (CAHB). This distinction may be possible because tissue staining almost always is negative in acute HB, whereas it often is focally positive in CAHB. This application of immunoperoxidase may be especially useful in patients who are drug addicts.

Primary gastrin cell hyperplasia. Report of five cases and a review of the literature.

Primary gastrin cell hyperfunction of the gastric antrum as a clinical syndrome consists of basal hypergastrinemia, an exaggerated gastrin response to feeding, the absence of any ectopic source of gastrin secretion, and peptic ulcer disease. The number of G-cells were quantitated in the gastric antrum of five patients with clinically diagnosed primary G-cell hyperfunction, and the results were compared to controls with a variety of gastric diseases. Patients with the clinical diagnosis of primary G-cell hyperfunction had a significantly increased number of antral G-cells (p less than 0.05). The clinical syndrome of primary G-cell hyperplasia appears to be associated with hyperplasia of G-cells rather than with the hypersecretion of gastrin by a normal number of G-cells.

Gastric dysplasia: the Padova international classification.

A worldwide-accepted histologic, classification of the gastric carcinomatous and precancerous lesions is a prerequisite for a consistent recording of epidemiologic data and for both developing and evaluating primary and secondary preventive efforts. Different nomenclatures have been proposed for gastric precancerous lesions in eastern countries and in Japan. This article presents a classification of gastric precancerous lesions resulting from an international consensus conference involving pathologists of different countries. Five main diagnostic categories are identified. To allow comparisons with the nomenclature proposed by the Japanese Research Society for Gastric Cancer, each category was also assigned a numeric identification: 1 = normal, 2 = indefinite for dysplasia, 3 = noninvasive neoplasia, 4 = suspicious for invasive cancer, and 5 = cancer. The interobserver reproducibility of the histologic classification was tested in a series of 46 cases. By collapsing benign alterations (categories 1+2) versus noninvasive neoplasia (category 3) versus suspicious for invasive cancer and fully appearing carcinomatous lesions (categories 4+5), the general agreement value was 77.7%, whereas kappa coefficient was 0.63. By examining gastric precancerous lesions from diverse populations, the authors agreed that the gastric precancerous process is universal and the differences in nomenclatures are merely semantics. The international Padova classification of the gastric precancerous lesions is submitted to the attention of the international scientific community, which is invited to test and to improve on it.

Gastrointestinal lymphomas. Immunohistochemical studies on the cell of origin.

The classification of primary malignant lymphomas of the gastrointestinal tract by their cell of origin has been a subject of great controversy in recent years, with the proportion of histologic subtypes varying substantially in different published series. Much of this controversy was initially due to the widely recognized inherent difficulty of classifying lymphomas based on routine histologic sections alone. However, the advent of immunohistochemical techniques has also yielded disparate results. Particularly contentious has been the notion of true histiocytic lymphomas, which some investigators have claimed to be relatively frequent in the gastrointestinal tract, whereas others doubt whether they exist at all. We present here a classification of 25 gastrointestinal lymphomas seen in the surgical pathology services of UCLA Hospital and Stanford University Medical Center. Unlike all previously reported series, we have utilized frozen tissue sections for the performance of immunohistochemical studies, which we and others have found to be far more reliable than the use of formalin-fixed, paraffin-embedded tissues, particularly in detecting monoclonal surface staining of immunoglobulin light- and heavy-chain markers. We find that this technique lessens the likelihood of overinterpreting the stains for histiocyte markers (alpha 1-antitrypsin and lysozyme), which are often difficult to read owing to strong positive staining of benign reactive histiocytes within the tumor. Utilizing these techniques, we have been able to classify definitely 21 of our 25 lymphomas (84%) as of B-cell origin, whereas none appeared to be histiocytic. We conclude that true histiocytic lymphomas of the gastrointestinal tract must be very rare, and we recommend the routine use of frozen tissue sections for more accurate classification of these interesting lesions.

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.

Cryopreserved microencapsulated hepatocytes--transplantation studies in Gunn rats.

Hepatocyte transplantation has been shown to provide significant metabolic support in several animal models of liver diseases. However, for it to be a viable alternative for supplementation of liver function in disease, large quantities of isolated hepatocytes would be necessary. At the present time there are no inexpensive routine methods for cryopreservation of hepatocytes. Existing procedures are cumbersome and require expensive programmable freezers. Hepatocyte cultures are sensitive and easily damaged in handling. By utilizing techniques of microencapsulation and cryopreservation we have attempted to overcome these problems. We have developed a simple, convenient, and inexpensive technique for the long-term storage of hepatocytes. Biological activity of the nonfrozen isolated encapsulated hepatocytes (IEH) and cryopreserved IEH (cIEH) was assessed both in tissue culture and by transplantation in Gunn rats. Significant urea and protein syntheses were detectable during the 10-day culture period even in the 30-day cIEH. Additionally, transplanted IEH and cIEH significantly reduced hyperbilirubinemia in Gunn rats for up to 30 days posttransplantation. Control (empty) microcapsules did not lower serum bilirubin levels. Thus we conclude: (1) cryopreservation of IEH is a convenient and cost-effective method for preserving and storing hepatocytes; (2) cryopreserved IEH function as well as nonfrozen IEH both in vitro and in vivo; (3) microencapsulation may protect hepatocytes from the adverse effects of cryopreservation.