Am J Clin Pathol

Hepatobiliary lymphoepithelioma-like carcinoma associated with Epstein-Barr virus.

Vortmeyer AO. Kingma DW. Fenton RG. Curti BD. Jaffe ES. Duray PH.
Laboratory of Pathology, National Institutes of Health, Bethesda, MD 20892, USA.
We describe the clinical and pathologic features of a lymphoepithelioma-like carcinoma (LELC) that originated in the hepatobiliary system. A woman, aged 71 years, was first seen with a noncholangiolar adenocarcinoma with lymphoid stroma, which was discovered by open liver biopsy in 1993. In 1995, retroperitoneal and peripancreatic lymph nodes were involved by LELC. There currently is no evidence of distant metastasis outside the hepatobiliary peripancreatic region. Review of the biopsy material revealed a well-differentiated adenocarcinoma with transition into LELC. Epstein-Barr virus (EBV) transcripts were expressed in all histologic phases of the tumor by in situ hybridization using immunoalkaline phosphatase-labeled oligonucleotide probes for EBV-encoded RNA 1 on formalin-fixed, paraffin-embedded sections. Polymerase chain reaction analysis for EBV nuclear antigen 2 was consistent with EBV strain type A. The LMP-1 gene was found to be wild type by polymerase chain reaction analysis. To our knowledge, this is the first report of a primary hepatobiliary adenocarcinoma associated with EBV infection that transformed into an undifferentiated LELC.

Routes of hepatic metastasis of gallbladder carcinoma.

Ohtsuka M. Miyazaki M. Itoh H. Nakagawa K. Ambiru S. Shimizu H. Nakajima N. Akikusa B. Kondo Y.
First Department of Surgery, School of Medicine, Chiba University, Japan.
This clinicopathologic study aims to clarify routes of hepatic metastasis of gallbladder carcinoma. Nineteen liver specimens obtained by extensive hepatectomy performed for the treatment of advanced gallbladder carcinoma were analyzed. We defined hepatic metastasis as a discrete hepatic lesion separate from the primary tumor and paid special attention to portal tracts at the margins of direct hepatic invasion. Eleven early metastatic foci were demonstrated histologically in 6 cases, most commonly in segments adjacent to the gallbladder. All cases with hepatic metastasis had direct hepatic invasion. Nine of the 11 metastatic lesions were located within the portal tracts or accompanied by invasion into the portal tracts. Because they are in continuity with areas of direct hepatic invasion, the portal tracts at the invasive margin often were involved by cancer cells that spread along these tracts. These results suggest that the most important route in development of hepatic metastasis from gallbladder carcinoma is along the portal tracts after direct hepatic invasion.

The relationship between MIB-1 proliferation index and outcome in pancreatic neuroendocrine tumors.

Year 1998
Gentil Perret A. Mosnier JF. Buono JP. Berthelot P. Chipponi J. Balique JG. Cuilleret J. Dechelotte P. Boucheron S.
Service d'Anatomie Pathologique, Centre Hospitalo-Universitaire de Saint-Etienne, France.
The expression of the cell-cycle-associated Ki-67 antigen by MIB-1 monoclonal antibody was retrospectively assessed in 35 surgically resected neuroendocrine tumor specimens of the pancreas embedded in paraffin. The MIB-1 proliferation index was correlated with the classification of the neuroendocrine tumors of the pancreas proposed by Kloppel et al. Four prognostic factors showed a significant correlation with MIB-1: local invasion, metastases, tumor differentiation, and production of insulin. However, analysis by the Cox Proportional Hazards Regression Model showed that only local invasion was an independent predictor of outcome. Finally, our study showed a statistically significant increase in the number of deaths and a statistically significant decrease in survival time when the MIB-1 proliferation index was higher than 4%. We conclude that MIB-1 proliferation index is a simple and reliable tool to predict the clinical outcome of the neuroendocrine tumors of the pancreas. The index might be useful for determining the prognosis for an individual because of the significant decrease in survival when the index is higher than 4%.

Cholangiocarcinomas arising in cirrhosis and combined hepatocellular-cholangiocellular carcinomas share apomucin profiles.

Year 1998
Sasaki M. Nakanuma Y. Ho SB. Kim YS.
Department of Pathology (II), Kanazawa University School of Medicine, Japan.
Cholangiocarcinomas occasionally arise in the nonbiliary cirrhotic liver, but their pathobiologic features remain unsettled. To characterize such cholangiocarcinomas, we examined immunohistochemically the expression of MUC3, MUC5AC, MUC6, and MUC7 apomucins in hepatic tissue specimens from 4 patients with cholangiocarcinoma and viral cirrhosis, 24 patients with cholangiocarcinoma without cirrhosis, and 16 patients with combined hepatocellular-cholangiocellular carcinoma. The cholangiocarcinomas associated with cirrhosis and the cholangiocarcinoma elements of combined hepatocellular-cholangiocellular carcinoma rarely expressed MUC3 and MUC5AC, but the cholangiocarcinomas not associated with cirrhosis frequently expressed these apomucins. MUC6 apomucin was widely expressed in cholangiocarcinomas, irrespective of the association with cirrhosis and also in the cholangiocarcinoma elements of the combined hepatocellular-cholangiocellular carcinomas. MUC7 apomucin was expressed frequently in cholangiocarcinomas associated with cirrhosis and combined hepatocellular-cholangiocellular carcinomas and infrequently in cholangiocarcinomas without cirrhosis, particularly those arising at the hepatic hilus. The similarity of the apomucin profiles between cholangiocarcinomas associated with cirrhosis and the cholangiocarcinoma elements of combined hepatocellular-cholangiocellular carcinoma suggests a similar or common histogenesis and that cholangiocarcinoma associated with cirrhosis might be derived from the combined type.

Vernix caseosa peritonitis: report of two cases with antenatal onset.

Year 1998
Davis JR. Miller HS. Feng JD.
Department of Pathology, University Medical Center, University of Arizona, Tucson 85724, USA.
Maternal peritonitis secondary to fetal vernix caseosa is considered an infrequent complication of cesarean section in which commonly spilled amniotic fluid is incompletely lavaged. Nine of the 10 reported cases have been diagnosed in the postpartum period after an uneventful cesarean section. Characteristically, vernix elicits granulomatous inflammation, occasionally with a mass lesion simulating bowel perforation and leading to colectomy. One case of antenatal leakage of amniotic fluid has been reported, also with granulomatous inflammation. We report two additional cases of antenatal leakage, both with acute inflammation lacking granulomatous features or mass lesions. The interval between amniotic fluid contamination and histopathologic evaluation is the basis for variations in the inflammatory pattern.

An approach to handling pediatric liver tumors.

Year 1998
Stocker JT.
Uniformed Services University of the Health Sciences, Bethesda, Maryland 20814-4799, USA.
Tumors and pseudotumors of the liver account for fewer than 2% of the tumors in children and vary considerably in incidence throughout the pediatric age range, with hepatoblastoma, infantile hemangioendothelioma, and mesenchymal hamartoma seen most frequently in the first 2 years of life and hepatocellular carcinoma, focal nodular hyperplasia, and undifferentiated "embryonal" sarcoma noted in older children. Despite the variety of malignant tumors seen in children and the number of patterns in individual tumors (eg, hepatoblastoma), the most important criterion for long-term prognosis is the stage of the tumor at the time of first resection. Accurate staging by the surgeon and pathologist is therefore the primary objective in examination of malignant hepatic tumors.

Optimal screening and diagnosis of microsporida in tissue sections: a comparison of polarization, special stains, and molecular techniques.

Year 1998
Lamps LW. Bronner MP. Vnencak-Jones CL. Tham KT. Mertz HR. Scott MA.
Department of Pathology, Vanderbilt University Medical Center, Nashville, Tennessee 37232-5310, USA.
With improving therapeutic protocols, confirmation of microsporidiosis has become increasingly important. We designed a study to determine the best screening method(s) for microsporidian detection in biopsy specimens. Forty-two small intestinal biopsy specimens from 31 immunocompromised patients (68% AIDS) were stained (hematoxylin-eosin [H & E], modified trichrome, Warthin-Starry, and Brown-Brenn) and polarized. Polymerase chain reaction and Southern blot assays were performed on all positive cases. Microsporida were detected in nine cases (21%) by modified trichrome (all patients with AIDS). Of these, seven were Brown-Brenn positive, and five Warthin-Starry positive. Two cases polarized on H & E and three on special stains. Four of nine positive cases were confirmed by molecular studies. We found polarization to be the least sensitive screening method. The modified trichrome was the most sensitive when screening for microsporidiosis in paraffin-embedded biopsy specimens. Furthermore, combining Brown-Brenn or Warthin-Starry with the trichrome stain helps exclude false-positive results due to granular artifacts (eg, eosinophils, Paneth cells).

Fine-needle aspiration of gastrointestinal stromal tumors.

Year 1998
Dodd LG. Nelson RC. Mooney EE. Gottfried M.
Department of Pathology, Duke University Medical Center, Durham, North Carolina 27710, USA.
Gastrointestinal stromal tumors are a group of neoplasms encompassing leiomyoma, leiomyosarcoma, and an epithelioid variant of leiomyosarcoma, as well as lesions expressing neural differentiation. These neoplasms are rare and account for 1% of all gastrointestinal tumors. With increasing frequency, fine-needle aspiration (FNA) has been used to diagnose intra-abdominal neoplasms before institution of definitive treatment. We encountered four patients with gastrointestinal stromal tumors diagnosed by FNA who ultimately underwent surgical excision of their tumors. The age of the patients ranged from 57 to 88 years. Smears from the aspirates were cellular and consisted of numerous small spindle cells distributed as cohesive fragments and individual cells. The dispersed cell population appeared largely as stripped nuclei. Several nuclei had perinuclear or paranuclear vacuoles, similar to the "halos" seen in sections. Cytologic evidence of malignancy (pleomorphism, nuclear irregularity, mitoses) were not identified in smears. Corresponding histologic sections demonstrated varying degrees of malignancy ranging from benign or low grade to frankly sarcomatous gastrointestinal stromal tumors. We conclude that the diagnosis of gastrointestinal stromal tumors can be made with a certain degree of confidence by using FNA findings. However, predictions about potential aggressiveness are best reserved for gross and histologic examination of the resected specimen.

Detection of K-ras point mutations in the supernatants of peritoneal and pleural effusions for diagnosis complementary to cytologic examination.

Year 1998
Yamashita K. Kuba T. Shinoda H. Takahashi E. Okayasu I.
Department of Pathology, Kitasato University East Hospital, Sagamihara, Kanagawa, Japan.
To determine whether DNA analysis can be performed using the supernatants of body fluids after centrifugation at 2,000 rpm for 10 minutes, peritoneal or pleural effusions or bile were examined for K-ras mutations in 34 cases of pancreatic, colorectal, gastric, esophageal, or hepatocellular carcinoma and 15 noncancer cases. The polymerase chain reaction products for K-ras gene codons 2 to 97 of exons 1 and 2 were generated with 41 (93%) of 44 body cavity fluid and 5 (100%) of 5 bile samples. By the single strand conformation polymorphism method, point mutations were detected in the ascites supernatants of 8 (89%) of 9 cases of pancreatic carcinoma. In the remaining case, no point mutation was demonstrated because few malignant cells were present in the ascites fluid. Furthermore, K-ras point mutations were observed in the ascites supernatants of 2 cases of colorectal carcinoma and 1 case of gastric carcinoma. The DNA analysis of the supernatant of ascites fluid showed a K-ras point mutation in 3 cases of false-negative cytologic diagnosis (2 cases of pancreatic carcinoma and 1 case of colorectal carcinoma). Direct sequencing confirmed identical point mutations in the supernatants, whole cell pellets, malignant cells from the cytologic smears of ascites fluid, and cancer tissues. This novel method allows simultaneous testing for genetic abnormalities in supernatants of body fluid, after removing cells for cytologic diagnosis.

Tumor angiogenesis in stage II colorectal carcinoma: association with survival.

Year 1998
Banner BF. Whitehouse R. Baker SP. Swanson RS.
Department of Pathology, University of Massachusetts Medical Center, Worcester 01655, USA.
We studied the frequency of microvessels in T3 N0 M0 colorectal carcinomas from patients with widely different survival times. Microvessels (

Familial adenomatous polyposis: from bedside to benchside.

Year 1998
O'Sullivan MJ. McCarthy TV. Doyle CT.
Department of Pathology, Cork University Hospital, Ireland.
Familial adenomatous polyposis (FAP) is a dominantly inherited cancer-predisposition syndrome with an incidence of between 1:17,000 and 1:5,000. The condition has been causally linked to mutation of the adenomatous polyposis coli (APC) gene located at 5q21. Virtually all mutations in the APC gene are truncating mutations, resulting in loss of function of the APC protein. Spontaneous germline mutation of this gene occurs frequently and accounts for the high incidence of FAP. The gene is somatically mutated at an early point in the colorectal adenoma-carcinoma progression. Somatic mutations of the APC gene are also frequently observed in a variety of other human carcinomas. Isolation of the APC gene has led to the recognition of genotype-phenotype correlations and, together with protein studies, has helped to elucidate the structure and function of the APC protein. This report aims to take the reader from a clinical appreciation to a molecular understanding of FAP.

Diagnostic value of brush cytology in the diagnosis of duodenal, biliary, and ampullary neoplasms.

Year 1998
Bardales RH. Stanley MW. Simpson DD. Baker SJ. Steele CT. Schaefer RF. Powers CN.
Department of Pathology, University of Arkansas for Medical Sciences, and John L. McClellan Memorial Veterans Hospital, Little Rock 72205, USA.
Endoscopy is a valuable tool in the diagnosis and management of duodenal lesions and biliary strictures. We assessed the value of cytology in the evaluation of these lesions and analyzed the causes of discrepancy among clinical, histologic, and cytologic parameters. The study included 118 patients with duodenal ulcers, ampullary neoplasms, or biliary strictures who were examined between 1975 and 1995; 120 cytologic examinations were performed. The specimens included brushings of the duodenum (DB, n = 50), ampulla (AB, n = 32), and biliary ducts (BB, n = 38). Endoscopic biopsies performed concurrently included the duodenum (n = 37), the ampulla (n = 22), and the biliary ducts (n = 23). Comparison of cytologic and histologic results showed the following sensitivity and specificity: DB, 40% and 97%, respectively; AB, 100% each; BB, 75% and 93%, respectively. The DB, AB, and BB revealed malignant neoplasms in 2 of 5, 7 of 7, and 6 of 8 cases, respectively. Twenty-three duodenal neoplasms were diagnosed by either modality and included 11 adenocarcinomas, 9 villous tumors, 2 metastatic renal cell carcinomas, and 1 large cell non-Hodgkin's lymphoma. Endoscopic brush cytology is an effective means of diagnosing ampullary neoplasms, and it complements tissue biopsy in cases of bile duct stricture. Location, predominance of tumor-induced stroma, an extramucosal growth pattern, sampling error, and interpretative experience influence the diagnostic evaluation. Cytologic diagnosis of an adenoma does not exclude an underlying malignant neoplasm in ampullary tumors. In some instances, it may be difficult to distinguish between villous tumors with severe dysplasia and adenocarcinomas by cytology alone.

Evaluation of esophageal cytology using a neural net-based interactive scanning system (the PAPNET system): its possible role in screening for esophageal and gastric carcinoma.

Year 1998
Koss LG. Morgenstern N. Tahir-Kheli N. Suhrland M. Schreiber K. Greenebaum E.
Department of Pathology, Montefiore Medical Center/Albert Einstein College of Medicine, Bronx, New York 10467, USA.
A neural net-based, semiautomated, interactive computerized cell analysis system (The PAPNET system, Neuromedical Systems, Suffern, NY) was used to examine cells from 138 esophageal smears obtained by lavage, brushings, or balloon from as many patients. From each smear, trained human observers examined 128 cell images selected by the machine. Abnormal cells were identified in all 35 patients with cancer, whether esophageal, gastric, oral, or metastatic. Further, in 11 smears, the displayed images allowed the recognition of effects of radiotherapy and, in 14 smears, the diagnosis of a specific tumor type, such as squamous cell carcinoma (8 patients) or adenocarcinoma (6 patients). In 3 additional cases, the diagnosis of "carcinoma, not further specified," was established. One case of esophageal carcinoma in situ, not previously recognized on a smear or in the biopsy specimen, and one case of gastric adenocarcinoma, not recognized in the smear, were identified in PAPNET-generated images. The possible application of the apparatus to the triage of smears and population screening for esophageal and gastric carcinoma precursors is discussed.

Histopathologic changes are not specific for diagnosis of gastric antral vascular ectasia (GAVE) syndrome: a review of the pathogenesis and a comparative image analysis morphometric study of GAVE syndrome and gastric hyperplastic polyps.

Year 1998
Vesoulis Z. Naik N. Maseelall P.
Department of Pathology, Akron City Hospital (Summa Health Systems), Ohio 44304, USA.
We studied the nonspecific nature of the histologic findings in the gastric antral vascular ectasia (GAVE) syndrome by using a morphometric comparison with common gastric lesions including hyperplastic polyps and gastritis. Five clinicopathologically confirmed cases of GAVE syndrome and 41 cases of gastric hyperplastic polyps were diagnosed during a 5-year interval at Summa Health Systems (Akron, Ohio). These cases, as well as 16 randomly selected cases of nonspecific gastritis and 9 normal gastric antral biopsy specimens, were evaluated. A semiquantitative comparison of the light microscopic findings believed to be essential in diagnosis of GAVE syndrome, including vascular hyperplasia, mucosal vascular ectasia, intravascular fibrin thrombi, and fibromuscular hyperplasia, was performed. Image analysis morphometric measures of the area ratio (vascular area/total biopsy area), mean vascular area, and number of ectatic vessels per square millimeter of tissue were performed on the CAS 200 Image Analyzer (Becton Dickinson, San Jose, Calif). By morphometric and statistical parametric analysis, several histopathologic variables, including area ratio, mean vascular area, mucosal vascular ectasia, and fibromuscular hyperplasia, did not confidently differentiate the histologic features of gastric hyperplastic polyp from those of GAVE syndrome, but did apparently differentiate GAVE syndrome from gastritis and normal gastric mucosa. The propensity of gastric hyperplastic polyps to undergo prolapse changes and prolapse as one proposed mechanism for development of the GAVE syndrome lesion probably accounts for this morphologic similarity. Specific diagnostic histopathologic changes probably do not exist for the GAVE syndrome.

Hepatic iron overload: direct HFE (HLA-H) mutation analysis vs quantitative iron assays for the diagnosis of hereditary hemochromatosis.

Year 1998
Press RD. Flora K. Gross C. Rabkin JM. Corless CL.
Department of Pathology, Oregon Health Sciences University, Portland 97201-3098, USA.
Among patients with hepatic iron overload, the distinction between hereditary hemochromatosis (HH), a common yet treatable genetic disease, and other causes of siderosis remains problematic. The recent discovery of a specific homozygous mutation (C282Y) in a novel major histocompatibility complex class I-like gene (named HLA-H or HFE) in 80% to 100% of well-characterized cases of HH suggests that direct DNA-based mutation analysis may help resolve this dilemma. To assess the clinical utility of direct HLA-H mutation analysis in a typical diagnostic setting, we measured genotypic and phenotypic parameters of iron overload in 37 subjects with biopsy-proven hepatic siderosis (2+ or greater) and in 127 healthy control subjects. The prevalence of C282Y homozygotes was significantly greater in the hepatic siderosis group (32%) than in the control group (0%), confirming the association between this homozygous mutation and hepatic iron overload. In the hepatic siderosis group, C282Y homozygotes had significantly higher hepatic iron and ferritin levels, a significantly lower prevalence of hepatitis C virus or alcoholic liver disease, but no significant difference in the saturation of serum transferrin. Of the 20 subjects with a hepatic iron index (HII) in the previously defined "hemochromatosis range" (>1.9), 9 (45%) were C282Y homozygotes. Of the 11 nonhomozygous subjects with an HII greater than 1.9 (presumed false-positive HIIs), 10 (91%) had hepatic cirrhosis compared with 3 of 9 (33%) homozygotes with an HII greater than 1.9 who had cirrhosis (P

Extranodal lymphomas associated with hepatitis C virus infection.

Year 1998
Ascoli V. Lo Coco F. Artini M. Levrero M. Martelli M. Negro F.
Anatomia Patologica, Dipartimento di Medicina Sperimentale e Patologia, Universita La Sapienza, Rome, Italy.
Hepatitis C virus (HCV) infection may be complicated by non-Hodgkin's lymphoma. We describe eight cases of B-cell extranodal non-Hodgkin's lymphoma occurring during the course of chronic HCV-related hepatic disease (low-grade of mucosa-associated lymphoid tissue [MALT]-type; diffuse large cell; Burkitt; diffuse small cell). Some were localized to the liver (2), liver and spleen (1), spleen (1), peritoneal cavity (1), parotid gland (1); others manifested in the nasopharynx (1) and eyelid (1) but were accompanied by nodal disease. Four lymphomatous specimens available for molecular analysis exhibited clonal immunoglobulin gene rearrangements, lacked bcl-2, bcl-6, c-myc genes and p53 alterations, and did not contain replicative intermediate HCV RNA, as documented by a strand-specific reverse transcriptase-polymerase chain reaction. Low levels of positive-strand HCV RNA were detected in a single hepatic lymphoma, suggesting the presence of the virus in residual hepatocytes. The antigen-driven properties of HCV-associated B-cell malignant neoplasms may be considered for hepatic MALT-type lymphoma, which probably originated from lymphoid tissue acquired during long-standing HCV infection.

Clinicopathologic significance of transitional cell carcinoma pattern in nonlocalized ovarian epithelial tumors (stages 2-4).

Year 1998
Costa MJ. Hansen C. Dickerman A. Scudder SA.
Department of Pathology, University of California at Davis Medical Center, Sacramento 95819, USA.
The transitional cell carcinoma (TCC) pattern has been associated with favorable outcome in patients with late-stage ovarian epithelial tumors who receive chemotherapy. We examined the clinicopathologic significance of TCC and explored other histopathologic prognostic indicators for patients with ovarian epithelial tumor. The surgical records of patients at the University of California at Davis Medical Center who underwent treatment for stages 2 to 4 ovarian epithelial tumor were studied retrospectively; the histopathologic features were correlated with outcome. The TCC pattern was identified in 32 of 136 ovarian epithelial tumors (23.5%): 18 (13.2%) as a predominant (> 50%) and 14 (10.3%) as a focal (< or = 50% but > 25%) histologic pattern. The other predominant histopathologic types were serous (65.4%), mucinous (11.7%), endometrioid (3.6%), clear cell (3.6%), and small cell (1.5%) carcinoma. Architectural grade was as follows: low malignant potential, 13 cases; grade I, 34 cases; grade II, 63 cases; grade III, 26 cases. Nuclear grade was as follows: low grade, 27 cases; high grade, 109 cases. One hundred seven patients had dominant ovarian tumors, and 29 had diffuse primary peritoneal epithelial tumor. One hundred twenty-three cases (90%) of peritoneal disease were invasive; 11 (10%) were noninvasive. Peritoneal disease histopathologic density was 50% or less cross-sectional involvement in 68 patients (50%) and greater than 50% in 68 (50%). Follow-up data were available for 118 patients: 46 patients had persistent disease that was unresponsive to chemotherapy; 36 of these patients died of disease at 0 to 41 months (mean, 15.6 months; median, 23.5 months). Ten patients were alive at 16 to 40 months (mean, 24.5 months; median, 20.5 months). Thirty-six patients had recurrent disease after 6 to 66 months (mean, 23.5 months; median, 18.5 months); 20 of these patients died of disease after 10 to 69 months (mean, 33.7 months; median, 30 months), and 16 were alive after 12 to 159 months (mean, 33.7 months; median, 30 months). Thirty-six patients had no evidence of disease at 12 to 159 months of follow-up (mean, 49.5 months; median, 31 months). The TCC pattern, either predominant or focal, was not associated with disease status or survival time (P > .05). Predictors of recurrent or persistent disease and survival, respectively, were invasive peritoneal disease (P < .05, P < .0001) and greater than 50% cross-sectional area histologic density of peritoneal disease (P < .01, P < .01). Grade, histologic type, and diffuse primary peritoneal vs ovarian location were not predictors of outcome. The TCC pattern was present in at least a focal (> 25%) component in 23% of epithelial tumors; however, this finding did not reach significance as a predictor of outcome in this study. The histologic pattern of the peritoneal disease (invasiveness and density) was a much stronger predictor of disease response and survival.

Novel subtyping of intestinal metaplasia in the human stomach: brain-type glycogen phosphorylase expression in the proliferative zone and its relationship with carcinogenesis.

Year 1998
Matsuzaki H. Shimada S. Uno K. Tsuruta J. Ogawa M.
Department of Surgery II, Kumamoto University School of Medicine, Japan.
Although reports have suggested the incomplete type of intestinal metaplasia (IM) had a close correlation with carcinoma, considerable data showed no apparent relationship between the particular type of IM and the intestinal type carcinoma. The purpose of this study was to establish a novel classification of IM using brain-type glycogen phosphorylase (BGP) from a carcinogenetic viewpoint. The only isoform expressed in gastric cancer was BGP using polymerase chain reaction analysis. We studied 136 specimens with gastric carcinoma and the adjacent IM using specific anti-BGP antibody with its correlation to subtypes of IM, proliferating cell nuclear antigen-labeling index, and various oncogene products. Brain-type glycogen phosphorylase was expressed in 80.5% of the intestinal type and 18.8% of the diffuse type of carcinoma and in 87.5% and 41.6% in the generative zone of IM adjacent to cancer foci, respectively, whereas no reactivity was observed in the normal gastric mucosa. The proportion of the positivity in the cancer and IM was significantly greater in the intestinal-type carcinoma than in the diffuse type. The expression of BGP in the generative cells of IM had no significant correlation with the conventional type of IM. Intestinal metaplasias with BGP expression were significantly higher in a proliferating state than in those without BGP, and some of them that were coexpressed accumulated p53 in the generative cells. The relationship between IM with BGP in the generative cells and intestinal-type carcinoma was apparently closer than the conventional subtype of IM and gastric cancer. Intestinal-type carcinoma might arise from some of these proliferating cells with BGP.