 |
|
|
|
|
|
|
|
|
 |
 |
 |
 |
 |
 |
 |
 |
|
Background
Stomach cancer is a worldwide disease but shows interesting geographic distribution. Patients may present with weight loss or early satiety (premature fullness after eating) and stools may contain blood. Unfortunately, this is a highly aggressive cancer and overall survival is poor. The Japanese, because of the high rates of stomach cancer, have embarked upon a very aggressive screening program. This has enabled them to identify very early presentations of the disease resulting in cures in some of their patients. There is no reliable blood screening test at this time.
OUTLINE
DISEASE ASSOCIATIONS CHARACTERIZATION Atrophic gastritis 95% of malignancies with this as a precursor Chronic gastric ulceration 0.7% of malignancies with this as a precursor Adenoma 2.5% of malignancies with this as a precursor Chronic erosive gastritis 1.4% of malignancies with this as a precursor Hyperplastic polyp 0.5% of malignancies with this as a precursor Stomach remnant 0.1% of malignancies with this as a precursor
There is a risk of cancer in patients who have had a gastrectomy and still have a small residual portion of stomach
It usually occurs 15-25 years post surgeryImmunodeficiency disorders Overall 2-10%
X-linked immunodeficiency
Infantile X-linked agammaglobulinemia
Common variable immunodeficiencyMenetrier's disease Rare H. pylori infection With severe infections
Since H. pylori is responsible for the majority of gastric ulcers, its role may be underestimated
Caveats:CA develops in only a small propotion of infected patients
Pts. with diffuse antral gastritis associated with duodenal ulceration and infection have a lower risk
Some populations such as China and Africa have high prevalence of infection but low risk of CA
Risk related to childhood geography, greater risk if migrated after childhood from a high risk countryGastric Dysplasia Important risk factor, present in 50-100% of early cancers and 80% of advanced cancers
Dyplasia progresses from mild to severe to CAMultiple gastric carcinomas 21 years after gastrojejunostomy without gastrectomy. Report of a case.
Takeno S, Noguchi T, Sato T, Uchida Y, Yokoyama S.
Department of Surgery II, Oita Medical University, Oita, Japan.
Dig Surg 2000;17(5):531-7 Abstract quote
We report a case of gastric carcinoma after gastrojejunostomy (GJ-stomy) without gastrectomy.
Multiple gastric carcinomas were discovered 21 years after GJ-stomy without gastrectomy which had been performed for treatment of pyloric stenosis due to severe gastric ulcer. Multiple gastric carcinomas were found in the stomach, or the esophagocardiac junction, and in the corpus and anastomotic lesion of the GJ-stomy. Under the light microscope, intestinal metaplasia was detected in the antral mucosa and the area around the anastomosis.
In immunohistochemical analysis, p53-specific antibodies gave a positive reaction in every gastric carcinoma and in the noncancerous gastric glands around the carcinoma at the anastomosis and in the corpus. Cells positive for immunostaining with Ki-67-specific antibodies were more numerous in all gastric carcinomas and in the area around the anastomotic lesion than in the normal gastric mucosa. Hsp70-specific antibodies reacted with cells in the noncancerous glands around the carcinoma in the anastomotic area.
Mucosal injury and the potential for carcinogenesis due to exposure to gastroduodenal reflux are discussed. The results of this study suggest that similar cases with gastroduodenal reflux should be followed carefully.
Synchronous multiple primary cancers of the stomach and duodenum in aged patients: report of two cases.
Onoue S, Katoh T, Chigira H, Matsuo K, Suzuki M, Shibata Y, Maeda M.
Department of Surgery, Toyohashi Municipal Hospital, Aichi, Japan.
Surg Today 2000;30(8):735-8 Abstract quote
We describe herein the cases of two aged patients found to have synchronous multiple primary cancers of the stomach and duodenum.
The first patient was an 82-year-old man who was preoperatively diagnosed as having gastric cancer after presenting with signs of pyloric stenosis. At laparotomy, duodenal cancer was incidentally found to have infiltrated the transverse colon. A pancreatoduodenectomy and right hemicolectomy with radical lymph node dissection was performed. Two early well-differentiated adenocarcinomas of the stomach and an advanced poorly differentiated adenocarcinoma of the duodenum were confirmed. This patient is now well without any evidence of recurrence more than 5 years after surgery.
The second patient was a 77-year-old man who was also diagnosed as having gastric cancer after presenting with signs of pyloric stenosis. Preoperatively, duodenal cancer was detected by endoscopy. A pancreatoduodenectomy and partial colectomy with radical lymph node dissection was performed because the duodenal cancer was suspected of having infiltrated the transverse colon. An early moderately differentiated adenocarcinoma of the stomach and an advanced moderately differentiated adenocarcinoma of the duodenum were confirmed, but the duodenal cancer was not seen to invade the transverse colon microscopically. This patient died of cancer 7 months after surgery.
Because multiple primary cancers commonly develop in elderly patients, a precise preoperative diagnosis must be made and optimal treatment applied.
PATHOGENESIS CHARACTERIZATION GENERAL ONCOGENE ABERRANT EXPRESSION Aberrant expression of oncogenes bcl-2, cadherin-e, K-sam, p53 Amplification of erb-B2 Indicator of metastatic ability Synchronous expression of EGF, TGF-alpha, and ras p21 Associated with tumor invasion and metastasis Overexpression of TGF-beta, IGF, and PDGF Collagen synthesis in poorly differentiated cancers
- Early-onset gastric cancers have a different molecular expression profile than conventional gastric cancers.
Milne AN, Carvalho R, Morsink FM, Musler AR, de Leng WW, Ristimaki A, Offerhaus GJ.
1Department of Pathology, Academic Medical Center, Amsterdam, The Netherlands.
Mod Pathol. 2006 Apr;19(4):564-72. Abstract quote
Many studies examine the molecular genetics of gastric cancer, but few look at young patients in particular and there is no comparison of molecular expression between early-onset gastric cancer (</=45 years old) and conventional gastric cancers.
Expression of cycloxygenase-2 (COX-2) is elevated in gastric adenocarcinomas compared to non-neoplastic mucosa, and in light of studies showing reduced risk of gastric cancer in nonsteroidal anti-inflammatory drug users, we have chosen to investigate the expression of COX-2 and related molecules in 113 early-onset gastric cancers and compare it with 91 conventional gastric cancers, using tissue microarrays.
These markers include molecules known to be important in conventional gastric carcinogenesis, such as E-Cadherin, p53, COX-2, Trefoil Factor-1 (TFF1), beta-catenin, p16 and c-myc; as well as molecules not yet described as being important in gastric cancer, such as the transcription factor c-jun, the COX-2 mRNA stabilizer HuR, and C/EBP-beta, a transcription factor for COX-2. All markers showed a statistically significant difference between early-onset gastric cancers and conventional gastric cancers, using a chi(2) test. In particular, early-onset gastric cancers displayed a COX-2 Low, TFF1-expressing phenotype, whereas COX-2 overexpression and loss of TFF1 was found in conventional cancers, and this difference between early-onset gastric cancers and conventional cancers remained statistically significant when adjusted for location and histology (P<0.0001 and P=0.002 respectively). We found that COX-2 overexpression correlates significantly with loss of TFF1 (P=0.001), overexpression of C/EBP-beta (P<0.001) and cytoplasmic HuR (P=0.016). COX-2 was significantly associated with p53 positivity (P=0.003). Abnormalities in E-Cadherin correlated significantly with diffuse phenotype, whereas high expression of COX-2, loss of TFF1 and overexpression of C/EBP-beta correlated with the intestinal phenotype.
Our results provide further evidence that early-onset gastric cancer exhibits a distinctive expression profile that may have practical implications.Chromosomal Imbalances in Gastric Cancer Correlation With Histologic Subtypes and Tumor Progression
Tsyoshi Noguchi, MD, Hans-Christian Wirtz, MD, Sonja Michaelis, Helmut E. Gabbert, MD, and Wolfram Mueller, MD
Am J Clin Pathol 2001;115:828-834 Abstract
DNA copy number changes were analyzed by comparative genomic hybridization (CGH) in 38 gastric carcinomas and correlated with tumor histologic type and progression. Gains of copy numbers were observed in all tumors, affecting all chromosomes except chromosome 16. The average number of copy number gains was 7 (range, 1-13), most frequently located on chromosomes 11, 12, 15, 17, and 20 in 45% to 97% of tumors. High-level amplifications were found on chromosomes 12, 15, 17, and 20; the latter was affected most frequently (66%). Loss of DNA copy numbers was detected in 14 tumors affecting 7 chromosomes.
No statistically significant differences in the frequency and pattern of chromosomal imbalances were observed in tumor histologic type (Lauren classification) and grade of differentiation, as well as the prognostic parameters depth of invasion (pT) and lymph node involvement (pN). Our results indicate that in gastric cancer there is no specific recurrent pattern of DNA aberrations to be correlated with tumor histologic type or stage. However, CGH analysis could reveal new, recurrent genetic changes in gastric cancer affecting chromosomes sites that harbor genes known to participate in tumorigenesis and progression of several human malignant neoplasms.
CADHERIN Inactivation of the E-Cadherin Gene in Sporadic Diffuse-Type Gastric Cancer
Jennifer J. Ascańo, M.S., Henry Frierson, Jr., M.D., Christopher A. Moskaluk, M.D., Ph.D., Jeffrey C. Harper, B.S., Franco Roviello, M.D., Charles E. Jackson, M.D., Wa’el El-Rifai, M.D., Ph.D., Carla Vindigni, M.D., Piero Tosi, M.D. and Steven M. Powell, M.D.
Department of Medicine (JJAJCH, WE, SMP) and Department of Pathology (HF, CAM), University of Virginia Health System, Charlottesville, Virginia; Istituto Policattedva di Scienze Chirurgiche (FR), Istituto di Anatomia Eistologia Patologica (CV, PT), and Universita’ Degli Studi di Siena, Via della Scotte, Siena, Italy; and Henry Ford Hospital (CEJ), Detroit, Michigan
Mod Pathol 2001;14:942-949 Abstract quote
Loss of the cell adhesion molecule E-cadherin has been observed in a variety of human carcinomas, and germline E-cadherin mutations have been found in several familial cases of diffuse gastric cancer.
We sought to determine the prevalence and nature of E-cadherin alterations in "sporadic" gastric carcinomas.
We performed comprehensive sequencing of the coding region, loss of heterozygosity (LOH) analysis, and immunohistochemical protein expression determination on 40 sporadic gastric adenocarcinomas. In total, 7 of 25 diffuse-type cancers harbored genetic alterations in the E-cadherin gene. Novel mutations predicted to significantly compromise protein function were found within 4 of these cancers, 2 of which harbored alterations resulting in biallelic inactivation of the gene product. Three diffuse cancers failed to amplify Exon 8 of E-cadherin, suggesting the presence of a homozygous abnormality. Notably, one germline E-cadherin mutation was also identified within these "sporadic" diffuse cancers. Significant gene mutations were not found in the 14 intestinal-type or histologically mixed cancer. Immunohistochemistry revealed aberrant or negative protein expression in seven diffuse-type tumors, four of which correlated with the genetic alterations. Both diffuse and intestinal-type tumors exhibited low rates of LOH, suggesting that allelic loss at the locus is not a common mechanism for E-cadherin inactivation during gastric tumorigenesis.
Our observations suggest that inactivation of the E-cadherin gene occurs only in a subset of diffuse-type gastric cancers, as the majority of cases did not contain genetic alterations or identifiable protein abnormalities. Germline E-cadherin alterations, although rare, may underlie some diffuse gastric cancer cases that have important biologic and practical implications
Paranuclear E-Cadherin in Gastric Adenocarcinoma
Philip M. Carpenter, MD,
Rasha A. Al-Kuran, MD
and Charles P. Theuer, MDAm J Clin Pathol 2002;118:887-894 Abstract quote
Decreased E-cadherin expression permits dissociation and widespread dissemination of gastric adenocarcinoma cells.We studied the relationship between paranuclear E-cadherin distribution and the histopathologic characteristics of gastric adenocarcinomas. E-cadherin immunostains of 173 gastric adenocarcinoma sections revealed paranuclear, punctate to vesicular staining in 18% (16/87) of the intestinal-type adenocarcinomas, 30% (17/56) of the diffuse-type adenocarcinomas, and 30% (9/30) of the mixed adenocarcinomas.
These data suggest that in some gastric adenocarcinomas, there is a defect in transport of E-cadherin to the cell surface, which may prevent intercellular adhesion and encourage dissemination. Of 34 cancers with paranuclear E-cadherin staining, 20 (59%) had paranuclear staining within the nonneoplastic epithelium, but only 22.0% of 100 carcinomas with absent or membranous E-cadherin staining were accompanied by morphologically benign epithelium with paranuclear E-cadherin. In surface epithelium, paranuclear E-cadherin staining colocalized with Griffonia simplicifolia lectin II in the Golgi apparatus.
The presence of paranuclear E-cadherin in cancer-associated benign epithelium suggests that the alteration in the E-cadherin molecule responsible for the paranuclear distribution may be an early change in gastric adenocarcinoma progression.
CDKN2A PROMOTER METHYLATION
CDKN2A promoter methylation in gastric adenocarcinomas: Clinical variables.Vo QN, Geradts J, Boudreau DA, Bravo JC, Schneider BG.
Department of Pathology, Louisiana State University Health Sciences Center, New Orleans, LA; Roswell Park Cancer Institute, Buffalo, NY; and Universidad Del Valle, Cali, Colombia.
Hum Pathol 2002 Dec;33(12):1200-4 Abstract quote The CDKN2A gene encodes a cyclin-dependent kinase inhibitor, p16, which promotes cell cycle arrest. Methylation of the promoter region of the gene transcriptionally inactivates the gene. We have analyzed the methylation status of the promoter region of the CDKN2A gene in gastric adenocarcinomas using methylation-specific polymerase chain reaction.
We also examined the tumors by immunohistochemistry for p16 protein. Of 114 gastric adenocarcinomas analyzed by immunohistochemistry, 34 cases (30%) were negative for p16 protein. Twenty-four of these 34 cases (71%) had methylation of the promoter region of the CDKN2A gene. Methylation of the promoter was strongly associated with loss of p16 protein by immunohistochemistry (P <0.0001).
Neither stage, grade, anatomic site, or histologic subtype of the tumor nor age, gender, ethnic origin, or survival time of the patient were significantly different between the groups characterized by tumors with and without methylation. CDKN2A promoter methylation was not significantly associated with microsatellite instability.
CHROMOSOMAL ALTERATIONS
- Genetic alterations in 102 primary gastric cancers by comparative genomic hybridization: gain of 20q and loss of 18q are associated with tumor progression.
Kimura Y, Noguchi T, Kawahara K, Kashima K, Daa T, Yokoyama S.
1Department of Oncological Science (Pathology), Faculty of Medicine, Oita University, Oita, Japan.
Mod Pathol. 2004 Nov;17(11):1328-37. Abstract quote
Gastric cancer is one of the most common cancers. Molecular events in the carcinogenesis of gastric cancer remain, however, largely undefined.
We investigated changes in DNA copy number in 102 gastric cancers by CGH. We found changes in DNA copy number in all cases, with frequent (>==30% of patients) gains at 20q, 8q, 20p, 7q, 17q, 5p, and 13q. Frequent (>==20%) losses were found at 19p, 18q, 5q, 21q, 4p, 4q, 15q, and 17p. The mean number of total alterations was significantly lower in grade 3 and scirrhous-type carcinomas (10.81 in grade 3 vs 13.98 in grade 1 and grade 2, 9.31 in scirrhous-type vs 13.18 in medullary- and intermediate-type). The mean number of losses and total alterations were higher in tumors at pT2, pT3 and pT4 (4.68 and 12.77 in pT2, pT3, and pT4 vs 2.55 and 9.22 in pT1). The mean number of losses was higher in carcinomas with lymph node metastasis (4.83). The mean number of gains and total alterations were higher in carcinomas with venous invasion (8.44 and 13.28).
Several chromosomal alterations were linked in a statistically significant manner to specific clinicopathological parameters. Gain of 17q, 20p, and 20q and loss of 4p were associated with the pattern of the cancer-stroma relationship; loss of 18q was associated with pT category; gain of 5p was associated with pN category; loss of 4q and loss of 21q were associated with lymphatic invasion; gain of 7p and loss of 4q and 18q were associated with venous invasion; and loss of 18q was associated with pathological stage.
These data suggest that gain of 20q and loss of 18q might play an important role in the development and progression of gastric cancer. Moreover, some genes on 20q and 18q might be target genes of gastric cancer.CYCLOOXYGENASE-2
Cyclooxygenase-2 expression correlates with angiogenesis and apoptosis in gastric cancer tissue.
Tatsuguchi A, Matsui K, Shinji Y, Gudis K, Tsukui T, Kishida T, Fukuda Y, Sugisaki Y, Tokunaga A, Tajiri T, Sakamoto C.
Third Department of Internal Medicine, Nippon Medical School, Tokyo, Japan.
Hum Pathol. 2004 Apr;35(4):488-95. Abstract quote
In vitro studies suggest that cyclooxygenase-2 (COX-2) induces angiogenesis by stimulating angiogenic growth factors while inhibiting apoptosis in cancer cell lines.
A series of 107 gastric adenocarcinoma cases that had undergone gastrectomy was studied to determine the correlation between COX-2 expression, angiogenesis, and apoptosis in human gastric cancer tissue. COX-2, vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF), and Bcl-2 were stained by single and dual immunoassaying methods. Microvessel density was determined by immunostaining for CD34. Apoptosis was evaluated with the TUNEL assay. COX-2 expression was positive exclusively in cancer cells in 46 cases (43%). COX-2 expression significantly correlated with VEGF and PDGF expression. Dual staining for COX-2 and VEGF showed that colocalization of these proteins was most frequent at the advancing edge of cancer cells. Microvessel density was higher in COX-2-and VEGF-positive cases than in COX-2- and VEGF-negative cases. In addition, COX-2 expression correlated with Bcl-2 expression. The apoptotic index was lower in COX-2-positive cancer cells than in COX-2-negative cases. Multivariate analysis revealed that coexpression of COX-2 and VEGF, age, lymph node status, and serosal invasion were independent prognostic factors for overall survival in gastric cancer patients.
Therefore, these data suggest that COX-2 contributes to gastric cancer development by promoting angiogenesis and inhibiting apoptosis.EPSTEIN-BARR VIRUS Simultaneous EBV-Positive Lymphoepithelioma-like Carcinoma and EBV-Negative Intestinal-Type Adenocarcinoma in a Patient With Helicobacter pylori –Associated Chronic Gastritis
Goran Torlakovic, MD, Dale C. Snover, MD, and Emina Torlakovic, MDAm J Clin Pathol 2004;121:237-243 Abstract quote
We report the case of a 72-year-old man with 2 simultaneous gastric carcinomas. The larger, ulcerated mass in the antrum was a conventional infiltrating intestinal-type adenocarcinoma. The associated antral-type mucosa showed moderate chronic gastritis, foci with complete and incomplete intestinal metaplasia, and mild to moderate Helicobacter pylori infection.
The second, smaller tumor was found within fundic-type mucosa and was a lymphoepithelioma-like carcinoma associated with Epstein-Barr virus (EBV) infection shown by the EBV-encoded small RNA (EBER) test. The EBER test result was negative in the intestinal type adenocarcinoma. To our knowledge, this is the first report of simultaneous gastric carcinomas with 2 different morphologic phenotypes, in which only one tumor was associated with EBV infection, while the second tumor was related to H pylori –associated chronic gastritis.
Our report demonstrates 2 different but simultaneous etiologic pathways of gastric carcinogenesis in the same patient.
A Rapid and Reliable Enzyme Immunoassay PCR-Based Screening Method to Identify EBV-Carrying Gastric Carcinomas.Van Beek J, Zur Hausen A, Kranenbarg EK, Warring RJ, Bloemena E, Craanen ME, Van De Velde CJ, Middeldorp JM, Meijer CJ, Van Den Brule AJ.
Departments of Pathology (JvB, AzH, RJW, EB, JMM, CJLMM, AJCvdB) and Gastroenterology (MEC), Vrije Universiteit Medical Center, Amsterdam.
Mod Pathol 2002 Aug;15(8):870-7 Abstract quote Epstein-Barr virus (EBV) is associated with a substantial number of gastric adenocarcinomas worldwide, as confirmed by EBER1/2-RNA in situ hybridization (RISH).
In the present study, we developed a rapid and sensitive PCR-based prescreening method for the detection of EBV in gastric carcinomas to reduce the amount of laborious EBER1/2-RISH assays to be performed. The method was evaluated by testing gastric adenocarcinomas (n = 242) using both BamHI W PCR-enzyme immunoassay (EIA) and EBER1/2-RISH, in combination with appropriate DNA and RNA quality controls. Seventy-four percent of the paraffin-embedded gastric adenocarcinomas had good DNA quality as shown by beta-globin polymerase chain reaction (PCR) after proteinase K and boiling pretreatment, whereas after DNA purification this was increased to 90%. Thirty-two percent of all cases were EBV-DNA positive after PCR-EIA, whereas 10% of these gastric cancers contained EBV transcripts in the neoplastic cells as confirmed by EBER1/2-RISH. Interestingly, only samples with high optical density (OD) 405/630 values in PCR-EIA, equivalent to the maximum reading of the assay as determined by the positive control, contained EBV-positive tumor cells in the EBER1/2-RISH. In contrast, the weak positive samples, as determined by low OD readings in the PCR-EIA were EBER1/2-RISH negative.
In conclusion, high OD values in EBV PCR-EIA are very valuable to prescreen EBV-carrying gastric carcinomas as confirmed by EBER1/2-RISH. Only these samples and those with poor DNA quality will require testing in the EBER1/2-RISH, thereby reducing the amount of laborious RISH assays with 85%.
HELICOBACTER PYLORI Helicobacter pylori infection and the development of gastric cancer.
Uemura N, Okamoto S, Yamamoto S, Matsumura N, Yamaguchi S, Yamakido M, Taniyama K, Sasaki N, Schlemper RJ.
Department of Gastroenterology, Kure Kyosai Hospital, Kure City, Japan.
N Engl J Med 2001 Sep 13;345(11):784-9 Abstract quote
BACKGROUND: Although many studies have found an association between Helicobacter pylori infection and the development of gastric cancer, many aspects of this relation remain uncertain.
METHODS: We prospectively studied 1526 Japanese patients who had duodenal ulcers, gastric ulcers, gastric hyperplasia, or nonulcer dyspepsia at the time of enrollment; 1246 had H. pylori infection and 280 did not. The mean follow-up was 7.8 years (range, 1.0 to 10.6). Patients underwent endoscopy with biopsy at enrollment and then between one and three years after enrollment. H. pylori infection was assessed by histologic examination, serologic testing, and rapid urease tests and was defined by a positive result on any of these tests.
RESULTS: Gastric cancers developed in 36 (2.9 percent) of the infected and none of the uninfected patients. There were 23 intestinal-type and 13 diffuse-type cancers. Among the patients with H. pylori infection, those with severe gastric atrophy, corpus-predominant gastritis, and intestinal metaplasia were at significantly higher risk for gastric cancer. We detected gastric cancers in 21 (4.7 percent) of the 445 patients with nonulcer dyspepsia, 10 (3.4 percent) of the 297 with gastric ulcers, 5 (2.2 percent) of the 229 with gastric hyperplastic polyps, and none of the 275 with duodenal ulcers.
CONCLUSIONS: Gastric cancer develops in persons infected with H. pylori but not in uninfected persons. Those with histologic findings of severe gastric atrophy, corpus-predominant gastritis, or intestinal metaplasia are at increased risk. Persons with H. pylori infection and nonulcer dyspepsia, gastric ulcers, or gastric hyperplastic polyps are also at risk, but those with duodenal ulcers are not.
HEPARANASE
Heparanase: a key enzyme in invasion and metastasis of gastric carcinoma.Tang W, Nakamura Y, Tsujimoto M, Sato M, Wang X, Kurozumi K, Nakahara M, Nakao K, Nakamura M, Mori I, Kakudo K.
Department of Pathology (WT, YN, MS, XW, MiN, IM, KeK), Wakayama Medical University, Wakayama, Japan.
Mod Pathol 2002 Jun;15(6):593-8 Abstract quote Previous reports have shown that the biochemical activity of heparanase is significantly correlated with the invasion and metastasis of malignant cells in vitro. Recently, it was found that the human heparanase gene was cloned and highly expressed in malignant cell lines and human solid malignant tumors.
In the present study, we investigated the heparanase mRNA expression by using in situ hybridization in 116 paraffin-embedded tissues of primary gastric carcinomas. To explore its clinicopathologic significance, it was detected in the various steps of tumor progression and then compared with prognostic indicators. As a result, the heparanase expression was more prevalent in late-stage rather than early-stage carcinomas (P <.0001) and was more frequent in tumors of large size (P =.0212). Expression also correlated with lymphatic (P =.0086) and venous (P =.0171) invasion and with negative prognostic factors such as lymph nodal (P <.0001) and distant (P =.0221) metastases. However, in a multivariate analysis, messenger RNA expression of heparanase was not an independent prognostic factor.
It was concluded that heparanase might play an important role in the development of invasion and metastasis of the gastric cancer. It was indicated that patients with heparanase-positive gastric carcinoma would have a greater chance of metastasis with a poor prognosis.
LOSS OF HETEROZYGOSITY Chromosomes 7p, 17p, 1q, 5q
- Clinicopathological significance of loss of heterozygosity in intestinal- and solid-type gastric carcinomas: a comprehensive study using the crypt isolation technique.
Jiao YF, Sugai T, Habano W, Uesugi N, Takagane A, Nakamura S.
1Division of Pathology, Central Clinical Laboratory, School of Medicine, Iwate Medical University, Morioka, Japan.
Mod Pathol. 2006 Apr;19(4):548-55. Abstract quote
The clinicopathological significance of loss of heterozygosity (LOH) in gastric carcinoma remains poorly understood. We and other researchers have previously demonstrated that LOH is fairly common in intestinal- and solid-type gastric carcinomas, but rare in diffuse-type tumors. In this study, we investigated the relationship between clinicopathological variables and LOH status in intestinal- and solid-type gastric carcinomas. The crypt isolation technique was utilized to analyze LOH at 1p36, 3p14, 4p15, 5q21-22, 8p11-12, 9p21, 13q22, 17p13.1 18q21 and 22q13.31 in 113 intestinal- and solid-type gastric carcinomas using a polymerase chain reaction assay.
Immunostaining with D2-40 and Elastica van Gieson staining were used to detect lymphatic invasion and vessel invasion, respectively. High LOH rates (49-71%) were observed in all chromosomal regions tested. 1p36 loss was significantly associated with advanced tumors and lymph node metastasis. 8p11-12 loss was significantly associated with lymph node metastasis, lymphatic invasion, and vessel invasion. 17p13.1 (TP53) loss was significantly associated with vessel invasion. 22q13.31 loss was significantly associated with advanced tumors, lymph node metastasis, lymphatic invasion, vessel invasion and late TNM stage. No significant associations were observed between LOH at other chromosomal regions and aggressive behaviors. In addition, significantly higher LOH rates at 1p36, 9p21, 18q21 and 22q13.31 were observed in cardiac tumors compared with noncardiac tumors.
These results suggest that in intestinal- and solid-type gastric carcinomas, LOH on 3p14, 4p15, 5q21-22, 9p21, 13q22 and 18q21 is associated with carcinogenesis, while LOH on 1p36, 8p11-12, 17p31.1 and 22q13.31 is associated with tumor progression.MICROSATELLITE INSTABILITY
Standardized approach for microsatellite instability detection in gastric carcinomas.
Musulen E, Moreno V, Reyes G, Sancho FJ, Peinado MA, Esteller M, Herman JG, Combalia N, Rey M, Capella G.
Hum Pathol 2004;35:335-342 Abstract quote
Microsatellite instability (MSI) defines a specific type of genetic instability. Although consensus diagnostic criteria for MSI definition in colorectal cancer have been established, their utility in other tumor types remain to be proven. Previously we developed a mathematical model for MSI definition in colorectal cancer.
The aim of this study was to establish diagnostic criteria for MSI evaluation in human gastric cancer. We designed an algorithm for the efficient characterization of MSI and used it to analyze data on 7 microsatellite markers in 35 gastric carcinomas. Theoretical models considering 1, 2, or 3 populations were tested against the data collected. Also, hypermethylation of hMLH1 gene promoter and hMLH1 protein expression were studied. The observed frequencies of MSI in our series of samples best fit a 2-population model: stable and unstable, defined by instability in 2 or more of a minimum of 7 markers analyzed. MSI was observed in 29% of the tumors.
Misclassification rate was <4% when any 7 loci were analyzed. MSI(+) tumors inversely associated with p53 protein overexpression. A good correlation between hMLH1 status (either protein or promoter hypermethylation) and MSI classification was observed.
We have developed a simple, sensitive, and specific approach to assess the presence of MSI in gastric cancer that may have clinical applications.Microsatellite Instability in Double Primary Cancers of the Colorectum and Stomach
Hee Sung Kim, M.D., Ph.D., Nam Bok Cho, M.D., Ph.D., Jae Hyung Yoo, M.D., Ph.D., Ki-Hyuk Shin, Ph.D., Jae-Gahb Park, M.D., Ph.D., Yong Il Kim, M.D., Ph.D. and Woo Ho Kim, M.D., Ph.D.
Department of Pathology (HSK, YIK, WHK) and Surgery (JGP) and Cancer Research Institute (KHS, JGP, WHK), Seoul National University College of Medicine, Seoul, Korea; and Department of Pathology (NBC, JHY), Chung-Ang University College of Medicine, Seoul, Korea
Mod Pathol 2001;14:543-548 Abstract quote
Little is known about genetic alterations of patients who present multiple primary cancers. We hypothesized that microsatellite instability (MSI) is one of the underlying genetic factors in the development of double primary cancers in colorectal cancer patients.
We examined for MSI in 41 colorectal cancer patients who presented with extra-colonic primary cancers consisted of 17 gastric and 24 non-gastric cancers.
Coincident MSI+ in tumors of two organs were observed in 3 (17.7%) of 17 patients with colon and stomach cancers and 0 of 24 patients with colon and non-gastric cancers (P = .03). In 17 patients with colon and stomach cancers, 6 (31.6%) of 19 colon cancers and 3 (17.7%) of 17 gastric cancers exhibited MSI+. Among four patients with metachronous colon cancers who were identified within the 41 double primary cancer patients, two patients were associated with the MSI+ phenotype.
In summary, the prevalent coincidence of MSI suggests that genetic defect of mismatch repair deficiency may be responsible for a small subset of double primary cancers of the colorectum and stomach.
Epstein-Barr virus, p53 protein, and microsatellite instability in the adenoma-carcinoma sequence of the stomach.Chang MS, Kim HS, Kim CW, Kim YI, Lan Lee B, Kim WH.
Department of Pathology and Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea.
Hum Pathol 2002 Apr;33(4):415-20 Abstract quote To elucidate the adenoma-carcinoma sequence in the stomach, we investigated Epstein-Barr virus (EBV) incorporation, p53 overexpression, and microsatellite instability (MSI) in gastric adenomas and carcinomas.
The study involved 66 cases of gastric carcinomas within or adjacent to adenomas (adenoma-carcinoma cases), 81 cases of simple adenomas (without carcinoma), and 306 de novo carcinomas (without adenoma focus). EBV incorporation was revealed in 1 (1.5%) of the adenoma-carcinomas, in none of the adenomas, and in 17 (5.6%) of the de novo carcinomas. p53 overexpression was observed in 24.2% (16 of 66) of the adenomas in the adenoma-carcinoma cases and in 36.5% (23 of 63) of corresponding carcinomas (kappa = 0.63, P = 0.00). MSI was positive in 12.3% (8 of 65) of the adenomas in the adenoma-carcinoma cases and in 18.8% (12 of 64) of the corresponding carcinomas (kappa = 0.77, P = 0.00).
In conclusion, EBV incorporation is not possibly associated with the gastric adenoma-carcinoma sequence, whereas the gastric adenoma-carcinoma sequence seems to be supported in terms of p53 overexpression or MSI. The transcriptional activation of EBV may occur relatively late (after the adenoma stage) in the gastric adenoma-carcinoma sequence.
RAS
ras Gene mutations and expression of Ras signal transduction mediators in gastric adenocarcinomas.Yoo J, Park SY, Robinson RA, Kang SJ, Ahn WS, Kang CS.
Department of Pathology, St Vincent's Hospital, Catholic University, Suwon, Kyungkido, South Korea.
Arch Pathol Lab Med 2002 Sep;126(9):1096-100 Abstract quote OBJECTIVE: To investigate ras gene alteration in human gastric adenocarcinomas and its potential relationship to ras signal transduction mediators.
DESIGN: Genomic DNA from 104 gastric tumors were analyzed by sequencing of polymerase chain reaction-amplified products for the presence of ras mutations. All the samples were further investigated with the use of immunohistochemical analysis for ERK1 and ERK2.
SETTING: Tertiary care teaching hospital.
PATIENTS: Seventy patients from a Korean population and 34 from a Midwestern US population composed of white Americans and African Americans.
RESULTS: Fifteen tumors (14%) were positive for either H-ras or K-ras mutation: 9 (13%) of 70 Korean patients and 6 (18%) of 34 US patients. Seven (78%) of the 9 mutated tumors from Korean patients and all 6 (100%) from the US patients were intestinal-type lesions. Either ERK1 and/or ERK2 was overexpressed in 68 samples (65%). No association was established between ras mutations and overexpression of ERK1/2. However, the correlation between ERK1/2 and progression (early vs late) was statistically significant (P =.007).
CONCLUSIONS: These data suggest that ras mutations are uncommon in gastric adenocarcinomas and that differing racial and/or geographic mechanisms may not underlie ras gene alteration. Most ras mutations were, however, observed in the group of intestinal-type samples, supporting the different genetic mechanisms of carcinogenesis between the intestinal- and diffuse-type tumors. It is noteworthy that enhanced ERK1/2 activity could be one of the characteristics of tumor invasiveness in gastric cancers.
RETINOBLASTOMA GENE
Abnormal expression of pRb, p16, and cyclin D1 in gastric adenocarcinoma and its lymph node metastases: relationship with pathological features and survival.
Feakins RM, Nickols CD, Bidd H, Walton SJ.
Department of Histopathology, The Royal London Hospital, Whitechapel, London, UK.
Hum Pathol. 2003 Dec;34(12):1276-82 Abstract quote.
The retinoblastoma (Rb) pathway controls the G1-S checkpoint of the cell cycle. Inactivating mutations and deletions of p16 and Rb and up-regulation of cyclin D1 disrupt this pathway and occur in many cancers. However, the concurrent expression of these genes in primary and metastatic gastric cancer is unknown, and the prognostic value of their expression is unclear.
In this study, the expression of cyclin D1, retinoblastoma protein (pRb), and p16 in 67 resected gastric adenocarcinomas, and of pRb and p16 in 40 associated lymph node metastases, was determined using a streptavidin-biotin-peroxidase immunohistochemical method. Relationships with clinical and pathological features were analyzed. Cyclin D1 overexpression (>/=5% expression) was seen in 55% of cancers; pRb loss (<20% expression), in 33%; p16 loss (<10% expression), in 49%; and at least 1 of these abnormalities, in 92.5%. Cyclin D1 overexpression was associated with poor differentiation (P = 0.027) and signet ring cell type (P = 0.029). pRb expression was lower in lymph node metastases than in the corresponding primary tumors (P <0.001). Univariate and multivariate survival analysis (minimum follow-up 72 months or until death) revealed that <20% pRb expression, <30% pRb expression, and International Union Against Cancer stage >2 were associated with worse overall survival.
The results suggest that Rb pathway disturbances play an important role in gastric carcinogenesis. The poor prognosis of cancers with low pRb expression and the reduced pRb expression in lymph node metastases raise the possibility that Rb and related genes also influence progression.
LABORATORY/
RADIOLOGIC/CHARACTERIZATION Endoscopic evaluation Shelf effect-Sharply demarcated area between tumor and adjacent normal mucosa
Loss of mucosal tenting-In diffusely infiltrating tumors, the mucosa is firmly attached to the submucosa, preventing it being pulled outFlow cytometry 70% are aneuploid Application of the crypt isolation technique to the flow cytometric analysis of DNA content in gastric carcinoma.
Jiao YF, Sugai T, Suzuki M, Uesugi N, Habano W, Nakamura S, Takagane A, Suto T, Yoshida T.
Hum Pathol. 2004 May;35(5):587-93. Abstract quote
An inevitable limitation of conventional flow cytometric analysis of gastric cancer DNA content is that the preparations of tumor cell nuclei are contaminated with stromal cell nuclei.
Using the crypt isolation technique, we separated tumor tissues from stromal tissues and analyzed the DNA content in samples of pure gastric cancer cells (64 intestinal-type and 46 diffuse-type) by flow cytometry. Morphologically, crypts from well-differentiated and moderately differentiated adenocarcinomas usually showed large tube-like or sheet structures, whereas tumor tissues isolated from poorly differentiated adenocarcinomas usually exhibited small tumor cell clumps or clusters of varying sizes. Tumor ploidy was divided into diploid, aneuploid, and multiploid subgroups. Aneuploidy and multiploidy were observed in 12% (13 of 110) and 64% (71 of 110) of gastric cancers, respectively. A high frequency of DNA aneuploidy or multiploidy was associated with intestinal-type tumors, but not with any of the other clinicopathologic variables tested. In contrast, high S-phase fraction values demonstrated a close association with tumors with abnormal ploidy, advanced stage, intestinal type, and late TNM stage. Our results suggest that S-phase fraction may be a more useful indicator of aggressive behavior in gastric cancers than DNA aneuploidy.
To our knowledge, the present study is the first to report flow cytometric DNA content in a large number of gastric cancer samples obtained using the crypt isolation technique.
GROSS APPEARANCE/
CLINICAL VARIANTSCHARACTERIZATION Early gastric cancer Japanese Research Society for Gastric Carcinoma has identified 3 main groups:
I. Protruded
IIA. Superficial-elevated
IIB. Superficial-flat
IIC. Superficial-depressed
III. ExcavatedMost occur on the lesser curvature and angulus
Superficial type II most common -80%Advanced gastric cancer Borrmann's Growth patterns, four main groups:
I. Polypoid or fungating
II. Excavating
III. Ulcerated and infiltrating
IV. Infiltrating (diffuse thickening)Most occur in antrum (50%) and lesser curvature (15%)
Linitis plastica (Scirrhous carcinoma) Diffusely infiltrating carcinomas associated with marked desmoplasia (fibrosis) creating a leather bottle stomach Minute gastric carcinoma Tiny cancers <5 mm
May be present with larger cancerSuperficial spreading carcinoma Early cancer which measure at least 25 cm2 in area
Remain confined to mucosa and submucosaAdenocarcinoma of the gastric cardia and proximal stomach Similar to esophageal adenocarcinomas both histologically and clinically
Defined as tumors arising in the proximal stomach
Usually within 1 cm proximal and 2 cm distal to the GE junction
Overall incidence is increasing
Lower mean age of 65 years
Male:female of 6:1
Greater frequency of hiatal hernia, esophageal reflux, and duodenal ulcer
Strong association with alcohol and tobacco
Tumors spread into the esophagus and usually present with advanced stage
HISTOLOGICAL TYPES CHARACTERIZATION Dysplasia (Carcinoma precursor) Tubular, villous, or mixed pattern-Divided into low and high grade lesions
Low grade has the atypical cells present in the superficial portion of the mucosa with little glandular branching
Retain basal nuclear polarity with small indistinct nucleoli
High grade has complex architectural branching and budding with dysplastic cells showing variation in size and shape with irregular chromatin and large nucleoliGastric epithelial dysplasia and adenoma: historical review and histological criteria for grading.
Goldstein NS, Lewin KJ.
Department of Pathology, William Beaumont Hospital, Royal Oak, MI 48073, USA.
Hum Pathol 1997 Feb;28(2):127-33 Abstract quote
Gastric epithelial dysplasia (GED) hypothetically is a straight-forward concept: dysplastic epithelium replacing the normal gastric epithelium of the stomach. However, since its inception several decades ago, the term GED has become progressively complex and confusing because of differences in definitions and nomenclature that have been based on cytological, microscopic, endoscopic, or gross features.
This has resulted in the terms "dysplasia," "adenoma," "flat adenoma," and "depressed adenoma." Some authors have also included reactive changes under the term "dysplasia."
Early gastric carcinoma Defined as cancer confined to the mucosa and submucosa Advanced gastric cancers Defined as cancer that has invaded into or beyond the muscularis propria Intraglandular necrotic debris in gastric biopsy and surgical specimens
Watanabe Y, etal.
Ann Diagn Pathol 2001;5:141-147
135 gastric biopsies and 55 surgical specimens
Defined as eosinophilic material with necrotic epithelial fragments within the lumen of a dilated atypical glandUsing the Vienna classification, incidence in category 4 (noninvasive high-grade neoplasia) and category 5 (invasive neoplasia) was higher than other categories
SPECIFIC HISTOLOGIC TYPES CHARACTERIZATION Simple or branching tubules Papillary clusters Abundnant intra and extracellular mucin >50% of tumor Pure squamous cell carcinoma
Thought to arise from squamous metaplasiaCombined areas of adenocarcinoma and squamous cell carcinoma
Poor prognosisSignet rings with large cytoplasmic vacuole of mucin peripherally displacing the nucleus >50% of tumor cells Poor prognosis
Sheets, cords, and trabeculae of small hyperchromatic cells with stippled chromatinResemble nasopharyngeal carcinomas
Male:Female 3:1
Nests of tumor cells with a dense lymphoplasmacytic infiltrate adn lymphoid follicles
5 Year survival better than other types at 77%Poorly differentiated signet ring carcinomas with neuroendocrine cells interspersed Elderly patients
Usually large tumors
Solid sheets of polygonal cells with abundant eosinophilic cytoplasm
Less aggressive than usual variants
Oncocytic Adenocarcinoma of the Stomach: Parietal Cell Carcinoma.Takubo K, Honma N, Sawabe M, Arai T, Izumiyama-Shimomura N, Kammori M, Sasajima K, Esaki Y.
Departments of Clinical Pathology (K.T., N.H., M.S., T.A., N.I.-S., M.K., Y.E.), Tokyo Metropolitan Institute of Gerontology and Tokyo Metropolitan Geriatric Hospital, Tokyo; the Department of Surgery (M.K.), University of Tokyo, Tokyo; the First Department of Surgery (K.S.), Nippon Medical School, Tokyo; and the Department of Pathology (Y.E.), Sekishinkai Sayama Hospital, Sayama-city, Saitama-ken, Sayama-city, Japan.
Am J Surg Pathol 2002 Apr;26(4):458-465 Abstract quote We report 10 cases of an unusual type of gastric adenocarcinoma that occurred in elderly patients 58-81 years of age. Histologically, the tumors were well to moderately differentiated tubular adenocarcinomas with very eosinophilic, finely granular cytoplasm. Immunohistochemical stains for antimitochondrial antibody were strongly positive.
Ultrastructurally, the tumor cells had numerous mitochondria in their cytoplasm and occasional intracytoplasmic lumina with associated long microvilli. These histologic and ultrastructural features are similar to those of parietal cells in normal gastric fundic mucosa, but immunohistochemical staining of the tumors using four different antiparietal cell antibodies (anti-H+-K+-adenosine triphosphatase antibodies) was negative in all cases.
Therefore, we think that these tumors were not parietal cell carcinomas but could be termed oncocytic adenocarcinomas, or adenocarcinomas with oncocytic differentiation. Previously reported cases of parietal cell carcinoma have been said to have a favorable prognosis, but it will be necessary to study a larger number of cases to determine the prognosis of oncocytic adenocarcinoma.
Cancer admixed with areas resembling mature and neoplastic hepatocytes
Have poor prognosis with widespread tumor dissemination and high serum alpha fetoprotein levelsCarcinoma with two discrete types of neoplastic differentiation such as adenocarcinoma and carcinoid tumor Carcinoma with a predominance of Paneth cells, having large, eosinophilic cytoplasmic granules Poor prognosis
Cells are round to polygonal with eosinophilic to clear cytoplasm and large eccentric vesicular nuclei resembling rhabdoid tumors of the kidneyFeatures of choriocarcinoma and gastric adenocarcinoma
Usually elderly and male
Poor prognosisVARIANTS CLEAR CELL (GLYCOGEN-RICH)
Clear cell (glycogen-rich) gastric adenocarcinoma.
Govender D, Ramdial PK, Clarke B, Chetty R.
Ann Diagn Pathol. 2004 Apr;8(2):69-73. Abstract quote
Clear cells have been described in many tumors of varying differentiation. Although clear cell carcinoma is well-recognized in the lower urinary and female genital tracts, its occurrence in the gastrointestinal tract and related structures is uncommon. There have been only a few case reports and small series reporting this morphologic phenomenon in the stomach, colon, and biliary tract. Clear cell carcinoma of the endometrium has been associated with poor prognosis, but the prognostic significance of clear cells in gastric adenocarcinoma is unknown.
Herein we describe three cases of clear cell, glycogen-rich, gastric adenocarcinoma and evaluate the frequently used classification systems for gastric cancer. Two tumors showed a tubulopapillary pattern and one showed a predominantly diffuse sheet-like growth. The proliferation (MIB) index in all cases was approximately 20%. Only case 1 showed focal staining for alpha-fetoprotein and both cases 1 and 2 showed focal carcinoembryonic antigen reactivity.
- In conclusion, we describe three cases of clear cell gastric carcinoma that presented as high-stage disease.
INTESTINAL TYPE
Advanced gastric carcinoma with a complete intestinal metaplasia phenotype associated with early intestinal-type carcinoma.
Rivera-Hueto F, Lag-Asturiano E, Utrilla-Alcolea JC, Herrerias-Gutierrez JM.
Department of Pathology, Virgen Macarena University Hospital, Seville, Spain.
Arch Pathol Lab Med. 2004 Feb;128(2):218-21. Abstract quote
An unusual case of synchronous gastric carcinomas occurred in a 28-year-old man with a family history of gastric disease. Two tumor foci were identified: a well-differentiated advanced carcinoma with the phenotypic properties of complete intestinal metaplasia and an early intestinal-type carcinoma.
Histochemical and immunohistochemical stains to demonstrate complete intestinal metaplasia, ie, Alcian blue pH 2.5/periodic acid-Schiff, high iron diamine/Alcian blue pH 2.5, CD10, and MUC2, were all positive in the advanced adenocarcinoma. Of all markers used, only high iron diamine/Alcian blue pH 2.5 and Alcian blue pH 0.5 were positive in the early carcinoma. In these cases, mistakes frequently are made during examination of endoscopic biopsies. Fortunately, the advanced adenocarcinoma was low grade (the patient has shown no signs of disease at 6 years postsurgery).
Histopathologic, histochemical, and immunohistochemical findings suggest that an extensive substrate of complete intestinal metaplasia (corpus) and of complete and incomplete intestinal metaplasia (antrum) can be associated with two independent tumors with different phenotypes.LARGE CELL NEUROENDOCRINE
*Department of Pathology, Kitasato University School of Medicine, Sagamihara, Kanagawa 228-8555 daggerPathology Division, Shizuoka Cancer Center Hospital and Research Institute, Shizuoka 411-8777, Japan.
The current histologic classifications of gastric cancers define only carcinoids and small cell carcinomas in the neuroendocrine (NE) category. This study aimed to characterize the histologic and clinical features of high-grade gastric NE carcinomas of nonsmall cell type, tentatively named large cell neuroendocrine carcinoma (LCNEC).
Tumors with histologic features suspicious of NE differentiation were selected by a histologic review of 2835 resected gastric cancers, and those with a NE phenotype in >50% and 1% to approximately 50% tumor cells assessed by expressing chromogranin A and/or synaptophysin were defined as LCNEC and adenocarcinoma with neuroendocrine differentiation (ACNED), respectively. One hundred ninety-nine tumors were selected and of the 109 positive for chromogranin A and/or synaptophysin, 42 and 44 met the criteria for LCNEC and ACNED, respectively. Generally, LCNECs demonstrated less predominant NE morphology than carcinoids, and could be roughly divided into solid (30 cases), tubular (7 cases), and scirrhous (5 cases) subtypes with reference to their main growth pattern.
The prognosis of LCNECs was significantly worse than that of conventional adenocarcinomas (P<0.0001). Thus, this study shows that the spectrum of gastric NE tumors is broader than has previously been recognized and LCNEC is not only a distinct histopathologic entity, but also a distinct clinical entity.
Furthermore, the prognosis of ACNEDs was also significantly worse than that of adenocarcinomas (P<0.0001), and some ACNEDs might actually have been LCNECs, and survival analysis showed that >20% positivity of NE markers could be enough to characterize LCNEC, as long as light microscopic NE morphology was present in the tumor.PANCREATIC LIKE
Gastric carcinoma resembling pancreatic mixed acinar-endocrine carcinoma.Fukunaga M.
Department of Pathology, Jikei University School of Medicine, Tokyo, Japan.
Hum Pathol 2002 May;33(5):569-73 Abstract quote A case of gastric carcinoma resembling pancreatic mixed acinar-endocrine carcinoma of 77-year-old female is presented. This type of gastric tumor has not been previously reported. The endoscopic mucosal resection specimen of the fundus contained a 1.2 x 0.9 x 0.3 cm, well-circumscribed, tan, soft nodular tumor with protruded configuration with a central recess.
Histologically, the tumor was confined to the mucosa and submucosa and was characterized by three growth patterns; acinar, solid, and glandular. The growth patterns were intermingled. The tumor cells in the acinar component had round nuclei with prominent nucleoli and diastase-resistant, periodic acid-Schiff-positive, eosinophilic cytoplasm. Immunohistochemically, the tumor cells were positive for CAM5.2, cytokeratin (CK) 7, CK 20, trypsin, lipase, alpha-1-antitrypsin, and alpha-1-antichymotrypsin. The tumor cells in the solid component were positive for Grimelius stain and chromogranin A. The findings indicated that the tumor showed acinar and endocrine differentiation. There was no heterotopic pancreas tissue in the specimen.
The patient was well without tumor at the 7-month follow-up. It is important to know the existence of this type of gastric cancer and to not confuse it with a metastatic lesion of the pancreatic origin.
SPECIAL STAINS/
IMMUNOPEROXIDASE
CHARACTERIZATION Mucicarmine
Alcian blue with PASMay highlight cytoplasmic vacuoles of signet ring cells GENERAL
- Utility of immunohistochemistry in distinguishing primary adenocarcinomas from metastatic breast carcinomas in the gastrointestinal tract.
O'Connell FP, Wang HH, Odze RD.
Department of Pathology, Brigham and Women's Hospital, Boston, Mass 02115, USA.
Arch Pathol Lab Med. 2005 Mar;129(3):338-47. Abstract quote
CONTEXT: Breast carcinoma often metastasizes to the gastrointestinal tract, especially the stomach, where it is frequently difficult to distinguish from a primary gastric carcinoma.
OBJECTIVE: To evaluate the utility of immunohistochemical stains in differentiating primary gastric carcinomas from metastatic breast carcinomas.
DESIGN: Mucosal biopsy specimens from 47 adenocarcinomas involving the gastrointestinal tract (28 primary gastric carcinomas and 19 metastatic breast carcinomas) and 16 control cases of primary breast carcinomas without metastasis were immunohistochemically stained for estrogen receptor protein (ER), progesterone receptor protein (PR), gross cystic disease fluid protein (GCDFP), human epidermal growth factor receptor 2 protein, cytokeratin (CK) 5/6, CK/7, CK/20, a panel of mucin glycoprotein antigens (MUC2, MUC3, MUC5AC, and MUC6), monoclonal antibody DAS-1, and caudal-type homeobox transcription factor CDX2 and compared between primary and metastatic adenocarcinomas.
RESULTS: Highly significant proportions of metastatic breast carcinomas were positive for ER (72%), PR (33%), GCDFP (78%), and CK5/6 (61%) compared with primary gastric carcinomas (ER, 0%; PR, 0%; GCDFP, 0%; and CK5/6, 14%) (P < .001, P = .002, P < .001, and P = .004, respectively). Of these immunostains, ER, PR, and GCDFP were 100% specific. Primary breast tumors and their metastases showed a similar phenotypic profile. In contrast, primary gastric carcinomas showed significantly higher proportions of cases that stained with CK20 (50%), MUC2 (54%), MUC5AC (71%), MUC6 (39%), DAS-1 (43%), and CDX2 (67%) compared with metastatic breast carcinomas (CK20, 0%; MUC2, 24%; MUC5AC, 6%; MUC6, 0%; DAS-1, 0%; and CDX2, 0%) (P = .001, P = .01, P < .001, P = .02, P = .009, and P < .001, respectively). No significant differences were observed with regard to any of the other immunostains (human epidermal growth factor receptor 2 protein, CK7, and MUC3) between the patient groups.
CONCLUSIONS: Estrogen receptor protein, PR, GCDFP, CK5/6, CK20, MUC5AC, MUC6, DAS-1, and CDX2 are helpful in distinguishing primary gastric carcinomas from metastatic breast carcinomas. Of these, ER, PR, and GCDFP are highly specific for metastatic breast carcinomas, whereas CK20, DAS-1, MUC2, MUC5AC, MUC6, and CDX2 are highly specific for primary gastric carcinomas.CYTOKERATINS Cytokeratin expression profile in gastric carcinomas.
Kim MA, Lee HS, Yang HK, Kim WH.
Hum Pathol. 2004 May;35(5):576-81. Abstract quote
Cytokeratin (CK) is observed mainly in epithelial cells, and the diverse expression pattern of CK subtypes may be helpful in discriminating between primary and metastatic carcinomas in various organs, including the stomach.
To clarify the CK expression profiles in gastric carcinomas, 329 consecutive specimens were immunohistochemically evaluated in terms of their CK subtypes using the tissue array method. The overall positive rates were 84.7% for CK4, 3.2% for CK5, 28.7% for CK6, 71.1% for CK7, 96.6% for CK8, 0% for CK10, 81.6% for CK13, 0.3% for CK14, 4.1% for CK16, 0% for CK17, 99.4% for CK18, 89.7% for CK19, and 30.0% for CK20.
Well-differentiated or moderately differentiated carcinomas were related to several CKs, and mucinous carcinoma was associated with CK20 expression. Interestingly, CK7 and CK20 expression was associated with the mucin phenotype of gastric carcinoma, but this association had no diagnostic value. Epstein-Barr virus (EBV)-associated gastric carcinomas showed a tendency toward negative expression of CK7. CK6 expression was related to microsatellite instability (MSI), early pTNM stage, and better clinical outcome. In conclusion, CK expression profiles in consecutive gastric carcinomas demonstrate heterogeneity, and no single CK has diagnostic value by itself.
CK expression is associated with various clinicopathologic parameters, mucin phenotype, EBV positivity, MSI status, and patient survival.
Expression of cytokeratins 7 and 20 in primary carcinomas of the stomach and colorectum and their value in the differential diagnosis of metastatic carcinomas to the ovary.Park SY, Kim HS, Hong EK, Kim WH.
Center for Colorectal Cancer, Center for Gastric Cancer, and Department of Pathology, National Cancer Center, Goyang, Gyeonggi, Korea and the Department of Pathology, Seoul National University College of Medicine, Seoul, Korea.
Hum Pathol 2002 Nov;33(11):1078-85 Abstract quote The expressions of cytokeratin (CK) 7 and 20 have been studied in various primary and metastatic carcinomas, and their determination may help distinguish the site of origin of metastatic carcinomas. However, little is known about the factors that determine variations in their expression patterns in primary gastric and colorectal carcinomas.
We investigated the expressions of CK7 and CK20 in 289 cases of gastric carcinoma and 225 cases of colorectal carcinoma using a tissue microarray. To evaluate CK7 and CK20 expression patterns of ovarian metastases from gastric or colorectal carcinomas, 54 cases of metastatic carcinomas to the ovary were examined. It was found that 71% (207 of 289) of the gastric carcinomas stained positively for CK7, whereas only 9% (21 of 225) of the colorectal carcinomas proved to be CK7 positive, and that 41% (117 of 289) of the gastric carcinomas and 73% (165 of 225) of the colorectal carcinomas were CK20 positive.
The proportion of CK7+/CK20- was highest in the gastric carcinomas at 46% (132 of 289), and was independent of the histologic classification of Lauren (46% of the intestinal type, 45% of the diffuse type). The CK7 and CK20 expression patterns were different in colorectal carcinomas according to histologic grade and location of the tumor. CK7-/CK20+ had the greatest proportion (68%) in colorectal carcinomas, and this was dependent on the tumor's histologic grade (75% of low-grade versus 52% of high-grade) and location (46% of right-sided versus 76% of left-sided). Moreover, 42% (18 of 43) of gastric carcinomas metastatic to the ovary were CK7+/CK20-, whereas 19% (8 of 43) were CK7-/CK20+. All colorectal cancers metastatic to the ovary were CK7-/CK20+, except 1 case that was CK7-/CK20-.
In conclusion, the CK7 and CK20 expression patterns in primary gastric carcinomas vary considerably, and those in colorectal carcinomas are associated with histologic grade and tumor location. The CK7-/CK20+ expression pattern is specific for metastatic colorectal carcinomas to the ovary, but has low predictability for colorectal origin in metastatic ovarian carcinoma.
HER-2 NEU
Department of Pathology, Seoul National University College of Medicine, Seoul 110-799, Korea.
HER-2 gene amplification and the overexpression of HER-2 protein have been observed in various solid tumors, including gastric carcinomas. HER-2 gene amplification has attracted research attention since the development of the new therapeutic agent trastuzumab.
Here, we evaluated HER-2 status in the surgically resected tissues of 248 gastric carcinoma cases using immunohistochemistry (IHC), fluorescence in situ hybridization (FISH), and real-time quantitative polymerase chain reaction (q-PCR) and compared the results. In addition, we compared clinicopathologic characteristics with the presence of HER-2 gene amplification and with protein overexpression. Among the 248 cases, 56 (22.6%) cases showed HER-2 overexpression (2+ or 3+) by IHC and 19 cases (7.7%) showed HER-2 gene amplification by FISH. Four (2.1%) of the 192 cases negative (0 or 1+) by IHC showed amplification by FISH, whereas 15 (26.8%) of the 56 cases with HER-2 protein overexpression showed HER-2 amplification by FISH. The correlation between IHC and FISH results was statistically significant (P < .001).
HER-2 protein overexpression and HER-2 gene amplification were common in cases with a well- or moderately differentiated histology according to the World Health Organization classification (P < .001) and in cases of intestinal type by the Lauren classification (P < .001). Real-time q-PCR results showed that calculated HER-2/GAPDH ratios were higher in amplified cases with 100.0% sensitivity and 96.9% specificity using FISH results as the standard.
Measurements of HER-2 expression by FISH and real-time q-PCR and of HER-2 protein by IHC were found to be highly concordant at determining HER-2 status in gastric carcinoma.
DIFFERENTIAL DIAGNOSIS KEY DIFFERENTIATING FEATURES Gastric Dysplasia-Like Epithelial Atypia Associated with Chemoradiotherapy for Esophageal Cancer: A Clinicopathologic and Immunohistochemical Study of 15 Cases
Thomas P. Brien, etal.
Mod Pathol 2001;14:389-396 Abstract quote
Preoperative chemotherapy combined with radiotherapy (chemrad) is a common type of neoadjuvant treatment for esophageal adenocarcinoma or squamous cell carcinoma.
The purpose of this study was to describe the clinical, histologic, proliferative (MIB-1), and oncogenetic (p53) features of 15 patients with gastric dysplasia-like epithelial atypical changes associated with preoperative chemrad for esophageal cancer. Two of these cases were initially misinterpreted as dysplasia, which led to partial gastrectomy. The findings were compared with 12 age- and sex-matched patients with known gastric dysplasia.
Cases with gastric dysplasia-like epithelial atypia were significantly associated with a flat gross appearance, a patchy distribution, foveolar and gland involvement, surface maturation, an open nuclear chromatin pattern with prominent nucleoli, retention of nuclear polarity, mitoses confined to the pits, lack of atypical mitoses, cytoplasmic hypereosinophila and/or vacuolization, a lack of association with intestinal metaplasia, and finally, irregular glandular microcystic change, in comparison to the dysplasia controls. Furthermore, the study cases showed MIB-1 positivity restricted to the deep foveolar epithelium and an absence of p53 staining in 14 of 15 cases, in contrast to the dysplasia controls, in which MIB-1 stained both the deep and superficial foveolar epithelium and surface epithelium, and p53 was positive in all cases (100%).
In summary, a number of histologic and immunohistochemical features may distinguish gastric dysplasia-like epithelial atypia associated with chemrad for esophageal cancer from true dysplasia. Pathologists should be aware of this entity and its histologic and immunohistochemical features to avoid misinterpretation and prevent unnecessary treatment.
PROGNOSIS AND TREATMENT CHARACTERIZATION PROGNOSIS Varies according to stage and geographic location
Tumor size and depth of invasion most important
GENERAL The role of histological investigation in prognostic evaluation of advanced gastric cancer. Analysis of histological structure and molecular changes compared with invasive pattern and stage.
Chiaravalli AM, Cornaggia M, Furlan D, Capella C, Fiocca R, Tagliabue G, Klersy C, Solcia E.
Department of Pathology, University of Insubria, Varese, Italy.
Virchows Arch 2001 Aug;439(2):158-69 Abstract quote
The relative contribution of tumour histology or molecular changes, compared with invasion pattern or stage, to prognostic assessment of gastric cancer was investigated in a series of 185 advanced (T2 to T4, stage IB to IV) cancers that had undergone intentionally curative surgery at Varese General Hospital.
Survival analysis of the histological types considered in commonly used classifications, such as Lauren, Kubo, the World Health Organization (WHO) and related classifications, allowed separation of a small high-grade (Hg, 12 cases) group of adenosquamous, anaplastic and small cell endocrine carcinomas from a large cohesive group (C, 86 glandular or solid cancers) and from another large (87 cases) group of tumours with dissociated cells [29 diffuse (D) and 58 mixed (M) tumours]. Univariate and multivariate analysis showed the independent prognostic value of this C/M+D/Hg classification approach, which proved superior to other classifications and to cell dissociation at the growing front or angio, lympho and neuro-invasion. Expression of sialyl Lewis(c), the DUPAN-2 antigen, proved to be an independent predictor of worse survival among tumours beyond stage I, showing an exclusively or predominantly cohesive structure. Microsatellite instability (MSI) predicted favourable survival in purely cohesive tumours of intermediate (II) stage, especially of solid/medullary and lymphoid stroma/lympho-epithelioma-like structure, among which two distinct tumour subsets were characterised, one MSI-positive and the other Epstein-Barr virus positive. T2NOM0 (stage IB) tumours showed mostly favourable survival independently from histological type, invasive pattern, DUPAN-2 or MSI status.
It is concluded that an appropriate histological evaluation, coupled with sialylated glycoproteins histochemistry and, for stage-II tumours, MSI tests may contribute significantly to prognostic assessment of tumours beyond stage I. However, the stage itself, with special reference to lymph-node metastases and invasion level beyond subserosa, remains the most important prognostic clue for gastric cancer.
EPIDERMAL GROWTH FACTOR RECEPTOR
Epidermal growth factor receptor expression correlates with poor survival in gastric adenocarcinoma from Mexican patients: a multivariate analysis using a standardized immunohistochemical detection system.
Gamboa-Dominguez A, Dominguez-Fonseca C, Quintanilla-Martinez L, Reyes-Gutierrez E, Green D, Angeles-Angeles A, Busch R, Hermannstadter C, Nahrig J, Becker KF, Becker I, Hofler H, Fend F, Luber B.
Department of Pathology, Instituto Nacional de Ciencias Medicas y Nutricion Salvador Zubiran, Mexico City, Mexico.
Mod Pathol. 2004 May;17(5):579-87. Abstract quote
The aim of the study was to determine epidermal growth factor receptor (EGFR) expression in gastric adenocarcinoma by standardized immunohistochemistry and to correlate EGFR expression with clinical features and patient survival. EGFR expression was investigated in paraffin sections of resection specimens of 89 gastric carcinomas from Mexican Mestizo patients using standardized immunohistochemistry with antigen retrieval (Dako EGFRpharmDx assay detection system). Membrane staining of EGFR was evaluated in the neoplastic cells and graded using a semiquantitative score (0-3+).
Of the 89 carcinomas examined, staining of neoplastic cells was weak in 17 (19.1%, score 1+), moderate in 16 (18.0%, score 2+), and strong in nine cases (10.1%, score 3+). EGFR reactivity was heterogeneous, frequently showing completely negative up to 3+ positive areas within an individual tumor. EGFR reactivity score correlated with distant metastases (P=0.002) and clinical stage (P=0.033). EGFR score 0/1+ was significantly associated with an increase in patient survival when compared to score 2+/3+ (P=0.0006). In a multivariate analysis, EGFR positive cells in muscularis or subserosa (P=0.004), distant metastases (P=0.016) and residual disease (P=0.039) were significantly correlated with decreased survival.
The prognosis was associated with the EGFR reactivity score (P=0.003), distant metastases (P=0.0001) and residual disease (P=0.012) in a univariate analysis. EGFR reactivity in neoplastic cells is an independent prognostic factor in gastric adenocarcinoma. The relevance of the heterogeneity in EGFR expression with regard to tumor progression, metastasis and anti-EGFR therapy needs to be studied.INTRAMUCOSAL CARCINOMA Relationship between biologic behavior and phenotypic expression in intramucosal gastric carcinomas
Akira Kabashima, MD
Takashi Yao, MD
Keizo Sugimachi, MD
Masazumi Tsuneyoshi, MDHum Pathol 2002;33:80-86 Abstract quote
We investigated the biologic behavior of gastric phenotype carcinoma of the stomach, especially in association with degradation of the extracellular matrix.
One hundred fourteen lesions of intramucosal gastric carcinoma (IMGC) of differentiated type were studied. IMGCs were classified into 4 phenotypic categories—complete intestinal type (C type), incomplete intestinal type (I type), gastric type (G type), and unclassified type—through a combination of the expression of CD10, MUC2, HGM, and Con A. The expression of MMP-2, MMP-9, TIMP-2, and type IV collagen was investigated by immunohistochemical staining. The incidence of C-type IMGC, I-type IMGC, and G-type IMGC was 7.9%, 55.3%, and 36.8%, respectively. The incidence of positive MMP-9 expression in G-type IMGCs (57%) was significantly higher than that in C-type IMGCs (11%) or I-type IMGCs (35%) (P < .01). There was no significant correlation between phenotypes and expression of MMP-2, TIMP-2, or type IV collagen. There was a reverse correlation between the expression of type IV collagen and the expression of type IV collagenase (P < .001).
In conclusion, gastric phenotype carcinomas have been shown to be highly invasive and metastatic, However, although they can potentially degrade the extracellular matrix via overexpression of MMPs compared with intestinal phenotype carcinoma, our data show no statistically significant separation of subtypes of intramucosal gastric cancer based on gross classification, histologic type, lymphatic or venous invasion, or lymph node metastases.
LYMPH NODE STATUS
- Clinical Relevance of Occult Tumor Cells in Lymph Nodes From Gastric Cancer Patients.
Doekhie FS, Mesker WE, Krieken JH, Kok NF, Hartgrink HH, Kranenbarg EK, Putter H, Kuppen PJ, Tanke HJ, Tollenaar RA, Velde CJ.
From the Departments of *Surgery, daggerMolecular Cell Biology, and section signMedical Statistics and Bioinformatics, Leiden University Medical Center, Leiden, The Netherlands; and double daggerDepartment of Pathology, University Medical Center, St. Radboud, Nijmegen, The Netherlands.
Am J Surg Pathol. 2005 Sep;29(9):1135-1144. Abstract quote
The current method for staging in gastric cancer is not sufficient as even after a complete primary tumor resection, patients with node-negative gastric cancer suffer from disease recurrence.
In this study, the relation between disease recurrence and the presence of occult tumor cells (OTC) in lymph nodes from gastric cancer patients was evaluated. In a case-control design, lymph nodes from 40 cases (disease recurrence) and 41 controls (no disease recurrence and followed for at least five years) with gastric cancer were examined for the presence of OTC, that comprised micrometastases (MM; >0.2 mm and </=2.0 mm) and isolated tumor cells (ITC; </=0.2 mm). The original hematoxylin and eosin-stained sections of all lymph nodes from cases and controls were previously considered as tumor-negative by the local pathologist. Fresh hematoxylin and eosin-stained sections were screened by conventional microscopy.
Histologic sections stained by immunohistochemistry with anticytokeratin antibodies CAM5.2 were screened by conventional and automated microscopy. Tumor cells were detected in lymph nodes from 40 of 81 (49%) patients. There was no significant difference in the presence of OTC, MM, or ITC between the case and control groups (P = 0.658, P = 0.691, P = 0.887, respectively). However, significantly more cases presented with 20% or more OTC-positive lymph nodes (P = 0.015). A multivariate logistic regression analysis showed that examination of less than five lymph nodes (odds ratio, 13.8; 95% confidence interval, 1.6-120.6, P = 0.018) was the only significant independent risk factor for disease recurrence, especially for locoregional disease recurrence (odds ratio, 20.4; 95% confidence interval, 2.2-190.8, P = 0.008). A similar analysis for distant disease recurrence showed a percentage of 20% or more OTC-positive lymph nodes to be the only significant independent risk factor (odds ratio, 15.6, 95% confidence interval, 1.6-151.4, P = 0.018). The sensitivity of immunohistochemistry evaluated by microscopy to identify cases with 20% or more OTC-positive lymph nodes increased from 8% for conventional microscopy to 22% for automated microscopy (McNemar's test, P = 0.063).
The mere presence of OTC-positive lymph nodes in gastric cancer patients did not predict disease recurrence. However, the number of examined lymph nodes and the percentage of OTC-positive lymph nodes were independent risk factors for locoregional disease recurrence and distant disease recurrence, respectively. Automated microscopy was essential in identifying patients with 20% or more OTC-positive lymph nodes.
Therefore, a maximum number of lymph nodes should be removed and meticulously examined for OTC to identify high-risk patients. These patients should be considered for additional treatment.Lymph node metastasis as a significant prognostic factor in early gastric cancer: analysis of 1,136 early gastric cancers.
Kim JP, Hur YS, Yang HK.
Department of Surgery, Seoul National University College of Medicine, Korea.
Ann Surg Oncol 1995 Jul;2(4):308-13 Abstract quote
BACKGROUND: Gastric cancer is the most frequent cancer and the leading cause of death from cancer in Korea. Early gastric cancer has been defined as a gastric carcinoma confined to mucosa or submucosa, regardless of lymph node status, and has an excellent prognosis with a > 90% 5-year survival rate. From 1974 to 1992, we encountered 7,606 cases of gastric cancer and performed 6,928 gastric resections. Among them, 1,136 cases were early gastric cancer (14.9% of all gastric cancer cases and 16.4% of resected gastric cancer cases).
METHODS: A retrospective analysis of 1,136 cases of early gastric cancer was performed to evaluate the prognostic significance of clinicopathologic features (sex, age, tumor location, gross type, histologic type, depth of invasion, status of lymph node metastasis, resection type). Lymph node metastasis was classified into three groups: N(n = 0) for no lymph node metastasis; N(n = 1-3) for one to three lymph node metastases; and N(n > 3) for more than three lymph node metastases. All patients received radical total or subtotal gastrectomy with lymph node dissection.
RESULTS: In univariate and multivariate analysis of these nine factors, the only statistically significant prognostic factor was regional lymph node metastasis (p < 0.001). The others had no statistically significant association with prognosis. Lymph node metastasis was present in 178 cases (15.7%). The factors associated with the lymph node metastasis were depth of invasion and gross type [protruding type (e.g., types I, IIa)]. One hundred twenty-five of these patients had one to three lymph node metastases, and 53 cases had more than three lymph node metastases. The difference in 5-year survival rates among these groups was statistically significant: 94.5% for N(n = 0), 88.3% for N(n = 1-3), and 77.3% for N(n > 3).
CONCLUSION: We propose that for early gastric cancer, lymph node dissection is necessary in addition to gastric resection, at least in patients with a high risk of lymph node metastasis.
Risk Factors for Lymph Node Metastases and their Prognostic Significance in Early Gastric Cancer (EGC) for the Italian Research Group for Gastric Cancer (IRGGC).
Folli S, Morgagni P, Roviello F, Manzoni GD, Marrelli D, Saragoni L, Leo AD, Gaudio M, Nanni O, Carli A, Cordiano C, Dell'Amore D, Vio A. U. O. di Chirurgia Toracica, Ospedale G. B. Morgagni, Forli, U. O. di Chirurgia Generale 1, Ospedale G.B.Morgagni, Forli,
Istituto di Scienze Chirurgiche, Universita di Siena, Siena, Istituto di Semeiotica Chirurgica, Universita di Verona, Verona, Servizio di Anatomia Patologica, Ospedale L. Pierantoni, Forli and Istituto Oncologico Romagnolo di Forli, Forli, Italy.
Jpn J Clin Oncol 2001 Oct 1;31(10):495-499 Abstract quote
BACKGROUND: Lymph node metastases are present in only about 15% of patients with early gastric cancer (EGC) and for this reason, the majority of these patients do not require lymphadenectomy. In Japan, EGC patients undergo less invasive treatment (endoscopic mucosal resection, wedge resection, laparoscopy). However, the indications for and results of these types of treatment are still uncertain.
METHODS: In a multicentre retrospective study, we analysed the clinicopathological data referring to 584 early gastric cancer patients who underwent D2 gastrectomy. A comparison was made between patients with and without lymph node metastases in relation to numerous pre- and postoperative variables. Long-term survival and risk factors for lymph node metastases were analysed. The primary aim was to compare our results with those of Western and Japanese authors; we also evaluated the possibility of identifying a subset of patients at low risk of lymph node metastases who may be candidates for endoscopic treatment.
RESULTS: The incidence of lymph node metastasis was 14.4%. Univariate and multivariate analyses showed that submucosal infiltration, diffuse histotype, tumour size and Kodama Pen A type were all related to the presence of lymph node metastases. Patients with types I, IIa and IIb mucosal tumours did not present lymph node metastases. Postoperative mortality was 2.2%. Five-year survival in relation to lymph node groups was 95% in N0 patients, 77% in N1 patients and 60% in N2 patients (p = 0.0001, Japanese N-stage). The number of positive lymph nodes also had a prognostic value. Patients with three or fewer positive lymph nodes presented a better 5-year prognosis (83%) than those with more than three positive lymph nodes (48%) (p = 0.0001).
CONCLUSIONS: Our study confirms that lymph node involvement is an extremely important prognostic factor. For this reason, the therapeutic strategy of our surgical units is as follows: 1) D2 gastrectomy is the standard treatment even in early gastric cancer (EGC); 2) endoscopic mucosal resection (EMR) could be considered first in types I, IIa and IIb tumours that are diagnosed as limited to the mucosal layer.
MATRILYSIN
Inverse relationship between matrilysin expression and proliferative activity of cells in advanced gastric carcinoma.Liu XP, Oga A, Suehiro Y, Furuya T, Kawauchi S, Sasaki K.
Department of Pathology, Yamaguchi University School of Medicine, Ube, Yamaguchi, Japan.
Hum Pathol 2002 Jul;33(7):741-7 Abstract quote Matrilysin is known to play an important role in tumor invasion, but it is not known yet whether there is a direct relationship between matrilysin expression and cell proliferation.
Therefore, we compared expression of matrilysin with expression of Ki-67, a marker of cell proliferation, at different tumor areas in 130 advanced gastric carcinomas. Both matrilysin and Ki-67 were distributed heterogeneously in tumor tissue. Matrilysin frequently was expressed at the invasive front, whereas Ki-67-positive cells frequently were located both at the tumor surface and in central tumor cell nests. The patterns of gastric cancer cell invasion into the surrounding tissues are described as alpha-infiltration, beta-infiltration, and gamma-infiltration, respectively, according to the guidelines of the Japanese Research Society for Gastric Cancer Study. The mean matrilysin labeling index (LI) of gamma-infiltration tumors at the invasive front was significantly greater than that of alpha- and beta-infiltration tumors (P =.01). In contrast to the matrilysin LI, the mean Ki-67 LI of gamma-infiltration tumors was significantly lower than that of alpha- and beta-infiltration tumors (P =.02). Moreover, Ki-67 antigen was absent in matrilysin-positive tumor cells and vice versa.
We concluded that matrilysin expression was related inversely with proliferative activity of tumor cells and that matrilysin expression could possibly serve as a useful marker of tumor invasion.
MICROSATELLITE INSTABILITY
Distinct clinical features and outcomes of gastric cancers with microsatellite instability.Lee HS, Choi SI, Lee HK, Kim HS, Yang HK, Kang GH, Kim YI, Lee BL, Kim WH.
Departments of Pathology (HSL, SIC, GHK, YIK, WHK) and Surgery (HKL, HY) and Cancer Research Institute (HY, BLL, WHK), Seoul National University College of Medicine, Seoul, Korea.
Mod Pathol 2002 Jun;15(6):632-40 Abstract quote Microsatellite instability (MSI) is a hallmark of the DNA mismatch repair deficiency that is one of the pathways of gastric carcinogenesis. Clinicopathologic characteristics of MSI+ gastric cancers remain unclear.
To determine the correlation between MSI status and clinical features, we analyzed 327 consecutive gastric cancers for the occurrence of MSI in the BAT-26 marker. Because it has been proven that MSI at BAT-26 reflects the MSI+ phenotype, cancers with alteration at BAT-26 were categorized as having the MSI+ phenotype. The expressions of hMLH1, hMSH2, p53, MUC1, MUC2, and CEA were evaluated immunohistochemically using the tissue array method. The MSI+ phenotype was found in 9.5% () of gastric cancers examined. MSI+ gastric cancers were significantly associated with older age, antral location, Borrmann's gross Type II, intestinal subtype, lower prevalence of lymph node metastasis, and lower pTNM stage (P <.05).
By multivariate logistic regression, MSI+ gastric cancers had a lower prevalence of lymph node metastasis independent of tumor invasion (P <.001). MSI+ gastric cancers displayed frequent frameshift mutations of transforming growth factor-beta type II receptor (90.3%), BAX (61.3%), hMSH3 (38.7%), and E2F4 (61.3%) genes and diminished hMLH1 () or hMSH2 () expressions. The MSI+ phenotype correlated with patient survival in advanced gastric carcinoma (P =.046).
In conclusion, MSI+ phenotype in gastric cancers was found to have distinct clinicopathologic characteristics and to be predictive of a favorable outcome in advanced carcinoma.
MUCIN PHENOTYPE
Cell kinetics and genetic instabilities in differentiated type early gastric cancers with different mucin phenotype.Shibata N, Watari J, Fujiya M, Tanno S, Saitoh Y, Kohgo Y.
Third Department of Internal Medicine, Asahikawa Medical College, Asahikawa, Japan.
Hum Pathol 2003 Jan;34(1):32-40 Abstract quote To clarify the biological impact and molecular pathogenesis of cellular phenotype in differentiated-type gastric cancers (DGCs), we investigated cell kinetics and genetic instabilities in early stage of DGCs. A total of 43 early gastric cancers (EGCs) were studied. EGCs were divided into 3 phenotypic categories: gastric (G type, n = 11), ordinary (O type, n = 20), and complete intestinal (CI type, n = 12) based on the combination of HGM, ConA, MUC2, and CD10.
Proliferative index (PI), apoptotic index (AI), and p53 overexpression were investigated by immunohistochemical staining with anti-Ki-67, the terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling method, and p53 antibody, respectively.
Using a high-resolution fluorescent microsatellite analysis system, microsatellite instability (MSI) and loss of heterozygosity (LOH) were examined. Frameshift mutation analysis of transforming growth factor-beta type II receptor (TGF-betaRII) and bcl-2-associated X (BAX) in cancers with MSI was also performed. The mean AI/PI ratio values were 0.04 for G-type, 0.10 for O-type, and 0.13 for CI-type cancers-significantly lower in G type than in O and CI types (P = 0.02 and P = 0.001, respectively). No difference in the incidence of MSI and LOH was seen among the 3 cellular phenotypes. However, the major pattern of MSI, which showed drastic and widely dispersed changes and is related to an increased risk for cancer, was significantly higher in G and O types than in CI type (P <0.005). No frame shift mutations of TGF-betaRII or BAX were found in CI-type cancers.
These results indicate that G-type cancers are likely to show more aggressive behaviors than CI-type cancers, and that O-type cancers show the intermediate characteristics of both types. However, the molecular pathogenesis of each phenotypic cancer is not associated with microsatellite alterations.
NEUTROPHILS
Prognostic value of intratumoral neutrophils in advanced gastric carcinoma in a high-risk area in northern Italy.Caruso RA, Bellocco R, Pagano M, Bertoli G, Rigoli L, Inferrera C.
Dipartimento di Patologia Umana (RAC, CI) and Cattedra di Genetica Medica (LR), Policlinico Universitario "G. Martino," Messina, Italy.
Mod Pathol 2002 Aug;15(8):831-7 Abstract quote Several lines of evidence indicate that neutrophils act nonspecifically against tumor cells. The correlation between tumor-infiltrating neutrophils (TINs) and clinicopathological features remains unclear and deserves to be investigated.
To analyze the prognostic influence of TINs in gastric carcinoma, the authors selected 273 patients with advanced gastric carcinoma who underwent gastrectomy at Cremona Hospital (Lombardia, Italy) between 1990 and 1995 and followed them for a period of 5 years. The number of TINs was assessed in a semiquantitative manner using the mean value of 20 nonoverlapping high-power fields (magnification, 400x; 0.08 mm(2)). The patients were divided into two groups: patients with a moderate or extensive amount of TINs (n = 76; >10 TINs per 20 high-power fields) and patients with a minor amount of TINs (n = 197; </=10 TINs per 20 high-power fields). The Kaplan-Meier method and Greenwood formula were used to estimate the crude survival rates in the two groups. Multivariate analyses based on the Cox proportional hazard regression model were performed to assess the effect of the prognostic factors on survival. Among the potential prognostic factors analyzed by univariate analysis, sex, age, location of neoplasia, pTNM stage, TINs, and surgical curability were significantly associated with higher survival rate. The study of the possible interaction effects of the clinical-pathological factors with TINs reveals that female patients with a moderate or extensive amount of TINs have about a 39% reduction in their risk of mortality, whereas male patients do not seem to be affected by the level of TINs. These results suggest that women appear to have a better prognosis than men in advanced gastric carcinoma.
Gender differences in some host defense mechanisms and particularly in neutrophil function may be responsible for this event. Confirmation of these findings would give valuable insights about host reaction to gastric cancer growth and, ultimately, possibly would have implications regarding the identification of low-risk patients who could be spared adjuvant therapy.
p53 AND KI-67 Usefulness of p53 and Ki-67 Immunohistochemical Analysis for Preoperative Diagnosis of Extremely Well-Differentiated Gastric Adenocarcinoma
Chikanori Niimi, MD,1 Hidemi Goto, MD, PhD,1,2 Naoki Ohmiya, MD, PhD,1 Yasumasa Niwa, MD, PhD,1 Tetsuo Hayakawa, MD, PhD,1,2 Tetsuro Nagasaka, MD, PhD,3 and Nobuo Nakashima, MD, PhDAm J Clin Pathol 2002;118:683-692 Abstract quote
Of 987 cases of gastric adenocarcinoma seen at Nagoya University School of Medicine, we found 6 rare, extremely well-differentiated advanced gastric adenocarcinomas that could not be diagnosed as malignant tumors with only H&E staining, even with repeated biopsies under preoperative endoscopy.The aim of this study was to determine whether an immunohistochemical method using p53 and Ki-67 antibody would be helpful for preoperative pathologic diagnosis. The cancer control cases were 16 cases of ordinary well-differentiated advanced gastric adenocarcinoma, while the gastritis control cases were 22 cases of Helicobacter pylori–positive chronic gastritis. The p53 labeling index and the localization of Ki-67+ cells showed that the special adenocarcinomas in biopsy specimens were distinct from the surrounding normal mucosa and chronic gastritis, but not from the cancer control cases.
These methods are useful markers for preoperative pathologic diagnosis of extremely well-differentiated gastric adenocarcinoma, which sometimes is confused with regenerative atypical glands before operation.
SURVIVAL 5 YEAR Early cancer
Japan 95%
USA 70%Advanced cancer
10%TREATMENT CHEMOTHERAPY Phase II study of a modified combination of etoposide, doxorubicin, and cisplatin for patients with advanced gastric cancer.
Icli F, Karaoguz H, Akbulut H, Dincol D, Demirkazik A, Cay F.
Ankara University School of Medicine, Ibn-i Sina Hospital, Ankara, Turkey.
J Surg Oncol 1997 Apr;64(4):318-23 Abstract quote
BACKGROUND: Based on the promising results of EAP (etoposide, doxorubicin, and cisplatin) combination, a phase II study of modified EAP combination was performed in patients with advanced gastric cancer to evaluate the response, toxicity, and survival.
METHOD: Fifty-two consecutive patients with measurable or evaluable advanced gastric cancer, who had no prior therapy except surgery, were treated every 28 days with etoposide 120 mg/m2/day, doxorubicin 25 mg/m2/day, and cisplatin 40 mg/m2/day on days 1 and 8, intravenously. Forty-seven patients were evaluable for response and toxicity.
RESULTS: Overall response rate was 40.5% (95% CI = 37-54.7%), including 12.8% complete response. Responses were higher in patients with locally advanced disease (57.89%) as compared to those with distant metastases (28.57%) (P = 0.044). The median overall survivals of the entire group and the responders were 7 months and 11 months, respectively. Complete responders had significantly longer response duration and overall survival (31.5 months and 45.5 months, respectively), as compared to partial responders (6 months and 9 months, respectively). Six of the responders (31.6%) were alive at 2 years. Disease extension and pretreatment performance status had significant effects on survival. Grade 3-4 toxicity was observed in 33% of patients. There were no deaths related to toxicity.
CONCLUSIONS: EAP as used in this trial is an effective treatment in advanced gastric cancer. The effect is more pronounced in patients with locally advanced disease.
COMBINED MODALITIES A prospective, randomized trial of pre-operative and intraoperative radiotherapy versus surgery alone in resectable gastric cancer.
Skoropad VY, Berdov BA, Mardynski YS, Titova LN.
Department of Surgical and Combined Treatment of Abdominal Tumours, Medical Radiological Research Center of Russian Academy of Medical Sciences (MRRC RAMS), Koroliova Street 4, Obninsk, 249020, Russia.
Eur J Surg Oncol 2000 Dec;26(8):773-9 Abstract quote
INTRODUCTION: Worldwide, gastric cancer remains one of the most common malignancies. Discouraging survival rates after surgical treatment promote the study of adjuvant therapy. A prospectively, randomized, controlled clinical trial was performed in order to determine whether pre-operative and intraoperative radiotherapy improves treatment results of gastrectomy for stomach carcinoma.
METHODS: From 1993 to 1998, 112 patients were randomized and underwent exploratory laparotomy; among them 78 satisfied protocol requirements and entered in the trial. Patients in the experimental group were treated with pre-operative radiotherapy (20 Gy/5 days), gastrectomy and intraoperative radiotherapy (20 Gy using 8-12 electrons). Patients in the control group underwent surgery alone.
RESULTS: Incidence and distribution of post-operative complications were similar in both groups except significantly higher incidence of pancreatitis after surgical treatment. No late radiation-related morbidity was registered. There was no significant difference in survival between the two treatment groups (Chi(2)=1.026, df=1, P=0. 311) as well as in N0 (Chi(2)=0.0029, df=1, P=0.956) and T1-2 subgroups (Chi(2)=0.1928, df=1, P=0.660). In contrast, combined treatment had marked survival advantage in more advanced stages: in the case of lymph-node involvement (Chi(2)=4.19, df=1, P=0.04) and extragastric tumour extension (Chi(2)=4.118, df=1, P=0.042).
CONCLUSION: The proposed intensive treatment programme is feasible, shows good acute and late tolerance and has the potential to improve survival in patients with locally advanced gastric cancer.
SURGERY
Endoscopic mucosal resection for gastric epithelial neoplasms: a study of 39 cases with emphasis on the evaluation of specimens and recommendations for optimal pathologic analysis.
Lauwers GY, Ban S, Mino M, Ota S, Matsumoto T, Arai S, Chan HH, Brugge WR, Shimizu M.
1Department of Pathology, Gastrointestinal Pathology Service, Massachusetts General Hospital, Boston, MA, USA.
Mod Pathol. 2004 Jan;17(1):2-8. Abstract quote
Endoscopic mucosal resection of gastric neoplasms is a curative technique that avoids surgery and its potential complications. Infrequently performed in the West, the limitations, pitfalls and challenges provided by this new therapeutic modality are not well known by general surgical pathologists.
We evaluated a series of 39 endoscopic mucosal resections and assessed the correlation between original biopsies and final diagnoses, depth of excision, status of deep and lateral margins, artifactual changes and recurrence rate. The tumors consisted of 24 intramucosal carcinomas, six high-grade dysplasias, eight low-grade dysplasias and one submucosal invasive carcinoma. The preresection diagnoses corresponded to the final evaluation in 63% of the cases with previous biopsies. In 37% of the cases, the biopsies under-diagnosed the neoplasia. The rate of positive margins was 38%. Iatrogenic changes, that is, intramucosal hemorrhage and electrodiathermic burn, were noted in 44% of the cases but hindered the pathologic evaluation in only 10% of the cases.
Persistence or recurrence was observed in only seven cases and there was no progression to advanced adenocarcinoma. Based on our experience, we offer some recommendations in order to provide optimal pathologic analysis of endoscopic mucosal resection specimens.Is extended lymph node dissection necessary for gastric cancer in elderly patients?
Eguchi T, Takahashi Y, Ikarashi M, Kasahara M, Fujii M.
3rd Department of Surgery, Nihon University School of Medicine, Tokyo, Japan.
Eur J Surg 2000 Dec;166(12):949-53 Abstract quote
OBJECTIVE: To compare the outcome after limited and extended gastric resections to find out whether extended lymph node dissection is indicated for gastric cancer in elderly patients.
DESIGN: Retrospective study.
SETTING: University hospital, Japan.
SUBJECTS: 182 patients over 75 years of age with gastric cancer who had gastric resections from 1980 to 1995.
INTERVENTIONS: 161 patients had limited lymph node dissection (limited group) and 21 had extended lymph node dissection (extended group).
MAIN OUTCOME MEASURES: Histopathological features, morbidity, mortality, and long-term survival. RESULTS: Postoperative morbidity was 27% (n = 44) in the limited group and 57% (n = 12) in the extended group, and postoperative mortality was 1% (n = 2) in the limited group and 10% (n = 2) in the extended group; these differences are significant (p = 0.005 and p = 0.002). The 5-year survival did not differ significantly between the two groups. Only the T classification and presence of lymph node metastases had a significant influence on the outcome of gastric cancer in elderly patients.
CONCLUSIONS: The presence of lymph node metastases is a critical factor in the prognosis of gastric cancer, and extended lymph node dissection has therefore been recommended. However, extended lymph node dissection in elderly patients did not influence the 5-year survival; in addition, the mortality and morbidity in the extended group were higher than in the limited group. Extended lymph node dissection is therefore usually not indicated for gastric cancer in elderly patients.
Comparison of quality of life and nutritional parameters after total gastrectomy and a new type of pouch construction with simple Roux-en-Y reconstruction: preliminary results of a prospective, randomized, controlled study.
Kalmar K, Cseke L, Zambo K, Horvath OP.
First Department of Surgery, University Medical School of Pecs, Hungary.
Dig Dis Sci 2001 Aug;46(8):1791-6 Abstract quote
The aim of the study was to introduce a new type of gastric substitute, the aboral pouch, after total gastrectomy and to compare nutritional, motility, and quality of life parameters of patients with an aboral pouch to those undergoing simple Roux-en-Y reconstruction in a prospective, randomized, and controlled trial.
To date 40 patients have entered the study. In 22 of them the aboral pouch was created; the remaining 18 patients with simple Roux-en-Y reconstruction served as the control group. Laboratory measurements, passage studies, lipid and carbohydrate absorption tests, and quality of life interviews were carried out as follow-up examinations.
Preliminary results suggest that the aboral pouch has some advantages over simple Roux-en-Y reconstruction. Serum immunoglobulin M level and the quality of life estimated by the gastrointestinal quality of life index, yielded significantly better results in the pouch group.
Indication of splenectomy for gastric carcinoma involving the proximal part of the stomach.
Sakaguchi T, Sawada H, Yamada Y, Fujimoto H, Emoto K, Takayama T, Ueno M, Nakajima Y.
First Department of Surgery, Nara Medical University, 840 Shijo-cho, Kashihara City, Nara, 634-8522, Japan.
Hepatogastroenterology 2001 Mar-Apr;48(38):603-5 Abstract quote
BACKGROUND/AIMS: The role of splenectomy in the surgical management of gastric carcinoma is controversial and there is no consensus of opinion regarding the therapeutic value of splenectomy. The aim of this study was to search for possible metastasis to lymph nodes in the splenic hilum or along the splenic artery to avoid unnecessary splenectomy and to determine its indication.
METHODOLOGY: The clinical records of 204 patients who underwent total gastrectomy combined with splenectomy for gastric carcinomas involving the proximal part of the stomach were analyzed.
RESULTS: The incidence of nodal involvement to the splenic hilum and/or along the splenic artery was 49 (24.0%) of 204 gastric carcinomas involving the proximal part of the stomach that underwent combined gastrectomy and splenectomy. The characteristics of gastric carcinoma with metastasis to these nodes included a larger tumor, deeper penetration (T3, 4 tumors), a number of lymph node metastasis, and infiltrative type. In T2 cases, all the tumors with cancerous involvement to these nodes showed intraoperative gross serosal change). When the tumor size was less than 40 mm, nodal metastatic rate to the splenic hilum and/or along the splenic artery was very low.
CONCLUSIONS: In conclusion, splenectomy should be conducted in T2 cases with gross serosal change and T3, 4 cases. With regard to tumor size, in the cases with a tumor whose size was less than 40 mm, it is possible to preserve the spleen in most cases. In the near future, splenectomy should be clarified precisely by randomized trials in advanced gastric carcinoma.
Early gastric cancer--excellent prognosis after curative resection in 87 patients irrespective of submucosal infiltration, lymph-node metastases or tumor size.
Piso P, Werner U, Benten D, Bektas H, Meuer U, Klempnauer J.
Klinik fur Viszeral- und Transplantationschirurgie, Zentrum Chirurgie, Medizinische Hochschule Hannover, Carl Neuberg Strasse 1, 30625 Hannover, Germany.
Langenbecks Arch Surg 2001 Feb;386(1):26-30 Abstract quote
BACKGROUND AND AIMS: Despite a decreasing incidence of primary gastric carcinoma over the last decade, the incidence of early gastric cancer has remained unchanged. Some aspects of the surgical treatment (e.g., extent of resection, lymphadenectomy) are still controversially discussed in the literature.
PATIENTS/METHODS: Between May 1986 and July 1999, 87 patients were operated upon due to primary early gastric adenocarcinoma. All patients data were analyzed retrospectively.
RESULTS: Of 626 patients with primary gastric carcinoma, 87 (13.9%) had an early carcinoma (54 men, 33 women; median age 61 years). In all patients, curative (R0-) gastrectomy could be performed, total in 62 patients (71.4%) and subtotal in 25 patients (28.6%). Postoperative morbidity was 23% and mortality 4.5%. Mucosal tumors were found in 34 (39.1%) and submucosal in 53 (60.9%) patients. Multicentricity was present in eight cases (9.1%). Twelve patients (13.8%) had lymph-node metastases. The 5-year survival rate was 88.8%. The submucosal infiltration, the lymph-node infiltration, the histological type, and the tumor size had no statistically significant impact on prognosis.
CONCLUSION: Radical resection of early gastric cancer cured most of the patients, irrespective of lymph-node metastases or tumor size. Multicentricity, increasing incidence of proximal cancers, and low mortality suggest that total gastrectomy may be indicated. Patients with early gastric cancer may benefit from D2-lymphadenectomy, but this has to be assessed in further randomized studies, in particular for those with small mucosal tumors.
Macpherson and Pincus. Clinical Diagnosis and Management by Laboratory Methods. Twentyfirst Edition. WB Saunders. 2006.
Rosai J. Ackerman's Surgical Pathology. Ninth Edition. Mosby 2004.
Sternberg S. Diagnostic Surgical Pathology. Fourth Edition. Lipincott Williams and Wilkins 2004.
Robbins Pathologic Basis of Disease. Seventh Edition. WB Saunders 2005.
DeMay RM. The Art and Science of Cytopathology. Volume 1 and 2. ASCP Press. 1996.
Weedon D. Weedon's Skin Pathology Second Edition. Churchill Livingstone. 2002
Fitzpatrick's Dermatology in General Medicine. 6th Edition. McGraw-Hill. 2003.
Weiss SW and Goldblum JR. Enzinger and Weiss's Soft Tissue Tumors. Fourth Edition. Mosby 2001.
Basic Principles of Disease
Learn the basic disease classifications of cancers, infections, and inflammation
Commonly Used Terms
This is a glossary of terms often found in a pathology report.Diagnostic Process
Learn how a pathologist makes a diagnosis using a microscopeSurgical Pathology Report
Examine an actual biopsy report to understand what each section meansSpecial Stains
Understand the tools the pathologist utilizes to aid in the diagnosisHow Accurate is My Report?
Pathologists actively oversee every area of the laboratory to ensure your report is accurateGot Path?
Recent teaching cases and lectures presented in conferences
Last Updated September 18, 2007
Send mail to The Doctor's Doctor with questions or comments about this web site.
Read the Medical Disclaimer.
Copyright © The Doctor's Doctor