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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.

SYNONYMS Adenocarcinoma of the stomach
INCIDENCE Japan 80/100,000
United States 10/100,000
25,000 new cases/year
AGE-RANGE AND MEDIAN 5th-7th decades
Generally decreasing in North American and Western Europe
Nitrosamines Used in preserving foods in Japan and Asia
High salt consumption  
Smoked foods  
Blood group A  
Race Black males: white males 6.9:4.0

A prospective study of diet and stomach cancer mortality in United States men and women.

McCullough ML, Robertson AS, Jacobs EJ, Chao A, Calle EE, Thun MJ.

Epidemiology and Surveillance Research, American Cancer Society, Atlanta, Georgia 30309.

Cancer Epidemiol Biomarkers Prev 2001 Nov;10(11):1201-5 Abstract quote

Frequent consumption of fruits, vegetables, and whole grains has been associated with a reduced risk of stomach cancer in the majority of case-control studies of these factors: however, prospective studies have been less consistent.

We examined the association between selected major food groups (citrus fruits, vegetables, whole grains, and processed meats) and risk of fatal stomach cancer in the Cancer Prevention Study (CPS) II cohort of 1.2 million United States men and women.

During 14 years of follow-up, we documented 439 stomach cancer deaths in women and 910 in men after exclusion of individuals with prevalent cancers, inadequate diet information, and recent weight loss at baseline in 1982.

After controlling for other risk factors, none of the food groups examined were associated with risk of stomach cancer except for an unexpected increased risk with vegetable consumption in women [relative risk (RR) = 1.25; 95% confidence interval (CI), 0.99-1.58; highest versus lowest tertile, P = 0.06 for trend]. A high overall plant food intake (a sum of vegetables, citrus fruit, and whole grains) was associated with reduced risk in men (RR = 0.79; 95% CI, 0.67-0.93; highest versus lowest tertile, P = 0.003 for trend), but not in women (RR = 1.18; 95% CI, 0.93-1.50; P = 0.16 for trend). Of individual foods examined, liver consumption greater than twice/week was associated with an increased risk of fatal stomach cancer in women (RR = 1.96; 95% CI, 1.09-3.53) and men (RR = 1.63; 95% CI, 1.02-2.62) compared with nonconsumers.

This study supports a modest role for plant foods in reducing the risk of fatal stomach cancer in men, but not in women.


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 surgery
Immunodeficiency disorders Overall 2-10%
X-linked immunodeficiency
Infantile X-linked agammaglobulinemia
Common variable immunodeficiency
Menetrier'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

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 country

Gastric Dysplasia Important risk factor, present in 50-100% of early cancers and 80% of advanced cancers
Dyplasia progresses from mild to severe to CA

Multiple 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.


Aberrant expression of oncogenes bcl-2, cadherin-e, K-sam, p53
Loss of heterozygosity Chromosomes 7p, 17p, 1q, 5q
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

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.

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.

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

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.


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 out
Flow cytometry 70% are aneuploid


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. Excavated

Most 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 cancer
Superficial spreading carcinoma Early cancer which measure at least 25 cm2 in area
Remain confined to mucosa and submucosa
Adenocarcinoma 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


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 nucleoli

Gastric 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
Simple or branching tubules
Papillary clusters
Mucinous (Colloid, mucoid)
Abundnant intra and extracellular mucin >50% of tumor
Squamous cell carcinoma
Pure squamous cell carcinoma
Thought to arise from squamous metaplasia
Adenosquamous cell carcinoma
Combined areas of adenocarcinoma and squamous cell carcinoma
Poor prognosis
Signet ring cell carcinoma
Signet rings with large cytoplasmic vacuole of mucin peripherally displacing the nucleus >50% of tumor cells
Small cell carcinoma
Poor prognosis
Sheets, cords, and trabeculae of small hyperchromatic cells with stippled chromatin
Undifferentiated carcinoma with lymphoid stroma (Medullary carcinoma, Gastric lymphoepithelioma-like carcinoma)

Resemble 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%

Diffuse gastric carcinoma with gastric endocrine cells
Poorly differentiated signet ring carcinomas with neuroendocrine cells interspersed
Parietal cell carcinoma
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.

Hepatoid adenocarcinoma
Cancer admixed with areas resembling mature and neoplastic hepatocytes
Have poor prognosis with widespread tumor dissemination and high serum alpha fetoprotein levels
Composite gastric carcinoma
Carcinoma with two discrete types of neoplastic differentiation such as adenocarcinoma and carcinoid tumor
Paneth cell carcinoma
Carcinoma with a predominance of Paneth cells, having large, eosinophilic cytoplasmic granules
Gastric carcinoma with rhabdoid features
Poor prognosis
Cells are round to polygonal with eosinophilic to clear cytoplasm and large eccentric vesicular nuclei resembling rhabdoid tumors of the kidney
Adenocarcinoma with choriocarcinoma features
Features of choriocarcinoma and gastric adenocarcinoma
Usually elderly and male
Poor prognosis

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 gland

Using the Vienna classification, incidence in category 4 (noninvasive high-grade neoplasia) and category 5 (invasive neoplasia) was higher than other categories



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.


Alcian blue with PAS
May highlight cytoplasmic vacuoles of signet ring cells


PROGNOSIS Varies according to stage and geographic location
Tumor size and depth of invasion most important

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.


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.


Relationship between biologic behavior and phenotypic expression in intramucosal gastric carcinomas

Akira Kabashima, MD
Takashi Yao, MD
Keizo Sugimachi, MD
Masazumi Tsuneyoshi, MD

Hum 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.

5 Year Survival

Early cancer
Japan 95%
USA 70%

Advanced cancer

Metastasis Regional lymph nodes

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.


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.


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.

Tumors of the Esophagus and Stomach in Atlas of Tumor Pathology. Fascicle 18. Third Series. AFIP. 1996.

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