Gastroenterology Grand Rounds

BCM Gastroenterology Grand Rounds - Discussion

Final Diagnosis: Gastric adenocarcinoma in a young person: Worldwide, gastric cancer is the second most frequent cancer and the second leading cause of death from cancer (1). Most cases occur in patients over 50 years old. Our patient was 19 years old when her cancer was diagnosed. There is an emerging literature about gastric cancer in young people (less than 40 years). Males and females are equally affected. The histology is almost always diffuse (as in our patient). The prognosis is poor (as in older adults). The answer to why this patient got cancer should begin with an update of what is known about the etiology of gastric cancer in general.
1. Does H. pylori infection cause gastric adenocarcinoma?: Many case-control and cohort studies have shown a relationship between H. pylori infection and gastric adenocarcinoma (2-4). A meta-analysis of 19 studies showed summary odds ratio for gastric cancer in H. pylori-infected patients is about 2 (4). The studies suggest that H. pylori-infected younger patients have a higher relative risk for gastric cancer than older patients with odds ratios of 9 at age 29 years but 1.05 at age 70 years. These studies indicated that H. pylori infection is equally associated with the intestinal or diffuse type of gastric cancer. Since many patients with gastric cancer may lose evidence of prior H. pylori infection and the studies did not consistently use the most sensitive methods of detecting H. pylori infection, the influence of H. pylori on gastric cancer was underestimated by these studies. A recent prospective study from Japan gave clearer data (5). They prospectively studied 1526 Japanese patients. 1246 had H. pylori infection and 280 did not. The mean follow-up was 7.8 years. Patients underwent endoscopy with biopsy at enrollment and then between one and three years after enrollment. 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. The youngest patients studied were about 40 and the youngest carcinoma was not stated. The risk of gastric cancer in H. pylori positive patients was about 5% every ten years.; An emerging idea that fits both this prospective study and previous cross sectional studies is that intestinal type carcinoma is a consequence of prolonged H. pylori with gastric atrophy and intestinal metaplasia. But diffuse carcinoma is associated with pan-gastritis and with active gastritis (Visual). Some of the genetic syndromes validate the usefulness of continuing to separate the pathogenesis of the two major histologic forms of gastric cancer.

2. Is there a strong genetic component to gastric adenocarcinoma?

About 10% of gastric cancers show familial clustering. Gastric cancer is part of the spectrum of cancers in hereditary non-polyposis colorectal cancer (HNPCC), familial adenomatous polyposis (FAP), and Peutz-Jeghers syndrome. There are several forms of predominantly hereditary gastric cancer, of both the intestinal and diffuse type. The best studied presents as linitis plastica and diffuse gastric cancer and is transmitted as an autosomal dominant (6). The age of presentation is highly variable (27-74 years) but earliest cases are reported in the 20's. Families from Europe, New Zealand, Japan, and the USA have been identified. Germ-line truncating mutations in the E-cadherin (CDH1) gene have been found in these families with hereditary diffuse gastric cancer. E-cadherin is an important adhesion molecule that sustains the differentiated state. Diminished E-cadherin expression is associated with aggressive, poorly differentiated carcinomas (7). Underexpression of E-cadherin is a prognostic marker of poor clinical outcome in many tumor types, and restored expression of E-cadherin in tumour models can suppress the invasiveness of epithelial tumor cells. A recent article described genetic screening, surgical management, and pathological findings in young persons with truncating mutations in CDH1 from two unrelated families with hereditary diffuse gastric cancer (8). A total gastrectomy was performed prophylactically in five carriers of mutations who were between 22 and 40 years old. In each case, the entire mucosa of the stomach was extensively sampled for microscopic analysis. Superficial infiltrates of malignant signet ring cells were identified in the surgical samples from all five persons who underwent gastrectomy. These early diffuse gastric cancers were multifocal in three of the five cases, and in one person infiltrates of malignant signet ring cells were present in 65 of the 140 tissue blocks analyzed. Principles of identifying affected families and the role of genetic testing and prophylactic gastrectomy is discussed in this and other articles (9). Hereditary diffuse gastric cancer (HDGC) was defined as any family that fits the following criteria: (1) two or more documented cases of diffuse gastric cancer in first/second degree relatives, with at least one diagnosed before the age of 50, or (2) three or more cases of documented diffuse gastric cancer in first/second degree relatives, independently of age of onset. (Visual )

3. Does Epstein-Barr virus cause gastric cancer?

Epstein-Barr virus (EBV) is the causative agent of infectious mononucleosis, and it may also be found in a wide variety of benign and malignant lesions including oral hairy leukoplakia, inflammatory pseudotumor, Hodgkin's disease, non-Hodgkin's lymphoma, and nasopharyngeal carcinoma. EBV is strongly associated with about 10% of gastric adenocarcinoma in high prevalence areas of the world (Japan, Hong Kong, China, Korea)(10). These EBV-associated tumors have an unusual histology: prominent lymphoid cell infiltration. They are called lymphoepithelioma-like carcinomas (LELCs) or gastric carcinoma with lymphoid stroma (GCLS) and have histologic features similar to a well known EBV-associated tumor, nasopharyngeal carcinoma. Both well-differentiated and poorly differentiated tumors have been described. The clinical features and natural history are not strikingly different from EBV negative tumors (11). One recent study did report that gastric LELCs tend to have a relatively higher frequency of proximal location, diffuse histological subtype but a lower frequency of lymph node metastasis (12). They are not as strongly associated with previous H. pylori infection. In Western patients these EBV-associated tumors may be more common in Hispanic patients (13). In each case of these EBV-associated tumors, every cancer cell has evidence of EBV genome and they express EBV messenger RNA identified by in situ hybridization and EBV antigens by immunostaining (14). EBV DNA is found in the serum of almost all of these patients, far exceding the 3-5% frequency found in healthy controls (15). EBV is not associated with other epithelial tumors from those areas, including breast, esophagus, colon, or pancreas (16). There is some hint that EBV-associated gastric cancer may be more common in cancers that are associated with gastrojejunostomy (17-18). One report highlighted the finding of EBV in a scirrhous carcinoma in a young woman (19). But in general EBV is not suspected as an important factor in young patients with gastric cancer (Visual ).