TUMORS OF THE STOMACH

TUMORS OF THE STOMACH

Current Diagnosis

• Intestinal metaplasia, which predisposes to cancer, results from chronic Helicobacter pylori infection.

• In the United States, screening studies are reserved for those with definite risk factors.

• Pretreatment staging drives subsequent treatment and involves endoscopy, endoscopic ultrasound, helical computed tomography, and often laparoscopy or mini-laparotomy.

• Mucosal abnormalities can be largely absent in early gastrointestinal stromal tumors, small carcinoids, and even diffuse- type linitis plastica. Deep endoscopic biopsies are required.

Current Therapy

Adenocarcinoma

• To ensure complete surgical resection, resection should be customized (e.g., gross margin, use of endoscopic mucosal resection for certain mucosal tumors).

•   Survival is highest with low Maruyama Index surgery.

• Adjuvant therapy options include preoperative chemotherapy (± postoperative treatment), or postoperative chemoradiation

Gastrointestinal Stromal Tumors

•   Node dissection is not indicated.

Gastric Lymphoma

• For aggressive diffuse-type lymphomas, chemotherapy with or without radiation therapy is now the mainstay of treatment. Surgery is reserved for complications such as acute perforation.

• Superficial mucosa-associated lymphoid tissue tumors can sometimes be treated by simply eliminating Helicobacter pylori infection. It comes back if reinfection occurs, however.

Gastric Adenocarcinoma

Thanks to happy accident rather than specific planning, over the past 80 years, gastric adenocarcinoma has changed from the most-common solid organ malignancy in the United States to a relatively uncommon disease. Worldwide, however, it remains a scourge second only to lung cancer.

Classification and Epidemiology

Several classification schemes exist. Two are commonly used. Bormann’s morphologic classification relies on gross characteristics of the tumor. The histologic classification of Lauren, first described by Jarvi and Lauren in 1951, divides gastric adenocarcinomas into intestinal (gland-forming) and diffuse (discohesive) types, based on their microscopic appearance. Several other classification schemes have been proposed, including Broder’s classification of differentiation, the World Health Organization (WHO) classification, the Nagayo–Komagome classification, the Ming classification, and the Goseki classification, but none eclipses the Lauren classification.

Epidemiologically, three patterns of disease can be discerned, with Helicobacter pylori infection playing an important role in the first two patterns: intestinal-type tumors arising from the lesser curve and distal stomach, related to H. pylori–associated atrophic gastritis and intestinal metaplasia; diffuse-type tumors involving the body of the stomach, often associated with intense H. pylori–associated inflammation but not associated with significant intestinal metaplasia; and intestinal-type tumors of the gastroesophageal junction.

In high-incidence regions of the world, such as Japan and Korea, up to two thirds of gastric adenocarcinomas are of the first type and are strongly associated with chronic multifocal atrophic gastritis and intestinal metaplasia from chronic H. pylori infection. The process usually begins at the antrum–corpus junction along the lesser curvature and predisposes to cancers of the intestinal type occurring in the sixth or seventh decades of life. The second type of gastric adenocarcinoma, also associated with H. pylori, afflicts younger persons in the fourth and fifth decades of life. The last type, seen in lower-incidence regions of the world such as the United States, is associated with chronic gastroesophageal reflux and Barrett’s esophagitis.

Epidemiologists and public health experts estimate that more than 40% of gastric adenocarcinomas worldwide can be attributed to chronic H. pylori infection. Strains containing the cagA gene appear more dangerous. The infection usually starts by the second or third decade, and unless it is successfully treated, it gives rise to chronic inflammation, atrophic gastritis, and eventually intestinal metaplasia, which is a premalignant histologic condition. Dietary factors such as high salt and high nitrates can accentuate this progression as well as the march to cancer. As the condition progresses, acid-producing oxyntic mucosa is progressively wiped out, gastric pH increases, and bacterial overgrowth with non–H. pylori bacteria is facilitated. The original H. pylori, which requires an acid environment to thrive, often disappears at this point.

Once intestinal metaplasia is established, dietary factors become particularly important in mitigating the risk of cancer development. Protective factors include intake of vitamin C, fresh fruits and vegetables, and antioxidants. The association of H. pylori infection with the development of intestinal metaplasia suggests that early detection and elimination of this infection might prevent gastric cancer. Unfortunately, in high-incidence areas, reinfection from contaminated water supply and other sources is common, thus undermining the strategy. Also, in prevention trials to date, benefit appears restricted to the subgroups without preexisting intestinal metaplasia.

Risk Factors

Risk factors other than H. pylori infection include low socioeconomic status, smoking, a diet deficient in fresh fruits and vegetables or high in salt-preserved high-nitrate foods, previous gastric ulcer, ionizing radiation, family history, and previous gastric resection. Blood group A is associated with higher risk of developing a diffuse-type tumor.

Predisposing genetic conditions include Lynch’s syndrome (hereditary nonpolyposis colorectal cancer [HNPCC], a condition with microsatellite instability due to deficient DNA repair enzymes), as well as dominantly inherited germline mutations in the E-cadherin gene.

Diagnosis

In Western populations, by the time gastric cancer causes symptoms, the disease is often relatively advanced. In a large National Cancer Data Base survey of U.S. patients, presenting ascribable symptoms included weight loss (62%), abdominal or epigastric pain (52%), nausea (34%), anorexia (32%), early satiety (32%), dysphagia (26%), and melena (18%).

Mass screening combining upper GI series, endoscopy, and serum pepsinogen I/II ratio have proved beneficial in high-incidence areas such as Japan, but they cannot be justified in the United States, where incidence is low. However, for defined risk groups, such as those with established atrophic gastritis and established intestinal metaplasia, strong family history, and those with HNPCC syndrome, surveillance screening should definitely be considered. For those with hereditary E-cadherin mutations associated with gastric cancer, prophylactic total gastrectomy is recommended.

In the United States, diagnosis is usually made by upper endoscopy.

One should be aware that diffuse-type cancers manifesting as linitis plastica are often associated with minimal visible mucosal changes, and deep biopsies are often required for establishing the diagnosis. Furthermore, small, early gastric cancers (defined by the Japanese as in situ and T-1 cancers, with or without node involvement) can be associated with particularly subtle mucosal changes, presenting a challenge for even the most experienced endoscopist.

Chromoendoscopy and other sophisticated mucosal imaging techniques have been used to identify such changes but are not yet standard.

Extent-of-disease studies for gastric adenocarcinoma include endoscopic ultrasound (good for estimating depth of tumor and visualizing immediately adjacent nodes), and helical CT scanning, which is good for evaluating extraluminal extent of disease, intraabdominal or mediastinal extension or spread, and liver or lung metastases. Because even high-resolution CT scanning can miss small peritoneal implants, extraregional nodal spread, and small liver metastases, staging laparoscopy or minilaparotomy are valuable adjuncts and should be considered mandatory if any preoperative chemotherapy is considered.

Staging

Seventh Edition American Joint Committee on Cancer/International Union Against Cancer (AJCC/UICC) staging, to be applied to cases diagnosed after Jan. 1, 2010, mandates a number of major changes. For example, any tumor arising in the upper 5 cm of the stomach and extending cephalad to involve the esophagogastric junction is now deemed an esophageal cancer. Also, to avoid confusion, 7th edition staging now harmonizes the T-category designations among esophagus, small intestine, and colon sites. T1 tumors, which involve mucosa or submucosa, are now sub-categorized T1a or T1b accordingly. T2 tumors involve the muscularis propria. T3 tumors penetrate to subserosal connective tissue without breaching the visceral peritoneum. T4 tumors breach the serosa (T4a) or invade adjacent structures (T4b). Nodal categories have also changed, with N1 now reflecting 1 to 2 nodes involved, N2 designating 3 to 6 nodes involved, and N3 designating 7 or more nodes involved. In the overall TNM staging matrix, Stage IV is now restricted to patients with documented peritoneal (including positive peritoneal washing cytology), distant-organ, or extraregional nodal metastases. As a result of these changes, stage migration between 6th edition and 7th edition AJCC/UICC staging is high, more than 50% in most reports.

Treatment

Curative treatment of gastric cancer involves, as main therapy, complete negative-margin surgical resection of disease. For select tumors, such resection sometimes follows up-front chemotherapy. For localized in situ and select T1 tumors, endoscopic mucosal resection and minimally invasive techniques have been successfully employed. Unfortunately, most tumors in the United States are discovered at a stage where formal open surgery is required.

To secure a histologically negative mural margin of resection, a gross margin of 2 cm is usually adequate for exophytic, noninfiltrating tumors, and a margin of at least 5 to 6 cm of grossly normal tissue is recommended for ulcerated or infiltrating tumors or diffuse histology. Closest mural margins are generally checked by frozen section at the time of surgery to confirm adequacy of resection. Total gastrectomy is not indicated as a routine procedure, except in diffuse-type tumors involving most of the stomach (linitis plastica), but it is warranted whenever required for a negative-margin resection.

Routine splenectomy in the treatment of gastric cancer, as well as routine distal pancreatectomy (performed in the past to clear splenic nodes), should be avoided unless definitely required for complete resection of visible or palpable disease.

The optimal extent of lymph node dissection in this disease has generated—and continues to generate—international controversy. Although several prospective randomized trials to date in non-Asian populations—none perfect—fail to demonstrate that routine extensive lymphadenectomy increases survival, it has also been shown that insufficient lymphadenectomy definitely compromises survival. A prospective randomized single-institution trial in Taipei has documented survival benefit associated with radical lymph node dissection. The adequacy of lymphadenectomy for a given case can be quantified using the Maruyama Index of Unresected Disease. In both a large U.S. adjuvant chemoradiation trial and in a blinded reanalysis of a large Dutch surgical trial, low Maruyama Index score correlates with survival. Moreover, a dose–response effect is seen for the extent of surgical clearance of node groups at risk. Using the Maruyama computer program to predict the extent of nodal spread for a given cancer case before surgery is one way to facilitate a low Maruyama Index operation.

Sentinel node biopsy, an established technique in the treatment of other cancers, has largely failed to win support in cancer of the stomach owing to the organ’s lymphatic complexity and relatively high reported false-negative rates.

A large North American prospective randomized trial of postoperative adjuvant 5-fluorouracil–based chemoradiation in completely resected gastric cancer revealed a significant increase in disease-free and overall survival with this treatment. The postoperative nature of this trial thwarted implementation of surgical guidelines, and the extent of node dissection for most patients in the trial was suboptimal. Practitioners in some countries, such as Japan, dismiss the necessity of adjuvant postoperative adjuvant chemoradiation with the (unproved but reasonable) argument that this is only a salvage technique for inadequate surgery. A separate Korean chemoradiation series has shown benefit even for radically treated cases, however. For patients with good postoperative performance status, good organ function, and adequate nutrition, postoperative adjuvant chemoradiation therapy remains the standard in North America.

A recent U.K. study of preoperative plus postoperative ECF (epirubicin [Ellence],1cis-platinum, and continuous-infusion 5- fluorouracil [Adrucil]) chemotherapy versus surgery alone has shown encouraging results for ECF, with a significant improvement in survival. Previous preoperative chemotherapy trials, using other regimens, have been negative, however. Preoperative ECF chemotherapy is now recommended by some, and this is especially the case for localized advanced tumors considered borderline resectable.

In Korea, a positive trial of adjuvant perioperative intraperitoneal chemotherapy has been reported. Considerable morbidity and mortality are associated with this adjuvant treatment, however, and it is unlikely it will be implemented without refinement and successful independent duplication of results.

For localized disease deemed not resectable to negative margins, both chemotherapy and chemoradiation have been used to convert such tumors to potentially resectable status. With successful negative- margin resection, some of these patients indeed survive free of disease long term. When localized unresected disease is documented to exist, administering chemoradiation with 5-fluorouracil as a radiation sensitizer can also result in some degree of 5-year survival (per reports, >10%).

Gastrointestinal Stromal Tumors

Gastrointestinal stromal tumors (GISTs) manifest as submucosal spindle cell tumors in the sarcoma family. In contrast to leiomyosarcomas and other spindle cell sarcomas, they express the antigen CD117 and most (>80%) tumors have activating mutations of c-KIT. Formerly considered rare, approximately 5000 of these tumors per year are now diagnosed in the United States. Owing to pattern of growth in the gastric wall, deep to the mucosa, early symptoms are unusual and these tumors often grow to massive size before mucosal ulceration and hemorrhage (or other major symptoms) finally develop. GISTs are classified as sarcomas. Even low-risk GISTs (<5 cm and <1 mitosis per 10 high-power fields) can metastasize, and no GIST can be considered truly benign.

Treatment of localized primary GISTs consists of complete surgical resection, and a 2-cm margin of grossly normal tissue usually accomplishes this. Specific lymph node dissection is not indicated for this histology. Surgical series indicate that approximately 50% of primary gastric tumors metastasize and recur within 5 years. For patients with widespread metastases, generally located in the peritoneal cavity or the liver, first-line therapy is now a well-tolerated oral agent, imatinib mesylate (Gleevec or STI-571) at an initial dose of 400 mg daily, which generates partial responses in more than 50% of cases and stable disease in an additional 25% of cases. Side effects are minimal, and 1-year survival in treated patients is approximately 85%. On the basis of a completed American College of Surgeons Oncology Group (ACOSOG) trial, patients who have all disease completely resected should receive postoperative adjuvant therapy for 1 year.

For tumors resistant to imatinib, SU11248, sunitinib malate (Sutent), is now used as effective second-line therapy. Additional targeted biological agents are under active investigation.

Carcinoid Tumors

Carcinoid tumors of the stomach are similar in behavior to small bowel carcinoids. When small (<1 cm), and unassociated with invasion of the muscularis propria, local excision to negative margins is generally deemed sufficient. For such tumors, endoscopic resection has an established role. However, even small tumors can metastasize to lymph nodes. Wider gastrectomy with lymph node dissection is generally recommended for gastric tumors larger than 1 cm. Many of these tumors are associated with serum hypergastrinemia; those without this finding tend to be more aggressive. When metastatic to the liver or other organs, surgical cytoreduction (or other means of tumor ablation) can offer considerable palliation to those with carcinoid syndrome, and this should always be considered. Octreotide therapy is now a palliative mainstay in all patients with carcinoid syndrome.

Gastric Lymphomas

Gastric lymphomas encompass most of the lymphoma subtypes, but low-grade, mucosa-associated B-cell lymphomas (B-cell MALT lymphomas) deserve special mention because they are strongly associated with H. pylori infection. Indeed, localized cases can be controlled simply by treating the H. pylori infection. In such cases, molecular studies indicate persistence of the offending lymphoid clone in about one half of cases. However, and, particularly if H. pylori infection recurs, the lymphoma in such cases returns.

Aggressive, high-grade, diffuse-type B-cell gastric lymphomas, stage IE and IIE, once treated with multimodal therapy, are now treated with chemotherapy alone as the primary treatment, with or without radiotherapy. Surgical intervention is now reserved for emergencies, such as perforation.

For further information on this and other gastrointestinal lymphomas, please see the chapter on lymphoma.

References

1.     Cunningham D., Allum W.H., Stenning S.P., et al. Perioperative chemotherapy versus surgery alone for resectable gastroesophageal cancer. N Engl J Med. 2006;355(1):11–20.

2.    Ferrucci P.F., Zucca E. Primary gastric lymphoma pathogenesis and treatment: What has changed over the past 10 years? Br J Haematol. 2007;136(4):521–538.

3.     Fritz A.G., Greene F.L., Trotti A., eds. AJCC Cancer Staging Manual. 7th ed. 2010 New York, 2010, Springer-Verlago.

4.    Hundahl S.A., Macdonald J.S., Benedetti J., et al. Surgical treatment variation in a prospective, randomized trial of chemoradiotherapy in gastric cancer: The effect of undertreatment. Ann Surg Oncol. 2002;9(3):278–286.

5.     Hundahl S.A., Peeters K.C., Kranenbarg E.K., et al. Improved regional control and survival with “low Maruyama Index” surgery in gastric cancer: Autopsy findings from the Dutch D1-D2 Trial. Gastric Cancer. 2007;10(2):84–86.

6.      Macdonald J.S., Smalley S.R., Benedetti J., et al. Chemoradiotherapy after surgery compared with surgery alone for adenocarcinoma of the stomach or gastroesophageal junction. N Engl J Med. 2001;345(10):725–730.

7.    Modlin I.M., Kidd M., Latich I., et al. Current status of gastrointestinal carcinoids. Gastroenterology. 2005;128(6):1717– 1751.

8.    Siehl J., Thiel E. C-kit, GIST, and imatinib. Recent Results. Cancer Res. 2007;176:145–151.

1  Not FDA approved for this  indication.

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