Anatomy

The first part of the stomach, also referred to as the cardia, starts at the abdominal diaphragm. The uppermost portion of the stomach is the fundus or fornix. The major portion of the stomach, the body or corpus, tapers to the pyloric portion; this is later divided into the pyloric antrum, which narrows into the pyloric canal, terminating it, and the pyloric valve, which empties into the first portion of the duodenum. The two borders of the stomach, the concave lesser curvature and the convex greater curvature, both join at the cardia.

Adenocarcinomas of the upper gastrointestinal tract include primaries in both the gastroesophageal (GE) junction and stomach. The treatment of adenocarcinoma of the GE junction is discussed in the esophageal cancer chapter.

Pathologic Conditions

The stomach wall has five layers: mucosal, submucosal, muscular, subserosal, and serosal. The mucosa of the whole stomach is glandular, and there are three distinctly different histologic and anatomic zones: (1) the cardia, which has a small area of predominantly mucous producing cells; (2) the gastric or fundic glands, which are composed of three cells: mucoid cells, chief or zymogenic cells, and parietal cells; and (3) the pyloric glands, which contain mucous-producing cells and associated endocrine cells that secrete the hormone gastrin into the blood vessels of the lamina propria.

The most common histologic condition (90%) is adenocarcinoma. Subtypes include papillary, tubular, mucinous, signet ring cell, adenosquamous, and squamous cell. Other histologic conditions include sarcoma, carcinoid, and small cell and undifferentiated carcinomas. Lymphomas (mucosa-associated lymphoid tissue [MALT]) and leiomyosarcomas can occur, albeit much more infrequently. MALT lymphomas are discussed in Chapter 54.

Most gastric carcinomas occur predominantly in the mid-portion of the lesser curvature and the distal stomach. The prognosis of patients with adenocarcinoma of the stomach depends on tumor type, site within the stomach, and the tumor-node-metastasis (TNM) stage. In a review of 5000 cases, the distribution of stomach cancers by site were 50% pyloric, 13% lesser curvature, 10% cardia, and 6% diffuse infiltration of the stomach.

The prognosis of proximal cancers is less favorable than distal lesions. Gastric cancers have been classified using both microscopic and gross pathologic features. Numerous classifications based on light microscopy of gastric cancer exist. The World Health Organization classification divides gastric adenocarcinoma into patterns common to carcinomas of other organs and include well, moderately, or poorly differentiated.

Jarvi and Lauren, based on epidemiologic studies, divided stomach cancers into two main groups: intestinal (expansile) or diffuse (infiltrative). In 1977, Ming proposed a modification of the Jarvi-Lauren classification.¹⁹ He emphasized the growth patterns rather than the tumor’s architectural subtypes. The classification divides tumors into two main patterns, expanding and infiltrative, which roughly correspond to the intestinal and diffuse types, respectively. The expanding pattern is more common in his series (67%) and describes tumors that tend to be fungating, whereas the infiltrating tumors tend to be diffuse.

Borrmann classified stomach cancer into four categories based on the gross morphology. These include type I: polypoid, type II: ulcerative, type III: ulcerating and infiltrating, and type IV: infiltrating. Type IV corresponds to the appearance of linitis plastica, in which infiltration by tumor causes rigidity of the gastric wall. Borrmann types I and II have a more favorable prognosis than Borrmann types III and IV, independent of lymph node involvement. Similarly, the Japanese Research Society for Gastric Cancer has a classification system based on gross appearance and divides lesions into protruded (I); superficial (II), with elevated (IIa), flat (IIb), and depressed (IIc) subtypes; and excavated (III) types.²⁴

Clinical Presentation

The initial symptoms of gastric cancer are vague and nonspecific. Symptoms generally become evident when tumor involvement has caused significant interference with the lumen or function of the stomach. Patients with proximal lesions may have dysphgsia as a presenting symptom. Later, symptoms such as indigestion, postprandial fullness, and loss of appetite may develop. Hematemesis is not common, but chronic blood loss may occur from an ulcerated lesion. Tumors involving the pylorus in advanced stages generally cause symptoms associated with obstruction. Weight loss and abdominal pain occur in more than half of patients and one third experience nausea and anorexia.

Routes of Spread

Gastric cancers extend through the gastric wall and into regional lymphatics as well as by direct invasion of adjacent organs (e.g., liver, pancreas, spleen, esophagus, colon, duodenum, gallbladder or the adjacent mesenteries). Hematogenous spread via the portal vein can involve the liver or the systemic circulation, and involve the lungs, bone, and other distant sites. Peritoneal seeding from tumor may involve the gastric serosa through the omentum, parietal peritoneum, ovary (Krukenberg tumor), and rectal shelf (Blumer shelf). These are signs of advanced carcinomatosis. The degree to which regional lymphatics are involved is determined by the location of the primary lesion in the stomach. Evidence of distant nodal metastases includes the left supraclavicular node (Virchow node) and left axillary nodes (Irish node).

Diagnostic and Staging Studies

The workup for gastric cancer is described in Table 37-1. Numerous tumor markers have been described in association with gastric cancer, including CEA carcinoembryonic antigen) and Ca 19-9. However, the clinical utility of these tumor markers for screening, diagnostic staging, monitoring response to therapy, or as predictors of recurrence is controversial. Carcinoembryonic antigen (CEA) is positive in approximately one third of gastric carcinomas and reflects the extent of tumor burden. Postoperative elevated values of CEA are not helpful in predicting recurrence.

Table 37-1 Diagnosis and Staging for Gastric Cancer

Endoscopy

Flexible fiberoptic endoscopy with biopsy is more than 90% accurate in diagnosing gastric cancer.²⁰ The positive yield per biopsy is higher in exophytic tumors than in nonexophytic tumors. In the advanced infiltrating lesion (Borrmann type IV), the diagnosis by biopsy is less accurate. The location of the tumor can affect the diagnostic accuracy. It is particularly difficult to obtain a tissue diagnosis from lesions in the gastric cardia and antrum located behind the incisure angularis. Numerous studies have examined the correlation between radiologic diagnosis, endoscopy, and biopsy. No method alone is usually 100% reliable. The proper combination of imaging and endoscopy results in the highest number of positive diagnoses. Such information helps the endoscopist direct the biopsy to suspicious areas in which there may not be mucosal abnormalities.

The application of endoscopic ultrasonography (EUS) allows the identification of the five gastric wall layers.²¹ In staging gastric tumors, EUS diagnoses the depth of penetration of the primary gastric carcinoma with approximately 90% accuracy.²² EUS can also be used to stage lymph node metastases. However, the EUS is is less accurate compared with the T stage. In one series, EUS had an accuracy of 83%, sensitivity of 54%, and a specificity of 97%. The positive predictive value was 88% and the negative predictive value was 82%.

Imaging

The use of positron emission tomography with fluorodeoxyglucose (FDG-PET) is currently considered an optional component in the workup of gastric cancer. Recent studies have shown some added benefit in preoperative staging, predicting response to preoperative chemotherapy, and for the evaluation of recurrent gastric cancer.²³ The role of FDG-PET in the evaluation of metastatic gastric cancer is unclear. Combination PET-CT may provide advantages over PET alone. Further studies are needed to validate this imaging modality in the evaluation of gastric cancer.²⁴

Staging System

In 1988 the American Joint Commission on Cancer (AJCC) and the Union Internationale Contre le Cancer proposed a joint TNM staging system. This was based on the fifth edition of the AJCC TNM staging system. The sixth edition of the AJCC TNM staging system is seen in Table 37-2.²⁵ The major change from the fifth edition is that T₂ lesions have been divided into T_2a (tumor invades the muscularis propria) and T_2b (tumor invades the subserosa). There are also additional descriptors that, although they do not affect the stage grouping, do indicate cases needing separate analysis.

Table 37-2 Classification of Gastric Cancer

As with most other gastrointestinal malignancies, T stage is based on the extension through the layers of the stomach. Lymph node staging is based on the number of positive regional lymph nodes. Whether a lymph node is staged as nodal (N) or metastatic (M) disease depends on the relationship of the nodes to the primary tumor. In general, regional nodes include those located in the greater and lesser curvatures, as well as those in the left gastric, common hepatic, splenic, and celiac arteries. Involvement of other intra-abdominal nodes, including hepatoduodenal, retropancreatic, mesenteric, and paraaortic, are staged as metastatic disease. A list of specific regional and distant nodal disease is seen in Table 37-2. Patients with Epstein-Barr virus–involved gastric cancers have a lower incidence of positive nodes.²⁶

Clinical TNM staging is based on physical examination, radiologic imaging, endoscopy, biopsy, and laboratory findings. Pathologic staging depends on data acquired clinically in addition to surgical and pathologic findings. If there is uncertainty regarding the appropriate T, N, or M staging, the lower (less advanced) category should be used.

Standard Therapeutic Approaches

The standard approach to the treatment of local/regional gastric cancer in the United States includes a combination of surgery, radiation and chemotherapy. These methods will be outlined below with attention paid to relative importance of each modality and timing. Outcomes of individual trials with be presented in a separate section.

Surgery

The primary treatment for local and regional gastric cancer is surgery. An analysis from the U.S. National Cancer Database of 50,169 patients treated from 1985 through 1996 who underwent a gastrectomy as a component of their therapy revealed a decrease in overall 5-year survival rate with increasing stage: IA, 78%; IB, 58%; II, 34%; IIIA, 20%; IIIB, 8%; and IV, 7%.²⁷ In most cases, the determination of resectability for cure or palliation can only be assessed at the time of surgical exploration. The specific surgical procedure is based on the location and extent of the primary tumor and the respective lymph node drainage areas. Laparoscopy can detect disease in the peritoneal cavity and is helpful prior to a laparotomy.²⁸ The most common site of failure is the abdomen.²⁹

Subtotal versus Total Gastrectomy

The first randomized prospective trial comparing subtotal with total gastrectomy for distal gastric cancers was reported by Gouzi and colleagues.³⁰ Both groups had similar morbidity (33%), mortality (1.3% versus 3.2% respectively), and 5-year survival (48%). Therefore, although elective total gastrectomy can be performed safely, subtotal and total gastrectomy offer equal long-term results in patients with carcinomas of the distal stomach. Most surgeons in the United States recommend a subtotal gastrectomy, providing that negative margins and an adequate lymphadenectomy can be achieved. Proper lymph node staging requires examination of 10 to 15 nodes.³¹ Negative margins usually require transection distally in the duodenum and at least 6 cm proximal to the palpable tumor. Margins must be confirmed with histopathology.

Conventional versus Extended Lymph Node Dissection

Lymphatic flow in the stomach is complex. Regardless of the location of the primary tumor, numerous nodal groups can be involved from either lymphatic spread occurring in a sequential manner or with metastases to distant lymph nodes without evidence of involvement of perigastric nodes (skipping). In rules established by the Japanese Research Society for Gastric Cancer, the lymph node groups are numbered 1 through 16, and are grouped into four lymph node levels or groups, N₁ through N₄. The determination of which nodal stations are placed in which nodal groups depends on the location of the primary tumor. By convention, N₁ and N₂ are considered regional nodes, whereas metastasis to N₃ and N₄ node groups is considered distant metastasis. Most Japanese surgeons recommend an extended dissection. The rationale is that improved local regional control results in improved patient survival. However, the data that support this hypothesis are controversial. In Japan, there is widespread endoscopic screening, and public health campaigns resulted in the diagnosis of a larger proportion of early stage tumors. The cure rates reported by Japanese investigators may be more related to the reduced stage of disease than the more radical surgical approach.³² Such “stage migration” may be responsible for the improved survival in each stage of the disease.

In Western countries, there is substantial debate regarding how radical the operation should be. Specifically, should the tumor and spleen be resected en bloc, and how many and which lymph nodes need to be removed? The extent of the resection is generally subdivided into three categories: D0, D1, and D2. The precise definitions vary, however; in general, D0 is a limited operation, whereas D1 includes resection of the primary tumor and the primary echilon nodes. The most radical is a D2 resection which includes dissection of the greater omentum and all the lesser curvature nodes from the origin of the left gastric artery and to the left of the common hepatic artery. The tail of pancreas and spleen should not be removed unless involved with tumor.

Three randomized trials have addressed the question of the extent of surgery.³³^–³⁵ The three trials confirm that not only was there not an improvement in survival with more radical surgery (D2 versus D1 versus D0), but there was a corresponding increase in the incidence of complications. For example, in the Dutch trial, compared with D1 resection, patients who underwent a D2 resection had a significantly higher incidence of complications (43% versus 25%, p < 0.001), mortality (10% versus 4%, p = 0.004), and no difference in 11-year survival (35% versus 30%, p = 0.53).³³ Almost all agree that a D0 resection is not adequate, and, in general, the recommended operation is at least a D1 for lesser curvature lesions and a full D2 for greater curvature lesions. The effect of a D2 resection on the results of the intergroup trial (INT) 0116 of postoperative adjuvant combined modality therapy³⁶ is discussed in the “Outcomes” section of this chapter.

Sasako and colleagues randomized 523 patients with stages T_2b through T₄ gastric cancer to D2 resection with or without a prophylactic para-aortic lymph node dissection.³⁷ There was no significant difference in 5-year survival (69% versus 70%, respectively).