Physical Examination
Physical examination may provide clues to diagnose gastric cancer. The presence of anemia, occult blood in the stool, and weight loss may suggest a malignancy. A midepigastric palpable mass or nodular liver may be helpful in localizing the process to the abdomen.
The patient may appear completely healthy on physical exam. Additional findings may include: abdominal mass, liver metastases, gastric distention, weight loss, supraclavicular adenopathy (Virchow’s node), rectal mass (Blumer’s shelf), enlarged ovary (Krukenberg’s syndrome), or umbilical metastases (Sister Mary Joseph’s node). Migratory phlebitis (Trousseau’s syndrome), seborrheic keratosis and freckles (Leser-Trélat sign), muscle weakness, splenomegaly, ascites, obstructive jaundice, and peritoneal carcinomatosis may be noted in more advanced disease. Immunohistochemical techniques are used to differentiate low-grade lymphomas of MALT from benign reactive lymphoid hyperplasia. Lymphomas show monoclonality of the lymphoid proliferation. Clinicians should be aware of the possibility that non-Hodgkin’s lymphoma of the stomach may be linked to acquired immunodeficiency syndrome (AIDS).
Genetic Screening
Genetic screening has been advocated in family members of young patients with the diffuse-type of gastric cancer. There are no mutational hotspots, so screening for CDH1 mutations requires a survey of the entire gene. Prophylactic gastrectomy has been performed on carriers of truncating germ-line CDH1 mutations. Remarkably, even asymptomatic individuals who had normal upper endoscopies have demonstrated malignant cells in their surgical resection specimens, suggesting that this could be a viable therapeutic option for highly selected individuals. Genetic counseling is necessary for all family members considering genetic testing and prophylactic gastrectomy. Women in these families who have a germline mutation of CDH1 are at an increased risk for developing lobular breast cancer and should be screened accordingly. Resources: The reader is referred to two excellent reviews on hereditary diffuse gastric cancer:
Graziano, F. et al. Annals of Oncology 14:1705-1713, 2003.
Nardone, G. Alimentary Pharmacology Therapeutics 2003: 17 (suppl.2):75-81. More information about E-cadherin mutations and prophylactic gastrectomy can be found in these two references:
Huntsman, DG, et al. NEJM 2001 344:1904-1909.
Guilford, P, et al. Nature 1998, 392:402-404.
Radiological Diagnosis
Radiography has limited diagnostic value in the diagnosis of gastric cancer. Although better studies (using state-of-the-art techniques performed by practiced technicians) suggest a high sensitivity of x-rays (80–95%), there are limitations. Upper gastrointestinal series may show thickened or enlarged gastric folds, filling defects that correspond to a mass or ulcer, or may demonstrate a failure of the stomach to distend normally to air and instilled barium (Figure 11). These contrast studies do not aid in accurate disease staging and do not allow differentiation of benign from malignant lesions.
Abdominal computed tomography (CT) has been used in gastric cancer tumor staging. The CT scan (Figure 12) can demonstrate the size and location of the cancer, wall thickness, presence or absence of fat between the mass and adjacent organs, as well as nodal, vascular, or visceral spread of tumor. The CT scan is unable to distinguish different layers of the gastric wall; hence, it cannot differentiate early from more advanced lesions. Additionally, CT scanning does not provide tissue confirmation for grading and typing. The ability to distinguish carcinoma from lymphoma is crucial to provide therapy in a timely fashion. Transabdominal ultrasonography may be useful in providing information about metastatic disease, particularly that which affects the liver. Transabdominal ultrasound is largely operator-dependent and has more limited usefulness than CT scanning because of its low sensitivity.
Endoscopic Diagnosis
Endoscopy provides the most specific and sensitive means of diagnosis of gastric cancers. Gastrointestinal endoscopy allows the physician to visualize and biopsy the mucosa of the esophagus, stomach, duodenum, and most of the jejunum (Figure 13).  | | Figure 13. Room set-up and patient positioning for endoscopy. |
During these procedures, the patient is situated in the left lateral position and may be administered a topical anesthetic to help prevent gagging. Pain medication and a sedative may also be administered prior to the procedure.
The endoscope (a thin, flexible, lighted tube) is passed through the mouth and pharynx and into the esophagus. It transmits an image of the esophagus, stomach, and duodenum to a monitor visible to the physician. Air may be introduced into the stomach through the scope to expand the folds of tissue and enhance examination (Figure 14). More than 90% of gastric cancers are detected by upper endoscopy and biopsy. Endoscopy facilitates accurate visualization, histological confirmation and typing. Tumor staging, localization and extent of tumor, and associated local complications may also be established during the procedure (Figure 15). In cases of known gastric cancer, endoscopy is helpful to establish treatment goals (cure or palliation), TNM stage, and assessment of response to previous therapeutic approaches. Biopsy leads to correct diagnosis in virtually 100% of cases when at least 7 specimens are obtained. The increasing use of endoscopy has resulted in detection of “early gastric cancer”, which is amenable to endoscopic therapy. Survival in patients with gastric cancer is largely dependent upon the tumor stage and histological type at the time of initial diagnosis. Correct staging is critical to determining appropriate treatment and course of action. The TNM staging system considers the depth of tumor invasion (T), lymph node involvement (N), and distant metastatases to lymph nodes outside specified regional nodes or to other organs (M) not involved in direct extension from the primary site. Several different methods are used in the staging of gastric cancer, including endoscopic ultrasound (EUS), computed tomography (CT) transabdominal ultrasound, endoscopy, and tumor markers. Endoscopic ultrasound accurately delineates the depth of tumor invasion through the layers of the gastric wall and lymph node involvement. However, evaluation of distant metastases is limited and requires additional information from chest x-ray and other abdominal cross imaging, such as CT scan. EUS is performed after the initial esophagogastroduodenoscopy (EGD). The tip of the echoendoscope is advanced into the stomach, air is aspirated, and water is injected. The patient is positioned to achieve optimal visualization. The EUS image reveals a five-layer structure, which includes the interface between the transducer and mucosa (layer 1), the muscularis mucosa (layer 2), the submucosa (layer 3), the muscularis propria (layer 4), and the serosa (layer 5) (Figure 16). The ability to delineate specific wall layers allows assessment of depth of penetration and classification of T in TNM staging. EUS is not useful in the definitive differentiation of benign from malignant ulcers, nor is it useful in separating infiltrating adenocarcinoma from lymphoma. Histology is essential in making these distinctions.  | | Figure 16. A, Endoscopic ultrasound image (EUS); B, cross-section of corresponding layers in the stomach wall. |
Endoscopy also plays a critical role in the diagnosis of patients with gastric lymphoma. It identifies the specific area and extent of the tumor. It can provide a visual diagnosis in many patients and may also identify associated lesions (H. pylori-related gastritis). Other findings may include infiltrative and polypoid patterns. Gross endoscopic appearance has led to diagnosis in the majority of patients with high sensitivity. However, noninvasive studies and endoscopy may understage primary gastric lymphoma compared to surgery.
Staging
The most significant prognostic factor is depth of tumor invasion at the time of diagnosis. There are three classifications of gastric tumors. The Boorman classification is based on the macroscopic appearance of the tumor; the Lauren classification divides tumors into intestinal and diffuse types; and the TNM classification reflects the depth of tumor infiltration (T) (Figure 17), node involvement (N) (Figure 18), and the presence of distant metastases (M).
Advanced TNM stages are associated with worse prognoses. Most patients present with stage III and IV disease, though the number of patients with stage IV disease at presentation at some U.S. centers has declined during the past 30 years. The five-year survival rate for patients without nodal involvement is about 40%, and is only 10% for those with metastatic disease. These figures are unchanged over the past several decades despite advances in medical and surgical therapy. Definitions:
Primary tumor (T):
Tis = carcinoma in situ: intraepithelial tumor without invasion of lamina propria
T1 = tumor invades lamina propria or submucosa
T2 = tumor invades muscularis propria or subserosa
T3* = tumor penetrates serosa (visceral peritoneum) without invasion of adjacent structures
T4**,*** = tumor invades adjacent structures *A tumor may penetrate the muscularis propria with extension into the gastrocolic or gastrohepatic ligaments or into the greater or lesser omentum without perforation of the visceral peritoneum.
**Structures adjacent to the stomach include the spleen, transverse colon, liver, diaphragm, pancreas, abdominal wall, adrenal gland, kidney, small intestine, and retroperitoneum.
***Intramural extension to the duodenum or esophagus is classified by the depth of greatest invasion in any of these sites, including the stomach). Regional lymph nodes (N):
Include the perigastric nodes along the lesser and greater curvatures, and the nodes along the left gastric, common hepatic, splenic, and celiac arteries.
N0 = no regional lymph node metastasis
N1 = metastasis to 1–6 regional lymph nodes
N2 = metastasis in 7–15 regional lymph nodes
N3 = metastasis in more than 15 regional lymph nodes Distant metastasis (M):
M0 = no distant metastasis
M1 = distant metastasis Worse prognoses are associated with tumors of the cardia, shorter duration of symptoms prior to diagnosis, tumor unresectability, and poorly differentiated histology. Studies are underway to correlate genetic abnormalities found in tumors to overall prognosis. One of the most important prognostic factors in gastric cancer is the depth of infiltration. Endoscopic ultrasound (EUS) has proven to be a very useful tool in staging and assessment of malignancy. EUS can accurately determine depth of penetration and, with the use of fine-needle aspiration cytology, can also assess lymph node status. EUS has been shown superior for locoregional staging of gastric cancers.
Laparoscopic Staging
Adenocarcinoma of the stomach may grow by direct extension into adjacent organs such as the colon, liver, pancreas and spleen. Distant metastases to the lung, as well as to the lymph nodes of the celiac axis, greater and lesser omentum, and retroperitoneal space, may occur. Metastases may present as a “Sister Mary Joseph's node” at the umbilicus, a “Virchow’s node” in the left supraclavicular fossa, or a "Krukenberg's tumor" in the ovary.
Laparoscopy has been demonstrated to be a sensitive method for establishing a definitive diagnosis of liver and other abdominal metastases in the presence of gastric adenocarcinoma. Laparoscopy may be helpful in patients with positive CT or EUS findings for which no histological confirmation of metastasis has been shown. The overall accuracy of laparoscopy for metastatic gastric cancer is 96.5%, 5–20% superior to the results obtained from imaging methods (Figure 19). Abdominal lavage with cytologic examination increases the sensitivity of laparoscopy.
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