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Gastric Adenocarcinoma

INTRODUCTION Epidemiology and Presentation More than 1 million cases of gastric cancer are estimated to occur worldwide per year, with more than 700,000 deaths each year. Thus, gastric cancer is the fourth most common cancer and the second leading cause of cancer death. Gastric adenocarcinoma accounts for about 95% of gastric cancer cases. The incidence rate of gastric adenocarcinoma varies tremendously throughout the world and country by country. Nearly three quarters of cases occur in developing countries, and the countries with the highest incidence rates are in Eastern Asia (e.g., Korea, Japan, and China). The incidence rate of gastric cancer in the United States and Western Europe has been steadily declining and is currently only about one sixth that of Eastern Asia. Despite this, the incidence rate of proximal gastric cancer in Western countries is rising. Overall, males are affected twice as frequently as females, and the average age of presentation is between 60 and 70 years old. Risk factors for gastric adenocarcinoma include Helicobacter pylori infection, diets high in smoked or salty foods, pernicious anemia, prior gastric surgery, chronic atrophic gastritis, and intestinal metaplasia. Genetic cancer syndromes that increase the risk of gastric cancer include hereditary nonpolyposis colon cancer (HNPCC), Li-Fraumeni syndrome, Peutz-Jeghers syndrome, and hereditary diffuse gastric cancer (HDGC) syndrome. Gastric adenocarcinoma is often asymptomatic in its early stages and in later stages causes weight loss, epigastric pain or discomfort, gastrointestinal bleeding, vomiting, and anorexia. In Japan and Korea, high awareness and common endoscopic screening for gastric cancer has led to the proportion of patients with early gastric cancer (i.e., T1 tumors) to reach about 50%. Unfortunately, in other countries, gastric cancer is found most frequently in advanced stages. Pathology Gastric adenocarcinoma arises in the inner mucosal lining of the stomach in the epithelial cell layer. As tumors grow deeper into the wall of the stomach (i.e., submucosa and muscularis propria), they can spread via lymphatics to regional lymph nodes and hematogenously to distant sites, most commonly to the liver. For T1b tumors (invading the submucosa), lymph node metastases are found in about 20% of patients. For T2 tumors (invading the muscularis propria), the lymph node metastasis rate increases to more than 50%. Tumors that penetrate the subserosa (T3) or serosa (T4a) of the stomach can progress to invade adjacent structures such as the pancreas, spleen, and colon (T4b) or disseminate via the peritoneal cavity, leading to carcinomatosis. Several systems have been developed to classify gastric adenocarcinomas by macroscopic or histologic appearance. The most widely used histologic classification is the Lauren classification. The Lauren intestinal type exhibits components of glandular, solid, or intestinal architecture and tubular structures. This type is more common in men and older patients, is associated with environmental exposures such as H. pylori infection, and arises often from precancerous areas, such as chronic atrophic gastritis or intestinal metaplasia. The Lauren diffuse type shows single cells or poorly cohesive cells infiltrating the gastric wall, and progressive disease can ultimately lead to linitis plastica (also known as leather bottle stomach). The diffuse type does not typically arise from precancerous areas, is slightly more common in women and in younger patients, and is more associated with familial occurrence, thus suggesting a more genetic etiology. The incidence rate of the intestinal type has been declining, but the incidence rate of the diffuse type has remained either stable or increased. Signet ring cells are neoplastic cells that contain a large amount of mucin, which pushes the nucleus to the periphery. The general perception is that the presence of these cells is a poor prognostic factor. However, signet ring cells can be found in early T1 tumors and may be associated with improved survival compared with T1 tumors without signet ring cells. Furthermore, for T2 or greater tumors, the presence of signet ring cells may not be an independent prognostic factor when patients are stratified by stage. Preoperative Evaluation The preoperative evaluation of patients with gastric adenocarcinoma involves establishing the diagnosis, assessing the extent of local disease, ruling out distant metastases, and assessing the patient’s general medical condition. All patients should have an upper endoscopy, and information should be obtained as to the location, size, and degree of infiltration of the tumor. If endoscopic ultrasound (EUS) is available, this modality can give additional information, especially regarding T stage. An abdominal computed tomographic (CT) scan should be performed to identify possible regional and distant nodal disease, local extension of tumor to adjacent organs, liver metastases, and peritoneal metastases. The role of chest CT scan to rule out lung metastases or mediastinal nodal disease is controversial because the yield is low in the absence of intraabdominal metastases. Positron emission tomography (PET) or PET/CT scans are not generally obtained for staging given the low yield, but PET scans may be useful in the assessment of response of tumors to neoadjuvant treatment. Small volume peritoneal carcinomatosis can be missed on abdominal CT scans, and so diagnostic laparoscopy can be performed. Furthermore, patients without overt peritoneal carcinoÂ� matosis may have microscopic free peritoneal tumor cells when peritoneal washings are performed. In one study from Memorial Sloan-Kettering Cancer Center, radiologically occult metastatic disease was identified with laparoscopy in 25% of patients who were determined with EUS to have T3-T4 or N+ disease and in only 4% of patient who were determined with EUS to have T1-T2 and N0 disease. The survival of patients without peritoneal carcinomatosis but with free peritoneal tumor cells in peritoneal washings may be similar to that of those with overt peritoneal carcinomatosis, although the increased efficacy of more recent chemotherapy regimens has called this into question. Staging The American Joint Committee on Cancer (AJCC) changed T and N definitions and the overall staging classifications of gastric adenocarcinoma in the seventh edition of the AJCC Cancer Staging Manual published in 2010 (Table 1). SURGERY Extent of Gastric Resection For tumors in the middle or distal stomach, several studies have compared distal or subtotal gastrectomy with total gastrectomy. In the French cooperative trial of 169 patients with antrum tumors, 93 patients underwent total gastrectomy, and 76 underwent subtotal gastrectomy. No significant difference was found in perioperative mortality rate, and no difference was seen in 5-year survival rate (48%). In the Italian Gastrointestinal Study group multicenter, randomized trial of 618 patients with tumors of the distal half of stomach, there was also no difference in 5-year survival rate between subtotal and total gastrectomy (65% vs 62%). Thus, for patients with middle or distal tumors, distal or subtotal gastrectomy is adequate and total gastrectomy does not improve survival. For proximal gastric cancers, few high-quality studies have examined the extent of gastric resection, and thus, the extent of gastric resection is largely governed by the preference of the surgeon. In one nonrandomized Norwegian study of 763 patients, complication and mortality rates were higher for patients who underwent proximal gastrectomy (52% and 16%) compared with total gastrectomy (38% and 8%). In another large study from Korea, An and colleagues examined a total of 89 patients who had a proximal gastrectomy and 334 patients who had a total gastrectomy for proximal gastric cancer. Complications were markedly higher in the proximal gastrectomy group, with major differences found in the rate of anastomotic stenosis and reflux esophagitis. Some groups, however, continue to advocate proximal gastrectomies for proximal gastric cancers. In terms of the surgical incision required to remove a tumor confined to the proximal stomach, a laparotomy incision is usually sufficient. The National Cancer Center (NCC) group in Tokyo randomized 167 patients with proximal gastric tumors to total gastrectomy and D2 lymphadenectomy via a laparotomy or via a left thoracoabdominal incision. Higher morbidity and mortality rates were seen in the left thoracoabdominal incision group, but no difference was found in survival rate. However, for proximal third tumors extending into the gastroesophageal junction (GEJ) or distal esophagus, a left thoracoabdominal or Ivor-Lewis approach may be necessary.

TABLE 1:╇ Seventh American Joint Committee on Cancer staging system for gastric adenocarcinoma Primary Tumor Tx Primary tumor cannot be assessed. T0 No evidence of primary tumor. Tis Carcinoma in situ: intraepithelial tumor without invasion of the lamina propria. T1 Tumor invades lamina propria, muscularis mucosae, or submucosa. T1a Tumor invades lamina propria or muscularis mucosae. T1b Tumor invades submucosa. T2 Tumor invades muscularis propria. T3 Tumor penetrates subserosal connective tissue without invasion of visceral peritoneum or adjacent structures. T3 tumors also include those extending into the gastrocolic or gastrohepatic ligaments or into the greater or lesser omentum, without perforation of the visceral peritoneum covering these structures. T4 Tumor invades serosa (visceral peritoneum) or adjacent structures. T4a Tumor invades serosa (visceral peritoneum). T4b Tumor invades adjacent structures, such as spleen, transverse colon, liver, diaphragm, pancreas, abdominal wall, adrenal gland, kidney, small intestine, and retroperitoneum. Regional Nodes Nx Regional lymph node(s) cannot be assessed. N0 No regional lymph node metastasis. N1 Metastasis in 1 to 2 regional lymph nodes. N2 Metastasis in 3 to 6 regional lymph nodes. N3 Metastasis in 7 or more regional lymph nodes. N3a Metastasis in 7 to 15 regional lymph nodes. N3b Metastasis in 16 or more regional lymph nodes. Metastases Mx Distant metastases cannot be assessed. M0 No distant metastases. M1 Distant metastases. Stage Groupings 0 Tis N0 M0 IIIA T2 N3 M0 IA T1 N0 M0 T3 N2 M0 IB T1 N1 M0 T4a N1 M0 T2 N0 M0 IIIB T3 N3 M0 IIA T1 N2 M0 T4a N2 M0 T2 N1 M0 T4b N0 or N1 M0 T3 N0 M0 IIIC T4a N3 M0 IIB T1 N3 M0 T4b N2 or N3 M0 T2 N2 M0 IV Any T Any N M1 T3 N1 M0 T4a N0 M0 Adapted from American Joint Committee on Cancer: AJCC cancer staging manual, ed 7, New York, 2010, Springer, 117–126.

Gastric Reconstruction Few good studies are found on the optimal reconstruction after distal or subtotal gastrectomy. In Japan and Korea, the preferred type of reconstruction is generally a Billroth I reconstruction; most United States surgeons prefer a Billroth II reconstruction. Roux-en-Y reconstruction results in less bile reflux into the stomach but can result in a Roux stasis syndrome. One Japanese study randomized 50 patients after distal gastrectomy for cancer to Billroth I or Roux-en-Y reconstruction. Five of 24 patients (21%) in the Roux group had gastrojejunal stasis develop in the early postoperative period, and this group had a longer mean hospital stay, but the Billroth I group had a higher incidence rate of bile reflux gastritis at 6 months after surgery (62% vs 30%). Reconstruction after total gastrectomy is generally performed with a Roux-en-Y esophagojejunostomy with or without a jejunal pouch. Lehnert and colleagues reviewed 14 small randomized trials of jejunal pouch versus no pouch, each with 20 to 70 patients. The pouch added minimal operative time and did not increase morbidity. Food intake was somewhat improved in the early months, but this advantage decreased with time. Only 2 of 12 trials found a difference is postoperative weight, and only 2 of 9 trials found an improvement in quality of life. More recently, Fein and colleagues randomized 138 patients and found no differences in operative morbidity or mortality rates; short-term and long-term weight loss were similar in both groups. However, quality of life was found to be improved in years 3 to 5 after surgery in the pouch group. Nodal Station and Lymphadenectomy Definitions The extent of lymphadenectomy has been a persistent area of controversy in the treatment of gastric adenocarcinoma. Before discussion of lymph node dissections for gastric adenocarcinoma, one must define the terms to be used. The lymph node stations that surround the stomach have been precisely defined by the Japanese Gastric Cancer Association (JGCA) (Figure 1 and Table 2). Table 3 shows the lymph node stations that should be removed for a D1 and D2 lymphadenectomy based on the extent of gastrectomy. The JGCA recommends D2 lymphadenectomy for any tumor T2 or deeper or with clinically positive nodes. Location of Metastatic Lymph Nodes For decades, centers in Japan and Korea have performed gastrectomies with extensive lymphadenectomies and then ex vivo dissected out and labeled the nodal stations. Pathologists then examine each nodal station separately and document which nodal stations contain metastatic disease. Thus, many excellent studies are found on the location of metastatic lymph nodes from gastric cancer based on tumor location and other tumor and patient factors. With use of a large database of patients treated with D2 or greater lymphadenectomy, Maruyama and colleagues at the NCC calculated the risk of the lymph node metastases in each lymph node station by location of primary tumor (Table 4). In 1989, the NCC database of 3843 cases was used to create the Maruyama computer program. This program estimates the risk of lymph node metastasis for each lymph node station based on the input of eight variables: gender, age, endoscopic or Bormann classification, depth of invasion, maximal diameter, location (upper, middle, or lower third), position (lesser or greater curvature, anterior or posterior wall, or circumferential), and World Health Organization (WHO) histologic classification. The Maruyama computer program was later expanded to include 4302 cases (WinEstimate 2.5, Springer, Berlin, Germany). By matching input variables to this large database of patients, the program gives a percent likelihood of disease in each of 16 lymph node stations. The applicability and accuracy of the Maruyama computer program have been confirmed in Western patients treated in Germany and in Italy. Potential Benefits of More Extensive Lymphadenectomy Lymphadenectomy for cancer can serve three potential purposes: staging of disease, prevention of locoregional recurrence, and improvement in overall survival. There is little doubt that more extensive lymphadenectomies for gastric adenocarcinoma lead to better staging of disease. The 2010 7th edition of AJCC Staging Manual for gastric adenocarcinoma recommends that at least 16 lymph nodes be examined for correct assessment of the N category. Despite this, one analysis of the United States Surveillance, Epidemiology and End Results (SEER) database found that only 29% of 10,807 resected gastric cancer patients had 15 or more lymph nodes examined. It is difficult to be confident that a gastric cancer is truly node negative when few lymph nodes are examined, and N1 tumors can be upstaged to N2 or even N3 tumors as more lymph nodes are harvested. Furthermore, it is impossible to be categorized as N3b if less than 16 lymph nodes are harvested. In our analysis of more than 18,000 patients with gastric cancer in the SEER database, we found that more than 50% of patients were misclassified because of inadequate lymph node sampling. Some evidence shows that more extensive lymphadenectomies result in lower rates of locoregional recurrence. Locoregional recurrence after potentially curative surgery for gastric adenocarcinoma can be quite high. In a 1982 series from the University of Minnesota, 107 patients with gastric adenocarcinoma underwent second look laparotomy, and 80% had a recurrence. Of these recurrences, 88% were locoregional, 54% were peritoneal, and 29% were distant. More recently, in United States Intergroup 0116 trial, 177 of 275 patients (64%) in the surgery-only group had recurrent disease develop. In terms of the site of first relapse, 29% had local recurrence, 72% had regional recurrence, and only 18% had distant recurrence. Rates of locoregional recurrence are generally lower in reports from both Western and Asian institutions that perform more extensive lymphadenectomies. The effect of more extensive lymphadenectomies on overall survival for gastric cancer is still quite controversial. Most gastric surgeons in Japan and Korea believe that D2 or greater lymphadenectomies improve overall survival and refuse to perform a prospective, randomized trial of D1 versus D2 lymphadenectomy. Maruyama and colleagues determined the 5-year survival rate of patients with positive lymph nodes in each of the nodal stations, and many D2 node stations, when positive for metastases, have a significant percentage of patients surviving 5 years. For example, a lower third tumor has a 25% incidence rate of metastases in the common hepatic artery nodes. When these nodes were positive and resected as part of a D2 lymphadenectomy, the 5-year survival rate was 31%. Several retrospective studies show that more extensive lymphadenectomies are correlated with improved survival. However, these retrospective studies suffer from the confounding issue of stage migration. Dissecting out additional lymph nodes results in patients often being upstaged, which makes subsequent comparisons regarding therapeutic benefit invalid. Two large prospective randomized trials in the United Kingdom and the Netherlands failed to identify a survival advantage for D2 over D1 lymphadenectomy. However, these two trials had fairly high morbidity (43% to 46%) and mortality (10% to 13%) rates for the D2 lymphadenectomy group. In these trials, the distal pancreas and spleen were often resected during dissection of station 10 and 11 nodes, which significantly increased morbidity. Of note, in the Dutch trial, if patients with hospital mortality are excluded, patients with N2 disease had significant survival advantage when treated with a D2 lymphadenectomy. Several more recent studies now show that D2 lymphadenectomies can be performed without the need for distal pancreatectomy or splenectomy. Furthermore, a recent randomized trial in Taiwan showed an overall survival advantage of more extensive lymphadenectomy over D1 lymphadenectomy, with an overall 5-year survival rate of 59.5% compared with 53.6%, respectively (P = 0.041). Fifteen-year follow-up results from the previously described Dutch trial now show decreased locoregional recurrence and gastric cancer–related death in the D2 group. Degiuli and colleagues in Italy have shown that Western surgeons, following extensive training, can perform D2 lymphadenectomies on Western patients with low morbidity and almost no mortality, and survival results from a prospective randomized trial of D1 versus D2 lymphadenectomy from this group are pending.

2:╇ Regional lymph nodes of the stomach Number Description 1 Right paracardial 2 Left paracardial 3 Lesser curvature a Along branches of left gastric artery b Along 2nd branch and distal part of right gastric artery 4 Greater curvature sa Along short gastric arteries sb Along left gastroepiploic artery d Along 2nd branch and distal part of right gastroepiploic artery 5 Suprapyloric along 1st branch and proximal part of right gastric artery 6 Infrapyloric along 1st branch and proximal part of right gastroepiploic artery 7 Left gastric artery 8 Common hepatic artery a Anterosuperior group p Posterior group 9 Celiac artery 10 Splenic hilum 11 Along splenic artery p Along proximal splenic artery d Along distal splenic artery 12 Hepatoduodenal ligament a Along proper hepatic artery b Along bile duct p Along portal vein 14 Along superior mesenteric vessels v Along superior mesenteric vein a Along superior mesenteric artery Adapted from Japanese Gastric Cancer Association: Japanese classification of gastric carcinoma: 3rd English edition, Gastric Cancer 14:101–112, 2011.

TABLE 3:╇ Extent of lymphadenectomy Extent of gastrectomy D1 dissection D2 dissection Distal/subtotal gastrectomy 1, 3, 4sb, 4d, 5, 6, 7 D1 + 8a, 9, 11p, 12a Proximal gastrectomy 1, 2, 3a, 4sa, 4sb, 7 N/A Total gastrectomy 1-7 D1 + 8a, 9, 10, 11p, 11d, 12a Adapted from Japanese Gastric Cancer Association: Japanese gastric cancer treatment guidelines 2010 (ver 3), Gastric Cancer 14:113–123, 2011.

TABLE 4:╇ Frequency of lymph node metastasis based on location of primary tumor Lymph node basin Upper third (% with metastasis) Middle third (% with metastasis) Lower third (% with metastasis) Paracardial (stations 1 and 2) 22 9 4 Lesser or greater curve (stations 3 and 4) 25 36 37 Right gastric artery/suprapyloric (station 5) 2 3 12 Infrapyloric (station 6) 3 15 49 Left gastric artery (station 7) 19 22 23 Common hepatic artery (station 8) 7 11 25 Celiac axis (station 9) 13 8 13 Splenic artery/hilum (stations 10 and 11) 11 3 2 Hepatodudodenal (station 12) 1 2 8 Other 0-5 0-5 0-5 Adapted from Maruyama K, Gunven P, Okabayashi K, et al: Lymph node metastases of gastric cancer. General pattern in 1931 patients. Ann Surg 210:596-602, 1989.

D2 LYMPHADENECTOMY TECHNIQUE FOR SUBTOTAL/DISTAL GASTRECTOMY Greater Curvature (Station 4sb and 4d) Node Dissection An upper midline incision is made from the xiphoid to just below the umbilicus. An Omni retractor can be used to provide optimal exposure. The abdomen should be explored to rule out intraabdominal or liver metastases. The primary tumor should be assessed for proximal and distal extent and possible invasion of adjacent structures. A marking suture can be placed on the anterior gastric wall to identify the proximal extent of the tumor. One or two lap pads should be placed behind the spleen to push the spleen forward and prevent capsular tears. The greater omentum is taken off the transverse colon, beginning from center and moving to the left, widely opening up the lesser sac (Figure 2, A). The dissection is continued such that the greater omentum is taken off the splenic flexure and the inferior aspect of the spleen. This dissection should expose the body and tail of the pancreas, and the left gastroepiploic vessels are divided near their origin from the splenic vessels just anterior to the pancreas (Figure 2, B). The greater curvature of the stomach between the end of the left gastroepiploic arcade and the start of the short gastric vessels should then be identified. This marks the left-most end of the greater omentum dissection. The omentum is divided from peripherally toward the gastric wall. On reaching the gastric wall, ultrasonic coagulating shears can be then used to dissect between the gastric wall and greater omentum from proximal to distal (Figure 2, C). Infrapyloric (Station 6) Node Dissection One should now return to where the mid portion of the greater omentum was taken off the transverse colon and continue this dissection toward the hepatic flexure. The infrapyloric lymph nodes are now dissected off the head of the pancreas. Dissection in this area should proceed cautiously to avoid tearing small vessels that lead to troublesome bleeding; use of ultrasonic coagulating shears is often helpful. Dissection should proceed such that all the soft tissue anterior to the pancreas is swept superiorly onto the specimen. The right gastroepiploic vein should be identified at its origin from the inferior pancreaticoduodenal arcade, ligated, and divided (Figure 2, D). The right gastroepiploic artery should also be divided at its origin from the gastroduodenal artery. A tunnel is then created between the first portion of the duodenum and the head of the pancreas. Hepatoduodenal Ligament Hepatic Artery (Station 12a) and Suprapyloric (Station 5) Node Dissection The peritoneal covering and soft tissue of the porta hepatis is opened from the mid lesser omentum near the undersurface of the liver toward the superior porta hepatis. One should then dissect on the lateral border of the proper hepatic artery from superior to inferior. The soft tissue between the suprapyloric nodes and proper hepatic artery nodes is then divided. This nodal tissue is then dissected from right to left, completely exposing the common hepatic artery/proper hepatic artery/gastroduodenal artery trifurcation. To the left of the proper hepatic artery, dissection continues posteriorly, exposing the left side of the portal vein. Once this portion of the dissection is completed, the right gastric artery (which usually originates from the proper hepatic artery or the gastroduodenal artery) is divided (Figure 3, A). The right gastric vein that originates from portal vein should also be divided. The plane between the superior first portion of the duodenum and underlying pancreas is developed until the prior dissection from inferiorly is reached. Small vessels to the first portion of the duodenum are ligated and divided with the harmonic sealing device, thus mobilizing the entire first portion of the duodenum. The duodenum can now be transected distal to the pylorus (Figure 3,B). Common Hepatic Artery Dissection (Station 8a), Celiac Axis (Station 9), Proximal Splenic Artery (Station 11p), and Left Gastric Artery (Station 7) Lymph Node Dissection This dissection begins with opening up the peritoneum overlying the superior border of the pancreas from the proximal splenic artery toward the common hepatic artery. Dissection proceeds from left to right and inferiorly to superiorly. All the nodal tissue anterior and superior to the proximal splenic artery should be cleared until retroperitoneal fat is reached. All the nodal tissue medial to the portal vein and anterosuperior to the common hepatic artery should be swept off the retroperitoneum and right crus. Again, this tissue tends to be vascular, and use of the ultrasonic coagulating shears is helpful. The left gastric vein (also known as coronary vein) originates from the portal vein and travels just to the right of the origin of the left gastric artery. This vessel should now be identified and divided. Dissection proceeds from inferior to superior, exposing the left gastric artery, which is taken at its origin. At the end of this dissection, the celiac axis and its branches are skeletonized (Figure 3,C). Lesser Curvature (Station 3) and Right Paracardial (Station 1) Node Dissection The lesser omentum is divided inferiorly to superiorly near its insertion onto the liver. A replaced/accessory left hepatic artery may be encountered and is generally divided unless the patient has underlying hepatic dysfunction. The lesser omentum dissection is continued to the GEJ, ensuring that the right paracardial nodes are incorporated. To ensure that the lesser curvature lymph nodes are included, all the soft tissue on the lesser curvature is taken off the lesser curvature of the stomach, from the GEJ to beyond where the stomach will be transected (Figure 3,D). The soft tissue in this region exists in two leaflets. A finger can be inserted between the leaflets, and soft tissue anterior and posterior to the finger can be divided off the stomach wall with the harmonic sealing device. The stomach can now be transected, and the proximal and distal margins should be sent for frozen section analysis. Specimen Processing for Pathology Back table ex vivo dissection of the operative specimen after removal of the specimen can aid the pathologist in identifying lymph nodes. Separate containers with each nodal station optimize the chances of having an adequate number of lymph nodes recovered by the pathologist. On the back table, the proximal and distal gastric staple lines are removed. The stomach is opened longitudinally along the lesser or greater curvature, whichever is away from the tumor. The gross proximal and distal margins are examined. The lymph node stations are then dissected out and sent as separate specimen. During initial cases, it may be best to mark these node stations with tags during the dissection to ensure proper ex vivo nodal dissection. D2 LYMPHADENECTOMY TECHNIQUE FOR TOTAL GASTRECTOMY Compared with a distal gastrectomy, the only additional nodal stations that require dissection for a total gastrectomy are the greater curvature nodes along the short gastric vessels (station 4sa), left paracardial nodes (station 2), distal splenic artery nodes (station 11d), and splenic hilum nodes (station 10). The station 4sa nodes can be taken early on after dividing the left gastroepiploic vessels near their origin. One can then continue the greater curvature dissection superiorly toward the GEJ, dividing the short gastric vessels near the medial border of the spleen. On reaching the GEJ, the left paracardial nodes can be dissected by dividing the phrenoesophageal ligament and sweeping all nodal tissue toward the GEJ. Dissection of the distal splenic artery nodes should be performed after dissection off the proximal splenic artery nodes. Nodal tissue anterior and superior to the splenic artery is dissected of the retroperitoneal fat (Figure 4, A). To facilitate dissection of the splenic hilum nodes, the spleen and tail of pancreas can be mobilized anterior and to the left. The splenic artery forms several segmental branches, and all the nodal tissue anterior to these branches is dissected (Figure 4, B). Reconstruction is generally performed with a Roux-en-Y method. The use of an end-to-end anastomosis (EEA) circular stapler may result in anastomotic stricture, which requires dilation. The authors now generally perform the side-to-side stapled technique, which is a modification of a technique described by Orringer. The esophagus is transected with endoscopic linear staples (3.5-mm staple size; Figure 4,C). The jejunal limb is brought posterior to the transected esophagus. A small enterotomy is made in the jejunal limb, 6 to 7╯cm proximal to the transected end, and the mid portion of the esophageal staple line is removed. An endoscopic linear stapler (3.5-mm staple size, 45╯mm in length) is used to create a side-to-side anastomosis (Figure 4,D), and the holes are closed with interrupted 3-0 silk sutures. NEOADJUVANT AND ADJUVANT THERAPY The risks of locoregional and distant recurrence are high for all T2 or more or node-positive gastric cancers even with surgical resection, thus providing rationale for the delivery of neoadjuvant and adjuvant therapies. The United States Intergroup 0116 trial was the first prospective randomized trial to show a survival benefit of 5-fluorouracil (5-FU) chemoradiation after surgery over surgery alone. Three-year overall survival rate was increased from 41% to 50% with chemoradiation (P = 0.005). In this trial, 54% of patients received less than a D1 lymphadenectomy and only 10% of patients received a D2 lymphadenectomy, and the chemoradiation appeared to primarily reduce logoregional recurrence. Thus, some have argued that the chemoradiation likely improved survival by making up for inadequate surgery. Of note, an observational study from Samsung Medical Center (Seoul, Korea) of 990 patients who underwent surgical resection along with D2 lymphadenectomy found that median survival rate was significantly increased in the 544 patients who underwent chemoradiation compared with the 446 patients who underwent no adjuvant therapy. More recently, the Adjuvant Chemoradiation Therapy in Stomach Cancer (ARTIST) trial randomized Korean patients after gastrectomy to capecitabine and cisplatin (XP) chemotherapy or XP plus radiation and capecitabine. The overall trial results were negative, but disease-free survival rate was improved with chemoradiation in the subgroup of patients with node-positive disease. Three prospective randomized trials, one from Europe and two from Asia, have shown survival benefits for neoadjuvant or adjuvant chemotherapy without radiation therapy. The European Organisation for Research and Treatment of Cancer (EORTC) Medical research Council Adjuvant Gastric Infusional Chemotherapy (MAGIC) trial randomized patients to three cycles of epirubicin, cisplatin, and 5-FU (ECF) chemotherapy before and after surgery or surgery alone and found a 5-year overall survival rate of 36% in the chemotherapy plus surgery group and 23% in the surgery-alone group (P = 0.009). Sakuramoto and colleagues randomized Japanese patients to surgery plus S-1, a 5-FU prodrug combined with an agent that lowers bowel toxicity and an agent that prevents 5-FU degradation, or surgery alone and found that the 3-year overall survival rate was 80% in the S-1 plus surgery group and 70% in the surgery-alone group (P = 0.002). Most patients in the EORTC MAGIC trial received at least a D1 lymphadenectomy, and most patients in the Japanese trial received a D2 lymphadenectomy, supporting the notion that chemotherapy alone can improve survival in patients with gastric cancer. The Adjuvant Capecitabine and Oxaliplatin for Gastric Cancer after D2 Gastrectomy (CLASSIC) trial randomized Asian patients after D2 gastrectomy to capecitabine and oxaliplatin chemotherapy or no chemotherapy; the 3-year disease-free survival rate was 74% in the chemotherapy group compared with 59% in the no-chemotherapy group (P = 0.0001). The Chemoradiation after Induction Chemotherapy in Cancer of the Stomach (CRITICS) multicenter trial is currently comparing MAGIC-style perioperative chemotherapy with preoperative chemotherapy followed by postoperative chemoradiation. FOLLOW-UP The utility of intensive follow-up of patients with gastric cancer after surgical resection is controversial, and significant differences are found in the recommendations of various groups. The European Society for Medical Oncology (ESMO) clinical recommendations for the follow-up of gastric cancer state, “there is no evidence that regular intensive follow-up improves patient outcomes, [and] symptomdriven visits are recommended for most cases.” However, many patients are uncomfortable with minimal or no follow-up. The National Comprehensive Cancer Network practice guidelines for gastric cancer recommend a history and physical examination every 3 to 6 months for 1 to 3 years, every 6 months for 3 to 5 years, and then annually. Complete blood cell count (CBC), chemistry profile, tumor markers (carcinoembryonic antigen [CEA] and carbohydrate antigen 19-9 [CA19-9]), radiologic imaging, and endoscopy are recommended as clinically indicated. Ultimately, the decision regarding the intensiveness of follow-up is left to the treating physician after discussion with the patient. SUMMARY The surgical management of patients with gastric adenocarcinoma varies significantly around the world, and much of this is related to the wide range in incidence rates and thus wide range in exposure of surgeons to this disease. Useful diagnostic studies include upper endoscopy, EUS, abdomen and pelvis CT scan, and diagnostic laparoscopy with peritoneal washings. The extent of gastric resection is governed by the location of the tumor. For mid and distal tumors, distal or subtotal gastrectomy can be performed, but for proximal tumors, total gastrectomy is generally performed. The extent of lymphadenectomy is also governed by the location of the tumor, but controversy exists as to whether a D1 or D2 lymphadenectomy is optimal. Unfortunately, more than half of patients in the United States receive less even a D1 lymphadenectomy. Two large randomized studies from Western countries that compared D1 and D2 lymphadenectomy showed no survival benefit for a D2 lymphadenectomy when performed with high morbidity and mortality. Performance of a D2 lymphadenectomy requires surgical training. Experienced surgeons in countries with high incidence rates such as Japan and Korea perform D2 lymphadenectomies for gastric with low morbidity and almost no mortality. Long-term results from the Dutch randomized trial and a Taiwanese trial suggest there may be a survival benefit for D2 lymphadenectomy. Overall survival results are pending from an Italian prospective randomized trial of D1 versus D2 lymphadenectomy in which the D2 group had low morbidity and mortality. S u g g e s t e d R e a d i n g s Japanese gastric cancer treatment guidelines 2010 (ver. 3), Gastric Cancer 14:113–123, 2011. Maduekwe UN, Yoon SS: An evidence-based review of the surgical treatment of gastric adenocarcinoma, J Gastrointest Surg 15:730–741, 2011. Songun I, Putter H, Kranenbarg EM, et al: Surgical treatment of gastric cancer: 15-year follow-up results of the randomised nationwide Dutch D1D2 trial, Lancet Oncol 11:439–449, 2010.

Figure 1: Locations of lymph node stations. A, Lymph node stations 1-9. B, Lymph node stations 6-17. (Adapted from

Japanese Gastric Cancer Association: Japanese classification of gastric carcinoma: 3rd English edition, Gastric Cancer 14:101–112,


Figure 2: Operative

photographs show: A, dissection of greater omentum off transverse colon; B, dissection of left gastroepiploic vessels near their origin from splenic vessels; C, dissection of greater curvature nodes; and D, dissection of right gastroepiploic vein from inferior

pancreaticoduodenal arcade.

Figure 3: Operative

photographs show: A, dissection of right gastric artery near origin from proper hepatic artery; B, transection of duodenum; C, completed dissection of proximal splenic artery, celiac axis, common hepatic artery, and divided left gastric artery; and D, dissection of right paracardial nodes off the gastroesophageal

junction and lesser curvature.

Figure 4: Operative

photographs show: A, dissection of distal splenic artery; B, dissection of splenic hilum; C, transection of esophagus; and D, side-to-side esophagojejunostomy

with linear stapler.

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