Srinivas Kavuturu
Jussuf T. Kaifi
Kevin F. Staveley-O’carroll
Presentation
A 52-year-old male presents with history of epigastric discomfort and dysphagia for 6 months. He describes two previous episodes of black tarry stools and a 30-lb weight loss over the past 3 months. His past medical history is significant for hypertension, hypercholesterolemia, and benign prostatic hypertrophy. He had an open appendectomy as a child. He drinks about eight beers a day and has a 30-pack-year history of smoking cigarettes. He has family history of heart disease and hypertension. His medications include tamsulosin, metoprolol, omeprazole, and Lipitor. He is not allergic to any known medications.
Differential Diagnosis
Based on his age and clinical presentation (e.g., dysphagia, weight loss, and melena), esophageal/gastric cancer should be considered as the first differential but the following alternative diagnoses could also be taken into account. Benign diseases to consider include esophagitis, gastritis, peptic ulcer disease, or esophageal varices. Malignant diseases to consider include gastric or esophageal carcinoma, MALT (mucosa-associated lymphoid tissue) lymphoma of the stomach, primary gastric lymphoma (non-MALT type), and gastrointestinal (GI) stromal tumor.
Workup
Workup includes a thorough history and physical examination, laboratory testing, diagnostic imaging, and invasive tests (e.g., endoscopy). In case it turns out to be a malignancy, the diagnostic workup should have two goals: (1) determine the extent of disease, that is, clinical staging and (2) risk stratification for any proposed surgery.
Personal history of previous gastric surgery and family history of upper GI cancers (e.g., Lynch syndrome II, BRCA2 mutation, and familial polyposis coli) are strongly suggestive of malignancy.
Most patients with malignancy have normal physical exams. Positive findings on physical examination are most often associated with locally advanced or metastatic disease. These findings may include palpable abdominal mass from a large primary tumor, liver or ovarian metastases (Krunkenberg’s tumor), palpable left supraclavicular node (Virchow’s node), periumbilical nodule (Sister Mary Joseph node), pelvic deposits (rectal Blummer’s shelf), jaundice, or ascites. Paraneoplastic syndromes associated with gastric cancer include acanthosis nigricans, thrombophlebitis, cir-cinate erythemas, dermatomyositis, pemphigoid, and seborrheic keratosis.
When malignancy is suspected, flexible endoscopy is the diagnostic modality of choice. The diagnostic accuracy of upper GI endoscopy for gastric cancer approaches 98%. In a study of 100 randomly selected patients, endoscopy was more sensitive (92% vs. 54%) and specific (100% vs. 91%) than double-contrast barium studies. Barium studies also cannot distinguish benign from malignant ulcers.
Preoperative staging evaluates local extent of the tumor, resectability, lymph node involvement, and presence of metastasis. Imaging modalities include computerized tomography (CT) scan, upper endoscopy, endoscopic ultrasound (EUS), positron emission tomography (PET), magnetic resonance imaging (MRI) and laparoscopic exploration. CT scan of the abdomen is valuable in determining hepatic metastasis (≥1 cm), bulky lymphadenopathy, visceral metastasis, ascites, and extragastric extension to surgically unresectable structures. CT scan also helps in planning the extent of surgery if en bloc resection of nearby organs is necessary. However, its value is limited in detecting peritoneal disease and hepatic metastasis less than 1 cm in size. CT scan of the chest should be included for tumors at the gastroesophageal (GE) junction to evaluate the extent of disease in the mediastinum. EUS can assess the depth of the tumor (T stage) and local nodal status (N stage) with overall accuracy of up to 80%. Although limited by technical challenges, EUS-guided fine needle aspiration (FNA) biopsy of the regional lymph nodes, aspiration of small volume ascites, and accessible distant metastatic sites (e.g., mediastinal lymph nodes, liver) improve the accuracy of lymph nodal staging and could prove distant metastasis avoiding noncurative laparotomy. PET-CT improves preoperative staging of gastric adenocarcinoma and can alter treatment options in up to 20% of patients. PET combined with CT is more accurate for preoperative staging than either modality alone and can facilitate the selection of patients for a curative resection by confirming a nodal status identified by CT. PET-CT is also the most sensitive noninvasive imaging modality for the diagnosis of hepatic metastases from gastric cancer.
Performing diagnostic laparoscopy prior to definitive surgery has several advantages. Laparoscopy detects small metastases (<0.5 cm) of the peritoneum and liver in up to 40% patients who are eligible for potentially curative resection based on CT scan. Laparoscopy also helps in staging by cytopathologic analysis of peritoneal fluid for free intraperitoneal gastric cancer cells, placement of feeding jejunostomy in obstructing GE junction mass, and in palliation by avoiding nontherapeutic laparotomy in advanced gastric cancer. Currently, staging laparoscopy is recommended in select patients with high probability of having distant metastatic disease in the abdomen, based on the tumor location (GE junction and whole-body tumors), and in patients who are medically fit but have unresectable disease by noninvasive staging investigations. The role of laparoscopic intraoperative ultrasonography to stage the gastric cancer is still to be defined by systematic studies.
Preoperative risk stratification for surgery includes nutritional, cardiovascular, pulmonary, central nervous system and functional assessment, clinically and by appropriate investigations and to optimize the medical comorbidities.
The patient described in the scenario above had an unremarkable clinical examination. He had no relevant family history. He had an upper GI endoscopy that revealed a Siewert type III GE junction tumor (i.e., tumor lying within 2 to 5 cm distal to the GE junction). Upper endoscopy revealed an irregular mass below the GE junction. Biopsies from the mass were consistent with moderately differentiated adenocarcinoma. A multiphase CT scan of his chest, abdomen, and pelvis with contrast revealed thickening of stomach wall at the GE junction and a few perigastric lymph nodes less than 1 cm in size. There was no evidence of invasion/encasement of any major vascular structures, distant metastasis, or peritoneal seeding. PET-CT showed an FDG (flurodeoxyglucose) avid lesion in the proximal stomach corresponding to the lesion seen on the CT scan. The subcentimeter lymph nodes seen on the CT scan were also FDG avid on the PET-CT, indicating metastatic spread. EUS showed the lesion to be invading muscularis propria (T2) and EUS-guided FNA of the perigastric lymph nodes were positive for adenocarcinoma (N1).
Diagnosis and Treatment
The diagnosis of gastric cancer is established by histopathologic assessment of biopsies or cytology from gastric washes/brushing. Two most commonly used pathologic classifications of gastric cancer based on microscopic configuration are that of Lauren and World Health Organization (WHO) systems. The Lauren classification divides gastric cancer into two major histologic types: intestinal and diffuse. The intestinal form is often seen arising in a setting of chronic atrophic gastritis (e.g., Helicobacter pylori and autoimmune gastritis), whereas the diffuse form is less related to environmental influences and may arise as single cell mutations within normal gastric glands. The WHO classification has five subtypes: adenocarcinoma (intestinal and diffuse), papillary, tubular, mucinous, and signet-ring cell. Staging of gastric cancer is currently based on the American Joint Committee on Cancer recommendation of the TNM staging (seventh edition, 2010) with the addition of the term “R status” denoting the status of resection margins after surgery (R0, negative margins; R1, microscopic residual disease; R2, gross residual disease).
Surgical resection is the mainstay of treatment of gastric cancer. However, a multidisciplinary team approach with combined modality therapy (surgery, chemotherapy, and radiation) is most effective especially in patients who have locoregional disease. Clinically, gastric cancer can be classified into early, locoregionally advanced (but resectable), nonresectable, and metastatic.
For patients with early gastric cancer (Tis, T1 tumors limited to mucosa), gastrectomy with D1/D2 lymphadenectomy remains the treatment of choice. Endoscopic mucosal resection (EMR) is being performed on select patients but is not yet the standard of care.
For patients with locoregionally advanced resectable gastric cancer, recent evidence supports neoadjuvant therapy prior to surgery. In a recent randomized trial, preoperative chemotherapy has been shown to improve survival, improve local failure rates, and increase the proportion of patients with R0 resection rates (MAGIC trial).
For patients with locally advanced but initially nonresectable disease, neoadjuvant chemotherapy or chemoradiotherapy has also been tried in with an intention to convert it into a potentially resectable disease with a curative intent, but the approach has not yet been standardized. Patients with metastatic disease need palliative therapy, depending on their symptoms and functional status.
Postoperatively, after gastric resection, current NCCN guidelines recommend adjuvant chemoradiation with 5FU following R0 resection of T3, T4, or node-positive cancers.
Surgical Approach
The extent of gastric resection is a crucial part of surgical plan. Since gastric carcinoma has the propensity to spread via submucosal and subserosal lymphatics, a resection margin of at least 5 cm is advocated. Curative resection with microscopically negative margins (R0 resection) involves resection of the tumor with lymphatics and lymph nodes and any adjacent organ involved by direct extension of the tumor (e.g., tail of pancreas, spleen). Hence, selection of appropriate surgical procedure is determined by location of the tumor, lymph nodal status, and extragastric extension into the adjacent organs.
A total gastrectomy with esophagojejunostomy is appropriate for proximal (upper third) gastric tumors. GE junction tumors predominantly involving cardia (Siewert type III—tumor lying within 2 to 5 cm distal to the “Z” line) should be treated by an extended total gastrectomy with a segment of esophagus for a safe margin. On the other hand, GE junction tumors with predominant involvement of the esophagus (Siewert type I—tumor lying within 1 to 5 cm proximal to the “Z” line) should be treated by transhiatal/transthoracic esophagectomy with proximal gastrectomy and gastric pull-up with cervical/thoracic esophagogastrostomy. The necessary extent of resection for Siewert type II (tumor lying within 1 cm proximal or 2 cm distal to the “Z” line) has been controversial and intraoperative assessment of the tumor by an experienced surgeon and frozen section of the resected margins help decide the course—either a total gastrectomy or a transhiatal esophagectomy. For tumors in the distal stomach (lower two-thirds), a subtotal gastrectomy with Bilroth II or Roux-en-Y reconstruction is appropriate (Tables 1 and 2).
TABLE 1. Total Gastrectomy—Key Technical Steps
TABLE 2. Total Gastrectomy—Potential Intraoperative Pitfalls
The extent of lymphadenectomy for gastric cancer remains controversial. Western as well as Asian studies could not show any survival benefit with D2 dissections (lymph nodes along the named arteries of the stomach) over D1 (immediate perigastric lymph nodes). Moreover, few studies demonstrated increased morbidity and mortality with extended lymph nodal dissections. Current AJCC guidelines state that pathologic examination of at least 15 lymph nodes is required for adequate staging (Tables 3 and 4).
TABLE 3. American Joint Committee on Cancer (AJCC) TNM Staging Classification for Staging of the Stomach (7th ed., 2010)
TABLE 4. American Joint Committee on Cancer (AJCC) TNM Staging Classification for Staging of the Stomach (7th ed., 2010, Table 2)
Used with the permission of the American Joint Committee on Cancer (AJCC), Chicago, Illinois. The original source for this material is the AJCC Cancer Staging Manual, 7th ed. (2010) published by Springer Science and Business Media LLC, www.springer.com.
It is our preference and practice to perform gastrectomy with D2 lymphadenectomy after neoadjuvant chemotherapy. Depending on the extent of tumor, a splenectomy and/or a distal pancreatectomy is performed to achieve negative margins (R0 resection). This strategy maximizes the chances of R0 resection and provides adequate number of lymph nodes for accurate staging of the disease.
The patient in our case scenario had a moderately differentiated adenocarcinoma of the stomach (Siewert type III) with T3, N1, M0—stage IIB, that is, locally advanced but was resectable. Hence, as a part of multimodality treatment, he underwent neoadjuvant chemotherapy with Etoposide, Cisplatin, and 5-FU. He then underwent a total gastrectomy with Roux-en-Y esophagojejunostomy.
Operative procedure The patient is placed in a supine position with consideration given to the possibility of right thoracic or cervical approach in case of GE junction tumors needing esophagectomy. The skin from the chin to the pubic symphysis is prepared and draped. We prefer a midline incision extending from the xiphoid process to just below the umbilicus for most patients undergoing a total gastrectomy. A fixed retractor (e.g., Thomson) is used for adequate exposure of the GE junction. Careful methodical exploration of the abdomen is performed to exclude metastasis, assess extent of resection, resectability, and local extension to other viscera. The gastrohepatic omentum is divided closer to the liver, closely watching for accessory left hepatic artery, which should be preserved in most cases. Dissection in the region of the esophagus and the fundus of the stomach starts by taking a ring of diaphragmatic crura, dividing the phrenic vein en route and taking the pericardial lymph node packet en bloc with the specimen (Figure 1). The omentum and the lesser sac with the lining are separated en bloc from the transverse colon. The short gastric vessels along the greater curvature of the stomach are divided close to the spleen (Figure 2), dissection facilitated by a vessel-sealing device. The celiac, splenic, and common hepatic arteries are skeletonized and the nodal tissue swept up the left gastric artery. The left and right gastric arteries and the gastroepiploic vessels are ligated at their bases and the lymph nodes are taken with the specimen. Duodenum is then divided with a GIA stapler 2 to 3 cm distal to the pyloric vein (Figure 3). GE junction is mobilized and esophagus is divided with a transverse anastomosis (TA) stapler. The specimen is sent to pathology and a frozen section obtained from the proximal and distal margins of the specimen to check for adequacy of resection. Reconstruction after a standard D2 total gastrectomy is by a Roux-en-Y esophagojejunostomy (Figure 4). We prefer to perform this with an end-to-end anastomosis (EEA) stapling device. Alternately a hand-sewn anastomosis or anastomosis to a jejunal pouch could also be performed. A jejunostomy feeding tube is placed routinely. We use two closed suction drains to drain the duodenal stump and the esophagojejunal anastomosis.
FIGURE 1 • Mobilization of esophageal hiatus is completed by detaching the peritoneal reflection from the diaphragm. (From Fischer et al. Mastery of Surgery. 5th ed. Philadelphia, PA: Lippincott Williams & Wilkins, 2007, with permission.)
FIGURE 2 • Division of the short gastric vessels close to the spleen. (From Fischer et al. Mastery of Surgery. 5th ed. Philadelphia, PA: Lippincott Williams & Wilkins, 2007, with permission.)
FIGURE 3 • The duodenum being divided with the GIA stapler. (From Fischer et al. Mastery of Surgery. 5th ed. Philadelphia, PA: Lippincott Williams & Wilkins, 2007, with permission.)
FIGURE 4 • Completed Roux-en-Y reconstruction. (From Fischer et al. Mastery of Surgery. 5th ed. Philadelphia, PA: Lippincott Williams & Wilkins, 2007, with permission.)
There are several potential pitfalls during a routine gastrectomy. The gastrohepatic ligament might contain an accessory left hepatic artery (15% to 20%) and sometimes it represents the only arterial flow to the left lobe of the liver. Proximal ligation of left gastric artery in such case may result in hepatic ischemia. Injury to the spleen or its vessels may sometimes need splenectomy to control hemorrhage. Positive esophageal resection margin may require re-resection of the distal esophageal margin. When a transhiatal esophagetomy is attempted for a GE junction tumor, a positive gastric resection may sometimes need a total esophagogas-trectomy with colon/jejunum interposition. Stapled duodenal stump often does not need further reinforcement with additional sutures; however, when it looks ischemic, we recommend oversewing it with Lembert sutures to prevent duodenal stump leak, which is a disastrous postoperative complication.
Special Intraoperative Considerations
GE junction tumors extending into the body of the stomach, where a 5 cm margin could not be achieved, will require total gastrectomy with esophagectomy. We prefer colon interposition in this situation. The left colonic segment based on the ascending branch of the left colic vessels is used. When the colon is absent or has extensive diverticulosis, jejunal conduit can be used.
Postoperative Management
We place a nasogastric tube (threaded beyond the gastrojejunal anastomosis intraoperatively), which is maintained on low intermittent suction. Postoperative pain control and early ambulation is the key to faster recovery. Jejunostomy feeding is started on post-op day 2. Drains are removed on the fourth postoperative day if the bilirubin and amylase in the drain fluid is less than three times the serum values. Oral feeding is started once it is established that the patient does not have an intra-abdominal leak from esophagojejunostomy. A contrast swallow study can effectively rule out a leak in this situation if it is suspected. A dietitian can help the patient adapt to the changed eating habit of small frequent meals. Multivitamin, B12, and iron supplementation will be needed for life in case of total gastrectomy. If the patient does not experience complications, they are discharged home around sixth to seventh postoperative day.
TAKE HOME POINTS
· Upper GI endoscopy is diagnostic and EUS provides the tumor and lymph node stage.
· PET-CT is emerging as a vital diagnostic tool in diagnosing regional as well as distant metastasis.
· Most Siewert type II GE junction tumors are staged and treated like an esophageal cancer.
· Neoadjuvant chemotherapy has shown to improve survival rate in locally advanced tumors and is being recommended by many surgeons and oncologists.
· Total gastrectomy with Roun-en-y esophagojejunostomy remains the operation of choice for locally advanced resectable proximal (upper one-third) gastric carcinoma.
· Current NCCN guidelines state that at least 15 lymph nodes should be retrieved for adequate staging, mostly achieved through a D2 lymph nodal dissection.
· Postoperative chemotherapy and radiation is advised for locally advanced cancers.
SUGGESTED READINGS
Ajani JA, Komaki R, Putnam JB, et al. A three-step strategy of induction chemotherapy then chemoradiation followed by surgery in patients with potentially resectable carcinoma of the esophagus or gastroesophageal junction. Cancer. 2001;92(2):279–286.
Avella D, Garcia L, Staveley-O’ Carroll K, et al. Esophageal extension encountered during transhiatal resection of gastric or gastroesophageal tumors: attaining a negative margin. J Gastrointest Surg. 2009;13(2):368–373.
Bonenkamp JJ, Hermans J, Sasako M, et al. Extended lymph-node dissection for gastric cancer. N Engl J Med. 1999;340(12):908–914.
Bozzetti F, Bonfanti G, Bufalino R, et al. Adequacy of margins of resection in gastrectomy for cancer. Ann Surg. 1982;196(6):685–690.
Cascinu S, Scartozzi M, Labianca R, et al. High curative resection rate with weekly cisplatin, 5-fluorouracil, epidoxorubicin, 6S-leucovorin, glutathione, and filgastrim in patients with locally advanced, unresectable gastric cancer: a report from the Italian Group for the Study of Digestive Tract Cancer (GISCAD). Br J Cancer. 2004;90(8):1521–1525.
Chen J, Cheong JH, Yun MJ, et al. Improvement in preoperative staging of gastric adenocarcinoma with positron emission tomography. Cancer. 2005;103(11):2383–2390.
Chua YJ, Cunningham D. The UK NCRI MAGIC trial of perioperative chemotherapy in resectable gastric cancer: implications for clinical practice. Ann Surg Oncol. 2007;14(10):2687–2690.
Cunningham D, Allum WH, Stenning SP, et al. Perioperative chemotherapy versus surgery alone for resectable gastroesophageal cancer. N Engl J Med. 2006;355(1):11–20.
Cuschieri A, Fayers P, Fielding J, et al. Postoperative morbidity and mortality after D1 and D2 resections for gastric cancer: preliminary results of the MRC randomized controlled surgical trial. The Surgical Cooperative Group. Lancet. 1996;347(9007):995–999.
Dooley CP, Larson AW, Stace NH, et al. Double-contrast barium meal and upper gastrointestinal endoscopy. A comparative study. Ann Intern Med. 1984;101(4):538–545.
Ganpathi IS, So JB, Ho KY. Endoscopic ultrasonography for gastric cancer: does it influence treatment? Surg Endosc. 2006;20(4):559–562.
Gotoda T, Iwasaki M, Kusano C, et al. Endoscopic resection of early gastric cancer treated by guideline and expanded National Cancer Centre criteria. Br J Surg. 2010;97(6):868–871.
Kinkel K, Lu Y, Both M, et al. Detection of hepatic metastases from cancers of the gastrointestinal tract by using noninvasive imaging methods (US, CT, MR imaging, PET): a meta-analysis. Radiology. 2002;224(3):748–756.
Lee YT, Ng EK, Hung LC, et al. Accuracy of endoscopic ultrasonography in diagnosing ascites and predicting peritoneal metastases in gastric cancer patients. Gut. 2005;54(11):1541–1545.
Power DG, Schattner MA, Gerdes H, et al. Endoscopic ultrasound can improve the selection for laparoscopy in patients with localized gastric cancer. J Am Coll Surg. 2009;208(2):173–178.
Saikawa Y, Kubota T, Kumagai K, et al. Phase II study of chemoradiotherapy with S-1 and low-dose cisplatin for inoperable advanced gastric cancer. Int J Radiat Oncol Biol Phys. 2008;71(1):173–179.
Sarela AI, Lefkowitz R, Brennan MF, et al. Selection of patients with gastric adenocarcinoma for laparoscopic staging. Am J Surg. 2006;191(1):134–138.
Smith JW, Moreira J, Abood G, et al. The influence of (18) flourodeoxyglucose positron emission tomography on the management of gastroesophageal junction carcinoma. Am J Surg. 2009;197(3):308–312.
Yang SH, Zhang YC, Yang KH, et al. An evidence-based medicine review of lymphadenectomy extent for gastric cancer. Am J Surg. 2009;197(2):246–251.