Molecular alterations

Multiple molecular alterations are important in the pathogenesis of gastric cancer (Table 1). Epigenetic phenomena include hypermethylation of promoter regions for many genes including CDH1, hMLH1, and p16, which may be involved in early carcinogenesis.^21–27 Further, MSI caused by mutations in DNA repair genes has been reported in up to 39% of gastric cancers.²⁸ Tumor suppressor genes such as p53, APC, MCC, and DCC are also mutated in gastric cancer, and the incidence often varies with histology and stage.^29–31

Loss of normal cellular adhesion is an important feature of human cancer development and prevalent in genetic alterations of gastric cancer. Diffuse-type gastric cancer is characterized by aberrant cellular adhesion with a pattern of infiltrative growth by a small cluster of or sometimes single tumor cells. The cadherin–catenin complex at the cell surface plays a critical role in cell adhesion and polarity, and up to 90% of gastric cancer cases have an abnormality in at least one component of the complex including CDH1 and α- and γ-catenin.^{32, 33} The CD44 transmembrane glycoprotein, expressed in 31–72% of gastric cancers, may modulate invasion and metastasis.³⁴

Similar to other adenocarcinomas, alterations in cellular signaling pathways occur in gastric cancer and provide potential targets for biologic therapies. HER2/neu, an oncogene in the erbB family of membrane receptor tyrosine kinases, is overexpressed in 10–38% of gastric cancer cases and is associated with intestinal-type distal cancer and worse prognosis.^{30, 35} Expression of other cellular receptors in gastric cancer correlates with oncogenic behavior, such as associations between the transmembrane receptor EGFR (epidermal growth factor receptor) with invasion and c-Met with peritoneal metastasis.³⁶ Angiogenesis appears essential for growth of gastric cancer and other solid tumors, and increased angiogenesis in gastric tumor specimens portends an unfavorable prognosis.³⁷ Vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF) are major regulators of angiogenesis, have prognostic value, and are potential targets for antiangiogenic therapy in patients with gastric cancer.^{38, 39} Expression of multiple transcription factors by gastric cancer cells, such as Sp1 and mTOR, promotes abnormal cell growth, survival, and angiogenesis.^{40, 41}

Progression and patterns of metastasis

Gastric cancers metastasize in several ways. Adjacent organs such as the liver, diaphragm, pancreas, spleen, and colon (or its mesentery) may become involved by direct extension. Gastric cancers have a high tendency to spread through the lymphatic system to regional and distant nodes. Hematogenous metastatic disease is often found in the liver. Peritoneal metastatic disease is also common in the metastatic setting and may result in abdominal pain, bowel obstruction, cachexia, or all three. Japanese investigators have noted that histology and patient age may affect the pattern of spread of gastric cancer. In an autopsy study of 173 cases of gastric cancer, they found diffuse histology to be associated with peritoneal metastasis and intestinal histology to be associated with hepatic metastasis.⁴² They also found peritoneal metastasis to be more common in younger patients. In another study, case records of 216 patients with synchronous peritoneal or hepatic metastasis found at surgical exploration more commonly had poorly differentiated histology associated with peritoneal metastases and well to moderately differentiated histology associated with hepatic metastases.⁴³

On a molecular level, expression of VEGF and its receptor KDR has been associated with liver metastasis.^{37, 44} Expression of VEGF-C, which can cause neogenesis of lymphatic vessels, is associated with lymph node metastasis.^{45, 46} In addition, dysregulation of cellular adhesion is likely central to the development of peritoneal metastasis. CD44H has been linked with increased gastric cancer cell adhesion to mesothelial cells and increased peritoneal metastasis in animal models.⁴⁷ C-met amplification has also been linked with peritoneal metastasis.^{36, 48} Further translational research of the molecular biology of metastasis may improve our ability to predict sites of failure and refine therapeutic strategies.

Surgery

The choice of operation for gastric cancer depends on tumor location, histological type, and disease stage. Gastrectomy is the most widely used approach for invasive gastric cancer, and the most common techniques are total gastrectomy, distal subtotal, and proximal subtotal gastrectomy. Segmental resection is less commonly used for invasive gastric cancer but is very common and appropriate for other gastric malignancies such as gastrointestinal stromal tumors. Prospective and randomized studies reveal no survival advantage of total gastrectomy for tumors of the distal stomach compared to distal subtotal gastrectomy when all disease is removed with adequate margins. Both techniques are associated with similar rates of mortality (1–3%), complications, and 5-year survival (around 60%).^{57, 58} In most series, the quality of life after subtotal gastrectomy is superior to that after total gastrectomy.^{59, 60}

Tumors of the proximal stomach and GEJ generally require more complex considerations for resection and reconstruction. Siewert’s classification is very useful and commonly used to describe GEJ tumors.^{61, 62}:

• Type I: adenocarcinoma of the distal esophagus, which usually arises in Barrett’s esophagus and may infiltrate the GE junction from above
  
• Type II: true carcinoma of the cardia arising immediately at the GEJ within 1 cm above and 2 cm below the junction
  
• Type III: subcardial gastric carcinoma infiltrating the junction and distal esophagus from below

In patients with an advanced tumor involving the GEJ, the site of origin (esophagus or stomach) may be unclear. Patients with type I tumors are often treated as distal esophagus cancers with consideration of preoperative chemoradiation for more advanced tumors and surgical resection using a gastric conduit with anastomosis in the neck or chest. In some cases, the jejunum or colon is used instead of the stomach for the conduit. Type II and III tumors may be removed with either total gastrectomy or proximal subtotal gastrectomy often through a transabdominal approach depending on the local extent of the tumor.^{63, 64} Total gastrectomy is generally favored in the United States over proximal gastrectomy because reflux esophagitis is rare after Roux-en-Y esophagojejunostomy reconstruction compared to roughly one-third of patients who will have significant reflux after proximal subtotal resection.^{59, 65, 66} Further, proximal subtotal gastrectomy may fail to remove enough nodal tissue from the lesser curvature, a common site of nodal metastasis. However, some surgeons continue to advocate for proximal subtotal gastrectomy.⁶⁴

The extent of lymph node dissection is one of the most controversial surgical topics in the management of gastric cancer. Radical lymph node dissection involves removal of lymph nodes beyond the usual field of gastrectomy. The Japanese Gastric Cancer Association defines extent of lymph node dissection using the designation “D.”⁶⁷ Generally, D1 dissection includes perigastric lymph nodes. D2 dissection extends the lymphadenectomy to include nodes along the hepatic, left gastric, celiac, and splenic arteries (Figure 2). D3 dissection includes nodes along the porta hepatis and in the retropancreatic and periaortic regions.

The largest prospective study examining the potential benefit of extended lymphadenectomy is the Dutch D1D2 lymphadenectomy trial which randomized more than 1000 patients (711 treated with curative intent) to D1 or D2 lymphadenectomy in the setting of gastrectomy for cancer, with surgical quality carefully controlled.^{68, 69} Operative morbidity and mortality rates were significantly greater in the D2 group than in the D1 group (43% and 10%, respectively, vs 25% and 4%, p < 0.01). However, the increase in mortality rate was associated with either male patients undergoing D2 dissection or patients undergoing splenectomy and distal pancreatectomy for complete nodal dissection. Patients who underwent D2 dissection with preservation of the spleen/tail of the pancreas had operative mortality similar to that of patients who underwent D1 dissection. After median follow-up of 15.2 years, the D2 lymphadenectomy group had a higher disease-specific survival (DSS) rate compared to the D1 group and lower rates of local (12% vs 22%, p = 0.02) and regional (13% vs 19%, p = 0.02) recurrence.⁷⁰

A recent trial from the Italian Gastric Cancer Study Group evaluated the role of modified organ-preserving D2 lymphadenectomy.⁷¹ Patients with potentially curable gastric cancer were randomized (intraoperative) to D1 or D2 dissection. Partial pancreatectomy or splenectomy was done only when local invasion was suspected. A total of 267 patients were randomized, and morbidity and mortality were 12% and 3%, respectively, for the D1 group and 18% and 2% for the D2 group. Five-year DSS rates were 71% and 73% for the D1 and D2 groups; subgroup analysis revealed that in patients with node-positive disease the 5-year DSS rate was 61% in the D2 group versus 46% in the D1 group. Further, in patients with T-stage 2–4 and positive lymph nodes, the 5-year DSS was 59% in the D2 arm versus 38% in the D1 arm (Figure 3). The National Comprehensive Cancer Network (NCCN) gastric cancer panel has recommended consideration of modified D2 lymphadenectomy sparing distal pancreas and spleen in the setting of gastrectomy for cancer if available from an experienced surgeon at a high-volume center.⁷²

Linitis plastica is an extremely virulent form of gastric cancer and is considered incurable by many clinicians. Some feel that patients with linitis plastica should never undergo gastrectomy since at best the 5-year survival is <10%.⁷³ One approach to patients with linitis plastica is to evaluate with staging laparoscopy and, in the absence of metastatic disease, treat first with neoadjuvant therapy in the hope of selecting patients who do not develop metastatic disease for eventual gastrectomy. If a patient with linitis plastica has a positive margin of resection after operation, one should be cautious as to whether this deserves consideration or specific therapy given that isolated local recurrences are uncommon and rarely impact survival compared to the risk of metastatic disease. Recent evidence from the U.S. Gastric Cancer Collaborative suggests the traditional teaching that wide > 5 cm proximal margins are best for resection of distal cancers may not be necessary.⁷⁴ In their retrospective cohort study combining data from seven academic medical centers, the proximal margin distance was not an independent factor associated with overall survival (OS). Rather, T and N-stage were the primary associated factors, and a 3 cm margin was adequate in most patients.

While studies mentioned earlier indicate multivisceral resection should not be done routinely during lymphadenectomy, resection of other organs is sometimes needed when involved by the primary tumor or grossly involved nodes. Investigators from Memorial Sloan-Kettering Cancer Center found that roughly one-third of 800 patients who underwent R0 resection of gastric cancer over 15 years required removal of at least one additional organ.^{75, 76} The operative mortality rate was 4% in these patients, similar to that reported in the Dutch trial for limited dissection and far lower than that for D2 dissection with adjacent organ resection. Interestingly, the likelihood of actual adjacent organ invasion was low (14%) after final pathological examination. The 5-year survival rate in these patients was 32% compared to 50% in patients who did not require multivisceral resection. These data support application of multivisceral resection when required to achieve R0 resection at centers where the operative mortality rate is low.

Minimally invasive approaches to the conduct of subtotal or total gastrectomy have increased in recent years using laparoscopy, computer-aided (robotic) surgery, or hybrid procedures. Prospective high-quality comparisons of these techniques to open surgery have not been done. There are multiple retrospective studies comparing them, which suggest that short- and long-term patient outcomes are improved or not adversely affected by minimally invasive techniques.^{77, 78} While operating time and cost may increase with these approaches, especially early in the surgeon’s learning curve, such costs may be balanced by other possible cost savings with shorter length of stay and more rapid overall recovery. However, all studies so far without randomization are subject to patient selection bias and, therefore, require caution when interpreting any possible benefits.

• EMR is considered with small T1a gastric cancers without adverse pathologic features
  
• Surgical resection is typically partial or total gastrectomy with upper abdominal (D1 or modified D2) lymphadenectomy
  
• Removal of other organs when needed due to local invasion is appropriate
  
• Use of laparoscopic and robotic techniques deserves further study

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