Figure 47-6. Computed tomography scan demonstrating mass along lesser curvature of the stomach (black arrow) and associated

lymph node enlargement (white arrow).

Computed tomography (CT) can provide information both about the primary tumor and visceral

metastatic disease. Because it is noninvasive and widely available, it is often the first staging modality

that is employed in a patient diagnosed with gastric cancer. Patients who are found to have metastatic

disease can be spared further, potentially invasive staging studies. When performed with intraluminal

and intravenous contrast, CT can demonstrate infiltration of the gastric wall by tumor, gastric

ulceration, and the presence of hepatic metastases (Figs. 47-6 and 47-7). CT may overestimate depth of

invasion, but serosal involvement can be reliably assessed (sensitivity 83% to 100%, specificity 80% to

97%).34 The technique is less reliable for detection of small peritoneal metastases, which may be missed

in 30% of cases.35 Similarly, evaluation of nodal disease by CT is limited, with accuracy of 70% to 80%

even with modern CT techniques.36

EUS is another useful method of preoperative evaluation for local staging and diagnosis. EUS can

assess subepithelial lesions that may be confused with gastric cancer and guide biopsy of submucosal

tumors within the wall of the stomach. Investigation of submucosal masses, infiltrative gastric

disorders, and enlarged gastric epithelial folds, as well as differentiation of gastric lymphoma from

gastric adenocarcinoma are all aided by EUS. This technique has the ability to assess the depth and

pattern of gastric wall penetration by the tumor as well as relationship to adjacent structures, and has

good correlation with intraoperative assessment and histologic findings. Perigastric lymph nodes

involved with tumor are also reliably identified by EUS, and therefore EUS provides the most accurate

assessment of local stage of disease (TN status), with an accuracy of 65% to 90% for staging depth of

tumor invasion34 and 50% to 78% for nodal involvement.37 EUS is generally not useful for detecting

metastatic disease, but it can help identify patients at risk for radiographically occult metastatic disease

(e.g., peritoneal metastases) for staging laparoscopy.35 Therefore, EUS serves as a useful adjunct to

cross-sectional imaging and can help guide selection of patients for further staging studies or

multimodality therapy.

Metabolic imaging with positive emission tomography (PET) using 18F-fluorodeoxyglucose has been

found to be less accurate than cross-sectional imaging and EUS for staging locoregional involvement,

but more sensitive for detecting distant metastases in patients with gastric cancer.37 A meta-analysis

comparing PET, ultrasound, CT, and magnetic resonance imaging (MRI) found that PET scan was the

most sensitive imaging modality for detecting hepatic metastases.38 A separate study found that tumors

which responded metabolically on PET to neoadjuvant chemotherapy correlated highly with

histopathologic response and improved patient survival.39 Therefore, current recommendations

regarding the use of PET for staging gastric cancer are for selective use for patients with locally

advanced tumors where the metastatic potential is high, and in cases where neoadjuvant therapy is

being considered.37 In these patients, the addition of PET can result in net cost savings by reducing the

number of futile surgical procedures.40

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Figure 47-7. Computed tomography scans of the upper abdomen showing extensive thickening of the gastric wall (black arrows)

caused by infiltrating adenocarcinoma and associated hepatic metastasis (white arrow).

Staging Laparoscopy

The peritoneal lining, omentum, and liver capsule are common sites for gastric cancer metastasis that

are difficult to evaluate preoperatively by CT scanning. In prospective studies, diagnostic laparoscopy

has been superior to preoperative CT or percutaneous ultrasound in detection of peritoneal, hepatic, or

lymphatic metastasis.41 Accurate identification of patients with metastatic disease is important in order

to spare them futile, ultimately noncurative surgical procedures. In up to 25% of patients, laparoscopy

will detect metastatic disease that precludes curative resection.42–44 Relative to laparotomy, the shorter

hospitalization and reduced operative trauma following laparoscopy may both hasten recovery and

facilitate earlier initiation of systemic chemotherapy. Most patients with systemic metastasis can be

treated without the need for palliative surgical resection.45

In addition to grossly evident intra-abdominal metastatic disease, patients with microscopic metastatic

disease are at high risk for early recurrence and death after attempted curative resection.46,47 Based on

this finding, patients with positive cytology in peritoneal washings are considered to have M1 disease.

Approximately one-fourth of patients subjected to staging laparoscopy prior to planned curative

resection of gastric cancer will have positive peritoneal cytology; one-third of these patients will not

have grossly apparent metastatic disease. Patients who clear their initially positive peritoneal cytology

after systemic chemotherapy have an improved prognosis, but cure remains highly unlikely.46

Diagnostic laparoscopy may be considered in patients being considered for surgical resection without

neoadjuvant therapy. In these situations, the procedure can be conducted at the beginning of the

planned resection so as to avoid an additional general anesthesia. Patients with locally advanced (T3–T4

or node-positive) tumors who would typically be selected for neoadjuvant therapy should be considered

for diagnostic laparoscopy with peritoneal washings prior to initiation of chemotherapy. The finding of

positive peritoneal cytology should prompt adoption of a noncurative paradigm of treatment in most

cases.

Pathology

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Gastric adenocarcinoma occurs in two distinct histologic subtypes—intestinal and diffuse. These

subtypes are characterized by differing pathologic and clinical features and by differing patterns of

metastatic spread.

In the intestinal form of gastric cancer, the malignant cells tend to form glands. The intestinal form of

malignancy is more frequently associated with gastric mucosal atrophy, chronic atrophic gastritis,

intestinal metaplasia, and dysplasia. Gastric cancer with the intestinal histologic subtype is more

common in populations at high risk (e.g., Japan), and it occurs with increased frequency in men and

older patients. Clinical studies suggest that this subtype more frequently demonstrates bloodborne

metastases.

The diffuse form of gastric adenocarcinoma does not demonstrate gland formation and tends to

infiltrate tissues as a sheet of loosely adherent cells. Lymphatic invasion is common. Intraperitoneal

metastases are frequent. The diffuse form of gastric adenocarcinoma tends to occur in younger patients,

in women, and in populations with a relatively low incidence of gastric cancer (e.g., the United States).

The prognosis is poorer for patients with the diffuse histologic subtype.

Sporadic gastric adenocarcinomas demonstrate a number of chromosomal and genetic abnormalities.

Cytometric analysis reveals that gastric tumors with a large fraction of aneuploid cells (with a greaterthan-normal amount of nuclear DNA) tend to be more highly infiltrative and have a poorer prognosis.

Amplifications of both the HER-2/neu and K-ras proto-oncogenes have been consistently detected in

gastric adenocarcinomas, and in a small percentage of tumors a lack of expression of the tumor

suppressor gene MKK4 is robustly associated with poor survival.48 The exact mechanisms by which

these genetic abnormalities contribute to gastric oncogenesis are currently unclear. Additionally, a

number of growth factors, including epidermal growth factor, platelet-derived growth factor, and

transforming growth factor-β, are overexpressed in gastric carcinoma cells.49

In the United States, the incidence of proximal gastric cancers has been increasing; such that in 2001

the rate of proximal cancers, defined as cancers arising in the cardia and fundus, exceeded that of distal

cancers, defined as cancers arising in the antrum and pylorus. Proximal cancers are more likely to occur

in young white men and distal cancers are more likely to occur in Asian, African American, and Hispanic

patients within the United States. The proportion of tumors involving the proximal stomach has

dramatically increased over the past decades; in the 1960s, only 16% involved this region, and a clear

explanation for this rise in proximal disease remains elusive. In 10% of cases, the stomach is diffusely

involved at the time of diagnosis.27 Prognosis is poorer for tumors arising from the proximal stomach or

for those with diffuse involvement of the organ relative to distal tumors, and these patients are much

more likely to need neoadjuvant and adjuvant therapy.9,50

Figure 47-8. Gastric cancer survival by stage. 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, Seventh Edition (2010) published by

Springer Science and Business Media LLC, www.springer.com

CLASSIFICATION AND STAGING

Table 47-2 Seventh Edition AJCC Staging System for Gastric Cancer

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The seventh edition American Joint Committee on Cancer (AJCC) staging system for gastric cancer is

presented in Table 47-2.51 The staging system accurately discriminates prognosis based on pathologic

factors for tumors located 5 cm distal to the esophagogastric junction (EGJ) and below or arising within

5 cm of, but not crossing, the EGJ (Fig. 47-8). The AJCC recommends that cancers arising within 5 cm

of the EGJ that cross into the EGJ or esophagus be staged and treated as esophageal cancers. A

consideration of staging data illustrates the high frequency with which lymph node metastases are

present at the time of diagnosis in the United States, and the severe impact lymphatic involvement has

on survival. Even early gastric cancers (tumors restricted to the mucosa and submucosa) have a 15%

prevalence of nodal metastasis.

Curative-Intent Treatment

Surgical resection is the only potentially curative therapy for gastric cancer, but an advanced stage of

disease at the time of diagnosis precludes curative resection for most patients.

Since the mid-1990s, the surgical treatment of gastric cancer has continued to evolve, with minimally

invasive approaches increasingly pursued for early cancers and increasingly radical operations

advocated by some for advanced tumors. Japanese surgeons have reported the largest experience with

early gastric cancer. The Japanese Gastric Cancer Association defines early gastric cancer as tumor in

which invasion is restricted to the mucosa or submucosa.52 The presence or absence of lymph node

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metastasis is not considered in this classification. While the presence of lymphatic metastasis cannot be

correctly judged by endoscopic findings, it is critically important in prognosis. For tumors confined to

the mucosa, lymphatic metastasis is present in 1-3% of cases; with submucosal involvement, the rate of

nodal positivity increases to 14-20%.53,54

Endoscopic Resection

For intestinal-type mucosal tumors less than 2 cm in size without ulceration or evidence of

lymphovascular invasion, endoscopic mucosal resection (EMR) may be performed. With this approach,

postoperative bleeding or perforation has been reported in 5%, and in 17% histologic examination

revealed submucosal invasion that required further operative treatment.55 Earlier reports suggested

underestimation of tumor invasion in 45% and missed lymphatic metastasis in 9% urged caution before

widespread acceptance of this technique.56 However, in experienced centers good results can be

obtained. A Japanese series of 131 patients reported disease-free survival of 99% at 10 years.57

Endoscopic submucosal dissection (ESD) is an emerging technique that may allow larger tumors to be

endoscopically resected than with EMR. In the absence of randomized trials comparing EMR and ESD

against surgical resection, surgical resection remains the gold standard for potentially curative therapy

in appropriate-risk patients.

Surgical Resection

4The fundamental principle of surgical resection of gastric cancer is complete extirpation of the primary

tumor. The extent of gastric resection is determined primarily by the need to obtain a resection margin

free of microscopic disease (R0 resection). Microscopic involvement of the resection margin by tumor

cells (R1 resection) is associated with poor prognosis.27 Patients with positive surgical margins are at

high risk for development of recurrent disease, and histologically positive margins are strongly

correlated with the development of anastomotic recurrence. In the setting of ≥5 positive nodes,

however, margin positivity does not impact survival,58 because these patients are at higher risk for

systemic recurrence. In contrast to other gastrointestinal malignancies such as colon cancer, gastric

cancer frequently demonstrates extensive intramural spread, especially the diffuse type. The propensity

for intramural spread is related, in part, to the extensive anastomosing capillary and lymphatic network

in the wall of the stomach. Retrospective studies suggest that when performing a subtotal gastrectomy,

a margin of 6 cm from the tumor mass proximally and 3 to 5.9 cm distally is necessary to minimize

anastomotic recurrence.59 Frozen section evaluation of resection margins may be obtained prior to

proceeding with reconstruction in order to improve the probability that R0 resection can be achieved.

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Figure 47-9. Surgical options for resection of gastric neoplasms. A: Subtotal gastrectomy with gastrojejunal reconstruction. B: Total

gastrectomy with esophagojejunostomy. C: Esophagogastrectomy with anastomosis in cervical or thoracic position.

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Figure 47-10. Postoperative radiograph after total gastrectomy with esophagojejunal anastomosis, showing esophagus (E) and

jejunum (J).

For lesions in the distal two-thirds of the stomach, distal subtotal gastrectomy is usually sufficient for

complete removal of the primary tumor. In contrast, lesions in the upper third of the stomach may

require total gastrectomy or esophagogastrectomy to encompass the tumor (Figs. 47-9 and 47-10). For

tumors involving the cardia without involvement of the gastroesophageal junction, some have

advocated proximal gastrectomy as an alternative to total gastrectomy with esophagojejunostomy with

the goal of preserving a gastric reservoir to lessen postoperative weight loss. This procedure does not

compromise oncologic outcomes,60,61 but there is a significantly higher incidence of severe reflux

esophagitis with proximal gastrectomy.37 Use of a jejunal interposition has been proposed to mitigate

reflux esophagitis, but quality-of-life data are conflicting.

Radical gastric operations can be performed with acceptable morbidity and low mortality rates in the

older age groups at greatest risk for gastric cancer. Mortality rates for total gastrectomy range from 3%

to 7%.62 There is some evidence that outcomes are superior at higher-volume centers. Defining what

constitutes a high-volume center is problematic, but one review suggests that hospitals with at least 21

gastric cancer resections per year may achieve optimal outcomes.63 Nutritional support in the

immediate postoperative period is an important adjunctive measure as patients resume oral intake,64

and many surgeons place a jejunal feeding tube at the time of total gastrectomy to ensure that optimal

enteral nutrition can be delivered in the postoperative period. Surgical reconstructions that interpose a

small intestinal reservoir between the esophagus and the jejunum have been advocated after total

gastrectomy, but a clear nutritional benefit has not been demonstrated.65–68

Because gastric cancer metastasizes so frequently to lymph nodes, radical extirpation of draining

lymph nodes has both therapeutic and staging implications.69 The value of routine-extended

lymphadenectomy beyond the perigastric lymph nodes in the treatment of gastric adenocarcinoma,

however, is controversial. The first favorable experience was reported from Japan.70,71 Resections in the

original Japanese system are shown in Table 47-3, and the current nomenclature used to define extent

of lymphadenectomy is shown in Table 47-4 and Figure 47-11. Only retrospective studies of extended

perigastric lymphadenectomy have been reported from Japan. Initial reports suggested an improvement

of approximately 10%, stage for stage, for patients with advanced disease treated with D2 or D3

operations.70–73 The benefits of extended lymphadenectomy have not been confirmed in non-Japanese

centers, and several randomized trials in Western centers have failed to show a survival benefit for

extended lymphadenectomy when the entire patient population was analyzed.74–78 Long-term (median

15-year) follow-up results from the Dutch trial of D1 versus D2 lymphadenectomy have shown a lower

gastric cancer–related death rate in the D2 group (37% vs. 48%) and lower rates of local and regional

recurrence.79 The significance of this finding is unclear given the absence of an overall survival benefit

and the long period of time it took for this difference to manifest. Improvements in adjuvant therapy

also complicate the interpretation of historical results of extended lymphadenectomy.

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MANAGEMENT

Table 47-3 Lymphadenectomy Resections in the Original System of the Japanese

Research Society for Gastric Cancer

The safety of extended lymphadenectomy is disputed. Data from a national Japanese registry indicate

a contemporary mortality of less than 1%.80 Low mortality risks have been reported from multiinstitutional trials conducted in Italy and Germany.78,81 Investigations from the United States, Britain,

and the Netherlands have been less optimistic, indicating increased short-term morbidity and in-hospital

mortality.74,75

MANAGEMENT

Table 47-4 Current Nomenclature Used to Describe the Extent of

Lymphadenectomy Performed in Conjunction with Gastrectomy

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Figure 47-11. Lymph node locations and groupings. D1 dissection: removal of N1 nodes. D2 dissection: removal of N1 and N2

nodes. D3 dissection: removal of N1, N2, and N3 nodes. D4 dissection: removal of N1–N4 nodes.79

Histologically positive lymph nodes are frequently present in the splenic hilum and along the splenic

artery, and routine splenectomy has been practiced in some centers. Splenectomy has not been

demonstrated to improve outcome for similarly staged patients.82,83 Likewise, resection of the tail or

body of the pancreas has not been demonstrated to improve survival. Thus, associated splenectomy or

pancreatosplenectomy is only beneficial when there is direct extension or bulky adenopathy at the

splenic hilum.84 Resection of adjacent organs may be required for local control if direct invasion has

occurred. In this circumstance, operative morbidity is increased and the long-term survival rate is

approximately 25%.85

In some centers in the United States, greater emphasis has been placed on the total number of nodes

removed and histologically examined rather than the location of the nodes (e.g., D1 vs. D2

lymphadenectomy). Current recommendations of the AJCC staging for gastric cancer suggest that a

minimum of 15 nodes be evaluated for accurate staging.51

Laparoscopic gastrectomy has also been reported for treatment of gastric malignancy, with

advantages of reduced pain, shorter hospitalization, and improved quality of life,86 and studies from

Japan, Korea, and Italy have demonstrated that distal, subtotal, and total gastrectomy with

lymphadenectomy is feasible with acceptable morbidity and mortality. However, the majority of the

patients in these studies had early gastric cancer.37 A meta-analysis of four small single-institution

randomized trials from Asia demonstrated lower nodal harvests with a laparoscopic approach for early

gastric cancer. Complication rates were lower in the laparoscopic group but did not translate into

differences in time to oral intake or length of stay.87 A single-institution Western randomized trial of

laparoscopic versus open subtotal gastrectomy for distal gastric cancer (both early and locally

advanced) did report equivalent lymph node retrieval (33.4 ± 7.4 in the open group vs. 30 ± 14.9 in

the laparoscopic group), as well as similar rates of perioperative morbidity and mortality. Five-year

overall and disease-free survival were also similar for both groups: 55.7% and 54.8% for the

laparoscopic group versus 58.9% and 57.3% for the open group.88 More recently, interim results of a

Korean multicenter randomized trial focused on early gastric cancer demonstrated equivalent

perioperative morbidity and mortality, but no data on oncologic outcomes have been published to

date.89 As such, there are still no published multi-institutional randomized data to confirm the oncologic

equivalency of laparoscopic gastrectomy as compared with the open approach.

Neoadjuvant and Adjuvant Therapies

5 Given the largely disappointing outcomes of locally advanced gastric cancer in Western countries,

significant interest has focused on the use of multimodality therapy. Several neoadjuvant and adjuvant

approaches have been explored. Although there is no consensus on the optimal approach, it is clear that

all patients with locally advanced disease should be considered for multimodality therapy. Two general

approaches are popular in the West.

Adjuvant chemoradiotherapy may be considered both for patients known to have locally advanced

disease from the outset as well as for those thought to have early gastric cancer who are subsequently

upstaged after surgical resection. The largest (n = 556) and most recent trial evaluating this approach

was the US Intergroup INT0116 trial, which compared surgical resection followed by 5-fluorouracil

(5FU), leucovorin, and external beam radiation versus resection alone in patients with gastric or EGJ

cancer.90 Most patients (69%) had T3/T4 tumors, and 85% had nodal metastases. Three-year overall

survival (50% vs. 41%) and 5-year overall survival (43% vs. 28%) were significantly improved with

multimodality therapy. Both local and distant failures were reduced by chemoradiation. The primary

criticism of this trial was that the extent of lymphadenectomy was not standardized, and less than D1

lymph node dissection was performed in 54% of the patients, which may have contributed to the poor

outcomes in the surgery-only group and led to overstatement of the true benefit of chemoradiation.

Additionally, one-third of patients were unable to complete their adjuvant chemoradiation due to

perioperative complications or treatment-associated toxicities. Finally, due to changes in the staging

system for gastric cancer, the benefit of this regimen for patients with T2N0 disease is questionable.

A more common approach in Europe is to administer preoperative chemotherapy, with or without

additional postoperative chemotherapy. The most influential trial evaluating this approach was the

Medical Research Council Adjuvant Gastric Infusional Chemotherapy (MAGIC) trial, which randomly

assigned 503 patients with gastric, distal esophageal, or EGJ adenocarcinomas to surgery plus

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