perioperative chemotherapy or surgery alone.91 Planned chemotherapy consisted of three preoperative

and three postoperative cycles of epirubicin, cisplatin, and 5FU (ECF regimen). Patients with T2 and

higher tumors were eligible. This study demonstrated a significant survival benefit in patients receiving

perioperative chemotherapy (5-year survival 36% vs. 23%), with reduced local and distant failures.

Extent of lymphadenectomy was improved as compared to the Intergroup trial, but there were

significantly more patients with T1/2 tumors and N0/1 disease in the perioperative chemotherapy

group, suggesting a baseline imbalance in prognosis. Additionally, only 42% of patients completed all

courses of chemotherapy. Finally, as with the Intergroup trial it is unclear whether T2N0 patients are as

likely to benefit from this approach as those with more advanced disease. Despite the limitations of

these studies, the improved survival observed in both trials makes it clear that a multimodality

approach is superior to surgery alone. Numerous ongoing studies are investigating the relative benefits

of various chemotherapeutic regimens as well as the incremental benefit of chemoradiotherapy versus

chemotherapy alone. Targeted therapies are also being investigated. For example, the Trastuzumab for

Gastric Cancer (ToGA) trial demonstrated a modest but statistically significant survival benefit with the

addition of trastuzumab to cytotoxic chemotherapy in patients with HER2-positive gastric cancer.92

Patients with locally advanced resectable gastric cancer are optimally treated in a center where a

collaborative multidisciplinary treatment approach can be devised and executed (Algorithm 47-1).

Palliative Treatment

When preoperative evaluation demonstrates disseminated disease, palliation of symptoms becomes a

primary consideration. Palliation does not usually require surgery. Obstruction and bleeding can be

managed nonoperatively with endoscopic techniques or radiotherapy in selected patients. Dysphagia

and bleeding caused by proximal lesions can also be alleviated endoscopically (laser therapy or stenting)

in the majority of patients. Nonetheless, for a minority of patients, surgical palliation may be indicated.

In the setting of metastatic gastric cancer, palliative resection does not improve survival. Noncurative

resection may be indicated, for example, in the setting of intractable bleeding from the primary tumor.

Surgical palliation of obstructive symptoms (resection or gastrojejunostomy) should generally be

reserved for cases in which less invasive methods are contraindicated, technically infeasible, or

unsuccessful. In addition to radiotherapy and endoscopic ablation or stenting, placement of a feeding

jejunostomy tube with or without venting gastrostomy may be used to palliate gastric outlet

obstruction, especially in patients with limited life expectancy.

Algorithm 47-1. Treatment of gastric adenocarcinoma.

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GASTRIC LYMPHOMA

Clinical Features

The stomach is the site of more than half of gastrointestinal lymphomas and is the most common organ

involved in extranodal lymphomas. Non-Hodgkin lymphomas account for approximately 5% of

malignant gastric tumors; lymphoma represents an increasing proportion of gastric neoplasms diagnosed

currently. Patients are considered to have primary gastric lymphoma if initial symptoms are gastric and

the stomach is exclusively or predominantly involved with the tumor. Patients who do not fulfill these

criteria are considered to have secondary gastric involvement from systemic lymphoma.

Gastric lymphoma is distinctly uncommon in children and young adults. The peak incidence is in the

sixth and seventh decades. Symptoms are usually indistinguishable from those of peptic ulcer disease

and gastric adenocarcinoma. Epigastric pain, weight loss, anorexia, nausea, and vomiting are common.93

Systemic B symptoms such as fever and night sweats occur in a minority of patients but may be

suggestive of the diagnosis. Although gross bleeding is uncommon, occult hemorrhage and anemia are

observed in more than half of patients. Patients rarely have spontaneous perforation.

Diagnosis

Radiologic findings are similar to those for adenocarcinoma (gastric thickening and lymphadenopathy).

Endoscopic examination is the diagnostic method of choice. The endoscopic appearance of lesions may

be ulcerated, polypoid, or infiltrative, and this morphology may be further characterized by EUS.

Gastric lymphoma is most commonly localized to the middle or distal stomach and unusually involves

the proximal stomach, in contrast to gastric adenocarcinoma. Endoscopic biopsy, combined with

endoscopic brush cytology and EUS, provides positive diagnosis in 90% of cases. Submucosal growth

without ulceration of the overlying mucosa can occasionally render endoscopic biopsy nondiagnostic.

EUS-guided biopsy is useful in this circumstance.

Appropriate staging should search for evidence of systemic disease. CT of the chest and abdomen (to

detect lymphadenopathy), bone marrow biopsy, and biopsy of enlarged peripheral lymph nodes are all

appropriate.

Mucosa-Associated Lymphoid Tissue

The concept that low-grade gastric lymphomas have features resembling mucosa-associated lymphoid

tissue (MALT) is a major advance in the understanding of gastric lymphomas. The gastric submucosa

does not ordinarily contain lymphoid tissue, and the development of lymphoid tissue resembling small

intestinal Peyer patches is believed to occur in response to infection with H. pylori.94 A number of

observations support a causal relationship between chronic H. pylori infection and gastric lymphoma

development. H. pylori is present in the stomachs of more than half of patients with gastric lymphoma 95

and 90% of those with gastric MALT lymphoma.96 As with gastric adenocarcinoma, geographic regions

with a high prevalence of H. pylori also have a high incidence of gastric lymphoma. Infection with H.

pylori has been noted to precede development of gastric lymphoma.97

Gastric MALT lymphoma is postulated to begin with chronic inflammation due to infection with H.

pylori. Chronic gastritis leads to the accumulation of CD4+ lymphocytes and B cells in the gastric

lamina propria. H. pylori-derived antigens drive T-cell activation, interleukin-2 (IL-2) release, and B-cell

proliferation.98 Progressive genetic rearrangements lead to IL-2–independent B-cell proliferation. With

cumulative genetic defects, low-grade MALT lymphoma progresses to high-grade disease.

Low-grade MALT lymphomas resemble Peyer patches. Lymphoma cells invade between follicles and

into gastric epithelium; invasion of gastric glands forms characteristic lymphoepithelial lesions. Lowgrade lesions are often multifocal. Low-grade MALT lesions are less likely than high-grade tumors to

invade transmurally, involve perigastric lymph nodes, or invade adjacent organs.97 Approximately 40%

of gastric lymphomas are low-grade MALT lymphomas.99

6 The concept that low-grade lymphoma depends on continued H. pylori antigenic stimulation

supports eradication of H. pylori with antibiotics as first-line antineoplastic therapy. Complete regression

of low-grade gastric MALT lymphomas with antibiotic treatment has been reported in 70% to 100% of

cases.100,101 The median time to complete response is 5 months.102 Most patients with partial responses

were subsequently determined also to have foci of high-grade lymphoma. Radiation and chemotherapy

have been proposed as salvage for antibiotic treatment failures or for the minority of patients with H.

pylori-negative gastric MALT lymphoma.

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Non-MALT Lymphomas

Most non-MALT gastric lymphomas are diffuse large B-cell lymphomas (DLBCL), including those that

were previously called “high-grade MALT lymphomas.” DLBCL typically exhibit more aggressive

behavior and worse prognosis than MALT lymphomas. Other histologies, such as mantle cell, follicular,

and peripheral T-cell lymphomas can also be seen. Survival for gastric lymphoma is closely linked to

stage at diagnosis (Fig. 47-12). In the past, a multimodality treatment program was used in most centers

for primary gastric lymphomas, with gastrectomy as the first step in the therapeutic strategy.103 This

approach evolved empirically, without prospective data to support it. Several advantages of this

approach had been cited: (a) more accurate histologic evaluation was possible; (b) in cases with

localized tumor, the procedure could be curative; and (c) gastrectomy eliminated the risk of lifethreatening hemorrhage or perforation which may occur with the treatment of tumors involving the full

thickness of the gastric wall.104 However, the role of gastrectomy for both staging and treatment of

gastric lymphoma has diminished significantly, based in part on results of a randomized trial

demonstrating superior outcomes with CHOP (cyclophosphamide, doxorubicin, vincristine, and

prednisone) chemotherapy than with surgery, surgery plus radiotherapy, or surgery with CHOP (Fig.

47-13).105. It has also been recognized that the incidence of perforation during chemotherapy is only

5%. Most patients are currently treated with chemotherapy (commonly CHOP with rituximab) with or

without radiotherapy. Surgical intervention is generally reserved for complications such as obstruction,

bleeding, or perforation.

Figure 47-12. Survival with gastric lymphoma, by stage.

Figure 47-13. Relapse-free survival by treatment assignment for primary gastric diffuse large B-cell lymphoma.

GASTRIC CARCINOIDS

Gastric carcinoid tumors were previously considered to be very rare tumors, but more recent studies

have reported that as many as 10% to 30% of all carcinoids occur in the stomach, and they account for

at least 1% of all gastric neoplasms.106 Most patients with small gastric carcinoids are asymptomatic,

and these tumors are most commonly diagnosed incidentally. Occasionally, however, larger tumors can

present with abdominal pain, bleeding, or symptoms related to the secretion of bioactive substances

which can be produced by the tumor. When viewed endoscopically at an early stage, carcinoids are

reddish-pink to yellow submucosal nodules in the proximal stomach. Endoscopic biopsy is usually

diagnostic if deep enough to sample submucosal tumor cells.

Four types of gastric carcinoids have been described. Type 1 is the most common (70% to 80%) and is

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associated with chronic atrophic gastritis and pernicious anemia. These tumors tend to be small (<1

cm) and multiple, and their behavior indolent. When they are less than 2 cm in size, they metastasize

less than 10% of the time.107 They can typically be followed and removed endoscopically, but surgery

may be necessary for larger or very numerous tumors. Type 2 tumors comprise approximately 5% of

gastric carcinoids and occur in patients with Zollinger–Ellison syndrome (gastrinomas), often in the

setting of multiple endocrine neoplasia type 1 (MEN1). Like type 1 tumors, they are often small,

multiple, and indolent, and they can be treated endoscopically for the most part. Both type 1 and type 2

gastric carcinoid tumors are associated with hypergastrinemia. Type 1 and 2 gastric carcinoids arise

from enterochromaffin-like (ECL) cells, which mediate the secretion of histamine and in turn stimulate

parietal cells to secrete acid. Hypergastrinemia (due to chronic atrophic gastritis in type 1 and

gastrinoma in type 2) is thought to cause ECL cell hyperplasia and lead to the development of gastric

carcinoids over time.108

Type 3 lesions account for 20% of gastric carcinoids. Type 3 gastric carcinoids tend to be larger,

solitary lesions. They are associated with normal gastrin levels and behave much more aggressively

than other gsatric carcinoid tumors.108 Metastases are common, and these tumors can cause an atypical

carcinoid syndrome. Type 3 carcinoids are best dealt with by resection and lymphadenectomy, the

extent of which depends on the size of the tumor.

GASTROINTESTINAL STROMAL TUMORS OF THE STOMACH

Gastrointestinal stromal tumors (GISTs) were historically misclassified as leiomyomas,

leiomyosarcomas, and leiomyoblastomas due to a mistaken belief that they arose from the smooth

muscle in the bowel wall. However, it is now recognized that GISTs represent a distinct mesenchymal

tumor type, and actually arise from the interstitial cells of Cajal, intestinal pacemaker cells located in

and around the myenteric plexus in the bowel wall. While GISTs can arise anywhere within the

gastrointestinal tract, approximately 50% of these tumors are found in the stomach. With a slight male

predominance, GISTs are typically present in middle-aged and elderly individuals, with a median age at

presentation of approximately 60. They are typically asymptomatic and are most commonly identified

incidentally during endoscopy performed for other reasons. Their endoscopic appearance is that of a

submucosal mass with normal overlying mucosa. If these tumors become large, however, they may

present with symptoms of abdominal pain and bleeding. GISTs frequently have prominent extraluminal

growth patterns, and central necrosis is common as these tumors become very large and outgrow their

blood supply (Fig. 47-14). If the majority of the growth is extraluminal, endoscopic examination may be

unrevealing or only demonstrate umbilication of the mucosa suggestive of an underlying mass. EUS or

CT imaging may be helpful for diagnosis in these cases. With large tumors, symptoms related to mass

effect may occur. Additionally, ulceration of the overlying gastric mucosa may occur with tumor

necrosis, and these patients may present with significant and intermittent gastrointestinal hemorrhage.

Figure 47-14. CT scan of GIST of stomach arising from lesser curvature. The arrow indicates central tumor necrosis. The lesion

caused mucosal erosion with gastrointestinal hemorrhage.

7 The molecular hallmark of GISTs is overexpression of the CD117 antigen, which is part of the KIT

transmembrane receptor tyrosine kinase. Mutations in c-kit, the proto-oncogene that encodes KIT, can

lead to constitutive activation of the receptor and abnormal cell proliferation. Approximately 95% of

GISTs overexpress KIT. Of those that do not, many have activating mutations in platelet-derived growth

factor receptor alpha (PDGFRA), another receptor tyrosine kinase. However, some GISTs lack mutations

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in either of these genes, and many of these are characterized by inactivating mutations in the succinate

dehydrogenase (SDH) complex. The molecular pathogenesis of GIST is important because of the

availability of tyrosine kinase inhibitors (TKIs), such as imatinib and sunitinib, which can inhibit GIST

cell growth. However, GISTs that lack KIT or PDGFRA mutations, as well as those with certain types of

KIT or PDGFRA mutations, may be variably resistant to TKI therapy.

All GISTs should be considered potentially malignant, especially those >1 cm in size.109 Tumor size

and mitotic index are the most important prognostic variables (Table 47-5).110 Site of origin is also

prognostic, with gastric GISTs behaving less aggressively than intestinal GISTs.111 For localized GISTs,

surgical resection is the treatment of choice. When GISTs do metastasize, they do so by a hematogenous

route (most commonly to peritoneal surfaces and the liver). Therefore, associated lymphadenectomy is

typically not performed at the time of gastric resection for GIST. Additionally, unlike adenocarcinoma,

GISTs do not present with an intramural growth pattern and thus gross margins of 1 to 2 cm are deemed

adequate for resection of a GIST. Ultimately the goal of resection is a negative microsopic margin. If the

tumor involves adjacent structures, then en bloc resection of nonvital structures should be performed

whenever possible. Due to the less radical nature of surgery required for appropriate oncologic

resection of these tumors as compared to adenocarcinoma of the stomach, minimally invasive surgical

techniques have become widely accepted as an appropriate and acceptable operative approach for these

tumors. A nomogram has been developed to allow prediction of outcomes following surgical resection

of GISTs.112

For patients with metastatic or locally advanced, unresectable GISTs, imatinib is first-line therapy.

Although most patients will respond to imatinib therapy, development of resistance is common, likely

due to selection of clones with secondary KIT mutations.113,114 These patients may be managed either

with imatinib dose escalation or by using another TKI (e.g., sunitinib). Imatinib is also indicated in the

adjuvant setting for tumors at high risk for recurrence. The ACOSOG Z9001 trial evaluated the efficacy

of 1 year of adjuvant imatinib versus placebo in patients with resected GIST ≥3 cm in size and KITpositive.115 Recurrence-free survival at 1 year was significantly lower in the imatinib arm (98% vs.

83%). No overall survival difference was shown, likely because patients were allowed to cross over to

the imatinib arm after the study was unblinded. The Scandinavian Sarcoma Group evaluated the effect

of 1 versus 3 years of adjuvant imatinib after resection of high-risk GIST and found differences in 5-year

recurrence-free survival (66% vs. 49%) and overall survival (92% vs. 82%).116 Based on these data, 3

years of imatinib therapy are recommended after resection of high-risk GIST. Rates of recurrence after

discontinuation of imatinib therapy are similar to those in untreated patients, suggesting that TKI

therapy may simply be delaying recurrences rather than actually preventing them. The use of imatinib

in the neoadjuvant setting has been reported in retrospective series and was found to be safe in a phase

II trial, but there are currently insufficient prospective data to guide this treatment approach.

CLASSIFICATION AND STAGING

Table 47-5 Risk of Aggressive Behavior in Gastrointestinal Stromal Tumors

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3. Haenszel W, Kurihara M. Studies of Japanese migrants. I. Mortality from cancer and other diseases

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