Case AnalysisGastric cancer is the second most common

cancer worldwide, with a frequency that varies

greatly across different geographic locations. It is a

relatively infrequent neoplasm in North America, yet

contributes substantially to the burden of cancer

deaths. In North America, gastric cancer is the third

most common gastrointestinal malignancy after

colorectal and pancreatic cancer, and the third most

lethal neoplasm overall. Despite the decreasing

worldwide incidence, gastric cancer accounts for 3%

to 10% of all cancer-related deaths. Although the survival rate for gastric cancer has

steadily improved in countries such as Japan, it has not in North America. The

substantial mortality associated with gastric cancer has prevailed despite technical

advances in surgery and the use of adjuvant therapy.

Ninety percent of all tumors of the stomach are malignant, and gastric adenocarcinoma

comprises 95% of the total number of malignancies. Curative therapy involves surgical

resection, most commonly a total or subtotal gastrectomy, with an accompanying

lymphadenectomy. The overall 5-year survival rate of patients with resectable gastric

cancer ranges from 10% to 30%

Stomach

The stomach begins at the gastroesophageal junction and ends

at the duodenum. The stomach has 3 parts: the uppermost part

is the cardia; the middle and largest part is the body, or fundus;

and the distal portion, the pylorus, connects to the duodenum.

These anatomic zones have distinct histologic features. The

cardia contains predominantly mucin-secreting cells. The fundus

contains mucoid cells, chief cells, and parietal cells. The pylorus is composed of mucus-

producing cells and endocrine cells.

The stomach wall is made up of 5 layers. From the lumen out, the layers include the

mucosa, the submucosa, the muscularis layer, the subserosal layer, and the serosal

layer. The peritoneum of the greater sac covers the anterior surface of the stomach. A

portion of the lesser sac drapes posteriorly over the stomach. The gastroesophageal

junction has limited or no serosal covering. The right portion of the anterior gastric

surface is adjacent to the left lobe of the liver and the anterior abdominal wall. The left

portion of the stomach is adjacent to the spleen, the left adrenal gland, the superior

portion of the left kidney, the ventral portion of the pancreas, and the transverse colon.

The site of stomach cancer is classified on the basis of its relationship to the long axis of

the stomach. Approximately 40% of cancers develop in the lower part, 40% in the

middle part, and 15% in the upper part; 10% involve more than one part of the organ.

Most of the decrease in gastric cancer incidence and mortality in the United States has

involved cancer in the lower part of the stomach; the incidence of adenocarcinoma in

the cardia has actually shown a gradual increase.

Case Definition/DescriptionThe diagnosis of gastric cancer requires histopathologic assessment of tissue or

cytologic assessment of gastric brushing/washes. Several classification systems have

been proposed to aid the description of gastric cancer either through macroscopic

features (Borrmann) or on the basis of microscopic configuration (Ming, Carniero, and

Goseki). The 2 most commonly used are the Lauren and World Health Organization

(WHO) systems.

The Lauren classification divides gastric cancer into 2 major histologic types: intestinal

or diffuse. This system describes tumors on the basis of microscopic configuration and

growth pattern. Diffuse-type cancers have noncohesive tumor cells diffusely infiltrating

the stroma of the stomach and often exhibit deep infiltration of the stomach wall with

little or no gland formation. Diffuse tumors may exhibit pronounced desmoplasia and

associated inflammation with relative sparing of the overlying mucosa. In comparison to

intestinal-type gastric cancers, diffuse-type gastric cancers are less related to

environmental influences, have increased in relative incidence, occur more often in

young patients, and are associated with a worse prognosis. These cancers are not

associated with intestinal metaplasia, are not localized to the antrum, and may arise out

of single-cell mutations within normal gastric glands, as is the case for the newly

described hereditary diffuse gastric carcinoma.

Intestinal-type cancers show recognizable gland formation similar in microscopic

appearance to colonic mucosa. Glandular formation ranges from well to poorly

differentiated tumors, which grow in expanding, rather than infiltrative,

patterns. Intestinal-type cancers are believed to arise secondary to chronic atrophic

gastritis.

H. pylori and autoimmune gastritis are the most common etiologic lesions that create an

environment conducive to gastric inflammation. If gastritis persists, gastric atrophy

occurs followed by intestinal metaplasia, which in turn may lead to dysplasia. Dysplasia

can arise in either the native gastric or “intestinalized” gastric epithelium. The term

adenoma is applied when dysplastic proliferation produces a macroscopic protruding

lesion and is described as tubular, tubulovillous, or villous adenoma

morphologically. Adenomas tend to occur in the distal stomach, often have a prolonged

precancerous phase and an expanding growth pattern. Carcinoma is diagnosed when

the tumor invades into the lamina propria or through the muscularis mucosae. Up to

80% of dysplastic lesions may progress to invasion.

The Lauren classification has proven useful in evaluating the natural history of gastric

carcinoma, especially with regard to incidence trends, clinicopathologic correlations,

and etiologic precursors. Despite the apparent use of the Lauren classification, the

WHO has revised the definition of gastric cancer to “malignant epithelial tumors of the

gastric mucosa with glandular differentiation.” The WHO system assigns grades to

adenocarcinoma based on the degree of resemblance to metaplastic intestinal tissue. It

categorizes the histologic patterns into 5 subtypes: adenocarcinoma (intestinal and

diffuse), papillary, tubular, mucinous, and signet-ring cell.

Clinical Manifestations

Gastric carcinoma often produces no specific symptoms when it is superficial and

potentially surgically curable, although up to 50% of patients may have nonspecific

gastrointestinal complaints such as dyspepsia. In Western countries, even with

endoscopic evaluation, gastric cancer is found in only 1% to 2% of patients with

dyspepsia. The lack of early pathognomic symptoms often delays the diagnosis.

Consequently, 80% to 90% of patients with gastric cancer present with locally advanced

or metastatic tumors that have poor rates of resectability. Patients may present with

anorexia and weight loss (95%) as well as abdominal pain that is vague and insidious in

nature. Nausea, vomiting, and early satiety may occur with bulky tumors that obstruct

the gastrointestinal lumen or infiltrative lesions that impair stomach

distension. Ulcerated tumors may cause bleeding that manifest as hematemesis,

melena, or massive upper gastrointestinal hemorrhage.

Physical examination of early gastric cancer is usually uninformative. Patients with

advanced tumors may present with a palpable abdominal mass, cachexia, bowel

obstruction, ascites, hepatomegaly, and lower extremity edema. Peritoneal seeding may

cause involvement of the ovaries (Krukenberg tumor) or pelvic cul-de-sac (Blumer's

shelf) detectable on rectal examination. Metastasis may manifest as an enlarged

supraclavicular lymph node (Virchow's node), left axillary lymph node (Irish's node), or a

periumbilical lymph node (Sister Mary-Joseph's node).

In the early stages of stomach cancer, you may have very few symptoms. These may

include:

Indigestion and stomach discomfort

A bloated feeling after eating

Mild nausea

Loss of appetite

Heartburn

These symptoms are similar to those caused by a peptic ulcer. If you are experiencing

any of these symptoms you should see a doctor so that a proper diagnosis can be

made and timely treatment given. A stomach cancer can grow very large before it

causes other symptoms.

In more advanced cancer, you may have:

Discomfort in the upper or middle part of the abdomen.

Blood in the stool (which appears as black, tarry stools).

Vomiting or vomiting blood.

Weight loss.

Pain or bloating in the stomach after eating.

Weakness or fatigue associated with mild anemia (a deficiency in red blood

cells).

EpidemiologyRace

The rates of gastric cancer are higher in Asian and South American countries than in

the United States. Japan, Chile, and Venezuela have developed a very rigorous early

screening program that detects patients with early stage disease (ie, low tumor burden).

These patients appear to do quite well. In fact, in many Asian studies, patients with

resected stage II and III disease tend to have better outcomes than similarly staged

patients treated in Western countries. Some researchers suggest that this reflects a

fundamental biologic difference in the disease as it manifests in Western countries.

In the United States, Asian and Pacific Islander males and females have the highest

incidence of stomach cancer, followed by black, Hispanic, white, American Indian, and

Inuit populations.

Sex

In the United States, gastric cancer affects slightly more men than women; the

American Cancer Society estimates that in 2009, 12,820 new cases will occur in men

and 8,310 in women. Worldwide, however, gastric cancer rates are about twice as high

in men as in women.

Age

Most patients are elderly at diagnosis. The median age for gastric cancer in the United

States is 70 years for males and 74 years for females. The gastric cancers that occur in

younger patients may represent a more aggressive variant or may suggest a genetic

predisposition to development of the disease.

Causes

Gastric cancer may often be multifactorial, involving both inherited predisposition and

environmental factors. Environmental factors implicated in the development of gastric

cancer include diet, Helicobacter pyloriinfection, previous gastric surgery, pernicious

anemia, adenomatous polyps, chronic atrophic gastritis, and radiation exposure.

Diet

A diet rich in pickled vegetables, salted fish, salt, and smoked meats correlates with an

increased incidence of gastric cancer.

A diet that includes fruits and vegetables rich in vitamin C may have a protective effect.

Smoking

Smoking is associated with an increased incidence of stomach cancer in a dose-

dependent manner, both for number of cigarettes and for duration of smoking.

Smoking increases the risk of cardiac and noncardiac forms of stomach

cancer. Cessation of smoking reduces the risk.

A meta-analysis of 40 studies estimated that the risk was increased by approximately

1.5- to 1.6-fold and was higher in men.

Helicobacter pylori infection

Chronic bacterial infection with H pylori is the strongest risk factor for stomach cancer.

H pylori may infect 50% of the world's population, but many fewer than 5% of infected

individuals develop cancer. It may be that only a particular strain of H pylori is strongly

associated with malignancy, probably because it is capable of producing the greatest

amount of inflammation. In addition, full malignant transformation of affected parts of the

stomach may require that the human host have a particular genotype of interleukin (IL)

to cause the increased inflammation and an increased suppression of gastric acid

secretion. For example, IL-17A and IL-17F are inflammatory cytokines that play a critical

role in inflammation. Wu et al found that carriage of IL-17F 7488GA and GG genotypes

were associated with an increased risk of gastric cancer.

H pylori infection is associated with chronic atrophic gastritis, and patients with a history

of prolonged gastritis have a sixfold increased risk of developing gastric cancer.

Interestingly, this association is particularly strong for tumors located in the antrum,

body, and fundus of the stomach but does not seem to hold for tumors originating in the

cardia.

Previous gastric surgery

Previous surgery is implicated as a risk factor. The rationale is that surgery alters the

normal pH of the stomach, which may in turn lead to metaplastic and dysplastic

changes in luminal cells.

Retrospective studies demonstrate that a small percentage of patients who undergo

gastric polyp removal have evidence of invasive carcinoma within the polyp. This

discovery has led some researchers to conclude that polyps might represent

premalignant conditions.

Genetic factors

Some 10% of stomach cancer cases are familial in origin.

Genetic factors involved in gastric cancer remain poorly understood, though specific

mutations have been identified in a subset of gastric cancer patients. For example,

germline truncating mutations of the E-cadherin gene (CDH1) are detected in 50% of

diffuse-type gastric cancers, and families that harbor these mutations have an

autosomal dominant pattern of inheritance with a very high penetrance.

Other hereditary syndromes with a predisposition for stomach cancer include hereditary

nonpolyposis colorectal cancer, Li-Fraumeni syndrome, familial adenomatous polyposis,

and Peutz-Jeghers syndrome.

Epstein-Barr virus

The Epstein-Barr virus may be associated with an unusual (< 1%) form of stomach

cancer, lymphoepithelioma-like carcinoma.

Pernicious anemia

Pernicious anemia associated with advanced atrophic gastritis and intrinsic factor

deficiency is a risk factor for gastric carcinoma.

Gastric ulcers

Gastric cancer may develop in the remaining portion of the stomach following a partial

gastrectomy for gastric ulcer.

Benign gastric ulcers may themselves develop into malignancy.

Obesity

Obesity increases the risk of gastric cardia cancer.

Radiation exposure

Survivors of atomic bomb blasts have had an increased rate of stomach cancer. Other

populations exposed to radiation may also have an increased rate of stomach cancer.

Bisphosphonates

A large cohort study examined whether use of oral bisphosphonates was associated

with an increased risk of esophageal or gastric cancers. No significant difference was

observed for increased risk of esophageal or gastric cancers between the

bisphosphonate cohort and the control group.

Diagnostic ProceduresEndoscopy is regarded as the most sensitive and specific diagnostic method in

patients suspected of harboring gastric cancer. Endoscopy allows direct visualization of

tumor location, the extent of mucosal involvement, and biopsy (or cytologic brushings)

for tissue diagnosis. When combined with endoscopy and radiologic modalities,

endoscopic ultrasound (EUS) can maximize tumor staging by providing information

about depth of tumor invasion and assess the extent of perigastric lymphadenopathy.

Willis et al suggest that EUS is currently the most valuable diagnostic tool for

preoperative staging of gastric cancer (82% accuracy in assessing the depth of tumor

invasion) and for determining tumor resectability. Karpeh et al suggest the combined

use of EUS and laparoscopic staging facilitates patient selection by providing

information about tumor depth and perigastric lymph node involvement. They do

caution, however, that EUS is less accurate (50–87%) in determining lymph node

status.

Esophagogastroduodenoscopy has a diagnostic accuracy of 95%. This relatively

safe and simple procedure provides a permanent color photographic record of the

lesion. This procedure is also the primary method for obtaining a tissue diagnosis of

suspected lesions. Biopsy of any ulcerated lesion should include at least 6 specimens

taken from around the lesion because of variable malignant transformation. In selected

cases, endoscopic ultrasound may be helpful in assessing depth of penetration of the

tumor or involvement of adjacent structures.

An upper gastrointestinal barium study (UGI) involves the instillation of liquid barium

into the stomach and a combination of 4 techniques: barium-filled evaluation, double-

contrast, mucosal relief views, and compression views of the stomach. The procedure

permits identification of mucosal irregularities. Halvorsen et al have suggested that,

although endoscopy is increasingly becoming the method of choice, the 2 methods are

complementary and have equivalent diagnostic efficacy.

Computed tomography (CT) is the most frequently used modality for staging gastric

cancer. CT can detect liver metastases, regional and distant lymphadenopathy, and can

predict direct invasion of adjacent structures. Kuntz et al suggested that CT has a

sensitivity of 88% for tumor detection. The ability of CT to accurately determine either

tumor infiltration (T stage 58%) or perigastric lymph node status (25–86%) varied widely

and was not considered a reliable predictor of disease extent in several studies.

Magnetic resonance imaging (MRI) has had limited use in the staging of gastric

cancer primarily as a result of difficulties with motion artifact, cost, time required for

examination, and lack of an appropriate oral contrast agent. However, in a recent study

comparing MRI with CT, Sohn et aldocumented advanced gastric cancers were easily

detected with both techniques. They showed MRI was slightly better than CT in the T

staging of gastric cancer. Similarly, Kim et al documented T staging accuracy of MRI

was superior to CT (81% vs. 73%, P <0.05). This study suggested MRI was prone to

overstaging pathologic tumor thickness. Overall T staging accuracy has been reported

to be between 73% and 88%. The use of MRI in N staging has been hindered by the

same difficulties encountered with CT staging, in which nodal status is judged on the

basis of lymph node size. Several studies show the accuracy of MRI nodal staging is

inferior to CT staging (65% vs. 73% respectively, P >0.05), with both techniques tending

to understage nodal status. Finally, Motohara et al reviewed the ability of MRI to detect

extragastric metastases and concluded MRI had a greater sensitivity than CT in

detecting liver, bone, and peritoneal dissemination. The obvious advantage of MRI

staging lies predominantly with its multiplanar capabilities, lack of ionizing radiation, and

use in patients with contrast hypersensitivity.44 Other staging modalities include

abdominal ultrasound, positron emission tomography scans, and staging laparoscopy.

Endoscopic ultrasound allows for a more precise preoperative assessment of the

tumor stage. Endoscopic sonography is becoming increasingly useful as a staging tool

when the CT scan fails to find evidence of T3, T4, or metastatic disease. Institutions that

favor neoadjuvant chemoradiotherapy for patients with locally advanced disease rely on

endoscopic ultrasound data to improve patient stratification.

Laboratory StudiesThe goal of obtaining laboratory studies is to assist in determining optimal therapy.

A CBC count can identify anemia, which may be caused by bleeding, liver dysfunction,

or poor nutrition. Approximately 30% of patients have anemia.

Electrolyte panels and liver function tests also are essential to better characterize the

patient's clinical state.

Carcinoembryonic antigen (CEA) is increased in 45-50% of cases.

Cancer antigen (CA) 19-9 is elevated in about 20% of cases.

Histologic FindingsAdenocarcinoma of the stomach constitutes 90-95% of all gastric malignancies. The

second most common gastric malignancies are lymphomas. Gastrointestinal stromal

tumors formerly classified as either leiomyomas or leiomyosarcomas account for 2% of

gastric neoplasms. Carcinoids (1%), adenoacanthomas (1%), and squamous cell

carcinomas (1%) are the remaining tumor histologic types.

Adenocarcinoma of the stomach is subclassified according to histologic description as

follows: tubular, papillary, mucinous, or signet-ring cells, and undifferentiated lesions.

Pathology specimens are also classified by gross appearance. In general, researchers

consider gastric cancers ulcerative, polypoid, scirrhous (ie, diffuse linitis plastica),

superficial spreading, multicentric, or Barrett ectopic adenocarcinoma.

Researchers also employ a variety of other classification schemes. The Lauren system

classifies gastric cancer pathology as either Type I (intestinal) or Type II (diffuse). An

appealing feature of classifying patients according to the Lauren system is that the

descriptive pathologic entities have clinically relevant differences.

Intestinal, expansive, epidemic-type gastric cancer is associated with chronic atrophic

gastritis, retained glandular structure, little invasiveness, and a sharp margin. The

pathologic presentation classified as epidemic by the Lauren system is associated with

most environmental risk factors, carries a better prognosis, and shows no familial

history.

The second type, diffuse, infiltrative, endemic cancer, consists of scattered cell clusters

with poor differentiation and dangerously deceptive margins. Margins that appear clear

to the operating surgeon and examining pathologist often are determined retrospectively

to be involved. The endemic-type tumor invades large areas of the stomach. This type

of tumor is also not recognizably influenced by environment or diet, is more virulent in

women, and occurs more often in relatively young patients. This pathologic entity is

associated with genetic factors (such as E-cadherin), blood groups, and a family history

of gastric cancer.

StagingThe 2006 American Joint Committee on Cancer (AJCC) Cancer Staging

Manual presents the following TNM classification system for staging gastric carcinoma:[16]

Primary tumor

TX - Primary tumor (T) cannot be assessed

T0 - No evidence of primary tumor

Tis - Carcinoma in situ, intraepithelial tumor without invasion of lamina propria

T1 - Tumor invades lamina propria or submucosa

T2 - Tumor invades muscularis propria or subserosa

T3 - Tumor penetrates serosa (ie, visceral peritoneum) without invasion of

adjacent structures

T4 - Tumor invades adjacent structures

Regional lymph nodes

NX - Regional lymph nodes (N) cannot be assessed

N0 - No regional lymph node metastases

N1 - Metastasis in 1-6 regional lymph nodes

N2 - Metastasis in 7-15 regional lymph nodes

N3 - Metastasis in more than 15 regional lymph nodes

Distant metastasis

MX - Distant metastasis (M) cannot be assessed

M0 - No distant metastasis

M1 - Distant metastasis

GradeGrade refers to the degree of differentiation of tumor cells and has been shown to

correlate with the aggressiveness of the neoplasm. Pathologic grade classifies tumors

into 1 of 3 categories: well, moderately, or poorly differentiated/anaplastic. Although

grade is routinely reported in pathologic reports, the prognostic impact in gastric cancer

remains to be elucidated, because several retrospective studies have failed to identify

grade as an independent prognostic factor.

SizeSize of the primary tumor, measured in greatest dimension, has been identified in

several retrospective studies to be of prognostic significance. These studies suggest

increasing tumor diameter is associated with lymph node metastasis and 5-year

survival.

Tumor LocationThe influence of tumor location has several important implications in the treatment and

prognosis of gastric cancer. Although there are studies that have shown no association

between location and prognosis, several studies have shown that gastric carcinoma of

the proximal third of the stomach represents a distinct clinical entity with prognostic

implications. A recent study suggested proximal tumors have a higher frequency of

larger size, extensive wall penetration, venous invasion, nodal metastasis, and more

advanced stage, with an overall worse survival relative to distal tumors. Proximal tumors

may require a different surgical approach based on a potentially different biologic

behavior.

Lymphatic and Vascular InvasionThe presence of tumor emboli within peritumor vessels and lymphatics has recently

generated interest as a potential independent prognostic indicator. Studies have

demonstrated that lymph node involvement is a statistically significant predictor of

survival, and the presence of tumor emboli significantly influences tumor recurrence and

death after curative resection. Yokota et al found lymphatic invasion retained its

significance (relative risk, 11.43; CI, 2.63–49.55), even in competition with other

significant variables in multivariate analysis. These findings were recently supported in a

report by Hyung et al,1 who reported a poor prognosis associated with advanced T

stage and the presence of vascular invasion. Kooby et al similarly demonstrated, in

adequately staged node-negative patients, vascular invasion was an independent

negative prognostic factor and may be a predictor of biologic aggressiveness.

Surgical CareType of surgery

In general, most surgeons in the United States perform a total gastrectomy (if required

for negative margins), an esophagogastrectomy for tumors of the cardia and

gastroesophageal junction, and a subtotal gastrectomy for tumors of the distal stomach.

A randomized trial comparing subtotal with total gastrectomy for distal gastric cancer

revealed similar morbidity, mortality, and 5-year survival rates.

Because of the extensive lymphatic network around the stomach and the propensity for

this tumor to extend microscopically, traditional teaching is to attempt to maintain a 5-

cm surgical margin proximally and distally to the primary lesion.

Lymph node dissection

The extent of the lymph node dissection is somewhat controversial.

Many studies demonstrate that nodal involvement indicates a poor prognosis, and more

aggressive surgical approaches to attempt to remove involved lymph nodes are gaining

popularity.

Two randomized trials compared D1 (perigastric lymph nodes) with D2 (hepatic, left

gastric, celiac, and splenic arteries, as well as those in the splenic hilum)

lymphadenectomy in patients who were treated for curative intent. In the largest of

these trials, postoperative morbidity (43% versus 25%) and mortality (10% versus 4%)

were higher in the D2 group.

Most critics argue that these studies were underpowered and overestimated benefit. In

addition, a recent randomized trial found a much lower rate of complications than those

earlier trials. Degiuli et al reported complication rates of 17.9% and 12% with D2 and D1

dissections, respectively—a statistically insignificant difference— and postoperative

mortality rates of 2.2% and 3%, respectively.

D2 dissections are recommended by the National Comprehensive Cancer Network over

D1 dissections. A pancreas- and spleen-preserving D2 lymphadenectomy is suggested,

as it provides greater staging information, and may provide a survival benefit while

avoiding its excess morbidity when possible

Surgery, called gastrectomy, to remove all or part of the stomach, as well as some of

the tissue surrounding the stomach.

Chemotherapy.Radiation therapy.

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