Worldwide, gastric cancer affects almost 800,000

individuals per year

1
and is most commonly seen in
eastern Asia. In North America, adenocarcinoma of
the stomach occurs less frequently. The clinical
manifestations and physical findings of gastric can-
cer are nonspecific and overlap with benign disease,
frequently resulting in a delay in diagnosis. As out-
come is largely related to stage, patients in the
United States, as a whole, have poor outcomes due
to their late presentation.
2,3
Surgical resection remains the treatment of
choice. However, improvements in multimodal
chemotherapy and radiotherapy have influenced
treatment algorithms. This therapy can be adminis-
tered prior to resection (neo-adjuvant or induction)
or postoperatively. Increasing interest in the neo-
adjuvant approach has required the development of
accurate and cost-efficient preoperative staging.
Currently, gastric cancer staging is based on the
tumor-node-metastasis (TNM) system and relies on
tumor depth, nodal spread, and distant metastases.
Endoscopy and biopsy are the most common
method of initial diagnosis. Computed tomography
is the most accepted radiologic modality for diag-
nosing advanced disease. Other methods for staging
disease include endoscopic ultrasonography, mag-
netic resonance imaging, and positron emission
tomography. Laparoscopy and laparoscopic ultra-
sonography are minimally invasive procedures that
have recently become important components in the
staging algorithm for gastric cancer patients. Inves-
tigational modalities include peritoneal-fluid cytol-
ogy and molecular staging techniques.
DIAGNOSIS OF GASTRIC CANCER
Clinical Manifestations
Two-thirds of patients with gastric cancer in the
United States will present with advanced disease.
4,5
Early symptoms, including nonspecific abdominal
pain and dyspepsia, are usually ignored or treated
with empiric antiulcer therapy. As the disease pro-
gresses, the symptoms become more pronounced and
commonly include anorexia, weight loss, and nausea.
In a review of more than 18,000 patients with gastric
cancer by the American College of Surgeons, over
half of the patients presented with weight loss and
abdominal pain.
5
Nausea, anorexia, and dysphagia
were noted in approximately 30 percent of patients,
and melena was noted in 25 percent. Approximately
20 percent of patients had a prior history of gastric
ulcer. Despite the nonspecific nature of the present-
ing symptoms, some complaints may suggest the
location of the primary tumor. For instance, dyspha-
gia is usually associated with tumors of the cardia or
the gastroesophageal junction. Antral tumors can be
associated with gastric-outlet obstruction, and early
satiety is seen with a diffusely infiltrating tumor that
produces a nondistensible gastric wall.
The majority of patients show no significant
findings on examination, and the development of
237
12
Diagnosis and Staging
of Gastric Cancer
MARTIN R. WEISER, MD
KEVIN C. CONLON, MD, MBA
238 CANCER OF THE UPPER GASTROINTESTINAL TRACT
specific physical signs usually indicates metastatic
disease. The presence of an intra-abdominal mass,
hepatomegaly, or ascites is usually due to extensive
and incurable disease. Other physical findings con-
sistent with widely metastatic disease include a pal-
pable umbilical mass (Sister Mary Joseph node), a
palpable supraclavicular lymph node (Virchows
node), peritoneal implants in the pelvis (Blumers
shelf), and an ovarian mass (Krukenbergs tumor).
Diagnostic Modalities
In the United States, the majority of gastric cancers
currently are diagnosed by endoscopy. Although less
widely used today, the barium contrast study previ-
ously played an important role in the detection of
stomach malignancies and remains a sensitive
modality. In experienced hands, a double-contrast
upper-gastrointestinal series will diagnose 99 percent
of abnormalities and 96 percent of gastric malignan-
cies.
6,7
The radiologic characteristics of gastric
malignancy include rigidity or thickening of the gas-
tric wall, prominent and irregular gastric rugae, large
ulcers with irregular nodular margins and elevated
borders, and intraluminal masses.
8
Figure 121
shows a lesion at the gastroesophageal junction.
Endoscopy is used to confirm abnormalities seen
by a contrast study and can visualize both early and
advanced malignancies. Since the clinical manifes-
tations of gastric cancer overlap with those of benign
ulcer disease, the early use of endoscopy with
biopsy is recommended in symptomatic patients.
For this reason, most centers currently perform
endoscopy as the initial diagnostic procedure.
The diagnostic accuracy of endoscopic biopsy
appears to be related to the number of samples
obtained, the location of the biopsy, and the histol-
ogy of the cancer. In a series of over 200 patients
with esophageal and gastric cancer, a diagnosis was
made for 70 percent of patients after the first biopsy,
95 percent of patients after the fourth biopsy, and
98.9 percent of patients after seven biopsies.
9
The
site examined also influences the accuracy of endo-
scopic biopsy; in a study by Hatfield and colleagues,
diagnosing a malignancy was most successful if
biopsy specimens were taken from the base and rim
of an ulcerated lesion.
10
Winawer noted that the
accuracy of the biopsy is related to histology. Fifty
percent of diffusely infiltrating lesions were cor-
rectly identified on biopsy, compared to 92 percent
of exophytic lesions.
11
The addition of brush cytol-
ogy to biopsy increases the diagnostic yield of can-
cers located in the cardia and in stenotic lesions.
12
Mass population screening with endoscopy is effi-
cacious in regions with a high incidence of gastric
cancer, such as Japan.
13
In Western countries, early
endoscopy to confirm benign lesions and diagnose
malignant disease is advocated although such use is
probably not cost-effective in such low-risk popula-
tions. In a British prospective trial of symptomatic
patients over 45 years of age, endoscopy diagnosed an
abnormality in 75 percent of patients. High-risk pre-
malignant disease was diagnosed in 493 (19%) of the
2,659 patients, and malignancy was found in 115
(4%).
14
The importance of diagnosing benign disease
should not be underestimated. Recent studies have
found an association between Helicobacter pylori
infection and gastric cancer,
15,16
and some evidence
suggests that treatment of H. pylori may have an
impact on the progression to gastric cancer.
The measurement of serum tumor markers has
not been useful in the diagnosis of gastric cancer.
Although tumor markers such as carcinoembryonic
Figure 121. Esophagogram of a patient with a lesion at the gastro-
esophageal junction. Endoscopy and biopsy proved adenocarcinoma.
Diagnosis and Staging of Gastric Cancer 239
antigen (CEA), CA19-9, CA72-4, and -fetoprotein
can be abnormally elevated in 15 to 60 percent of
patients,
1723
they are not specific for gastric cancer.
Some authors have advocated the measurement of
serum markers preoperatively since recurrence may
be detected by a postoperative rise in these mark-
ers.
22
Currently, the use of serum markers is of
research interest only.
PATHOLOGIC STAGING OF
GASTRIC CANCER
Gastric malignancies are pathologically staged
according to depth of invasion (T stage), number of
lymph node metastases (N stage), and presence of
distant disease (M stage). There is now an interna-
tional agreement among the American Joint Com-
mittee on Cancer (AJCC), the Union Internationale
Contre le Cancer (UICC), and the Japanese
Research Society for Gastric Cancer (JRSFC) to use
the TNM staging system (Tables 121 and 122).
In this system, tumors designated as T1 tumors
invade the mucosa or submucosa, T2 tumors pene-
trate through the muscularis propria or subserosa, T3
tumors penetrate the serosa, and T4 tumors invade
other structures. The 1997 edition of the AJCC can-
cer staging manual has adopted a new N stage defi-
nition based on the number of positive lymph nodes:
N1 disease for 1 to 6 positive nodes, N2 for 7 to 15
positive nodes, and N3 for more than 15 positive
nodes. The older 1992 classification system was
based on a determination of the location of positive
nodes and their distance from the primary tumor that
was often subjective. The revised nodal staging sys-
tem has been verified recently in the German Gas-
tric Cancer Study.
24
This study concluded that the N
classification, based on the number of positive
nodes, was superior to the old 1992 classification
system for estimating a prognosis and that it elimi-
nated the subjectivity inherent in determining lymph
node location and distance from the primary tumor.
However, the new classification of N status relies on
a systematic and reproducible approach to resecting
and analyzing perigastric lymph nodes. The UICC
and the AJCC suggest that to improve the quality of
staging, at least 15 negative nodes be analyzed
before the diagnosis of N0 is rendered.
PREOPERATIVE STAGING OF
GASTRIC CANCER
The limited efficacy of adjuvant chemotherapy in
gastric cancer has resulted in renewed interest in
preoperative therapy. Patients who are found to have
locally advanced disease (serosal invasion with
nodal disease) and no evidence of distant metastases
will often be treated with neoadjuvant chemotherapy
followed by surgical resection (Figure 122). Preop-
erative staging is critical when selecting patients for
this approach. At our institution, we currently rely
on a combination of computed tomography, endo-
scopic ultrasonography, magnetic resonance imag-
ing, and the selective use of laparoscopy and laparo-
scopic ultrasonography. Investigational techniques
that have had preliminary success include positron
Table 121. TUMOR-NODE-METASTASIS CATEGORIES
FOR GASTRIC CANCER
Primary Tumor
T1 Invasion of lamina propria into submucosa
T2 Invasion of muscularis propria/subserosa
T3 Invasion of serosa
T4 Invasion of adjacent structures
Regional Lymph Nodes
N0 No regional lymph node metastasis
N1 Metastasis in 1 to 6 regional lymph nodes
N2 Metastasis in 7 to 15 regional lymph nodes
N3 Metastasis in more than 15 regional lymph nodes
Distant Metastasis
M0 No distant metastasis
M1 Distant metastasis
Table 122. STAGING FOR GASTRIC CANCER*
Stage Tumor Node Metastasis
0 T1s N0 M0
IA T1 N0 M0
IB T1 N1 M0
T2 N0 M0
II T1 N2 M0
T2 N1 M0
T3 N0 M0
IIIA T2 N2 M0
T3 N1 M0
T4 N0 M0
IIIB T3 N2 M0
IV T4 N1 M0
T13 N3 M0
T4 N23 M0
Any Any M1
*American Joint Committee on Cancer classification.
240 CANCER OF THE UPPER GASTROINTESTINAL TRACT
emission tomography, peritoneal cytology, and mol-
ecular staging.
Computed Tomography
Computed tomography (CT) is the most frequently
used radiologic staging modality for gastric cancer.
Computed tomography detects intraluminal tumors,
a thickened gastric wall, and direct invasion of the
primary tumor into surrounding structures; it
appears to be optimal for determining locally
advanced and metastatic disease. Enlarged perigas-
tric, celiac, or preaortic lymph nodes can be
detected, as can liver, lung, or adrenal metastases.
8
Luminal distension is key to the evaluation of the
gastric wall. A wall thickness > 1 cm is considered
abnormal when the stomach is well distended.
25
The
use of water as a distending agent for the stomach,
with bolus administration of intravenous contrast,
improves the accuracy of CT for staging gastric can-
cer.
26,27
Antimotility agents can be given to reduce
peristalsis and gastric emptying, which minimize
motion artifact. With these techniques, the stomach
appears as three layers: an inner layer that enhances
and corresponds to the mucosa; a low-attenuation
intermediate layer that corresponds to the submucosa;
and an outer layer of slightly higher attenuation,
which corresponds to the muscularis and serosa.
28
Gastric cancer can be seen as an intraluminal mass or
as a markedly thickened enhancing wall.
27
Figure
123 shows diffuse wall thickening in a nondistensi-
ble stomach with linitis plastica. Using helical and
dynamic techniques with optimal gastric distension,
CT detects approximately 90 percent of gastric cancer
cases and accurately assesses wall invasion (T stage)
in 40 to 80 percent of cases.
2931
Computed tomogra-
phy appears to be more useful in diagnosing locally
advanced disease than early disease;
3032
it will detect
95 to 100 percent of bulky advanced gastric cancers
and will accurately determine tumor depth (T stage)
in over 80 percent of these cases.
2633
However, CT
can have difficulty in determining tumor invasion of
contiguous organs (ie, T4 tumor) since this modality
cannot differentiate inflammation from tumor.
25
Sev-
eral recent series have noted an improved accuracy
for helical techniques in identifying invasion of the
pancreas and colon.
34,35
Figure 124 shows a locally
advanced gastric cancer with bulky disease at the
lesser curve of the stomach and in the gastrohepatic
ligament. In contrast to its ability to detect advanced
lesions, CT detects only 25 to 50 percent of early
gastric lesions and correctly stages wall invasion in
15 percent of these cases.
26,32,33
Computed tomography has been relatively poor
at staging lymph node metastases,
34
with an accu-
racy of between 25 percent and 70 percent reported
in the literature.
26,30,31,3537
Computed tomography
Endoscopy
CT
Diagnostic laparoscopy
Advanced
T3/T4
N1/N2
Early
T1/T2
N0
Metastatic
M1
Neoadjuvant
chemotherapy
Surgical
resection
Surgical
resection
Systemic
chemotherapy
Figure 122. Memorial Sloan-Kettering Cancer Center staging
and treatment algorithm for patients with gastric adenocarcinoma.
(CT = computed tomography.)
Figure 123. A nondistensible gastric wall shown by computed
tomography indicates a diffusely infiltrating cancer.
Diagnosis and Staging of Gastric Cancer 241
mostly relies on nodal size to diagnose metastases.
However, CT cannot differentiate inflammatory or
reactive nodes from those with metastatic disease.
25
Fukuya and colleagues studied the efficacy of heli-
cal CT in detecting lymph nodes in gastric cancer
patients;
38
CT detected only 1 percent of nodes < 5
mm in size, 45 percent of nodes between 5 and 9
mm, and over 70 percent of nodes > 9 mm in size.
Lymph node size correlated with the potential for
harboring metastatic disease. Over 80 percent of
nodes > 14 mm in size seen by CT contained metas-
tases. However, not all the metastases were found in
enlarged lymph nodes. Metastatic cancer was noted
in 5 percent of lymph nodes < 5 mm in size, 21 per-
cent of nodes from 5 to 9 mm in size, and 23 percent
of nodes from 10 to 14 mm in size. In this study,
involved nodes were hyperdense, with a greater
short-to-long axis ratio (ie, a rounder shape) than
nodes without tumor. Overall, diagnosing lymph
node metastases remains a challenge, especially in
nodes < 15 mm in diameter. Figure 125 is an exam-
ple of CT detecting a discrete enlarged lymph node
in the gastrohepatic ligament. In general, it can be
stated that CT will understage the extent of nodal
disease.
31
The strength of CT lies in its ability to diagnose
distant metastatic disease.
30,32,34,35,39
Carcinomatosis
with diffuse peritoneal seeding, malignant ascites,
and adnexal and pelvic metastases are well demon-
strated by CT.
25
Figure 126 shows an example of
carcinomatosis and omental caking. Computed
tomography will accurately assess the liver for metas-
tases in 79 to 96 percent of gastric cancer cases.
35,37,40
However, small-volume metastatic disease in the peri-
toneal cavity and liver will be missed.
30,34,35,37,4143
Endoscopic Ultrasonography
Endoscopic ultrasonography (EUS) overcomes the
two-dimensional limitation of conventional endo-
scopy and allows the evaluation of the gastric
mucosa and underlying layers. In the normal stom-
ach, EUS identifies five gastric wall layers: mucosa,
submucosa, muscularis propria, subserosa, and
serosa. Disruption of the normal ultrasonographic
appearance of these layers determines the depth of
invasion (Figure 127).
Figure 126. Computed tomography depicts metastatic gastric
adenocarcinoma with omental carcinomatous implants.
Figure 124. Computed tomography scan of a patient with a
locally advanced tumor of the lesser curve of the stomach.
Figure 125. Computed tomography scan of a patient with a
tumor of the lesser curve of the stomach. Computed tomography
correctly identifies locally advanced disease with an enlarged lymph
node in the gastrohepatic ligament.
242 CANCER OF THE UPPER GASTROINTESTINAL TRACT
The accuracy of EUS for determining the depth
of the primary tumor ranges from 60 to 90 per-
cent.
36,4449
Endoscopic ultrasonography has diffi-
culty differentiating inflammation and fibrosis from
tumor, and this is the most common reason for mis-
diagnosis.
47,5052
The ability to visualize tumor by
EUS is related to the tumors morphology and to the
stage of disease. Endoscopic ultrasonography most
accurately stages early well-differentiated polypoid
cancers.
44
Difficulty arises in differentiating deep T2
tumors from superficial T3 cancers or in recognizing
adjacent organ infiltration.
46,53
There is a tendency
to overestimate the depth of penetration in cases of
extensive perigastric adenopathy and fibrosis.
51
Endoscopic ultrasonography is sensitive for diag-
nosing enlarged perigastric lymph nodes. It will
detect 40 percent of nodes > 5 mm and 60 percent
of nodes > 10 mm in size.
54
Large nodes detected by
EUS are more likely to contain metastases than are
smaller nodes. Heinz and colleagues found that over
70 percent of lymph nodes > 10 mm contained dis-
ease.
55
Other criteria for determining lymph node
metastases include shape and the inability to visual-
ize the lymph node hilum. Aibe and colleagues
noted that round lymph nodes contained metastases
more frequently than ellipsoid lymph nodes of sim-
ilar size.
54
Tio and Tytgat found that sharply demar-
cated lymph nodes with an inhomogeneous echo
pattern that was either similar to or more hypoe-
choic than that of the primary lesion were more
likely to contain metastases. In contrast, inflamma-
tory lymph nodes were homogeneous, had indistinct
boundaries, and were more hyperechoic than the
primary lesions.
56
The accuracy of EUS for predicting metastases is
reduced in distant lymph nodes. Akahoshi and col-
leagues noted that EUS diagnosed 86 percent of peri-
gastric lymph nodes; 25 percent of left gastric, com-
mon hepatic, splenic, or celiac artery lymph nodes;
and only 14 percent of retropancreatic- and mesen-
teric-root lymph nodes.
46
Other studies confirmed
that EUS predicts regional lymph node disease with
80 percent accuracy but predicts distant lymph node
disease with less than 60 percent accuracy.
4448,53,57
Recent technological advances have allowed EUS-
guided fine-needle aspiration of suspicious nodes,
thus improving the accuracy of the evaluation.
Laparoscopy and Laparoscopic
Ultrasonography
The introduction of laparoscopy to the diagnostic
armamentarium has had a dramatic effect on the
staging of gastric cancer. Laparoscopy allows direct
visualization of the primary tumor as well as assess-
ment of the liver and peritoneal cavity. Figure 128
illustrates a locally advanced tumor with serosal
involvement (T3). Subradiologic metastatic disease
can be identified. Proponents of laparoscopy note
that 20 to 40 percent of patients with clinically local-
ized M0 disease will be up-staged by laparoscopy
and have their management changed.
5864
Laparo-
scopy is especially sensitive for detecting small peri-
toneal and hepatic implants that are not detected by
CT.
58,59,62,65
Figures 129 and 1210 are laparoscopic
images that reveal small-volume metastatic disease
not seen on the preoperative work-up (including heli-
cal CT). Since curative resection was not possible,
these asymptomatic patients were able to avoid the
morbidity of a laparotomy.
The laparoscopic experience is typified in a
study from our institution by Burke and col-
leagues.
62
In this study of 111 patients with gastric
cancer judged to be free of metastatic disease by
preoperative CT, laparoscopy diagnosed metastatic
disease in 32 patients, with an overall accuracy of 94
percent. The peritoneum and liver made up 97 per-
Figure 127. Endoscopic ultrasonography in a patient with a gas-
tric adenocarcinoma. The tumor disrupts all layers of the stomach
wall, indicating a T3 lesion.
Diagnosis and Staging of Gastric Cancer 243
cent of the metastatic disease that was detected by
laparoscopy only (Figure 1211). The asymptomatic
patients diagnosed with M1 disease at laparoscopy
avoided a laparotomy and were discharged, usually
the day after surgery. In contrast, patients who had
M1 disease noted at open laparotomy were hospital-
ized for an average of 7 days. Interestingly, patients
diagnosed with M1 disease by laparoscopy did not
require a subsequent open procedure for bleeding,
perforation, or obstruction. Further, these patients
had similar survivals to those of historical controls
with M1 disease. These data question the role of
prophylactic bypass or resection in asymptomatic
patients with M1 disease.
Concern has been expressed regarding the possi-
bility that laparoscopy could lead to tumor dissemi-
Figure 128. Laparoscopy in a patient with gastric adenocarcinoma reveals serosal
invasion (a T3 lesion). This constitutes locally advanced disease, and this patient would
be offered preoperative (neoadjuvant) chemotherapy.
Figure 129. Laparoscopy in a patient with gastric adenocarcinoma without evidence of
metastatic disease on preoperative helical computed tomography. Small-volume disease
is seen in the liver. Since curative resection is not possible, this patient can be spared the
morbidity of laparotomy.
244 CANCER OF THE UPPER GASTROINTESTINAL TRACT
nation and subsequent port site implantation. How-
ever, recent work suggests that the incidence of port
site implantation is less than 1 percent after
laparoscopy for abdominal malignancy.
66
The addition of ultrasonography to laparoscopy
(laparoscopic ultrasonography [LUS]) partially com-
pensates for the lack of tactile sensation and may
improve the surgeons ability to determine tumor
depth and to detect lymph node metastases.
6769
Artic-
ulating LUS probes that can be placed through a 10-
mm port have been developed (Figure 1212). With
LUS, the stomach wall appears as alternating hyper-
and hypoechnoic layers (Figure 1213). Invasion is
seen as disruption of the normal architecture. Figure
1214 shows a deep T2 lesion with interruption of the
second hypoechoic layer of the stomach wall.
Evidence suggests that LUS complements
laparoscopy. Smith and colleagues noted that 18 of
93 patients found to have resectable disease by stan-
dard preoperative imaging had additional disease
identified by laparoscopy, which negated attempts at
curative resection.
70
Laparoscopic ultrasonography
provided evidence of unresectability in 7 additional
patients. Overall, 27 percent of patients in this study
avoided a laparotomy.
Common to most studies on laparoscopic stag-
ing for gastric cancer is the difficulty of diagnosing
occult lymph node disease. In the study of 111
patients by Burke and colleagues, 6 patients at
laparotomy were found to have M1 disease by
virtue of distant nodal disease that was not docu-
mented by laparoscopy.
62
By improving the nodal
assessment, LUS may reduce the incidence of false-
negative laparoscopies. By using laparoscopy and
LUS, Rau and colleagues noted enlarged lymph
nodes in the M1 position in 8 of 40 patients with
esophageal and gastric cancer.
71
Biopsy specimens
Figure 1210. Laparoscopy in a patient (different from patient represented in Figure 129)
with gastric adenocarcinoma without evidence of metastatic disease as seen by preopera-
tive helical computed tomography. Small-volume disease is seen in the peritoneum. Since
curative resection is not possible, the patient can be spared the morbidity of laparotomy.
Figure 1211. Pie chart depicting the location of metastatic dis-
ease seen in patients by laparoscopy but missed by routine preop-
erative imaging. The majority of disease is small-volume disease
located in the liver and on the peritoneal surface. (Reproduced with
permission from Burke EC, Karpeh MS, Conlon KC, Brennan MF.
Laparoscopy in the management of gastric adenocarcinoma. Ann
Surg 1997;225:2627.)
Diagnosis and Staging of Gastric Cancer 245
Figure 1212. Laparoscopic ultrasonog-
raphy, using a 10-mm probe.
Figure 1213. Laparoscopic ultrasonog-
raphy depicts the normal stomach wall as
alternating hyper- and hypoechoic layers.
The probe is placed on the anterior gastric
wall, and the posterior gastric wall is visu-
alized. The stomach is filled with saline.
Figure 1214. Laparoscopic sonogram,
depicting a posterior gastric adenocarci-
noma with interruption of the second
hypoechoic layer (muscularis propria) of
the stomach wall. This image represents a
deep T2 lesion.
246 CANCER OF THE UPPER GASTROINTESTINAL TRACT
of these lymph nodes showed metastases in 6 (75%)
of these 8 patients.
Other techniques, including peritoneal-fluid
sampling, can be performed at the time of laparo-
scopy (Figure 1215). Patients with viable tumor
cells in the peritoneal fluid have poor outcomes, and
peritoneal cytology is expected to become a compo-
nent of routine staging in the future (see below).
Magnetic Resonance Imaging
Magnetic resonance imaging (MRI) has gained pop-
ularity as an imaging modality for gastrointestinal
and liver pathology. Currently the greatest benefit of
MRI is its increased sensitivity for detecting liver
metastases. Some reports suggest that MRI appears
to have greater resolution than CT for this indica-
tion.
7274
There is evidence that MRI can accurately
stage tumor depth of gastric cancer as well; however,
this remains investigational.
75
Positron Emission Tomography
Positron emission tomography (PET) is an investi-
gational imaging tool with potential for detecting
metastatic disease and measuring the response of the
primary tumor to chemotherapy. Malignant tissue
consumes glucose more avidly than does normal tis-
sue. Intravenous 18F-fluorodeoxyglucose (FDG) is
transported into tumor cells, where it emits positrons
that are detected by a gamma camera (Figure
1216). Beneficial results in esophageal cancer have
suggested that PET may be useful in gastric cancer
as well. In a study of 91 patients with esophageal
cancer, PET detected 30 percent of metastases
missed by CT.
76
Although more accurate than CT,
PET was less sensitive than laparoscopy.
76
Although there are few PET studies specifically
involving gastric cancer, there are data indicating that
gastric tumors are avid consumers of FDG and are
detectable by PET.
77
The data on the ability of PET to
diagnose lymph node metastases in patients with gas-
troesophageal cancer is somewhat mixed.
7781
A num-
ber of studies indicate that PET has approximately a
90 percent accuracy in detecting lymph node metas-
tases
79
whereas other studies have reported an accu-
racy of less than 50 percent.
81
In addition to the ability
to assess metastatic disease, PET may have the ability
to determine responses to neoadjuvant chemotherapy
and radiotherapy. By comparing a post-treatment PET
scan to pretreatment scans, one can determine if a
residual mass contains metabolically active cells.
82
Peritoneal Cytology
The impact of peritoneal cytology as an adjunct to
staging has recently been investigated. Studies have
demonstrated reduced survival when viable tumor
Figure 1215. Peritoneal fluid is easily sampled at the time of laparoscopy. (At the
authors center, fluid is currently collected for research purposes.)
Diagnosis and Staging of Gastric Cancer 247
cells are noted in the peritoneal lavage fluid taken at
the time of gastric resection.
8388
Figure 1217 shows
tumor cells in a cytology specimen stained by the
Papanicolaou technique. The likelihood of detecting
positive peritoneal cytology appears related to the
stage of disease. Of 127 patients in a study in which
peritoneal cytology was analyzed by the Papanicolaou
method, no patients with T1 or T2 tumors, 10 percent
of patients with T3 and T4 tumors, and 59 percent of
patients with M1 disease had positive cytology.
84
Within the subgroup of completely resected patients
with stage III gastric cancer, positive cytology pre-
dicts reduced survival. In fact, the outcome is similar
to that of patients with M1 disease.
84
This has led
many groups to suggest that cytology be included in
the staging of gastric cancer.
84,87,88
Figure 1217. Malignant cells, stained by the Papanicolaou technique, in the peritoneal
fluid of a gastric cancer. patient. Patients with positive peritoneal cytology have survival
rates similar to those of patients with M1 disease. (Reproduced with permission from
Burke EC, Karpeh MS, Conlon KC, Brennan MF. Laparoscopy in the management of gas-
tric adenocarcinoma. Ann Surg 1997;225:2627.
Figure 1216. Two sagittal views produced by positron emission tomography (PET),
showing metastatic disease involving the supraclavicular, periaortic, and perigastric lymph
nodes and the liver.
248 CANCER OF THE UPPER GASTROINTESTINAL TRACT
The sensitivity of peritoneal-fluid cytology can
be dramatically increased by the use of immunohis-
tochemistry and reverse transcriptase polymerase
chain reaction (PCR) techniques. Using these meth-
ods, the proportion of stage III and IV patients with
positive cytology increases to 46 to 64 percent.
85,86
However, these methods also result in a positive
peritoneal cytology rate of 10 percent for stage I and
II patients. The clinical relevance of such a sensitive
method is yet to be determined.
Molecular Staging
Advances in molecular biology have provided new
methods for predicting outcomes in gastric cancer
patients. The expression of various molecular mark-
ers has been correlated with poor outcomes. The
tumor-suppressor gene p53 has been implicated in
the sequence of gastric carcinogenesis,
89
and over-
expression of p53 is associated with reduced sur-
vival in patients with diffuse-type gastric cancer.
90
Similarly, adhesion molecule overexpression has
been implicated in the development of early metas-
tases. These molecules are believed to control the
migration of tumor cells through the vasculature.
Tumor expression of the cell adhesion receptor sia-
lyl-Le(x) is associated with venous invasion and a
poor outcome.
91
Similarly, the cell adhesion mole-
cule CD44 is elevated in the serum of some patients
with advanced gastric cancer. This molecule plays
an important role in cell-cell adhesion, and
increased serum concentrations are associated with
increased tumor burden and tumor metastases.
92
Elevated serum levels of more traditional tumor
markers in gastric cancer patients have also been
noted. Specifically, abnormal levels of CEA, CA19-
9, CA72-4, and -fetoprotein are seen in 15 to 60
percent of patients
1723
and prognosticate poor out-
comes since they are associated with advanced tumor
depth, nodal metastases, and distant spread.
1823,93
Some series have also shown that serum markers are
independent predictors of poor outcome.
1719,23,93,94
Tachibana and colleagues described a 5-year survival
rate of 32 percent following the resection of gastric
cancer in patients with an elevated preoperative CEA
level, compared to 77 percent for patients with a nor-
mal preoperative CEA level.
19
Similarly, high serum
levels of CA72-4 (a glycoprotein associated with
gastric cancer) are associated with lymph node
metastases and a poor outcome.
94
The value of molecular staging and its ability to
predict survival over and above factors such as
tumor depth, nodal status, and distant metastases
needs to be proven in a prospective manner. It is
expected that molecular staging will have an
increased role in the future as the mechanisms of
disease are more fully elucidated.
THE MEMORIAL SLOAN-KETTERING
CANCER CENTER STAGING ALGORITHM
The staging algorithm followed at Memorial Sloan-
Kettering Cancer Center for gastric cancer patients
is depicted in Figure 122. Diagnosis is usually
accomplished with endoscopy. Endoscopic ultra-
sonography may be used to determine the depth of
invasion and perigastric adenopathy for patients
with early lesions and for those whose tumor is
located at the gastroesophageal junction. For lesions
involving the body and antrum of the stomach, EUS
has been mostly replaced by LUS. In all cases, CT is
performed to detect obvious metastases that would
preclude a curative resection. Biopsies of metastatic
disease to the liver are usually performed under the
guidance of CT. For patients without evidence of M1
disease, laparoscopy is performed to rule out small-
volume peritoneal and/or hepatic metastases.
Laparoscopic ultrasonography is frequently used to
stage the primary tumor depth and the extent of
nodal disease. Peritoneal fluid is currently sampled
at the time of laparoscopy, for research purposes.
Patients with locally advanced disease (T3/T4
lesions with N1/N2 adenopathy) are at high risk for
local recurrence. If medically fit, these patients are
preferably entered into neoadjuvant chemotherapy
trials prior to surgical resection. Patients with early
disease (T1 or T2, N0) are treated by immediate gas-
tric resection. Patients with M1 disease and no evi-
dence of bleeding or obstruction usually receive
chemotherapy without resection.
SUMMARY
The diagnosis and staging of gastric cancer have
evolved in recent years as improvements in diagnostic
Diagnosis and Staging of Gastric Cancer 249
modalities have been coupled with the development of
a multimodal approach to therapy. Further advances
are expected in the future as our understanding of the
molecular basis of the disease progresses.
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