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GASTRIC ADENOCARCINOMA AND OTHER GASTRIC NEOPLASMS (EXCEPT GASTROINTESTINAL STROMAL TUMORS)
John T. Langell • Sean J. Mulvihill
22
EPIDEMIOLOGY OF GASTRIC CANCER
Gastric cancer describes a broad mix of malignant neoplasms
derived from the di erent histological components that make
up the stomach. ese include adenocarcinoma, lymphoma,
carcinoid, and sarcoma. Gastric adenocarcinoma accounts for
over 90% of all cases of gastric cancers globally.
dence of gastric cancer decreased dramatically in the latter half
of the 20th century; however, a recent rise in proximal gastric cancer incidence has been noted. Gastric cancer remains
the second leading cause of cancer-related deaths worldwide
( Fig. 22-1 ).
logical distribution of gastric cancer demonstrates a marked
variation in regional incidence—with as much as a 10-fold
di erence between the highest- and lowest-risk populations.
An estimated 900,000–950,000 newly diagnosed gastric cancer cases per year occurred worldwide at the beginning of the
21st century, with the great majority of these cases found in
developing countries and China.
continue to see a marked decline in the incidence of gastric
cancer, particularly in the body and antrum. In the United
States, the estimated number of new cases diagnosed in 2009
was 21,130 with the number of gastric cancer–associated
deaths estimated to be 10,620.
continued decreasing trend in both gastric cancer incidence
and mortality ( Table 22-1 ). In fact, death rates attributed to
gastric cancer in the Unites States fell by over 40% for males
and 32% for females between the years 1990 and 2005.
e diagnosis of gastric cancer portends a poor progno-
sis with reported overall 5-year survival rates between 20
1–4
As is the case for many cancers, the epidemio-
2,
5–7
3,
Industrialized nations
7
ese numbers highlight the
1,
2 e inci-
7
5
and 25% in most industrialized nations. 1, 6, 8 Stage of disease
at time of diagnosis is clearly one of the most important
correlates of cancer survival. Patients diagnosed with earlier
stages of gastric cancer have a distinct advantage in 5-year
survival compared to those with more advanced-stage disease
( Fig. 22-2 ). Although the 5-year survival rate for all cases of
gastric cancer in the United States between the years 1996
and 2004 was 25%, it was as little as 3% for patients with
distant disease and as high as 61% for those who had only
localized disease at time of diagnosis.
of early diagnosis is best exempli ed by Japan’s overall 5-year
gastric cancer survival rate of 52%. is has been attributed
to a high percentage of early-stage diagnosis due to mass
photo uoroscopic screening of their population.
United States where the relatively low incidence of gastric
cancer does not support routine population screening, only
about one-quarter of all patients are found to have localized
disease at the time of diagnosis.
7
e survival advantage
6
ASSOCIATED RISK FACTORS
e risk of developing gastric cancer is associated with a
complex interrelationship between environmental factors and their in uence on an individual’s genetic and
epigenetic make up.
infection, smoking, and possibly a high dietary salt intake,
very few proposed environmental risk factors have been validated through scienti c analysis.
environmental in uences seems apparent given the marked
1,
2, 6, 9, 10 Aside from Helicobacter pylori
1–3
e e ect of regional
2,
6 In the
463
464 Part IV Stomach and Duodenum
14
Incidence per 100,000
80
Percent 5-year survival
11.68
12
10
7
6
4
2
0
FIGURE 22-1 Incidence of invasive gastric cancer in the United
States. (From the SEER Cancer Database, 1975–2007.)
11.29
10.22
9.27
Year
8.34
8.1
7.36
6.99
200720052000199519901980 19851975
variation in the incidence of gastric cancer between di erent
6
geographical regions of the world.
Although regional and
racial genetic variation could account for a portion of this
e ect, mass global migration of the population and immigrant cancer susceptibility studies indicate a large environ-
11–15
mental e ect.
Epidemiological studies have shown that
immigrants who travel from high- to low-prevalence regions
still maintain an overall gastric cancer risk about equal to
3
the region they emigrated from.
e progenies of these
immigrants who are born in the low-prevalence regions, on
the other hand, exhibit a prevalence similar to local peoples
11–15
of comparable ethnic origin.
is e ect points to likely
environmental factors that impact an individual’s risk of
gastric cancer development at an early age of exposure.
In addition to environmental factors, a clear impact of
genetic susceptibility on the risk of developing gastric cancer
9
has been identi ed.
is includes not only familial associated
genetic cancer syndromes but the e ects of similar common
genomic composition in individuals sharing ethnic origins. is
may account for the notable ethnic variations in gastric cancer
observed among members of a population in the same geo-
1,
graphic region.
7, 10 Not only does a geographic subpopulation’s
TABLE 22-1: U.S. GASTRIC CANCER
INCIDENCE AND MORTALITY PER 100,000
POPULATION, 2001-2005
Asian
American
African
White
Incidence 14.7 26.3 29.1 24.5 25
Mortality 7.5 17 16 15.1 13.6
Data from Jemal A, Siegel R, Ward E, et al. Cancer statistics 2009. CA Cancer J
Clin. 2009;59:225-249.
American
Paci c
Islander
American
Indian Hispanic
70
60
50
40
30
20
10
0
All stages Local
disease
Cancer stage at diagnosis
FIGURE 22-2 Gastric cancer 5-year survival rate in the United
States. (From the SEER Cancer Database, 1999–2006.)
Regional
disease
All patients
Males
Females
Metastatic
disease
ethnicity seem to impact their risk of developing gastric cancer,
it also a ects their average age of presentation and response to
10
therapy.
What is not clear is what proportion of these observed
a ects are secondary to a subpopulations’ shared genetic background and what may be due to shared local cultural di erences
within their geographic regions.
Helicobacter pylori
H. pylori infection has been demonstrated to be linked to
the development of distal gastric cancers but not cancer
16,
of the gastric cardia.
17 e clear association between H.
pylori infection and the development of gastric cancer led
the International Agency for Research on Cancer (IARC) to
classify H. pylori infection as a type I human carcinogen in
18
is has been supported by numerous prospective
1994.
trials that have estimated that H. pylori infection confers an
increased relative risk for the development of gastric cancer
1,
19,
2,
of 2.1–20 fold.
20 Further, a prospective Japanese study
of patients tested for H. pylori by serology found that gastric
cancer developed in 2.9% of patients who were H. pylori
seropositive, but in none of the patients in the H. pylori –
21
seronegative group.
Based on early data, Correa proposed
a model of gastric carcinogenesis whereby H. pylori initiated
an in ammatory cascade leading to the sequential development of chronic gastritis, gastric atrophy, intestinal metapla-
22
sia, and dysplasia followed by carcinoma.
is concept is
supported by the linkage between chronic in ammation and
cancer development in many other organs.
Smoking
Convincing evidence has been derived from the European Prospective Investigation into Cancer and Nutrition
(EPIC) trial showing cigarette smoking as a causal factor in
Chapter 22 Gastric Adenocarcinoma and Other Gastric Neoplasms (Except Gastrointestinal Stromal Tumors) 465
the development of gastric cancer. In this study, there was
a marked increased risk for developing gastric cancer in
patients who had a history of smoking tobacco products with
a hazard ratio (HR) of 1.45. e HR increased to 1.73–1.87
for current smokers with an increased risk of gastric cancer
proportional to the duration and intensity of the smoking history. Further, cigarette smoking had a more profound eect
on the development of gastric cardia cancer (HR 4.10) than
of antral cancer (HR 1.94). Overall, the large populationbased EPIC trial found that 17.6% of gastric cancer cases
may be attributable to smoking tobacco products.
23
Obesity
Obesity has also emerged as a possible signicant risk factor for the development of several cancer types, including
cancer of the gastroesophageal junction and gastric car-
1,2,24–27
dia.
by Lagergren et al demonstrated a 2.3-fold increased risk
of gastric cancer in the heaviest-weight quartile of the
population compared to the lightest-weight quartile and
a 4.3-fold increased risk for patients classied as obese.
ese ndings were supported by the results of a large
case-control study performed in the United Kingdom that
demonstrated a strong association between an increased
body mass index and the development of gastric cardia
cancer (odds ratio [OR] 1.46), but not noncardia gastric
cancer.
seemed independent of the presence of gastroesophageal
reux disease. e mechanism of increased cancer risk in
the obese population has not been elucidated but has been
hypothesized to be linked to altered metabolism and/or
increased gastroesophageal reux disease.
A Swedish population-based study completed
25
Furthermore, this eect was dose-dependent and
24–26
26
found no association between dietary salt intake and can-
30
Despite these ndings, the majority of studies support
cer.
a possible association between a high dietary salt intake and
the development of gastric cancer in higher-risk populations.
Hereditary Forms of Gastric Cancer
One of the rst documented cases of hereditary gastric cancer
dates back to the 17th century and was described for the family
of the French emperor Napoleon Bonaparte.
that up to 3% of gastric cancers are the result of hereditary
4
syndromes.
Although many more are likely to be characterized, several well-studied hereditary syndromes include hereditary diuse gastric cancer (HDGC), Li- Fraumeni syndrome,
hereditary nonpolyposis colon cancer, and BRCA2.
e majority of known hereditary gastric cancers are due
to HDGC that carries a high penetrance and incidence of
gastric cancer in the studied kindreds.
ally present at an early age with a diuse multifocal form of
gastric cancer. Between 30 and 40% of kindreds with HDGC
demonstrate a germline mutation of a single CDH1 allele, the
gene encoding for the structural glycoprotein E-cadherin.
complete understanding of the sequence of events that lead
to gastric cancer through this single allelic mutation is still
unfolding, but there is evidence for loss of heterozygosity
though somatic cell epigenetic dysregulation of the normal
CDH1 allele via promoter site methylation in several wellstudied cases. Because these patients have a 60–90% lifetime
risk of developing a diuse-type gastric cancer, they present
an unusual therapeutic challenge.
9,33
curative early prophylactic gastrectomy in patients who carry
the CDH1 mutation, while others advocate early and routine
surveillance endoscopy reserving surgery for patients found
to have cancer on surveillance biopsy.
31
We now know
4,9
ese patients usu-
Some have advocated
33,34
9
32
A
Diet
Numerous studies have examined the possible association
between dietary intake and either the development or prevention of gastric cancer.
and vegetables has been proposed to be protective against
the development of gastric cancer. Although evidence from
several retrospective studies support an association between
a high dietary intake of fruits and vegetables and a decreased
gastric cancer risk, this association proved not to be statistically signicant in prospective trial analyses.
Another dietary association that has been extensively studied is the possible increased risk of gastric cancer in patients
who consume a high intake of salts and nitrates.
evidence for this association is still heavily debated, though
most published cohort and case-control studies have found
a strong association between a high dietary salt intake and
28,29
gastric cancer.
ese ndings, however, have not been
uniform. In fact a well-publicized population-based study
out of Norway evaluating a cohort of over 73,000 patients
1,2
Specically, a diet rich in fruits
2
28,29
e
CLINICAL PRESENTATION
Signs and Symptoms of Gastric Cancer
e signs and symptoms of gastric cancer are nonspecic
and commonly found in unaected individuals in the general population. ey include dyspepsia, fatigue, and malaise
among others. Other, more concerning symptoms that are
often referred to as alarm symptoms, include weight loss,
dysphagia, persistent vomiting, gastrointestinal bleeding,
anemia, and a palpable abdominal mass.
Dyspepsia is a very common complaint among patients
presenting to primary care physicians.
frequent complaint in patients with gastric cancer; however,
peptic ulcer disease, gastroesophageal reux disease, and functional dyspepsia are far more common causes of dyspepsia.
e presence of alarm symptoms presents a more concerning
clinical picture in patients with a history of dyspepsia and
should alert the evaluating physician that a more extensive
35
36
Dyspepsia is also a
35
466 Part IV Stomach and Duodenum
workup to rule out malignancy may be indicated. e
presence of alarm symptoms is not specic for malignancy; in
fact the incidence of alarm symptoms in dyspeptic patients is
35
high, whereas the incidence of gastric cancer is low.
Despite
this, prospective and retrospective studies have shown that
56–90% of patients with gastric cancer had alarm symptoms
37–40
at the time of endoscopy.
A meta-analysis of seven prospective endoscopic studies involving over 13,000 patients
reported the presence of alarm symptoms in 30% of all
patients and in 62% of patients found to have gastrointesti-
41
nal cancer.
Of these, no single alarm symptom was present
in more than 30% of patients with malignancy.
Another study analyzing patients who underwent urgent
endoscopy for the presence of alarm symptoms or dyspepsia
unresponsive to empiric therapy found that 3.8% had a
42
gastrointestinal malignancy.
In this study, the only alarm
symptoms that were predictive of cancer were dysphagia and
weight loss with ORs of 3.1 and 2.6, respectively. e presence
of uncomplicated dyspepsia, on the other hand, was found to
be a negative predictor for cancer with an OR of 0.1.
Although the presence of alarm symptoms is poorly predictive for the presence of cancer, when they are present in
gastric cancer patients, the presence and number of alarm
symptoms has been shown to correlate with an advanced stage
43,44
of disease.
erefore, the presence of specic alarm symptoms may be of prognostic value in gastric cancer patients.
is notion is supported by a recent study completed by
Stephens et al where the presence or absence of alarm symptoms correlated with patient survival time. Here, patients
were followed from their initial diagnosis of gastric cancer to
their date of death. ose patients who presented with alarm
symptoms had a survival range of only 7–11 months, whereas
patients without alarm symptoms survived between 24 and
44
Physical examination abnormalities in early gastric cancer
are generally not present. In patients with advanced disease, a
palpable supraclavicular mass, generally on the left side, can
be a sign of distant nodal metastasis (the Virchow node). A
bulky antral tumor or extensive nodal metastases will occasionally lead to jaundice from bile duct obstruction in the
hepatoduodenal ligament. A palpable abdominal mass may
be found, sometimes from a bulky primary tumor, but more
commonly from omental caking with metastases. Abdominal
distension and ascites is a nding concerning for peritoneal
carcinomatosis, as is the nding of a palpable nodule at the
umbilicus (the Sister Mary Joseph node). Rectal examination
may identify an anterior mass in the pouch of Douglas related
to peritoneal carcinomatosis and drop metastasis to the pelvis
(the Blumer shelf). In advanced disease, pallor related to anemia and evidence of weight loss may be present.
DIAGNOSIS AND STAGING
In symptomatic patients or those with a history of familial
gastric cancer undergoing screening evaluation, the diagnosis of cancer is most commonly made by the nding of
a mass lesion or concerning ulceration during upper endoscopy. Other patients presenting with more advanced disease
may have the diagnosis of malignancy made by CT scan and
biopsy of metastatic lesions. Although commonly used in the
past, upper gastrointestinal contrast studies with barium or
water-soluble contrast agents have largely been replaced by
the complementary nature of the combination of endoscopy
and CT. Once the diagnosis of gastric cancer has been made,
the patient must undergo a staging workup to determine the
extent of the disease and potential for curative resection.
Preoperative Staging and
Selection of Patients for Surgery
Accurate preoperative staging is essential for appropriate treatment planning. e workup should include upper
endoscopy with or without endoscopic ultrasonographic
(EUS) evaluation to assess the extent of local and regional
disease. e addition of EUS to the preoperative evaluation
may improve the accuracy of preoperative staging because it
has been shown to be slightly superior to computed tomography (CT) imaging in assessing tumor depth of invasion
and locoregional lymph node involvement.
may provide only limited additional information to CT
scan in most cases, the recent 2010 Practice Guidelines of
the National Comprehensive Cancer Network consider it an
optional adjunctive study.
4
A CT scan of the abdomen with contrast should be performed on all patients along with pelvic CT or ultrasound
in females and thoracic imaging in all patients to evaluate
the tumor (T) stage, nodal (N) stage, and distant metastatic
disease (M) stage, for the purpose of treatment planning.
ough CT scan is a recommended and routine part of the
preoperative evaluation, it has a relatively low sensitivity for
evaluating tumor depth and the presence of metastatic lymph
4
Newer modalities such as multidetector CT, heli-
nodes.
cal CT, and positron emission tomography CT (PET-CT)
have been shown to provide better preoperative staging data;
however, their routine use has not yet been advocated as an
essential or necessary part of the preoperative staging workup.
In addition to radiographic staging, a complete history
and physical examination, an assessment of exercise tolerance,
relevant laboratory testing, and indicated physiological
evaluations must be performed. ese studies help provide
evidence of advanced disease as well as the presence and extent
of comorbid conditions that may need to be considered prior
to treatment. In some patients, the presence of signicant
comorbid illness or limited performance status may preclude
certain treatment options.
Preoperative laboratory testing should include a comprehensive metabolic panel to assess the patient’s nutritional
status, renal and hepatic function. Patients with a poor
nutritional status may benet from preoperative nutritional
supplementation before considering surgical resection. ose
with evidence of reduced renal function or poor hepatic synthetic function may not tolerate radical surgical resection or
45,46
Because EUS
4
Chapter 22 Gastric Adenocarcinoma and Other Gastric Neoplasms (Except Gastrointestinal Stromal Tumors) 467
may be demonstrating signs of advanced disease that will need
more extensive staging studies. A complete blood (cell) count
(CBC) and basic coagulation studies should be performed
to assess the status of known or possible bleeding disorders.
Anemia is common in gastric cancer and may represent bleeding from the primary tumor or a vitamin B
de ciency from
12
associated atrophic gastritis
Patients who have signs and symptoms suggestive of
cardiopulmonary disease should have at minimum an electrocardiogram (ECG) and chest x-ray (CXR) performed.
Additional more extensive testing will be guided by the
extent of the patient’s symptoms and the ndings of the
ECG and CXR.
NCCN guidelines recommend that all patients with a diagnosis of gastric cancer, and particularly those with gastroesophageal
junction lesions, should undergo comprehensive review of their
staging, ndings, and treatment planning options by a multidisciplinary cancer treatment team. Unless the patient is to be
enrolled in a treatment study protocol approved by an institutional review board, treatment should be based on the current
4
NCCN Practice Guideline recommendations.
Staging
In the United States and the majority of the Western world,
staging is based on the TNM (tumor-node-metastasis) system
jointly developed by the American Joint Committee on Cancer
(AJCC) and the International Union Against Cancer.
22-2 summarizes the TNM-based staging system for gastric
cancer. is system strati es patients to a stage of disease that
correlates strongly with patient survival. is staging system is
based on tumor depth relative to the gastric wall histological
layers, presence and number of involved regional lymph nodes,
and the presence or absence of distant metastatic disease.
NCCN Practice Guidelines for treatment recommendations for initial therapy are based on the preoperative TNM
4
stage of the disease.
To be considered a candidate for curative resection, a patient must be found medically t to withstand a major abdominal surgery, have limited locoregional
disease amenable to resection with negative margins, and
be free of evidence of distant metastatic disease. ose who
have local disease but are found medically un t to undergo
a major surgical procedure may be candidates to undergo
endoscopic mucosal resection (EMR) as discussed below.
ose with advanced disease who are otherwise good surgical candidates may be candidates for palliative procedures if
indicated. Patients with unresectable disease and those with
extensive locoregional disease who are medically un t to safely
withstand radical surgery should be treated in a nonsurgical
treatment arm based on current treatment guidelines.
Patients with advanced locoregional disease who are
medically t and have a marked response to a neoadjuvant
treatment protocol should undergo complete preoperative
restaging once treatment has been completed to determine
whether their response to therapy renders them a potential
candidate for curative surgical resection.
47
Table
TABLE 22-2: AJCC TNM CLASSIFICATION
OF GASTRIC CANCER
Regional
Stage Primary Tumor
Stage 0 Tis N0 M0
Stage IA T1 N0 M0
Stage IB T1
T2a/b
Stage II T1
T2a/b
T3
Stage IIIA T2a/b
T3
T4
Stage IIIB T3 N2 M0
Stage IV T4
T1–3
Any T
Primary Tumor
De nition
Tis: Carcinoma
in situ
T1: Invades lamina
propria
or submucosa
T2a: Invades
muscularis
propria
T2b: Invades
subserosa
T3: Penetrates
serosa
T4: Invades
adjacent structures
AJCC, American Joint Committee on Cancer; TNM, tumor-node-metastasis.
Data from Greene FL, Page DL, Fleming ID, et al. AJCC Cancer Staging
Manual . 6th ed. Philadelphia, PA: JB Lippincott; 2002:111–118.
Lymph Node
N1
N0
N2
N1
No
N2
N1
N0
N1–3
N3
Any N
Regional
Lymph Node
De nition
N0: No nodes
involved
N1: 1–6 regional
nodes involved
N2: 7–15
regional nodes
involved
N3: >15 regional
nodes involved
Distant
Metastasis
M0
M0
M0
M0
M0
M0
M0
M0
M0
M0
M1
Distant
Metastasis
De nition
M0: No
distant
metastasis
M1: Distant
metastasis
ADJUNCTIVE THERAPIES
e 5-year survival rate for gastric cancer remains dismally
low even for resectable disease. Surgical resection with curative
intent remains the mainstay of therapy; however, the addition
of neoadjuvant and/or adjuvant therapy has been shown to
improve both disease-free survival and overall survival rates
in patients with select stages of disease.
is replete with case series, retrospective studies, and a few
prospective randomized control trials (RCTs) that sought
to investigate the e cacy of various adjunctive therapeutic
regimens in patients who have undergone a curative surgical resection for gastric cancer. In general, these studies have
been plagued with inconsistent results and complicated by
4,
48–50
e literature
468 Part IV Stomach and Duodenum
the use of diverse therapeutic regimens, many of which are
thought to be suboptimal. Fortunately, a handful of welldesigned studies and more recent meta-analysis of these data
have demonstrated their therapeutic ecacy.
Neoadjuvant therapy consists of a combination of
chemotherapeutic agents or chemotherapy plus radiation
therapy instituted in the preoperative setting. e theoretical
advantages of preoperative treatment include assessing tumor
chemosensitivity preoperatively to help tailor postoperative
therapy, potential early treatment of micrometastatic disease, better tolerance of therapeutic side eects, and disease
down-staging to improve the number of potentially curative
48,49
resections.
Preoperative radiation therapy alone or in
combination with chemotherapy has been demonstrated to
provide a signicant increase in down-staging, tumor resectability, and overall 5-year survival rates. Unfortunately, these
data were obtained from RCTs of patients with predominantly gastroesophageal junction tumors and therefore may
not have similar ecacy with cancers of the gastric body or
antrum.
48
e MAGIC (Medical Research Council Adjuvant Gastric
51
Infusional Chemotherapy) trial
demonstrated that the
addition of combined preoperative and postoperative chemotherapy consisting of epirubicin, cisplatin, and 5-uorouricil
leads to a signicant increase in overall survival and reduced
disease progression when compared to patients who received
surgery alone, establishing the benet of neoadjuvant chemotherapy without radiation. Currently, the NCCN guidelines
recommend the addition of neoadjuvant chemotherapy or
combined chemoradiation therapy for any patient without
metastatic disease who is either node positive or staged as
T2or greater in the preoperative setting.
4
e role of combined modality chemoradiation adjuvant
therapy in the postoperative period has been established to
4
signicantly increase patient overall survival rates.
Until
recently, the benet of adjuvant chemotherapy in the absence
of radiation has been more controversial. A recent metaanalysis published in the Journal of the American Medical
Association by the Global Advanced/Adjuvant Stomach
Tumor Research International Collaboration (Gastric) Group
provided the rst level I evidence to support the benets of
50
uorouracil-based adjuvant chemotherapy.
ey reported a
statistically signicant increase in both overall survival and
disease-free survival, when compared to surgery alone. e
current NCCN guidelines recommend adjuvant therapy
for patients without distant disease based on their pathological disease stage and resection margin status. e addition of adjuvant therapy is optional for those who undergo
an R0 resection with stage T2/N0/M0 or lesser disease. For
those who underwent an R1 resection or an R0 resection
with greater than T2 or node-positive disease, an adjuvant
uoropyrimidine-based chemoradiation regimen (preferred)
or alternative chemotherapy alone is recommended. Patients
who undergo an R2 resection, regardless of T or N stage, have
the option of undergoing therapy as noted previously for an
R1 section or alternatively may be treated with best supportive care in the absence of adjuvant therapy. Unless patients
are enrolled in an approved study protocol, we recommend
adherence to the most current published treatment guidelines
outlined by the NCCN.
4
SURGICAL APPROACH TO
GASTRIC CANCER
e principles of surgical resection are to obtain resection
margins that are grossly at least 5 cm from the visible or palpable mass.
pathological analysis to access margin status. Ideally, margins
should be microscopically free from cancer, often referred to
as an R0 resection.
free of microscopic disease, an additional resection should be
performed if anatomically feasible. Obtaining an R0 resection
is the guiding principle in determining whether to perform a
distal gastrectomy, a total gastrectomy, or an esophagogastrectomy. e long-term survival rates for patients undergoing
a total gastrectomy and a distal gastrectomy are similar provided that negative surgical margins are obtained.
a more limited surgical resection may provide a lower rate
of postoperative complications and a higher quality of life.
Although some authors advocate performing a proximal gastrectomy for limited proximal gastric cancers, the authors of
this chapter have not found consistent convincing evidence
for its benet over total gastrectomy. In proximal gastrectomy, the antrum can be preserved; however, it is not highly
distensible and provides little capacity advantage compared to
total gastrectomy. We have therefore decided not to include
the technique for proximal gastrectomy in this chapter but
recognize that it is a reasonable surgical option practiced at
some centers.
It is important to acknowledge that preoperative staging
is not always correct and that some patients will be found
to be unable to undergo curative resection at the time of
surgery. ese include patients found to have previously
undiagnosed distant metastatic disease, carcinomatosis, or
advanced locoregional disease. It is for this reason that many
authors advocate laparoscopic staging prior to advancing to a
full laparotomy.
have unresectable disease on laparoscopic evaluation can be
referred for nonsurgical treatment options without suering
the attendant risks of a full laparotomy or radical surgical
resection. Functional, but symptomatic, patients presenting
with marked anemia or obstructive symptoms may benet
from a limited surgical approach to include intestinal bypass
or partial gastric resection as a palliative measure. ese
patients do not necessarily need to undergo laparoscopic
staging because they will need a palliative procedure if they
are found to be unresectable for cure.
In experienced centers, patients with limited disease may
be candidates for laparoscopic gastrectomy for cancer. Recent
published case series and one randomized control study have
shown patients undergoing laparoscopic gastric resections to
have similar oncological outcomes to patients undergoing
52
e specimen should be sent for frozen-section
53
If the surgical margins are not initially
54
However,
4
Relatively asymptomatic patients found to
55
Chapter 22 Gastric Adenocarcinoma and Other Gastric Neoplasms (Except Gastrointestinal Stromal Tumors) 469
open gastrectomy techniques.
56–58
e data from these studies are limited, and the selection criteria dening patients
appropriate for laparoscopic resection have not yet been well
dened. Sucient randomized data have not convincingly
demonstrated equivalent or superior survival following laparoscopic resection compared to laparotomy and resection. If
applied, the laparoscopic approach should follow the same
surgical principles as for open gastric resection. e major
dierences will lie in the unique requirements of the laparoscopic approach. Because it has not been studied suciently
to regard it as the standard of care, we have elected not to
include a detailed description of nuances of the laparoscopic
approach in this chapter.
Extent of Lymph Node Dissection
e importance of the presence and extent of lymph node
metastasis is reected in the system used to stage the disease
and provide prognosis for the patient’s extent of disease. What
is less clear, however, is the impact of surgical resection of
regional lymph nodes on survival. e locoregional gastric
nodes have been characterized based on their anatomical location relative to the stomach and are described according to
their stations 1–11.
1, 3, and 5 lymph nodes are located along the lesser curvature
of the stomach. Stations 2, 4, and 6 nodes lie along the greater
curvature of the stomach. Station 7 nodes are found in the
tissue along the left gastric artery, station 8 nodes along the
common hepatic artery, station 9 nodes along the celiac artery,
and stations 10 and 11 nodes along the splenic artery.
e perigastric lymphatics located at nodal stations 1–6
make up a subset of lymph nodes referred to as N1 nodes.
Lymph nodes located at nodal stations 7–11 are referred to
FIGURE 22-3 Gastric lymph node stations.
59
As demonstrated in Fig. 22-3, stations
as N2 nodes. All other nodes encountered in the surgical
dissection are considered distant nodes and are thought to
preclude a curative resection when positive for metastasis. e
extent of surgical lymph node dissection has traditionally been
categorized as a D1 resection when care is taken to completely
dissect and remove all of the N1 nodes with the surgical specimen, a D2 resection when all N1 and N2 nodes are completely dissected and removed, or a D0 resection when stations
4
1–6 are not completely removed.
e extent of resection is
important when the Japanese gastric cancer staging system
is used; however, it is not used as a prognostic factor in the
TNM staging system adopted by Western nations. When the
TNM staging system is used, the most important principles
of lymph node dissection that have emerged are to remove
all grossly involved nodes and to obtain at least 15 perigastric
lymph nodes for pathological sampling.
47
e extent of lymph node dissection to be performed
and its impact on postoperative survival is perhaps the most
debated topic in surgery for gastric cancer. e Japanese
and, more recently, several European centers have published
studies advocating more extensive D2 and D3 lymph node
dissections for patients undergoing surgery with curative
60–62
intent.
e literature on this topic contains a large number of small case series, retrospective studies, and uncontrolled
noncomparative studies on the impact of various degrees of
lymph node dissection concurrent with both partial and total
gastrectomy for gastric cancer. Only two RCTs from Western centers that had adequate study designs and appropriate
statistical analysis of outcomes measures have been published
comparing D1 and D2 lymph node dissections in gastric
63–67
cancer patients.
Both studies evaluated similar primary
outcomes measures looking at 5-year survival rates, postop-
5
erative morbidity, and postoperative mortality. Both studies
concluded that a more extensive D2 dissection provided no
signicant benet to 5-year survival, while those patients
undergoing D2 lymph node dissections had signicantly
more postoperative complications and a higher in-hospital
mortality rate. Other, nonrandomized single-arm trials evaluating outcomes after D2 dissections completed at specialized
centers noted much lower postoperative morbidity and mortality rates, similar to rates reported for D1 dissections. ese
authors have criticized the data from the previously described
RCT, stating that they suered from lack of surgeon experience and operative standardization.
62,68
In 2004 the Cochrane collaboration attempted to
determine the superiority of D1 versus D2 lymph node
dissections for gastric cancer through a meta-analysis and
68
systematic review of the literature.
Here they critically analyzed the literature, then evaluated properly conducted studies from both randomized control trials and nonrandomized
trials with similar outcomes measures. Based on a meta-analysis of RCT, they concluded there was no survival benet to
patients undergoing a D2 dissection, with the possible exception of patients with T3-positive disease. ey also concluded
that there was a markedly higher operative mortality rate specically associated with D2 dissection and concurrent spleen
and pancreas resection. ey also noted that both RCTs were
470 Part IV Stomach and Duodenum
confounded by a lack of surgeon compliance and inexperience. Based on published nonrandomized comparative studies, they concluded that D2 dissections may provide a survival
bene t to patients with intermediate-stage gastric cancer. In
addition, based on their analysis of published observational
studies, they found that patients undergoing D2 dissections
may have an overall survival advantage without a markedly
increased operative mortality rate when performed at experienced centers. Overall, they noted the available published
data comparing D1 and D2 lymph node dissections to be
68
limited and seriously awed.
Since the publication of the Cochrane review, numerous
nonrandomized comparative studies and single-armed
observational studies have continued to argue the case for
the bene t of a D2 dissection over a D1 dissection. e
majority of these studies have shown that patients undergoing D2 dissections have superior 5-year survival rates with
equivalent or better rates of operative-associated morbidity and mortality. Most authors attribute these ndings to
improved surgical skill and experience along with performance of D2 dissections without performing concurrent
spleen and pancreas resections, as was standard for both of
60–62,
69–71
the published RCTs.
In support of this, the Dutch
RCT study group recently published a 15-year follow-up
of their trial and noted an increased trend in the overall
15-year survival rate of patients undergoing D2 resections
(29%) compared to patients undergoing D1 resections
(21%), though the di erence proved not to be statistically
signi cant ( p = .34). ey did, however, nd a signi cantly
lower gastric cancer–related death rate and lower rate of
locoregional recurrence in the D2 population. Based on
these data, and contrary to previous recommendations from
this group, they now advocate D2 lymphadenectomy for
patients undergoing curative resection when performed at
experienced high-volume centers using safer spleen-preserving
71
techniques.
Despite the increasing trend in the literature
advocating D2 lymph node dissections, it is clear that further multicenter RCTs are needed to determine the risks
and bene ts of more extensive lymph node dissection techniques. Currently, the question of whether to perform a
D1 versus a D2 dissection for patients undergoing surgery
with curative intent remains to be determined by individual
surgeons and their associated multidisciplinary cancer treatment teams ( Table 22-3 ).
e system of lymph node staging in gastric cancer also
continues to be a topic of debate. In a recent study of over
700 gastric cancer patients, four lymph node staging systems,
including the Japanese and TMN systems were compared for
their ability to predict patient outcomes. In this study the
system found to be easiest to use and most predictive of postoperative outcomes was a method based on the ratio of nodes
positive for metastatic disease to the total number of nodes
collected, independent of the total number of nodes sampled.
72
In light of data from this and other recent studies and the
ongoing intense debate regarding the optimal staging of lymph
nodes in gastric cancer, we are likely to see modi cations to
the current systems in the future.
TABLE 22-3: RANDOMIZED CONTROLLED
TRIAL RESULTS COMPARING D1 VERSUS
D2 LYMPH NODE DISSECTION IN PATIENTS
UNDERGOING GASTRECTOMY WITH
CURATIVE INTENT
Number
Authors
Bonenkamp
63
et al
Bonenkamp
64
et al
Hartgrink
67
et al
Songun
71
et al
Cuschieri
65
et al
Cuschieri
66
et al
Study
Groups
Dutch 711 Perioperative
Dutch 711 Mean 5-y
Dutch 711 Mean 11-y
Dutch 711 Mean 15-y
British 400 Perioperative
British 400 Mean 5-y
of
Patients
Outcomes
Measure Findings
D2 dissection
mortality
survival rate
survival rate
survival rate
mortality
survival rate
had signi cantly
higher mortality
rate
No di erence in
5-y survival rate
between groups
No di erence in
11-y survival rate
between groups
No di erence in
overall survival
rate between
groups
Statistically
higher local
recurrence rate
in D1 group
Statistically
higher cancerspeci c death
rate in D1 group
D2 dissection
had signi cantly
higher mortality
rate
No di erence in
5-y survival rate
between groups
Endoscopic Submucosal Resection
Endoscopic submucosal resection (ESR) is a minimally
invasive resection technique usually performed by gastroenterologists, primarily in Japan and a few specialized centers
worldwide.
(<2 cm) mucosal lesions that have a very low risk of lymph
node metastasis and no ndings consistent with metastatic
disease.
lesions at high risk for lymph node metastasis in patients
with a poor performance status or in higher-risk lesions
when ESR is accompanied by a laparoscopic lymph node
dissection. e results of ESR case series on patients meeting these later criteria are published in the literature, but
appropriate controlled studies and scienti c analysis of this
technique for higher-risk lesions are absent.
4,
73 is procedure is reserved for relatively small
74
Recently this technique was extended to include
75,
76
Chapter 22 Gastric Adenocarcinoma and Other Gastric Neoplasms (Except Gastrointestinal Stromal Tumors) 471
SURGICAL TECHNIQUES FOR
GASTRIC CANCER
Distal Gastrectomy
Laparoscopic exploration of the peritoneal cavity should
be considered prior to initiation of a formal laparotomy to
ensure absence of carcinomatosis or distant disease that would
preclude a curative resection. Patients in whom the yield of
laparoscopy may be higher include those with a prolonged
duration of symptoms, those with weight loss, and those with
equivocal CT ndings of metastatic disease. NCCN guidelines suggest that the use of laparoscopy may be helpful in
complete clinical staging prior to resection, but the level of
evidence supporting its use is not high enough to make it
the standard of care for all patients.
or bilateral subcostal incision is made of adequate length to
allow placement of a xed surgical retractor and facilitate adequate operative exposure. e operative sequence that follows
may vary depending on the extent of lymph node dissection
and the reconstructive technique chosen.
Step 1 is to identify the location of the tumor through
manual palpation, or for smaller lesions, visualization of an
endoscopically placed tattoo. is rst step is essential in
order to determine the extent of resection necessary to obtain
an adequate resection margin. It is critically important in
proximal lesions to ensure that a negative esophageal margin can be obtained before transaction of the duodenum.
Next, if there is a high concern for metastatic disease, the
duodenum and pancreatic head are mobilized in order to
expose the para-aortic lymph nodes that may demonstrate
signs of distant nodal spread and help establish whether there
is potential for a curative resection. e retroperitoneum is
then incised along the lateral border of the second portion
of the duodenum. Medial visceral rotation of the duodenum
and pancreatic head is performed, exposing the inferior vena
cava (IVC) and aorta. e exposed para-aortic lymph nodes
located in the aortocaval space are dissected and sampled. If
pathologic-appearing nodes are encountered, frozen-section
analysis should be performed to exclude distal nodal spread,
as this would preclude a curative resection. Once the absence
of distal nodal spread is conrmed, we commence with the
inferior portion of the dissection.
e gastrocolic ligament is detached from the transverse colon along the avascular plane using electrocautery
(Fig. 22-4). e anterior layer of the transverse mesocolon
is sharply dissected to the level of the inferior border of
the pancreas. is step separates the anterior mesocolonic
peritoneum from the underlying vessels and posterior layer,
thus skeletonizing the mesocolonic vessels (Fig. 22-5). e
exposed right gastroepiploic vessels are ligated and transected. Dissection of the anterior layer of the mesocolon
is typically continued to its conuence with the anterior
capsule of the pancreas. e dissection will expose the left
gastroepiploic vessels, which must be ligated and transected.
Continued dissection of the anterior pancreatic capsule is
continued to the superior margin of the pancreas, allowing
4
Next, an upper midline
FIGURE 22-4 Detachment of the greater omentum from the colon
through the avascular plane.
FIGURE 22-5 e anterior mesocolon is separated from the
underlying vessels and posterior layer.