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1. MALIGNANT NEOPLASMS OF THE STOMACH
By solomon L.(MD,R)

2. • The three most common primary malignant gastric neoplasms are
– adenocarcinoma (95%),
– lymphoma (4%),
– and malignant GIST (1%)
• Other rare primary malignancies include
– carcinoid,
– angiosarcoma,
– carcinosarcoma, and
– squamous cell carcinoma.
• Occasionally the stomach is the site of hematogenous metastasis from other sites (e.g., melanoma or
breast)
• More commonly, malignant tumors from adjacent organs invade the stomach by direct extension (e.g.,
colon or pancreas) or by peritoneal seeding (e.g., ovary)

3. • Adenocarcinoma
• Epidemiology
• Globally, gastric cancer is the fourth most common cancer type and the second leading cause of cancer
death
• There has been a dramatic decrease in the gastric cancer incidence and death rate in most Western
industrialized countries (Fig. 26-49)
• This decrease has been largely in the so-called intestinal form rather than in the diffuse form of gastric
cancer
• In Asia and Eastern Europe, gastric cancer remains a leading cause of cancer death
• In 2012 in the United States, 21,320 new cases (13,020 in men and 8300 in women), and 10,540 deaths
from this disease (6190 men and 4350 women.
• The estimated 5-year survival rate is 27%, up from about 15% in 1975

4. • In general, gastric cancer is a disease of the elderly, and it is twice as common in blacks as in whites
• In younger patients, tumors are more often of the diffuse variety and tend to be large, aggressive, and
more poorly differentiated, sometimes infiltrating the entire stomach (linitis plastic)
• Gastric cancer has a higher incidence in groups of lower socioeconomic status.
• Etiology
• more common in patients with pernicious anemia, blood group A, or a family history of gastric cancer
• When patients migrate from a high-incidence region to a low-incidence region, the risk of gastric cancer
decreases in the subsequent generations born in the new region
– strongly suggests an environmental influence on the development of gastric cancer
• Environmental factors appear to be more related etiologically to the intestinal form of gastric cancer
than the more aggressive diffuse form
• The commonly accepted risk factors for gastric cancer are listed in Table 26-15.

5. • Diet and Drugs
• Typically, a starchy diet high in pickled, salted, or smoked food
• Dietary nitrates
• Gastric bacteria (more common in the achlorhydric stomach of patients with atrophic gastritis) convert
nitrate into nitrite, a proven carcinogen
• A diet high in fresh fruits and vegetables and rich in vitamin C and E has been shown to decrease the
population’s risk of gastric cancer
• The reduced consumption of nitrate-rich preserved foods seen with the growth of refrigeration has
been suggested as a cause of the dramatic decrease in gastric cancer seen in North America and
Western Europe over the last century
• Tobacco use probably increases the risk of stomach cancer, and alcohol use probably has no effect
• Regular aspirin use may be protective

6. • Helicobacter pylori
• The risk is increased about threefold in patients with chronic H. pylori infection
• patients with a history of GU are more likely to develop gastric cancer
• patients with a history of DU are at decreased risk for gastric cancer
– Due to the fact that some patients develop antral-predominant disease (predisposing to duodenal
ulcer and somehow protecting )
• patients with corpus-predominant gastritis, resulting in hypochlorhydria and somehow predisposing to
gastric ulcer and gastric cancer
• The theoretical sequence for development of gastric adenocarcinoma Fig. 26-51.
• Recently, bone marrow-derived stem cells play a key role in the pathogenesis of gastric adenocarcinoma
in patients with chronic H. pylori infection
• A gastric adenocarcinoma is a multifactorial disease
• Not all patients with gastric cancer have H. pylori, and there are some geographic areas with a high
prevalence of chronic H. pylori infection and a low prevalence of gastric cancer (the “African enigma”)

9. • Finally, H. pylori-infected patients seem to be at decreased risk for the development of adenocarcinoma
of the distal esophagus and cardia region
– The corporeal gastritis decreases acid secretion, creating a less damaging refluxate and thus
reducing the risk for Barrett’s esophagus, the precursor lesion for these tumors
• Epstein-Barr Virus
• About 10% of gastric adenocarcinomas carry the EBV virus
• Recently it has been suggested that EBV infection is a rather late step in gastric carcinogenesis, since
EBV transcripts are present in cancer cells but not in the metaplastic cells of precursor epithelium

10. • Genetic Factors
• A variety of genetic abnormalities have been described in gastric cancer (Table 26-16)
• Most gastric cancers are aneuploid
• The most common genetic abnormalities in sporadic gastric cancer affect the p53 and COX-2genes
• Over two thirds of gastric cancers have deletion or suppression of the important tumor-suppressor gene
p53
• Additionally, approximately the same proportion have overexpression of COX-2
• In the colon, tumors with upregulation of this gene have suppressed apoptosis, more angiogenesis, and
higher metastatic potential
• Gastric tumors that overexpress COX-2are more aggressive tumors
• Recently, a germline mutation in the CDH1 gene encoding E-cadherin associated with hereditary diffuse
gastric cancer
• Prophylactic total gastrectomy should be considered in patients with these mutations

12. • microRNA are small short sequence molecules (18 to 25 nucleotides) which inhibit the translation or
promote the degradation of messenger RNA with complementary sequences
• MicroRNAs are important regulators of gene expression, and abnormalities in microRNA have been
identified in gastric cancer which effect the cell cycle, apoptosis, and cellular invasiveness and/or
metastatic potential
• microRNA will have increasing diagnostic, therapeutic, and prognostic significance

13. • Premalignant Conditions of the Stomach Figure 26-52 shows the prevalence of some premalignant
conditions associated with the development of early gastric cancer in a series of 1900 cases from Tokyo
• By far the most common precancerous lesion is atrophic gastritis
• chronic inflammatory milieu has important influence on the genome of mucosal cells
• Chronic inflammation leads to both genetic and epigenetic changes in mucosal cells which in the
stomach leads to the development of gastritis associated cancer

15. • Polyps
• Benign gastric polyps are classified as
– neoplastic (adenoma and fundic gland polyps) or
– nonneoplastic (hyperplastic polyp, inflammatory polyp, hamartomatous polyp)
– Inflammatory and hamartomatous polyps have little or no malignant potential
• Gastric adenomas are premalignant, similar to colon adenomas
• Fundic gland polyps, commonly seen in patients on long term PPI, are not premalignant but in patients
with FAP, dysplasia in these lesions is not uncommon
• Hyperplastic polyps usually occur in the setting of chronic inflammation
– Large hyperplastic polyps (>2cm) may harbor dysplasia or carcinoma in situ
• Patients with FAP have a high prevalence of gastric adenomatous polyps (about 50%)
– 10 times likely to develop adenocarcinoma of the stomach than the general population

16. • Gastric polyps greater than 1cm should be removed to confirm the diagnosis and to eliminate any risk of
malignant degeneration
• Patients with gastric adenomatous polyps and FAP should have periodic upper endoscopy, which may
also be considered in selected patients with hyperplastic polyps and chronic gastric inflammation
• Atrophic Gastritis
• Chronic atrophic gastritis (Fig. 26-53) is by far the most common precursor particularly the intestinal
subtype (see Fig. 26-52)
• The prevalence of atrophic gastritis is higher in older age groups, but it is also common in younger
people in areas with a high incidence of gastric cancer
• In many patients, it is likely that H. pylori is involved in the pathogenesis of atrophic gastritis
• Correa described three distinct patterns of chronic atrophic gastritis
– autoimmune (involves the acid-secreting proximal stomach),
– hypersecretory (involving the distal stomach), and
– environmental (involving multiple random areas at the junction of the oxyntic and antral mucosa)

18. • Intestinal Metaplasia
• Gastric carcinoma often occurs in an area of intestinal metaplasia
• an individual’s risk of gastric cancer is proportional to the extent of intestinal metaplasia of the gastric
mucosa
• These observations strongly suggest that intestinal metaplasia is a precursor lesion to gastric cancer.
• There are different pathologic subtypes of intestinal metaplasia in the stomach, based upon the
histologic and biochemical characteristics of the changed mucosal glands
• In the complete type of intestinal metaplasia,
– the glands are completely lined with goblet cells and intestinal absorptive cells (Fig. 26-54)
– These cells are indistinguishable histologically and biochemically from their small bowel counterparts, and are not seen in the
normal stomach
– There is evidence that eradication of H. pylori infection leads to significant regression of intestinal metaplasia and
improvement in atrophic gastritis
– Therefore, treatment of H. pylori infection is a reasonable recommendation for patients with these pathologic diagnoses and
H. pylori infection

20. • Benign Gastric Ulcer
• Although once considered a premalignant condition, it is likely that the older literature was confounded
by mistakenly labeling inadequately biopsied ulcers and healing ulcers as “benign,” when, in fact, they
were malignant to begin with
• It is now generally recognized that all gastric ulcers are cancer until proven otherwise with adequate
biopsy and follow-up
• Even today, carcinomas are occasionally found when adequately biopsied “benign” ulcers are resected
for nonhealing
• It is more than likely that the factors previously discussed are more significant etiologically in the
development of gastric cancer than the history of a benign gastric ulcer

21. • Gastric Remnant Cancer
• stomach cancer can develop in the gastric remnant, usually years following distal gastrectomy for PUD
• Most tumors develop >10 years following the initial operation, and they usually arise in an area of
chronic gastritis, metaplasia, and dysplasia
• often near the stoma, but many of these tumors are quite large at presentation, and are equally divided
between intestinal and diffuse subtypes.
• Most cases have been reported following Billroth II ,but also cases following Billroth I procedure
• Whether simple loop gastrojejunostomy increases a patient’s risk of gastric cancer, and whether a
Rouxen-Y anastomosis following gastric resection lowers their risk of gastric cancer is unknown
• Stage for stage, the prognosis for gastric stump cancer is similar to proximal gastric cancer

22. • Other Premalignant States
• A mutated E-cadherin gene is associated with hereditary diffuse gastric cancer
• Prophylactic total gastrectomy should be considered
• A myriad of genetic and environmental factors will affect members of the same family, and up to 10% of
gastric cancer cases appear to be familial without a clear-cut genetic diagnosis
• First-degree relatives have a two- to threefold increased risk
• Patients with HNPC carcinoma have a 10% risk ,predominantly the intestinal subtype
• The mucous cell hyperplasia of Ménétrier’s disease is generally considered to carry a 5% to 10% risk of
adenocarcinoma
• Periodic surveillance EGD is prudent in all the above conditions
• The glandular hyperplasia associated with gastrinoma is not premalignant, but ECL hyperplasia and/or
carcinoid tumors can occur

23. • Pathology
• Dysplasia
• Gastric dysplasia is the universal precursor to gastric adenocarcinoma
• Patients with severe dysplasia should be considered for
– gastric resection if the abnormality is widespread or multifocal, or
– EMR if the severe dysplasia is localized
• Patients with mild dysplasia should be followed with endoscopic biopsy surveillance, and Helicobacter
eradication

24. • Early Gastric Cancer
• Defined as adenocarcinoma limited to the mucosa and submucosa of the stomach, regardless of lymph
node status
• The entity is common in the Orient, where gastric cancer is a common cause of cancer death, and
aggressive surveillance programs have been established
• 10% of patients will have lymph node metastases
• There are several types and subtypes of early gastric cancer (Table 26-17 and Fig. 26-55)
• Approximately 70% of early gastric cancers are well differentiated, and 30% are poorly differentiated
• The overall cure rate with adequate gastric resection and lymphadenectomy is 95%
• In some Japanese centers, 50% of the gastric cancers treated are early gastric cancer
• In USA, less than 20% of resected gastric adenocarcinomas are early gastric cancer
• Small intramucosal lesions can be treated with EMR

26. • Gross Morphology and Histologic Subtypes
• There are four gross forms of gastric cancer
– polypoid, fungating, ulcerative, and scirrhous
• In the first two, the bulk of the tumor mass is intraluminal
• Polypoid tumors are not ulcerated; fungating tumors are elevated intraluminally, but also ulcerated
• In the latter two gross subtypes, the bulk of the tumor mass is in the wall of the stomach
• Ulcerative tumors are self-descriptive; scirrhous tumors infiltrate the entire thickness of the stomach
and cover a very large surface area
• Scirrhous tumors (linitis plastica) have a particularly poor prognosis, and commonly involve the entire
stomach
• Although these latter lesions may be technically resectable with total gastrectomy, it is common for both
the esophageal and duodenal margins of resection to show microscopic evidence of tumor infiltration,
and death from recurrent disease within 6 months is common
• Palliative chemotherapy may prolong median survival

27. • The location of the primary tumor in the stomach is important in planning the operation
• Several decades ago, the large majority of gastric cancers were in the distal stomach
• Recently, there has been a proximal migration of tumors, so that currently, the distribution is closer to
40% distal, 30% middle, and 30% proximal
• Histology
• The most important prognostic indicators are both histologic: lymph node involvement and depth of
tumor invasion
• Tumor grade (degree of differentiation: well, moderately, or poorly) is also important prognostically

28. • There are several histologic classifications of gastric cancer
• The WHO recognizes several histologic types (Table 26-18)
• The Japanese classification is similar but more detailed
• The commonly used Lauren classification separates gastric cancers into
– intestinal type (53%),
– diffuse type (33%), and
– unclassified (14%)
• The intestinal type is associated with chronic atrophic gastritis, severe intestinal metaplasia, and
dysplasia, and tends to be less aggressive than the diffuse type
• The diffuse type of gastric cancer is poorly differentiated and is associated with younger patients and
proximal tumors
• The Ming classification also is useful and easy to remember, only two types—
– expanding (67%) and
– infiltrative (33%)

29. • Recently, the significance of human epidermal growth factor receptor-2 (HER2) was reported in patients
with gastric cancer
• In breast cancer, overexpression of HER2 has been reported in 15% to 25% and is well recognized as one
of the unfavorable prognostic factors
• However, the development of molecular targeted agents such as trastuzumab has improved the survival
of HER2 positive patient
• Likewise, recently in gastric cancer, HER2 overexpression has been reported in 13% to 30% of patients
• According to the result of large clinical trial, Immunohistochemistry (IHC) staining of HER2 has become
the important examination for recurrent or metastatic gastric cancer to decide the treatment strategy

31. • Pathologic Staging
• Ultimately, prognosis is related to pathologic stage
• The most widespread system for staging of gastric cancer is the tumor-node-metastasis (TNM) staging
system
• This system was developed by the American Joint Committee on Cancer and the International Union
Against Cancer, and has under gone several modifications since it was originally conceived (Table 26-19)

33. • Clinical Manifestations
• Most patients who are diagnosed in the United States have advanced stage III or IV disease at the time
of diagnosis
• The most common symptoms are weight loss and decreased food intake due to anorexia and early
satiety
• Abdominal pain (usually not severe and often ignored) also is common
• Other symptoms include nausea, vomiting, and bloating
• Acute GI bleeding is somewhat unusual (5%), but chronic occult blood loss is common and manifests as
iron deficiency anemia and heme-positive stool Dysphagia is common if the tumor involves the cardia of
the stomach
• Paraneoplastic syndromes such as Trousseau’s syndrome (thrombophlebitis), acanthosis nigricans
(hyperpigmentation of the axilla and groin), or peripheral neuropathy are rarely present

34. • Physical examination
• typically is normal
• Other than signs of weight loss, specific physical findings usually indicate incurability
• A focused examination in a patient in whom gastric cancer is a likely part of the differential diagnosis
should include an examination of the neck, chest, abdomen, rectum, and pelvis
• Cervical, supraclavicular (on the left referred to as Virchow’s node), and axillary lymph nodes may be
enlarged, and today can be sampled in the office with fine-needle aspiration cytology
• There may be a metastatic pleural effusion, or aspiration pneumonitis in a patient with vomiting and/or
obstruction

35. • An abdominal mass could indicate a large (usually T4 incurable) primary tumor, liver metastases, or
carcinomatosis (including Krukenberg’s tumor of the ovary)
• A palpable umbilical nodule (Sister Joseph’s nodule) is pathognomonic of advanced disease, or there may be
evidence on exam of malignant ascites
• Rectal exam may reveal
– heme-positive stool and
– hard nodularity extraluminally and anteriorly,
• so-called drop metastases, or rectal shelf of Blumer in the pouch of Douglas

36. • Diagnostic Evaluation
• Distinguishing between peptic ulcer and gastric cancer on clinical grounds alone is usually impossible
• Patients over the age of 45 years old who have new-onset dyspepsia, as well as all patients with dyspepsia
and alarm symptoms (weight loss, recurrent vomiting, dysphagia, evidence of GI bleeding, or anemia) or with
a family history of gastric cancer should have prompt upper endoscopy and biopsy if a mucosal lesion is noted
• Essentially, all patients in whom gastric cancer is part of the differential diagnosis should have endoscopy and
biopsy
• If suspicion for cancer is high and the biopsy is negative, the patient should be re-endoscoped and more
aggressively biopsied
• In some patients with gastric tumors, upper GI series can be helpful in planning treatment
• Although a good double-contrast barium upper GI examination is sensitive for gastric tumors (up to 75%
sensitive), in most centers, endoscopy has become the gold standard for the diagnosis of gastric malignancy

37. • In addition, recent advances in endoscopy have contributed to the earlier diagnosis of gastric cancer
• Magnifying endoscopy with narrow-band imaging (NBI) has undergone technological improvements and
can observe the microvascular architecture of the mucosa and microsurface pattern of the lesion
• Magnifying endoscopy with NBI has been reported to be accurate and reliable in the diagnosis of early
gastric cancer.
• Furthermore, endocytoscopy, a technique allowing microscopic visualization of the mucosal surface, has
been developed and has the potential for pathological diagnosis.
• Another diagnostic innovation is virtual endoscopy which is an imaging examination of the
gastrointestinal tract reconstructed by multidetector-row computed tomography
• The image of virtual endoscopy is now quite similar to that of upper endoscopy
• In the near future, this novel technology may play a role in the screening of the stomach

38. • Preoperative staging of gastric cancer is best accomplished with abdominal/pelvic CT scanning with IV
and oral contrast
• MRI is probably comparable
• The best way to stage the tumor locally is via EUS, which gives fairly accurate (80%) information about
the depth of tumor penetration into the gastric wall, and can usually show enlarged (>5 mm) perigastric
and celiac lymph nodes
• In some centers, if the tumor is transmural (T3) or involves lymph nodes (enlarged nodes can usually be
needled under endoscopic ultrasound guidance), preoperative (neoadjuvant) chemotherapy is given
• However, there are limitations to tumor staging with EUS
• It largely is operator dependent and may underestimate lymph node involvement because normal-sized
nodes (<5 mm) can harbor metastases
• EUS is most accurate in distinguishing early gastric cancer (T1) from more advanced tumors

39. • Positron Emission Tomography Scanning
• Whole-body PET scanning uses the principle that tumor cells preferentially accumulate positron-
emitting 18F-fluorodeoxy glucose
• This modality is most useful in the evaluation of distant metastasis in gastric cancer but can also be
useful in locoregional staging
• PET scan is accurate when combined with spiral CT (PET-CT)and should be considered before major
surgery in patients with particularly high-risk tumors or multiple medical comorbidities
• Staging Laparoscopy and Peritoneal Cytology
• To some extent, the usefulness of these modalities depends on the individual patient’s situation as well
as the treatment philosophy of the cancer team

40. • The fundamental question is “will it make a difference to this patient’s management? disease) Patients
with gastric cancer who undergo R0 resection (i.e., no gross residual disease) and
• Are found to have positive peritoneal cytology (no gross carcinomatosis) have a much worse prognosis
than the cytology negative group (median survival 14.8 months vs. 98.5 months)
• It is controversial how much this information adds prognostically to that of pathologic staging (TNM)
• Whether this poor prognosis can be improved postresection with aggressive adjuvant treatment
(systemic, or local intraperitoneal hyperthermic chemotherapy) is unknown
• Unfortunately, it is also unclear how much these patients benefit from gastric resection
• Currently peritoneal cytology information is unlikely to change the treatment of patients with gastric
cancer, and most patients without detectable distant metastases will have (and should have) gastric
resection regardless of the peritoneal cytology results

41. • A quick laparoscopic examination can occasionally reveal small peritoneal implants or liver metastases
that were not detected on preoperative imaging studies and, in some patients (e.g., high risk for surgery
or impressive carcinomatosis), this will change the operative plan and avoid a major but futile surgical
procedure
• Laparoscopy may be most useful in patients with proximal tumors or with adenopathy on spiral CT scan
• An extensive laparoscopic staging procedure, although quite accurate, has not been widely adopted

42. • Treatment
• Surgical resection is the only curative treatment for gastric cancer and most patients with clinically
resectable locoregional disease should have gastric resection
• Obvious exceptions include patients who cannot tolerate an abdominal operation, and patients with
overwhelming metastatic disease
• The goal of curative surgical treatment is resection of all tumor (i.e., R0 resection)
• Thus, all margins (proximal, distal, and radial) should be negative and an adequate lymphadenectomy
performed
• Generally, the surgeon strives for a grossly negative margin of at least 5 cm
• Some gastric tumors, particularly the diffuse variety, are quite infiltrative and tumor cells can extend
well beyond the tumor mass; thus, gross margins beyond 5 cm may be desirable

43. • Frozen section confirmation of negative margins is important when performing operation for cure, but it
is less important in patients with nodal metastases beyond the N1 nodal basin
• It should be strongly emphasized that many patients with positive lymph nodes are cured by adequate
surgery
• It should also be stressed that often lymph nodes that appear to be grossly involved with tumor turn out
to be benign or reactive on pathologic examination
• More than 15 resected lymph nodes are required for adequate staging
• Therapeutic nihilism should be avoided and, in the low-risk patient, an aggressive attempt to resect all
tumor should be made
• The primary tumor may be resected en bloc with adjacent involved organs (e.g., distal pancreas,
transverse colon, or spleen) during the course of curative gastrectomy
• Palliative gastrectomy may be indicated in some patients with obviously incurable disease, but most
patients presenting with stage IV gastric cancer can be managed without major operation

44. • Extent of Gastrectomy
• The standard operation for gastric cancer is radical subtotal gastrectomy
• Unless required for R0 resection, total gastrectomy confers no additional survival benefit and may have
adverse nutritional or quality-of-life consequences, and higher peri-operative morbidity and mortality
• Subtotal gastric resection typically entails ligation of the left and right gastric and gastroepiploic arteries
at the origin, as well as the en bloc removal of the distal 75% of the stomach, including the pylorus and 2
cm of duodenum, the greater and lesser omentum, and all associated lymphatic tissue (Fig. 26-56).
• Reconstruction is usually by Billroth II gastrojejunostomy, but if a small gastric remnant is left, a Roux-
en-Y reconstruction is considered

46. • In East Asia especially in Japan, Billroth-I gastroduodenostomy was usually performed after distal
gastrectomy
• Billroth-I gastroduodenostomy consists of one anastomosis (which is usually straightforward and keeps
the duodenum in the food stream)
• In the United States, traditional surgical teaching eschews gastroduodenostomy following gastric cancer
resection because of the possibility of anastomotic recurrence and obstruction
• The operative mortality is around 2% to 5%
• Radical subtotal gastrectomy is generally deemed to be an adequate cancer operation in most Western
countries, provided that tumor-free margins are obtained, >15 lymph nodes are removed, and all gross
tumor is resected
• In the absence of involvement by direct extension, the spleen and pancreatic tail are not removed

47. • Total gastrectomy with Roux-en-Y esophagojejunostomy may be required for R0 resection (Fig. 26-57),
and may be the best operation for patients with proximal gastric adenocarcinoma
• The construction of a jejunal pouch can be beneficial nutritionally, particularly for those patients with a
good prognosis

48. • Proximal subtotal gastric resection, a technically feasible alternative to total gastrectomy for some
proximal gastric tumors, requires an esophagogastrostomy to a vagotomized distal gastric remnant, and
the functional outcome is poor
• Pyloroplasty in this setting virtually guarantees bile esophagitis, and if the pylorus is left intact, gastric
emptying may be problematic
• An isoperistaltic jejunal interosition (Henley loop) between the esophagus and antrum could be
considered an alternative reconstruction, but, all things considered, total gastrectomy usually results in
superior functional, if not oncologic, results for most patients with proximal gastric cancer

49. • Extent of Lymphadenectomy
• According to the 3rd edition of Japanese classification of gastric carcinoma, lymph node stations are
numbered by anatomical definition
• Lymph node stations from 1 to 12, and 14V are classified as regional lymph nodes and metastasis of any
other lymph node is classified as distant metastasis (M1) (see Fig. 26-4)
• According to the type of gastrectomy, the definition of extent of lymphadectomy is different
• D1 lymphadenectomy in distal gastrectomy requires the dissection of the stations 1, 3, 4sb, 4d, 5, 6, 7
• Furthermore, additional resection of stations 8a, 9, 11p and 12a is needed for D2 lymphadenectomy
• D1 lymphadenectomy in total gastrectomy requires dissection of stations 1 through 7 and in D2, from 8a
to 12a too

50. • The operation described above (radical subtotal gastrectomy in the Extent of Gastrectomy section),
which is by far the most commonly performed procedure in the United States for gastric cancer, is called
a D1 resection because it removes the tumor and the perigastric D1 nodes
• The standard operation for gastric cancer in Asia and specialized U.S. centers is the D2 gastrectomy,
which involves a more extensive lymphadenectomy (removal of the D1 and D2 nodes
• In addition to the tissue removed in a D1 resection, the standard D2 gastrectomy removes the
peritoneal layer over the anterior mesocolon and selectively over the pancreas, along with nodes along
the hepatic and splenic arteries, and the crural nodes
• Splenectomy and distal pancreatectomy are not routinely performed, because this clearly has been
shown to increase the morbidity of the operation

51. • The purported survival advantage of D2 gastrectomy in gastric cancer is shown in Table 26-20, which
shows the 5-year survival rates for gastric cancer stratified by pathologic stage for the United States and
Japan
• Unfortunately, the randomized prospective trials that have been performed have not confirmed this
survival advantage, but the morbidity and mortality in the D2 group was higher (Table 26-21)
• This was mostly attributable to the splenectomy and distal pancreatectomy, which are no longer
routinely done as part of the D2 gastrectomy in the United States
• However, since D2 lymphadenectomy in total gastrectomy requires the dissection of station 10 which is
splenic hilar lymph node as described above, splenectomy is recommended to fulfill the criteria of D2

53. • In Japan, pancreas-preserving splenectomy is generally performed to avoid the severe postoperative
complications such as pancreas fistula in patients with advanced upper gastric cancer who underwent
total gastrectomy
• Some experts have argued that the D2 operation is simply a better staging procedure, and that the
apparent improved survival with this more extensive dissection is simply an epiphenomenon of
improved pathologic staging
• This stage shift suggests that many patients in the U.S. series treated with D1 gastrectomy really had
metastatic nodes at the D2 level that went unresected and undetected
• Therefore, in the U.S. series, there were patients classified as stage I, who, if they had undergone a D2
gastrectomy, would be classified as stage II; and there were patients classified as stage II, who, if they
had undergone a D2 gastrectomy, would be classified as stage III

54. • The stage I survival in the United States would then actually be closer to the (more accurately staged)
stage II survival in Japan, because this group includes some patients who really are stage II, but the
nodes were not found in the D1 resection
• All experts would agree that to avoid under staging of gastric cancer, a minimum of 15 nodes should be
resected with the gastrectomy specimen
• Despite the lack of strong data from RCTs supporting a survival advantage of D2 gastrectomy for gastric
cancer, this has become standard practice in Asia and has been adopted by an increasing number of
large Western centers
• Reasons for this are safety of operation in experienced hands as well as data from observational studies
and subgroup analysis of RCTs suggesting a survival benefit

55. • Chemotherapy and Radiation for Gastric Cancer
• In general, the actuarial 5-year survival for resected gastric adenocarcinoma stages I, II, and III is about
75%, 50%, and 25%, respectively
• Because most surgical patients have stage II disease or greater, it is common to refer gastric cancer
patients postoperatively to a medical and/or radiation oncologist
• The existing data suggest that the incremental survival benefit attendant to adjuvant treatment is
marginal, particularly in those patients who have had an adequate resection
• In one prospective randomized study, adjuvant treatment with chemotherapy (5-fluorouracil and
leucovorin) and radiation (4500 cGy) has demonstrated a survival benefit in resected patients with stage
II and III adenocarcinoma of the stomach
• Unfortunately, only 10% of patients entered in the study actually had D2 gastrectomy, and most (54%)
had less than an adequate D1 gastrectomy

56. • Because adequacy of lymphadenectomy has clearly been shown to impact survival, particularly in
patients with stage III gastric cancer
• it has been suggested that the benefits of adjuvant chemoradiation shown in this study would be
vitiated by an adequate operation
• Recent clinical trials suggest the potential importance of adjuvant chemotherapy after D2
lymphadenectomy in patients with advanced gastric cancer
• These trials compared surgery alone and surgery plus adjuvant chemotherapy including oral
fluoropyrimidines for curatively resected advanced gastric cancer
• After D2 lymphadenectomy, the benefit of adjuvant chemotherapy has also been established and
further improvement in prognosis is expected

57. • A recently published study from the Japan Clinical Oncology Group showed a 69% overall 5-year survival
rate in patients with clinically curable T2b, T3, and T4 gastric cancer, treated with D2 gastrectomy alone
(no chemotherapy)
• There was no incremental benefit from para-aortic lymph node dissection
• There is no indication for the routine use of radiation alone in (D3) the adjuvant setting, but in certain
patients, it can be effective palliation for bleeding or pain
• Although the prognosis of metastatic or recurrent gastric cancer is poor, systemic chemotherapy
provides a significant survival benefit over the best supportive care

58. • Agents that have shown activity against gastric cancer include 5-fluorouracil (5-FU), cisplatin,
doxorubicin, methotrexate, taxanes, and camptothecin
• Until recently, 5-FU based chemotherapy especially in combination with platinums played a key role in
the treatment for the unresectable gastric cancer as well as several types of cancer, such as colon and
lung
• In the 1990s, the introduction of novel anticancer agents such as camptothecin, taxanes, third-
generation platinums, and new oral fluoropyrimidines, improved the prognosis of unresectable gastric
cancer
• Recently, although the risk of the toxicities is increased, triple combination chemotherapy is associated
with better prognosis than double agent therapy
• In the United States, triple chemotherapy consists of 5-FU, cisplatin and docetaxel and is now
recognized as a standard first-line regimen

59. • In Europe, triple therapy is more often epirubicin, cisplatin, and 5-FU
• Sometimes 5-FU may be replaced by capecitabine which is an oral fluoropyrimidine, and cisplatin can be
replaced by oxaliplatin which does not require hydration, respectively
• Neoadjuvant treatment of gastric adenocarcinoma is being evaluated, particularly in patients with
clinical T3 or N1 disease
• It is likely that targeted molecular agents will have an increasing role in treating gastric cancer
• Recently, Trastuzumab, a humanized molecular antibody reactive against the extracellular domain of
HER2, increased the effectiveness of cytotoxic chemotherapy in patients with advanced gastric cancer
• Other large trials are ongoing
• Determination of HER2 gene amplification status may have prognostic significance

60. • Endoscopic Resection
• It has been demonstrated initially at numerous East Asian centers that some patients with early gastric
cancer can be adequately treated by an endoscopic mucosal resection (EMR)
• EMR is a minimally invasive procedure that provides curative resection and has dramatically changed
the treatment of early gastric cancer
• EMR is indicated for patients in whom the probability of lymph node metastasis is low
• According to the Japanese treatment guidelines for gastric cancer, EMR is a standard treatment for
differentiated mucosal gastric cancer measuring less than 2 cm and without signs of ulceration, which
has almost no risk of lymph node metastasis

61. • En bloc resection is required to evaluate the surgical margin for confirmation of curative resection
• Furthermore, the development of endoscopic submucosal dissection (ESD) allows en bloc resection of
larger tumors
• Therefore, the indications for endoscopic treatment of patients with gastric cancer may be broadened
• New indications for minimally invasive treatment will require evaluation before implementation
• Small tumors (<3 cm) confined to the mucosa have an extremely low chance of lymph node metastasis
(3%), which approaches the operative mortality rate for gastrectomy

62. • If the resected specimen demonstrates no ulceration, no penetration of the muscularis mucosae, no
lymphatic invasion, and size <3 cm, then the risk of lymph node metastases is less than 1%
• Thus, some patients with early gastric cancer might be better treated with the endoscopic technique
• Currently, this should be limited to patients with tumors <2 cm in size that are node negative and
confined to the mucosa on EUS, in the absence of other gastric lesions
• The addition of laparoscopic lymph node sampling may be considered in selected patients

63. • Prognosis
• The 5-year survival for gastric adenocarcinoma has increased from 15% to 22% in the United States over
the past 25 years
• Survival is dependent on pathologic stage (TNM stage) and degree of tumor differentiation
• Other important prognostic factors are sex, age, primary gastric tumor site, tumor size, and tumor depth
• Palliative gastrectomy may be indicated in some patients with obviously incurable disease, but most
patients presenting with stage IV gastric cancer can be managed without major operation

64. • Screening for Gastric Cancer
• In Japan, it clearly has been shown that patients participating in gastric cancer screening programs have
a significantly decreased risk of dying from gastric cancer
• Thus, screening is effective in a high-risk population
• Screening the general population in the United States (a low risk country) does not make sense, but
patients clearly at risk for gastric cancer probably should have periodic endoscopy and biopsy
• This includes patients with familial adenomatous polyposis, hereditary nonpolyposis colorectal cancer,
gastric adenomas, Ménétrier’s disease, intestinal metaplasia or dysplasia, and remote gastrectomy or
gastrojejunostom

65. • Gastric Lymphoma
• Generally account for about 4% of gastric malignancies
• Over half of patients with non-Hodgkin’s lymphoma have involvement of the GI tract
• The stomach is the most common site of primary GI lymphoma, and over 95% are nonHodgkin’s type
• Most are B-cell type, thought to arise in mucosa associated lymphoid tissue (MALT),
• although most high-grade gastric lymphomas are without any characteristics of the low grade MALT neoplasm
• About half of gastric lymphomas are histologically low grade, and about half are high grade
• Interestingly, the normal stomach is relatively devoid of lymphoid tissue
• However, in the setting of chronic gastritis, the stomach acquires MALT, which can undergo malignant
degeneration
• Again, H. pyloriis thought to be the culprit(responsible cause)
• In populations with a high incidence of gastric lymphoma, there is a high incidence of H. pylori infection;
• patients with gastric lymphoma also usually have H.pyloriinfection

66. • Low-grade MALT lymphoma, essentially a monoclonal proliferation of B cells, presumably arises from a
background of chronic gastritis associated with H. pylori
• These relatively innocuous(harmless) tumors then undergo degeneration to high-grade lymphoma,
which is the usual variety seen by the surgeon
• Remarkably, when the H. pylori is eradicated and the gastritis improves, the low-grade MALT lymphoma
often disappears
• Thus, low-grade MALT lymphoma is not a surgical lesion
• Careful follow-up is necessary particularly in those lesions with a t(11:18) translocation, thought to be a
risk factor for a more aggressive MALT lesion
• If low-grade lymphoma persists after H. pylori eradication, radiation should be considered for disease
clinically confined to the stomach (stage I), while chemotherapy with or without radiation is used for
more advanced lesions (Fig. 26-58)

67. • Patients with high-grade gastric lymphoma require aggressive oncologic treatment for cure and present
with many of the same symptoms as gastric cancer patients
• However, systemic symptoms such as fever, weight loss, and night sweats occur in about 50% of patients
with gastric lymphoma
• The tumors may bleed and/or obstruct
• Lymphadenopathy and/or organomegaly suggest systemic disease
• Diagnosis is by endoscopy and biopsy
• Much of the tumor may be submucosal, and an assiduous(very careful) attempt at biopsy is necessary
• Primary lymphoma is usually nodular with enlarged gastric folds
• A diffusely infiltrative process akin to linitis plastica is more suggestive of secondary gastric involvement
by lymphoma
• A diligent search for extragastric disease is necessary before the diagnosis of localized primary gastric
lymphoma is made
• This includes EUS; CT scanning of the chest, abdomen,and pelvis; and bone marrow biopsy

68. • Most patients with highgrade gastric lymphoma are currently treated with chemotherapy and radiation,
without surgical resection
• Treatment-related perforation or bleeding is unusual but recognized
• For disease limited to the stomach and regional nodes, radical subtotal D2 gastrectomy may be
performed, especially for bulky tumors with bleeding and/or obstruction
• Palliative gastrectomy for tumor complications also has a role

69. • Gastrointestinal Stromal Tumor
• GISTs arise from interstitial cells of Cajal (ICC) and are distinct from leiomyoma and leiomyosarcoma,
which arise from smooth muscle
• Prognosis in patients with GIST tumors depends mostly on tumor size and mitotic count, and metastasis,
when it occurs, is typically by the hematogenous route
• Any lesion >1 cm can behave in a malignant fashion and may recur
• Thus, all GISTs are best resected along with a margin of normal tissue
• Almost all GISTs (and almost no smooth muscle tumors) express c-KIT (CD117) or the related PDGF
receptor A, as well as CD34;
• almost all smooth muscle tumors (and almost no GISTs) express actin and desmin

70. • These markers can often be detected on specimens obtained by fine-needle aspiration and are useful in
differentiating between GIST and smooth muscle tumor histopathologically
• Lesions that are definitively leiomyoma by current histopathologic criteria are adequately treated by
enucleation
• Lesions that are definitively GIST or leiomyosarcoma are best treated by resection with negative margins
• Most equivocal lesions should be resected provided that the patient is a reasonable operative risk

71. • Two-thirds of all GISTs occur in the stomach
• Epithelial cell stromal GIST is the most common cell type arising in the stomach,
• cellular spindle type is the next most common
• The glomus tumor type is seen only in the stomach
• GISTs are submucosal tumors that are slow growing
• Smaller lesions are usually found incidentally, although they occasionally may ulcerate and cause
impressive bleeding
• Larger lesions generally produce symptoms of weight loss, abdominal pain, fullness, early satiety, and
bleeding
• An abdominal mass may be palpable
• Metastasis is by the hematogenous route, often to liver and/or lung, although positive lymph nodes are
occasionally seen in resected specimens

72. • Diagnosis is by endoscopy and biopsy, although the interpretation of the latter may be problematic
• EUS may be helpful, but symptomatic tumors and tumors >1 cm in size should be removed
• Metastatic work-up entails CT of the chest, abdomen, and pelvis (chest X-ray may suffice in lieu of CT of
the chest)
• Most gastric GISTs occur in the body of the stomach, but they also can occur in the fundus or antrum
• They are almost always solitary
• Wedge resection with clear margins is adequate surgical treatment
• True invasion of adjacent structures by the primary tumor is evidence of malignancy
• If safe, en bloc resection of involved surrounding organs is appropriate to remove all tumor when the
primary is large and invasive

73. • Five-year survival following resection for GIST is about 50%
• Most patients with low-grade lesions are cured (80% 5-year survival), but most patients with high-grade
lesions are not (30% 5-year survival)
• According to the tumor size and mitotic count, the risk of aggressive behavior was classified into four
groups
– Very low risk was defined as <2 cm and <5/50 HPF (high-power field)
– low risk was defined as 2 to 5cm and <5/50 cm
– Intermediate risk was defined as <5 cm and 6 to 10/50 HPF or 5 to 10cm and >5/50 HPF
– high risk was defined as >5 cm and >5/50HPF, >10cm with any mitotic rate or >10/50/ HPF with any
size
– It was known that the risk of recurrence differs by the primary site of the tumor
– Recently, new classification based on tumor location, size, and mitotic rate has been used to
evaluate the risk of recurrence and metastasis

74. • GISTs are usually positive for the protooncogene, c-kit, a characteristic shared with the ICC. Imatinib
(Gleevec), a chemotherapeutic agent that blocks the activity of the tyrosine kinase product of c-kit,
yields excellent results in many patients with metastatic or unresectable GIST
• Up to 50% of treated patients develop resistance to imatinib by 2 years, and several newer agents show
promise for patients with refractory disease
• The efficacy of imatinib as adjuvant therapy for high risk patients has been demonstrated in large clinical
trials
• According to the NCCN guidelines for soft tissue sarcoma (version 2, 2012), the administration of
imatinib was recommended in high risk groups as an adjuvant therapy
• An algorithm for the treatment of patients with GIST is shown in Fig. 26-59.

76. • Gastric Carcinoid Tumors
• Compared to midgut and hindgut locations, carcinoid tumors of the stomach are rather unusual
• Gastric carcinoids comprise about 1% of all carcinoid tumors and less than 2% of gastric neoplasms
• They arise from gastric enterochromaffin-like (ECL) cells and some have malignant potential
• The apparent incidence of gastric carcinoids is increasing, perhaps related to the more common use of
upper endoscopy and/or the increasing use of acid suppressive medication
• The latter may cause hypergastrinemia, and gastrin has a recognized trophic effect on gastric ECL cells
• Gastric carcinoid is equivalent to neuroendocrine tumor (NET) or well-differentiated neuroendocrine
tumor/carcinoma according to WHO classification

77. • Gastric carcinoids are classified into one of three different types
• Type I is the most common type of gastric carcinoid, accounting for about 75% of patients
• Type I carcinoids occur in patients with chronic hypergastrinemia secondary to pernicious anemia or
chronic atrophic gastritis
• These lesions occur more frequently in women, are often multiple and small, and have low malignant
potential (<5% metastasize)
• The role of long-term acid suppression with resultant hypergastrinemia in the pathogenesis of type I
gastric carcinoids is unclear
• Type II gastric carcinoids are associated with MEN1 and ZES
• These lesions also tend to be small and multiple, but have a somewhat higher malignant potential than
type I lesions (10% metastasize)
• Type II gastric carcinoids are more strongly associated with MEN1; they are quite uncommon in patients
with sporadic ZES without MEN1
• Gastric acid hypersecretion, hypergastrinemia, and gastric carcinoid imply gastrinoma until proven
otherwise

78. • Type III gastric carcinoids are sporadic tumors
• They are most often solitary (usually >2 cm) and occur more commonly in men
• They are not associated with hypergastrinemia and biopsy shows a heterogeneous cell population
• Most patients have nodal or distant metastases at the time of diagnosis, and some present with symptoms of
carcinoid syndrome
• Gastric carcinoids are usually diagnosed with endoscopy and biopsy. Some tumors are submucosal and may
be quite small. They are often confused with heterotopic pancreas or small leiomyomas.
• Biopsy may be difficult because of the submucosal location, and EUS can be helpful in defining the size and
depth of the lesion.
• Plasma chromogranin A levels are elevated in patients with gastric carcinoid. CT scan and octreotide scan are
useful for staging.
• Gastric carcinoids should be resected. Small lesions confined to the mucosa (typically type I or type II lesions)
may be treated endoscopically with EMR if there are only a few lesions (<5)
• and if margins are histologically negative. Careful follow-up is necessary. Larger lesions should be removed by
D1 or D2 gastrectomy. Survival is excellent for node-negative patients (>90% 5-year survival); node-positive
patients have a 50% 5-year survival. Gastrinoma should be resected if located in patients with type II
carcinoid.

79. • The 5-year survival for patients with type I gastric carcinoid is close to 100%; for patients with type III
lesions, the 5-year survival is less than 50%
• Somatostatin analogue treatment is useful in controlling the symptoms of carcinoid syndrome but
apparently does not prolong survival in patients with metastatic gastric carcinoid.
• Surgical debulking may have a role in selected patients with metastatic disease
• Because somatostatin has an antiproliferative effect on gastric ECL cells, there may be a possible
primary treatment role for octreotide in poor-risk surgical patients with gastric carcinoid

80. • BENIGN GASTRIC NEOPLASMS
• Leiomyoma
• The typical leiomyoma is submucosal and firm
• If ulcerated, it has an umbilicated appearance and may bleed
• Histologically, these lesions appear to be of smooth muscle origin
• Lesions <2 cm are usually asymptomatic and benign
• Larger lesions have greater malignant potential and a greater likelihood to cause symptoms such as
bleeding, obstruction, or pain
• Asymptomatic lesions <2 cm may be carefully observed or enucleated if fine-needle aspiration and
immune markers confirm smooth muscle tumor
• larger lesions and symptomatic lesions should be removed by wedge resection
• When lesions thought to be leiomyoma are observed rather than resected, the patient should be made
aware of their presence and the small possibility for malignancy

81. • Lipoma
• Lipomas are benign submucosal fatty tumors that are usually asymptomatic, found incidentally on upper
GI series or EGD
• Endoscopically, they have a characteristic appearance
• there also is a characteristic appearance on EUS
• Excision is unnecessary unless the patient is symptomatic

82. Reference
• Schwartz 10th ed.