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2006 7:41 Page 37

CHAPTER 3

Tumours of the Stomach

The incidence of adenocarcinoma of the stomach is declining


worldwide. In some Western countries, rates have been
reduced to less than one third within just one generation. In
countries with a traditionally high incidence, e.g. Japan and
Korea, the reduction is also significant but it will take more
time to diminish the still significant disease burden. The main
reasons for these good news is a change in nutrition, in par-
ticular the avoidance of salt for meat and fish preservation, the
lowering of salt intake from other sources, and the availability
in many countries of fresh fruits and vegetables throughout
the year. Mortality has been further dercreased by significant
advances in the early detection of stomach cancer.

Infection with Helicobacter pylori appears to play an important


additional aetiological role since it leads to chronic atrophic
gastritis with intestinal metaplasia as an important precursor
lesion.

The stomach is the main gastrointestinal site for lymphomas


and most of these are also pathogenetically linked to H. pylori
infection. Regression of such tumours often follows H. pylori
eradication.
03 19.7.2006 7:41 Page 38

WHO histological classification of gastric tumours1


Epithelial tumours Non-epithelial tumours
Intraepithelial neoplasia Adenoma 8140/0 2
Leiomyoma 8890/0
Carcinoma Schwannoma 9560/0
Adenocarcinoma 8140/3 Granular cell tumour 9580/0
intestinal type 8144/3 Glomus tumour 8711/0
diffuse type 8145/3 Leiomyosarcoma 8890/3
Papillary adenocarcinoma 8260/3 GI stromal tumour 8936/1
Tubular adenocarcinoma 8211/3 benign 8936/0
Mucinous adenocarcinoma 8480/3 uncertain malignant potential 8936/1
Signet-ring cell carcinoma 8490/3 malignant 8936/3
Adenosquamous carcinoma 8560/3 Kaposi sarcoma 9140/3
Squamous cell carcinoma 8070/3 Others
Small cell carcinoma 8041/3
Undifferentiated carcinoma 8020/3 Malignant lymphomas
Others Marginal zone B-cell lymphoma of MALT-type 9699/3
Mantle cell lymphoma 9673/3
Carcinoid (well differentiated endocrine neoplasm) 8240/3 Diffuse large B-cell lymphoma 9680/3
Others

Secondary tumours
_____________
1
The classification is modified from the previous WHO histological classification of tumours {2066} taking into account changes in our understanding of these lesions. In the case of
endocrine neoplasms, the classification is based on the recent WHO clinicopathological classification {1784}, but has been simplified to be of more practical utility in morphological
classification.
2
Morphology code of the International Classification of Diseases for Oncology (ICD-O) {542} and the Systematized Nomenclature of Medicine (http://snomed.org). Behaviour is coded
/0 for benign tumours, /3 for malignant tumours, and /1 for unspecified, borderline or uncertain behaviour. Intraepithelial neoplasia does not have a generic code in ICD-O. ICD-O codes
are available only for lesions categorized as glandular intraepithelial neoplaia grade III (8148/2), and adenocarcinoma in situ (8140/2).

TNM classification of gastric tumours


TNM classification1

T Primary Tumour M Distant Metastasis


TX Primary tumour cannot be assessed MX Distant metastasis cannot be assessed
T0 No evidence of primary tumour M0 No distant metastasis
Tis Carcinoma in situ: intraepithelial tumour M1 Distant metastasis
without invasion of the lamina propria

T1 Tumour invades lamina propria or submucosa Stage Grouping


T2 Tumour invades muscularis propria or subserosa2
T3 Tumour penetrates serosa (visceral peritoneum) Stage 0 Tis N0 M0
without invasion of adjacent structures2,3,4,5 Stage IA T1 N0 M0
T4 Tumour invades adjacent structures2,3,4,5 Stage IB T1 N1 M0
T2 N0 M0
N Regional Lymph Nodes Stage II T1 N2 M0
NX Regional lymph nodes cannot be assessed T2 N1 M0
N0 No regional lymph node metastasis T3 N0 M0
N1 Metastasis in 1 to 6 regional lymph nodes Stage IIIA T2 N2 M0
N2 Metastasis in 7 to 15 regional lymph nodes T3 N1 M0
N3 Metastasis in more than 15 regional lymph nodes T4 N0 M0
Stage IIIB T3 N2 M0
Stage IV T4 N1, N2, N3 M0
T1, T2, T3 N3 M0
Any T Any N M1

____________
1
{1, 66}. This classification applies only to carcinomas.
2
A help desk for specific questions about the TNM classification is available at http://tnm.uicc.org.
3
A tumour may penetrate muscularis propria with extension into the gastrocolic or gastrohepatic ligaments or the greater and lesser omentum without perforation of the visceral peri-
toneum covering these structures. In this case, the tumour is classified as T2. If there is perforation of the visceral peritoneum covering the gastric ligaments or omenta, the tumour
is classified as T3.
4
The adjacent structures of the stomach are the spleen, transverse colon, liver, diaphragm, pancreas, abdominal wall, adrenal gland, kidney, small intestine, and retroperitoneum.
5
Intramural extension to the duodenum or oesophagus is classified by the depth of greatest invasion in any of these sites including stomach.

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Gastric carcinoma C. Fenoglio-Preiser


F. Carneiro
N. Muoz
S.M. Powell
P. Correa M. Rugge
P. Guilford M. Sasako
R. Lambert M. Stolte
F. Megraud H. Watanabe

Definition Asia {1471}. There is about a 20-fold dif- frequently has hereditary characteristics,
A malignant epithelial tumour of the ference in the incidence rates when com- perhaps modulated by environmental
stomach mucosa with glandular differen- paring the rates in Japan with those of influences {1738, 1633}.
tiation. Its aetiology is multifactorial; most some white populations from the US and
commonly it develops after a long period those of some African countries. A pre- Aetiology
of atrophic gastritis. dominance of the intestinal type of ade- Diet
Tumours of the oesophagogastric junc- nocarcinoma occurs in high-risk areas, Epidemiological studies in different pop-
tion are dealt with in the preceding while the diffuse type is relatively more ulations show that the most consistent
chapter. common in low-risk areas {1296}. association is diet. This is especially true
of intestinal type carcinomas. An ade-
ICD-O codes Time trends quate intake of fresh fruits and vegeta-
Adenocarcinoma 8140/3 A steady decline in the incidence and bles lowers the risk {1450}, due to their
Intestinal type 8144/3 mortality rates of gastric carcinoma has antioxidant effects. Ascorbic acid,
Diffuse type 8145/3 been observed worldwide over the past carotenoids, folates and tocopherols are
Papillary adenocarcinoma 8260/3 several decades, but the absolute num- considered active ingredients. Salt intake
Tubular adenocarcinoma 8211/3 ber of new cases per year is increasing strongly associates with the risk of gas-
Mucinous adenocarcinoma 8480/3 mainly because of the aging of the pop- tric carcinoma and its precursor lesions
Signet-ring cell carcinoma 8490/3 ulation {1296}. Analysis of time trends by {869}.
histological types indicates that the inci- Other foods associated with high risk in
Epidemiology dence decline results from a decline in some populations include smoked or
Geographical distribution the intestinal type of carcinoma {1296}. cured meats or fish, pickled vegetables
Gastric cancer was the second common- and chili peppers.
est cancer in the world in 1990, with an Age and sex distribution Alcohol, tobacco and occupational
estimated 800,000 new cases and Gastric carcinoma is extremely rare exposures to nitrosamines and inorganic
650,000 deaths per year; 60% of them below the age of 30; thereafter it increas- dusts have been studied in several pop-
occurred in developing countries {1469}. es rapidly and steadily to reach the high- ulations, but the results have been incon-
The areas with the highest incidence est rates in the oldest age groups, both in sistent.
rates (> 40/100,000 in males) are in males and females. The intestinal type
Eastern Asia, the Andean regions of rises faster with age than the diffuse Bile reflux
South America and Eastern Europe. Low type; it is more frequent in males than in The risk of gastric carcinoma increases
rates (< 15/100,000) are found in North females. 5-10 years after gastric surgery, espe-
America, Northern Europe, and most Diffuse carcinoma tends to affect cially when the Bilroth II operation, which
countries in Africa and in Southeastern younger individuals, mainly females; it increases bile reflux, was performed.

45.5
7.4
18.0 77.9
49.1

7.4
7.4

25.9
10.8

< 6.7 < 11.6 < 17.1 < 25.0 < 77.9

Fig. 3.01 Worldwide annual incidence (per 100,000) of stomach cancer in males. Fig. 3.02 The mortality of stomach cancer is decreasing worldwide, including
Numbers on the map indicate regional average values. countries with a high disease burden.

Gastric carcinoma 39
03 19.7.2006 7:41 Page 40

some, could be associated with gastric


H. Pylori Infection
carcinogenesis. H. pylori can also pro-
duce a vacuolating cytotoxin named
Gastritis Nitrate Reductase
VacA. This cytotoxin, responsible for
Diet. Saliva epithelial cell damage, also associates
iNOS Gene Expression
with gastric carcinogenesis {1771}. The
Acid (HCI)
aetiological role of H. pylori in gastric
NO Nitrite
carcinogenesis was confirmed when
ONOOH N2O3
inoculation of a cag and VacA positive
strain was able to induce intestinal meta-
Ascorbic Acid
plasia and gastric carcinoma in
Mongolian gerbils {2069}.
Cell Damage Antimicrobial
(DNA, lipids, mitochondria...) Excessive cell proliferation. Cell replica-
-Carotene
Nitrosamines tion, a requisite of carcinogenesis, poten-
tiates action of carcinogens targeting
DNA. The higher the replication rate, the
Apoptosis Repair Mutation greater the chance that replication errors
become fixed and expressed in subse-
quent cell generations. Spontaneous
Atrophic gastritis CANCER mutations lead to subsequent neoplastic
transformation, but whether or not they
Fig. 3.03 Pathogenetic scheme of carcinogenesis in the stomach. cause epidemic increases in cancer
rates is debatable. The latter is better
explained by the presence of external or
Helicobacter pylori infection cinogenic cascade. H. pylori is the most endogenous carcinogens. Proliferation is
The most important development in the frequent cause of chronic gastritis. It higher in H. pylori infected than in non-
epidemiology of adenocarcinoma is the decreases acid-pepsin secretion and infected stomachs; it declines signifi-
recognition of its association with interferes with anti-oxidant functions by cantly after infection eradication {187}
Helicobacter pylori infection. Strong epi- decreasing intragastric ascorbic acid supporting the mitogenic influence of
demiological evidence came from three (AA) concentrations. The organisms pre- H. pylori on gastric epithelium. Ammonia,
independent prospective cohort studies dominantly occur in the mucus layer a substance stimulating cell replication,
reporting a significantly increased risk in overlying normal gastric epithelium. They is abundantly liberated by the potent ure-
subjects who 10 or more years before the are absent in areas overlying intestinal ase activity of H. pylori in the immediate
cancer diagnosis had anti-H. pylori anti- metaplasia where neoplasia originates. vicinity of gastric epithelium.
bodies, demonstrable in stored serum Thus, H. pyloris carcinogenic influences Oxidative stress. Gastritis is associated
samples {1371, 1473, 519}. At the patho- are exerted from a distance, via soluble with increased production of oxidants
logical level, H. pylori has been shown to bacterial products or the inflammatory and reactive nitrogen intermediates,
induce the phenotypic changes leading response generated by the infection. including nitric oxide (NO). There is an
up to the development of adenocarcino- H. pylori genome. H. pylori is genetically increased expression of the inducible
ma (i.e. mucosal atrophy, intestinal meta- heterogeneous, and all strains may not isoform of nitric oxide synthase in gastri-
plasia and dysplasia) in both humans play the same role in the development of tis {1157}. This isoform causes continu-
and in experimental animals {1635, 350, malignancy. Strains containing a group ous production of large amounts of NO.
2069}. of genes named cag pathogenicity NO can also be generated in the gastric
A prolonged precancerous process, last- island {264} induce a greater degree of lumen from non-enzymatic sources.
ing decades, precedes most gastric inflammation than strains lacking these Acidification of nitrite to NO produces the
cancers. It includes the following genes. The mechanism involves epithe- reactive nitrogen species dinitrogen tri-
sequential steps: chronic gastritis, multi- lial production of interleukin 8 via a oxide (N2O3), a potent nitrosating agent
focal atrophy, intestinal metaplasia, and nuclear factor KappaB pathway. There is that forms nitrosothiols and nitrosamines
intraepithelial neoplasia {342}. Gastritis an association between an infection with {628}. Nitrosated compounds are recog-
and atrophy alter gastric acid secretion, a cag positive H. pylori strain and the nized gastric carcinogens in the experi-
elevating gastric pH, changing the flora development of gastric carcinoma mental setting.
and allowing anaerobic bacteria to colo- {1549}. Interference with antioxidant functions.
nize the stomach. These bacteria pro- The determination of the complete DNA Ascorbic acid (AA), an antioxidant, is
duce active reductases that transform sequence of two H. pylori strains has actively transported from blood to the
food nitrate into nitrite, an active mole- shown other similar 'islands are also gastric lumen by unknown mechanisms.
cule capable of reacting with amines, present in the H. pylori genome. Re- Its putative anti-carcinogenic role is by
amides and ureas to produce carcino- search is ongoing to determine whether preventing oxidative DNA damage.
genic N-nitroso compounds {2167}. strain-specific genes located in one of H. pylori infected individuals have lower
H. pylori acts as a gastric pathogen and these islands named the plasticity zone, AA intragastric concentrations than non-
it is important in several steps in the car- or outside on the rest of the chromo- infected subjects. Following H. pylori

40 Tumours of the stomach


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treatment, intragastric AA concentrations testinal complaints such as dyspepsia.


increase to levels resembling those of Among patients in Western countries who
non-infected individuals {1613}. have endoscopic evaluations for dyspep- Type I
Protruded
DNA damage. Free radicals, oxidants sia, however, gastric carcinoma is found
and reactive nitrogen species all cause in only 1-2% of cases (mostly in men over
DNA damage {344}. These usually gener- the age of 50). Symptoms of advanced
Type IIa
ate point mutations, the commonest being carcinoma include abdominal pain that is
Elevated
G:CA:T, the commonest type of trans- often persistent and unrelieved by eating.
formation in cancer with a strong link to Ulcerated tumours may cause bleeding
chemical carcinogenesis. Peroxynitrite and haematemesis, and tumours that
Type IIb
forms nitro-guanine adducts that induce obstruct the gastric outlet may cause
Flat
DNA damage, generating either DNA vomiting. Systemic symptoms such as
repair or apoptosis. The latter process anorexia and weight loss suggest dis-
removes cells containing damaged DNA seminated disease.
Type IIc
from the pool of replicating cells in order The lack of early symptoms often delays Depressed
to avoid introduction of mutations into the the diagnosis of gastric cancer.
genome and an associated heightened Consequently, 80- 90% of Western
cancer risk. NO impairs DNA repair by patients with gastric cancers present to Type III
compromising the activity of Fpg, a DNA the physician with advanced tumours that Excavated
repair protein. Thus, NO not only causes have poor rates of curability. In Japan,
DNA damage but it also impairs repair where gastric cancer is common, the Fig. 3.04 Growth features of early gastric carcinoma.
mechanisms designed to prevent the for- government has encouraged mass
mation of genetic mutations. screening of the adult population for this
As noted, cell proliferation increases in tumour. Approximately 80% of gastric Gastric cancers can be classified endo-
H. pylori infection. This increased replica- malignancies detected by such screen- scopically according to the growth pat-
tion is balanced by increased cell death. ing programs are early gastric cancers. tern {1298, 63} The patterns I. II and III of
It is likely that the increased mitoses are a However, many individuals do not choose superficial cancer (Fig. 3.03) reflect the
response to increased epithelial loss. to participate in these screening pro- gross morphology of the operative speci-
However, the replicative rate exceeds grams, and consequently only approxi- men. The risk of deep and multifocal pen-
apoptotic rates in patients infected with mately 50% of all gastric cancers in etration into the submucosa and the risk
the virulent cagA vacA s1a H. pylori Japan are diagnosed in an early stage. of lymphatic invasion is higher in type IIc,
{1481} suggesting that cell loss also the depressed variant of type II. Infiltration
occurs via desquamation in patients Imaging and endoscopy of the gastric wall (linitis plastica) may not
infected by toxigenic H. pylori strains. Endoscopy is widely regarded as the be apparent endoscopically. This lesion
Antitoxin derived from H. pylori also most sensitive and specific diagnostic may be suspected if there is limited flexi-
induces apoptosis. In patients with test for gastric cancer. With high resolu- bility of the gastric wall. Diagnosis may
H. pylori gastritis, treatment with anti-oxi- tion endoscopy, it is possible to detect require multiple, jumbo biopsies. The
dants attenuates the degree of apoptosis slight changes in colour, relief, and archi- depth of invasion of the tumour is staged
and peroxynitrite formation {1481}. tecture of the mucosal surface that sug- with endoscopic ultrasound. A 5-layer
It seems more than coincidental that gest early gastric cancer. Endoscopic image is obtained at 7.5/12 MHz: in
dietary nitrite, nitrosamines and H. pylori- detection of these early lesions can be superficial (T1) cancer the second hyper-
induced gastritis share so much chem- improved with chromoendoscopy (e.g. echoic layer is not interrupted.
istry and their association with cancer. As using indigo carmine solution at 0.4 %). Radiology with barium meal is still used
this process is chronic, the opportunity Even with these procedures, a substan- in mass screening protocols in Japan,
for random hits to the genome to occur at tial number of early gastric cancers can followed by endoscopy if an abnormality
critical sites increases dramatically. be missed {745A}. has been detected. For established gas-

Localization
The most frequent site of sub-cardial
stomach cancer is the distal stomach,
i.e. the antro-pyloric region. Carcinomas
in the body or the corpus of the stomach
are typically located along the greater or
lesser curvature.

Clinical features
Symptoms and signs
Early gastric cancer often causes no
symptoms, although up to 50% of A B
patients may have nonspecific gastroin- Fig. 3.05 Endoscopic views of early, well differentiated adenocarcinoma. A Polypoid type. B Elevated type.

Gastric carcinoma 41
03 19.7.2006 7:41 Page 42

A B A

C D B
Fig. 3.06 Endoscopic views of gastric cancer (A, C) and corresponding images with dye enhancement (B, D). Fig. 3.08 Gastric adenocarcinoma of (A) polypoid
A, B Depressed early gastric cancer. C, D Deep ulcer scar surrounded by superficial early gastric cancer infil- and (B) diffusely infiltrative type.
trating the mucosa and submucosa.

tric cancers, radiology usually is not nec- Macroscopy through the submucosa or subserosa or
essary, but may complement endoscop- Dysplasia may present as a flat lesion via the submucosal lymphatics.
ic findings in some cases. Tumour stag- (difficult to detect on conventional endo- Duodenal invasion occurs more fre-
ing prior to treatment decision involves scopy, but apparent on dye-staining quently than expected based on gross
percutaneous ultrasound or computer- endoscopy) or polypoid growth. Appear- examination. Therefore, resection mar-
ized tomography to detect liver metas- ances intermediate between them gins should be monitored by intraopera-
tases and distant lymph node metas- include a depressed or reddish or discol- tive consultation.
tases. Laparoscopic staging may be the ored mucosa. The macroscopic type of Intestinal carcinomas preferentially meta-
only way to exclude peritoneal seeding in early gastric carcinoma is classified using stasize haematogenously to the liver,
the absence of ascites. critera similar to those in endoscopy (Fig. whereas diffuse carcinomas preferentially
3.03) {1298, 63}. The gross appearance metastasize to peritoneal surfaces {1273,
of advanced carcinoma forms the basis 245}. An equal incidence of lymph node
of the Borrmann classification (Fig. 3.06) metastases occurs in both types of
{63, 175}. tumours with T2 or higher lesions. Mixed
Ulcerating types II or III are common. tumours exhibit the metastatic patterns of
Diffuse (infiltrative) tumours (type IV) both intestinal and diffuse types. When
spread superficially in the mucosa and carcinoma penetrates the serosa, peri-
submucosa, producing flat, plaque-like toneal implants flourish. Bilateral massive
lesions, with or without shallow ulcera- ovarian involvement (Krukenberg tumour)
tions. With extensive infiltration, a linitis can result from transperitoneal or haema-
plastica or leather bottle stomach results. togenous spread.
Type I Type II
Mucinous adenocarcinomas appear gela- The principal value of nodal dissection is
Polypoid Fungating
tinous with a glistening cut surface. the detection and removal of metastatic
disease and appropriate tumour staging.
Tumour spread and staging The accuracy of pathological staging is
Gastric carcinomas spread by direct proportional to the number of regional
extension, metastasis or peritoneal dis- lymph nodes examined and their loca-
semination. Direct tumour extension tion. When only nodes close to the
involves adjacent organs. Tumours inva- tumour are assessed, many cancers are
ding the duodenum are most often of the classified incorrectly.
Type III Type IV diffuse type and the frequency of seros-
Ulcerated Infiltrative al, lymphatic, and vascular invasion and Histopathology
Fig. 3.07 Borrmann classification of advanced gas- lymph node metastases in these lesions Gastric adenocarcinomas are either
tric carcinoma. is high. Duodenal invasion may occur gland-forming malignancies composed

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A B C

D E F
Fig. 3.09 A Depressed adenocarcinoma. B Depressed signet ring cell carcinoma. C Gastric cancer, dye sprayed (pale area). D, E, F Advanced gastric carcinoma
with varying degrees of infiltration.

of tubular, acinar or papillary structures, present. Individual tumour cells are (papillotubular). Rarely, a micropapillary
or they consist of a complex mixture of columnar, cuboidal, or flattened by intra- architecture is present. The degree of
discohesive, isolated cells with variable luminal mucin. Clear cells may also be cellular atypia and mitotic index vary;
morphologies, sometimes in combination present. The degree of cytological atypia there may be severe nuclear atypia. The
with glandular, trabecular or alveolar solid varies from low to high-grade {466, invading tumour edge is usually sharply
structures {243}. Several classification 1362}. A poorly differentiated variant is demarcated from surrounding structures;
systems have been proposed, including sometimes called solid carcinoma. the tumour may be infiltrated by acute
Ming, Carniero, and Goseki {1623}, but Tumours with a prominent lymphoid stro- and chronic inflammatory cells.
the most commonly used are those of ma are sometimes called medullary car-
WHO and Laurn {419, 87}. cinomas or carcinomas with lymphoid Mucinous adenocarcinomas
stroma {2063}. The degree of desmopla- By definition, > 50% of the tumour con-
WHO classification sia varies and may be conspicuous. tains extracellular mucinous pools. The
Despite their histological variability, usu- two major growth patterns are (1) glands
ally one of four patterns predominates. Papillary adenocarcinomas lined by a columnar mucous-secreting
The diagnosis is based on the predomi- These are well-differentiated exophytic epithelium together with interstitial mucin
nant histological pattern. carcinomas with elongated finger-like and (2) chains or irregular cell clusters
processes lined by cylindrical or floating freely in mucinous lakes. There
Tubular adenocarcinomas cuboidal cells supported by fibrovascu- may also be mucin in the interglandular
These contain prominent dilated or slit- lar connective tissue cores. The cells stroma. Scattered signet-ring cells, when
like and branching tubules varying in tend to maintain their polarity. Some present, do not dominate the histological
their diameter; acinar structures may be tumours show tubular differentiation picture. Grading mucinous adenocarci-

A B C
Fig. 3.10 Features of tubular adenocarcinoma. A Well differentiated tumour with invasion into the muscularis propria. B Solid variant. C Clear cell variant.

Gastric carcinoma 43
03 19.7.2006 7:41 Page 44

other diffuse carcinomas contain cells


with central nuclei resembling histiocytes,
and show little or no mitotic activity; (3)
small, deeply eosinophilic cells with
prominent, but minute, cytoplasmic gran-
ules containing neutral mucin; (4) small
cells with little or no mucin, and (5)
anaplastic cells with little or no mucin.
These cell types intermingle with one
A B another and constitute varying tumour
Fig. 3.11 A, B Tubular adenocarcinoma.
proportions. Signet-ring cell tumours may
also form lacy or delicate trabecular glan-
dular patterns and they may display a
zonal or solid arrangement.
Signet-ring cell carcinomas are infiltra-
tive; the number of malignant cells is
comparatively small and desmoplasia
may be prominent. Special stains,
including mucin stains (PAS, muci-
carmine, or Alcian blue) or immunohisto-
chemical staining with antibodies to
B cytokeratin, help detect sparsely dis-
A persed tumour cells in the stroma. Cyto-
Fig. 3.12 A Papillary adenocarcinoma. B Well differentiated mucinous adenocarcinoma.
keratin immunostains detect a greater
percentage of neoplastic cells than do
nomas is unreliable in tumours containing Superficially, cells lie scattered in the lam- mucin stains. Several conditions mimic
only a few cells. The term mucin-produ- ina propria, widening the distances signet-ring cell carcinoma including
cing is not synonymous with mucinous in between the pits and glands. The tumour signet-ring lymphoma, lamina propria
this context. cells have five morphologies: (1) Nuclei muciphages, xanthomas and detached
push against cell membranes creating a or dying cells associated with gastritis.
Signet-ring cell carcinomas classical signet ring cell appearance due
More than 50% of the tumour consists of to an expanded, globoid, optically clear Laurn classification
isolated or small groups of malignant cytoplasm. These contain acid mucin The Laurn classification {1021} has
cells containing intracytoplasmic mucin. and stain with Alcian blue at pH 2.5; (2) proven useful in evaluating the natural
history of gastric carcinoma, especially
with regard to its association with envi-
ronmental factors, incidence trends and
its precursors. Lesions are classified into
one of two major types: intestinal or dif-
fuse. Tumours that contain approximately
equal quantities of intestinal and diffuse
components are called mixed carcino-
mas. Carcinomas too undifferentiated to
fit neatly into either category are placed
in the indeterminate category.
A B Intestinal carcinomas
These form recognizable glands that
range from well differentiated to moder-
ately differentiated tumours, sometimes
with poorly differentiated tumour at the
advancing margin. They typically arise
on a background of intestinal metaplasia.
The mucinous phenotype of these can-
cers is intestinal, gastric and gastro-
intestinal.
C D
Fig. 3.13 Signet-ring cell carcinomas. A Overview showing Infiltration of the lamina propria. B Dispersed Diffuse carcinomas
signet-ring cells. C Accumulation of neoplastic signet ring cells in the mucosa. D Alcian green positive They consist of poorly cohesive cells dif-
signet-ring cells expanding the lamina propria in this Movat stain. fusely infiltrating the gastric wall with little

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Fig. 3.14 Undifferentiated gastric carcinoma.

B
Fig. 3.15 Hepatoid variant of gastric carcinoma. Fig. 3.16 Gastric choriocarcinoma composed of syncytiotrophoblastic and cytotrophoblastic cells next to
thin-walled vascular structures. A Papillary carcinoma component is adjacent to the choriocarcinoma.
B High magnification of the choriocarcinoma.

or no gland formation. The cells usually Adenosquamous carcinoma Undifferentiated carcinoma


appear round and small, either arranged This lesion combines an adenocarcino- These lesions lack any differentiated fea-
as single cells or clustered in abortive, ma and squamous cell carcinoma; nei- tures beyond an epithelial phenotype
lacy gland-like or reticular formations. ther quantitatively prevails. Transitions (e.g. cytokeratin expression). They fall
These tumours resemble those classified exist between both components. A into the indeterminate group of Laurns
as signet-ring cell tumours in the WHO tumour with a distinct boundary between scheme. Further analysis of this heteroge-
classification. The mitotic rate is lower in the two components may represent a neous group using histochemical meth-
diffuse carcinomas than in intestinal collision tumour. Tumours containing dis- ods may allow their separation into other
tumours. Small amounts of interstitial crete foci of benign-appearing squa- types.
mucin may be present. Desmoplasia is mous metaplasia are termed adenocarci-
more pronounced and associated inflam- nomas with squamous differentiation Other rare tumours include mixed adeno-
mation is less evident in diffuse cancers (synonymous with adenoacanthoma). carcinoma-carcinoid (mixed exocrine-
than in the intestinal carcinomas. endocrine carcinoma), small cell
Squamous cell carcinoma carcinoma, parietal cell carcinoma, cho-
Rare variants Pure squamous cell carcinomas develop riocarcinoma, endodermal sinus tumour,
Several other carcinomas exist that are rarely in the stomach; they resemble embryonal carcinoma, Paneth cell rich-
not an integral part of the Laurn or WHO squamous cell carcinomas arising else- adenocarcinoma and hepatoid adenocar-
classifications. where in the body. cinoma.

Early gastric cancer


Early gastric cancer (EGC) is a carcino-
ma limited to the mucosa or the mucosa
and submucosa, regardless of nodal sta-
tus. Countries in which asymptomatic
patients are screened have a high inci-
dence of EGCs ranging from 30-50%
{1410, 908, 718}, contrasting with a
smaller fraction of 16-24% {620, 253,
627} in Western countries. The follow-up
A B of dysplastic lesions does appear to
Fig. 3.17 A, B Adenocarcinoma, poorly differentiated. These two lesions show both intestinal and diffuse increase the prevalence of EGC. The
components (Laurn classification). cost effectiveness of such an integrated

Gastric carcinoma 45
03 19.7.2006 7:41 Page 46

A B C
Fig. 3.18 Tubular adenocarcinoma. A Well differentiated; intramucosal invasion. B Moderately differentiated. C Poorly differentiated.

endoscopic/biopsy approach remains to categories: PenA and PenB) the invasion Precursor lesions
be evaluated {1634, 1638}. Histological- of the submucosa is more extensive than Gastritis and intestinal metaplasia
ly, most subtypes of carcinoma occur in in the two above-mentioned variants. Chronic atrophic gastritis and intestinal
EGC in either pure or mixed forms. PenA is defined by a pushing margin, metaplasia commonly precede and/or
Elevated carcinomas with papillary, gran- and is less frequent than PenB, which accompany intestinal type adenocarci-
ular or nodular patterns and a red colour penetrates muscularis mucosae at multi- noma, particularly in high-incidence
are more often well or moderately differ- ple sites. areas {780}. H. pylori associated gastritis
entiated, tubular or papillary tumours The prognosis is worse in PenA carcino- is the commonest gastric precursor
with intestinal features; sometimes a pre- mas (in contrast to adenocarcinomas of lesion.
existing adenoma is recognizable. Flat, the colon, where a pushing margin is However, autoimmune gastritis also
depressed, poorly differentiated carcino- associated with a better prognosis). The associates with an increased carcinoma
mas may contain residual or regenerative coexistence of more than one of the risk. If gastritis persists, gastric atrophy
mucosal islands. Ulcerated lesions are described patterns results in the mixed occurs followed by intestinal metaplasia,
either intestinal or diffuse cancers. variant {950}. beginning a series of changes that may
Adenocarcinoma limited to the mucosal result in neoplasia, especially of intestin-
thickness has also been divided into Stromal reactions al type cancers. In contrast, diffuse gas-
small mucosal (< 4cm=SM) and superfi- The four common stromal responses to tric cancers often arise in a stomach
cial (> 4cm=SUPER) {950}. Both of them gastric carcinoma are marked desmo- lacking atrophic gastritis with intestinal
may be strictly confined at the mucosal plasia, lymphocytic infiltrates, stromal metaplasia.
level (small mucosal M and superficial M) eosinophilia and a granulomatous res-
or focally infiltrate the sub-mucosa (small ponse. The granulomatous reaction is
mucosal SM and superficial SM). In the characterized by the presence of single
penetrating variant, (including two sub- and confluent small sarcoid-like granulo-
mas, often accompanied by a moderate-
ly intense mononuclear cell infiltrate. The
lymphoid response is associated with an
improved survival.

Grading
Well differentiated: An adenocarcinoma
with well-formed glands, often resem-
bling metaplastic intestinal epithelium.
Moderately differentiated: An adenocar-
cinoma intermediate between well differ-
A entiated and poorly differentiated.
Poorly differentiated: An adenocarcino-
ma composed of highly irregular glands
that are recognized with difficulty, or sin-
gle cells that remain isolated or are
arranged in small or large clusters with
mucin secretions or acinar structures.
They may also be graded as low-grade
(well and moderately differentiated) or
high-grade (poorly differentiated). Note
B that this grading system applies primari- Fig. 3.20 Intestinal metaplasia. The two glands on
Fig. 3.19 A, B Tubular adenocarcinoma, well differ- ly to tubular carcinomas. Other types of the left exhibit complete intestinal metaplasia,
entiated. gastric carcinoma are not graded. others show the incomplete type.

46 Tumours of the stomach


03 19.7.2006 7:41 Page 47

There are two main types of intestinal inflammation, and the distinction between less common than hyperplastic polyps;
metaplasia: complete (also designated intraepithelial and invasive carcinoma overall, they account for approximately
as small intestinal type or type I), and {1683, 1025}. Several proposals have 10% of gastric polyps {1843}. They tend
incomplete (types II and III) {843}. been made for the terminology of the to arise in the antrum or mid stomach in
Different mucin expression patterns char- morphological spectrum of lesions that lie areas of intestinal metaplasia.
acterize the metaplasias: complete shows between non-neoplastic changes and Morphologically, adenomas can be
decreased expression of gastric (MUC1, early invasive cancer, including the described as tubular (the most com-
MUC5AC and MUC6) mucins and recent international Padova classification mon), tubulovillous, or villous; the latter
expression of MUC2, an intestinal mucin. {1636}. two have also been called papillotubular
In incomplete intestinal metaplasia, gas- and papillary. Most have epithelium of
tric mucins are co-expressed with MUC2 Indefinite for intraepithelial neoplasia intestinal type, but some have gastric
mucin. These findings show that incom- Sometimes, doubts arise as to whether a foveolar features.
plete intestinal metaplasia has a mixed lesion is neoplastic or non-neoplastic (i.e.
gastric and intestinal phenotype reflect- reactive or regenerative), particularly in Low-grade intraepithelial neoplasia
ing an aberrant differentiation program small biopsies. In such cases, the dilem- This lesion shows a slightly modified
not reproducing any normal adult gas- ma is usually solved by cutting deeper mucosal architecture, including the pres-
trointestinal epithelial phenotype {1574}. levels of the block, by obtaining addition- ence of tubular structures with budding
al biopsies, or after removing possible and branching, papillary enfolding, crypt
Intraepithelial neoplasia sources of cellular hyperproliferation. One lengthening with serration, and cystic
Intraepithelial neoplasia (dysplasia) arises important source of a potentially alarming changes. Glands are lined by enlarged
in either the native gastric or of intestinal- lesion is the regeneration associated with columnar cells with minimal or no mucin.
ized gastric epithelia. Pyloric gland ade- NSAID-induced injury or superficial ero- Homogeneously blue vesicular, rounded
noma is a form of intraepithelial neoplasia sion/ulceration caused by gastric acid. or ovoid nuclei are usually pseudostrati-
arising in the native mucosa {2066, 1885}. Cases lacking all the attributes required fied in the proliferation zone located at
In the multi-stage theory of gastric onco- for a definitive diagnosis of intraepithelial the superficial portion of the dysplastic
genesis, intraepithelial neoplasia lies neoplasia may be placed into the catego- tubules.
between atrophic metaplastic lesions ry indefinite for intraepithelial neoplasia.
and invasive cancer (Table 3.01). In native gastric mucosa, foveolar hyper- High-grade intraepithelial neoplasia
Problems associated with diagnosing proliferation may be indefinite for dyspla- There is increasing architectural distortion
gastric intraepithelial neoplasia include sia, showing irregular and tortuous tubular with glandular crowding and prominent
the distinction from reactive or regenera- structures with epithelial mucus depletion, cellular atypia. Tubules can be irregular in
tive changes associated with active a high nuclear-cytoplasmic ratio and loss shape, with frequent branching and fold-
of cellular polarity. Large, oval/round,
hyperchromatic nuclei associate with
prominent mitoses, usually located near
the proliferative zone in the mucous neck
region.
In intestinal metaplasia, areas indefinite
for intraepithelial neoplasia exhibit a
hyperproliferative metaplastic epithelium.
The glands may appear closely packed,
lined by cells with large, hyperchromatic,
rounded or elongated, basally located
nuclei. Nucleoli are an inconsistent find-
ing. The cyto-architectural alterations tend
to decrease from the base of the glands to
their superficial portion.

Intraepithelial neoplasia
It has flat, polypoid, or slightly depressed
growth patterns; the flat pattern may lack
any endoscopic changes on convention-
al endoscopy, but shows an irregular
appearance on dye endoscopy. In
Western countries, the term adenoma is
applied when the proliferation produces
a macroscopic, usually discrete, protrud-
ing lesion. However, in Japan, adenomas Fig. 3.22 Tubular adenoma of gastric antrum.
Fig. 3.21 Reactive gastritis with marked foveolar include all gross types (i.e. flat, elevated Uninvolved pyloric glands below the lesion show
hyperplasia. and depressed). Gastric adenomas are cystic dilatation.

Gastric carinoma 47
03 19.7.2006 7:41 Page 48

Polyps
Hyperplastic polyps
Hyperplastic polyps are one of the com-
monest gastric polyps. They are sessile
or pedunculated lesions, usually < 2.0
cm in diameter, typically arising in the
antrum on a background of H. pylori gas-
tritis. They contain a proliferation of sur-
face foveolar cells lining elongated, dis-
torted pits extending deep into the
stroma. They may contain pyloric glands,
chief cells and parietal cells. The surface
often erodes. In a minority of cases, car-
cinoma develops within the polyps in
areas of intestinal metaplasia and dys-
plasia.

Fundic gland polyps


Fundic gland polyps are the commonest
gastric polyp seen in Western popula-
A B tions. They occur sporadically, without a
Fig. 3.23 A, B Examples of low-grade intraepithelial neoplasia of flat gastric mucosa. The atypia extends to
relationship to H. pylori gastritis. They
the surface.
also affect patients on long-term proton
pump inhibitors or patients with familial
ing; there is no stromal invasion. Mucin sive cancer already may be present in adenomatous polyposis (FAP), who may
secretion is absent or minimal. The pleo- patients found to have high-grade intra- have hundreds of fundic gland polyps
morphic, hyperchromatic, usually pseu- epithelial neoplasia with no obvious {2064, 2065}.
dostratified nuclei often are cigar-shaped. tumour mass. The extent of intestinal The lesions consist of a localized hyper-
Prominent amphophilic nucleoli are com- metaplasia associated with intraepithelial plasia of the deep epithelial compart-
mon. Increased proliferative activity is neoplasia, together with a sulphomucin- ment of the oxyntic mucosa, particularly
present throughout the epithelium. secreting phenotype of the intestinalized of mucous neck cells, with variable
mucosa (type III intestinal metaplasia), degrees of cystic dilatation. Sporadic
Progression of intraepithelial neoplasia to correlate with an increased risk of carci- fundic gland polyps have no malignant
carcinoma noma development. potential. Exceptionally, patients with
Carcinoma is diagnosed when the tumour attentuated FAP may develop dysplasia
invades into the lamina propria (intramu- Adenomas and carcinoma in their fundic gland
cosal carcinoma) or through the muscu- Adenomas are circumscribed, benign polyps {2214, 1204}
laris mucosae. Some gastric biopsies lesions, composed of tubular and/or vil-
contain areas suggestive of true invasion lous structures showing intraepithelial Polyposis syndromes
(such as isolated cells, gland-like struc- neoplasia. The frequency of malignant Peutz-Jeghers polyps, juvenile polyps,
tures, or papillary projections). The term transformation depends on size and his- and Cowden polyps generally do not
suspicious for invasion is appropriate tological grade. It occurs in approximate- occur spontaneously, but rather as part
when the histological criteria for an inva- ly 2% of lesions measuring < 2 cm and in of hereditary polyposis syndromes. In the
sive malignancy are equivocal. 40-50% of lesions > 2 cm. Flat adenomas stomach, Peutz-Jeghers polyps are char-
Up to 80% of intraepithelial neoplasias may have a greater tendency to progress acterized histologically by branching
may progress to invasion. Indeed, inva- to carcinoma. bands of smooth muscle derived from

A B C
Fig. 3.24 High-grade intraepithelial neoplasia in flat gastric mucosa (flat adenoma). A Architectal distortion of the gastric glands. B High degree of cellular atypia.
C Papillary pattern.

48 Tumours of the stomach


03 19.7.2006 7:41 Page 49

Table 3.01 carcinoma (HDGC) {640, 568}. Predis-


Histological follow-up studies of gastric intraepithelial neoplasia. Proportion progressing to carcinoma and posing germline CDH1 mutations gener-
mean interval.
ally resulting in truncated proteins are
Reports Low-grade dysplasia High-grade dysplasia spread throughout the gene with no
apparent hotspots {641, 640, 568, 1581}.
Saraga, 1987 {2355} 2% (1/64) 4 yr. 81% (17/21) 4 mos. HDGC has an age of onset ranging
upwards from 14 years and a penetrance
Lansdown, 1990 {2356} 0 (0/7) 85% (11/13) 5 mos. of approximately 70% {641, 568}.
Histologically, HDGC tumours are dif-
Rugge, 1991 {2008} 17% (12/69) 1yr. 75% (6/8) 4 mos. fuse, poorly differentiated infiltrative ade-
nocarcinomas with occasional signet-
Fertitta, 1993 {2357} 23% (7/30) 10 mos. 81% (25/31) 5 mos.
ring cells {641, 640, 568}.
Di Gregorio, 1993 {2358} 7% (6/89) 2 yr. 60% (6/10) 11 mos.
HNPCC
Rugge, 1994 {2009} 14% (13/90) 2 yr. 78% (14/18) 9 mos. Gastric carcinomas can develop as part
of the hereditary nonpolyposis colon
Kokkola, 1996 {2359} 0% (0/96) 67% (2/3) 1.5 yr. cancer (HNPCC) syndrome {1130, 922}.
They are intestinal type cancers, without
an association with H. pylori infection;
most exhibit microsatellite instability
muscularis mucosae, and hyperplasia, Gastric carcinoma occasionally devel- (MSI) {4} with a trend that is opposite to
elongation and cystic change of foveolar ops in families with germline mutations in that found in tumours arising in young
epithelium; the deeper glandular compo- ATM5, TP53 (Li Fraumeni syndrome) patients {1739}.
nents tend to show atrophy. {2001, 743, 1652}, and BRCA2 {1934}.
Rare site-specific gastric carcinoma pre- Gastrointestional polyposis syndromes
Genetic susceptibility disposition traits have been reported in Gastric carcinomas also occur in
Most gastric carcinomas occur sporadi- several families {1147, 2130}, including patients with gastrointestinal polyposis
cally; only about 8-10% have an inherited that of Napoleon. syndromes including FAP and Peutz-
familial component {996}. Familial clus- Jeghers syndrome.
tering occurs in 12 to 25% with a domi- Hereditary diffuse gastric carcinoma Overall, gastric carcinoma is rare in
nant inheritance pattern {597, 864}. Germline mutations in the gene encoding these settings, and the exact contribution
Case-control studies also suggest a the cell adhesion protein E-cadherin of the polyposis and underlying germline
small but consistent increased risk in (CDH1) lead to an autosomal dominant alterations of APC and LKB1/STK11 to
first-degree relatives of gastric carcino- predisposition to gastric carcinoma, cancer development is unclear.
ma patients {2200}. referred to as hereditary diffuse gastric
Blood group A
The blood group A phenotype associ-
ates with gastric carcinomas {27, 649}.
H. pylori adhere to the Lewisb blood
group antigen and the latter may be an
important host factor facilitating this
chronic infection {244} and subsequent
cancer risk.

Molecular genetics
Loss of heterozygosity studies and com-
parative genomic hybridization (CGH)
A B
analyses have identified several loci with
significant allelic loss, indicating possi-
ble tumour suppressor genes important
in gastric carcinoma. Common target(s)
of loss or gain include chromosomal
regions 3p, 4, 5q, (30 to 40% at or near
APCs locus) {1656, 1577}, 6q {255}, 9p,
17p (over 60 percent at TP53s locus)
{1656}, 18q (over 60 percent at DCCs
locus) {1981}, and 20q {1287, 449,
C D 2192}. Similar LOH losses at 11p15
Fig. 3.25 A Large hyperplastic polyp of the stomach. B, C Typical histology of gastric hyperplastic polyp. D occur in proximal and distal carcinomas,
Hyperplastic polyp with florid epithelial hyperplasia. suggesting common paths of develop-

Gastric carcinoma 49
03 19.7.2006 7:41 Page 50

A B
Fig. 3.26 A, B Fundic gland polyp. Cystic glands are typical.

ment {1288}. Loss of a locus on 7q inactivation of both alleles by mecha- E-cadherin splice site alterations pro-
(D7S95) associates with peritoneal nisms such as hypermethylation {1050, duce exon deletion and skipping. Large
metastasis. 510}. deletions including allelic loss and mis-
The frequency of MSI in sporadic gastric Genes with simple tandem repeat sense point mutations also occur; some
carcinoma ranges from 13% to 44% sequences within their coding regions tumours exhibit alterations in both alleles
{1713}. MSI+ tumours tend to be that are altered in MSI+ tumours include {135}. Somatic E-cadherin gene alter-
advanced intestinal-type cancers. The the TGF- II receptor, BAX, IGFRII, ations also affect the diffuse component
degree of genome-wide instability varies hMSH3, hMSH6, and E2F-4. A study of of mixed tumours {1136}. Alpha-catenin,
with more significant instability (e.g., gastric cancers displaying the MSI-H which binds to the intracellular domain of
MSI-H: > 33% abnormal loci) occurring phenotype reveal that a majority contain E-cadherin and links it to actin-based
in only 16% of gastric carcinoma, usually mutated TGF- type II receptors in a cytoskeletal elements, shows reduced
of the subcardial intestinal or mixed type, polyadenine tract {1420, 1462}. Altered immunohistochemical expression in
with less frequent lymph node or vessel TGF- II receptor genes can also be many tumours and correlates with infiltra-
invasion, prominent lymphoid infiltration, found in MSI-lesions. tive growth and poor differentiation
and better prognosis {430}. Loss of either Allelic loss of TP53 occurs in > 60% of {1189}. Beta catenin may also be abnor-
hMLH1 or hMSH2 protein expression cases and mutations are identified in mal in gastric carcinoma.
affects all MSI-H cases {654} suggesting approximately 30-50% of cases depend- There is evidence of a tumour suppres-
ing on the mutational screening method sor locus on chromosome 3p in gastric
and sample sizes {729, 1937}. TP53 carcinomas {893, 1688}. This area
mutations are identifiable in some intes- encodes the FHIT gene. Gastric carcino-
tinal metaplasias; {497} most alterations mas develop abnormal transcripts, delet-
affect advanced tumours. TP53 muta- ed exons {1411}, a somatic missense
tions in gastric lesions resemble those mutation in exon 6 and loss of FHIT pro-
seen in other cancers with a predomi- tein expression {102}.
nance of base transitions, especially at Somatic APC mutations, mostly mis-
CpG dinucleotides. Immunohistochemi- sense in nature and low in frequency,
cal analyses to detect TP53 overexpres- affect Japanese patients with in situ and
sion can indirectly identify TP53 muta- invasive neoplasia {1309}. Significant
tions but do not have consistent allelic loss (30%) at the APC loci suggest
prognostic value in gastric carcinoma that there is a tumour suppressor gene
patients {557, 766}. Finally, with respect important in gastric tumourigenesis near-
to TP53, there is a polymorphism in by. Indeed, alternative loci have been
codon 72 encoding a proline rather than mapped to commonly deleted regions in
an arginine that strongly associates with gastric carcinomas {1891}.
antral cancers {1735}. Amplification and overexpression of the
Sporadic gastric carcinomas, especially c-met gene encoding a tyrosine kinase
diffuse carcinomas, exhibit reduced or receptor for the hepatocyte growth factor
abnormal E-cadherin expression {1196, occurs in gastric carcinoma {976}. Other
1135}, and genetic abnormalities of the growth factor and receptor signal systems
E-cadherin gene and its transcripts. that may be involved include epidermal
Fig. 3.27 Peutz-Jeghers polyp with hyperplastic Reduced E-cadherin expression is asso- growth factor, TGF-alpha, interleukin-1-a,
glands. ciated with reduced survival {848}. cripto, amphiregulin, platelet-derived

50 Tumours of the stomach


03 19.7.2006 7:41 Page 51

A B C
Fig. 3.28 E-cadherin expression in gastric adenocarcinoma. A Intestinal type of adenocarcinoma showing a normal pattern of membranous staining. B Diffuse type
of adenocarcinoma with reduced E-cadherin expression. Normal expression can be seen in the non-neoplastic gastric epithelium overlying the tumour. C Undiffer-
entiated gastric carcinoma with highly reduced membranous expression and dot-like cytoplasmic expression.

growth factor, and K-sam {1879}. Ampli- advanced cases. Lymph node status, classification scheme for reporting nodal
fication of c-erbB-2, a transmembrane which is part of the TNM system, is also involvement in gastric cancer.
tyrosine kinase receptor oncogene, an important prognostic indicator. The 5th Roder et al recently published data sup-
occurs in approximately 10% of lesions edition of the UICC TNM Classification of porting the value of this reporting sys-
and overexpression associates with a Malignant Tumours {66} and the AJCC tem. These authors found that for
poor prognosis {375}. Telomerase activity Manual for the Staging of Cancer {1} pub- patients who had nodal involvement in
has been detected by a PCR-based lished in 1997, have a number-based 1-6 lymph nodes (pN1), the 5-year sur-
assay frequently in the late stages of gas-
tric tumours and observed to be associat-
ed with a poor prognosis {719}.

Prognosis and predictive factors


Early gastric cancer
In early gastric cancers, small mucosal
(< 4 cm), superficial (> 4 cm) and Pen B
lesions have a low incidence of vessel
invasion and lymph node metastasis and
a good prognosis after surgery (about
90% of patients survive 10 years). In con-
trast, penetrating lesions of the Pen A
type are characterized by a relatively
high incidence of vessel invasion and
lymph node metastasis and a poor prog-
nosis after surgery (64.8% 5-year sur-
vival).

Advanced gastric cancer


Staging. The TNM staging system for
gastric cancer is widely used and it pro-
vides important prognostic information. Fig. 3.29 CGH analysis of a poorly differentiated gastric adenocarcinoma: copy number gains at chromo-
Lymphatic and vascular invasion carries somes 3q21, 7p15, 8q, 10p12-15, 11q13, 12q24, 13q13-14, 15q23-25, 17q24, 20 and 21q21. Copy number losses
a poor prognosis and is often seen in at chromosomes 4q12-28 and 5.

Gastric carcinoma 51
03 19.7.2006 7:41 Page 52

survival of approximately 95%. Tumours validated these findings {1788}. Another


that invade the muscularis propria have a classification scheme for gastric carcino-
60-80% 5-year survival, whereas tumours ma was proposed by Carneiro et al that
invading the subserosa have a 50% may also have prognostic value {610}.
5-year survival {2181}. Unfortunately, The recognition of mixed carcinoma may
most patients with advanced carcinoma be important since patients harbouring
already have lymph node metastases at this type of carcinoma may also have a
the time of diagnosis. poor outcome {610}.
Histological features. The value of the his- Some patients with medullary carcino-
tological type of tumour in predicting mas with circumscribed, pushing growth
Fig. 3.30 TP53 mutations in gastric carcinoma. The tumour prognosis is more controversial. margins and a marked stromal inflamma-
mutations are shown by both single-strand confor- This relates in part to the classification tory reaction exhibit a better prognosis
mation polymorphisms (SSCP) as well as direct scheme that is used to diagnose the can- than those with other histological tumour
sequencing. There is a G to A substitution indicated cers. Using the Laurn classification, types {430}. Some of these patients are
by the right hand panel. some believe that diffuse lesions general- in HNPCC kindreds who have MSI-H, a
ly carry a worse prognosis than intestinal feature associated with better survival.
carcinomas. The prognosis is particularly However, not all studies agree that stro-
vival rate was 44% compared with a 30% bad in children and young adults, in mal response and pushing margins pre-
survival rate in patients with 7-15 lymph whom the diagnosis is often delayed dict a better prognosis {1788, 1177}.
nodes involved with tumour (pN2). {1986, 1554} and likely fit into the catego- In summary, gastric carcinoma is a hete-
Patients with more than 15 lymph nodes ry of HDGC. However, others have not rogeneous disease biologically and
involved by metastatic tumour (pN3) had found the Laurn classification to predict genetically, and a clear working model of
an even worse 5-year survival of 11% prognosis {1788, 1177}. One study found gastric tumourigenesis has yet to be for-
{1602}. Gastric carcinoma with obvious that only the Goseki classification {610} mulated. More tumours appear to be
invasion beyond the pyloric ring, those added additional prognostic information related to environmental than to genetic
with invasion up to the pyloric ring, and to the TNM stage {610}. 5-year survival of causes, although both may play a role in
those without evidence of duodenal inva- patients with mucus rich (Goseki II and individual cases. Characterization of the
sion have 5-year survival rates of 8%, IV) T3 tumours was significantly worse various pathways should afford multiple
22%, and 58%, respectively {671}. than that of patients with mucus poor opportunities to design more specific
Patients with T1 cancers limited to the (Goseki I and III) T3 tumours (18% vs. and therefore more effective therapies.
mucosa and submucosa have a 5-year 53% p<0.003) {1177}. A second study

52 Tumours of the stomach


03 19.7.2006 7:41 Page 53

C. Capella
Endocrine tumours of the stomach E. Solcia
L.H. Sobin
R. Arnold

Definition observed mainly in male patients (M:F


Most endocrine tumours of the stomach ratio, 2.8:1) at a mean age of 55 years
are well differentiated, nonfunctioning (range 21-38 years) {1590}.
enterochromaffin-like (ECL) cell carci- Small cell carcinoma (poorly differentiat-
noids arising from oxyntic mucosa in the ed endocrine carcinoma) accounts for
corpus or fundus. Three distinct types 6% of gastric endocrine tumours and pre-
have are recognized: (1) Type I, associ- vails in men (M:F ratio, 2:1) at a mean age
ated with autoimmune chronic atrophic of 63 years (range 41-61 years) {1590}.
gastritis (A-CAG); (2) type II, associated Gastrin cell tumours represent less than
with muliple endocrine neoplasia type 1 1% of gastric endocrine tumours {1590}
(MEN-1) and Zollinger-Ellison syndrome and are reported in adults (age range Fig. 3.31 Chromogranin A immunostain demon-
(ZES); type III, sporadic, i.e. not associ- 55-77). strates hyperplasia of endocrine cells at the base of
glandular tubules.
ated with hypergastrinaemia or A-CAG.
Aetiology
ICD-O Code Gastrin has a trophic effect on ECL-cells
Carcinoid 8240/3 both in humans and experimental ani- contribute to tumourigenesis {1785}.
Small cell carcinoma 8041/3 mals {172, 652}. Hypergastrinaemic Several growth factors, including trans-
states, resulting either from unregulated forming growth factor- (TGF) and
Epidemiology hormone release by a gastrinoma or from basic fibroblast growth factor (bFGF)
In the past, carcinoid tumours of the a secondary response of antral G cells to seem to be involved in tumour develop-
stomach have been reported to occur achlorhydria, are consistently associated ment and progression as well as stromal
with an incidence of 0.002-0.1 per with ECL-cell hyperplasia {172}. and vascular proliferation of ECL-cell
100,000 population per year and to carcinoids {171}.
account for 2-3 % of all gastrointestinal Autoimmune chronic atrophic gastritis
carcinoids {587} and 0.3 percent of gas- (A-CAG) Localization
tric neoplasms {1132}. More recent stud- This disease is caused by antibodies to Type I, II, and III ECL-cell carcinoids are
ies, however, based on endoscopic tech- parietal cells of the oxyntic mucosa. It all located in the mucosa of the body-
niques and increased awareness of such leads to chronic atrophic gastritis (with or fundus of the stomach, whereas the rare
lesions, have shown a much higher inci- without pernicious anaemia) which leads G-cell tumours are located in the antro-
dence of gastric carcinoids, which may to an increase in gastrin production. pyloric region. Small cell carcinomas
now account for 11-41% of all gastroin- prevail in the body/fundus, but some are
testinal carcinoids {1588, 1764, 1782}. Zollinger-Ellison syndrome located in the antrum {1590}.
The incidence of gastric carcinoids is This disease results from hypergastri-
higher in Japan, where they re-present naemia due to gastrin-producing neo- Clinical features
30% of all gastrointestinal carcinoids, plasms that are preferentially located in The three distinct types of ECL-cell car-
which may be due to the high incidence the small intestine and pancreas. ECL- cinoids are well differentiated growths
of chronic atrophic gastritis in this country cell proliferation is usually limited to but with variable and poorly predictable
{1277}. hyperplastic lesions of the simple linear behaviour.
type {1042, 1777}.
Age and sex distribution Type I ECL-cell carcinoids
Type I gastric ECL-cell carcinoids have MEN-1 These are associated with A-CAG involv-
been reported to represent 74% of gas- This inherited tumour syndrome causes a ing the corpus and fundus mucosa.
tric endocrine tumours and to occur most variety of endocrine neoplasms, includ- Clinical signs include achlorhydria and,
often in females (M:F ratio, 1:2.5). The ing gastrinomas. In patients with MEN-1 less frequently, pernicious anemia.
mean age at biopsy is 63 years (range associated ZES (MEN-1/ZES), ECL-cell Hypergastrinaemia or evidence of antral
15-88 years). Type II ECL-cell carcinoids lesions are usually dysplastic or overtly gastrin-cell hyperplasia is observed in all
represent 6% of all gastric endocrine carcinoid in nature {1779}. In the MEN-1 cases of A-CAG. In patients with a carci-
tumours and show no gender predilec- syndrome, the mutation or deletion of the noid, ECL-cell hyperplastic changes are
tion (M:F ratio, 1:1) at a mean age of 50 suppressor MEN-1 oncogene in 11q13 a constant feature and dysplastic
years (range 28-67 years) {1590}. Type may be involved {394} as an additional growths are frequently observed {1590}.
III ECL-cell carcinoids constitute 13% of pathogenetic factor. In A-CAG, achlorhy- A-CAG associated carcinoids are typi-
all gastric endocrine tumours and are dria or associated mucosal changes may cally small (usually less than 1 cm), mul-

Endocrine tumours 53
03 19.7.2006 7:41 Page 54

tiple and multicentric. Of 152 cases stud- which, though larger than those of type I,
ied by endoscopy, 57% had more than are generally smaller than 1.5 cm in size
two growths {1561}. in 75% of cases {1590}.
Type III ECL-cell tumours are usually sin-
Type II ECL-cell carcinoids gle and in 33% of the cases larger than 2
Hypertrophic, hypersecretory gastropa- cm in diameter. Infiltration of the muscu-
thy and high levels of circulating gastrin laris propria is found in 76%, and of the
are critical diagnostic findings. In all serosa in 53% of cases {1590}.
cases, ECL-cell hyperplasia and/or dys-
plasia were noted in the fundic peritu- Histopathology
moural mucosa {1590}. These gastric The histopathological categorization of Fig. 3.32 Sporadic (type III) ECL-cell carcinoid of the
carcinoids are usually multiple and small- endocrine tumours of the stomach gastric body. The surrounding mucosa is normal.
er than 1.5 cm in size in the majority of described here, is a modification of the
cases {1590}. WHO classification of endocrine tumours
{1784}. specimens {1865}. The ECL-cell nature of
Type III (sporadic) ECL-cell carcinoids argyrophil tumours is ultimately assessed
These lesions are not associated with Carcinoid tumour by demonstrating ECL-type granules by
hypergastinaemia or A-CAG. They are A carcinoid is defined morphologically electron microscopy {232, 1591}.
generally solitary growths, and arise in the as a well differentiated neoplasm of the Sporadic ECL-cell carcinoids are usually
setting of gastric mucosa devoid of diffuse endocrine system. more aggressive than those associated
ECL-cell hyperplasia/dysplasia and of with A-CAG or MEN-1. Histopathologi-
significant pathologic lesions except for ECL-cell carcinoid cally, these tumours show a prevalence
gastritis (other than A-CAG). Rare multi- The majority of type I and type II of solid cellular aggregates and large tra-
ple tumours have been observed {1590}. ECL-cell carcinoids are characterized beculae, crowding, and irregular distri-
Clinically, type III tumours present (1) as a by small, microlobular-trabecular aggre- bution of round to spindle and polyhedral
mass lesion with no evidence of endo- gates formed by regularly distributed, tumour cells, fairly large vesicular nuclei
crine symptoms (nonfunctioning carci- often aligned cells (mosaic-like pattern), with prominent eosinophilic nucleoli, or
noid) and with clinical findings similar to with regular, monomorphic nuclei, usual- smaller, hyperchromatic nuclei with irreg-
those of adenocarcinoma, including gas- ly inapparent nucleoli, rather abundant, ular chromatin clumps and small nucle-
tric haemorrhage, obstruction and metas- fairly eosinophilic cytoplasm, almost oli, considerable mitotic activity, some-
tasis, or (2) with endocrine symptoms of absent mitoses, and infrequent angioin- times with atypical mitotic figures and
an atypical carcinoid syndrome with red vasion. scarce necrosis.
cutaneous flushing and absence of diar- Tumours with these features (grade 1 Tumours with these histological features
rhoea, usually coupled with liver metas- according to Rindi et al {1589}) are gen- or grade 2 features {1589} show a higher
tases and production of histamine and erally limited to mucosa or submucosa mitotic rate (mean of 9 per 10 HPF), a fre-
5-hydroxytryptophan {1386, 1598}. {1589} and can be considered as quent expression of p53 (60%), a higher
tumours with benign behaviour. The ECL
Non ECL-cell gastric carcinoids. nature of the tumours is confirmed by Table 3.02.
These uncommon tumours may present strong argyrophilia by Grimelius or Histological classification of endocrine neoplasms
with ZES due to their gastrin production Sevier Munger techniques and positive of the stomach1
(which is more frequently found in duo- immunoreactivity for chromogranin A, in 1. Carcinoid
denal gastrinomas) or with Cushing syn- the absence of reactivity for the well differentiated endocrine neoplasm
drome due to secretion of adrenocorti- argentaffin or diazonium tests for sero- 1.1 ECL-cell carcinoid
cotrophic hormone (ACTH) {711, 1791}. tonin, and no or only occasional 1.2 EC-cell, serotonin-producing
immunoreactivity for hormonal products carcinoid
Macroscopy {1591}. Minor cell sub-populations ex- 1.3 G-cell, gastrin-producing tumour
Type I ECL-cell carcinoids are multiple in pressing serotonin, gastrin, somato- 1.4 Others
57% of cases {1590}, usually appearing statin, pancreatic polypeptide (PP), or
as small tan nodules or polyps that are -hCG have been detected in a minority 2. Small cell carcinoma
poorly differentiated endocrine neoplasm
circumscribed in the mucosa or, more of tumours {1591}. A few ECL-cell
often, to the submucosa. Most tumours tumours produce histamine and 3. Tumour-like lesions
(77%) are < 1 cm in maximum diameter 5-hydroxy-tryptophan; these lesions, Hyperplasia
and 97% of tumours are < 1.5 cm. The when they metastasize, can produce Dysplasia
muscularis propria is involved in only a atypical carcinoid syndrome {1591}
minority of cases (7%) {1590}. Vesicular monoamine transporter type 2 1
Benign behaviour of ECL-cell carcinoid is associated
with the following: tumour confined to mucosa-sub-
The stomachs with type II tumours are (VMAT-2) is a suitable and specific marker mucosa, nonangioinvasive, < 1cm in size, nonfunc-
enlarged and show a thickened gastric for ECL-cell tumours {1592} while hista- tioning; occurring in CAG or MEN-1/ ZES. Aggressive
behaviour of ECL-cell carcinoid is associated with the
wall (0.6-4.5 cm) due to severe hyper- mine or histidine decarboxylase immuno- following: tumour invades muscularis propria or
beyond, > 1cm in size, angioinvasive, functioning, and
trophic-hypersecretory gastropathy and histochemical analysis, although specific, sporadic occurrence.
multiple mucosal-submucosal nodules is less suitable for routinely processed

54 Tumours of the stomach


03 19.7.2006 7:41 Page 55

A B
Fig. 3.33 A Type I ECL-cell carcinoid in a patient with pernicious anaemia. B Type II ECL-cell carcinoid in a patient with MEN1 and ZES.

Ki67 labelling index (above 1000 per 10 Large cell neuroendocrine carcinoma is a Mixed exocrine-endocrine carcinomas
HPF) and more frequent lymphatic and malignant neoplasm composed of large These consist of neoplastic endocrine
vascular invasion than well differentiated cells having organoid, nesting, trabecular, cells composing more than 30% of the
ECL-cell carcinoids {1589}. In addition, rosette-like and palisading patterns that whole tumour cell population. They are
deeply invasive tumours are associated suggest endocrine differentiation, and in relatively rare in the stomach, despite the
with local and/or distant metastases in which the last can be confirmed by frequent occurrence of minor endocrine
most cases. immunohistochemistry and electron components inside the ordinary adeno-
microscopy. In contrast to small cell carci- carcinoma. They should generally be
EC-cell, serotonin-producing carcinoid noma, cytoplasm is more abundant, classified as adenocarcinomas.
This is a very rare tumour in the stomach nuclei are more vesicular and nucleoli are
{1591}. It is formed by rounded nests of prominent {1954}. These tumours have Precursor lesions
closely packed small tumour cells, often not been well described in the gastroin- ECL-cell carcinoids arising in hypergas-
with peripheral palisading, reminiscent of testinal tract because of their apparent trinaemic conditions (types I and II)
the typical type A histologic pattern of low frequency {1188}. develop through a sequence of hyperpla-
the argentaffin EC-cell carcinoid of the sia-dysplasia-neoplasia that has been
midgut. The tumour cells are argentaffin, well documented in histopathological
intensely argyrophilic and reactive with studies {1777}. The successive stages of
chromogranin A and anti-serotonin anti- hyperplasia are termed simple, linear,
bodies. Electron microscopic examina- micronodular, and adenomatoid. Dyspla-
tion confirms the EC-cell nature by sia is characterized by relatively atypical
detecting characteristic pleomorphic, cells with features of enlarging or fusing
intensely osmiophilic granules similar to micronodules, micro-invasion or newly
those of normal gastric EC-cells. formed stroma. When the nodules
increase in size to > 0.5 mm or invade
Gastrin-cell tumours into the submucosa, the lesion is classi-
Most well differentiated gastrin-cell fied as a carcinoid. The entire spectrum
tumours are small mucosal-submucosal of ECL-cell growth, from hyperplasia to
nodules, found incidentally at endoscopy dysplasia and neoplasia has been
or in a gastrectomy specimen. They may observed in MEN-1/ZES and autoimmune
show a characteristic thin trabecular- chronic atrophic gastritis (A-CAG). A sim-
gyriform pattern or a solid nest pattern. ilar sequence of lesions has been shown
The cells are uniform with scanty cyto- in experimental models of the disease,
plasm and show predominant immunore- mostly based on hypergastrinaemia sec-
activity for gastrin. ondary to pharmacological inhibition of
acid secretion in rodents {1896}.
Small cell carcinoma (poorly differentiat-
ed endocrine neoplasm) Genetic susceptibility
These are identical to small cell carcino- ECL-cell carcinoids are integral compo-
mas of the lung. They correspond to nents of the MEN-1 syndrome {1042}. In
grade 3 tumours according to Rindi et al. patients with familial MEN-1/ZES, type II
{1589}, and are particularly aggressive, Fig. 3.34 ECL-cell carcinoid showing immunoex- gastric carcinoids arise in 13-30% of
malignant tumours {1591}. pression of chromogranin A. cases {854, 1042}. However, patients

Endocrine tumours 55
03 19.7.2006 7:41 Page 56

A B
Fig. 3.35 Sporadic (type III) ECL carcinoid. A Tumour extends from mucosa into submucosa with well delineated inferior border. B The carcinoid (left) has round,
regular, isomorphic nuclei.

with sporadic ZES rarely develop gastric These findings support the concept that of causing ECL-cell tumours without
carcinoids despite serum gastrin levels, these gastric tumours are integral com- requiring the promoting effect of hyper-
which persist 10 fold above normal for a ponents of the MEN-1 phenotype, shar- gastrinaemia.
prolonged time. ing with parathyroid and islet cell The role of MEN-1 in non MEN-associat-
tumours the highest frequency of LOH at ed gastric carcinoids is more controver-
Diagnostic criteria of MEN-1 11q13. In multiple carcinoids from the sial. Analysing six type I gastric carci-
This rare dominantly inherited disorder is same stomach, the deletion size in the noids, Debelenko et al. {394} found
characterized by the synchronous or wild-type allele differed from one tumour 11q13 LOH in one tumour while DAdda
metachronous development of multiple to another, suggesting a multiclonal ori- et al. {363} detected 11q13 LOH in 12
endocrine tumours in different endocrine gin {394}. One of the type II tumours out of 25 cases (48%). Large deletions in
organs by the third decade of life. The showing LOH at 11q13 was in a patient both the 11q13 and 11q14 regions were
parathyroid glands are involved in who had neither ZES nor hypergastri- observed in two poorly differentiated
90-97%, endocrine pancreas in 30-82%, naemia {173}, suggesting that inactiva- endocrine carcinomas {363}.
duodenal gastrinomas in 25%, pituitary tion of the MEN-1 gene alone is capable
adenomas in more than 60%, and foregut Prognosis and predictive factors
carcinoids (stomach, lung, thymus) in The prognosis of carcinoids is highly
5-9% of cases {394}. Other, so-called variable, ranging from slowly growing
non-classical MEN-1 tumours, such as benign lesions to malignant tumours with
cutaneous and visceral lipomas, thyroid extensive metastatic spread.
and adrenal adenomas, and skin angiofi- Benign behaviour of ECL-cell carcinoids
bromas, may occur {394, 1444}. is associated with the following: tumour
confined to mucosa-submucosa, nonan-
MEN-1 gene gioinvasive, < 1 cm in size, nonfunction-
MEN-1 has been mapped to chromo- ing; occurring in CAG or MEN-1/ ZES.
some 11q13 {107, 1015}. It encodes for a Type I, A-CAG associated tumours, have
610 amino acid nuclear protein, termed an excellent prognosis, as do most type
menin, whose suppressor function II MEN-1/ZES tumours.
involves direct binding to JunD and inhi- Aggressive behaviour of ECL-cell carci-
bition of JunD activated transcription noid is associated with the following:
{271, 18}. The tumour suppressor function tumour invades muscularis propria or
of the gene has been proposed based on beyond, is > 1 cm in size, angioinvasive,
the results of combined tumour deletion functioning, with high mitotic activity and
and pedigree analysis {107, 271, 394}. sporadic occurrence {1591, 1590, 1589}.
High rates of loss of heterozygosity (LOH) Metastasis. Lymph node metastases are
at the MEN-1 gene locus have been detected in 5% of type I and 30% of type
reported in classic tumours of the MEN-1, II cases, while distant (liver) metastases
such as endocrine pancreatic, pituitary are found respectively in 2.5% and 10%
and parathyroid neoplasms {1553, 1923}. of cases. No tumour-related or only
LOH at 11q13 of type II gastric carcinoids exceptional death was observed among
was found in 9 of 10 MEN-1 patients Fig. 3.36 Gastrin cell tumour (gastrinoma) of the patients with type I carcinoid, while only
investigated {123, 173, 219, 394}. pylorus with trabecular growth pattern. 1/10 patients died of type II carcinoid. On

56 Tumours of the stomach


03 19.7.2006 7:41 Page 57

death from the tumour occurs in 27% of more than on the behaviour of gastric
patients with a mean survival of 28 tumours, although some aggressive
months {1590}. ECL-cell carcinomas may be fatal {173}.
In such patients, careful search for asso-
Therapy ciated pancreatic, duodenal, parathyroid,
Polypoid type I carcinoids < 1cm, fewer or other tumours and family investigation
than 3-5 in number, associated with for the MEN-1 gene mutation are needed.
A-CAG can be endoscopically excised Type III (sporadic) ECL-cell carcinoids
and have an excellent prognosis. If larg- > 1 cm generally require surgical resec-
er than 1 cm or more than 3-5 lesions are tion even when they are histologically
Fig. 3.37 Small cell carcinoma of the stomach. present, antrectomy and local excision of well differentiated.
all accessible fundic lesions is recom-
mended.
the other hand, lymph node metastases In type II carcinoids the clinical evolution
are found in 71% and distant metastases depends on the behaviour of associated
in 69% of patients with type III tumours; pancreatic and duodenal gastrinomas

Lymphoma of the stomach A. Wotherspoon


A. Chott
R.D. Gascoyne
H.K. Mller-Hermelink

Definition row involvement. Today, stomach lym- the neoplastic nature of lesions previous-
Primary gastric lymphomas are defined phomas are considered primary if the ly termed pseudolymphoma {677}.
as lymphomas originating from the stom- main bulk of disease is present in the Gastric lymphoma has a worldwide dis-
ach and contiguous lymph nodes. stomach. Recognition of morphological tribution; somewhat higher incidences
Lymphomas at this site are considered features characteristic of primary extra- have been reported for some Western
primary if the main bulk of disease is nodal lymphomas of mucosa-associated communities with a high prevalence of
located in the stomach. The majority of lymphoid tissue-type helps in defining Helicobacter pylori infection {420}.
gastric lymphomas are high-grade B-cell these lesions as primary to the stomach Primary Hodgkin disease is very rare in
lymphomas, some of which have devel- irrespective of the degree of dissemina- the gastrointestinal tract.
oped through progression from tion.
low-grade lymphomas of mucosa associ- Age and sex distribution
ated lymphoid tissue (MALT). The low- Epidemiology Incidence rates are similar in men and
grade lesions are almost exclusively Approximately 40% of all non-Hodgkin women. The age range is wide but the
B-cell MALT lymphomas. lymphomas arise at extranodal sites majority of patients are over 50 years at
{1438, 527}, with the gastrointestinal tract presentation.
Historical annotation as the commonest extranodal site,
Classically, primary gastric lymphomas accounting for about 4-18% of all Aetiology
have been considered to be lymphomas non-Hodgkin lymphomas in Western Helicobacter pylori infection
that are confined to the stomach and the countries and up to 25% of cases in the Initial studies of low-grade MALT lym-
contiguous lymph nodes {378}. While Middle East. Within the gastrointestinal phoma suggested that the tumour was
this excludes cases of secondary tract, the stomach is the most frequent associated with H. pylori in 92-98% of
involvement of the stomach by nodal- site of involvement in Western countries cases {447, 2135}; subsequent studies
type lymphomas which may occur in while the small intestine is most frequent- have suggested an association in
up to 25% of nodal lymphomas {508} ly affected in Middle Eastern countries. 62-77% {1316, 583, 2146, 890, 178}.
this definition is excessively restrictive Lymphoma constitutes up to 10% of all H. pylori infection is seen less frequently
and excludes more disseminated, higher gastric malignancies; its incidence in high-grade lymphomas with a low-
stage lymphomas arising within the appears to be increasing but this may, at grade component (52-71%) and in pure
stomach as well as those with bone mar- least in part, be due to the recognition of high-grade lymphomas (25-38%) {583,

Lymphoma 57
03 19.7.2006 7:41 Page 58

890, 178}. The organism has been shown sea and vomiting. High-grade lesions
to be present in 90% of cases limited to may appear as a palpable mass in the
the mucosa and submucosa, falling to epigastrium and can cause severe
76% when deep submucosa is involved, symptoms, including weight loss.
and is present in only 48% of cases with
extension beyond the submucosa Imaging
{1316}. It has been shown that the infec- Low-grade MALT lymphomas present as
tion by H. pylori precedes the develop- intragastric nodularity with preferential
ment of lymphoma, both by sequential location in the antrum {2180}. A more
serological studies {1474} and by retro- precise assessment is obtained with spi-
spective studies of archival gastric biop- ral CT, particularly if this is used in con- Fig. 3.38 Multifocal malignant lymphoma of the
sy material {2211, 1314}. junction with distension of the stomach stomach. The two larger lesions are centrally ulcer-
There is some controversy surrounding by water. This technique can identify up ated.
the role of the organisms genetic fea- to 88% of cases, most of which have
tures and the risk of lymphoma develop- nodularity or enlarged rugal folds, and it
ment. Studies of the association between can assess the submucosal extent of the Helicobacter heilmannii {1842} and in
MALT lymphoma and cagA bearing tumour {1493}. High-grade lymphomas association with coeliac disease {227}.
H. pylori strains have produced conflict- are usually larger and more frequently This organised lymphoid tissue shows all
ing results, ranging from a lack of asso- associated with the presence of a mass the features of MALT, including the infil-
ciation between cagA and lymphoma and with ulceration. In some cases, the tration of the epithelium by B-lympho-
{1492, 384} to a strong association {441}. radiological features may mimic diffuse cytes reminiscent of the lymphoepitheli-
One study claimed no association with adenocarcinoma {1059}. Endoscopic um seen in Peyer patches {2135}.
low-grade lymphoma but a high frequen- ultrasound is emerging as the investiga- The cellular basis of the interaction
cy of cagA strains in high-grade lesions tion of choice in the assessment of the between H. pylori and MALT lymphoma
{1492}. Recently, a truncated form of an extent of lymphoma infiltration through cells has been studied in detail. When
H. pylori associated protein, fldA, has the gastric wall. Local lymph node unseparated cells isolated from low-
been shown to be closely associated involvement can also be assessed by grade gastric MALT lymphomas are incu-
with gastric MALT lymphoma. All strains this technique. bated in vitro with heat treated whole cell
of H. pylori associated with MALT lym- preparations from H. pylori, the tumour
phoma showed a nucleotide G insertion Endoscopy cells proliferate while those cultured in
at position 481 of the fldA gene, com- Some cases show enlarged gastric folds, the absence of the organism or stimulat-
pared to 6/17 stains unassociated with gastritis, superficial erosions or ulcera- ing chemical mitogen rapidly die {768}.
lymphoma. This mutation causes a short tion. In these cases the surrounding nor- The proliferative response appeared to
truncation in the protein and antibodies mal appearing gastric mucosa may har- be strain specific for individual tumours
to this truncated protein could be detect- bour lymphoma, and accurate mapping but varied between tumours from differ-
ed in 70% of the patients studied with of the lesion requires multiple biopsies ent patients {768}. When T-cells were
MALT lymphoma, compared to 17% of from all sites including areas appearing removed from the culture system the pro-
control patients {274}. macroscopically normal. In a proportion liferative response was not seen and this
of cases, endoscopic examination shows could not be induced if the T-cells were
Immunosuppression very minor changes such as hyperaemia replaced by supernatant from other cul-
Lymphomas may arise or involve the and in a few cases random biopsies of tures containing unseparated tumour
stomach in patients with both congenital apparently entirely normal mucosa may derived cells {769}. Together these stud-
and acquired immunodeficiencies. In reveal lymphoma. High-grade lymphoma ies show that the proliferation of the
general, the incidence, clinical features is usually associated with more florid MALT lymphoma is driven by the pres-
and the histology of the lesions is indis- lesions, ulcers and masses. It is often ence of the H. pylori but that this, rather
tinguishable from those that develop out- impossible to distinguish lymphoma from than being a direct effect on the tumour
side the stomach. Up to 23% of gastroin- carcinoma endoscopically.
testinal tract non-Hodgkin lymphomas
arising in HIV infected patients occur in MALT lymphomas
the stomach and the vast majority of Pathogenesis
these are large B-cell or Burkitt/Burkitt- The normal gastric mucosa contains
like lymphomas, {122} although occa- scattered lymphocytes and plasma cells
sional low-grade MALT lymphomas are but is devoid of organised lymphoid tis-
described {2132}. sue. The initial step in the development of
primary gastric lymphoma is the acquisi-
Clinical features tion of organised lymphoid tissue from
Symptoms and signs within which the lymphoma can develop.
Patients with low-grade lymphomas often In most cases, this is associated with Fig. 3.39 Low-grade B-cell MALT lymphoma.
present with a long history of non-specif- infection by H. pylori {572}, although it Perifollicular distribution of centrocyte-like cells
ic symptoms, including dyspepsia, nau- has also been seen following infection by with a predominant monocytoid morphology.

58 Tumours of the stomach


03 19.7.2006 7:41 Page 59

some cases, the CCL cell may be more tritis, the infiltrate surrounding the lym-
reminiscent of a mature small B lympho- phoid follicles in the lamina propria is
cyte while in other cases, the cell may plasma cell predominant while in MALT
have a monocytoid appearance with lymphoma the infiltrate contains a domi-
more abundant, pale cytoplasm and a nant population of lymphocytes with CCL
well defined cell border. Plasma cell dif- cell morphology, infiltrating through the
ferentiation is typical and may be very lamina propria and around glands.
prominent. Dutcher bodies may be iden- Prominent lymphoepithelial lesions,
tified. The CCL cells infiltrate and destroy Dutcher bodies and moderate cytologi-
adjacent gastric glands to form lym- cal atypia are associated only with lym-
phoepithelial lesions. Lympho-epithelial phoma. All of these features may not be
lesions typical for MALT lymphoma are present in biopsy material from a single
defined as infiltration of the glandular case. In some cases it is justifiable to
epithelium by clusters of neoplastic lym- make the diagnosis of low-grade MALT
phoid cells with associated destruction lymphoma in the absence of one or more
of gland architecture and morphological of these features if the overall histological
changes within the epithelial cells, appearances are those of lymphoma.
including increased eosinophilia. Rare or questionable lymphoepithelial
lesions, dense lymphoid infiltration, mild
Immunohistochemistry cytological atypia and muscularis muco-
The immunophenotype of the CCL cell is sae invasion are features more often
similar to that of the marginal zone B-cell. associated with, but not limited to, lym-
There is expression of pan-B-cell anti- phoma {2212}.
Fig. 3.40 Low-grade B-cell MALT lymphoma. Small
lymphoid cells form a diffuse infiltrate extending
gens such as CD20 and CD79a and the In some cases it will not be possible to
into the submucosa. more mature B-cell markers CD21 and make a definite distinction between reac-
CD35. The cells do not express CD10. tive infiltrates and lymphoma and in
They are usually positive for bcl-2 protein these cases a diagnosis of atypical lym-
cells, is due to a mechanism mediated and may express CD43 but do not phoid infiltrate of uncertain nature is
via T-cells and that this help is contact express CD5 or CD23. They express sur- appropriate.
dependant. Further studies have shown face and, to a lesser extent, cytoplasmic
that the T-cells responsible for the prolif- immunoglobulin (usually IgM or IgA, Effect of H. pylori eradication
erative drive are specifically those found rarely IgG) and show light chain restric- The histological appearances of gastric
within the tumour and their function can- tion. Immunostaining with anti-cytoker- biopsies from patients showing complete
not be replaced by T-cells derived from atin antibodies is useful in demonstrating regression of lymphoma after H. pylori
elsewhere (e.g. the spleen) in the same lymphoepithelial lesions. Immunostaining
patient {769}. with antibodies that highlight follicular
dendritic cells (anti-CD21, anti-CD23 or
Histopathology anti-CD35) help to demonstrate underly-
The organisation of the lymphoma mim- ing follicular dendritic cell networks in
ics that of normal MALT and the cellular those cases in which the lymphoid folli-
morphology and immunophenotype is cles have been completely overrun by
essentially that of the marginal zone the lymphoma.
B-cell. The neoplastic cells infiltrate
between pre-existing lymphoid follicles, Differential diagnosis
initially loca-lised outside the follicular The distinction between florid gastritis
mantle zone in a marginal zone pattern. and low-grade MALT lymphoma may be A
As the lesion progresses, the neoplastic difficult. In such cases it is essential to
cells erode, colonize and eventually have sufficient biopsy material (up to
overrun the lymphoid follicles resulting in eight biopsies from endoscopically sus-
a vague nodularity to an otherwise dif- picious areas) with good preservation of
fuse lymphomatous infiltrate {800}. The morphology and correct orientation of
morphology of the neoplastic cell can be the biopsy specimen. For the distinction
variable even within a single case. between reactive and neoplastic infil-
Characteristically, the cell is of intermedi- trates, histological evaluation remains the
ate size with pale cytoplasm and an gold standard, but accessory studies
irregular nucleus. The resemblance of may be helpful. In both reactive and neo- B
these cells to the centrocyte of the follicle plastic cases, lymphoid follicles are pres- Fig. 3.41 Low-grade B-cell MALT lymphoma. The
centre has led to the term centrocyte-like ent and these may be associated with centrocyte-like cells show prominent plasma cell
(CCL) cell being applied to the neoplas- active inflammation, crypt abscesses differentiation with (A) extracellular immunoglobu-
tic component of MALT lymphomas. In and reactive epithelial changes. In gas- lin deposition, and (B) prominent Dutcher bodies.

Lymphoma 59
03 19.7.2006 7:41 Page 60

A B

C D
Fig. 3.42 A, B, C Low-grade B-cell MALT lymphoma. A, B Lymphoepithelial lesions. C Immunostaining for cytokeratin highlights lymphoepithelial lesions. D Diffuse
large B-cell lymphoma; the neoplastic cells focally infiltrate glandular epithelium to form structures reminiscent of lymphoepithelial lesions.

eradication are characteristic. The lami- PCR based diagnosis regression. Some, but no all of these will
na propria appears empty with gland The role of genetic analyses in the diag- eventually show molecular regression but
loss. Scattered lymphocytes and plasma nosis and follow up of low-grade MALT there may be a prolonged time lag
cells are seen within the lamina propria lymphoma remains controversial. Up to between histological and molecular
and there are usually focal nodular col- 10% of well characterized cases of MALT regression {1677}. In the absence of his-
lections of small lymphocytes. These col- lymphoma identified as clonal through tological evidence of residual lymphoma,
lections frequently contain a mixture of demonstration of rearrangement of the the clinical significance of a persistent
B- and T-cells and may be based on fol- immunoglobulin heavy chain gene by clonal population remains uncertain.
licular dendritic cell networks. Southern blot fail to show a clonal pattern
In most cases, the appearances are when examined for immunoglobulin Progression to high-grade lymphoma
insufficient for a diagnosis of residual heavy chain gene rearrangement by PCR The emergence of clusters of large trans-
lymphoma. The significance of these using fresh frozen tissue {418}. This false formed blastic B-cells reflects transfor-
lymphoid nodules remains uncertain. In negative rate increases if paraffin embed- mation to high-grade lymphoma {383}.
cases showing partial regression or no ded material is studied {417}. Several Eventually, these areas become conflu-
change following H. pylori eradication, studies have revealed by PCR the pres- ent to form sheets of cells indistinguish-
the lamina propria contains an infiltrate ence of clonal B-cell populations in biop- able from the cells of a diffuse large
morphologically indistinguishable from sies from patients with uncomplicated B-cell lymphoma. As long as a low-grade
that seen at diagnosis, but in these treat- chronic gastritis and no morphological component remains, these tumours may
ed cases lymphoepithelial lesions may evidence of lymphoma {1677, 225, 388}. be termed high-grade MALT lymphomas
be very scanty or absent. In some cases In conjunction with histological assess- but during further progression, all traces
of partial regression and in cases with ment, PCR studies may be useful in mon- of the pre-existing low-grade lymphoma
relapsed low-grade MALT lymphoma fol- itoring regression of MALT lymphomas are lost, making it impossible to distin-
lowing H. pylori eradication, the lymph- following conservative therapy {25}. guish the lesion from a diffuse large
oma may be largely confined to the sub- However, PCR detected clonal B-cell B-cell lymphoma of unspecified type. In
mucosa with only minimal involvement of populations may still be detected in cases with both low- and high-grade
the mucosa. cases showing complete histological components, genetic studies have con-

60 Tumours of the stomach


03 19.7.2006 7:41 Page 61

firmed the transformation of low-grade to mutations in diffuse large B-cell lym- areas of endemic HTLV-1 infection and
high-grade lymphoma in the majority of phomas independent of a rearrangement probably represent gastric manifesta-
cases {1263} while in other cases both of the gene {1070}. Epstein-Barr virus is tions of adult T-cell leukemia/lymphoma
components appear clonally unrelated, not associated with low-grade lym- (ATLL). In these regions, T-cell lymphoma
suggesting the development of a second phomas and has only been seen in some may represent up to 7% of gastric lym-
primary lymphoma {1184, 1491}. high-grade lymphomas {1038, 1437}. phomas {1741}. Most of the remainder
are similar to peripheral T-cell lym-
Molecular genetics of MALT lymphomas Mantle cell lymphoma phomas encountered in lymph nodes but
Early studies confirmed the presence of Mantle cell lymphoma of the stomach is occasionally, gastric NK cell lymphomas
immunoglobulin gene rearrangement in typically a component of multiple lym- are also seen {1741}. It has recently
each case {1803} and suggested that phomatous polyposis of the gastrointesti- been demonstrated that some gastric
there was no involvement of the bcl-1 or nal tract and infrequently encountered T-cell lymphomas display features of
bcl-2 oncogenes {2136}. The transloca- outside this clinical context {1380}. intraepithelial T lymphocyte differentia-
tion t(11;18)(q21;q21) has been identified Morphologically and immunophenotypi- tion (e.g. expression of the human
in a significant number of low-grade cally, the lymphoma is indistinguishable mucosal lymphocyte 1 antigen, CD103),
MALT lymphomas and may be the sole from mantle cell lymphomas of lymph similar to those seen in intestinal T-cell
genetic alteration in these cases. How- nodes, with a diffuse and monotonous lymphomas {520}.
ever, this translocation appears to be less infiltrate of cells with scanty cytoplasm
common in high-grade lesions {1435, 95}. and irregular nuclei that express B-cell Hodgkin disease
Trisomy 3 has been detected in up to 60% markers together with CD5 and cyclinD1. Hodgkin disease may involve the gas-
of cases in some studies using both trointestinal tract but this is usually sec-
metaphase and interphase techniques Other low-grade B-cell lymphomas ondary to nodal disease. Primary gastric
{2134, 2137}, but this finding has not Although the lymphoid tissue in the stom- Hodgkin disease is very rare {2210}.
been confirmed by other studies {1434}. ach contains all the B-cell populations
The translocation t(1;14) (p22; q32) has encountered in nodal lymphoid tissue, Prognosis and predictive factors
also been described in a small proportion other low-grade B-cell lymphomas, such Studies on the regression of low-grade
of cases {2138} and this is associated as follicle centre cell lymphomas, are MALT lymphoma through H. pylori eradi-
with increased survival of tumour cells in very rare and usually indistinguishable cation have shown remission in 67-84%
unstimulated cell culture. Cloning of the from their nodal counterparts. of cases {1926, 1520, 2133}, but this
breakpoint involved in this translocation applies only to low-grade lesions and is
has led to the discovery of a novel gene, Diffuse large B-cell lymphoma most effective for lesions showing super-
bcl-10, on chromosome 1 that may be These lymphomas are morphologically ficial involvement of the gastric wall.
significant in determining the behaviour of indistinguishable from diffuse large B-cell Although remission following H. pylori
MALT lymphomas {2116}. lymphomas that arise within lymph eradication has occasionally been seen
Studies of the immunoglobulin gene of nodes. There is complete destruction of in advanced tumours, the highest suc-
MALT lymphoma cells has shown the the gastric glandular architecture by cess rate of 90-100% is seen in tumours
sequential accumulation of somatic large cells with vesicular nuclei and confined to the mucosa and superficial
mutations, consistent with an ongoing, prominent nucleoli. Variants of large B- submucosa. The time taken to achieve
antigen driven selection and proliferation cell lymphoma (e.g. plasmablastic lym- remission in these patients varies from
{279, 434, 1546}. Study of the third com- phoma) may also be encountered {1541}. 4-6 weeks to 18 months. The stability of
plementary determining region of the these remissions remains to be deter-
immunoglobulin heavy chain gene shows Burkitt lymphoma mined; one study has reported a relapse
a pattern of changes associated with the Although rare, classical Burkitt lym- in 10% of patients after a mean follow-up
generation of antibody diversity and phomas may be encountered in the period of 24 months {1338} while others
increased antigen binding affinity {131}. stomach {55}. The morphology is identi- have found sustained remissions for up
Transformation of low-grade MALT lym- cal to that of Burkitt lymphoma encoun- to six years {801}.
phoma to a high-grade lesion has been tered elsewhere, with diffuse sheets of Surgical resection is associated with pro-
associated with several genetic alter- medium sized cells with scanty cyto- longed survival {552} in many cases.
ations. While the t(11;18) chromosomal plasm and round/oval nuclei containing Involvement of the resection margins and
translocation is not seen in high-grade small nucleoli. Within the sheets there are advanced stage are poor prognostic fea-
MALT lymphoma and may be protective numerous macrophages, giving a starry- tures, but not with the addition of
against transformation, alterations in the sky appearance. Mitoses are frequent chemotherapy {1262}. Irrespective of
genes coding for p53, p16, c-myc and and apoptotic debris abundant. The treatment modality, the only significant
trisomy 12 have all been identified in cells express CD10 in addition to independent prognostic variables are
high-grade lesions {1489, 1490, 1341, pan-B-cell markers. Close to 100% of stage and tumour-grade {260, 1653,
270, 435, 1992}. Bcl-6 protein has also nuclei are immunoreactive for Ki-67. 1262, 320, 383}.
been described in high-grade lym-
phomas while being absent from low- T-cell lymphoma
grade lesions {1425}. Some studies have Primary gastric T-cell lymphomas are
shown a high level of bcl-6 gene hyper- rare. Most have been reported from

Lymphoma 61
03 19.7.2006 7:41 Page 62

M. Miettinen
Mesenchymal tumours of the stomach J.Y. Blay
L.H. Sobin

Definition may be primary in the omentum and tion occurs in 20-30% of cases. Infiltra-
Most gastrointestinal mesenchymal neo- mesentery. They are most common in the tion by direct extension to the pancreas
plasms are gastrointestinal stromal stomach (60-70%), followed by small or liver occurs. On sectioning GISTs vary
tumours (GIST) or smooth muscle types. intestine (20-30%), colorectum and from slightly firm to soft, tan, often with
They are predominantly located in the oesophagus (together < 10%) {1227}. foci of haemorrhage. Larger tumours
stomach. The definitions of other mes- may undergo massive haemorrhagic
enchymal lesions follow the WHO histo- Clinical features necrosis and cyst formation leaving only
logical classification of soft tissue GISTs present a spectrum from clinically a narrow rim of peripheral viable tissue;
tumours {2086}. benign, small to medium-sized tumours, malignant tumours may form complex
to frank sarcomas. According to our esti- cystic masses. Multinodular peritoneal
Terminology mate, approximately 30% of GISTs are seeding is typical of malignant GISTs.
The designation GIST was originally intro- clinically malignant, and a substantial
duced as a neutral term for tumours that number of patients with apparent radical Histopathology
were neither leiomyomas nor schwanno- surgery will relapse {1344, 462}. Typical Typically GISTs are immunohistochemi-
mas. The term GIST is now used for a of the malignant GISTs at all locations is cally positive for KIT tyrosine kinase
specific group of tumours comprising the intra-abdominal spread as multiple receptor (stem cell factor receptor),
majority of all gastrointestinal mesenchy- tumour nodules, and distant metastases which is perhaps their single best defin-
mal tumours. These tumours encompass most commonly to liver followed by lung ing feature {920, 713, 1665, 1762}.
most gastric and intestinal mesenchymal and bone in decreasing frequency The c-kit positivity of GISTs parallels that
tumours earlier designated as leiomyoma, {478A, 1984, 1855}. Vague abdominal seen in the interstitial cells of Cajal, the
cellular leiomyoma, leiomyoblastoma and discomfort is the usual complaint in pacemaker cells regulating autonomic
leiomyosarcoma {80, 76, 78, 79, 1227}. symptomatic tumours. Both benign and motor activity {1139, 1654}. Based on
Currently, the terms leiomyoma and sarcomatous GISTs that project into the this, and on the expression of an embry-
leiomyosarcoma are reserved for those lumen may ulcerate and be a source of onic form of smooth muscle myosin
tumours that show smooth muscle differ- bleeding {80, 78, 79}. heavy chain in GISTs and Cajal cells
entiation, histologically or by immunohis- {1648} the origin from Cajal cells has
tochemistry, e.g. with strong and diffuse Macroscopy been proposed {920, 1762}. However,
actin and desmin positivity. Most tumours Small gastric GISTs appear as serosal, considering the origin of Cajal cells and
historically called leiomyosarcoma {31, submucosal or intramural nodules that smooth muscle from a common precur-
1559, 1750} are now classified as GISTs; are usually incidental findings during sor cell {1035, 2186}, the hybrid Cajal
hence the old literature on gastric (and abdominal surgery or endoscopy. Some cell and smooth muscle differentiation
intestinal) leiomyosarcomas largely tumours may ulcerate, especially the seen in many GISTs, and the occurrence
reflects GISTs. epithelioid stromal tumours. The larger of GISTs in the omentum and mesentery
tumours protrude intraluminally or to the {1225}, their origin from such a precursor
Epidemiology serosal side, and may have a massive cell pool with differentiation towards a
GIST accounts for 2.2% of malignant gas- extragastric component that masks the Cajal cell phenotype is more likely.
tric tumours in SEER data. There is no gen- gastric origin. Intraluminal tumours are Electron microscopic observations show-
der preference (M:F, 1.1:1), in contrast to often lined by intact mucosa, but ulcera- ing hybrid autonomic nerve and smooth
carcinomas which have a M:F of 2:1 muscle features in many GISTs are also
{1928}. Adults between the 6th and 8th consistent with origin from a multipoten-
decade are primarily affected. The ratio of tial precursor cell {474, 1227}.
the age-adjusted incidence rates for Morphology. GISTs may resemble
Blacks and Whites is greater for sarcomas smooth muscle tumours histologically as
(3 to 1) than for carcinomas (2 to 1). Black well as grossly. The majority of gastric
women are affected six times more fre- GISTs are spindle cell tumours that show
quently than white women (0.6 versus 0.1 a variety of histological patterns {1866}.
per 100,000 per year, analogous to the Some, including many of the smaller
ratio for uterine leiomyosarcomas) {1584}. ones, are collagen-rich and paucicellular.
A perinuclear vacuolization pattern is
Localization common. Tumours with moderate cellu-
GISTs occur at every level of the tubular Fig. 3.43 Cajal cells immunoexpress KIT antigen larity and focal nuclear palisading can
gastrointestinal tract and additionally (CD117) in fetal small intestine. resemble nerve sheath tumours. Peri-

62 Tumours of the stomach


03 19.7.2006 7:41 Page 63

greater than 5 per 50 HPF, or tumours


showing as many as 5 mitoses per 10
HPF. Tumours over 5 cm, but with fewer
than 5 mitoses per 50hpf, are often
assigned to the category of uncertain
malignant potential. However, large
tumours (especially over 10 cm) with no
detected mitotic activity may develop
late recurrences and even metastases.
DNA-aneuploidy, high proliferative index A
Fig. 3.44 Radiograph demonstrating mass defect in (over > 10%) by proliferation markers
stomach due to a stromal tumour. (especially Ki67 analogs, such as MIB1)
may reflect higher malignant potential
{338, 362, 929, 525, 1048, 1632, 461,
vascular hyalinization can accompany 462}.
myxoid change. The epithelioid pattern Histological grading follows the systems
occurs in approximately one-third of gas- commonly used for soft tissue sarcomas.
tric GISTs and corresponds to tumours Mitotic activity is the main criterion,
previously designated as leio-myoblas- namely those tumours with over 10
toma or epithelioid leiomyosarcoma. mitoses per 10 hpf are considered high- B
Some of the epithelioid tumours show grade. Lower mitotic activity (over 1-5
mild pleomorphism. Marked pleomor- mitoses/10 HPH) is considered low-
phism is rare. grade.
Immunohistochemistry. Most GISTs are
positive for KIT (CD117), which may show Genetics
membrane, diffuse cytoplasmic or a perin- Both benign and malignant GISTs com-
uclear accentuation pattern. Approxi- monly show losses in chromosomes 14
mately 70-80% of GISTs are positive for and 22 in cytogenetic studies and by
CD34 (typically membrane pattern). comparative genomic hybridization. Los-
30-40% are focally or diffusely positive for ses in 1p and chromosome 15 have been
-smooth muscle actin, very few show shown less frequently. Gains and high C
reactivity for desmin (< 5%), and very few level amplifications occur in malignant Fig. 3.46 Benign stromal tumours. A Vague palisa-
ding pattern reminiscent of a nerve sheath tumour.
for S100-protein (< 5%, usually weak reac- GISTs in 3q, 8q, 5p and Xp {450, 451}.
B Spindle cells with prominent cytoplasmic vacuo-
tivity) {526, 1229, 1260, 1991, 1227, 1232}. A proportion of GISTs, more commonly lation. C An epithelioid pattern corresponding to the
Assessment of malignancy and grading. the malignant examples, show mutations previous designation of leiomyoblastoma.
Histological assessment of malignancy is in the regulatory juxtamembrane domain
essentially based on mitotic counts and (exon 11) of the c-kit gene. A family with
size of the lesion. Tumours less than 5 cm germline KIT mutations and GISTs has
are usually benign. Different limits have also been described. These c-kit
been applied for low-grade malignant mutations have been shown to represent
tumours. This designation has been used gain-of-function mutations leading to lig-
for tumours showing mitotic counts and-independent activation (autophos-

A B
Fig. 3.45 Gastrointestinal stromal tumour. A Ulceration is present at the summit of the lesion. B Cut surface showing transmural extension.

Mesenchymal tumours 63
03 19.7.2006 7:41 Page 64

Fig. 3.47 Examples of mutations of the exon 11 of the c-kit gene in gastrointestinal stromal tumours. A Nucleotide sequence of the c-kit gene. B Predicted amino
acid sequences of the mutant KIT. The top line in each figure represents the germline I and the wild type KIT protein, respectively. Each line below them re-pres-
ents one case. The codons are indicated by numbers. The shaded areas correspond to deletions (black) or point mutations (gray). Courtesy of Dr. J. Lasota,
Washington D.C.

phorylation) of the tyrosine kinase and pulmonary chondroma, gastric epithe- sarcomas varied considerably, e.g. 49%
further the phosphorylation cascade that lioid GIST and paraganglioma in the 5-year survival for males versus 74% for
leads into mitogenic activation {928, 713, Carney triad has probably a common yet females; 37% for Blacks versus 66% for
1310, 1356}. The most common muta- unknown genetic link {246}. Whites {1928}.
tions appear to be in-frame deletions of
3-21 base pairs, followed by point muta- Prognosis and predictive factors Other mesenchymal tumours
tions and occasionally described inser- The prognosis of GISTs is largely Gastrointestinal autonomic nerve tumour
tions {475, 713, 1018, 1289}. Association dependent on the mitotic rate, size, (GANT)
of neurofibromatosis type I has been depth of invasion, and presence or Gastrointestinal autonomic nerve tumour
described in rare cases; these tumours absence of metastasis {462}. Although (GANT), or the previous designation plex-
represent phenotypical GISTs, but race and gender did not play a role in osarcoma, has been applied to mes-
molecular genetic studies are not avail- survival rates in the SEER data for gastric enchymal tumours that have shown ultra-
able {1681A}. The rare combination of carcinomas, the 5-year survival rates for structural features of autonomic neurons:

A B
Fig. 3.48 Malignant gastrointestinal stromal tumours. A Tumour cells form perivascular collars surrounded by necrosis. B Numerous mitotic figures are present.

64 Tumours of the stomach


03 19.7.2006 7:41 Page 65

Fig. 3.49 Glomus tumour. Uniform tumour cells and Fig. 3.50 Gastric schwannoma including part of the Fig. 3.51 Gastric lipoma.
dilated thin-walled blood vessels. lymphoid cuff.

cell processes with neurosecretory type ly in the gastric antrum as small intramu- active. Schwannomas are positive for
dense core granules and arrays of micro- ral masses (1-4 cm in diameter, average S100-protein and negative for desmin,
tubules {702, 701, 1023, 2038}. Histologi- 2 cm). They occur in older adults (mean actin and KIT.
cally, such tumours have shown a variety 6th decade) with equal sex incidence
of spindle cell and epithelioid patterns {77}. One-third manifests as ulcer, Lipoma
similar to those seen in GISTs; at least one-third as bleeding, and one-third is Lipomas composed of mature adipose
some of these tumours are positive for asymptomatic. The lesions are often sur- tissue may be observed in the stomach.
KIT. It therefore appears that GANT and rounded by hyperplastic smooth muscle They typically protrude into the lumen.
GIST groups overlap, and may even and have sheets of rounded or epithe-
merge. Because electron microscopy is lioid cells with sharp cell borders outlined Granular cell tumour
currently applied less widely for tumour by well-defined basement membranes Lesions similar to those in peripheral soft
diagnosis than before, GAN-type differen- demonstrable by PAS-stain or immunos- tissues are occasionally encountered in
tiation in gastrointestinal tumours is prob- taining for basement membrane proteins the stomach, where they principally
ably underestimated. Correlative light such as laminin and collagen type IV. occur as small submucous nodules and
microscopic, ultrastructural, immuno- The tumour cells have small, uniform less commonly as intramural or sub-
histochemical and molecular genetic nuclei and mitotic activity is virtually serous masses. These lesions occur pre-
studies are needed to resolve the ques- absent. The tumour cells are positive for dominantly in middle age, and show a
tion of the relationship of GANT and GIST. smooth muscle actin and negative for strong predilection for Blacks. Associa-
keratins. Multiple glomus tumours with ted gastric ulcer symptoms are common.
Leiomyoma and leiomyosarcoma apparent intravascular spread have See chapter on mesenchymal tumours of
Well-documented true gastric leiomy- been described {666}. the oesophagus for pathological features
omas and leiomyosarcomas are so infre- {862}.
quent that there is no significant data on Schwannomas
demographic, clinical or gross features. These lesions are rare in the gastroin-
Leiomyomas are composed of bland testinal tract, but the stomach is their
spindle cells showing low or moderate most common site within the digestive
cellularity and slight if any mitotic activity. system. They are not associated with
There may be focal nuclear atypia. The neurofibromatosis types I or II and occur
cells have eosinophilic, fibrillary, often predominantly in older adults (average
clumped cytoplasm. Leiomyosarcomas 58 years in the largest series). They
are tumours that show histologically and grossly and clinically resemble GISTs.
immunohistochemically evident smooth Schwannomas are usually covered by
muscle differentiation. They usually pres- intact mucosa and principally involve the
ent in older age and are typically of high- muscularis propria. The tumours vary
grade malignancy. As defined here, from 0.5-7 cm (mean 3 cm) in diameter, Fig. 3.52 Kaposi sarcoma of the stomach.
leiomyomas and leiomyosarcomas are and are spherical or ovoid, occasionally
typically globally positive for desmin and showing a plexiform multinodular pattern.
smooth muscle actin, and are negative Histologically, gastrointestinal schwanno- Kaposi sarcoma
for CD34 and CD117 (KIT). Tumours with mas usually show a spindle cell pattern Kaposi sarcoma may occur in the stom-
mitotic counts exceeding 10 mitoses per like cellular schwannoma with vague ach as a mucosal lesion or, less com-
10 high power fields are classed as high- nuclear palisading. The tumours often monly, as a mural mass, usually in HIV-
grade. have sprinkled lymphocytes and a nodu- positive patients.
lar lymphoid cuff {366, 1666}. The dis-
Glomus tumours tinction between schwannoma and GIST
Lesions similar to glomus tumours of is important because the former is
peripheral soft tissue occur predominant- benign even when large and mitotically

Mesenchymal tumours 65
03 19.7.2006 7:41 Page 66

C. Niederau
Secondary tumours of the stomach L.H. Sobin

Definition
Tumours of the stomach that originate
from an extra-gastric neoplasm or which
are discontinuous with a primary tumour
elsewhere in the stomach.

Incidence
Metastatic disease involving the stomach
is unusual. An autopsy study from the
USA found 17 metastases to the stomach
in 1010 autopsies of cancer patients, giv- Fig. 3.53 Multiple gastric metastases from rhab- Fig. 3.54 Metastatic lobular carcinoma of the
ing a frequency of 1.7% {1220}. In a large domyosarcoma of the spermatic cord in a 15-year breast. Typical single file growth pattern.
series of autopsies from Malm (Table old boy.
3.02), 92 gastric metastases were found
in 7165 patients (1.28%) who had cancer
at the time of death {130}. metastases are described as volcano- in 10 of 747 (1.3%) of patients with lung
like ulcers {618; 1108}. On endoscopy, cancer (see Table 4.01) {1220}. Several
Clinical features pigmentation may not be evident in some studies have shown lung, breast, other
Gastrointestinal symptoms may occur in melanomas {1069}. In patients with meta- gastrointestinal carcinomas, and mela-
up to 50% of patients with gastric metas- static lobular breast carcinoma the endo- noma to be the most frequent primary
tases. Bleeding and abdominal pain are scopic appearance may be that of linitis lesions {1220, 158, 873, 618}. Less fre-
the most common clinical features, fol- plastica. In such cases, conventional quently, cancers of the ovary, testis, liver,
lowed by vomiting and anorexia. Intesti- biopsies may be too superficial to colon, and parotid metastasize to the
nal and gastric metastases were found include diagnostic tissue in the submu- stomach {1220; 618; 1148; 1872}.
after a median interval of 6 years (range, cosa. Endosonography may help direct Of all the primary cancers that can lead
0.12-12.5 years) following the diagnosis attention to the deeper infiltrate {1097}. to gastric metastasis, breast cancer
of primary breast cancer {1700}. Gastric Gastric melanomas often appear as does so most frequently. Some reports
metastasis from a breast cancer has polypoid or target lesions on barium show that between 50% and 75% of
occurred up to 30 years after diagnosis X-ray studies {1718} and, less commonly, patients with breast cancer develop gas-
of the primary neoplasm {1148}. Occa- as a submucosal mass {1148}. tric metastases {1148; 455}. However, in
sionally, metastatic breast cancer in the a Dutch study covering a 15-year-period,
stomach is detected before the primary Origin there were only 27 patients with gastric
tumour is diagnosed. In a large Swedish autopsy series {130} , metastases from primary breast cancer
most gastric metastases were from pri- {1872}.
Imaging and endoscopy mary breast cancer, followed by mela- There is no preferential localization of
An upper gastrointestinal endoscopy noma and lung cancer (Table 3.02). metastases to subsites in the stomach.
study identified 14 metastatic tumours in There were gastric metastases in 25 of Cancers at any site can produce gastric
the upper gastrointestinal tract, 13 of 695 (3.6%) patients with breast cancer, metastases through haematogeneous
which were in the stomach {873}. Many whereas gastric metastases were found spread. Lesions of the pancreas, oeso-

Table 3.02
Metastases to the stomach, small intestine, colon and appendix. Data are from 16,294 autopsies {130}.

Site of metastasis No. of cases with metastasis % of all autopsies Most frequent primary cancer Next most frequent primary cancer

Stomach 92 0.58% Breast (25 cases) Melanoma (19)

Small intestine 125 0.78% Lung (33 cases) Melanoma (33)

Colon 62 0.39% Lung (14 cases) Breast (10)

Appendix 7 0.04% Breast (2 cases) Various

66 Tumours of the stomach

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