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					                       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.
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.




38 Tumours of the stomach
Gastric carcinoma                                                                                            C. Fenoglio-Preiser
                                                                                                             F. Carneiro
                                                                                                                                              N. Muñoz
                                                                                                                                            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
                                                                                                            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-
       β-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. pylori’s 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
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:C→A: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
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


42    Tumours of the stomach
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 Laurén {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
                                                                                                            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              Laurén classification
isolated or small groups of malignant                 cytoplasm. These contain acid mucin                   The Laurén 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


44    Tumours of the stomach
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 Laurén’s
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 Laurén 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 (Laurén classification).                                                                        cost effectiveness of such an integrated


                                                                                                                                Gastric carcinoma        45
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
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
                                                                                                                  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
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
                                                                                                               APC’s locus) {1656, 1577}, 6q {255}, 9p,
                                                                                                               17p (over 60 percent at TP53’s locus)
                                                                                                               {1656}, 18q (over 60 percent at DCC’s
                                                                                                               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
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-β 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-β 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-β 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
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
                                                       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 Laurén 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 Laurén 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
                                                                                               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-α (TGFα) 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
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         α-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
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
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 D’Adda
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
                                                 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. Müller-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
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 organism’s 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
                                                     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
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
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
                                                                                                 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
                                                       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
α-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
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
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
                                                                                                               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 Malmö (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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