THE STOMACH

        : Familial, multifactorial inheritance

GASTRITIS

   <Classification>

¡¡    1. Acute gastritis

¡¡         - (Early) Acute gastritis
           - Acute hemorrhagic gastritis
           - Acute erosive gastritis
           - Acute ulcerative gastritis (Acute gastric ulceration)

      2. Chronic gastritis

¡¡         - Type A (Fundal) gastritis
               = Autoimmune gastritis
           - Type B (Antral) gastritis
               = Environmental gastritis (Type AB gastritis)

¡¡    3. Others

¡¡         - Lymphocytic gastritis
¡¡         - Eosinophilic gastritis
           - Granulomatous gastritis

  <Morphology>

     : Edema, hyperemia
       Acute infl. cell (neutrophils) infiltration,
         within the epithelial layer (by definition)
        Superficial mucosal sloughing, hemorrhage
       Erosion or ulceration; multiple, gastric and duodenal
         * Erosion; confined within the mucosa
         * Ulceration; extended beyond the mucosa,
                       penetrating the muscluaris mucosae

     <Pathogenesis>

¡¡      Autoimmune
          - Autoantibodies = Anti-parietal cell Ab.
                               ¡Õ Anti-H⁺,K⁺-ATPase Ab.
                               ¡Õ Anti-intrinsic factor Ab.
          - Cell-mediated immunity

¡¡   <Morphology>

        : Body-fundic mucosa

        : (See Environmental gastritis.)
        * G-cell hyperplasia of antral mucosa
           Pyloric metaplasia, intestinal metaplasia

     <Clinical>

        : Hypo- or achlorhydria, hypergastrinemia
          Pernicious anemia

- Type B (Antral) Gastritis
  (Environmental gastritis, Type AB gastritis)
  (Chronic atrophic gastritis)

¡¡ <Pathogenesis>

           : H. pylori infection

¡¡         : Multifactorial
             Environmental factors, yet to be defined

¡¡      <Morphology>

¡¡         : Antral mucosa, extending into body-fundic mucosa,
             esp., along the lesser curvature, hence, Type AB gastritis

¡¡         - Chronic nonatrophic gastritis (Chronic superficial gastritis)

¡¡             : Chronic infl. cell (lymphocytes, plasma cells) infiltration
                   in the foveolar region and unaccompanied by glandular
                   atrophy (by definition)

¡¡         - Chronic atrophic gastritis

¡¡             : Chronic infl. cell infiltration to the deeper layers about
                   the glands (by definition)
                 Glandular atrophy: Mild, moderate, marked
                 Cystic dilatation of glands
                 Intestinal metaplasia of pyloric glands, pyloric metaplasia
                   of fundic glands

¡¡         - Chronic gastric atrophy

¡¡             : Mucosal thinning
                 No infl. changes
                 : The end stage of chronic atrophic gastritis (?)

¡¡      <Clinical>

           : The most common form

           : Often hypochlorhydric (but not achlorhydric),
             due to atrophy of body-fundic mucosa (but not complete)

           : Increased risk for peptic ulcer disease
             and gastric dysplasia-carcinoma

       : Binding to GASTRIC epithelial cells
           via a bacterial adhesin
             (Binding is enhanced with epithelail cells
                bearing the blood group O antigen) ¡æ
         Production of ammonia by urease and
           breakdown of glycoproteins by proteases
             ¡æ Acid-peptic digestion ¡æ
                Acute gastritis ¡æ (persistence of organisms)
                Chronic gastritis (more susceptible to                                    acid-peptic injury)

¡¡  <Morphology> (IMAGE)

¡¡     : Neutrophilic infiltration in the superficial lamina propria,
           backgrounded by chronic gastritis
         Lymphoid follicles with germinal centers
       : Antrum
         Duodenal bulb and Barrett esophagus with gastric metaplasia

¡¡  <Clinical - Suggested Natural History of Infection with H. pylori>

¡¡                               H. pylori infection
                                         ¡é
                            Chronic superficial gastritis¡¡
                                         ¡é
      Chronic atrophic gastritis    Peptic ulcer d.   Lymphoproliferative d.
            ¡é  Intestinal metaplasia
            ¡é  Dysplasia
   ¡¡Adenocarcinoma, noncardiac

PEPTIC ULCER DISEASE

¡¡        : Normal or below normal acid output
          : Decr. gastric mucosal defense
              - Chronic antral gastritis, due to
                    = H. pylori infection
                    = pyloric sphincter incontinence and
                      reflux of bile acids and lysolecithins

            : Almost all benign GUs are found immediately distal to the
            junction of the antral mucosa and the acid-secreting mucosa of
            the body of the stomach. 

          : It has been proposed that H. pylori infection at a young age is
            more likely to result in chronic gastritis, with a subsequent
            decrease in gastric acid secretion and therefore a lower risk of
            DU but a higher rist of GU and gastric cancer.

    <Morphology>

     SITE

       : 1. Duodenum, (first portion, ant. wall)
         2. Stomach, (antrum, lesser curvature)
         3. Esophagus in glandular mucosa
              e.g., Barrett esophagus 
         4. Gastroenterostomy - Stoma
         5. Meckel diverticulum - Heterotopic gastric mucosa
         6. Stomach to Treitz ligament of the small intestine
            in Zollinger-Ellison syndrome 

¡¡   GROSS (Differentials between benign and malignant ulcer)

                       BENIGN                           MALIGNANT

¡¡       1. Shape    ¡Þ Round to oval,                 ¡Þ Irregular
                       sharply punched-out

         2. Mucosal  ¡Þ Radiating (converging) in      ¡Þ Club-shaped,
            folds      a spokelike fashion              abruptly ended

         3. Mucosal  ¡Þ Proximal: Slight overhanging   ¡Þ Heaped-up beading,
            margin   ¡Þ Distal: Sloping                  nodular
                     ¡Þ Usually level with, or         ¡Þ Overhanging  
                       only slightly elevated           the crater base

         4. Base     ¡Þ Smooth, clean,                 ¡Þ Shaggy, necrotic
                       due to peptic digestion

¡¡   MICRO of Active Ulcers

¡¡      1. Necrotic fibrinoid debris
        2. Active cellular infiltrate - neutrophils
        3. Granulation tissue
        4. Fibrosis, thickened vessel walls and thrombosis

¡¡  <Clinical>

¡¡     : Chronic, recurrent

         Peptic ulcers more often impair the quality of life
         than shorten it. 

       : Although DU is identified clinically more frequently than GU, most
         autopsy studies show an equal or greater proportion of GUs.

       ¡Ø Differentiation of gastric ulcer from gastric carcinoma

: A benign ulcer tends to be less than 4 cm in diameter. But size does
NOT differentiate a benign from a malignant ulcer.
  The medical treatment of gastric ulcer consists of neutralization of acid (antacids), promotion of mucus secretion, and/or inhibition of acid secretion (H₂ receptor antagonists and parietal cell H⁺,K⁺-ATPase inhibitors). The usual criterion for adequate healing is a reduction in crater size of at least 50% over a 6- to 8-week period of intensive medical treatment. As many as 15% of gastric carcinomas may pass this ¡®healing test¡¯ and some benign ulcers may actually enlarge during the test.

         : A total of at least six biopsy samples from the inner margin of
          an ulcer are recommended to differentiate benign and malignant
          ulcers

¡¡  <Complication>

¡¡     1^st. Hemorrhage
         2. Perforation
         3. Obstruction
         4. ? Malignant transformation: < 1% of gastric ulcers

                  i. Complete destruction of muscle layer in the ulcer base
                 ii. Fusion of muscularis mucosae and muscle layer in the ulcer base
                iii. Intimal thickening of blood vessels
                 iv. Presence of carcinoma in only one part of the wall

NON-NEOPLASTIC PROLIFERATIVE DISEASES

'Hypertrophic' Gastropathy (Hyperplastic Gastropathy, 'Hypertrophic Gastritis')

¡¡      : Protein loss from the mucosa, resulting in
            hypoalbuminemia ( = protein-losing
            gastroenteropathy)
          Hypo-, a-chlorhydria

¡¡      : Hypergastrinemia ¡æ
          Hyperplasia of parietal cells and
          enterochromaffin-like (ECL) cells

¡¡      : Peptic ulcer disease

¡¡ 3. Hypertrophic hypersecretory gastropathy

¡¡      : A variant of Menetrier disease or Zollinger-Ellison syndrome (?)
¡¡      : Variable hyperplasia of foveolar mucous cells and parietal cells
¡¡      : Peptic ulcer disease

TUMORS - NEOPLASTIC PROLIFERATIVE DISEASES

Benign - Epithelial = Hyperplastic polyp (> 90%)
                        Var) Focal foveolar hyperplasia
                       = Neoplastic polyp (5-10%)
                        ¡Õ Adenoma / Dysplasia
                             : Larger than hyperplastic polyp
                               Carcinomatous transformation
                                 in up to (?) 40%
                       = Hamartomatous polyp
                        ¡Õ Fundic gland polyp (Fundic gland hyperplasia)
                        ¡Õ Juvenile (Retention) polyp
                        ¡Õ Peutz-Jeghers polyp

                    * Familial polyposis syndrome, Gardner syndrome

                        1^st. Fundic gland polyp
                          2. Hyperplastic polyp
                          3. Adenoma, adenocarcinoma, carcinoid tumor

       - Mesenchymal = Leiomyoma among GISTs (GI Stromal Tumors)

Malign - Epithelial  = Carcinoma (90 - 95%)
                     = Carcinoid (3%)
       - Mesenchymal = Lymphoma (4%)
                     = GIST (GastroIntestinal Stromal Tumor) (2%)

Adenoma vs. Dysplasia of the Stomach

  An adenoma is defined by the WHO as ¡°a circumscribed benign neoplasm composed of tubular and/or villous structures lined by dysplastic epithelium.¡± In this lecture note, the designation adenoma is limited to dysplasias that are circumscribed or localized and polypoid or elevated. The ¡°flat or depressed adenoma¡± is referred to dysplasia. The cytologic features of all gastric adenomas and dysplasias are the same, whether they are polypoid, elevated, flat, or depressed. As a result, the concept of adenoma/dysplasia as a single entity has emerged.

  Adenomas are uncommon neoplasms in the stomach, in contrast to the colon where they are frequent. Usually, they arise sporadically in the background of nonimmunologic chronic atrophic gastritis and almost always antral.

  Dysplasia is defined by the WHO as ¡°atypical changes in the epithelium considered to be precancerous.¡± It is characterized by a set of morphologic features that include cytoplasmic changes such as mucin loss, cellular crowding, nuclear stratification, increased N/C ratio, nuclear hyperchromatism, nuclear and cellular pleomorphism, and increased mitosis. The grade of dysplasia is based on the intensity of each of these changes. Differentiation of high grade dysplasia from carcinoma in situ is often difficult, if not impossible, and behavior and management of both lesions are similar.

Carcinoma

  <Incidence>

¡¡   : Male
¡¡      > 40 yrs of age (Earlier age at high-risk countries)

¡¡<Etiology>

¡¡   1. Dietary factors

                        Refrigeration, Vit. C (-)
           - Nitrates -----------------------------¡æ Nitrites
                      Nitrate-converting bacteria (+)

                      Amines, amides from protein digestion
             Nitrites ------------------------------------¡æ Nitrosamines, nitrosamides

           - Smoked and salted foods, pickled vegetables
           - Lack of fresh fruits and vegetables

      2. Host factors

           - Chronic atrophic gastritis
               Hypochlorhydria favors colonization with H. pylori.
               Extensive intestinal metaplasia
           - Infection by H. pylori
               Present in most cases of intestinal type carcinoma
           - Partial gastrectomy
               Favors reflux of bilious, alkaline intestinal fluid.
           - Adenoma/Dysplasia
               Forty percent harbor cancer at time of diagnosis.
               Thirty percent have cancer in adjacent gastric mucosa at diagnosis.
           - Barrett esophagus 

      3. Genetic factors

           - Slightly increased risk with blood group A
           - Close relatives have an above-average attack rate.
           - Increased incidence on some racial groups
           - Hereditary nonpolyposis colon cancer syndrome

¡¡<Morphology>

¡¡   SITE

¡¡     : Lesser curvature of the antropylorus; cf. Chronic peptic ulcer
         cf. Greater curvature of the antropylorus

     GROSS

¡¡         * The common types in Korea: 1^st. Type IIc
                                        2^nd. Type IIc+III

                          INTESTINAL TYPE          DIFFUSE (GASTRIC) TYPE

Macro features            Polypoid - Ulcerative    Infiltrative
Micro features
   Differentiation        Well-differentiated;     Poorly differentiated;
                          cohesive(gland-forming)  dyscohesive
   Mucin production       Limited                  Marked (signet ring cells)
   Growth pattern         Expansile                Infiltrative
   Intestinal metaplasia  Almost universal         Less frequent
Clinical features
   Mean age (years)        Old (55)                  Young (48)
   Gender ratio (M:F)      Male prevalent (2:1)      Equal (1:1)
   Decreasing incidence    Yes (Environmental)      No
     in developed countries
   Metastasis              Hemato-/Lymphogenous     Lymphogenous
   Prognosis               Better than diffuse type

  <Metastasis>

     - Hematogenous metastasis: 1^st. Liver, lungs, bones

     * Sister Mary Joseph node: A node deep in the subcutis
        in the umbilical area associated with metastasizing
        intra-abdominal cancer, usually of gastric, ovarian,
        colorectal, or pancreatic origin.

Virchow [fi:r¡¯kou] Rudolf Ludwig Karl Virchow (1821-1902). German writer and editor, politician and statesman, anthropologist, ethnologist, archaeologist, and pathologist; Virchow¡¯s Cellularpathologie (1858) finally overthrew humoralism and marked the beginning of modern pathology. He regarded the body as a cell-state in which every cell is a citizen, and disease as a civil war brought about by external forces among the cells; he thought all cells arose from other cells, and that cell theory applied to diseased tissue.

 

      2. GIST, neural type = Gastrointestinal autonomic nerve tumor (GANT)

       : Malignant

      3. GIST, combined smooth muscle-neural type

             : Malignant or potentially malignant

      4. GIST, uncommitted

             : Malignant or potentially malignant

   <Clinical>

       LOCATION - Body (40%)
                  Antrum (25%)
                  Pylorus (20%)
          GROSS - Submucosal (60%)
                  Intramural (10%)
                  Subserosal (30%)

Gastrointestinal Lymphoma

  <Introduction>

                Primary Sites - Nodal lymphoma
                              - Extranodal lymphoma
                                  = 1^st. GI lymphoma

     International Formulation of Non-Hodgkin Lymphomas

¡¡     LOW GRADE
          ML, small lymphocytic
          ML, follicular, small cleaved cell
          ML, follicular, mixed (small cleaved and large cells)
        INTERMEDIATE GRADE
          ML, follicular, large cell
          ML, diffuse, small cleaved cell
          ML, diffuse, mixed (small cleaved and large cells)
          ML, diffuse, large cell
        HIGH GRADE
          ML, large cell, immunoblastic
          ML, lymphoblastic
          ML, small noncleaved cell - Burkitt
        MISCELLANEOUS
          Composite
          Mycosis fungoides
          Histiocytic
          Extramedullary plasmacytoma
          Unclassifiable
          Others

     WHO Classification for Neoplastic Diseases of Lymphoid Tissues,
     Based on REAL Classification : Revised European-American Classification
                     by International Lymphoma Study Group 

        NON-HODGKIN LYMPHOMAS

¡¡      B-CELL NEOPLASMS

 ¡¡         I. Precursor B-cell lymphoblastic leukemia/lymphoma
           II. Mature B-cell neoplasms
                 1. B-cell chronic lymphocytic leukemia/
                    small lymphocytic lymphoma
                 2. B-cell prolymphocytic leukemia
                 3. Lymphoplasmacytic lymphoma
                 4. Mantle cell lymphoma
                 5. Follicle lymphoma
                      Cytologic grades: Small cell, mixed small and large cells,
                                        large cell
                      Provisional subtype: Diffuse, predominantly small cell type
                 6. Marginal zone B-cell lymphoma of MALT type
                 7. Nodal marginal zone lymphoma +/- monocytoid B cells
                 8. Splenic marginal zone B-cell lymphoma
                 9. Hairy cell leukemia
                10. Diffuse large B-cell lymphoma
                    Subtypes: Mediastinal (thymic), intravascular,
                              primary effusion lymphoma
                11. Burkitt lymphoma
                12. Plasmacytoma
                13. Plasma cell myeloma

¡¡      T-CELL AND NK-CELL NEOPLASMS

            I. Precursor T-cell lymphoblastic leukemia/lymphoma
           II. Peripheral T-cell and NK-cell neoplasms
                 1. T-cell prolymphocytic leukemia
                 2. T-cell large granular lymphocytic leukemia (LGL)
                 3. NK-cell leukemia
                 4. Extranodal NK/T-cell lymphoma, nasal type (angiocentric lymphoma)
                 5. Mycosis fungoides/Sezary syndrome
                 6. Angioimmunoblastic T-cell lymphoma
                 7. Peripheral T-cell lymphoma, unspecified
                    Provisional subtypes: Medium-sized cell, mixed medium and large
                                          cells, large cell, lymphoepithelioid cell
                 8. Adult T-cell leukemia/lymphoma (ATL/L) (HTLV1⁺)
                 9. Systemic anaplastic large cell lymphoma (ALCL),
                    CD30 (Ki1) - positive, T-cell and null-cell types
                10. Primary cutaneous anaplastic large cell lymphoma
                11. Subcutaneous panniculitis-like T-cell lymphoma
                12. Enteropathy-type intestinal T-cell lymphoma
                13. Hepatosplenic type ¥ã/¥ä T-cell lymphoma

        UNCLASSIFIABLE

                 1. B-cell lymphoma, unclassifiable (low grade/high grade)
                 2. T-cell lymphoma, unclassifiable (low grade/high grade)
                 3. Malignant lymphoma, unclassifiable

        HODGKIN LYMPHOMA (HODGKIN DISEASE)

            I. Nodular lymphocyte predominance Hodgkin lymohoma
           II. Classic Hodgkin lymphoma
                 1. Hodgkin lymphoma, nodular sclerosis (grades I and II)
                 2. Classical Hodgkin lymphoma, lymphocyte-rich
                 3. Hodgkin lymphoma, mixed celluarity
                 4. Hodgkin lymphoma, lymphocytic depletion (includes some
                    "Hodgkin-like anaplastic large cell lymphoma") 

  <General Features of Primary GI Lymphoma>

¡¡   : By defintion, primary GI lymphomas exhibit no evidence of liver,
       spleen, or bone marrow involvement at the time of diagnosis -
       regional lymph node involvement may be present.

       Almost all primary GI lymphomas are non-Hodgkin lymphomas.

       The GI tract is the most common site of primary extranodal lymphomas.

       Many primary GI lymphomas are of MALT origin.
 

¡¡      : 1^st. Stomach
          2^nd. Ileum
          3^rd. Large intestine
          4^th. Appendix

¡¡   <MORPHOLOGY & CLINICAL>

¡¡      - Low grade B-cell lymphoma of MALT type

¡¡          : Usually shows a superficial spreading or ulcerated lesion,
              not a discrete mass lesion of a high-grade B-cell lymphoma.

¡¡          : Centrocyte-like cells, monocytoid B-cells, small lymphoid cells;
              Plasmacytoid differentiation with Dutcher bodies
              Lymphoepithelial lesions (IMAGE)
              Presence of reactive follicles
              Follicular colonization
              Eosinophilic metaplasia of epithelial cells

¡¡          : A slow clinical evolution
              A tendency to remain localized for a long time
              A propensity to involve other mucosal sites when spreading

       - Intermediate/High grade B-cell lymphoma of MALT type

¡¡         : Large cells, noncleaved (centroblasts)

    <Genetics>

       : t(11,18)
         c-Myc rearrangement 

Variants of GI Lymphoma, Associated with Malabsorption

      - Sprue-associated lymphoma

          : In the proximal small intestine (jejunum)
            Usually T-cell lymphoma (Enteropathy-associated T-cell lymphoma,
                                     Enteropathy-type intestinal T-cell lymphoma -WHO)

      - Mediterranean lymphoma
        (= Immunoproliferative small intestinal disease, IPSID)

          : Small intestine
            B-cell lymphoma, plasmacytoid,
              secreting ¥á heavy chain ( = alpha chain disease)