Adenocarcinoma of the Stomach

Definition

• Malignant gland forming neoplasm of the stomach, exclusive of the EGJ and gastric cardia

Covered separately:

• Adenocarcinoma of the esophagus and esophago-gastric junction

Diagnostic Criteria

• Carcinomas of the proximal stomach that cross the EGJ and have their centers within 5 cm of the junction are considered with and staged as esophageal
• There are a number of classifications proposed for gastric adenocarcinoma
• Based on macroscopic and/or microscopic features
• Literature comparing these classifications as independent prognostic features is conflicting
• Staging is far more important for prediction of survival than any of these classifications
• Early carcinoma is defined as limited to mucosa and/or submucosa (lymph nodes may or may not be involved)
• I  Protuberant
• IIa  Flat, superficially elevated
• IIb  Flat, not elevated
• IIc  Flat, slightly depressed
• III  Excavated (full thickness of submucosa)
• Borrmann classification (gross)
• I  Polypoid
• II  Fungating, ulcerated with sharp raised margins
• III  Ulcerated with poorly defined infiltrative margins
• IV  Infiltrative, predominantly intramural lesion, poorly demarcated
• WHO classification (microscopic)
• Tubular
• Tubules and acini
• Becomes solid if poorly differentiated
• Papillary
• Fibrovascular stalks
• Mucinous
• >50% of tumor is mucin
• Poorly cohesive
  • Includes signet ring
    • >50% of carcinoma is composed of signet ring cells
• Mixed
• Other types
  • Adenosquamous
  • Carcinoma with lymphoid stroma (medullary carcinoma)
  • Hepatoid carcinoma
  • Squamous carcinoma
  • Undifferentiated carcinoma
• Lauren classification (microscopic)
• Intestinal type
• Cohesive, forms glands
• Associated with atrophic gastritis
• Metastasizes to nodes, liver
• Diffuse type
• Poorly cohesive, little or no gland formation
• Metastasizes to nodes, ovaries, serosa
• Mixtures of above two types
• Indeterminate
• Goseki classification (microscopic)

• Ming classification (microscopic)
  • Expanding
    • Infiltrating cohesive cell aggregates
  • Infiltrative
    • Diffuse permeative infiltration by single noncohesive cells or individual glands
  • Unclassified
• Special types
  • Clear cell variant may be the same as pylorocardiac type (Carr)
    • Both described as having clear to pale eosinophilic cytoplasm
      • Tubulo-papillary architecture
      • Dysplasia ranges from minimal to severe
        • Round basal or mid-level nuclei in lower grades
      • Location in cardia and pylorus
    • Clear cell variant has one recent description (Ghotli)
      • Clear cells make up 30-100% of cells
      • Glycogen positive, rare mucin positive cells
      • CK7 67%, CK20 33%
      • CEA, CDX2, E cadherin (membrane), cyclin D1 100%
      • AFP negative
    • Pylorocardiac type reported variably as mucin positive and negative
      • Not well described in recent literature
  • Hepatoid
    • Closely resembles hepatocellular carcinoma
      • Frequently associated with intestinal type / tubulo-papillary gastric adenocarcinoma
      • Trabecular, solid, pseudoglandular growth patterns
        • May have canaliculi
        • May have sinusoidal vessels
      • Eosinophilic to clear cytoplasm
      • Round to oval nuclei with prominent nucleoli
      • Alpha fetoprotein is not specific and may be seen in other types
      • Frequent vascular invasion and liver metastasis
  • Adenosquamous
    • Mixture of two patterns, more than just focal
  • Micropapillary
    • Uncertain if behavior differs from other adenocarcinomas with lymphvascular invasion
  • Carcinoma with lymphoid stroma (medullary, lymphoepithelioma)
    • Most are EBV positive
  • Hereditary diffuse gastric carcinoma
    • Autosomal dominant, 70% penetrance
    • Prophylactic gastrectomies show many foci (median 10-20) of intramucosal signet ring cells in most stomachs
      • Unexpectedly low proliferation rate in the foci (<2%)
      • Raises the possibility of an indolent state
      • Foci primarily proximal
      • Foci are infrequently found on endoscopy
        • Too small to detect
    • See Supplemental Studies for testing criteria
  • Recently described gastric adenocarcinoma with chief cell differentiation (Ueyama 2010) appears to be better considered an adenoma (Singhi 2012)

Robert V Rouse MD
Department of Pathology
Stanford University School of Medicine
Stanford CA 94305-5342

Original posting/updates : 11/29/09, 8/21/10, 11/26/11, 12/25/12

Supplemental studies

Immunohistology

• Hepatoid variant
  • Albumin positive
  • CD10 frequently stains canaliculi
  • CDX2 variable
    • Adjacent gastric carcinoma positive
  • Heppar1 usually negative or weak focal staining
  • Alpha fetoprotein variable
    • Not specific for hepatoid
  • PLUNC positive but very focal
    • (Palate, LUng, Nasal epithelium Carcinoma associated protein)
    • Associated carcinomas more extensively positive
    • Gastric adenocarcinomas NOS 7%
    • Hepatocellular carcinoma 0%
    • Only one report so far (Sentani) and the staining looks very focal
• Hereditary diffuse gastric carcinoma
  • E cadherin and beta catenin negative or reduced in intramucosal carcinoma foci
    • Both may be positive in deeply invasive carcinomas
  • Ki67 <2% in microscopic carcinoma foci found on prophylactic gastrectomy
    • Normal antrum is 24%

Genetic studies

• Hepatoid variant
  • Albumin FISH positive
• Hereditary diffuse (poorly cohesive) gastric carcinoma
  • Most common abnormality is mutation in E cadherin CDH1 gene (40% of families)
    • No other consistent mutations found yet
  • Criteria for testing (Fitzgerald 2010)
    • Two gastric carcinomas in family, one diffuse and under age 50
    • Three diffuse carcinomas in 1st or 2nd degree relatives, any age
    • Diffuse carcinoma under age 40
    • Personal or family history of diffuse gastric carcinoma and lobular breast carcinoma, either one under age 40
    • Consider testing if signet ring carcinoma in situ is detected adjacent to diffuse gastric carcinoma (WHO 2010)

Differential Diagnosis

• Gastric Adenoma with High Grade Dysplasia vs. Adenocarcinoma
  • Adenocarcinoma is defined by the presence of invasion into lamina propria or deeper
• Gastric Adenoma vs. Clear Cell / Pylorocardiac Adenocarcinoma
• Pylorocardiac carcinoma may have bland cytologic features leading to confusion with an adenoma on a biopsy
• Adenocarcinoma is defined by the presence of invasion into lamina propria or deeper
• Hepatoid Gastric Adenocarcinoma vs. Hepatocellular Carcinoma
• May be a problem in cases with possible liver metastases
• Hepatoid components are identical
• Hepatoid gastric adenocarcinoma (HGA) is commonly associated with an intestinal type carcinoma component
• Heppar1 is typically weak or negative in HGA and strong in HCC
• Furthermore, HEPPAR1 stains about half of gastric adenocarcinomas NOS
• PLUNC is proposed as a sensitive and specific marker for HGA (see Supplemental Studies)
• HCC usually arises in a setting of cirrhosis
• Endoscopy to rule out a gastric primary may be necessary
• Metastatic adenocarcinoma of unknown type
• Metastatic gland forming and especially signet ring carcinoma in the abdomen and pelvis should always raise the possibility of gastric adenocarcinoma
• Tall columnar cells with prominent dirty necrosis should suggest colorectal primary instead
• Immunohistochemistry is usually not definitive
• Biliary and pancreatic carcinomas can be especially difficult to distinguish microscopically
• Diagnosis frequently rests on location

Clinical

• Hepatoid variant has very poor prognosis
• Hereditary diffuse gastric carcinoma
• Autosomal dominant, 70% penetrance
• Carcinomas present at mean age 38
• Diagnosis requires either
• 2 cases in 1st or 2nd degree relatives, with one case <50 years, OR
• 3 cases in 1st or 2nd degree relatives, any age
• Females also at risk for lobular carcinoma of breast
• Endoscopy may be too insensitive to be of value

Grading / Staging

Grading

• WHO gastric adenocarcinoma grading criteria
  • Low grade
    • Well differentiated – well formed glands
      • In areas may be difficult to distinguish from benign atypia
    • Moderately differentiated - may be combined with well as low grade
  • High grade
    • Poorly differentiated
      • Highly irregular glands, difficult to discern, or
      • Single cells and clusters
    • Undifferentiated

Staging

• EGJ TNM is staged as esophagus
  • Tumor center must be within 5 cm of and cross junction
• Intramucosal carcinoma is variably defined and has poor interobserver agreement
  • A strict definition requires at least focal identification of detached single infiltrating cell(s)
  • A looser definition requires a cribriform pattern or growth in a pattern incompatible with pre-existing glands
    • Marked crowding, branching, budding
  • In either case, there is no invasion beyond the muscularis mucosae

Bibliography

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