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Surgical Pathology Criteria

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Adenocarcinoma of the Esophagus, Esophago-gastric Junction and Gastric Cardia


  • Malignant gland forming neoplasm of the esophagus, and esophago-gastric junction

Diagnostic Criteria

  • Most are papillary and/or tubular
    • May have focal other differentiation
      • Endocrine, Paneth cell or squamous
    • Adenocarcinoma NOS is defined by invasion, significant dysplasia and evidence of glandular/mucinous differentiation
  • 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
    • Pylorocardiac type reported variably as mucin positive and negative
      • Not well described in recent literature
    • 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
  • Mucinous and signet ring types rare
    • Both defined as in the large intestine
      • >50% of tumor area must be composed of mucin or >50% of cells must be signet ring
  • Rare variants and types
    • Adenosquamous
      • Mixture of two patterns, more than just focal
    • Mucoepidermoid
      • Same features as salivary gland tumors
  • There has been debate about how to describe the location of tumors near the esophago-gastric junction (EGJ)
    • AJCC 7th edition includes as EJG adenocarcinomas all tumors that cross the junction unless the center of the tumor is >5cm from the junction
      • Such carcinomas are staged as esophageal
      • Tumors of the proximal stomach that are >5cm from the junction or do not cross the junction are staged as gastric

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

    Original posting/last update: 11/29/09, 7/17/11, 11/24/11, 11/26/11


Differential Diagnosis

Esophageal and EGJ High Grade Dysplasia Esophageal and EGJ Intramucosal Adenocarcinoma
Atypia confined by basement membrane Invasion beyond basement membrane
No individual epithelial cells in lamina propria Individual atypical cells in lamina propria
Architectural pattern compatible with pre-existing glands Looser definition used by some is growth in a pattern incompatible with pre-existing glands
These features are difficult to apply and subject to individual interpretation


  • Gastric adenoma may involve the cardia and thus could be considered in the differential diagnosis of an esophageal or EGJ adenocarcinoma
    • High grade dysplasia and invasion are not seen in adenoma
  • Esophageal Submucosal Gland Duct Adenoma Esophageal or EGJ Adenocarcinoma NOS
    Cytologically bland Cytologically dysplastic
    Two cell layers Varies from single to multiple cell layers
    Outer layer has myoepithelial phenotype No myoepithelial component
    Circumscribed Invasive


    Esophageal Submucosal Gland Duct Adenoma Esophageal or EGJ Adenocarcinoma, Clear Cell / Pylorocardiac Type
    Two cell layers Varies from single to multiple cell layers
    Inner layer has intensely eosinophilic cytoplasm Clear cells line tubules and papillae
    Outer layer has myoepithelial phenotype No myoepithelial component
    Lacks tumor cell necrosis Frequent coagulative tumor cell necrosis
    Circumscribed Invasive
    Clear cell / pylorocardiac adenocarcinoma may have bland cytologic features leading to confusion with an adenoma on a biopsy

    Grading / Staging


    • WHO recommends well, moderately, poorly and undifferentiated
      • No precise criteria given
      • 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


    • EGJ TNM is the same as that used for esophagus
    • 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
        • Dense crowding, extensive branching and budding
      • In either case, there is no invasion beyond the muscularis mucosae
    • Duplication of muscularis mucosae can make staging difficult
      • Common in Barrett esophagus (92% of cases)
        • Not caused by the carcinoma
      • Outer layer of duplication (or triplication) is generally continuous with the original layer
      • Invasion between the duplicated layers is still considered T1 (intramucosal)
        • Lewis 2008 reports 17% lymphatic invasion rate and 10% nodal metastases
          • Higher than expected for T1
          • Lower than expected for T2
        • Estrella 2011 found no increase in nodal metastases
        • Level of invasion should be described and thickness measured and given in report
      • Recognition of this phenomenon can avoid over staging
        • Duplicated muscularis mucosae is generally fragmented and not tightly bundled
        • Normal muscularis propria is composed of well defined bundles of muscle
        • Endoscopic biopsies and EMRs rarely contain muscularis propria
        • Attention to edge of larger specimens can also be helpful
        • True submucosa contains thick walled vessels and thick ropey collagen
          • Stroma between muscularis mucosae layers contains thin walled vessels and fine collagen (in areas not involved by carcinoma)
            • Collagen may become thicker in areas of desmoplasia


    • Bosman FT, Carneiro F, Hruban RH, Thiese ND (Eds). WHO Classifiication of Tumors of the Digestive System, IARC, Lyon 2010
    • Sarbia M, Becker KF, Höfler H. Pathology of upper gastrointestinal malignancies. Semin Oncol. 2004 Aug;31(4):465-75.
    • Ghotli ZA, Serra S, Chetty R. Clear cell (glycogen rich) gastric adenocarcinoma: a distinct tubulo-papillary variant with a predilection for the cardia/gastro-oesophageal region. Pathology. 2007 Oct;39(5):466-9.
    • Carr N. Tubulopapillary clear cell carcinoma of the stomach may be a type of pylorocardiac carcinoma. Pathology. 2008 Apr;40(3):333.
    • Mandal RV, Forcione DG, Brugge WR, Nishioka NS, Mino-Kenudson M, Lauwers GY. Effect of Tumor Characteristics and Duplication of the Muscularis Mucosae on the Endoscopic Staging of Superficial Barrett Esophagus-related Neoplasia. Am J Surg Pathol. 2008 Nov 26.
    • Abraham SC, Krasinskas AM, Correa AM, Hofstetter WL, Ajani JA, Swisher SG, Wu TT. Duplication of the muscularis mucosae in Barrett esophagus: an under recognized feature and its implication for staging of adenocarcinoma. Am J Surg Pathol. 2007 Nov;31(11):1719-25.
    • Lewis JT, Wang KK, Abraham SC. Muscularis mucosae duplication and the musculo-fibrous anomaly in endoscopic mucosal resections for barrett esophagus: implications for staging of adenocarcinoma. Am J Surg Pathol. 2008 Apr;32(4):566-71.
    • Siewert JR, Feith M, Stein HJ. Biologic and clinical variations of adenocarcinoma at the esophago-gastric junction: relevance of a topographic-anatomic subclassification. J Surg Oncol. 2005 Jun 1;90(3):139-46
    • Estrella JS, Hofstetter WL, Correa AM, Swisher SG, Ajani JA, Lee JH, Bhutani MS, Abraham SC, Rashid A, Maru DM. Duplicated Muscularis Mucosae Invasion has Similar Risk of Lymph Node Metastasis and Recurrence-free Survival as Intramucosal Esophageal Adenocarcinoma. Am J Surg Pathol. 2011 Jul;35(7):1045-53.
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