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Adenocarcinoma of the Stomach

Definition

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

Covered separately:

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)
Type Tubules Intracytoplasmic Mucin
I Well differentiated Poor
II Well differentiated Rich
III Poorly differentiated Poor
IV Poorly differentiated Rich
  • 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%
Adenocarcinoma Type CDX2 Staining
Colorectal 70-98%
Small intestine 60%
Stomach 60-70%
Endocervix 30%
Ovary primary mucinous 40-70%
Uterus 10-15%
Bile duct 13-25%
Lung 0-12%
Pancreas 0-32%
Liver 0%
Breast 0%

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

CK7 and CK20 expression in carcinomas

CK7+20+ CK7-20+
Ovary mucinous 90% Colorectal adeno 80%
Transitional cell 65% Merkel cell 70%
Pancreas adeno 65% Gastric adeno 35%
Cholangio 65%  
Gastric adeno 40%  
Excluded tumors 5% or less Carcinoid; Germ cell; Esoph squam; Head/neck squam; Hepato-cellular; Lung small cell & squam; Ovary non-mucinous; Renal adeno Excluded tumors 5% or less Breast; Carcinoid lung; Cholangio; Esoph squam; Germ cell; Lung all types; Hepato-cellular; Ovary; Pancreas adeno; Renal adeno; Transitional cell; Uterus endometrioid
CK7+20- CK7-20-
Ovary non-mucinous 100% Adrenal 100%
Thyroid (all 3 types) 100% Seminoma & Yolk Sac 95%
Breast 90% Prostate 85%
Lung adeno 90% Hepatocellular 80%
Uterus endometrioid 85% Renal adeno 80%
Embryonal 80% Carcinoid intestinal & lung 80%
Mesothelioma 65% Lung small cell & squam 75%
Transitional cell 35% Esoph squam 70%
Pancreas adeno 30% Head/neck squam 70%
Cholangio 30% Mesothelioma 35%
Excluded tumors 5% or less Colorectal adeno; Ovary mucinous; Yolk Sac; Seminoma Excluded tumors 5% or less Breast; Cholangio; Lung adeno; Ovary; Pancreas adeno
  • Derived from Chu PG, Weiss LM. Histopathology 2002, 40:403-439 and other sources
  • 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

    • 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.
    • Vauhkonen M, Vauhkonen H, Sipponen P. Pathology and molecular biology of gastric cancer. Best Pract Res Clin Gastroenterol. 2006;20(4):651-74.
    • 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.
    • Kumashiro Y, Yao T, Aishima S, Hirahashi M, Nishiyama K, Yamada T, Takayanagi R, Tsuneyoshi M. Hepatoid adenocarcinoma of the stomach: histogenesis and progression in association with intestinal phenotype. Hum Pathol. 2007 Jun;38(6):857-63.
    • Sentani K, Oue N, Sakamoto N, Arihiro K, Aoyagi K, Sasaki H, Yasui W. Gene expression profiling with microarray and SAGE identifies PLUNC as a marker for hepatoid adenocarcinoma of the stomach. Mod Pathol. 2008 Apr;21(4):464-75.
    • Terracciano LM, Glatz K, Mhawech P, Vasei M, Lehmann FS, Vecchione R, Tornillo L. Hepatoid adenocarcinoma with liver metastasis mimicking hepatocellular carcinoma: an immunohistochemical and molecular study of eight cases. Am J Surg Pathol. 2003 Oct;27(10):1302-12.
    • Maitra A, Murakata LA, Albores-Saavedra J. Immunoreactivity for hepatocyte paraffin 1 antibody in hepatoid adenocarcinomas of the gastrointestinal tract. Am J Clin Pathol. 2001 May;115(5):689-94.
    • Barber ME, Save V, Carneiro F, Dwerryhouse S, Lao-Sirieix P, Hardwick RH, Caldas C, Fitzgerald RC. Histopathological and molecular analysis of gastrectomy specimens from hereditary diffuse gastric cancer patients has implications for endoscopic surveillance of individuals at risk. J Pathol. 2008 Nov;216(3):286-94.
    • Rogers WM, Dobo E, Norton JA, Van Dam J, Jeffrey RB, Huntsman DG, Kingham K, Chun N, Ford JM, Longacre TA. Risk-reducing total gastrectomy for germline mutations in E-cadherin (CDH1): pathologic findings with clinical implications. Am J Surg Pathol. 2008 Jun;32(6):799-809.
    • Roh JH, Srivastava A, Lauwers GY, An J, Jang KT, Park CK, Sohn TS, Kim S, Kim KM. Micropapillary carcinoma of stomach: a clinicopathologic and immunohistochemical study of 11 cases. Am J Surg Pathol. 2010 Aug;34(8):1139-46
    • Fitzgerald RC, Hardwick R, Huntsman D, Carneiro F, Guilford P, Blair V, Chung DC, Norton J, Ragunath K, Van Krieken JH, Dwerryhouse S, Caldas C; International Gastric Cancer Linkage Consortium. Hereditary diffuse gastric cancer: updated consensus guidelines for clinical management and directions for future research. J Med Genet. 2010 Jul;47(7):436-44. Erratum in: J Med Genet. 2011 Mar;48(3):216. Van Krieken, Nicola [corrected to Van Grieken, Nicola C].
    • Fujita H, Lennerz JK, Chung DC, Patel D, Deshpande V, Yoon SS, Lauwers GY. Endoscopic surveillance of patients with hereditary diffuse gastric cancer: biopsy recommendations after topographic distribution of cancer foci in a series of 10 CDH1-mutated gastrectomies. Am J Surg Pathol. 2012 Nov;36(11):1709-17.
    • Ueyama H, Yao T, Nakashima Y, Hirakawa K, Oshiro Y, Hirahashi M, Iwashita A, Watanabe S. Gastric adenocarcinoma of fundic gland type (chief cell predominant type): proposal for a new entity of gastric adenocarcinoma. Am J Surg Pathol. 2010 May;34(5):609-19
    • Singhi AD, Lazenby AJ, Montgomery EA. Gastric adenocarcinoma with chief cell differentiation: a proposal for reclassification as oxyntic gland polyp/adenoma. Am J Surg Pathol. 2012 Jul;36(7):1030-5.
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