Stomach
Carcinoma
Hereditary diffuse gastric cancer


Topic Completed: 16 April 2020

Minor changes: 17 April 2020

Copyright: 2020, PathologyOutlines.com, Inc.

PubMed Search: Hereditary diffuse gastric cancer[TI] stomach pathology

Runjan Chetty, M.B.B.Ch., Ph.D.
Page views in 2020 to date: 1,107
Cite this page: Nowak K, Chetty R. Hereditary diffuse gastric cancer. PathologyOutlines.com website. http://www.pathologyoutlines.com/topic/stomachhdgc.html. Accessed October 24th, 2020.
Definition / general
  • Autosomal dominant associated cancer syndrome
  • Associated with diffuse gastric and invasive lobular breast cancers
  • Caused by inactivating germline mutations in CDH1 (E-cadherin)
Essential features
  • Autosomal dominant associated cancer syndrome
  • Caused by inactivating germline mutations in CDH1 (E-cadherin)
  • Associated with poorly cohesive carcinoma (signet ring carcinoma)
  • Precursor lesions include signet ring carcinoma in situ and signet ring cells with pagetoid spread (pTis)
  • Loss of membranous E-cadherin immunohistochemical staining
  • Associated risk of developing lobular breast cancer
Terminology
  • Older terms include: E-cadherin associated hereditary gastric cancer, familial diffuse gastric cancer, hereditary diffuse gastric adenocarcinoma
Epidemiology
Sites
  • No predilection for specific area of stomach
Pathophysiology
Etiology
  • CDH1 germline mutation
Clinical features
  • Variable presentation
  • 40% lifetime risk of developing lobular breast cancer (JAMA Oncol 2015;1:23)
  • Risk of developing gastric cancer by the age of 80 years: ~ 70% in men and ~ 56% in women (JAMA Oncol 2015;1:23)
Radiology description
Case reports
Treatment
  • Prophylactic total gastrectomy
Gross description
  • Range:
    • No gross lesions identified
    • Linitis plastica
    • Multiple polyps
  • Summary of grossing a total gastrectomy specimen:
    • Open the specimen along the greater curvature
    • Ink margins
    • Record all measurements
    • Pin and allow to fix overnight
    • Record any lesions and distance to margins
    • Current recommendations include submitting the prophylactic gastrectomy specimen in toto (J Med Genet 2015;52:361)
    • Take pictures in order to map out the specimen as to where sections came and where lesions occur
Gross images

Images hosted on other servers:

Total gastrectomy specimen

Microscopic (histologic) description
  • Signet ring cell carcinoma in situ (pTis)
    • Signet ring cells within basal membrane
  • Signet ring cells with pagetoid spread (pTis)
    • Second row of signet rings cells beneath normal epithelium in a gastric gland within the basal membrane
  • Intramucosal signet ring carcinoma (pT1a)
    • Signet ring cells restricted to the lamina propria
  • Advanced HGDC (> pT1a)
    • Poorly cohesive carcinoma with signet ring cells
  • NB
    • If no foci of signet ring cell carcinoma or in situ component is identified in a prophylactic total gastrectomy specimen , it should not be reported as negative for carcinoma, but as 'no carcinoma found in xx% of mucosa examined' (J Med Genet 2015;52:361)
Microscopic (histologic) images

Contributed by Runjan Chetty, M.B.B.Ch., Ph.D. and Altaf Taher, M.B.B.S., M.D.

Signet ring carcinoma in situ

Loss of membranous E-cadherin staining




Contributed by Raul S. Gonzalez, M.D.

Signet ring carcinoma in situ

Obvious poorly cohesive carcinoma

Subtle poorly cohesive carcinoma

Positive stains
Negative stains
Molecular / cytogenetics description
Sample pathology report
  • Stomach, total gastrectomy:
    • Poorly cohesive carcinoma with signet ring features (see comment and synoptic report)
    • Comment: A poorly cohesive carcinoma with signet ring features is seen arising in a background of signet ring cell carcinoma in situ. The tumor cells are diffusely positive for pankeratin and demonstrate a loss of membranous E-cadherin staining. In the appropriate clinical context, genetic counseling is recommended to exclude hereditary diffuse gastric cancer, which is associated with a germline mutation in CDH1.
Differential diagnosis
Board review style question #1
Which mutation is most commonly associated with hereditary diffuse gastric cancer?

  1. BRCA2
  2. CDH1
  3. NF1
  4. SMARCA4
Board review answer #1
Board review style question #2
The following morphology is associated with which answer?



  1. Loss of cytoplasmic keratin staining
  2. Loss of membranous E-cadherin staining
  3. Overexpression of CD68
  4. Overexpression of DOG1
Board review answer #2
B. Loss of membranous E-cadherin staining

Reference: Hereditary diffuse gastric cancer

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