Definition/General
Introduction:
Gastric signet ring cell carcinoma (SRCC) is a distinct variant of gastric adenocarcinoma
It is characterized by malignant cells containing intracytoplasmic mucin
The mucin accumulation displaces the nucleus to the cell periphery
This creates the characteristic signet ring appearance
It constitutes 10-15% of all gastric cancers.
Origin:
Originates from the gastric epithelial cells
Specifically from the surface foveolar epithelium and gastric glands
The neoplastic transformation involves mucin overproduction
It leads to intracytoplasmic accumulation of mucin
This results in the characteristic signet ring morphology.
Classification:
Classified as a variant of adenocarcinoma in WHO classification
Forms part of diffuse-type gastric cancer according to Lauren classification
Associated with hereditary diffuse gastric cancer syndrome
Grading follows WHO criteria
High-grade malignancy with poor differentiation.
Epidemiology:
Peak incidence in 4th-6th decades
Female predominance (F:M ratio 2:1)
Higher prevalence in Asian populations
Associated with CDH1 mutations in hereditary cases
Environmental factors include H
pylori infection
Salt-rich diet increases risk
Indian population shows increasing incidence in urban areas.
Clinical Features
Presentation:
Nonspecific symptoms in early stages
Epigastric pain (most common)
Weight loss (60-70% cases)
Dysphagia and early satiety
Gastric outlet obstruction in advanced cases
Palpable mass in late stages
Linitis plastica appearance on imaging.
Symptoms:
Abdominal pain (70-80%)
Loss of appetite and weight loss
Nausea and vomiting
Dyspepsia and bloating
Hematemesis in advanced cases
Ascites due to peritoneal spread
Dysphagia due to gastroesophageal junction involvement.
Risk Factors:
CDH1 germline mutations (hereditary diffuse gastric cancer)
H
pylori infection
Salt-preserved foods and nitrates
Family history of gastric cancer
Smoking and alcohol consumption
Atrophic gastritis
Previous gastric surgery.
Screening:
Genetic counseling for CDH1 mutation carriers
Prophylactic gastrectomy in high-risk individuals
Upper endoscopy with multiple biopsies
Chromoendoscopy for early detection
High-risk surveillance protocols
Family screening for hereditary cases.
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Gross Description
Appearance:
Thickened gastric wall with rigidity (linitis plastica)
Absence of discrete mass in many cases
Mucosal surface may appear normal or ulcerated
Leather bottle stomach appearance
Cut surface shows gray-white thickening.
Characteristics:
Wall thickness 2-5 cm or more
Rigid, non-distensible stomach wall
Loss of normal gastric folds
Serosal involvement with granular surface
Cut surface shows gelatinous consistency due to mucin.
Size Location:
Often involves entire stomach (pan-gastric)
Most common in antrum and body
May extend to gastroesophageal junction
Multifocal distribution common
Size difficult to assess due to diffuse nature.
Multifocality:
Diffuse growth pattern is characteristic
Peritoneal seeding common (70-80%)
Ovarian metastases (Krukenberg tumors)
Omental involvement frequent
Liver metastases less common than other gastric cancers.
Microscopic Description
Histological Features:
Signet ring cells with eccentric nuclei and intracytoplasmic mucin
Cells infiltrate singly or in small groups
Desmoplastic stromal reaction
Minimal gland formation
Transmural infiltration pattern
Lymphovascular invasion common.
Cellular Characteristics:
Large intracytoplasmic mucin vacuole
Nucleus compressed to cell periphery
Nuclear hyperchromasia and pleomorphism
Prominent nucleoli
Mitotic activity variable
PAS-positive intracytoplasmic mucin.
Architectural Patterns:
Single file infiltration pattern
Lack of cohesive growth
Scattered individual cells in stroma
Minimal tubular differentiation
Indian file pattern around normal structures
Perigastric extension common.
Grading Criteria:
Considered poorly differentiated by definition
High nuclear grade with pleomorphism
Lack of glandular differentiation
High mitotic index
Extensive stromal invasion
WHO Grade 3 (poorly differentiated).
Immunohistochemistry
Positive Markers:
CK7 (90-95%)
CK20 (70-80%)
CEA (cytoplasmic pattern)
MUC1 (membrane pattern)
MUC5AC (gastric-type mucin)
CDX2 may be positive
E-cadherin loss characteristic.
Negative Markers:
E-cadherin (characteristic loss)
CK5/6 and CK14
TTF1 and napsin A
PSA and PSAP
Hepatocyte markers
Neuroendocrine markers (chromogranin, synaptophysin).
Diagnostic Utility:
Loss of E-cadherin supports diagnosis
CDX2 positivity suggests intestinal differentiation
MUC pattern helps classify gastric vs intestinal type
CK7/CK20 profile aids in determining primary site
p53 mutation associated with poor prognosis.
Molecular Subtypes:
Diffuse type in Lauren classification
Genomically stable subtype in TCGA classification
CDH1 mutation subtype (hereditary)
Microsatellite stable (MSS)
EBV-negative subtype.
Molecular/Genetic
Genetic Mutations:
CDH1 mutations (40-50% of cases)
TP53 mutations (30-40%)
PIK3CA mutations (20-25%)
ARID1A mutations (15-20%)
SMAD4 mutations (10-15%)
APC mutations (5-10%).
Molecular Markers:
E-cadherin loss (hallmark feature)
β-catenin cytoplasmic localization
p53 overexpression
Ki-67 proliferation index (variable)
HER2 amplification (rare, <5%)
PD-L1 expression (low).
Prognostic Significance:
CDH1 mutation indicates hereditary syndrome
E-cadherin loss associated with poor prognosis
High Ki-67 correlates with aggressive behavior
p53 mutation indicates poor outcome
MSI status affects treatment response
HER2 status guides targeted therapy.
Therapeutic Targets:
Limited targeted options compared to intestinal type
HER2 targeting in rare amplified cases
Immunotherapy limited due to low PD-L1 expression
Anti-VEGF therapy (ramucirumab)
CDK4/6 inhibitors under investigation
Prophylactic surgery for CDH1 carriers.
Differential Diagnosis
Similar Entities:
Lobular breast carcinoma metastasis (E-cadherin loss, morphology)
Primary peritoneal carcinoma
Mucinous adenocarcinoma of stomach
Adenocarcinoma from other GI sites
Malignant mesothelioma (peritoneal).
Distinguishing Features:
SRCC: Intracytoplasmic mucin
SRCC: E-cadherin loss
SRCC: Gastric mucin markers positive
Lobular breast: GCDFP-15 and mammaglobin positive
Lobular breast: ER/PR positive
Mucinous adenocarcinoma: Extracellular mucin pools
Mucinous: Goblet cell morphology.
Diagnostic Challenges:
Distinguishing from metastatic signet ring cell carcinoma
Differentiating from benign signet ring cells in inflammation
Sampling issues due to diffuse nature
Early detection challenges
Distinguishing hereditary from sporadic cases
Peritoneal involvement assessment.
Rare Variants:
Mixed signet ring cell and conventional adenocarcinoma
Mucinous signet ring variant
Poorly cohesive carcinoma with signet ring features
Hepatoid variant with signet ring cells
Neuroendocrine differentiation in SRCC.
Sample Pathology Report
Template Format
Sample Pathology Report
Complete Report: This is an example of how the final pathology report should be structured for this condition.
Specimen Information
[specimen type], measuring [size] cm in greatest dimension
Diagnosis
Gastric Signet Ring Cell Carcinoma
Classification
Lauren Classification: Diffuse type, WHO Grade: [grade]
Histological Features
Signet ring cells comprise [percentage]% of tumor cells with intracytoplasmic mucin and peripheral nuclei
Growth Pattern
Diffuse infiltrative pattern with [single file/small clusters] arrangement
Extent
Transmural involvement: [present/absent], Peritoneal involvement: [present/absent]
Margins
Margins are [involved/uninvolved] with closest margin [X] mm
Lymphovascular Invasion
Lymphovascular invasion: [present/absent]
Lymph Node Status
Lymph nodes: [X] positive out of [X] examined
Special Studies
IHC: E-cadherin: [positive/negative], CK7: [positive/negative], MUC5AC: [positive/negative]
CDH1 mutation: [detected/not detected]
PAS stain: [positive/negative] for intracytoplasmic mucin
TNM Staging
pT[X] pN[X] pM[X] - Stage [stage]
Final Diagnosis
Gastric Signet Ring Cell Carcinoma, Diffuse Type, WHO Grade [grade], Stage [stage]