Definition/General
Introduction:
Gastric squamous cell carcinoma is an extremely rare malignant tumor of stomach
It shows pure squamous differentiation without glandular components
Must arise from native gastric mucosa
It constitutes <0.1% of all gastric cancers
Also called primary gastric squamous cell carcinoma.
Origin:
Arises from squamous metaplasia of gastric mucosa
May develop from gastric heterotopia
Can originate from embryonic rests
Chronic irritation and inflammation predispose
Results from multipotent stem cells with squamous differentiation.
Classification:
Classified as rare variant in WHO classification
Must exclude esophageal extension for diagnosis
Distinguished from adenosquamous carcinoma
Grading follows conventional SCC criteria
Usually high-grade malignancy.
Epidemiology:
Peak incidence in 6th-7th decades
Male predominance (M:F ratio 4:1)
Higher prevalence in Asian populations
Associated with smoking and alcohol
Chronic gastritis and ulceration
Extremely rare worldwide.
Clinical Features
Presentation:
Aggressive clinical presentation
Severe epigastric pain
Rapid weight loss
Dysphagia and odynophagia
Hematemesis and melena
Palpable abdominal mass
Poor performance status at diagnosis.
Symptoms:
Abdominal pain (95%)
Significant weight loss
Nausea and vomiting
Gastrointestinal bleeding
Loss of appetite
Early satiety
Systemic symptoms of malignancy.
Risk Factors:
Heavy smoking and alcohol consumption
Chronic gastritis
Previous gastric surgery
Chemical irritants
Helicobacter pylori infection
Genetic predisposition
Environmental carcinogens.
Screening:
Upper endoscopy with extensive biopsy
High-index of suspicion in risk factors
Complete staging workup
Exclude esophageal primary
Molecular profiling
Multidisciplinary consultation.
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Gross Description
Appearance:
Large, ulcerated tumor with raised borders
Fungating or excavating growth pattern
Cut surface shows gray-white appearance
Areas of necrosis and hemorrhage
Hard consistency due to keratinization.
Characteristics:
Irregular, infiltrative margins
Central ulceration common
Hard, woody consistency
White to gray-yellow cut surface
Areas of cystic degeneration
Hemorrhagic appearance.
Size Location:
Size typically 6-20 cm
Most common in middle third of stomach
May involve multiple sites
Cardia and fundus also affected
Extensive transmural invasion.
Multifocality:
Usually unifocal
High metastatic potential
Early lymph node involvement
Local invasion into adjacent organs
Peritoneal and hepatic metastases
Poor prognosis due to advanced stage.
Microscopic Description
Histological Features:
Malignant squamous epithelium with keratinization
Intercellular bridges between cells
Keratin pearl formation
Nuclear pleomorphism and hyperchromasia
High mitotic activity
Absence of glandular differentiation.
Cellular Characteristics:
Polygonal squamous cells
Eosinophilic cytoplasm
Prominent intercellular bridges
Hyperchromatic nuclei
Prominent nucleoli
Individual cell keratinization
High nuclear-to-cytoplasmic ratio.
Architectural Patterns:
Solid nests and sheets of squamous cells
Invasive growth pattern
Keratin pearl formation
Surface ulceration
Desmoplastic stromal reaction
Infiltration through gastric wall.
Grading Criteria:
Graded as well, moderately, or poorly differentiated
Based on keratinization degree
Nuclear pleomorphism assessment
Mitotic count
Most cases are moderately to poorly differentiated
WHO Grade 2-3.
Immunohistochemistry
Positive Markers:
p63 (nuclear, strong and diffuse)
p40 (nuclear, specific)
CK5/6 (cytoplasmic)
CK14 (squamous epithelium)
34βE12 (high molecular weight keratin)
Involucrin (squamous differentiation).
Negative Markers:
CK7 (glandular marker)
CK20 (intestinal marker)
CDX2 (intestinal transcription factor)
TTF1 (lung/thyroid marker)
CEA (adenocarcinoma marker)
Mucin stains (PAS, mucicarmine).
Diagnostic Utility:
p63/p40 positivity confirms squamous differentiation
CK5/6 expression supports squamous nature
Absence of glandular markers excludes adenocarcinoma
TTF1 negativity helps exclude lung primary
Pattern recognition crucial for diagnosis.
Molecular Subtypes:
Squamous cell carcinoma subtype
HPV-negative in most cases
p53 pathway alterations
CDKN2A deletions common
PIK3CA mutations possible.
Molecular/Genetic
Genetic Mutations:
TP53 mutations (80-90%)
CDKN2A/p16 deletions (60-70%)
PIK3CA mutations (20-30%)
PTEN deletions (15-25%)
FGFR1 amplifications (10-15%)
CCND1 amplifications (10-20%).
Molecular Markers:
p53 overexpression (majority of cases)
Loss of p16 expression
High Ki-67 index
EGFR overexpression
Cyclin D1 amplification
PTEN loss.
Prognostic Significance:
TP53 mutations associated with poor prognosis
High proliferation index indicates aggressive behavior
EGFR overexpression correlates with metastasis
p16 loss associated with progression
Overall poor prognosis.
Therapeutic Targets:
EGFR inhibitors (cetuximab, panitumumab)
PI3K/AKT pathway inhibitors
CDK4/6 inhibitors
Immunotherapy (PD-1/PD-L1 inhibitors)
Radiation sensitizers
Combination approaches.
Differential Diagnosis
Similar Entities:
Esophageal SCC extending to stomach
Metastatic SCC from other sites
Adenosquamous carcinoma
Squamous metaplasia in adenocarcinoma
Poorly differentiated adenocarcinoma.
Distinguishing Features:
Primary gastric SCC: Pure squamous differentiation
Primary: No esophageal involvement
Esophageal extension: Bulk in esophagus
Metastatic: History of primary elsewhere
Adenosquamous: Glandular component present
Metaplasia: Benign squamous epithelium.
Diagnostic Challenges:
Excluding esophageal extension
Ruling out metastatic disease
Distinguishing from adenosquamous carcinoma
Adequate tissue sampling
Clinical correlation essential
Imaging correlation required.
Rare Variants:
Basaloid squamous carcinoma
Spindle cell squamous carcinoma
Papillary squamous carcinoma
Verrucous carcinoma
Adenoid squamous carcinoma.
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
Primary Gastric Squamous Cell Carcinoma
Differentiation
[well/moderately/poorly] differentiated with [keratinization pattern]
Histological Features
Pure squamous differentiation with intercellular bridges and keratin formation
Keratinization
Keratinization: [extensive/moderate/minimal] with keratin pearl formation
Extent
Invasion depth: [mucosa/submucosa/muscularis propria/serosa]
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: p63: [positive/negative], p40: [positive/negative], CK5/6: [positive/negative]
Molecular: TP53: [mutated/wild-type]
CK7/CK20: [negative/negative] excluding glandular differentiation
TNM Staging
pT[X] pN[X] pM[X] - Stage [stage]
Final Diagnosis
Primary Gastric Squamous Cell Carcinoma, [differentiation], WHO Grade [grade], Stage [stage]