Definition/General
Introduction:
Large cell carcinoma is an undifferentiated non-small cell lung cancer
Represents 5-10% of all lung cancers
Shows large cells without specific differentiation
Diagnosis of exclusion
Aggressive behavior.
Origin:
Arises from bronchial epithelium
Lacks specific differentiation markers
Peripheral location typical
Associated with tobacco exposure
High-grade features.
Classification:
WHO 2021: Large cell carcinoma
Large cell neuroendocrine carcinoma
Basaloid carcinoma
Clear cell carcinoma
Large cell carcinoma with rhabdoid phenotype.
Epidemiology:
Peak incidence 6th-7th decades
Male predominance
Strong smoking association
Peripheral location
Decreasing incidence with better classification.
Clinical Features
Presentation:
Cough
Dyspnea
Chest pain
Hemoptysis
Weight loss
Peripheral mass
Advanced stage at presentation.
Symptoms:
Persistent cough
Shortness of breath
Chest discomfort
Constitutional symptoms
Fatigue
Loss of appetite
Bone pain (metastases).
Risk Factors:
Tobacco smoking (primary)
Environmental tobacco smoke
Occupational exposures
Air pollution
Radon exposure
Genetic susceptibility.
Screening:
Low-dose CT screening (high-risk)
Chest imaging
Staging workup
Tissue diagnosis essential
Molecular profiling.
Master Large Cell Carcinoma Pathology with RxDx
Access 100+ pathology videos and expert guidance with the RxDx app
Gross Description
Appearance:
Large, peripheral mass
Gray-white, firm
Well-circumscribed to infiltrative
Necrosis common
Hemorrhage
Pleural involvement.
Characteristics:
Bulky tumor
Firm consistency
Tan-gray color
Central necrosis
Irregular margins
Satellite nodules.
Size Location:
Peripheral location (80%)
Upper lobe predilection
Large size at presentation (>3 cm)
Pleural extension
Chest wall invasion.
Multifocality:
Usually solitary
Multiple nodules possible
Synchronous tumors
Intrapulmonary metastases
Distant metastases common.
Microscopic Description
Histological Features:
Large polygonal cells
Abundant cytoplasm
Prominent nucleoli
High nuclear grade
No specific differentiation
High mitotic rate.
Cellular Characteristics:
Large cell size (>4x lymphocyte)
Pleomorphic nuclei
Vesicular chromatin
Prominent nucleoli
Abundant eosinophilic cytoplasm
Distinct cell borders.
Architectural Patterns:
Solid sheets
Nests and clusters
No glandular formation
No keratinization
Extensive necrosis
Desmoplastic stroma.
Grading Criteria:
High-grade by definition
Marked nuclear atypia
High mitotic count
Extensive necrosis
Poor differentiation.
Immunohistochemistry
Positive Markers:
Pan-cytokeratin - positive
CK7 - variable
EMA - positive
p53 - often positive
Ki-67 - high (>50%).
Negative Markers:
TTF1 - negative (vs adenocarcinoma)
Napsin A - negative
p40 - negative (vs squamous)
p63 - negative
Neuroendocrine markers - negative.
Diagnostic Utility:
Diagnosis of exclusion
Negative squamous markers (p40, p63)
Negative adenocarcinoma markers (TTF1, Napsin A)
No neuroendocrine differentiation
Extensive IHC panel required.
Molecular Subtypes:
Large cell NOS: Non-specific markers
Large cell neuroendocrine: Neuroendocrine markers+
Basaloid variant: Basaloid features
Clear cell variant: Clear cytoplasm.
Molecular/Genetic
Genetic Mutations:
KRAS mutations (30%)
TP53 mutations (80%)
STK11 mutations
KEAP1 mutations
EGFR mutations (rare)
ALK rearrangements (rare).
Molecular Markers:
p53 pathway disruption
KRAS/MAPK activation
Cell cycle dysregulation
DNA repair defects
High mutational burden.
Prognostic Significance:
Poor prognosis
Stage most important
Large tumor size
High proliferation
Metastatic potential
Response to therapy variable.
Therapeutic Targets:
Platinum-based chemotherapy
Immunotherapy (anti-PD-1/PD-L1)
Targeted therapy limited
Molecular profiling recommended
Clinical trials.
Differential Diagnosis
Similar Entities:
Poorly differentiated adenocarcinoma
Poorly differentiated squamous carcinoma
Large cell neuroendocrine carcinoma
Sarcomatoid carcinoma
Metastatic carcinoma.
Distinguishing Features:
Large cell carcinoma: No specific differentiation
Adenocarcinoma: TTF1+, Napsin A+
Squamous: p40+, keratinization
LCNEC: Neuroendocrine markers+
Metastatic: Organ-specific markers.
Diagnostic Challenges:
Extensive sampling required
Immunohistochemistry panel
Poorly differentiated carcinoma
Mixed differentiation
Crush artifact.
Rare Variants:
Large cell neuroendocrine carcinoma
Basaloid carcinoma
Clear cell carcinoma
Large cell carcinoma with rhabdoid phenotype.
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
[Lobectomy/wedge resection] specimen with tumor
Tumor Description
Large cell carcinoma measuring [X] cm in [location]
Microscopic Features
Large polygonal cells with abundant cytoplasm, prominent nucleoli, and no specific differentiation
Differentiation Assessment
No glandular, squamous, or neuroendocrine differentiation identified
pT Stage
pT[stage] - [staging details]
Immunohistochemistry
Pan-CK: Positive, TTF1: Negative, p40: Negative, Napsin A: Negative, Neuroendocrine markers: Negative
Molecular Studies
[Molecular profiling results if performed]
Final Diagnosis
Large cell carcinoma, pT[stage]N[stage]M[stage]