Lung Squamous Cell Carcinoma

~Introduction

Lung cancer remains one of the most significant global health challenges, accounting for millions of deaths annually. Among the different types of lung cancers, Lung Squamous Cell Carcinoma (LSCC) stands out as a major subtype of non-small cell lung cancer (NSCLC)—one that is strongly linked to tobacco smoking and arises mostly in the central airways of the lungs. Although medical science has made remarkable progress in lung cancer detection and treatment, LSCC continues to pose serious diagnostic and therapeutic challenges due to its aggressive behavior, delayed detection, and limited availability of targeted treatment options.

This article provides a detailed and comprehensive examination of LSCC, including its epidemiology, causes, risk factors, pathophysiology, clinical presentation, diagnostic pathways, staging, treatment modalities, emerging therapies, prognosis, and prevention strategies.

~Epidemiology

Lung squamous cell carcinoma is one of the three major subtypes of non-small cell lung cancer, alongside adenocarcinoma and large cell carcinoma. While adenocarcinoma has become the most common form of lung cancer in many parts of the world, LSCC still accounts for 20–30% of all lung cancers.

Global and regional variation

LSCC is more prevalent in regions with high smoking rates, especially in Asia, Eastern Europe, and parts of the Middle East.
Historically, it was the most common lung cancer among men; however, smoking trends and improvements in filtration cigarettes shifted this pattern.
It is more common in males than females, although the gender gap is narrowing as smoking patterns evolve.

Age distribution

LSCC incidence increases significantly after age 50.
Most patients are diagnosed between 60 and 70 years of age.

Trends

The advent of low-tar cigarettes has pushed smoke deeper into the lungs, increasing adenocarcinoma rates, but LSCC continues to be closely associated with chronic tobacco exposure.

~Causes and Risk Factors

Tobacco smoking: The dominant risk factor

The single greatest cause of lung squamous cell carcinoma is cigarette smoking, responsible for up to 90% of cases.
Important considerations:

Both active and passive smoking contribute significantly.
The risk increases with:
- total years of smoking
- number of cigarettes per day
- early age of smoking initiation
- depth of inhalation

Other notable risk factors

Secondhand smoke – increases risk even in non-smokers.
Occupational exposure:
- Asbestos
- Chromium
- Arsenic
- Nickel
- Diesel exhaust
Environmental exposure:
- Radon gas
- Air pollution (PM2.5 and industrial pollutants)
Chronic lung conditions:
- Chronic obstructive pulmonary disease (COPD)
- Pulmonary fibrosis
- Long-standing inflammation
Genetic susceptibility:
- Family history of lung cancer
- Variations in DNA repair genes
Alcohol consumption:
- Heavy alcohol use may increase risk synergistically with smoking.

~Pathophysiology

Lung squamous cell carcinoma arises from the squamous epithelial cells lining the central airways (the main bronchi and segmental bronchi). Chronic exposure to carcinogens in cigarette smoke leads to a sequence of cellular changes:

Transformation sequence:

Squamous metaplasia – normal columnar epithelium replaced by squamous cells to adapt to smoking damage.
Dysplasia – abnormal growth and disordered architecture of squamous cells.
Carcinoma in situ – precancerous lesion localized to epithelium.
Invasive squamous cell carcinoma – cancer spreads beyond basement membrane.

Key features of LSCC tumors

Usually centrally located in the lungs.
Cauliflower-like or nodular masses that can obstruct bronchi.
Can cause cavitation due to central necrosis.
Strong association with paraneoplastic syndromes, such as:
- Hypercalcemia (due to parathyroid hormone–related peptide secretion)
- Clubbing
- Leukocytosis

Molecular abnormalities

Unlike adenocarcinoma, which often carries targetable mutations, LSCC generally has:

TP53 mutations
FGFR1 amplification
SOX2 overexpression
PIK3CA mutations

This molecular profile affects responsiveness to targeted treatments.

~Clinical Presentation

Signs and symptoms often arise due to:

Local invasion
Airway obstruction
Paraneoplastic effects
Metastasis

Common symptoms

Chronic cough – often worsening in smokers.
Hemoptysis (coughing blood).
Shortness of breath – due to airway blockage.
Chest pain – localized and persistent.
Recurrent pneumonia – from obstructed airways.
Wheezing – new onset in smokers.
Unintended weight loss and fatigue.

Paraneoplastic symptoms

Hypercalcemia – causing nausea, confusion, constipation, muscle weakness.
SIADH is less common than in small cell carcinoma but may occur.

Symptoms of advanced disease

Hoarseness (recurrent laryngeal nerve involvement)
Difficulty swallowing
Superior vena cava (SVC) syndrome
Bone pain (bone metastasis)
Neurological deficits (brain metastasis)

~Diagnostic Evaluation

Evaluation of LSCC involves a multi-step approach combining imaging, laboratory testing, and tissue biopsy.

A. Imaging Studies

1. Chest X-ray

May reveal central lung masses or collapse.
Often the first test but not definitive.

2. CT Scan (Chest and Upper Abdomen)

Most important imaging test.
Identifies tumor size, lymph nodes, cavitation, metastasis.

3. PET-CT Scan

Helps in accurate staging.
Detects metabolically active disease.

4. MRI Brain

Recommended for stage II–IV to rule out brain metastasis.

B. Bronchoscopy

The preferred method to visualize the central lesion, obtain:

Biopsy samples
Brushings
Washings

C. Histopathology

Microscopic features include:

Keratin pearls
Intercellular bridges
High keratin content

Immunohistochemistry:

Positive for p40, p63, CK5/6
Helps differentiate from adenocarcinoma (TTF-1 negative)

D. Molecular testing

Less extensive than in adenocarcinoma, but testing may include:

PD-L1 levels (to guide immunotherapy)
FGFR1 amplification

~Staging (TNM Classification)

Staging determines treatment approach and prognosis.
The tumor is staged using the TNM system:

T (Tumor size and extent)
N (Lymph node involvement)
M (Distant metastasis)

Stages range from:

Stage I (localized)
Stage II (local + lymph nodes)
Stage III (locally advanced)
Stage IV (metastatic)

Most LSCC cases are diagnosed at stage II or later, partly due to delayed symptoms and late healthcare seeking.

~Treatment Options

Treatment depends on the stage, patient fitness, molecular profile, and comorbidities.

A. Surgery

Suitable for early-stage (I or II) and select stage III tumors.
Procedures include:

Lobectomy (most common)
Pneumonectomy
Segmentectomy or wedge resection (selected cases)

Surgery may be combined with chemotherapy or radiation.

B. Radiation Therapy

1. External Beam Radiation Therapy (EBRT)

Used for:

Non-resectable tumors
Medically unfit patients
Combined chemoradiation in stage III
Palliative management

2. Stereotactic Body Radiation Therapy (SBRT)

Preferred for:

Small, localized tumors in non-operable patients

C. Chemotherapy

Used in:

Stage II and III (adjuvant or neoadjuvant)
Stage IV (palliative)

Common regimens:

Cisplatin + gemcitabine
Cisplatin + docetaxel
Carboplatin-based combinations

D. Immunotherapy

A major breakthrough for LSCC, especially in advanced disease.

PD-1/PD-L1 inhibitors

Pembrolizumab
Nivolumab
Cemiplimab
Atezolizumab

These agents significantly improve survival in metastatic LSCC, especially in tumors with high PD-L1 expression.

E. Targeted Therapy

Limited due to fewer actionable mutations.
Research is ongoing for:

FGFR1 inhibitors
PI3K pathway inhibitors

F. Palliative and Supportive Care

Important for advanced disease to manage:

Pain
Breathing difficulty
Cough
Hypercalcemia
Infection

~Prognosis

Prognosis depends on stage, tumor biology, and response to therapy.

5-year survival rates

Approximate estimates:

Stage I: 50–70%
Stage II: 30–50%
Stage III: 10–25%
Stage IV: <5%

Immunotherapy has improved outcomes significantly in stage III–IV.

Factors associated with poorer prognosis

Late-stage diagnosis
Large tumor size
Nodal involvement
High tumor grade
Comorbid COPD or heart disease
Continued smoking

~Prevention Strategies

1. Smoking cessation

The most important preventive measure:

Quitting smoking dramatically reduces risk.
Even long-term heavy smokers benefit from cessation.

2. Avoid exposure to carcinogens

Occupational safety measures
Reduce radon exposure
Control air pollution

3. Healthy lifestyle

Balanced diet
Regular exercise
Avoiding heavy alcohol use

4. Screening

Low-dose CT (LDCT) screening is recommended for:

Adults aged 50–80
With a 20 pack-year smoking history
Current smokers or those who quit within 15 years

Screening can significantly reduce lung cancer mortality.

~Conclusion

Lung Squamous Cell Carcinoma remains a formidable health burden, strongly linked to tobacco smoking and environmental exposures. Although advancements in imaging, pathology, and treatment—especially immunotherapy—have improved clinical outcomes, LSCC continues to have high morbidity and mortality due to late diagnosis and limited targeted therapy options.

The keys to combating LSCC lie in:

Prevention, especially smoking cessation
Early detection through screening
Timely treatment using a multimodal approach
Continuous research to expand targeted therapy opportunities

As global awareness increases and healthcare access improves, the future holds promise for better outcomes and survival in patients suffering from this aggressive form of lung cancer.

Tuesday, December 2, 2025