What is the definition, etiology, pathophysiology, diagnosis, and comprehensive treatment plan for lung cancer, including radiology and blood reports analysis?

Lung Cancer: Comprehensive Clinical Overview

Definition

Lung cancer is a malignant epithelial neoplasm arising from the respiratory tract, classified into two major histologic categories: non-small cell lung carcinoma (NSCLC) representing 85-90% of cases, and small cell lung carcinoma (SCLC) representing 13-20% of cases. 1, 2 NSCLC is further subdivided into adenocarcinoma (approximately 40-47% of all lung cancers), squamous cell carcinoma (approximately 30%), and large cell carcinoma (5-10%). 3, 1, 2

Etiology

Primary Risk Factors

• Cigarette smoking causes approximately 80-90% of all lung cancer cases, with SCLC demonstrating virtually 100% attribution to smoking. 3, 2, 4
• All four major histological types are caused by cigarette smoking but with varying strength of association, with squamous cell carcinoma and SCLC showing the strongest correlation. 3
• Asbestos exposure confers a mean relative risk of 1.59 for lung cancer development. 3
• Residential radon demonstrates a linear relationship with lung cancer risk (RR 1.14,95% CI 1.0-1.3). 3
• Environmental factors including air pollution and chronic infections contribute to carcinogenesis. 4, 5

Cellular Susceptibility Patterns

• Squamous bronchial epithelial cells are most susceptible to dysplasia in smokers, arising from bronchogenic squamous metaplasia and dysplasia. 3, 6
• Peripheral alveolar cells are more susceptible in those exposed to radon and other environmental carcinogens, with adenocarcinoma typically presenting as peripheral lesions. 3, 1

Pathophysiology

Molecular Mechanisms

Lung cancer results from molecular deregulation of pathways controlling normal cellular growth, differentiation, and apoptosis, involving mutations in proto-oncogenes and tumor suppressor genes. 5 The pathogenesis involves:

• Progressive accumulation of genetic alterations in epithelial cells 5
• Deregulation of cell cycle control mechanisms 5
• Loss of apoptotic pathways 5
• Activation of angiogenic pathways 6

Histologic Progression

• Squamous cell carcinomas arise in bronchogenic squamous metaplasia and squamous dysplasia, showing infiltrative growth patterns with retraction of visceral pleura. 6
• Adenocarcinomas tend to present peripherally, show retraction or invasion of visceral pleura, and are associated with tumor desmoplasia or scar. 6
• Preinvasive lesions include squamous dysplasia, carcinoma in situ, and atypical adenomatous hyperplasia (AAH). 3

Diagnosis

Clinical Presentation

The most common but nonspecific symptom is cough, with associated hemoptysis, shortness of breath, anorexia, or weight loss greatly increasing likelihood of lung cancer. 7 Presentation varies by tumor type:

• Squamous cell carcinomas present as near-hilar masses in cigarette smokers with COPD and chronic bronchitis. 3
• Adenocarcinomas present peripherally, more common in never-smokers and women. 1
• SCLC presents with metastatic disease in approximately 66-70% of patients at diagnosis. 1

Pathologic Diagnostic Criteria

Synoptic reporting of histologic type, tumor size and location, tumor grade (if appropriate), lymphovascular invasion, pleural involvement, surgical margins, and status and location of lymph nodes by station is recommended (Grade 1B). 6

Critical Pathologic Distinctions

For parenchymal-based tumors, distinguishing between small cell carcinoma and non-small cell carcinoma is recommended, with diagnostic immunohistochemical panels or ultrastructural analysis for challenging cases (Grade 1B). 6

For pathologically diagnosed NSCLC, additional discrimination between adenocarcinoma and squamous cell carcinoma, even on cytologic material or small tissue samples, is recommended (Grade 1B). 6

Immunohistochemical Panels

A minimal panel of p40 and TTF-1 is recommended for distinguishing squamous cell carcinoma from adenocarcinoma, with p40 (DNp63) showing superior sensitivity and specificity reaching 100%. 6

• TTF-1 and/or napsin A immunoreactivity support adenocarcinoma diagnosis 6
• p40 favors squamous cell carcinoma with superior specificity over p63 6
• Mucin stains (mucicarmine or PAS with/without diastase) reveal intracytoplasmic vacuoles indicative of glandular expression 6

For pleural-based tumors, a designated limited panel of histochemical and immunohistochemical assays or ultrastructural analysis is recommended to distinguish pleural adenocarcinoma from malignant mesothelioma (Grade 1B). 6

For lung tumors with differential including primary versus metastatic carcinoma, a directed panel of immunohistochemical assays is recommended (Grade 1C). 6

• Primary lung adenocarcinomas are typically TTF-1 positive, CK7 positive, and CK20 negative 6
• Colorectal adenocarcinomas are TTF-1 negative, CK7 negative, CK20 positive, and CDX-2 positive 6

Tissue Acquisition Methods

Histologic diagnosis may be obtained through: 8

• Sputum cytology 8
• Thoracentesis 8
• Accessible lymph node biopsy 8
• Bronchoscopy 8
• Transthoracic needle aspiration 8
• Video-assisted thoracoscopy 8
• Thoracotomy 8

Staging Evaluation

Initial evaluation for metastatic disease relies on patient history and physical examination, laboratory tests, chest computed tomography, positron emission tomography, and tissue confirmation of mediastinal involvement. 8 Macroscopic and microscopic examination provides diagnostic and prognostic staging information regarding tumor size, location, visceral pleura permeation, lymphovascular and perineural invasion, and spread to hilar and mediastinal lymph nodes. 6

Radiology Analysis

Imaging Characteristics by Histology

• Squamous cell carcinomas typically present as near-hilar masses with associated COPD and emphysematous changes on imaging. 6
• Adenocarcinomas present as peripheral lesions with retraction or invasion of visceral pleura. 6
• Metastatic tumors show more expansile growth rather than infiltrative growth with adjacent lung retraction. 6

Screening Recommendations

Annual lung cancer screening using low-dose computed tomography starting at 50 years of age in patients with a 20 pack-year smoking history is recommended. 7

Blood Reports Analysis

While the provided guidelines focus primarily on histopathologic diagnosis, blood work evaluation includes:

• Laboratory tests as part of initial metastatic disease evaluation 8
• Functional patient evaluation parameters 8
• Assessment for systemic manifestations (anorexia, weight loss) 7

Note: Specific tumor markers and molecular biomarker testing (EGFR, ALK, PD-L1) are essential for treatment planning but are detailed in separate molecular biology guidelines. 6, 9

Comprehensive Treatment Plan

Treatment Algorithm by Stage and Histology

Non-Small Cell Lung Cancer (NSCLC)

For stages I through IIIA NSCLC, surgical resection is preferred. 8

For resectable NSCLC (tumors ≥4 cm or node positive), combination platinum-containing chemotherapy with pembrolizumab as neoadjuvant treatment, followed by single-agent pembrolizumab as adjuvant treatment after surgery is indicated. 9

For Stage IB (T2a ≥4 cm), II, or IIIA NSCLC, single-agent pembrolizumab as adjuvant treatment following resection and platinum-based chemotherapy is indicated. 9

For metastatic nonsquamous NSCLC with no EGFR or ALK genomic tumor aberrations, pembrolizumab in combination with pemetrexed and platinum chemotherapy as first-line treatment is indicated. 9

For metastatic squamous NSCLC, pembrolizumab in combination with carboplatin and either paclitaxel or paclitaxel protein-bound as first-line treatment is indicated. 9

For Stage III NSCLC where patients are not candidates for surgical resection or definitive chemoradiation, or metastatic NSCLC with PD-L1 TPS ≥1%, no EGFR or ALK genomic tumor aberrations, single-agent pembrolizumab as first-line treatment is indicated. 9

For metastatic NSCLC with PD-L1 TPS ≥1% and disease progression on or after platinum-containing chemotherapy, single-agent pembrolizumab is indicated (patients with EGFR or ALK genomic tumor aberrations should have disease progression on FDA-approved therapy for these aberrations prior to receiving pembrolizumab). 9

Advanced NSCLC is treated with a multimodality approach that may include radiotherapy, chemotherapy, and palliative care. 8

Small Cell Lung Cancer (SCLC)

Chemotherapy combined with radiotherapy for limited disease is the mainstay of treatment for SCLC. 8 SCLC is classified into limited stage (typically TNM stage I-III) and extensive stage (TNM stage IV or tumor/nodal volume too extensive for tolerable radiation planning). 1

Treatment Modalities

Available treatment options include: 4, 8

• Surgical resection 4, 8
• Radiation therapy 4, 8
• Chemotherapy 4, 8
• Targeted therapy 4, 8
• Immunotherapy 9, 10

Treatment recommendations depend on type and stage of cancer, with responses to current standard therapies being poor except for the most localized cancers. 4

Critical Treatment Considerations

Tissue preservation for molecular studies requires an algorithmic approach to maximize efficiency of immunohistochemical assays and minimize tissue utilization. 6 This is essential because molecular biomarker testing determines eligibility for targeted therapies and immunotherapy. 9

Referral to a multidisciplinary lung cancer team is recommended for optimal treatment planning. 7

Prognosis

• Overall 5-year survival rate for lung cancer is approximately 25.4% 2
• Adenocarcinoma has a 32.2% 5-year survival rate 2
• Positive resection margins are a significant indicator for tumor recurrence and decreased survival 6

Common Pitfalls and Caveats

Diagnostic Pitfalls

• The designation of "carcinoma not otherwise specified" or "non-small cell carcinoma" should only be rendered in a minority of cases, as precise subclassification is critical for treatment decisions. 6
• Pathologic discrimination among adenocarcinoma in situ, minimally invasive adenocarcinoma, and invasive adenocarcinoma must be made on complete review of the tumor and not on needle biopsies. 6
• In small samples where tumor lacks histologic hallmarks of glandular or squamous differentiation, immunohistochemical panels are essential for accurate diagnosis. 6
• Distinguishing primary lung cancer from metastatic disease requires clinical history, radiographic correlation, and directed immunohistochemical panels. 6

Treatment Pitfalls

• Patients with EGFR or ALK genomic tumor aberrations must have disease progression on FDA-approved therapy for these aberrations prior to receiving pembrolizumab. 9
• PD-L1 testing using an FDA-approved test is required for determining eligibility for single-agent pembrolizumab in specific clinical scenarios. 9