Can non-small cell carcinoma (NSCLC) originate in the lung?

Non-Small Cell Lung Cancer Origin

Yes, non-small cell lung carcinoma (NSCLC) primarily originates in the lung, accounting for 80-85% of all lung cancers. 1

Types of Lung Cancer

Lung cancer is classified into two main categories:

1. Non-Small Cell Lung Cancer (NSCLC):

   • Accounts for 80-85% of all lung cancers 1
   • Main subtypes include:
     • Adenocarcinoma
     • Squamous cell carcinoma
     • Large cell carcinoma

2. Small Cell Lung Cancer (SCLC):

   • Accounts for 15-20% of lung cancers
   • Has been decreasing in frequency over the last two decades 1

Pathological Characteristics of NSCLC

NSCLC arises from the epithelial cells of the lung and has distinct pathological features:

• Adenocarcinoma:

  • Often presents as peripheral nodules
  • May show lepidic, acinar, papillary, micropapillary, or solid growth patterns 1
  • Frequently expresses TTF-1 (Thyroid Transcription Factor-1)

• Squamous Cell Carcinoma:

  • More often presents as central endobronchial lesions 2
  • Shows keratinization and intercellular bridges

• Large Cell Carcinoma:

  • Typically arises in the lung periphery 2
  • Lacks the definitive features of other subtypes

Molecular Characteristics

NSCLC is characterized by specific genetic alterations:

• Common Mutations:

  • EGFR mutations (more common in adenocarcinoma, never-smokers, women, and East Asian patients) 1
  • K-ras mutations (associated with poorer prognosis in adenocarcinomas) 3
  • ALK rearrangements
  • ROS1 rearrangements

• Chromosomal Abnormalities:

  • Loss of genetic material on chromosomes 3p, 11p, and 17p 2
  • Deletions or mutations in tumor suppressor genes such as rb and p53 2

Distinguishing NSCLC from SCLC

The distinction between NSCLC and SCLC is critical for treatment decisions:

• Morphologic Examination:

  • NSCLC cells: Larger with moderate cytoplasm, vesicular chromatin, and prominent nucleoli
  • SCLC cells: Small with scant cytoplasm, finely granular nuclear chromatin, nuclear molding, and chromatin smearing 4

• Immunohistochemistry:

  • TTF-1 is expressed in both NSCLC (especially adenocarcinoma) and SCLC, but at different rates
  • Neuroendocrine markers (chromogranin A, synaptophysin, CD56) are typically positive in SCLC but only in about 10% of NSCLC 1

Combined Histology

It's important to note that in some cases, tumors can show mixed histology:

• Up to 30% of specimens from patients with SCLC reveal areas of NSCLC differentiation (mainly large cell carcinoma) 1
• This finding suggests that pulmonary carcinogenesis occurs in a pluripotent stem cell capable of differentiation along divergent pathways 1

Clinical Implications

The distinction between NSCLC and SCLC is crucial because:

• NSCLC more frequently presents with localized disease at diagnosis
• NSCLC is more often amenable to surgical resection
• NSCLC typically responds less frequently to chemotherapy compared to SCLC 2
• Targeted therapies are available for specific molecular subtypes of NSCLC

Risk Factors

The primary risk factor for NSCLC is tobacco smoking, responsible for approximately 80% of cases 1. Other risk factors include:

• Exposure to asbestos, arsenic, radon, and polycyclic aromatic hydrocarbons
• Indoor air pollution (e.g., coal-fueled stoves and cooking fumes)
• Genetic predisposition

Non-smoking-associated lung cancer is increasingly recognized as a distinct entity with specific molecular characteristics, particularly in women and East Asian populations 1.