Non-Small Cell Lung Cancer (NSCLC) Pathophysiology

NSCLC has many risk factors; however, the single most important factor for any lung cancer development is smoking1,2. Smoking tobacco, including cigarettes, pipes and cigars, can result in an average tenfold increased lung cancer risk compared to lifetime nonsmokers (defined as those with <100 lifetime cigarettes)1. Despite former smokers having a persistent elevated cancer risk even years after quitting, smoking cessation results in decreased precancerous lesions as well as cancerous risk reduction.1

Other risk factors can come in the form of exposures, such as occupational and environmental.1,3 For those considered high-risk, screening with low-dose helical CT scanning is the only demonstrated modality altering mortality rates1, up to 20%2 (as opposed to chest x-ray and sputum cytology for screening).1 Screening is recommended for early diagnosis in asymptomatic patients at high risk;2 however, clinical features that may be present for symptomatic individuals include hemoptysis, malaise, weight loss, dyspnea, hoarseness, worsening cough or chest pain.1 Expert pathologic evaluation of biopsied tumor tissue is essential to the proper diagnosis of NSCLC, as it can be microscopically confused with small cell lung cancer (SCLC) and, thus, impact therapeutic approaches, including deterring potentially curative surgical intervention.1 Immunohistochemistry and electron microscopy are particularly useful adjuncts to classification via light microscopy.1

Classification of NSCLC

NSCLC has histological origins within pulmonary epithelial cells extending from the central bronchi to the terminal alveoli.1 Subtypes of NSCLC originate from differing lung cells;, however, these subtypes are categorized together as NSCLC since the diagnostic, staging, prognosis and therapeutic approaches can be similar.1,4

Lung cancer is broken down into two main classifications6 – NSCLC and SCLC, with >80% of cases falling within the NSCLC grouping2,4. Within the NSCLC category there exists two major types; nonsquamous and squamous-cell carcinoma2. Nonsquamous carcinoma is made up of two primary subtypes; adenocarcinoma and large-cell (undifferentiated) carcinoma.2

Adenocarcinoma is the most common lung cancer subtype within the United States2 (occurring in approximately 40% of cases),4 and is typically located in peripheral lung tissue4. Although this subtype is particularly associated with current or former smokers, is noted to be the most predominant histological subtype associated with the non-smoking population2,4. While females and younger patients tend to be more significantly affected, adenocarcinoma can be slow-growing compared to other lung-tumor types, increasing the likelihood of discovery before disease progression4. Alternatively, large-cell carcinoma is a fast-growing tumor type that can be located in any region of the lung with resultant rapid disease spread, hampering therapeutic efforts4.  While 10%-15% of lung cancers are attributed to this general subtype, several uncommon variants are recognized within large-cell histology.1,4  Pleomorphic, adenosquamous and sarcomatoid carcinomas are examples of “other” uncommon subtypes within the nonsquamous category.4,6

Squamous cell carcinoma is associated with 25%-30% of all lung cancers, with typical presentation of centrally located tumors near main bronchi.1,4  Historical smoking is often strongly associated with this particular subtype.1,4

Genetic mutation identification, particularly in the adenocarcinoma subtype, have been identified in the epidermal growth factor receptor (EGFR), mitogen-activated protein kinase (MAPK) and phosphatidylinositol 3-kinase (PI3K) signaling pathways.1 Mutations such as these can be related to therapeutic sensitivity or kinase inhibitor resistance, and have driven the development of molecularly targeted therapies to improve survival in metastatic disease.1

Genetic alterations can serve as predictive and prognostic biomarkers, which can respectively indicate therapeutic efficacy and survival independent of treatment.2 For instance, EGFR and ALK mutations are predominantly noted in the non-smoking population, with EGFR mutations strongly predicting an improved response rate and progression-free survival with EGFR inhibitors.1 Alternatively, KRAS and BRAF mutations are more commonly noted in current or former smokers,1 with KRAS serving as a prognostic indicator due to shorter survivals associated with the mutation.2


  1. National Cancer Institute. Non-Small Cell Lung Cancer Treatment (PDQ®) – Health Professional Version. Available at:  https://www.cancer.gov/types/lung/hp/non-small-cell-lung-treatment-pdq/#_4.  Accessed: July 8, 2019.
  2. Non-Small Cell Lung Cancer (NSCLC). NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines).  Version 5.2019 – June 7, 2019.  Available at:  https://www.nccn.org/professionals/physician_gls/pdf/nscl.pdf.  Accessed: July 8,, 2019.
  3. American Cancer Society. Non-Small Cell Lung Cancer Risk Factors. Available at: https://www.cancer.org/cancer/non-small-cell-lung-cancer/causes-risks-prevention/risk-factors.html. Accessed: July 8, 2019.
  4. American Cancer Society. About non-small cell lung cancer. Available at: https://www.cancer.org/cancer/non-small-cell-lung-cancer/about/what-is-non-small-cell-lung-cancer.html. Accessed: July 8, 2019.
  5. American Cancer Society. About small cell lung cancer. Available at: https://www.cancer.org/cancer/small-cell-lung-cancer/about.html. Accessed: July 8, 2019.
  6. National Cancer Institute. Surveillance, Epidemiology, and End Results Program.  Cancer Stat Facts: Lung and Bronchus Cancer.  Available at: https://seer.cancer.gov/statfacts/html/lungb.html.  Accessed: July 8, 2019.