Non-small-cell lung carcinoma

Non-small-cell lung carcinoma
File:Squamous carcinoma lung cytology.gif
Micrograph of a squamous carcinoma, a type of non-small-cell lung carcinoma. FNA specimen. Pap stain.
Classification and external resources
ICD-9 162
MedlinePlus 007194
eMedicine med/1333
NCI Non-small-cell lung carcinoma
Patient UK Non-small-cell lung carcinoma
MeSH D002289

Non-small-cell lung carcinoma (NSCLC) is any type of epithelial lung cancer other than small cell lung carcinoma (SCLC). As a class, NSCLCs are relatively insensitive to chemotherapy, compared to small cell carcinoma. When possible, they are primarily treated by surgical resection with curative intent, although chemotherapy is increasingly being used both pre-operatively (neoadjuvant chemotherapy) and post-operatively (adjuvant chemotherapy).


File:Pie chart of lung cancers.svg
Pie chart showing incidences of non-small cell lung cancers as compared to small cell carcinoma shown at right, with fractions of smokers versus non-smokers shown for each type.[1]

The most common types of NSCLC are squamous cell carcinoma, large cell carcinoma, and adenocarcinoma, but there are several other types that occur less frequently, and all types can occur in unusual histologic variants and as mixed cell-type combinations.[2]

Sometimes the phrase "non-small-cell lung cancer" ("not otherwise specified", or NOS) is used generically, usually when a more specific diagnosis cannot be made. This is most often the case when a pathologist examines a small amount of malignant cells or tissue in a cytology or biopsy specimen.[2]

Lung cancer in never-smokers is almost universally NSCLC, with a sizeable majority being adenocarcinoma.[3]

On relatively rare occasions, malignant lung tumors are found to contain components of both SCLC and NSCLC. In these cases, the tumors should be classified as combined small cell lung carcinoma (c-SCLC),[4] and are (usually) treated like "pure" SCLC.[5]

Lung adenocarcinoma

Adenocarcinoma of the lung is currently the most common type of lung cancer in "never smokers" (lifelong non-smokers).[6] Adenocarcinomas account for approximately 40% of lung cancers. Historically, adenocarcinoma was more often seen peripherally in the lungs than small cell lung cancer and squamous cell lung cancer, both of which tended to be more often centrally located.[7][8] Interestingly, however, recent studies suggest that the "ratio of centrally-to-peripherally occurring" lesions may be converging toward unity for both adenocarcinoma and squamous cell carcinoma.

Squamous cell lung carcinoma

File:Ca bronchus.jpg
Photograph of a squamous-cell carcinoma. Tumour is on the left, obstructing the bronchus (lung). Beyond the tumour, the bronchus is inflamed and contains mucus.

Squamous cell carcinoma (SCC) of the lung is more common in men than in women. It is closely correlated with a history of tobacco smoking, more so than most other types of lung cancer. According to the Nurses' Health Study, the relative risk of SCC is approximately 5.5, both among those with a previous duration of smoking of 1 to 20 years, and those with 20 to 30 years, compared to never-smokers.[9] The relative risk increases to approximately 16 with a previous smoking duration of 30 to 40 years, and approximately 22 with more than 40 years.[9]

Large-cell lung carcinoma

Large cell lung carcinoma (LCLC) is a heterogeneous group of undifferentiated malignant neoplasms originating from transformed epithelial cells in the lung. LCLC's have typically comprised around 10% of all NSCLC in the past, although newer diagnostic techniques seem to be reducing the incidence of diagnosis of "classic" LCLC in favor of more poorly differentiated squamous cell carcinomas and adenocarcinomas.[10] LCLC is, in effect, a "diagnosis of exclusion", in that the tumor cells lack light microscopic characteristics that would classify the neoplasm as a small-cell carcinoma, squamous-cell carcinoma, adenocarcinoma, or other more specific histologic type of lung cancer. LCLC is differentiated from small cell lung carcinoma (SCLC) primarily by the larger size of the anaplastic cells, a higher cytoplasmic-to-nuclear size ratio, and a lack of "salt-and-pepper" chromatin.


Further information: Lung cancer staging

The American Joint Committee on Cancer (AJCC) and the International Union Against Cancer (UICC) recommend TNM staging, using a uniform scheme for non-small cell lung carcinoma, small-cell lung carcinoma and broncho-pulmonary carcinoid tumors.[11] AJCC has provided an accessible poster version of these copyrighted TNM descriptors to which readers are directed.[11] Extensive presentation of prognostic data for both 6th and 7th edition individual TNM descriptors and overall groups is available.[12]

There are several components of NSCLC staging which then influence physicians' treatment strategies.[13] The lung tumor itself is typically assessed both radiographically for overall size as well as by a pathologist under the microscope to identify specific genetic markers or to see if there has been invasion into important structures within the chest (e.g., bronchus or pleural cavity). Next, the patient's nearby lymph nodes within the chest cavity known as the mediastinum will be checked for disease involvement. Finally, the patient will be evaluated for more distant sites of metastatic disease, most typically with brain imaging and or scans of the bones.


More than one kind of treatment is often used, depending on the stage of the cancer, the individual's overall health, age, response to chemotherapy, and other factors such as the likely side effects of the treatment. After full staging, the NSCLC patient can typically be classified in one of three different categories: patients with early, non-metastatic disease (Stage I, II and select III tumors), patients with locally advanced disease confined to the thoracic cavity (e.g., large tumors, tumors involving critical chest structures or patients with positive mediastinal lymph nodes) or patients with distant metastasis outside of the thoracic cavity.

Early/non-metastatic NSCLC

NSCLCs are usually not very sensitive to chemotherapy[14] and/or radiation, so surgery remains the treatment of choice if patients are diagnosed at an early stage.[15] If patients have small, but inoperable tumors, they may undergo highly targeted, high intensity radiation therapy. New methods of giving radiation treatment allow doctors to be more accurate in treating lung cancers. This means less radiation affects nearby healthy tissues. New methods include Cyberknife and stereotactic body radiation therapy(SBRT). Certain patients deemed to be higher risk may also receive adjuvant (ancillary) chemotherapy after initial surgery or radiation therapy. There are a number of possible chemotherapy agents which can be selected however most will involve the platinum-based chemotherapy drug called cisplatin.

Other treatments are radiofrequency ablation[16] and chemoembolization.[17]

Advanced/metastatic NSCLC

A wide variety of chemotherapies options exist for used in advanced (metastatic) NSCLC.[18] These agents include both traditional chemotherapies like cisplatin which indiscriminately target all rapidly dividing cells as well as newer targeted agents which are more tailored to specific genetic aberrations found within a patient's tumor. At present there are two genetic markers which are routinely profiled in NSCLC tumors to guide further treatment decision making: mutations within EGFR and Anaplastic Lymphoma Kinase.[19] There are also a number of additional genetic markers which are known to be mutated within NSCLC and may impact treatment in the future, including BRAF (gene), HER2/neu and KRAS.

Roughly 10-35% of NSCLC patients will have drug sensitizing mutations of the EGFR.[19] The distribution of these mutations have been found to be race-dependent, with one study estimating that 10% of Caucasians but 50% of Asians will be found to have such tumor markers.[20] A number of different EGFR mutations have been discovered, however certain aberrations will result in hyperactive forms of the protein. Patients with these mutations are more likely to have adenocarcinoma histology and be non-smokers or light smokers. These patients have been shown to be sensitized to certain medications which block the EGFR protein known as tyrosine kinase inhibitors specifically, erlotinib, gefitinib or afatinib.[21]

ALK gene rearrangements

Up to 7% of NSCLC patients have EML4-ALK translocations or mutations in the ROS1 gene; these patients may benefit from ALK inhibitors which are now approved for this subset of patients.[22] Crizotinib gained FDA approval in August 2011 and is an inhibitor of several kinases, specifically ALK, ROS1 and MET. Crizotinib has been shown in clinical studies to have response rates of ~60% if patients are shown to have ALK positive disease.[15] Several studies have also shown that ALK mutations and EGFR activating mutations are typically mutually exclusive. Thus, it is not recommended for patients who fail crizotinib to be switched to an EGFR-targeted drug such as erlotinib.[15]

Other treatment options

NSCLC patients with advanced disease who are not found to have either EGFR or AKT mutations may receive bevacizumab which is a monoclonal antibody medication targeted against the vascular endothelial growth factor (VEGF). This is based on an Eastern Cooperative Oncology Group study which found that adding bevacizumab to carboplatin and paclitaxel chemotherapy for certain patents with recurrent or advanced non-small-cell lung cancer (stage IIIB or IV) may increase both overall survival and progression free survival.[23] The FDA also recently approved the anti-PD-1 agent nivolumab for advanced or metastatic squamous cell carcinoma.[24]


  1. Smokers defined as current or former smoker of more than 1 year of duration. See image page in Commons for percentages in numbers. Reference: Table 2 in: Kenfield, S A; Wei, E K; Stampfer, M J; Rosner, B A; Colditz, G A (2008). "Comparison of aspects of smoking among the four histological types of lung cancer". Tobacco Control 17 (3): 198–204. PMC 3044470. PMID 18390646. doi:10.1136/tc.2007.022582. 
  2. 2.0 2.1 "Non-small cell lung cancer treatment - National Cancer Institute". Retrieved 2008-10-19. 
  3. Hanna, Nasser (2007). "Lung Cancer in the Never Smoker Population". Hematology-Oncology. Medscape. 
  4. Travis, William D; Brambilla, Elisabeth; Muller-Hermelink, H Konrad et al., eds. (2004). Pathology and Genetics of Tumours of the Lung, Pleura, Thymus and Heart (PDF). World Health Organization Classification of Tumours. Lyon: IARC Press. ISBN 92-832-2418-3. Retrieved 27 March 2010. 
  5. Simon GR, Turrisi A (September 2007). "Management of small cell lung cancer: ACCP evidence-based clinical practice guidelines (2nd edition)". Chest 132 (3 Suppl): 324S–339S. PMID 17873178. doi:10.1378/chest.07-1385. 
  6. Subramanian, J.; Govindan, R. (2007). "Lung Cancer in Never Smokers: A Review". Journal of Clinical Oncology 25 (5): 561–70. PMID 17290066. doi:10.1200/JCO.2006.06.8015. 
  7. Mitchell, Richard Sheppard; Kumar, Vinay; Abbas, Abul K.; Fausto, Nelson. "morphology of adenocarcinoma". Robbins Basic Pathology (8th ed.). Philadelphia: Saunders. ISBN 1-4160-2973-7. [page needed]
  8. Travis, William D.; Travis, Lois B.; Devesa, Susan S. (1995). "Lung cancer". Cancer 75 (1 Suppl): 191–202. PMID 8000996. doi:10.1002/1097-0142(19950101)75:1+<191::AID-CNCR2820751307>3.0.CO;2-Y. 
  9. 9.0 9.1 Kenfield, S. A.; Wei, E. K.; Stampfer, M. J.; Rosner, B. A.; Colditz, G. A. (2008). "Comparison of aspects of smoking among the four histological types of lung cancer". Tobacco Control 17 (3): 198–204. PMC 3044470. PMID 18390646. doi:10.1136/tc.2007.022582.  edit
  10. Popper, H. H. (2011). "Large cell carcinoma of the lung – a vanishing entity?". Memo - Magazine of European Medical Oncology 4: 4–9. doi:10.1007/s12254-011-0245-8. 
  11. 11.0 11.1 "Cancer Staging Posters: Lung" (PDF). AJCC Cancer Staging (PDF) (7th ed.). 
  12. De la Guerra, A. "New TNM Classification for Lung Cancer. Part II: A review". Doctors Lounge Website. 
  13. "National Cancer Institute Non-Small Cell Lung Cancer Treatment (PDQ®)". Retrieved 12 May 2015. 
  14. Cotran, Ramzi S.; Kumar, Vinay; Fausto, Nelson; Nelso Fausto; Robbins, Stanley L.; Abbas, Abul K. (2005). Robbins and Cotran pathologic basis of disease. St. Louis MO: Elsevier Saunders. p. 759. ISBN 0-7216-0187-1. 
  15. 15.0 15.1 15.2 "NCCN Clinical Practice Guidelines for NSCLC" (PDF). Retrieved 12 May 2015. 
  16. "Radiofrequency Ablation (RFA) of Lung Tumors". Cancer News.  ]
  17. "Chemoembolisation". Cancer Research UK. 
  18. Lung Cancer online
  19. 19.0 19.1 "Molecular Profiling of Lung Cancer". Retrieved 12 May 2015. 
  20. Hirsch, FR; Bunn, PA (May 2009). "EGFR testing in lung cancer is ready for prime time.". The Lancet. Oncology 10 (5): 432–3. PMID 19410185. 
  21. Kris MG (October 2005). "How today's developments in the treatment of non-small cell lung cancer will change tomorrow's standards of care". Oncologist 10 (Suppl 2): 23–9. PMID 16272456. doi:10.1634/theoncologist.10-90002-23. 
  22. Farmer (2010). "Non-Small-Cell Lung Cancer Standards of Care Challenged by a Cornucopia of New Drugs". 
  23. Sandler, A; Gray, R; Perry, MC; Brahmer, J; Schiller, JH; Dowlati, A; Lilenbaum, R; Johnson, DH (14 December 2006). "Paclitaxel-carboplatin alone or with bevacizumab for non-small-cell lung cancer.". The New England journal of medicine 355 (24): 2542–50. PMID 17167137. 
  24. "FDA Approves Nivolumab for Lung Cancer". Retrieved 12 May 2015. 

External links