Non-small-cell lung carcinoma

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Non-small-cell lung carcinoma
Classification and external resources

Micrograph of a squamous carcinoma, a type of non-small-cell lung carcinoma. FNA specimen. Pap stain.
MedlinePlus 007194
eMedicine med/1333
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).

Types

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

Main article: Adenocarcinoma of the lung

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

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]

It most often arises centrally in larger bronchi, and while it often metastasizes to locoregional lymph nodes (particularly the hilar nodes) early in its course, it generally disseminates outside the thorax somewhat later than other major types of lung cancer. Large tumors may undergo central necrosis, resulting in cavitation. A squamous cell carcinoma is often preceded for years by squamous cell metaplasia or dysplasia in the respiratory epithelium of the bronchi, which later transforms to carcinoma in situ. In carcinoma in situ, atypical cells may be identified by cytologic smear test of sputum, bronchoalveolar lavage or samples from endobronchial brushings. However, squamous-cell carcinoma in situ is asymptomatic and undetectable on X-ray radiographs. Eventually, it becomes symptomatic, usually when the tumor mass begins to obstruct the lumen of a major bronchus, often producing distal atelectasis and infection. Simultaneously, the lesion invades into the surrounding pulmonary substance. On histopathology, these tumors range from well differentiated, showing keratin pearls and cell junctions, to anaplastic, with only minimal residual squamous cell features.[10]

Currently, four variants (papillary, small cell, clear cell, and basaloid) of squamous cell carcinoma of the lung are recognized. Of these variants, there is some evidence that the basaloid[11] and poorly differentiated small-cell variants [4] may have worse prognoses than "conventional" squamous cell carcinomas. The papillary variant occurs more frequently as a primarily superficial, endobronchial lesion, with a modestly better prognosis[4][12] Very little data is currently available on the clear cell variant of squamous cell carcinoma, and no consensus has been reached on the prognostic implications of clear cell changes in lung cancer.[13][14]

Recently, four mRNA expression subtypes (primitive, basal, secretory, and classical) were identified and validated within squamous cell carcinoma. The primitive subtype correlates with worse patient survival. These subtypes, defined by intrinsic expression differences, provide a possible foundation for improved patient prognosis and research into individualized therapies.[15]

Large-cell lung carcinoma

Main article: 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 between 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.[16] 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.

Staging

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.[17] AJCC has provided an accessible poster version of these copyrighted TNM descriptors to which readers are directed.[17] Extensive presentation of prognostic data for both 6th and 7th edition individual TNM descriptors and overall groups is available.[18]

Treatment

Main article: Treatment of lung cancer
See also: Lung cancer surgery

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.

Early/non-metastatic NSCLC

NSCLCs are usually not very sensitive to chemotherapy[19] and/or radiation, so surgery is the treatment of choice if diagnosed at an early stage, often with adjuvant (ancillary) chemotherapy involving cisplatin. Other treatment choices are chemotherapy, radiation therapy (radiotherapy), and targeted 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 radiosurgery (SRS).

Other treatments are radiofrequency ablation[20] and chemoembolization.[21]

Advanced/metastatic NSCLC

A wide variety of chemotherapies are used in advanced (metastatic) NSCLC.[22] Some patients with particular mutations in the EGFR gene respond to EGFR tyrosine kinase inhibitors such as gefitinib.[23]

ALK mutations

About 7% of NSCLC have EML4-ALK translocations; these may benefit from ALK inhibitors which are in clinical trials.[24] Crizotinib gained FDA approval in August 2011.

Research

NSCLC treatments in Phase II/III & Phase III Development as of June 2013[25]
Company NameProduct NamesDescriptionPartnersLatest Stage of Development
Transgene S.A.TG4010 (Compound #), MVA-MUC1-IL2 (Informal)Recombinant Modified Vaccinia Ankara (MVA) virus vector encoding the mucin 1 (MUC1; CD227) tumor-associated antigen and IL-2NovartisPhase II/III
Amgen Inc.AMG 706 (Compound #), motesanib diphosphate (Generic)Small molecule antagonist of VEGF receptors 1, 2 and 3, platelet derived growth factor receptor (PDGFR) and c-KitTakeda Pharmaceutical Co. Ltd.Phase III
Amgen Inc.Aranesp (Brand), Nesp (Brand), Nespo (Brand), KRN321 (Compound #), darbepoetin alfa (Generic), Aranesp (Informal), NESP (Other), novel erythropoiesis stimulating protein (NESP) (Other)Erythropoiesis stimulating proteinPhase III
ArQule Inc.ARQ 197 (Compound #), tivantinib (Generic)Small molecule inhibitor of c-Met receptor tyrosine kinase Daiichi Sankyo Co. Ltd.; Kyowa Hakko Kirin Co. Ltd.Phase III
Chong Kun Dang Pharmaceutical Corp.CKD-602 (Compound #), belotecan (Generic), Camtobell (Informal)Camptothecin analoguePhase III
Eisai Co. Ltd.Halaven (Brand), E7389 (Compound #), eribulin mesylate (Generic), Halaven (Other)Synthetic analog of halichondrin BPhase III
Eli Lilly and Co.IMC-1121B (Compound #), LY3009806 (Compound #), ramucirumab (Generic)Human IgG1 mAb VEGFR-2 antagonistPhase III
Eli Lilly and Co.IMC-11F8 (Compound #), LY3012211 (Compound #), necitumumab (Generic)Human IgG1 mAb against EGFRBristol-Myers Squibb Co.Phase III
GlaxoSmithKline plcGSK1572932A (Compound #), Lung cancer vaccine (Informal), MAGE-A3 Antigen-Specific Cancer Immunotherapeutic (ASCI) (Other)Cancer vaccine against MAGE-A3 antigenPhase III
OncoGenex Pharmaceuticals Inc.OGX-011 (Compound #), TV-1011 (Compound #), custirsen sodium (Generic)Second-generation antisense inhibitor of serum clusterin mRNAIsis Pharmaceuticals Inc.; Teva Pharmaceutical Industries Ltd.Phase III
Oncothyreon Inc.Stimuvax (Former), BLP25 liposome vaccine (Other), L-BLP25 (Other)Liposomal vaccine containing a synthetic 25 amino acid peptide sequence from mucin 1 (MUC1; CD227)Merck KGaA; Ono Pharmaceutical Co. Ltd.Phase III
Ono Pharmaceutical Co. Ltd.BMS-936558 (Compound #), MDX-1106 (Compound #), ONO-4538 (Compound #), nivolumab (Other)Human mAb against PD-1 receptor (PDCD1; PD-1; CD279) Bristol-Myers Squibb Co.Phase III
Ono Pharmaceutical Co. Ltd.EMD531444 (Compound #), ONO-7165 (Compound #)Peptide vaccine targeting polymorphic epithelial mucin (PEM; MUC-1)Merck KGaAPhase III
Pfizer Inc.PF-00299804 (Compound #), dacomitinib (Generic)Inhibitor of human EGFR1, EGFR2 and EGFR4SFJ Pharmaceuticals Inc.Phase III
Synta Pharmaceuticals Corp.STA-9090 (Former compound #), ganetespib (Generic)Small molecule heat shock protein 90 (Hsp90) inhibitorPhase III
Eli Lilly and Co.pemetrexedPARAMOUNT trialnonePhase III

References

  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. doi:10.1136/tc.2007.022582. PMC 3044470. PMID 18390646. 
  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. ↑ 4.0 4.1 4.2 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. 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. doi:10.1378/chest.07-1385. PMID 17873178. 
  6. ↑ Subramanian, J.; Govindan, R. (2007). "Lung Cancer in Never Smokers: A Review". Journal of Clinical Oncology 25 (5): 561–70. doi:10.1200/JCO.2006.06.8015. PMID 17290066. 
  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. 
  8. ↑ Travis, William D.; Travis, Lois B.; Devesa, Susan S. (1995). "Lung cancer". Cancer 75 (1 Suppl): 191–202. doi:10.1002/1097-0142(19950101)75:1+<191::AID-CNCR2820751307>3.0.CO;2-Y. PMID 8000996. 
  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. doi:10.1136/tc.2007.022582. PMC 3044470. PMID 18390646. 
  10. ↑ Entire section, if not else specified, is taken from Mitchell, Richard Sheppard; Kumar, Vinay; Abbas, Abul K.; Fausto, Nelson. "Ch. 13, box on morphology of squamous cell carcinoma". Robbins Basic Pathology (8th ed.). Philadelphia: Saunders. ISBN 1-4160-2973-7. 
  11. ↑ Wang, LC; Wang, L; Kwauk, S; Woo, JA; Wu, LQ; Zhu, H; Zhan, LZ; Sun, NL et al. (2011). "Analysis on the clinical features of 22 basaloid squamous cell carcinoma of the lung". Journal of Cardiothoracic Surgery 6: 10. doi:10.1186/1749-8090-6-10. PMC 3037842. PMID 21269455. 
  12. ↑ Dulmet-Brender E, Jaubert F, Huchon G (April 1986). "Exophytic endobronchial epidermoid carcinoma". Cancer 57 (7): 1358–64. doi:10.1002/1097-0142(19860401)57:7<1358::AID-CNCR2820570719>3.0.CO;2-B. PMID 3948117. 
  13. ↑ Kitada M, Ozawa K, Sato K, Hayashi S, Miyokawa N, Sasajima T (February 2010). "Clear cell carcinoma of the lung". Gen Thorac Cardiovasc Surg 58 (2): 87–90. doi:10.1007/s11748-009-0471-8. PMID 20155345. , which are usually due to increased levels of intracellular glycogen (or, rarely, biotin).
  14. ↑ Garzon, JC; Lai, FM; Mok, TS; Manlulu, AV; Ng, CS; Lee, TW; Yim, AP (2005). "Clear cell carcinoma of the lung revisited". The Journal of thoracic and cardiovascular surgery 130 (4): 1198–9. doi:10.1016/j.jtcvs.2005.04.030. PMID 16214540. 
  15. ↑ Wilkerson, MD; Yin, X; Hoadley, KA; Liu, Y; Hayward, MC; Cabanski, CR; Muldrew, K; Miller, CR; Randell, SH; Socinski, M. A.; Parsons, A. M.; Funkhouser, W. K.; Lee, C. B.; Roberts, P. J.; Thorne, L.; Bernard, P. S.; Perou, C. M.; Hayes, D. N. (2010). "Lung squamous cell carcinoma mRNA expression subtypes are reproducible, clinically important, and correspond to normal cell types". Clinical cancer research : an official journal of the American Association for Cancer Research 16 (19): 4864–75. doi:10.1158/1078-0432.CCR-10-0199. PMC 2953768. PMID 20643781. 
  16. ↑ 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. 
  17. ↑ 17.0 17.1 "Cancer Staging Posters: Lung" (PDF). AJCC Cancer Staging (7th ed.). 
  18. ↑ De la Guerra, A. "New TNM Classification for Lung Cancer. Part II: A review". Doctors Lounge Website. 
  19. ↑ 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. 
  20. ↑ "Radiofrequency Ablation (RFA) of Lung Tumors". Cancer News.  ]
  21. ↑ "Chemoembolisation". Cancer Research UK. 
  22. ↑ Lung Cancer online
  23. ↑ 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. doi:10.1634/theoncologist.10-90002-23. PMID 16272456. 
  24. ↑ Farmer (2010). "Non-Small-Cell Lung Cancer Standards of Care Challenged by a Cornucopia of New Drugs". 
  25. ↑ http://www.biocentury.com/BCIQ

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