Non-small-cell lung carcinoma

Non-small-cell lung carcinoma (NSCLC) is any type of epithelial lung cancer other than small cell lung carcinoma (SCLC). NSCLC accounts for about 85% of all lung cancers.[1][2] 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 has been used increasingly both pre-operatively (neoadjuvant chemotherapy) and post-operatively (adjuvant chemotherapy).

Non-small-cell lung carcinoma
Micrograph of a squamous carcinoma, a type of non-small-cell lung carcinoma. FNA specimen. Pap stain.
SpecialtyOncology 

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.[3]

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. A few of the less common types are pleomorphic, carcinoid tumor, salivary gland carcinoma, and unclassified carcinoma.[4] All types can occur in unusual histologic variants and as mixed cell-type combinations.[5] Non-squamous cell carcinoma almost occupy the half of NSCLC. In the tissue classification, the central type contains about one-ninth.

Sometimes the phrase "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.[5]

Lung cancer in people who have never smoked is almost universally NSCLC, with a sizeable majority being adenocarcinoma.[6]

On relatively rare occasions, malignant lung tumors are found to contain components of both SCLC and NSCLC. In these cases, the tumors are classified as combined small cell lung carcinoma (c-SCLC),[7] and are (usually) treated like "pure" SCLC.[8]

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).[9] 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.[10][11] 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" (lifelong non-smokers).[12] 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.[12]

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 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.[13] 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.

Symptoms

Many of the symptoms of NSCLC can be signs of other diseases, but having chronic or overlapping symptoms may be a signal of the presence of the disease. Some symptoms are indicators of less advanced cases while some may signal that the cancer has spread. Some of the symptoms of less advanced cancer include chronic cough, coughing up blood, chest pain, hoarseness, shortness of breath, wheezing, chest pain, weight loss, and loss of appetite.[14] A few more symptoms associated with the early progression of the disease are feeling weak, being very tired, having trouble swallowing, swelling in the face or neck, and continuous or recurring infections like bronchitis or pneumonia.[4][14][15] Signs of more advanced cases include bone pain, nervous system changes (headache, weakness, dizziness, balance problems, seizures), jaundice, lumps near the surface of the body, numbness of extremities due to Pancoast Syndrome, and nausea, vomiting and constipation brought on by hypercalcemia.[14][15] Some more of the symptoms that indicate further progression of the cancer include shortness of breath, superior vena cava syndrome, trouble swallowing, large amounts of mucus, weakness, fatigue, and hoarseness.[15]

Cause

Smoking is by far the leading risk factor for lung cancer.[16] Cigarette smoke contains more than 6,000 components, many of which lead to DNA damage[17] (see table of tobacco-related DNA damages in Tobacco smoking).

Other causes include radon, exposure to secondhand smoke, exposure to substances such as asbestos, chromium, nickel, beryllium, soot, or tar, family history of lung cancer, and air pollution.[4][16]

In general, DNA damage appears to be the primary underlying cause of cancer.[18] Though most DNA damages are repairable,[17] leftover un-repaired DNA damages from cigarette smoke are the likely cause of NSCLC.

DNA replication past an un-repaired damage can give rise to a mutation because of inaccurate translesion synthesis. In addition, during repair of DNA double-strand breaks, or repair of other DNA damages, incompletely cleared sites of repair can lead to epigenetic gene silencing.[19][20]

DNA repair deficiency in NSCLC

Deficiencies in DNA repair underlie many forms of cancer.[21] If DNA repair is deficient, the frequency of un-repaired DNA damages will increase and these will tend to cause inaccurate translesion synthesis leading to mutation. Furthermore, increased damages can elevate incomplete repair, leading to epigenetic alterations.

As indicated as in the article Carcinogenesis, mutations in DNA repair genes occasionally occur in cancer. However, deficiencies of DNA repair due to epigenetic alterations that reduce or silence DNA repair gene expression occur much more frequently in cancer.

Epigenetic gene silencing of DNA repair genes occurs frequently in NSCLC. At least nine DNA repair genes that normally function in relatively accurate DNA repair pathways are often repressed by promoter hypermethylation in NSCLC (see table). One DNA repair gene, FEN1, that functions in an inaccurate DNA repair pathway, is expressed at an increased level due to hypo-, rather than hyper-, methylation of its promoter region (deficiency of promoter methylation) in NSCLC (see table).

Epigenetic promoter methylation in DNA repair genes in NSCLC
Gene Frequency of hyper- (or hypo-) methylation DNA repair pathway Ref.
NEIL1 42% base excision repair [22]
WRN 38% homologous recombinational repair, non-homologous end joining, base excision repair [23]
MGMT 13% - 64% direct reversal [22][24][25]
ATM 47% homologous recombinational repair [26]
MLH1 48% - 73% mismatch repair [26][27]
MSH2 42% - 63% mismatch repair [26][27]
BRCA2 42% homologous recombinational repair [28]
BRCA1 30% homologous recombinational repair [28]
XRCC5 (Ku80) 20% non-homologous end joining [28]
FEN1 100% hypomethylated (increased expression) microhomology-mediated end joining [29]

The frequent deficiencies in accurate DNA repair, and the increase in inaccurate repair, likely cause the high level of mutation in lung cancer cells of more than 100,000 mutations per genome (see Whole genome sequencing).

Staging

Staging is a formal procedure to determine how developed the cancer is. This determines treatment options.

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.[30] With TNM staging, the cancer is classified based on the size of the tumor and spread to lymph nodes and other organs. As the tumor grows in size and the areas affected become larger, the staging of the cancer becomes more advanced as well.

There are several components of NSCLC staging which then influence physicians' treatment strategies.[31] 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.[32]

Five-year survival rates

The survival rates for stages I through IV decrease significantly due to the advancement of the disease. For stage I, the five-year survival rate is 47%, stage II is 30%, stage III is 10%, and stage IV is 1%.[33]

Further information: Lung cancer staging

Treatment
Main article: Treatment of lung cancer

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[34] and/or radiation, so surgery (lung resection to remove the tumor), remains the treatment of choice if patients are diagnosed at an early stage.[35]

If the person has a small, but inoperable tumor, 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 people that are 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 include percutaneous ablation and chemoembolization.[36] The most widely used ablation techniques for lung cancer are radiofrequency ablation, cryoablation, and microwave ablation.[37] Ablation may be an option for patients whose tumors are near the outer edge of the lungs. Nodules less than 1 cm from the trachea, main bronchi, oesophagus and central vessels should be excluded from RFA given high risk of complications and frequent incomplete ablation. Additionally, lesions greater than 5 cm should be excluded and lesions 3 to 5 cm should be considered with caution given high risk of recurrence.[38] As a minimally invasive procedure, it can be a safer alternative for patients who are poor candidates for surgery due to co-morbidities or limited lung function. A study comparing thermal ablation to sublobar resection as treatment for early stage NSCLC in older people found no difference in overall survival of the patients.[39] It is possible that RFA followed by radiation therapy has a survival benefit due to synergism of the two mechanisms of cell destruction.[40]

Advanced/metastatic NSCLC

The treatment approach for people who have advanced NSCLC is first aimed at relieving pain and distress (palliative), however a wide variety of chemotherapy options exist.[41][42] 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 person's tumor. When choosing an appropriate chemotherapy approach, the toxicity profile (side effects of the drug) should be taken into account and balanced with the person's comorbidities (other conditions or side effects that the person is experiencing).[42] Carboplatin is a chemotherapy agent that has a similar effect on a person's survival when compared to cisplatin, and has a different toxicity profile from cisplatin.[42]

At present there are two genetic markers which are routinely profiled in NSCLC tumors to guide further treatment decision making: mutations within epidermal growth factor (EGFR) and Anaplastic Lymphoma Kinase.[43] 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. For advanced NSCLC, a combined chemotherapy treatment approach that includes cetuximab, an antibody that targets the EGFR signalling pathway, is more effective at improving a person's overall survival when compared to standard chemotherapy alone.[44]

Thermal ablations i.e. radiofrequency ablation, cryoablation, microwave ablation are appropriate for palliative treatment of tumor-related symptoms or recurrences within treatment fields. People with severe pulmonary fibrosis and severe emphysema with a life expectancy <1 year should be considered poor candidates for this treatment.[45]

EGFR mutations

Roughly 10–35% of people who have NSCLC will have drug sensitizing mutations of the EGFR.[43] 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.[46] A number of different EGFR mutations have been discovered, however certain aberrations will result in hyperactive forms of the protein. People with these mutations are more likely to have adenocarcinoma histology and be non-smokers or light smokers. These people have been shown to be sensitized to certain medications which block the EGFR protein known as tyrosine kinase inhibitors specifically, erlotinib, gefitinib, afatinib or osimertinib.[47] Reliable identification of mutations in lung cancer needs careful consideration due to the variable sensitivity of diagnostic techniques.[48]

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.[49] 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.[35] 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.[35]

Other treatment options
Micrograph showing a PD-L1 positive non-small cell lung carcinoma. PD-L1 immunostain.

NSCLC patients with advanced disease who are not found to have either EGFR or ALK 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 patients with recurrent or advanced non-small-cell lung cancer (stage IIIB or IV) may increase both overall survival and progression free survival.[50]

In 2015 the US FDA approved the anti-PD-1 agent nivolumab for advanced or metastatic squamous cell carcinoma.

October 2, 2015, the FDA approved pembrolizumab for the treatment of metastatic non-small cell lung cancer (NSCLC) in patients whose tumors express PD-L1 and who have failed treatment with other chemotherapeutic agents.

October 2016, pembrolizumab became the first immunotherapy to be used first line in the treatment of NSCLC if the cancer overexpresses PDL1 and the cancer has no mutations in EGFR or in ALK; if chemotherapy has already been administered, then pembrolizumab can be used as a second line treatment but if the cancer has EGFR or ALK mutations, agents targeting those mutations should be used first. Assessment of PDL1 must be conducted with a validated and approved companion diagnostic.

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Classification
External resources

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