Non-small-cell lung cancer
Non-small-cell lung cancer, or non-small-cell lung carcinoma, is a type of epithelial lung cancer other than small-cell lung cancer. Non-small-cell lung cancer accounts for about 85% of all lung cancers. As a class, non-small-cell lung cancers 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 preoperatively and postoperatively.
Types
The most common types of non-small-cell lung cancer are squamous-cell carcinoma, large-cell carcinoma, and adenocarcinoma, but several other types occur less frequently. A few of the less common types are pleomorphic, carcinoid tumor, salivary gland carcinoma, and unclassified carcinoma. All types can occur in unusual histologic variants and as mixed cell-type combinations.Sometimes, the phrase "not otherwise specified" is used generically, usually when a more specific diagnosis cannot be made. This is most often the case when a pathologist examines a small number of malignant cells or tissue in a cytology or biopsy specimen.
Lung cancer in people who have never smoked is almost universally non-small-cell lung cancer, with a sizeable majority being adenocarcinoma.
On relatively rare occasions, malignant lung tumors are found to contain components of both small-cell lung cancer and non-small-cell lung cancer. In these cases, the tumors are classified as combined small-cell lung carcinoma, and are treated as "pure" SCLC.
Lung adenocarcinoma
Adenocarcinoma of the lung is currently the most common type of lung cancer in "never smokers". Adenocarcinomas account for about 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. Recent studies, though, 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
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 around 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". The relative risk increases to about 16 with a previous smoking duration of 30 to 40 years and roughly 22 with more than 40 years.Large-cell lung carcinoma
Large-cell lung carcinoma is a heterogeneous group of undifferentiated malignant neoplasms originating from transformed epithelial cells in the lung. Large-cell lung carcinomas have typically comprised around 10% of all non-small-cell lung cancers in the past, although newer diagnostic techniques seem to be reducing the incidence of diagnosis of "classic" large-cell lung carcinoma in favor of more poorly differentiated SCCs and adenocarcinomas. Large-cell lung carcinoma 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 another more specific histologic type of lung cancer. Large-cell lung carcinoma is differentiated from small-cell lung cancer primarily by the larger size of the anaplastic cells, a higher cytoplasmic-to-nuclear size ratio, and a lack of "salt-and-pepper" chromatin.Signs and symptoms
Many of the symptoms of non-small-cell lung cancer 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, hoarseness, shortness of breath, wheezing, chest pain, weight loss, and loss of appetite. 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 such as bronchitis or pneumonia. Signs of more advanced cases include bone pain, nervous-system changes, jaundice, lumps near the surface of the body, numbness of extremities due to Pancoast syndrome, and nausea, vomiting, and constipation brought on by hypercalcemia. 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.Screening guidelines
The United States Preventive Services Task Force guidelines for lung cancer screening include everyone aged 50 to 80 years of age with a 20 pack-year history of smoking and still currently are or quit within the past 15 years. The recommended age to commence screening was recently lowered to 50 instead of 55 along with the pack-year smoking history which was lowered from 30 to 20. The recommended method of screening is a low-dose computed tomography annually.Cause
Smoking is the leading risk factor for lung cancer. Cigarette smoke contains more than 6,000 components, many of which lead to DNA damage.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.
Genetics can also play a role as a family history of lung cancer can contribute to an increased risk of developing the disease. Furthermore, research has revealed specific chromosome regions associated with increased risks of developing lung cancer.
In general, DNA damage appears to be the primary underlying cause of cancer. Though most DNA damages are repairable, leftover unrepaired DNA damages from cigarette smoke are the likely cause of non-small-cell lung cancer.
DNA replication past unrepaired 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.
DNA repair deficiency in non-small-cell lung cancer
Deficiencies in DNA repair underlie many forms of cancer. If DNA repair is deficient, the frequency of unrepaired DNA damages increases, and these tend to cause inaccurate translesion synthesis leading to mutation. Furthermore, increased damage can elevate incomplete repair, leading to epigenetic alterations.Mutations in DNA repair genes occasionally occur in cancer, but 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 non-small-cell lung cancer. At least nine DNA repair genes that normally function in relatively accurate DNA repair pathways are often repressed by promoter hypermethylation in non-small-cell lung cancer. 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 in non-small-cell lung cancer.
| Gene | Frequency of hyper- methylation | DNA repair pathway | Ref. |
| NEIL1 | 42% | base excision repair | |
| WRN | 38% | homologous recombinational repair, nonhomologous end joining, base excision repair | |
| MGMT | 13%–64% | direct reversal | |
| ATM | 47% | homologous recombinational repair | |
| MLH1 | 48%–73% | mismatch repair | |
| MSH2 | 42%–63% | mismatch repair | |
| BRCA2 | 42% | homologous recombinational repair | |
| BRCA1 | 30% | homologous recombinational repair | |
| XRCC5 | 20% | nonhomologous end joining | |
| FEN1 | 100% hypomethylated | microhomology-mediated end joining |
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.
Staging
Staging is a formal procedure to determine how developed the cancer is, which determines treatment options.The American Joint Committee on Cancer and the International Union Against Cancer recommend TNM staging, using a uniform scheme for non-small-cell lung cancer, small-cell lung cancer, and bronchopulmonary carcinoid tumors. With TNM staging, the cancer is classified based on the size of the primary tumor and whether it has invaded adjacent structures, 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.
Several components of non-small-cell lung cancer staging then influence physicians' treatment strategies. The lung tumor itself is typically assessed both radiographically for overall size and by a pathologist under the microscope to identify specific genetic markers or to see if invasion into important structures within the chest has occurred. Next, the patient's nearby lymph nodes within the chest cavity, known as the mediastinum, are checked for disease involvement. Finally, the patient is evaluated for more distant sites of metastatic disease, most typically with brain imaging and or scans of the bones.