Pulmonary fibrosis: Symptoms, treatment, and outlook

What Is Non-Small Cell Lung Cancer?

Medically reviewed by Susan Russell, MD

Lung cancer is an abnormal growth of cells in the lungs. These abnormal cells form tumors that damage the normal functioning of the lungs. Most lung cancer cases are non-small cell lung cancer (NSCLC), which can affect different types of cells in the lungs and airways.

Without treatment, non-small cell lung cancer can spread throughout the body, causing damage to other organ systems. This article will review the types of non-small cell lung cancer, how it is diagnosed, and its treatment options.

Types of Non-Small Cell Lung Cancer

Non-small cell lung cancer makes up approximately 85% of all lung cancer cases. It is subdivided into three main types, depending on the type of cells that the cancer affects, as follows:

Adenocarcinoma: This is the most common type of lung cancer, making up approximately 40% of all cases. It occurs in small cells located in the alveoli (air sacs) at the periphery of the lungs. Adenocarcinoma grows slowly and is more likely to be discovered before spreading to other areas of the body outside of the lungs. It can affect smokers and nonsmokers alike.

Squamous cell carcinoma of the lungs: This type of lung cancer makes up approximately 25% to 30% of all cases. It affects the squamous cells of the bronchi, the main airways that branch from the trachea (windpipe). Squamous cell carcinoma is very common among smokers.

Large cell carcinoma: A less common type of lung cancer, it makes up approximately 5% to 10% of cases. It affects the central portions of the lungs. It may spread into the chest, nearby lymph nodes, or other organs. It grows and spreads quickly.

Non-Small Cell Lung Cancer Symptoms

Symptoms of non-small cell lung cancer can relate to changes in your lungs, airways, and other body systems. Sometimes non-small cell lung cancer does not produce any noticeable signs and symptoms.

When asymptomatic, lung cancer may be detected through a chest X-ray if you have one done in diagnosing other conditions. For people at high risk (based on their age and smoking history), low-dose computed tomography (LDCT) imaging is now recommended for screening for lung cancer.

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Early Signs

Early signs of non-small cell lung cancer, if present, often include shortness of breath and a cough that does not go away. The growth of cancer cells within the lungs and airways affects your ability to breathe, making it difficult to get air in and out of the lungs effectively. This can also result in:

Symptoms After Spread

As lung cancer spreads to other parts of the body, symptoms start to involve your entire body. You may experience such systemic symptoms as:

Non-Small Cell vs. Small Cell Lung Cancer

The two main types of lung cancer are small cell lung cancer (SCLC) and non-small cell lung cancer. The main differences between the two are the size of the cancer cells when examined under a microscope.

As the names suggest, small cell lung cancer results from smaller cancer cells than non-small cell lung cancer. Small cell lung cancer tends to grow and spread more quickly, but non-small cell lung cancer is much more common.

Learn More: Small Cell vs. Non-Small Cell Lung Cancer: What's the Difference?

What Causes Non-Small Cell Lung Cancer?

Anyone can develop non-small cell lung cancer, but it is much more likely to occur in smokers. Smoking significantly damages the lungs, causing inflammatory changes that can increase the risk of cancer cell growth.

Exposure to secondhand smoke, air pollution, radiation, toxic chemicals, dust, and fumes can also increase the risk of developing non-small cell lung cancer.

Sometimes, lung cancer has a genetic link in which gene mutations that cause lung cancer can be passed down through generations. If you have a family history of lung cancer, you may be at an increased risk of developing lung cancer.

How Is Non-Small Cell Lung Cancer Diagnosed?

Non-small cell lung cancer is diagnosed through testing that examines the structure and function of your lungs. Diagnosis involves a variety of tests and procedures, which include:

Chest X-ray: Produces an image of your chest and lungs to check for abnormal growths and structural changes

Computed tomography (CT) scan: A series of X-rays used to produce a three-dimensional (3D) image of the chest from different angles to check for cancer growth

Sputum cytology: A procedure to examine a sample of mucus and other fluids coughed up from the lungs (sputum) for cancer cells

Thoracentesis: A procedure that removes fluid from the space between the lungs and chest wall lining to test the fluid for cancer cells

Biopsy: A procedure that removes fluid or tissue from the lungs or nearby lymph nodes to test for cancer cells

Bronchoscopy: A procedure in which an instrument is inserted through the nose or mouth into the airways to examine the inside of the airways in the lungs and remove tissue samples for cancer cell testing

Thoracoscopy: A surgical procedure in which an incision is made between the ribs to insert an instrument to examine the chest and lungs and remove tissue samples for cancer cell testing

Mediastinoscopy: A surgical procedure in which an incision is made at the top of the sternum (breastbone) through which an instrument is inserted to examine the chest and lungs and remove tissue samples for cancer cell testing

Lab tests: Can check for genetic markers to see if you are at risk for lung cancer and assess your overall health

Non-Small Cell Lung Cancer Stages

As lung cancer continues to grow, it can progress through different stages. A higher stage of non-small cell lung cancer indicates that the cancer is worsening and spreading to other parts of the body. The stage of non-small cell lung cancer will influence what type of treatment is most appropriate.

The stages of non-small cell lung cancer include:

Occult (hidden) stage: Cancer cells are found in samples taken from the airways or from sputum, but no cancer growths can be seen in the body through imaging tests.

Stage 0: Abnormal cells that may become cancer are found in the lining of the airways.

Stage 1: Cancer has formed in the lungs but has not spread to the lymph nodes, forming a tumor 3 centimeters (cm) or smaller (stage 1A) or between 3 and 4 cm in size (stage 1B). Stage 1B may involve the spreading of the tumor to the bronchus and/or inner lining of the lung.

Stage 2: Cancer in the lungs has formed a tumor between 4 and 5 cm in size (stage 2A) that involves spreading of the tumor to the bronchus and/or inner lining of the lung, or a tumor between 5 and 7 cm in size has spread to the lymph nodes on the same side of the body.

Stage 3: Cancer in the lungs has formed a tumor between 5 and 7 cm in size that has spread to lymph nodes on the same side of the body near the trachea or aorta that may also spread to the bronchus and/or inner lining of the lung (stage 3A), or a tumor of any size has spread to lymph nodes on the opposite side of the body with possible spread to the heart, esophagus, or diaphragm (stage 3B). Stage 3B may also involve a tumor of any size that has spread to the lymph nodes on either side of the body and one or more separate tumors in another lobe of the lung.

Stage 4: Cancer has formed multiple lung tumors and spread to one organ (stage 4A) or multiple organs (stage 4B) not located near the lung, such as the brain, liver, kidney, bones, or adrenal glands.

Non-Small Cell Lung Cancer Treatment

Treatment for non-small cell lung cancer will depend on the stage of cancer at diagnosis.

Surgery

Surgical removal of a cancerous tumor from the lung is the first treatment option for early stages of non-small cell lung cancer, including stages 1 and 2 and stage 3A, when the cancer is well-isolated with minimal spread to other areas of the body.

For all other stages of non-small cell lung cancer, the tumor has spread too much to other areas, making surgery ineffective at removing enough of the cancer.

Radiation Therapy

Radiation therapy, also called radiotherapy, involves exposing the areas of the body with cancer cells to targeted high-energy radiation beams. Radiation beams are powerful enough to damage the DNA within cancer cells to destroy them and stop them from dividing. Radiation therapy is often used together with chemotherapy to treat cancer.

Chemotherapy

Chemotherapy involves the use of powerful medications that kill rapidly growing cancer cells. Chemotherapy is often used for people with non-small cell lung cancer who are not eligible for immunotherapy treatment, especially if they have preexisting autoimmune conditions.

Chemotherapy and radiation therapy are typically the standard treatment for people with advanced non-small cell lung cancer (stages 3 to 4). Chemotherapy is often also administered after surgery to kill off any remaining cancer cells not removed from the body surgically.

Immunotherapy

Immunotherapy is a type of treatment that uses biologic medication to enhance the body's immune system to fight off cancer. Immunotherapy medications improve the function and activity of immune system cells so that they can better target cancer cells and stop or slow their growth.

Targeted Therapy

Targeted therapy involves using medications that target the genes that cause cancer cells to form and divide. Approximately 10% to 30% of cases of non-small cell lung cancer are linked to mutations in the EGFR gene, while 5% or less of cases are linked to mutations in other genes, including the ALK, ROS1, RET, and BRAF V600E genes.

Ongoing research is geared toward developing drugs targeting these genetic mutations to stop abnormal cellular activity and decrease cancer growth and development.

Non-Small Cell Lung Cancer Prognosis

Unfortunately, lung cancer has a poor prognosis, with a one-year survival rate of less than 50% and a five-year survival rate of less than 18%. Because lung cancer is not always symptomatic, almost 40% of people with it have already developed to stage 4 at the time they are diagnosed, making treatment less effective in slowing cancer growth.

Every case of lung cancer is different, however, and survival rates can vary from person to person depending on lifestyle factors and how early and aggressively treatment is administered after diagnosis.

Related: Lung Cancer Facts You Need to Know

Significant Progress In Small-cell Lung Cancer Research

Small-cell lung cancer is a particularly aggressive type of tumor with a consistently high mortality rate. In recent years, the research of scientists at MedUni Vienna's Department of Thoracic Surgery has significantly contributed to a better understanding and new therapeutic approaches in this malignant disease. Their comprehensive overview of new insights and advances in small-cell lung cancer has just been published in CA: A Cancer Journal for Clinicians, the highest-ranked international scientific journal.

The key findings of Balazs Döme's team from the Department of Thoracic Surgery at MedUni Vienna primarily consist of new insights into the biology and heterogeneity of small-cell lung cancer (SCLC). In collaboration with colleagues from Sweden, the Czech Republic, Hungary, and the United States, the researchers previously demonstrated that SCLC can be categorized into different subgroups which are associated with varying clinical behaviors and potentially new therapeutic strategies. They also demonstrated that certain combinations of multiple drugs represent a particularly promising therapeutic approach in patients with characteristic molecular SCLC profiles.

Based on these profound research contributions, the team from the Translational Thoracic Oncology Research Laboratory at MedUni Vienna's Department of Thoracic Surgery was recently invited to present a comprehensive overview of recent advances in small-cell lung cancer. The review from Balazs Döme and his team has now been published in the journal CA: A Cancer Journal for Clinicians, the flagship journal of the American Cancer Society with the highest impact factor (286) of any scientific journal worldwide.

"We are delighted that our research achievements have received such high recognition," says Konrad Hötzenecker from the Department of Thoracic Surgery. "This provides an optimal base to further expand the clinical and translational lung cancer research activities of the Department of Thoracic Surgery at the Medical University of Vienna as one of the leading centers," emphasizes the newly appointed Professor of Thoracic Surgery and Director of the Department Clemens Aigner.

Expediting the development of personalized therapies

Approximately 15 percent of lung cancer patients are affected by small-cell lung cancer. This particularly aggressive tumor, which usually occurs in smokers, grows rapidly, has an increased tendency to metastasize, and a high mortality rate. According to Balazs Döme, conventional therapies have reached their plateau of effectiveness in SCLC. "With our research work, we have already created the basis for the development of targeted, personalized therapeutic approaches, which we now want to advance further," Döme states, announcing further research.

Researchers Identify New Biomarkers Of The Most Frequent Lung Cancer

image: From left to right: Marselina Arshakyan (co-first author of the study), Rafael Ikemori, Paula Duch, Jordi Alcaraz and Marta Gabasa. View more 

Credit: UNIVERSITY OF BARCELONA

​​​​​​​Researchers of the University of Barcelona and the Institute of Bioengineering of Catalonia (IBEC) have identified new biomarkers for non-small cell lung cancer, the most common lung cancer. The results, published in the journal Modern Pathology, have been obtained thanks to a new technique that allows quantitative analysis of patient samples. It is a pioneering methodology that is cheaper and easier to apply than the traditional ones in hospitals and other clinical settings.   

The study notes that certain features of the collagen fibers —one of the most abundant components regarding cancer cells— would be a potential indicator for the diagnosis and prediction of the evolution of the disease.

"Our new tool can improve the clinical management of surgical patients with this type of cancer, since it identifies those at an increased risk of relapse and, therefore, can benefit from a comprehensive monitoring and even neoadjuvant therapies (complementary to the main treatment)", notes Jordi Alcaraz, lecturer at the Faculty of Medicine and Health Sciences of the UB and researcher at IBEC, who led the study together with Joan Montero, researcher at the same faculty, and Josep Samitier, professor at the Faculty of Physics and director of IBEC.

The study includes the participation of researchers from Hospital Clínic de Barcelona, the Respirtory Diseases Networking Biomedical Research Centre (CIBERES), the Bioengineering, Biomaterials and Nanomedicine Networking Biomedical Research Centre (CIBER-BBN), the University Hospital 12 de Octubre (Madrid) and the University Hospital Parc Taulí (Sabadell).

What is the role of collagen fibers in tumor progression?

Lung cancer is the main cause of death related to cancer in both men and women worldwide, with a five-year survival rate of 18%. Most of these patients are diagnosed with non-small cell lung cancer, which is subdivided into adenocarcinoma, squamous cell carcinoma and other less common subtypes. There is increasing evidence of the essential role of the collagen fiber-rich environment surrounding cancer cells in the progression of these cancers and other solid tumors.

In this tumor context, high expression of type I collagen has been associated with poor prognosis and increased risk of metastasis. "This evidence has pointed to fibrillar collagens as an important potential source of cancer-relevant biomarkers and has sparked therapeutic interest in understanding their roles in tumor development", says Jordi Alcaraz.

Faced with this challenge, researchers have developed and validated a new digital pathology approach — that is, the study of disease with digital tools — to quantitatively analyze collagen fibers in tissue samples from patients with non-small cell lung cancer.

A more accessible technique for hospital pathology units

The new methodology is based on digitized images of patient biopsies stained with a dye called picrosirius red (PSR) and imaged with polarized light. The researchers use the open-source software CT-FIRE to automatically segment the individual fibers in the images to quantify relevant characteristics such as length, width or straightness.

"The standard methodology for analysing collagen fibers is based on an advanced microscopy technique called second harmonic generation, which requires a double-photon confocal microscope, a type of microscope which is expensive and needs an expert operator", he notes. "In contrast — he continues —, our tool is a cheaper and easier-to-incorporate approach for pathology units, since it uses an inexpensive stain (PSR), free software such as CT-FIRE and a microscopy technique accessible to most hospitals, such as polarized light".  

Collagen density, an indicator of poor prognosis​​​​​​​The researchers have applied this methodology to analyze 195 samples from patients with adenocarcinoma and squamous cell carcinoma. The results show that fiber straightness would be a potential biomarker for diagnosing the disease while density would be a poor prognostic indicator. Moreover, the prognostic value of collagen density would be "independent of the clinical stage of the tumor, and it shows that analyzing collagen fibers provides additional relevant information", stresses Jordi Alcaraz.

Abnormal stiffening of tissues in patients with adenocarcinoma

The new methodology has also made it possible to compare the characteristics of collagen fibers in tissue samples from patients with non-cancerous tissue samples. Thus, for the first time, they have been able to describe quantitatively the changes that take place in the organization of collagen in non-small cell lung cancer.

The results show that, in tumor tissue samples, there is an increase in straightness, length and width that indicates an abnormal stiffening of the tissue, especially in patients with adenocarcinoma. According to the researchers, this stiffening would be related to different mechanisms to avoid the immune system response and, consequently, to tumor progression in this type of cancer. "This opens the door to identifying new therapies directed against abnormal stiffening", concludes the researcher.

This study was funded by the State Research Agency of the Spanish Ministry of Science and Innovation, La Caixa and Cellex Foundation.​​​​

Method of Research

Experimental study

Subject of Research

Cells

Article Title

Quantitative Image Analysis of Fibrillar Collagens Reveals Novel Diagnostic and Prognostic Biomarkers and Histotype-dependent Aberrant Mechanobiology in Lung Cancer

Article Publication Date

12-Mar-2023

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