How Non-Small Cell Lung Cancer Is Diagnosed

Diagnostic and Staging Tests Your Doctor May Recommend

The diagnosis of non-small cell lung cancer may be suspected based on a chest X-ray, chest CT scan, or sputum cytology, but a biopsy is needed to make the definitive diagnosis. Once it is determined that an abnormality is lung cancer, further tests such as a PET scan are done to stage the tumor, and this is a very important step in planning treatment. For tumors that are stage IV (and likely earlier stages in the near future), gene testing should be done for all people who have non-small cell lung cancer.

The test of choice is next-generation sequencing: a test that looks for many genetic changes in cancer cells at the same time, as well as PD-L1 levels.

While many people are anxious to begin treatment—and some of the tests can take two weeks to four weeks to complete—waiting for the results (if possible) before beginning treatment helps ensure that you receive the most precise therapies available to treat your cancer.

Common diagnostic tests for non-small cell lung cancer
Illustration by Cindy Chung, Verywell 

Imaging

The workup of a potential case of lung cancer usually begins with imaging studies based on symptoms and risk factors.

Chest-X-Ray

A chest X-ray is often the first test ordered and can be a good start if it finds something abnormal, but a chest X-ray cannot rule out the presence of a non-small cell lung cancer.

Chest X-rays can miss lung cancer, and they do for up to 25 percent of people.

If there is any concern whatsoever about lung cancer, a full (not low dose) chest CT scan should be done.

Chest CT

A chest CT is often the test of choice in the initial workup of lung cancer. Not all lung nodules, however, are lung cancer. There are a number of lung nodule findings suspicious for lung cancer, such as nodules that are "spiculated" (pointy) on imaging, nodules that occur in the upper lobes, and nodules that occur in people who have risk factors for non-small cell lung cancer such as smoking, older age, or COPD.

PET Scan

A PET scan may help in the diagnosis of lung cancer but is more commonly used to help stage a tumor. PET scans are the test of choice when looking for lymph node involvement of a tumor.

Other Tests

Less frequently, tests may include a chest MRI, chest fluoroscopy, pulmonary angiography, or a lung scan.

Labs and Tests

In addition to imaging tests, some procedures may assist in the diagnosis of lung cancer.

Sputum Cytology

With sputum cytology, a patient is asked to cough up a sample of sputum. Sputum differs from saliva in that it contains cells located lower in the respiratory system. Sputum cytology can sometimes identify cancer cells, especially with tumors such as squamous cell carcinomas that lie near the large airways.

The test cannot, however, be used to rule out lung cancer, and has not been found to be effective as a screening test. If sputum is positive for cancer cells, further tests are needed to find the location of the tumor from which they arose.

Bronchoscopy

A bronchoscopy is a procedure in which a physician inserts a flexible tube through the mouth and down into the bronchi. It can sometimes allow doctors to visualize a cancer that lies in or near the large airways, and a biopsy can be done. For tumors that lie near but not directly adjacent to the airways, an endobronchial ultrasound may be done during a bronchoscopy.

In this procedure, an ultrasound probe is attached to the bronchoscope to look deep to the airways. If a mass is noted, a biopsy can then be done with ultrasound guidance.

Mediastinoscopy

A mediastinoscopy is a procedure in which a scope is inserted through the skin (via small incisions) and into the mediastinum in the operating room. The end of the scope has a lighted camera that can be used to visualize structures in this region including lymph nodes. Abnormal appearing lymph nodes may be biopsied to look for evidence of cancer.

Blood Tests

Lab tests that are often done along with imaging tests for lung cancer include a complete blood count and blood chemistries. Tumors associated with paraneoplastic syndromes may include findings such as an elevated calcium level in the blood.

Other Tests

Tests such as oximetry, a test that determines the level of oxygen in the blood, or pulmonary function tests, tests that assess the function of the lungs, may also be done.

Biopsy

A lung biopsy is needed to make a definitive diagnosis of non-small cell lung cancer and is also needed to determine the subtypes and do genomic testing. Sometimes a sample is obtained during a bronchoscopy (transbronchial biopsy) or endobronchial ultrasound, but more often, a separate procedure is required. A biopsy may be done in a few different ways.

Fine Needle Aspiration Biopsy

In a fine needle aspiration (FNA) biopsy, a thin needle is inserted through the chest wall and into a lung nodule, guided by either CT or fluoroscopy. The procedure may also be called a percutaneous biopsy (through the skin) or transthoracic biopsy.

Thoracoscopic Biopsy

In a thoracoscopic biopsy, a few small incisions are made in the chest wall and a lighted scope with a camera is inserted into the chest. (This is also called video-assisted thoracoscopic surgery or VATS.) The procedure is done in the operating room under general anesthesia and may be done to obtain a biopsy sample, or sometimes itvmay involve removing the entire nodule or mass.

Open Lung Biopsy

An open lung biopsy may be done when it's thought that the other procedures will not be successful in obtaining a biopsy sample. In this procedure, a long incision is made in the chest, cutting through or sometimes removing a portion of the ribs to gain access to the lungs (a thoracotomy). A biopsy alone may be done, but often times the entire abnormality in the lungs is removed.

Thoracentesis

In some cases, a pleural effusion (fluid between the two membranes that surround the lungs) is present at the time of diagnosis. If cancer cells are present in the fluid (a malignant pleural effusion), thoracentesis may be done. In this procedure, a long, thin needle is inserted through the skin of the chest and into the pleural cavity to remove fluid. This fluid can be looked at under the microscope for the presence of cancer cells.

Genomics (Gene Testing)

It's now recommended that everyone with advanced non-small cell lung cancer (NSCLC) have genomic testing done on their tumor (including people with squamous cell carcinoma). Unlike small cell lung cancer, testing for targeted gene mutations and other genetic abnormalities can be very helpful in choosing the most appropriate therapy.

Unfortunately, a 2019 study found that only 80 percent of people with NSCLC are being tested for the most common mutations, and therefore many people are missing out on effective therapies. It's important to be your own advocate and ask about this testing.

Types of Genomic Testing

Molecular profiling (gene testing) can be done in a few different ways. One is sequential, in which the most common mutations are checked for first, and then subsequent tests are done based on the results. Another variation includes testing for three or four of the most common genetic abnormalities.

Sequential Testing

In sequential testing, doctors check for the most common gene mutations or abnormalities first, and further testing is done if initial studies are negative. This often begins with EGFR testing.

Gene Panel Testing

Gene panel testing tests for more than one mutations or rearrangement, but detects only the most common gene abnormalities for which FDA approved therapies are available.

Next Generation Sequencing

Since the number of mutations (and other gene abnormalities) in non-small cell lung cancer for which testing is available is growing rapidly, and since there are several mutations for which treatment is now available but only in clinical trials or off-label, next-generation sequencing is the ideal test for determining whether a person has a tumor that can be treated with targeted therapy (and when possible, tumors often have a very good response rate).

Next-generation sequencing tests for many genetic alterations in cancer cells at the same time, including those such as NTRK fusion genes that may be found in a number of different types of cancer.

A 2018 study noted that next-generation sequencing—in addition to providing people the greatest chance to receive an effective therapy for their tumor—was cost-effective.

The test also determines the PD-L1 level and tumor mutations burden (see below).

The downside of next-generation sequencing is that it can take two weeks to four weeks to get results, and this is already an anxiety-laden time period for those newly diagnosed. For people who are relatively unstable (when some form of treatment is needed very soon), physicians sometimes order a rapid EGFR test in addition to next-generation sequencing or may begin chemotherapy while awaiting results.

Targetable Gene Abnormalities

Treatments are currently available for tumors that have:

  • EGFR Mutations (and treatments can vary depending on the specific mutation, such as T790 mutations and more)
  • ALK Rearrangements
  • ROS1 Rearrangements
  • BRAF
  • NTRK fusion

Medications are available off-label or in clinical trials for some:

  • HER2 (ERRB2) mutations
  • MET abnormalities
  • RET rearrangements

Some abnormalities, such as KRAS mutations, are not currently treatable, but the test still offers information that can be helpful such as predicting prognosis.

PD-L1 Testing and Tumor Mutation Burden

Testing is also done to estimate how well a person may respond to immunotherapy drugs. While there is not currently a good, definitive test for this, PD-L1 testing and tumor mutation burden may give some idea.

PD-L1 testing

PD-L1 proteins are proteins that help tumors hide from the immune system. When these proteins are present in high numbers, they tell T cells (cells in our immune system that fight cancer) to stop their attack. Immune checkpoint inhibitors are a type of immunotherapy that essentially take the breaks off of the immune system so that T cells can "resume" their attack.

Tumor Mutation Burden (TMB)

TMB refers to the number of mutations found in a cancer cell on next-generation sequencing. Cells that have a higher tumor mutation burden are more likely to respond to immunotherapy drugs than those with a low number of mutations.

Unfortunately, some people who have low PD-L1 levels and low tumor mutation burden respond well to immunotherapy and vice versa, so researchers are looking for a better test to make this prediction.

Staging

Accurate staging with non-small cell lung cancer is extremely important when it comes to choosing the best treatment options.

Staging Work-Up

A PET scan can play an important role in the staging of non-small cell lung cancer, as it can often separate out tumors that are operable from those that are inoperable, and has replaced the need for a mediastinoscopy for many people. Imaging studies can also help determine the size of a tumor as well as evidence of local extensions, such as into nearby structures or the pleura.

Stages

There are four primary stages of non-small cell lung cancer. TNM staging separates these cancers based on the size of the tumor, lymph node involvement (the number and location), and whether metastases are present.

  • Stage I non-small cell lung cancer: Stage I tumors are present only in the lung and have not spread to lymph nodes
  • Stage II non-small cell lung cancer: Stage II tumors may have spread to nearby lymph nodes.
  • Stage III non-small cell lung cancer: Stage III cancers have often spread to lymph nodes in the middle of the chest (mediastinum).
  • Stage IV non-small cell lung cancer: Stage IV cancers are referred to as metastatic and have either spread to other regions of the body (such as bones, the liver, the brain, or the adrenal glands) or into the pleural space (with a malignant pleural effusion).

Re-Testing

While we talk about non-small cell lung cancer as if it is the same over time, these tumors actually change continuously, developing new mutations and sometimes changing into a different type of lung cancer altogether. For example, lung adenocarcinomas that are EGFR positive may transform to become small cell lung cancer (or another form of neuroendocrine tumor) over time. When this occurs, the treatment needs change as well.

For this reason, a re-biopsy (or in some cases a liquid biopsy) to look both at the tissue type of the tumor and gene profile is needed when a tumor progresses on a previously effective treatment.

Differential Diagnosis

Conditions that may appear similar to non-small cell lung cancer on imaging may include:

  • Benign lung nodules: The most common type of benign lung nodules are hamartomas.
  • Other cancers that may begin in the chest, such as lymphomas or thymomas
  • Pneumonia: Either bacteria or viral pneumonia may appear similar on imaging, as well as other infectious conditions such as a lung abscess, tuberculosis or empyema (infected fluid in the pleural space)
  • Fungal infections of the lungs, such as coccidiomycosis, cryptococcosis, and histoplasmosis
  • Pneumothorax: The collapse of a lung may look like a mass, but can also hide a mass.
  • Metastatic cancer to the lungs: Cancer that spreads to the lungs from other regions (such as breast cancer, bladder cancer, colon cancer, and others) may appear similar, but often involves several nodules.
  • Pulmonary fibrosis (scarring)
  • Sarcoidosis
  • Lung infarction (loss of blood supply to lung tissue similar to a heart attack but in the lungs)
  • Superior vena cava syndrome due to causes other than lung cancer

A Word From Verywell

It can be very anxiety provoking when undergoing the tests needed to look for non-small cell lung cancer, as well as determine the characteristics of a tumor once found. Many people are anxious to begin treatment to eliminate whatever is causing their symptoms, and waiting for tests can seem like an eternity.

Fortunately, the landscape of non-small cell lung cancer is changing, and taking the time to get an accurate diagnosis of both tissue type and genetic profile can frequently lead to effective therapies.

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Article Sources
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