How Small Cell Lung Cancer Is Diagnosed

A number of tests are often needed to make the diagnosis of small cell lung cancer. The evaluation begins with a careful history of symptoms and risk factors, as well as a physical exam. Sputum cytology may sometimes find cancer cells, but studies such as a computerized tomography (CT) scan of the chest and/or magnetic resonance imaging (MRI) are needed to locate a cancer. A biopsy may be done in one of several ways, and is usually needed to confirm the diagnosis. Small cell lung cancer tends to spread early, and staging tests such as an MRI of the brain and possibly a positron emission tomography (PET) scan, bone scan, or other tests may be needed to accurately stage the disease. Further testing is also recommended for people with limited stage disease or in never smokers.

Self-Checks/At-Home Testing

There are no "at home" tests for small cell lung cancer, but it's important to be aware of the potential symptoms of the disease. Unlike non-small cell lung cancer, the onset of symptoms with small cell lung cancer occurs more rapidly. The most common symptoms include a cough, wheezing, shortness of breath, or coughing up blood (hemoptysis).

The first symptoms may also be related to the spread of the cancer either locally or distantly, as small cell lung cancer tends to spread early. Small cell lung cancer most commonly spreads to the brain (brain metastases) which can cause headaches, visual changes, weakness, and more, liver (liver metastases), bones (bone metastases), bone marrow, and adrenal glands (adrenal gland metastases). Roughly 1 in 5 people will have metastases at the time of diagnosis.

With local spread, such as to the large blood vessels near the lungs or the esophagus, symptoms such as hoarseness (due to nerve compression) may occur. General symptoms of advanced cancer are also often present, such as unintentional weight loss, fatigue, pain, and/or loss of appetite.

Some small cell lung cancers may secrete substances that have hormone-like actions in the body (paraneoplastic syndromes), and for this reason, the first symptoms may appear unrelated to the lungs. Due to the wide range of potential symptoms, it's important to make an appointment to see your doctor if you have any concerns.

Physical Examination

When you see your doctor, she will ask you a number of questions in addition to asking about your symptoms. This will include questions about potential risk factors such as smoking, radon exposure in the home, occupational exposures, and family history of lung cancer or other cancers. A careful review of any other medical conditions you may have is important when considering treatments. It's important to let your doctor know if you have been having any pain, and current National Comprehensive Cancer Network (NCCN) guidelines state that discussing pain should be an essential part of the workup for small cell lung cancer.

A physical examination includes a careful examination of your lungs for abnormal breath sounds, a neurological exam, and a general assessment of your physical health.

Labs and Tests

Laboratory tests cannot usually make the diagnosis, but several tests are important as part of the evaluation.

Labs

Blood tests: A complete blood count (CBC) and chemistry panel (comprehensive metabolic panel) are recommended, including liver function tests (LFTs), electrolytes, and kidney function tests—blood urea nitrogen (BUN) and creatinine.

Paraneoplastic syndromes related to small cell lung cancer may lead to an elevated calcium level in the blood (hypercalcemia of malignancy) or a low sodium level (hyponatremia).

Sputum cytology: Sputum cytology is a test that is done by having a person cough up a sample of sputum (mucus). While not a good screening test (it is often negative with cancer), if cancer cells are found it can support the diagnosis. Further testing, however, is needed to determine the location of the cancer, and a biopsy may still be important.

Biopsy

While a biopsy is recommended for most people with possible small cell lung cancer. Other procedures may be recommended in some cases.

Bone Marrow Biopsy/Aspiration

A bone marrow biopsy and aspiration is a study done by inserting a long, thin needle through the skin (most often the iliac crest) to obtain a sample of bone marrow, the spongy material at the center of large bones. It is recommended for people who have signs that cancer has spread to the bone marrow (such as finding immature red blood cells on a blood smear). A unilateral (one-sided) bone marrow aspiration/biopsy is recommended per the NCCN guidelines for people who have limited stage small cell lung cancer. PET scans, however, have replaced the need for a bone marrow biopsy in some cases.

Thoracentesis

A thoracentesis may be done if a scan shows evidence of fluid build-up in the space between the membranes that line the lungs (a pleural effusion). Pleural effusions are very common with lung cancer, and may be either benign (not contain cancer cells) or malignant (contain cancer cells). When a malignant pleural effusion (a pleural effusion that contains cancer cells) is present, evaluating a sample of the fluid can help in the diagnosis by evaluating the sample under the microscope.

According to the NCCN Guidelines 2020, a thoracentesis should be done if there is a pleural effusion that can be seen on imaging scans (such as CT or X-ray).

Biopsy Methods

A biopsy is important in order to get a sample of the cancer to evaluate both under the microscope and with special stains (immunohistochemistry). The procedure can be done in a number of different ways, and often depends on the location of the tumor; for example, whether it is centrally located near the large airways or in the outer regions of the lungs (peripheral). Your doctor will discuss which procedure she recommends for you based on the characteristics of your tumor and whether there are any areas of metastases or lymph nodes that are more accessible.

With small cell lung cancers that are advanced (extensive stage), a biopsy of an involved lymph node, or a site of spread (metastasis) such as to the liver or under the skin (subcutaneous nodules) is preferred over a biopsy of the cancer in the lungs. These procedures carry less risk (the appearance of the cancer in these areas will be the same as that in the lungs) and can help with staging the cancer at the same time.

Fine Needle Aspiration Biopsy

In a fine needle aspiration biopsy, a long, thin needle is inserted through the chest wall and into a tumor with the guidance of a CT or ultrasound. A sample of the tumor is then aspirated. (describe more). Fine needle biopsies are often recommended if a tumor is in the periphery of the lungs. It is less invasive than other procedures, but may not obtain enough tissue to adequately evaluate a tumor.

Bronchoscopy with Endobronchial Ultrasound (EBUS) and Biopsy

Another method for obtaining a sample of a tumor is via bronchoscopy. A bronchoscopy is a procedure in which a tube is inserted through the most or nose (with sedation) and threaded down into the large airways of the lungs (the bronchi).

Once the bronchoscope is in place, an ultrasound probe (endobronchial ultrasound) on the bronchoscope allows doctors to see tumors and lymph nodes that lie near the large airways. With special instruments, and under guidance of the ultrasound, a physician can obtain a sample of either the tumor or lymph nodes to evaluate.

A 2016 study found that needle biopsies via endobronchial ultrasound were very safe and effective with regard to obtaining samples of both lung tumor tissue and hilar (near the airways) and mediastinal (between the lungs) lymph nodes.

There are a few new variations of this technique that may offer advantages in some cases:

  • Radial endobronchial ultrasound: Radial endobronchial ultrasound involves the use of a longer probe that can reach deeper into the lungs than a conventional endobronchial ultrasound. This can sometimes allow doctors to sample tumors that are located deeper in the lungs without using more invasive methods.
  • Electromagnetic navigation bronchoscopy: Navigation bronchoscopy is another newer technique designed to be less invasive. In this procedure, magnetic sensors are placed on the back and chest to create a magnetic field. A different sensor is inserted through the bronchoscope to create an electromagnetic field. The technique can be likened to using GPS on your phone rather than simply looking around to see where you are. Navigation bronchoscopy may be particularly helpful in performing biopsies of tumors deeper in the lungs or that are very small (in analogy, looking for rural roads or locations that are small and not easy to see from the road).

Thoracoscopy

In some cases, a needle biopsy or endobronchial biopsy technique cannot be used to access a tumor due to its location or other factors. When this occurs, a surgical biopsy may be needed. A thoracoscopy is a procedure in which a surgeon makes a few small incisions in the chest to gain access to the lungs. A camera and special instruments are then inserted in order to obtain a biopsy sample.

Mediastinoscopy

A mediastinoscopy was once a standard evaluation in the work-up of lung cancer, but similar results may now be obtained (most of the time) with a PET scan. A mediastinoscopy is a procedure that is done in the operating room under general anesthesia. Through a small incision in the chest wall, a surgeon inserts a tube (mediastinoscope) that is used to visualize the area of the chest between the lungs, and perform biopsies if needed.

Pathology

Tissue obtained during a lung, lymph node, or metastasis biopsy (or a thoracentesis, bone marrow exam, etc.) is evaluated by a pathologist to confirm the type of lung cancer.

Microscope Evaluation

Under the microscope, small cell lung cancer is visible as small spindle-shaped cells with a high mitotic index (evidence that the cells are dividing very rapidly).

Immunohistochemistry Staining

Immunohistochemistry involves applying a solution that contains antibodies combined with a dye or radioactive material to a sample of tumor tissue. The antibodies combine with certain tumor markers on a tumor, and due to the dye or radioactive material, light up when viewed under the microscope.

The tumor marker Ki-67 is important in discriminating between small cell lung cancer and carcinoid lung tumors (both are types of neuroendocrine tumors).

Some of the markers seen with small cell lung cancer that can be helpful in confirming the diagnosis include chromogranin A, CD56, synaptophysin, MIB-1, and thyroid transcription factor.

Molecular Profiling

While currently routine with non-small cell lung cancer, molecular gene profiling (such as via next generation testing) is done less frequently with small cell lung cancer. Gene profiling allows doctors to determine the genomic alternations (such as gene mutations) present in a particular tumor (and often responsible for its growth), and in the case of some cancers, select targeted therapies (precision medicine) that will best treat the tumor.

At the current time, molecular profiling is recommended only for people who have never smoked and have extensive stage small cell lung cancer. (The reason is not to discriminate against people who have smoked, but because there are not currently any targeted therapies that are effective with the type of mutations seen in smoking-related small cell cancers.)

Liquid Biopsy

A liquid biopsy is a blood test that is done to look for fragments of tumor DNA that have made their way to the bloodstream. A liquid biopsy may be used to look for gene mutations (and other genomic alteration) in a tumor without having to do an invasive biopsy (or, may also be used along with results from molecular profiling of a tumor sample). As with molecular profiling on tissue samples, this would be primarily a consideration for never smokers who have extensive stage small cell lung cancer.

Imaging

A number of imaging studies may be done to assist in the diagnosis of small cell lung cancer.

Chest X-Ray

A chest X-ray is often a first step when a person develops signs and/or symptoms of lung cancer. It's important to note, however, that a chest X-ray may allow a lung cancer to go undetected up to 20% or more of the time.

Chest (and Abdominal) CT

A CT scan of the chest and abdomen (to look for liver or adrenal gland metastases) is very important in the initial investigation of small cell lung cancer. CT scanning (computerized tomography) uses multiple cross-sectional X-ray images of the chest that a computer then analyzes to create a 3-dimensional picture of the inside of the body. A CT scan is usually done with contrast, a substance injected into a vein that makes the scan easier to interpret.

MRI of Brain, Possibly Chest

In some cases, an MRI of the chest may be needed to better understand a tumor. Magnetic resonance imaging uses powerful magnets to create a picture of the inside of the body.

A brain MRI is a very important test in the evaluation and staging of small cell lung cancer, and is currently recommended for anyone who has been diagnosed with the disease. If an MRI cannot be done for some reason (for example, if you have a pacemaker, insulin pump, cochlear implant, or other types of metal in your body), a CT scan of the brain with contrast may be done as an alternative.

Everyone who has small cell lung cancer should have a brain MRI, or a contrast-enhanced CT scan of the brain if an MRI is not possible.

Some people are anxious about having an MRI due to claustrophobia, and having the procedure can be anxiety-provoking as well (even with earphones) as you will hear loud clunks during the procedure. Understanding the importance of the study can sometimes help people cope with these temporary discomforts.

PET Scan

A PET scan is a test that is often used in both the diagnosis and staging of small cell lung cancer. In the test, a small amount of radioactive glucose is injected into a vein, and after it has been given time to be absorbed by cells in the body, a scan is done. Glucose is taken up more actively by more metabolically active cells (such as cancer cells), and areas of tumor will light up on a screen wherever they may be in the body.

Bone Scan

A bone scan is sometimes done to look for the spread of cancer to the bone, although a PET scan can often provide the same results and more, so it is done less frequently than in the past.

Long Bone X-Rays

If a bone scan or PET scan reveals any evidence of bone metastases to weight-bearing bones (such as the legs), the NCCN guidelines recommend doing plain X-rays of these areas. Bone metastases can lead to pathologic fractures, fractures of bones weakened by the presence of a tumor, that can add further discomfort to someone facing cancer.

Differential Diagnosis

There are a number of conditions that may mimic small cell lung cancer in symptoms and on imaging tests. While it seems like it should be straightforward to diagnose a small cell lung cancer, it can be challenging. In addition, roughly 10% of small cell lung cancers have characteristics of both small cell lung cancer and other types of lung cancer.

Understanding the differential diagnosis may be helpful when you are wondering why it is taking so long to diagnose your symptoms, and why so many tests must be done. Some of these conditions include:

Staging

After a diagnosis of small cell lung cancer is made, staging is done. Proper staging is very important in selecting the right treatments, and with limited stage disease, is critical in knowing whether surgery may be an effective treatment.

A PET scan combined with an MRI of the brain is most commonly used to evaluate for the spread of small cell lung cancer both near the heart (in the mediastinum) and in distant regions.

Two Stages, For Now

Small cell lung cancer is somewhat unique among cancers in that it is divided into only two stages: limited and extensive.

Limited stage small cell lung cancers are those that are present on only one side of the chest (one hemithorax) and can be safely included in a "tolerable" radiation field. The cancer may or may not have spread to lymph nodes, but there is no spread to distant regions. Only around one-third of small cell lung cancers are diagnosed at this earlier stage.

Extensive stage small cell lung cancers are those that cannot be safely encompassed in a tolerable radiation field.

Cancers within these two stages may behave very differently, and physicians are beginning to move beyond the consideration of only two stages when recommending treatments to patients.

TNM Staging

Other methods of staging may be discussed for those who have small cell lung cancer for which surgery is being considered. Doctors use the TNM staging systsem when selecting therapy. In this system:

T stands for tumor: T is combined with a number that depends on the size of the tumor. T1 tumors are less than or equal to 3 centimeters (cm) in diameter. T2 tumors are larger than 3 cm and less than or equal to 5 cm in diameter. T3 tumors are greater than 5 cm and less than or equal to 7 cm (or have spread locally to some regions), and T4 tumors are greater than 7 cm in diameter, or have spread to the diaphragm, mediastinum, heart, large heart vessels, trachea, recurrent laryngeal nerve, esophagus, or a different lobe of the lungs.

N stands for lymph nodes: N is combined with a number that describes whether cancer has spread to the lymph nodes and if so, where those lymph nodes are located relative to the original tumor. For example, N0 means that the cancer has not spread to any lymph nodes. N1 refers to cancers that have spread to hilar or peribronchial lymph nodes on the same side of the body as the cancer. N2 refers to cancers that have spread to mediastinal or subcarinal lymph nodes on the same side of the body, and N3 refers to cancers that have spread to the supraclavicular lymph nodes (lymph nodes just above the collar bone), or nodes such as hilar lymph nodes on the other side of the body from the cancer.

M stands for metastasis: M0 would mean that the cancer has not spread to distant regions of the body (brain, bones, liver, etc.), whereas M1 means that the cancer does have distant metastases.

In people who have limited stage lung cancer, surgery would only be considered an option for those who have tumors that are classified as T1 or 2/N0/M0.

A Word From Verywell

It can be very frightening if your doctor suspects you may have small cell lung cancer, and the time it takes to do all of the appropriate tests can be agonizing. These tests are important, however, both to know exactly what is causing your symptoms (whether cancer or not), and if so, to identify the best treatment options.

It can be empowering to ask a lot of questions and do some research on why these tests are being done. In some cases, there are a few different options for testing or tests that may or may not be necessary. Understanding these options and choices can help you work with your doctor to choose the approach that best meets your own needs and wishes.

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