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Last updated:
July 11, 2019
Years published: 2019
NORD gratefully acknowledges Marc Ladanyi, MD, Molecular Geneticist, Chief, Molecular Diagnostics Service; William J. Ruane Chair in Molecular Oncology, Memorial Sloan Kettering Cancer Center, for assistance in the preparation of this report.
Summary
Pediatric non-small cell lung cancer is the occurrence of non-small cell lung cancer (NSCLC) in children and adolescents (i.e. the pediatric population). This cancer is rare in individuals under 40 years of age and extremely rare in children and adolescents. NSCLC is the most common form of lung cancer; it is a general term for several different types of cancer in the lungs including adenocarcinoma, squamous cell carcinoma, large cell (undifferentiated) carcinoma, and other rare forms. ALK-positive NSCLC is a specific subtype generally associated with a younger age of onset than other forms of NSCLC and affected individuals have no history of smoking or a limited history of smoking. These tumors are usually adenocarcinomas. Because of the small number of children and adolescents that have been diagnosed with NSCLC, not much is known about this cancer in the pediatric population or how it differs from the adult population. Most of the literature and the treatment information and recommendations are based on research into adults. The treatment of NSCLC can include surgery, chemotherapy, and radiation therapy.
The clinical course and signs and symptoms associated with NSCLC lung cancer in children is unclear because so few children have been described in the medical literature. Sometimes, especially early in the disease, no symptoms may be present (asymptomatic). Common symptoms associated with lung cancer include a cough that doesn’t get better and doesn’t go away, chest pain that is worse when coughing, laughing or taking a deep breath, shortness of breath, coughing up of blood (hemoptysis), and the development of hoarseness or wheezing. Some affected individuals can develop loss of appetite, unintended weight loss, fatigue, and recurrent episodes of lung infections such as pneumonia or bronchitis, which is an infection that causes inflammation of the lining of the lungs or its airways.
NSCLC can potentially spread (metastasize) to affect other areas of the body. Specific signs and symptoms depend upon the exact location where the cancer has spread and the size of the tumor(s). Sometimes, symptoms of metastatic spread including bone pain, anemia, or unintended weight loss are the initial signs of pediatric NSCLC.
The exact underlying cause of pediatric non-small cell lung cancer is unknown. The exact reason normal cells become cancerous is not known. Most likely, multiple factors including genetic and environmental ones play a role in the disorder’s development. Current research suggests that abnormalities of DNA (deoxyribonucleic acid), which is the carrier of the body’s genetic code, are the underlying basis of cellular malignant transformation. Smoking is the major risk factor for NSCLC, but children and adolescents do not have decades or years of smoking in their medical history, meaning that other factors play a role in the development of this cancer in children and adolescents.
In NSCLC, genetic changes can affect oncogenes or tumor suppressor genes. These gene changes are acquired during life; they are not inherited. They are acquired because of exposure to environmental factors like smoking or they occur randomly for no known reason (spontaneously). These gene changes are altered or incomplete versions of ordinary genes that normally regulate cell growth and division. An altered oncogene promotes out-of-control growth (cancer). Tumor suppressor genes normally limit or stop the growth of cells. When the tumor suppressor genes are inactivated (mutated), cells can multiply (proliferate) wildly, causing cancer. The two genes most often associated with adenocarcinoma of the lungs are the EGFR gene and the KRAS gene which, when mutated, function as oncogenes.
Some affected children and adolescents have ALK-positive NSCLC. This form of lung cancer is associated with a specific genetic alteration, in which a segment of chromosome 2 is rearranged causing pieces of the chromosome to breakoff and reattach in the wrong areas. This causes two different genes to “fuse” together to form one abnormal gene. The two genes affected are the echinoderm microtubule-associated protein-like 4 (EML4) gene and the anaplastic lymphoma kinase (ALK) gene. This results in a “fusion” gene that produces an abnormal protein product. Researchers believe that this abnormal protein product may contribute to the growth and spread of cancer in such instances. A few drugs have been created that block the protein product of this fusion gene; they are called ALK inhibitors.
Research is ongoing to determine more genetic factors that can play a role in the development of NSCLC. As more gene or gene(s) are identified that contribute to lung cancer development and growth, the greater potential there will be for the development of targeted therapies.
There are reports of NSCLC developing in adolescents as a secondary cancer. Secondary cancer is one that develops as a late-effect of cancer treatment from years earlier for a different, unrelated cancer. Some teen-agers who received chemotherapy or radiation therapy during their childhood have been shown to develop lung cancer years later. This is known as a late effect of cancer treatment in children.
Non-small cell lung cancer is the most common form of lung cancer. There are about 230,000 people diagnosed each year in the United States with lung cancer, and about 80%-85% of all lung cancers are NSCLC. The majority of these individuals are over the age of 45. This cancer is rare in people under 45 years of age, and extremely rare in children and adolescents. The number of children and adolescents who have NSCLC is unknown.
The number of children and adolescents described in the medical literature with NSCLC has increased, but it is unclear whether this is due to an actual increase in the amount of people with this cancer or because of better recognition and diagnosis.
A diagnosis of pediatric non-small cell lung cancer is based upon identification of characteristic symptoms, a detailed family and patient history, a thorough clinical evaluation and a variety of specialized tests. Because NSCLC is extremely rare in children, the diagnosis is often not suspected in children with unexplained symptoms of lung disease and diagnosis is often delayed until more common diagnoses such as asthma are ruled out.
Clinical Testing and Workup
Most methods and tests developed or used for NSCLC have been studied in adults. Many of the same methods are used in pediatric patients. Some doctors will use a test called sputum cytology. This is a test in which sputum, the mucus that is coughed up from the lungs, is studied under a microscopic to look for abnormal, cancerous cells.
A plain x-ray (radiography) of the chest can show a tumor or mass in the lungs. Specialized imaging techniques can be used to determine whether cancer is present, the extent of the disease, and whether the cancer has spread to other areas. Such imaging techniques may include computerized tomography (CT), positron emission tomography (PET) scanning and magnetic resonance imaging (MRI). During CT scanning, a computer and x-rays are used to create a film showing cross-sectional images of certain tissue structures. A CT scan of the lungs can show smaller tumors that do not show up on conventional x-rays and can also show whether cancer has spread to nearby lymph nodes. A CT scan of other areas of the body can show whether cancer has spread (metastasized) to specific areas.
Another advanced imaging technique known as positron emission tomography or PET scan may also be used. During a PET scan, a radioactive sugar is injected into the body. This sugar will collect in areas of the body where there is a higher demand for energy. Tumors require a lot of energy to keep growing and spreading, and will soak up the radioactive sugar. When the x-ray (scan) is taken, areas that take up the radioactive sugar including NSCLC may show up as bright spots on the film. A PET scan is often used to help show whether NSCLC has spread or how well it is responding to treatment. A PET scan can determine whether cancer has spread to the bones. In the past, this required a bone scan, but when a PET scan is used, a bone scan is no longer necessary.
During a bone scan, a relatively harmless radioactive dye is injected into the affected bone. A special camera that can track the dye as it travels through the bone is used to create a picture of the skeleton and determine all affected areas and can help determine whether NSCLC has spread to other areas of the body.
Sometimes, doctors will recommend a combined PET/CT scan. This scan gathers information about how much metabolic activity (glucose uptake, measured by PET) a cancer has at the same time as mapping the adjacent body structures (CT).
An MRI uses a magnetic field and radio waves to produce cross-sectional images of particular organs and bodily tissues. An MRI of the brain may be ordered to determine whether cancer has spread to the brain.
Advanced imaging techniques are also used to help to stage NSCLC and to help plan and guide treatment.
Surgical removal (biopsy) of affected lung tissue can also be performed. In order to obtain a lung sample, physicians may recommend a bronchoscopy or fine-needle aspiration. During a bronchoscopy, a physician inserts a bronchoscope through the mouth and down an affected individual’s throat and obtains a sample of tissue to be analyzed (biopsy). Fine needle aspiration is another type of biopsy. It involves a thinner, hollow needle, which is inserted into the tumor to remove tissue. The needle is attached to a syringe, which is used to draw out (aspirate) a sample of tissue and fluid from the mass or tumor.
During video thoracoscopy, a thin tube with a built-in camera (thoracoscope) is inserted into the chest through a small surgical cut (incision) allowing a physician to view the lungs and obtain tissue samples. This is usually a formal operative procedure performed in an operating room, or similar setting, and may require a general anesthetic with a temporary breathing tube.
Sometimes, doctors may order a mediastinoscopy. This involves making a small cut near the top of the breastbone, which is the thin bone that runs down the center of the chest. A small thin tube called a mediastinoscope is passed through to allow doctors to view and take tissue samples from the mediastinum, which is the area between the lungs in the central region of the chest.
Distinguishing ALK-positive NSCLC from other forms is extremely important as there are targeted therapies for this form of cancer. A test known as fluorescent in situ hybridization or FISH may also be used to help diagnose specific subtypes. During a FISH exam, probes marked by a specific color of fluorescent dye are attached to a specific chromosome allowing to view a specific region of that chromosome. The test allows physicians to detect alterations in the genetic material of chromosomes including inversions such as the inversion on chromosome 2 that results in the fusion gene that causes EML4-ALK-positive NSCLC.
Staging
The International Association of the Study of Lung Cancer has proposed that physicians should adopt a different staging system called the Tumor Node Metastasis (TNM) Staging System, which is a common staging system for cancer developed by the American Joint Committee on Cancer. This system is based on the extent of the tumor, whether and to what extent cancer has spread to the lymph nodes, and whether cancer has spread (metastasized) to other areas of the body. It is a complex staging system. For more information on this staging system for NSCLC, visit the American Cancer Society: https://www.cancer.org/cancer/non-small-cell-lung-cancer/detection-diagnosis-staging/staging.html
It is important to note that prognostic information and survival rates for NSCLC are based on older adults since the majority of people with this cancer are over the age of 45. Many of these individuals have other health concerns that affect these percentages. Because NSCLC is so rare in the pediatric population, there are no prognostic or survival data for this age group.
Treatment
Treatment may require the coordinated efforts of a team of specialists. Physicians who specialize in the diagnosis and treatment of cancer in children (pediatric oncologists), physicians who specialize in the treatment of cancer with radiation (radiation oncologists), physicians who specialize in examining tissues and cells to find disease and determine what disease is present (pathologists), surgeons who specialize in removing cancer by surgery (thoracic surgeon), physicians who specialize in the diagnosis and treatment of lung disease (pulmonologists); nurses who specialize in the car and treatment of cancer (oncology nurses), psychiatrists, nutritionists, and other healthcare professionals may need to systematically and comprehensively plan treatment.
Psychosocial support for the entire family is essential as well. Several of the organizations listed in the Resources section provide support and information on lung cancer or lung disease.
Specific therapeutic procedures and interventions may vary, depending upon numerous factors, such as disease stage; tumor size; specific cancer subtype; the presence or absence of certain symptoms; an individual’s age and general health; and/or other elements. Decisions concerning the use of particular drug regimens and/or other treatments should be made by physicians and other members of the health care team in careful consultation with the patient based upon the specifics of his or her case; a thorough discussion of the potential benefits and risks, including possible side effects and long-term effects; patient preference; and other appropriate factors.
Because pediatric NSCLC is so rare, most treatment options are based on studies done on adult patients. The effectiveness of these treatment options, the optimal dosage, and the overall best treatment protocol for pediatric patients is unknown. Generally, there are three main treatment options: surgery, chemotherapy, and radiation therapy.
Surgery may be option for some individuals, especially those in whom the tumor that has not spread to other nearby lymph nodes. Surgical removal of the tumor may be curative, but there is a risk of recurrence of the cancer.
If surgery is not an option or the cancer has already spread to other areas of the body, then chemotherapy and radiation therapy, either separately or combined, will be recommended. Chemotherapy is the use of certain medications to slow down or stop the growth of cancer cells. Cancers cells grow and divide rapidly, which makes them susceptible to chemotherapy medications. Different combinations of medications may be used; this is called a chemotherapy regimen. The most common chemotherapeutic drugs used in adults are etoposide combined with cisplatin or carboplatin. This may be referred to as platinum-based chemotherapy because and carboplatin and cisplatin a platinum-containing compounds.
Radiation therapy is also often used to treat individuals with limited stage NSCLC. Radiation therapy uses x-rays or similar forms of radiation to directly destroy cancer cells. Radiation therapy is directed at the chest (thoracic radiotherapy) and is sometimes given at the same time as chemotherapy (chemoradiotherapy).
There is a risk of recurrence of NSCLC following successfully treatment with chemotherapy and radiation therapy.
According to the Genetic and Rare Diseases Information Center (GARD), there are three drugs that have been approved by the Food and Drug Administration (FDA) for childhood NSCLC (https://rarediseases.info.nih.gov/diseases/9343/non-small-cell-lung-cancer-childhood). These drugs are brigatinib (Alunbrig®), Crizotinib (Xalkori®), and Ceritinib (Zykadia®). These drugs are ALK-inhibitors, which means that they block the protein product from the EML4-ALK fusion gene. These drugs are approved for individuals with ALK-positive NSCLC.
Targeted therapies are being explored as potential treatments for individuals with NSCLC. Targeted therapies are drugs and other substances that prevent the growth and spread of cancer by blocking or inhibiting certain specific molecules (proteins) that are involved in the development of specific cancers. Generally, targeted therapies are less toxic than other treatments for cancer. Several research studies are ongoing to test various targeted therapies for NSCLC. More research is necessary to determine what genetic factors (e.g. altered genes) play a role in the development of NSCLC and what types of targeted therapies may be possible to treat these tumors.
Immunotherapy is the most recent addition to therapy for cancer. It is designed to enlist the body’s immune system to act against cancer. Clinical trials incorporating immune agents in SCLC are in the process of attempting to best define the use of these agents in treating this form of cancer. Several different immunotherapy drugs are being studied as potential treatments. A few of these drugs including atezolizumab, nivolumab, avelumab, and pembrolizumab are PD-L1 blockades, which release the “brakes” on the immune system that some cancers use to try to evade the immune cells. However, immunotherapy in NSCLC works best when patients have a lot of mutations in their cancer cells, which is not the case in pediatric NSCLC.
Information on current clinical trials is posted on the Internet at https://clinicaltrials.gov/. All studies receiving U.S. Government funding, and some supported by private industry, are posted on this government web site.
For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:
Toll-free: (800) 411-1222
TTY: (866) 411-1010
Email: prpl@cc.nih.gov
Some current clinical trials also are posted on the following page on the NORD website:
https://rarediseases.org/living-with-a-rare-disease/find-clinical-trials/
For information about clinical trials sponsored by private sources, contact:
https://www.centerwatch.com/
For information about clinical trials conducted in Europe, contact:
https://www.clinicaltrialsregister.eu/
JOURNAL ARTICLES
Kabir TF, Chauhan A, Anthony L, Hildebrandt GC. Immune checkpoint in pediatric solid tumors: status in 2018. Ochsner J. 2018;18:370-376. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6292483/
Mareng AS, Langer SW, Bodtger U. Primary pulmonary adenocarcinoma in a 16-year-old boy – a five-year follow-up. Eur Clin Respir J. 2016;3:10. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5102103/
Koodiyedath B, Owen A, Walker J, et al. Non small-cell lung cancer in a 15-year-old nonsmoker. J Thorac Oncol. 2012;7:e12-3. https://www.ncbi.nlm.nih.gov/pubmed/22895148
Goldstraw P, Ball D, Jett JR, et al. Non-small-cell lung cancer. Lancet. 2011;378:1727-1740. https://www.ncbi.nlm.nih.gov/pubmed/21565398
Yu DC, Grabowski MJ, Kozalewich HP, et al. Primary lung tumors in adolescents: a 90-year experience. J Pediatr Surg. 2010;45:1090-1095. https://www.ncbi.nlm.nih.gov/pubmed/20620301
Kayton ML, He M, Zakowski MF, et al. Primary lung adenocarcinomas in children and adolescents treated for pediatric malignancies. J Thorac Oncol. 2010;5:1764-1771. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4243865/
Dishop MK, Kuruvilla S. Primary and metastatic lung tumors in the pediatric population: a review and 25-year experience at a large children’s hospital. Arch Pathol Lab Med. 2008;132:1079-1103. https://www.ncbi.nlm.nih.gov/pubmed/18605764
INTERNET
Shaw AT, Solomon B. Anaplastic lymphoma kinase (ALK) fusion oncogene positive non-small cell cancer. UpToDate, Inc. Mar 25, 2019. Available at: https://www.uptodate.com/contents/anaplastic-lymphoma-kinase-alk-fusion-oncogene-positive-non-small-cell-lung-cancer Accessed May 7, 2019.
Keith RL. Lung Carcinoma. Merck Manual Online website. March 2018. Available at: https://www.merckmanuals.com/professional/pulmonary-disorders/tumors-of-the-lungs/lung-carcinoma Accessed May 7, 2019.
American Cancer Society. Non-Small Cell Lung Cancer. Available at: https://www.cancer.org/cancer/non-small-cell-lung-cancer.html Accessed May 7, 2019.
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