Ryan P. Smith, MD and Christine Hill-Kayser, MD
The Abramson Cancer Center of the University of Pennsylvania
Last Modified: February 26, 2008
The larynx, or voice box, is an area in the throat that contains an intricate mixture of cartilage and muscles. Not only is it responsible for producing our voice, but also performs other complex functions such as protecting our airway during swallowing. The larynx is divided into three separate regions: the supraglottic larynx, the glottis, and the subglottic larynx. The glottis is the region that contains the true vocal cords, thin strips of cartilage that vibrate together to produce sound. It is protected in the front by the large thyroid cartilage, which can be felt as the "Adam's apple" in our neck. When you feel for your Adam's apple, directly under that large piece of firm cartilage is the voice box, or the glottic portion of the larynx where the true vocal cords are located. Directly above the actual voice box is the supraglottic larynx, or supraglottis. This area contains some of the lining of the throat, cartilage and muscles that control the movement of the vocal cords, and the epiglottis, which is a flap of cartilage that closes over the voice box to protect our airway during swallowing. Below the vocal cords is the subglottic larynx, or subglottis. This area is the area of the throat and airway below the vocal cords but above the trachea. All three of these areas together are considered the larynx.
The definition of a tumor is a mass of abnormally growing cells. Tumors can be either benign or malignant. Benign tumors have uncontrolled cell growth, but without any invasion into normal tissues and without any spread. A tumor is called malignant (cancer) when tumor cells gain the propensity to invade tissues and spread locally as well as to distant parts of the body. In this sense, laryngeal cancer occurs when cells in the lining of the throat grow uncontrollably and form tumors that can invade normal tissues and spread to other parts of the body.
Cancers are described by the types of cells from which they arise. Over 95% of laryngeal cancers arise from the lining of the throat (not from the actual muscle or cartilage cells) and are called squamous cell carcinomas. Approximately 5% of these are called verrucous carcinoma, which have a wart-like appearance to them and are often less aggressive and slow-growing. Although there are other cancers that can arise in the larynx (salivary gland tumors-from minor salivary glands contained in the larynx, lymphomas of the larynx, and sarcomas-from muscle and cartilage cells), the vast majority are squamous cell carcinomas. Hence, these are the most commonly studied.
In addition to invasive cancers, patients are sometimes diagnosed with precancerous lesions, called carcinoma-in-situ. These most commonly occur in the glottis itself (where the true vocals cords are), as this area is more likely to produce early signs of disease. Carcinoma-in-situ occurs when the lining of the throat undergoes changes similar to cancerous changes without any invasion into the deeper tissues. Hence, while the cells themselves have cancer-like qualities, there is no risk of spread, as no invasion has occurred.
Laryngeal cancer occurs in approximately 12,000 Americans per year, causing about 4,200 deaths. It makes up one quarter to one third of all cancers of the throat. It has classically been thought of as a disease that affects older men. Most patients are diagnosed when they are in their fifties or sixties, and it only rarely occurs in younger people. In America, blacks have a significantly higher incidence of laryngeal cancer than do whites. In the 1950s and 1960s, 15 men had laryngeal cancer for every one woman. However, this ratio is decreasing, and in more recent studies, about five to six men are diagnosed with laryngeal cancer for every one woman. This almost certainly reflects the long-term effects of women starting to smoke as much as men.
Many risk factors have been implicated in the development of laryngeal cancer. These include chronic irritation from laryngitis or voice abuse, chronic gastric reflux, and exposure to certain chemicals, such as wood dust, nitrogen mustard, and asbestos. However, far and away the largest risk factor for the development of laryngeal cancer is smoking. Pipe smoking, cigar smoking, and cigarette smoking have all been strongly associated with the development of larynx cancer. There is also an association between heavy alcohol intake and laryngeal cancer. Although it has classically been thought of as a co-risk factor that only increases the risk of smoking, some more recent studies have shown that heavy alcohol use can increase the risk of laryngeal cancer by itself. It is estimated that heavy drinking increases the risk of laryngeal cancer by 2-6 times, while smoking increases the risk between 5-25 times, depending on how much one smokes. In a person who both smokes and drinks, the risk is increased to up to 40 times the risk of someone who neither smokes nor drinks. National public health measures have been implemented in the United States to attempt to decrease the abuse of tobacco and alcohol. Although no specific decrease has been seen yet, there is hope that these measures will lead to a decrease in the incidence of laryngeal cancers over the next 15 years.
Though there is some improvement in the smoking rates in younger people in the United States, there is still a large proportion using smokeless tobacco. This puts them at a higher risk of oral cavity, tongue, and lip cancer. People who use smokeless tobacco may also be at increased risk for developing cancer of the supraglottic larynx, although this risk is probably not as high as it is for people who smoke cigarettes, cigars, or a pipe.
Smoking is by far the strongest risk factor associated with the development of laryngeal cancer. Since it is fairly uncommon for a non-smoker to be diagnosed with laryngeal cancer, smoking cessation is the best way to prevent laryngeal cancer. In fact, not using tobacco of any kind, by either smoking or smokeless, is the healthiest thing anyone can do, both in terms of preventing laryngeal cancer, as well as the prevention of other throat cancers, lung cancers, and many other serious health problems.
Reducing alcohol intake may also be helpful in the prevention of laryngeal cancer, especially for people who smoke. Reducing other risk factors, such as chronic vocal irritation and gastroesophageal reflux may also be beneficial. A healthcare professional should be consulted for chronic health problems such as laryngitis or chronic heartburn.
Trials have been performed in the past investigating 13-cis-retinoic acid (found in vitamin A) for the prevention of second cancers after patients were cured of their first cancer. There was a large decrease in the incidence of these second cancers in patients who used 13-cis-retinoic acid. However, this has not yet been substantiated and is currently being tested in patients without a history of cancers. Regardless of the outcome, taking 13-cis-retinoic acid is by no means a substitute for smoking cessation.
Cancer of the larynx affects about 15,000 people per year, which is many fewer than breast cancer, lung cancer, and prostate cancer. Therefore, it is not large enough of a health problem to warrant screening of the general population. Some physicians have advocated screening in high-risk patients (heavy smokers), though screening program have not been proven to be beneficial, even in this population.
Hoarseness is often an early sign of laryngeal cancer; especially in cancer of the true vocal cords. Therefore, physicians should regularly screen their patients for complaints of hoarseness or changes in their voice quality and patients should bring the attention of their physicians to these symptoms. In these cases, patients should be referred to an otolaryngologist (an ear-nose-throat doctor) for evaluation. The laryngeal cancer detection rate in these situations is usually between 3-5%.
Signs or symptoms of larynx cancer are somewhat dependent on where the cancer is growing (supraglottis, glottis, subglottis). Patients with glottic cancer, or cancer that grows on the true vocal cords, often present with the early sign of hoarseness. This occurs because even a slight interference with the vibrating function of the vocal cords can produce voice changes. Hence, any long-standing hoarseness or voice changes should prompt a laryngeal examination. If hoarseness is ignored or if advanced disease occurs, airway obstruction, pain, or difficulty swallowing can result.
Supraglottic cancers usually do not produce early signs or symptoms, so supraglottic cancers are more often in advanced stage upon diagnosis. Hoarseness can also occur with supraglottic cancer, though usually later in the disease state. Also, in patients with supraglottic cancer, voice changes referred to as "hot potato voice" can occur. This can be described as the type of voice someone would speak in if they had a piece of hot food (potato) in their mouth. In addition to voice changes, patients can also present with pain, problems swallowing, or even ear pain, which can result from the involvement of nerves in the throat by the tumor. Supraglottic cancers often spread to lymph nodes in the neck, and many patients notice a lump in the neck as the first sign of cancer. Any lump or bump in the neck that does not go away within a few days should be evaluated by a physician.
Subglottic cancers are fairly rare, though they also fail to produce early symptoms. Therefore, they also present in more advanced stages and patients can have signs of disease similar to that of supraglottic cancers.
Again, these signs and symptoms are nonspecific and could represent a variety of different conditions-both benign and malignant. However, if you have any of these symptoms, especially if they are longstanding or if you are a smoker, you should see your physician.
The staging of a cancer basically describes how much it is grown before the diagnosis has been made, documenting the extent of disease. Glottic cancer often produces hoarseness early, causing it to be diagnosed earlier. Unfortunately, supraglottic and subglottic laryngeal cancer often present as a more advanced disease because of lack of early diagnosis, due mainly to the lack of specific symptoms that are associated with it. Before the staging systems are introduced, we will first discuss some background on how cancers grow and spread:.
Cancers cause problems because they spread and can disrupt the functioning of normal organs. One way larynx cancers can spread is by local extension to invade through the normal structures in the throat and into adjacent structures in the neck. These include the vocal cords themselves, the structures controlling voice and swallowing, the epiglottis (which is needed to prevent choking when swallowing), and even the cartilage and muscles surrounding the larynx. All cancers can spread via local extension, though this method of spread is particularly important in larynx cancer and other cancers of the throat. Tumor growth by local extension in the larynx can cause a patient's airway to be compromised or the swallowing function to be interrupted (which leads to problems eating and subsequent malnutrition), as well as causing the loss of the protection of the airway during swallowing which leads to choking and infection. Keep in mind that larynx cancers, when spreading via local extension, often spread from one subsite to the other (i.e.-glottis cancers can spread locally to involve the supraglottis). Sometimes, if cancers are locally advanced, it can be difficult to tell from which part of the larynx they originally grew.
Larynx cancer can also spread by accessing the lymphatic system. The lymphatic circulation is a complete circulation system in the body (somewhat like the blood circulatory system) that drains into various lymph nodes. When cancer cells access this lymphatic circulation, they can travel to lymph nodes and start new sites of cancer. This is called lymphatic spread. Larynx cancers differ in their propensity to spread, again based on the site of the larynx that the tumor involves. Supraglottic cancers have spread to the lymph nodes in over 50% of patients by the time a diagnosis has been made. This is in contrast to a pure glottic cancer (one that has not spread to the supraglottis or other sites within the throat by local extension) which spreads to the lymph nodes in less than 5% of patients upon diagnosis. However, keep in mind that once a cancer spreads from the glottis (the true vocal cords) to another subsite, it can spread to lymph nodes just as much as a cancer that originated in that other subsite. The first lymph nodes that cancer cells spread to are the "jugular chain" of lymph nodes which are found along the side of the neck. They can be found in front of the large muscles on either side of the neck that contract when the head is turned from side to side. Tumor cells that spread to the jugular lymph nodes can then spread to the "supraclavicular" lymph nodes (found behind the collar bone) and to other lymph nodes in the neck.
Larynx cancers can also spread through the bloodstream. Cancer cells gain access to distant organs via the bloodstream and the tumors that arise from this travel to other organs are called metastases. Cancers of the larynx generally spread locally or to lymph nodes before spreading distantly through the bloodstream. Hence, the incidence of distant metastases is generally thought to be 10% or less. However, as more patients are being cured of their local and lymph node disease, this incidence of distant metastases may climb. Although it increases with extent of disease in the throat and neck and is more common with supraglottic (and subglottic) tumors, distant metastases are still found in only a small number of patients diagnosed with laryngeal cancer (15% or less). If spread through the bloodstream does occur, the lungs are the most common site followed by the bones as the next most common site.
The staging system used in larynx cancer is designed to describe the extent of disease in both the throat itself and the neck (with spread to the lymph nodes). Both are important for treatment and need to be considered somewhat separately, as will be noted in the treatment section. The staging system used to describe laryngeal tumors is the "TNM system", as described by the American Joint Committee on Cancer. The TNM systems are used to describe many types of cancers. They have three components: T-describing the extent of the "primary" tumor (the tumor in the throat itself); N-describing the spread to the lymph nodes; M-describing the spread to other organs (i.e.-metastases). Since the different subsites of the larynx have different structures, the "T" portion (or local extent of disease) is described separately for each.
The "T" stage is as follows:
The "N" stage is as follows for any subsite:
The "M" stage is as follows:
The overall stage is based on a combination of these T, N, and M parameters:
Though complicated, these staging systems help physicians determine the extent of the cancer, and therefore make treatment decisions regarding a patient's cancer. The stage of cancer, or extent of disease, is based on information gathered through various tests done as the diagnosis and work-up of the cancer is being performed.
Clinical evaluation of a laryngeal cancer must include an evaluation of the throat. This can be done with a mirror, though it is more commonly done using a fiberoptic scope called a nasopharyngolaryngoscope. This is a camera attached to a long fiberoptic endoscope that is inserted into the patient's nose to view the throat. Medicine designed to numb the inside of a patient's nose is sprayed into the nostrils before the procedure to maintain comfort during the short exam during which the patient is awake. The entire throat down to the level of the vocal cords is evaluated with special attention to the surfaces of the throat and the movement of the vocal cords. This is followed by a direct laryngoscopy, which is done in the operating room under anesthesia. Since the patient is sleeping during this examination, a more thorough exam can be done with biopsies being done at that time. A careful examination of the neck is also required to detect spread of tumor to the lymph nodes.
Other procedures are needed to determine the stage of the tumor in a patient. CT scans ("CAT scans") or sometimes MRIs of the neck are done to further determine the extent of the disease, both in the throat and in the neck. A chest x-ray is also often ordered to rule out spread of tumor to the lungs. Other, more routine, tests done before treatment include blood screening tests, to insure that overall blood counts are within normal limits, and that a patient's liver, kidneys, and overall health are normal.
The treatment of laryngeal cancer has undergone changes in the past 10 years or so, mainly to reflect the desire to preserve a patient's voice box. In keeping with other aspects of laryngeal cancer, treatment can also differ greatly depending on subsite. In addition, there are different treatments available for early stage diseases that would not be used in someone with more advanced disease. Finally, treatment of larynx cancer should be thought of in two parts: Treatment of the throat itself (the primary tumor) and treatment of the neck (from spread to the lymph nodes). Your physician will need to address these somewhat separately, with a constant concern about spread through the bloodstream, or distant metastatic disease.
As stated above, glottic cancer (cancer of the true vocal cords) produces symptoms early. Therefore, patients can present with early lesions, or even pre-cancerous lesions (cancer-in-situ, or cancer that has not invaded into tissues). Cancer-in-situ of the vocal cords is highly curable and can be treated by microexcision, laser vaporization, or radiation therapy. Though all treatments produce sufficient cure rates, the treatment of choice is usually microexcision, with radiation therapy being reserved for more diffuse lesions.
As noted above, in patients with early glottic tumors (T1 or early T2-those without significant spread outside of the vocal cords), have very little chance of spread to the lymph nodes of the neck (<5%). Therefore, management can focus solely on the vocal cords themselves, and in a majority of cases, if the tumor is eradicated from the vocal cords, cure will result. This is especially true in patients with T1 tumors that, by definition, are limited to the vocal cords themselves. Again, in patients with T1 tumors, the treatment can be either radiation therapy or a fairly minor surgical procedure (laser excision or a partial laryngectomy-where a portion of the vocal cord is removed). Either radiation or surgery produces cure rates of approximately 90%. However, for patients with small, highly curable tumors, voice quality after therapy is also an important factor in selecting therapy. Many physicians feel that radiation offers patients the best chance of preserving voice quality, although it is still not the definitive choice over surgery in every case. The decision of which modality to choose must be an individual patient's decision and should be guided by the opinions of the treating physicians.
The management of T2 glottic cancers is similar to that of smaller tumors (T1). However, it is more complicated because a T2 glottic cancer can mean anything from a small tumor just outside the vocal cords to a larger tumor that causes some decreased movement in the vocal cord. Because it probably offers the best rate of vocal preservation, radiation is an excellent choice in early T2 lesions. For larger tumors, or if vocal cord movement is impaired by a tumor, a surgery called a hemilaryngectomy is often needed. A hemilaryngectomy removes a portion of the vocal cords, yet still leaves enough of the vocal cord behind to maintain a hoarse, but acceptable voice.
Many of the issues for early stage supraglottic cancers are the same as those for early stage glottic lesions. As far as treatment of the primary tumor in the throat, cure can often be achieved with radiation therapy alone or with voice-preserving surgery, such as the supraglottic laryngectomy, a specialized surgical procedure that removes the tumor but leaves much of the vocal cords intact.
A major difference between early stage glottic cancer and early stage supraglottic cancer is the chance of spread to the lymph nodes. As stated before, glottic cancer has very little risk of spread to the lymph nodes while a patient with a supraglottic cancer has a significant chance of having spread of tumor to the lymph nodes. Therefore, treatment of the neck must also be a concern. This is done in one of two ways: Either by using radiation therapy delivered to the entire neck, or through a surgical procedure called a neck dissection. Either modality can likely be used, and often it depends on which treatment is being used to treat the primary tumor. If radiation therapy is being used to treat the tumor in the throat, then radiation will likely be recommended as treatment to the neck. The same goes for surgery. Some patients who have surgery may also need radiation to the neck, if many lymph nodes are found to be involved with tumor or other features of the tumor warrant additional treatment.
Many times, cancer of the larynx grows too large to consider a minor surgical procedure for cure. For patients with more advanced tumors, radiation therapy alone is also unlikely to achieve cure. In the past, all of these patients would be required to have a total laryngectomy, a surgical procedure that removes the entire voice box. This leaves the patient with a hole in the neck to breathe through and without the ability to speak normally. This is still a very acceptable treatment, and the only treatment available in patients with very advanced tumors in their throat. Obviously, it leaves the patient with functional disabilities, but is efficacious in treating the cancer itself.
Some centers are currently making use of investigational robotic surgical procedures, referred to as “transoral robotic surgery” (TORS). These procedures allow surgeons to access the supraglottic and glottic regions by way of the mouth, to reduce surgical morbidity. They may also allow surgeons to perform more limited surgical procedures than total laryngectomy; however, the indications for robotic surgery are still dependent on in the individual patient and individual tumor.
Many physicians have investigated "organ-sparing" treatment for advanced laryngeal cancers. The organ preservation approach makes use radiation in combination with chemotherapy to attempt to cure the patient of his or her cancer without requiring a total laryngectomy. This type of treatment was first investigated by a large study conducted by the Veterans Affairs Medical Center. In this study, patients with advanced laryngeal cancer were randomized to one of two treatments – total laryngectomy or chemotherapy followed by radiation therapy. Patients in the two groups had similar cure rates and survival, but the rate of voice preservation was higher for group who had chemotherapy and radiation therapy. Recently, a large study was presented in which patients who had chemotherapy and radiation therapy at the same time had an even higher rate of keeping their larynx. Therefore, this is what many physicians offer their patients who desire to attempt to keep their larynx intact.
Organ preservation treatment, usually consisting of use of radiation and chemotherapy together, should not be undertaken lightly. The combined use of chemotherapy and radiation therapy can have severe side effects, both during treatment and after. Most patients who undergo this treatment will have severe pain with swallowing during their radiation therapy. The pain may be severe enough to cause malnutrition, so many patients require a feeding tube during the treatment. Symptoms of pain get better after the treatment is completed, and feeding tubes can usually be removed in the months after radiation therapy is complete.