Laryngeal cancer is among the life-threatening conditions that affect the head and neck region. The larynx is a structure that actively participates in the production of speech and facilitates the processes of respiration and swallowing, and malignancies that affect it have a significant impact on these functions. This paper is aimed at reviewing credible information about this type of cancer with attention to symptoms, risk factors, pathophysiology, detection, and treatment.
Laryngeal Cancer: Description and Epidemiology
As is clear from the term, laryngeal cancer refers to a type of cancer that is formed in the tissues of the larynx, also known as the voice box. Malignancies that affect this structure belong to the cancers of the head and the neck and present the second most common disease in this group. In the aforementioned group, cancers of the larynx account for about 25% of cancer cases in U.S. patients (Tamaki et al., 2017). However, this disease is by far not the most widespread type of cancer if all cancers are considered.
Laryngeal cancer is much less frequent compared to lung, breast, colorectal, and other cancers. On average, 12.000 new cases of laryngeal cancer are diagnosed in the U.S. every year (Tamaki et al., 2017). As per rough estimates, the disease claims the lives of more than 3.500 U.S. citizens every year, which makes it responsible for about 0.3% of all deaths caused by cancer (Tamaki et al., 2017). Together, cancers affecting the oral cavity, the larynx, and the pharynx represent almost 4% of cancer cases in the U.S. (National Comprehensive Cancer Network, 2018). The median age at which laryngeal cancer is diagnosed is 65 years, and modern researchers also note the presence of positive trends, including certain decreases in the number of new cases as a result of effective smoking cessation promotion measures (Tamaki et al., 2017). Notably, the disease is much rarer in female patients compared to men (Tamaki et al., 2017). This trend is probably associated with gender differences in the prevalence of pernicious habits, such as smoking.
Normal Physiology of the Larynx
The larynx can be defined as a tubular structure that is connected to the upper part of the trachea and houses the vocal cords. The structure’s functions include maintaining the airway, facilitating respiration, protecting the lungs from substances that could damage them if inhaled, and supporting phonation and coughing. The structure is composed of extrinsic muscles that connect the larynx to surrounding structures, intrinsic muscles, including respiratory and phonatory muscles, cartilage, and membranes. The respiratory muscles are involved in supporting breathing and moving the vocal cords apart, whereas the phonatory muscles move them together. The larynx is composed of three unpaired cartilages, including cricoid, epiglottis, and thyroid, and three smaller paired cartilaginous structures, such as cuneiform, the cartilage of Santorini, and the arytenoid cartilages (Tamaki et al., 2017). The superior and inferior laryngeal arteries that arise from thyroid arteries supply the upper and lower parts of the larynx with blood.
As for the internal structure, the larynx has three important subsites, including subglottis, glottis, and supraglottis. A variety of structures can be found in the supraglottic area, including aryepiglottic folds that protect the airway when swallowing food, the arytenoids that facilitate the movement of the vocal cords, and the epiglottis and false vocal cords that close the laryngeal inlet to prevent foreign bodies from accessing the airways (Tamaki et al., 2017). During the act of swallowing, the larynx rises to the epiglottis, thus temporarily blocking the respiratory tract, and then relaxes and returns to its natural position. The glottis is composed of the vocal cords that are involved in the production of voice, the anterior commissure, and the inter arytenoid area, whereas the subglottic area starts below the vocal cords and ends near the very first ring of the trachea.
Pathophysiology of Laryngeal Cancer
All three subsites of the larynx can be affected by laryngeal cancer, and the disease impacts the structure’s functions to a large extent. In the majority of cases, laryngeal cancers are represented by squamous cell carcinomas or cancers that begin to form in flat cells of the larynx that line the insides of the structure (Tamaki et al., 2017). Among other, less common pathologies are sarcomatoid, verrucous, and neuroendocrine carcinomas, adenocarcinomas, minor salivary gland tumors of the larynx, different types of neuroendocrine tumors, and so on (Tamaki et al., 2017). The effects of the discussed disease on the larynx and overall well-being are tremendous.
The formation and progression of laryngeal cancer lead to multiple difficulties when performing the vocal function. They include sudden abnormal changes of the voice without external stressors, such as intensive shouting or injuries to the vocal cords. Laryngeal cancer forming on or spreading to the vocal cords can affect this structure’s mobility, thus limiting the patient’s ability to produce sounds and control different characteristics of the voice. Aside from issues related to vocal function, the disease can result in constant pain in the affected region or the ears, as well as breathing difficulties.
Laryngeal cancers can be classified based on the three regions introduced in the previous section. Glottic cancers represent more than half of all cases of laryngeal cancer and typically have the form of squamous cell tumors that appear in the anterior part of the glottis, for instance, on the so-called medial surface of the vocal folds, and spread horizontally towards the anterior commission of the larynx (Tamaki et al., 2017). Due to their typical location, glottic tumors often interfere with the mechanism of voice production, which leads to early and easily distinguishable voice changes. If glottic tumors are large enough, they can also affect the respiratory system’s work by compromising the airway. As for the next subtype, cancers that originate in the subglottal area are extremely rare and account only for 2-5% of all laryngeal cancers (NCCN, 2018; Tamaki et al., 2017). In patients with tumors in the subglottic area of the larynx, airway obstruction is also common.
Tumors in the supraglottic area are rather common and involve substantial risks of metastasis formation. Supraglottic tumors represent about one-third of all laryngeal cancers and are associated with increased risks of spreading due to the patterns of lymphatic drainage in the area (Tamaki et al., 2017). Cancers that originate in the glottic area of the larynx are more likely to spread unilaterally and have a reduced tumor propagation rate compared to supraglottic cancers (Tamaki et al., 2017). These differences can affect the selection of treatment options depending on the primary site of disease and affected areas of the larynx.
Genetic Influences, Epigenetics, and Other Risk Factors
The key risk factors are mainly linked to patients’ poor lifestyle choices and pernicious habits. Common addictive habits, such as the use of alcohol and smoking, are positively associated with the risks of the disease, and the concurrent presence of both habits is known to increase the risks even more (NCCN, 2018). According to medical research, compared to other H&N cancers, cancer of the larynx is more likely to stem from pernicious habits, with only 5% of cases occurring in non-drinking and non-smoking populations (Tamaki et al., 2017). An individual’s risks of developing the disease also increase as a result of harmful labor conditions and unfavorable environmental factors, such as continuous exposure to the waste products of wood processing and long-term asbestos exposure (Tamaki et al., 2017). Currently known risk factors are also presented by age, diet, and medical history characteristics, including the history of acid reflux and radiation therapy to the neck (Gaździcka et al., 2020; Tamaki et al., 2017). Also, human papillomavirus positivity is common in laryngeal cancer patients, but the cause-effect relationship between HPV and laryngeal cancer has not been established yet.
Considering the degree to which laryngeal cancer is predicted by pernicious habits, genetic influences and the family history of the disease do not act as the primary risk factors. Laryngeal cancer and other H&N cancers are not regarded as hereditary diseases, but the history of cancer in first-degree relatives is still supposed to contribute to the risks of this condition (Tamaki et al., 2017). As it has been mentioned, the cases of laryngeal cancer are rare in non-smoking/non-drinking patients, and the role of family history of cancer in this population is yet to be studied.
The tumorigenesis of cancer of the larynx and other H&N cancers is known to be related to epigenetic mechanisms and changes. As for DNA methylation patterns, modern researchers report that exposure to tobacco smoke and alcoholic drinks, the key risk factors for the discussed type of cancer, may alter methylation levels in different genes, and the same is true for HPV status (Gaździcka et al., 2020). In humans, the MGMT gene plays an important role in DNA repair processes, and increased methylation in this gene’s promoter can be found in the cases of H&N squamous cell carcinomas, including tumors of the larynx (Gaździcka et al., 2020). However, the links between this finding and patient characteristics are not thoroughly discussed in research (Gaździcka et al., 2020). Additionally, similar to other types of cancer decreases in the expression of the TET-1 gene are common in laryngeal cancer and might be associated with a poor disease prognosis (Gaździcka et al., 2020).
Clinical Presentation and Typical Primary/Late Indicators
Tumors in the larynx are associated with a variety of symptoms that depend on the size of the tumor, location, and stage of the disease. Some common presenting complaints include sounding hoarse when speaking, other changes to the voice, pain or dryness in the throat, stridor or noisy breathing, lumps in the throat, persistent cough, ear pain, and the loss of weight for no reason (Tamaki et al., 2017). Typical early indicators include voice changes/hoarseness for cancers originating in the glottis and painful swallowing for supraglottic cancers, whereas late indicators are presented by substantial weight loss, severe swallowing difficulties, aspiration, and airway obstruction (Tamaki et al., 2017). Importantly, in supraglottic and subglottic cancers, hoarseness presents a late symptom. Early changes to the voice are the reason why glottic cancers are often diagnosed earlier than other subtypes and result in better outcomes. The persistence of the aforementioned worrying symptoms should be considered to distinguish between laryngeal cancer and other, less dangerous conditions affecting the larynx.
Diagnostic Tools Involved in the Diagnosis
The tools used to diagnose laryngeal cancer include physical examinations, laryngoscopy, biopsy, and imaging tests. A complete physical examination of the H&N region should be conducted to check for lymph node swelling and evaluate the insides of the mouth and the throat with the help of a mirror (Tamaki et al., 2017; NCCN, 2018). Fiberoptic laryngoscopy is the examination of the voice box with the help of a tiny and flexible telescope, and it can be performed to conclude the patient’s condition (NCCN, 2018). Other diagnostic methods mentioned in the NCCN (2018) guidelines related to the management of glottic and supraglottic tumors include the use of biopsy of the primary tumor and FNA (fine-needle aspiration) biopsies of the neck.
Different imaging tests also find extensive use in diagnostic interventions, and their results support stage identification by shedding light on whether the disease has started to spread. The tests used in the cases of suspected supraglottic and glottic laryngeal cancers include both contrast and non-contrast computer tomography scans of the chest, contrast magnetic resonance imaging of the neck, and contrast-enhanced computer tomography studies of the neck and the primary site “with thin angled cuts through larynx” (NCCN, 2018, p. 43). Imaging studies are extremely helpful in determining the stage of the disease since they help to visualize the region and the lymphatic system of the neck, including the parts that cannot be assessed and evaluated during laryngoscopy. Other tests that are sometimes used to check for the signs of cancer and determine the possible outcomes of surgical procedures include dental assessments, assessments of the speech/swallowing functions, and pulmonary function tests (NCCN, 2018). These tools may provide further information on the stage of the disease and the risks of complications during treatment, in particular, conservation surgeries.
Treatment and Management of Laryngeal Cancer
There are several surgical and non-surgical treatment options for patients with diagnosed laryngeal cancer. Non-surgical methods include external beam radiation therapy that can be used in stage 1 and 2 cancer, as well as in some stage 3 laryngeal tumors to direct specific doses of radiation at cancerous tissues, thus destroying their cells and causing tumors to shrink (Tamaki et al., 2017; NCCN, 2018). In more advanced tumors, radiation therapy can be implemented after surgical treatment or to treat patients that are classified as poor candidates for surgery (Tamaki et al., 2017). Chemotherapy is another recommended non-surgical method that is a systemic treatment aimed at inhibiting the spread of cancer by preventing the growth and multiplication of cancer cells, and it has prominent side effects, including damage to healthy cells. In laryngeal cancer, the recommended agent for chemotherapy is cisplatin. If combined with radiotherapy, cisplatin adds benefits to radiation treatment, and this combination of methods is recommended for use in fit individuals with locally advanced tumors (NCCN, 2018). Both options have been shown to positively affect cancer survival rates.
The currently used surgical treatments range from micro laryngeal minimally invasive surgeries to total removal of the larynx. Laser-assisted microsurgeries are mainly used to resect stage 1 and 2 tumors that do not involve bilateral arytenoids, but the adequacy of resection is not always easy to ensure (Tamaki et al., 2017; NCCN, 2018). Open surgeries used in laryngeal cancer include vertical hemilaryngectomy. It is often used in stage 1, 2, and 3 glottic tumors, involves total removal of the affected vocal cord and a part of the shield-like cartilage and is associated with rather high 5-year survival rates – 83% and 67% for patients with stage 1 and 2 cancer, respectively (Tamaki et al., 2017). Open partial supraglottic laryngectomies are used in stage 1 and 2 supraglottic tumors and some stage 3 cases (NCCN, 2018). Because of the risks of post-surgical aspiration, there are multiple contraindications for such surgeries, including decreased lung function. The effects of partial laryngectomies on the disease’s pathophysiology vary depending on multiple factors, but these operations are generally expected to facilitate the total removal of laryngeal tumors or increase the effectiveness of other treatments.
Near-total and total laryngectomies are surgical approaches implemented in more advanced cases. Near-total laryngectomies are used in stage 3 and 4 laryngeal cancer, but not often, and total laryngectomies are usually performed in stage 3 and 4 tumors that do not respond to non-surgical methods (Tamaki et al., 2017). Laryngectomies with thyroidectomies and lymph node dissections can be performed in these types of tumors. In very advanced laryngeal and other H&N cancers with distant metastases, NCCN (2018) recommends considering the aforementioned treatments and systemic therapy (single-agent or combination) and implementing appropriate palliative care.
Common Areas for Metastasis and Prognosis
The spread of tumors to secondary sites has a huge impact on the chances of recovery. The most common areas for metastasis include the lymph nodes of the neck. Tumors of the structures in the supraglottic area can grow superiorly and circumferentially, and the area’s rich lymphatic system (the area drains into the upper, middle, and lower jugular lymph nodes of the neck) promotes the spread of tumors and early formation of metastases, sometimes bilateral (Tamaki et al., 2017). In contrast to that, the lymphatic supply to the glottic larynx is quite poor, which has implications for the timing and the type of spread. Distant metastases are also possible in laryngeal and other H&N cancers, but they are uncommon at initial presentation (NCCN, 2018). The most common site of distant metastases in the lungs and chest CT scans are prescribed to check for their presence (NCCN, 2018).
As for disease prognosis, the chances of recovery vary based on the subsite of the larynx affected by the disease. Due to early symptoms related to voice changes, glottic cancers are detected earlier than other laryngeal cancers and have a survival rate between 80% and 90% (NCCN, 2018). For all cases of laryngeal cancer, a 5-year survival rate exceeds 60% (Tamaki et al., 2017). The known predictors of poor outcomes include lymph node involvement and the presence of a rapid tumor growth rate (Tamaki et al., 2017). Certain histological variants of laryngeal cancer are also supposed to affect disease prognosis. For instance, basaloid squamous cell carcinomas are reported to have a poorer prognosis compared to other known variants (Tamaki et al., 2017).
Finally, laryngeal cancers are mainly presented by squamous cell carcinomas and have different symptoms, incidence, and survival rates depending on the location of a primary tumor. Laryngeal cancer belongs to the number of diseases that mainly occur in individuals making poor lifestyle choices, including smoking. This risk factor has significant implications for disease prevention recommendations and acts as another reason to popularize a healthy lifestyle among the general population.
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Tamaki, A., Miles, B. A., Lango, M., Kowalski, L., & Zender, C. A. (2017). AHNS series: Do you know your guidelines? Review of current knowledge on laryngeal cancer. Head & Neck, 40(1), 170-181. Web.