Continuing Education Activity

Laryngeal cancer represents one-third of head and neck cancers and is a significant source of morbidity and mortality. A significant health concern worldwide, laryngeal cancer affects individuals of all ages and backgrounds, most often patients with a significant smoking history. Different sites of the larynx are involved, and the site involved influences the presentation, patterns of spread, and treatment options. Early-stage disease is usually highly curable with either surgical or radiation monotherapy, often larynx-preserving. Late-stage disease is associated with worse outcomes, warrants multimodal therapy, and is less likely to allow for the preservation of the larynx.

This course is designed to provide healthcare professionals with comprehensive knowledge and updates on the diagnosis, management, and treatment of laryngeal cancer. It reviews the prevalence, incidence, associated risk factors, and underlying disease pathophysiology. The clinical presentation, diagnostic modalities, and available treatment options for laryngeal cancer are thoroughly discussed. While highlighting the pivotal role of an interprofessional healthcare team, this activity will also explore the latest advancements in the field and the long-term survivorship needs of affected patients. 

Objectives:

• Identify the factors associated with an increased risk of developing laryngeal cancer.

• Assess the typical presenting features of patients with laryngeal cancers.

• Differentiate considerations that influence the management of laryngeal cancers.

• Communicate with a structured interprofessional team to provide effective care and appropriate surveillance of patients with laryngeal cancers.

Introduction

Laryngeal cancers represent one-third of all head and neck cancers and may be a significant source of morbidity and mortality. Laryngeal cancer encompasses cancers primarily originating from any of the 3 subdivisions of the larynx: the supraglottis, glottis, and subglottis, and each maintains its own staging system (see Image. Anatomy of the Larynx). Squamous cell carcinoma is the most common histologic subtype, with nearly all squamous cell carcinoma variants described in this anatomic location.[1][2] Other very rare histologies include sarcomas of the laryngeal skeleton, minor salivary gland carcinomas, melanoma, and lymphomas, among others.[3][4][5] All are most often diagnosed in patients with significant smoking history, who are also at risk for cancers in the remainder of the aerodigestive tract, though confounding associations with ethanol consumption (supraglottis) and various environmental exposures such as Agent Orange, asbestos, or various metal-working occupational fumes (all subsites), also exist.[6][7][8] Primary subglottic cancer portends a bleak prognosis and is also quite rare.[2] Unlike areas of the oropharynx, such as Waldeyer's ring, the association with Human Papillomavirus (HPV) is not nearly as robust. While HPV-related oncogenetic pathways, such as p16, have been described in laryngeal carcinomas, the etiologic and prognostic significance of viral-related oncogenetic pathways remains to be elucidated.[9][10]

Each primary subsite of laryngeal carcinoma carries different implications in symptomatic presentation, patterns of spread, prognosis, and treatment paradigms. Early-stage disease is often highly treatable or curable in the supraglottis and glottis, though prognosis remains poor in the subglottis. Early-stage (Stage I or II) can be treated successfully with monotherapy, meaning a single-modality of treatment, either surgical or radiation therapy, which is often larynx-preserving.[11] In contrast, advanced-stage disease (Stage III or IV) has a much poorer prognosis across all subsites, though the pattern is maintained in that glottic primaries often have the best outcome, followed by supraglottic and then subglottic primary tumors.[12] Advanced-stage laryngeal cancer warrants multimodal therapy, which can include surgery followed by radiation therapy, primary chemoradiation therapy, or a combination of all 3 methodologies.[13]

All of the above generalizations apply only to laryngeal squamous cell carcinoma. Minor salivary gland carcinoma of the larynx, melanoma of the larynx, and other, more esoteric carcinomas of the larynx are treated most often in clinical trials, as their rarity precludes definitive treatment recommendations.[14] Sarcoma of the larynx, particularly chondrosarcoma (the most common subtype), is best treated surgically and is a somewhat rare case where the overall prognosis is quite good, while the treatment cost (often total laryngectomy) is severe.[15]

Etiology

Smoking is the most significant single risk factor for cancers of the larynx, associated with more than 70% of all cases.[16] Any history of smoking portends higher risk, with current smokers exhibiting increased relative risk versus ex-smokers overall and increased relative risk for supraglottic versus glottic cancers. An association with heavy alcohol consumption has also been characterized, though the independent effect of alcohol is not clear given that combined use with tobacco is noted in most cases. Marijuana smoking may play a role as a risk factor in younger patients.[17]

Other risk factors for laryngeal cancer include the following:

• Long-term secondhand smoke exposure (odds ratio of 1.2 when lifelong secondhand exposure exceeds 20,000 hours) [18]                                                                                                                                          
• Male sex (Historically, laryngeal cancer is 4 to 5 times more common in men than women.)                                                   
• White or black race (North American data has documented significantly higher incidence of tobacco-related cancers in whites and blacks when compared to Asian-Americans and Hispanics.) [19]                                                   
• Genetic and other syndromes (Fanconi anemia, Plummer-Vinson syndrome, dyskeratosis congenita, among others, predispose to laryngeal cancer.) [2][20][21]                                                                                          
• Occupational and environmental exposures (Agent Orange, asbestos, nickel fumes, sulfuric acid mist, wood dust, and others all increase the risk of laryngeal carcinoma.) [2][22][23]

Epidemiology

Laryngeal cancer comprised 13,150 new cases in 2017, representing roughly one-third of all head and neck cancers, with 3710 associated deaths. The mean age of patients is 65 years, with a higher proportion of males versus females and Blacks versus Whites. In recent years, age-adjusted incidence rates have decreased by about 2% annually, attributed to decreased rates of tobacco use.[24] Approximately 98% of laryngeal cancers arise in either the supraglottic or glottic regions, with glottic cancers being 3 times more common than supraglottic cancers and subglottic cancers, representing approximately 2% of all cases.[25] Early-stage cancers are highly curable, with local control rates ranging from 90% to 95% for T1 glottic cancers and 80% to 90% for early-stage supraglottic cancers. Furthermore, such early-stage cancers are generally amenable to vocal cord-sparing surgical therapy, providing patients with curative options for surgical or radiation therapy.[26] In contrast, locally advanced cancers demonstrate control rates ranging from 40% to 70%, with bulky and/or T4 disease responding best to laryngectomy. However, advances over the years have allowed increased laryngeal preservation and improved speech rehabilitation in patients receiving laryngectomy (see Image. Laryngeal Cancer).[12]

Pathophysiology

The vast majority of laryngeal cancers are squamous cell carcinoma. A minority of cases represent squamous cell variants, including verrucous, sarcomatoid, and neuroendocrine carcinoma. Verrucous and sarcomatoid carcinomas historically were regarded as radioresistant, though recent experience contradicts this notion.[27] Patterns of spread depend on the location of the primary tumor and the inherent lymphatic supply at that location. Laryngeal cancers are divided into supraglottic, glottic, and subglottic subsites, with pathophysiology and treatment differing according to the subsite. Supraglottic Tumors

The supraglottis is subdivided into suprahyoid epiglottis, infrahyoid epiglottis, false vocal cords, aryepiglottic folds, and arytenoids. Suprahyoid epiglottic tumors may grow exophytically and superiorly before inducing symptoms. In other cases, they may invade inferiorly into the tip of the epiglottis and destroy associated cartilage. Infrahyoid epiglottic tumors tend to grow circumferentially, involving the aryepiglottic folds; they can then further infiltrate inferiorly into the false vocal cords. They also invade anteriorly into the pre-epiglottic fat space and, subsequently, the vallecula and base of the tongue.

Early lymphatic involvement is a hallmark of supraglottic cancers, with 55% of patients having clinical evidence of nodal metastasis at presentation and 16% with contralateral involvement. Levels II, III, and IV of the cervical nodal basins are most commonly involved, with the ipsilateral level II nodes (jugulodigastric nodes) at highest risk.[28] Locally advanced tumors present a higher risk of nodal metastasis, either by bilateral tumor involvement that likewise increases the risk of lymphatic spread in the bilateral neck and/or by superior extension and invasion into the base of the tongue, vallecula, and pyriform sinus. Glottic Tumors

The apex of the ventricle represents the transition from supraglottic to the glottic larynx. The vocal cords range from 3 mm to 5 mm thick and terminate posteriorly at a commissure with the vocal process. They have a sparse lymphatic supply and thus do not present a risk of lymphatic involvement unless there is a supraglottic or glottic extension. Glottic cancers typically present confined to the anterior portion of the upper free margin of 1 vocal cord. They can induce vocal cord fixation by pure bulk, the involvement of intrinsic muscles and ligaments, or, more rarely, the involvement of the recurrent laryngeal nerve.[29] Subglottic Tumors

The subglottis extends superiorly from a point 5 mm below the free margin of the vocal cord and inferiorly to the inferior border of the cricoid cartilage (or 10 mm below the apex of the ventricle). They also have sparse lymphatic supply, with drainage collecting into levels IV and VI of the cervical nodal chain.[30][31]

Histopathology

The vast majority of laryngeal cancers are squamous cell cancers. Rarely other malignancies are involved, including adenocarcinomas, sarcomas, lymphomas, and neuroendocrine tumors. 

History and Physical

Patients are historically male with a history of current or past tobacco smoking, and chronic alcohol abuse is an additional risk factor. Hoarseness is the most common presenting symptom of glottic cancers due to vocal cord immobility or fixation, with pain with swallowing and referred ear pain potentially indicating advanced disease.[32] In contrast, pain with swallowing is the most common early symptom of supraglottic cancer, with hoarseness presenting later and indicating more advanced disease extending into the glottis.[33] Nodal metastases often present as fixed, firm, painless masses in the neck. Late symptoms across all subsites include weight loss, dysphagia, aspiration and its sequelae, and airway compromise.[34]

Establishing the timing and duration of the onset of symptoms, especially the lack of any aggravating or alleviating factors, is essential in accurately diagnosing laryngeal malignancy. Viral and other upper respiratory tract infections and laryngopharyngeal reflux (LPR) are the most common mimics of laryngeal malignancy in patients with risk factors. While gastroesophageal reflux (GERD)/LPR was historically thought to be a potential predisposing condition to laryngeal malignancy, this association has not been borne out in multiple studies.[35] As LPR/GERD is extremely common, and GERD is also precipitated by smoking, this is the most common red herring when evaluating a potential laryngeal cancer patient.[36] A thorough head and neck examination and upper aerodigestive endoscopy remain the mainstay of screening examinations for patients with risk factors for laryngeal malignancy.[37] Routine, population-based screening has not been shown to be effective; there is some data to suggest that screening for the highest-risk patients may be effective.[38] The most crucial physical examination component is the observation of the primary lesion, which can occur via direct laryngoscopy, mirror laryngoscopy, or, most often, via fiberoptic endoscopy. The objective is to assess the local extent of the tumor, note the size and involvement of adjacent structures, and evaluate the vocal cords' mobility.[37] Direct laryngoscopy offers an enhanced ability to delineate the extent of disease as well as the ability to obtain tissue specimens. A thorough neck examination is imperative, not only to assess for nodal metastasis but also for the extension of the primary lesion. Tenderness of the thyroid cartilage indicates direct tumor extension, and firm fullness palpated just superior to the thyroid notch classically indicates pre-epiglottic space invasion, though as with all physical signs in laryngeal cancer, there is a tremendous false-positive rate on physical examination findings alone.[39] Imaging, therefore, is also a crucial component of the workup of a laryngeal mass. A detailed cranial nerve examination is also important. Immobility of the vocal fold can suggest the involvement of the recurrent and/or superior laryngeal nerves or the vagus nerve directly, depending on the position of the fold. Accessory nerve weakness suggests involvement via either primary extension or extranodal spread, and likewise, lingual or hypoglossal nerve weakness may suggest extranodal spread or massive local tumor burden.

Evaluation

In addition to history, physical examination, and visualization of the larynx, other studies are necessary to formally diagnose and stage the cancer. Multiple methods of obtaining tissue are feasible. The most valuable include biopsy during direct laryngoscopy of the suspected primary lesion and fine-needle aspiration (FNA) cytology of any suspected nodal disease.

For all laryngeal cancers, imaging of the primary lesion and draining lymph nodes is indicated, usually achieved with contrast-enhanced computed tomography (CT) of the neck. This study visualizes the neck lymphatics, as well as structures that cannot be assessed adequately even with direct laryngoscopy, such as the subglottic region, pre-epiglottic space, inner table of the thyroid cartilage, paralaryngeal space, and extranodal extension, all of which are crucial for accurate staging.[34][40] If the cancer is clinically suspicious for an advanced stage, contrast-enhanced CT of the chest, as well as positron emission tomography (PET)/CT, is indicated to rule out distant metastases. Suspected invasion into the hypopharynx or cervical esophagus may prompt esophagogastroduodenoscopy (EGD) and/or barium swallow, which may differentiate the correct aerodigestive tissue of cancer origin.[40]

Before any definitive treatment is begun, additional hematologic studies are necessary, including a complete blood count, platelet count, liver and renal function panel, blood type, thyroid function, electrolytes, and albumin levels.

Certain factors are considered during the workup of laryngeal cancer and when determining if the patient is a surgical candidate. These factors help define the extent of oncologic surgery required and if any reconstructive surgery is expected to be needed and include the following:

• Vocal cord mobility/function of the larynx
• Presence of cervical or distant metastatic lesions
• Involvement of the base of the tongue
• Involvement of the paraglottic and pre-epiglottic space
• Involvement of the thyroid cartilage
• Involvement of the carotid artery and sheath
• Invasion of the esophagus
• Invasion of soft tissue and adjacent laryngeal muscles
• Involvement of neck lymph nodes

Treatment / Management

The management of patients with laryngeal cancer depends upon the stage of the disease and the subsite of the tumor at the time of treatment.

Early-Stage Laryngeal Cancer

Early-stage laryngeal cancers, including T1-2N0 (stage I and II) disease, are treated successfully with a single treatment modality. This is either radiation therapy or surgery.

T1-2N0 Glottic Cancer

Local radiation therapy or surgery is recommended, with a choice of modality highly dependent on provider experience and patient preference. Given the sparse lymphatic drainage of the true glottis, these modalities all share a common fundamental principle: they only address the primary tumor. Local control rates from retrospective experience are historically comparable between surgical approaches and radiation therapy. Voice-sparing surgery is an option in many, but not all, of these cancers. Patient and anatomic considerations may affect a patient's candidate for any surgical intervention, whereas most all patients are potential candidates for primary radiation therapy. If the larynx is functional and the cancer can be adequately resected via endoscopic (either transoral laser microsurgery [TLM] or transoral robotic surgery [TORS]) techniques, the outcomes (disease-specific survival and larynx preservation) were shown to be superior with surgery in the sole trial that directly compared these 2 patient populations.[41] In patients whose cancer cannot be oncologically resected endoscopically and would therefore require open laryngofissure or total laryngectomy, primary radiation therapy is a vastly superior option owing to local morbidity and mortality of the surgical options in these cases.

T1-2N0, Selected T1-2N1/T3N0-1 Supraglottic Cancer

Similar to early-stage glottic cancers, early supraglottic cancers can be managed with either larynx-sparing surgical or radiation therapy monotherapy, with demonstrated overall comparable efficacy. The major difference between glottic cancers is the management of the neck, given the risk of nodal metastases is significant in supraglottic tumors and requires addressing bilateral neck nodal basins.[42] Surgical approaches include endoscopic resection (TLM or TORS) or open partial laryngectomy (supraglottic or supracricoid laryngectomy) for T1-2 and low-volume T3 disease, with neck dissections often indicated in T2 or T3 lesions. Adjuvant radiation therapy is given to many patients, with common indications including positive nodal disease, extracapsular extension, and positive surgical margins. Definitive radiation therapy often includes at-risk cervical nodal stations, generally levels II to IV bilaterally.

Locally Advanced Laryngeal Cancers

Locally advanced cancers, inclusive of T3-4N1-3 disease, are more complex to treat and involve multimodality therapy (meaning either surgery followed by radiation therapy or a combination of chemotherapy and radiation therapy). These cancers, if surgically resectable, are not typically amenable to laryngeal preservation surgery, while definitive radiation concurrent with cisplatin chemotherapy remains an option for laryngeal preservation. In contrast to early-stage disease, the therapeutic approach to locally advanced disease is based on level I evidence, with combined chemotherapy and radiation demonstrating improved locoregional control and larynx preservation in patients with a functional larynx and no erosion of laryngeal cartilages. In T4 disease, laryngectomy and adjuvant radiation therapy have demonstrated similar locoregional control rates compared to chemoradiation and salvage surgery but improved overall survival. Larynx-preserving chemoradiation is therefore not recommended for T4 disease and is associated with inferior survival unless the patient is not a surgical candidate for overall medical reasons.[43][44][45]

Postoperative radiation therapy is relatively indicated in the case of advanced tumor and nodal stage on surgical pathology (pT3-4, pN2-3), as well as other high-risk pathologic features, including close margins (<5 mm), perineural invasion, lymphovascular space invasion, and extracapsular extension, and emergent tracheostomy due to morbid tumor invasion (to reduce risk of tumor spread into the tracheostomy). Moreover, close or involved margins, multiple positive nodes, and extracapsular extension necessitate the addition of chemotherapy concurrent with radiation therapy, thought induction, adjuvant, and neoadjuvant protocols have all been used with varying degrees of success when concurrent therapy is not possible. This scenario is often based on patient physiologic factors and may be somewhat predicted based on the patient's Eastern Cooperative Oncology Group (ECOG) status.[46][47][48][49]

Metastatic Laryngeal Cancers

Laryngeal cancer most often metastasizes to the cervical lymph nodes regionally, but the most frequent site of distant metastasis is the lung (followed by the liver and bones). If a solitary lung lesion is present, it is important to obtain a histologic diagnosis to confirm it is not a concurrent primary lung cancer (owing to the overlapping risk factors), as the treatment goals, options, and prognosis are different in M1 lung cancer versus M0 lung cancer and a primary lung cancer. With the presence of distant metastases, treatment for laryngeal cancer becomes systemic (chemotherapy and/or immunotherapy) and largely palliative in nature.[50] Some centers will propose surgical resection of a single pulmonary metastasis as a part of the treatment plan with curative intent in select patients.[51] Experience with this will vary by center and treatment team, but in experienced locales, it has shown promising results. Treatment of advanced-stage laryngeal cancer in the setting of a new primary lung cancer will benefit immensely from a tumor board or multidisciplinary team, and will depend on the stage, histology, and genetics of both tumors.

Non-Squamous Cell Laryngeal Malignancies

Squamous cell carcinoma and its many variants comprise the vast majority of laryngeal malignancy. Rarer tumors include minor salivary gland malignancy, such as adenoid cystic carcinoma, and mesenchymal tumors, such as sarcomas and melanoma. Their histology dictates the treatment of these rare tumors, where the relevant protocols are implemented but must include airway protection. Mucosal melanoma is always considered a stage IV disease and requires systemic therapy, with surgery reserved for exceptional circumstances or tracheostomy to allow respiration.[52] Adenoid cystic carcinoma is famously challenging to treat, and primary surgical resection (with potential postoperative radiation) is the mainstay. Likewise, sarcomas, with chondrosarcoma being the most common laryngeal variant, are treated primarily surgically. Unfortunately, this may mean that extensive surgery, including total laryngectomy, is required for adequate oncologic control of even early-stage tumors of the larynx of these rare histologies.[53]

Differential Diagnosis

Differential diagnoses to consider and rule out regarding laryngeal cancer include the following:

• Acute sialadenitis
• Reactive lymphadenitis
• Benign tumors 
• Branchial cleft cyst   
• Fungal laryngitis
• Chronic sialadenitis
• Contact granuloma
• Hemangioma
• Laryngeal papilloma
• Laryngocele
• Vocal cord polyp 
• Vocal cord nodule (singer's nodule)                                                                   
• Reinke edema
• Thyroglossal duct cyst                                                     
• Gastroesophageal reflux disease                   
• Granulomatous disease (ie, Wegener granulomatosis)                                     
• Sarcoidosis                                                                                           
• Laryngeal tuberculosis                                                                                       
• Syphilis

Surgical Oncology

Three categories of surgery are employed in treating laryngeal cancer: endoscopic/transoral surgery, open framework surgery (partial laryngectomy), and total laryngectomy.

Endoscopic and Transoral Surgery

These operations are performed via the mouth or using a variety of laryngoscopes, and so may not be possible in all patients as some degree of line-of-sight exposure must be achievable. For the purposes of this review, laser ablation via flexible laryngoscopy is not included as it is most commonly used for premalignant lesions, though some authors are employing this technique for T1 disease.[54]

• Endoscopic cordectomy

This technique is suitable for T1 and select T2 glottic cancers and is most commonly performed using a CO2 laser, though it is technically possible to perform using cold micro-laryngeal instruments as well. This technique involves removing the affected vocal fold, and the European Laryngological Society has described a classification for the different types of cordectomy based on the extent of resection (see Table 1. European Laryngological Society Endoscopic Cordectomy Classification).[55] Tumors extending onto the laryngeal surface of the false vocal fold can also be addressed. Tumors that extend into the anterior commissure or onto the contralateral cord are associated with a higher recurrence rate at the anterior commissure and are likely better treated with radiation therapy or open surgery as a result. This is presumed to be due to tumor tracking along the insertion of the ligament into the thyroid cartilage.[56]

Table 1. European Laryngological Society Endoscopic Cordectomy Classification 

• Endoscopic supraglottic laryngectomy

This operation is performed for T1 and T2 cancers of the supraglottis and can be performed transorally using a laser or a robot; and is also known as a horizontal partial laryngectomy. This operation was initially developed as an open, transcervical surgery and then modified for endoscopic approaches. The open technique and tissue resected differs slightly from the endoscopic approach, and the open operation will be discussed later in this review. The European Laryngological Society has also published a classification system for endoscopic supraglottic laryngectomy based on the tissues removed (see Table 2. European Laryngological Society Endoscopic Supraglottic Laryngectomy Classification).[57] All involve removing tumors of the supraglottis, and as such, the baseline lung function of the patient is important to consider, as postoperative microaspiration is relatively common, but outcomes are good in properly selected candidates.[58] Extension of the tumor onto the true glottis, as well as transglottic extension, form the only absolute contraindications to supraglottic laryngectomy.[59]

Table 2. European Laryngological Society Endoscopic Supraglottic Laryngectomy Classification

Open Framework Surgery (Partial Laryngectomy)

• Vertical partial laryngectomy

Employed for T1, T2, and select T3 glottic tumors, this is the open counterpart to endoscopic cordectomy and, with the expanding use and availability of endoscopic resection, is used far less commonly today. The classic operation removes the entire vocal cord en bloc with the underlying portion of thyroid cartilage from the anterior commissure to the ipsilateral arytenoid, sparing it. An extended vertical partial laryngectomy can encompass resection of part of the arytenoid or the entire anterior commissure also, though this often necessitates resecting a portion of the contralateral vocal fold as well.[60] Subglottic extension, or involvement of more than one-third of the contralateral vocal fold are contraindications to vertical partial laryngectomy.[61]

• Open Supraglottic Laryngectomy

Employed for T1, T2, and select T3 tumors of the supraglottis, this operation involves the removal of all supraglottic structures, including the epiglottis, upper portion of the thyroid cartilage, hyoid, and false vocal folds. Contraindications include transglottic tumors, extensive tongue base involvement, cricoid cartilage involvement, pyriform sinus involvement beyond the uppermost edge, poor swallowing function or pulmonary reserve (as much of the protective function of the supraglottis will be compromised by resection and microaspiration is common postoperatively).[62] A temporary tracheostomy is typically required, but most patients are decannulated before discharge home from the hospital.

• Supracricoid laryngectomy

Supracricoid laryngectomy is employed for T3 and select T4 tumors of the glottis or supraglottis that are not amenable to supraglottic laryngectomy due to involvement of 1 or both vocal folds but spare at least 1 arytenoid. Resection includes the thyroid cartilage, both false vocal folds, and can include ipsilateral true cord and arytenoid but MUST spare at least 1 functioning arytenoid.[63] Once the resection is performed, the remaining larynx is then suspended to the hyoid (cricohyoidopexy) or epiglottis (unless this was resected- cricohyoepiglottopexy) to maximize postoperative swallowing function [63][64], and a tracheostomy is required at the time of surgery, and can be required permanently. The voice outcomes are commonly described as poor after supracricoid laryngectomy, though may be quite similar to their immediate preoperative voice. Most patients are able to phonate intelligibly and use a telephone.[65]

Total Laryngectomy

This surgery is employed for T3-4 disease when there is cartilage invasion or when the larynx is nonfunctional or as a salvage option in cases of recurrence after prior radiation therapy. Total laryngectomy involves the removal of all supraglottic, glottic, and subglottic tissue from the tongue base to the superior trachea and the creation of a permanent tracheostoma in the anterior neck for respiration.[12] This surgery can be extended to include portions of the tongue base or lateral pharynx if there is tumor involvement (extended total laryngectomy) or can include the entire pharynx as well (laryngopharyngectomy). This completely separates the lower airways from the oral and nasal cavities, so intubation via the mouth or nose is no longer possible, and the patient is an obligate neck-breather. Reconstruction of the neopharynx will depend on the extent of the tumor (and amount of additional pharynx resected) as well as prior treatment. Primary closure is often possible if the remaining pharyngeal mucosa can be closed over a 10 mm Montgomery tube without tension; if this is not possible, a reconstructive flap (regional or free flap) should be considered.[66] The use of a vascularized flap for closure has been shown to decrease the rate of pharyngocutaneous fistula in those at high risk (prior radiation, extra-laryngeal extension, extended laryngectomy), as well as decrease the duration of the fistula in those who developed that, and so should be routinely employed in such patients.[67]

Radiation Oncology

Radiation therapy for laryngeal cancer is given as external beam radiation therapy (as opposed to brachytherapy, where radiation-eluting implants are surgically placed into a tumor), and a cumulative dose of ≥60 Gy (average 60 Gy to 66 Gy) is considered curative for laryngeal carcinoma.[68][48] This total radiation dose must be broken up over the course of treatment (fractionated) into smaller doses given at each treatment session to minimize adverse effects. A typical schedule is 1 fraction daily, Monday to Friday, for 6 weeks.[48] The radiation fields (volumes) can be further tailored to the tumor's shape and at-risk lymphatic beds (conformal radiotherapy) while minimizing radiation sequelae to surrounding structures. The radiation dose given at each fraction and the time between fractions can also be adjusted to further minimize toxicity and maximize tumor effect.[69]

Intensity-Modulated Radiation Therapy 

Intensity-modulated radiation therapy (IMRT) is the primary type of radiation therapy used in the treatment of laryngeal cancer (and in head and neck cancers in general). It is a form of conformal radiation therapy that uses computers to generalize a map of the tumor and to use multiple external beam sources of varying intensities to maximize the radiation dose given to the tumor itself while minimizing exposure to surrounding structures. Despite this precision, there are significant potential adverse effects of IMRT, including dry mouth (xerostomia), dysphagia (which may be very delayed-onset, even developing years after the conclusion of treatment) [70], odynophagia, lymphedema of the neck, hypothyroidism, dysgeusia, and radiation dermatitis.[71] The most bothersome adverse effects during treatment include mucositis and dermatitis, as the epithelial cells are very radiosensitive. The most significant long-term effects include hypothyroidism, xerostomia (the thyroid and salivary glands are also extremely radiosensitive), and dysphagia.[72][73]

Volumetric Modulated Arc Therapy 

Volumetric modulated arc therapy (VMAT) is a variant of IMRT wherein a constant dose of radiation is given while the machine source rotates 360° (or 180° in half-arc planes) around the patient's body. This is 1 technique employed to minimize the exposure of non-tumor structures, particularly the carotid arteries, to treatment doses of radiation therapy.[74] Such protocols are sometimes used in treating laryngeal cancer, though perhaps not as frequently as static, opposed-wedge field IMRT plans.[75]

Hyperfractionated Radiation Therapy

This is a treatment protocol wherein a lower dose (fraction) of radiation is given more frequently (typically twice daily) over the standard treatment course, but the overall radiation dosage is the same. A lower dose given more frequently may mitigate some radiation therapy toxicities but can be extremely inconvenient for patients.[76]

Hypofractionated Radiation Therapy

This is a treatment protocol wherein a higher dose (fraction) of radiation is given each day over a shortened treatment course while the overall radiation dosage is the same.[77]

Accelerated Fractionation Radiation Therapy

This is a treatment protocol wherein the standard dose (fraction) of radiation is given each day over a shortened overall treatment course (for example, treating 6 days per week instead of 5), while the overall dosage remains the same.[78]

Treatment Planning

The basic tenet of laryngeal cancer treatment is that early-stage cancer (stages I and II) can be treated with single-modality therapy (surgery or radiation therapy; chemotherapy or immunotherapy is not used as a single-modality when treating with curative intent) [11], while late-stage cancer (stage III and IV) must be treated with multimodality therapy (surgery followed by radiation therapy, or primary radiation therapy with chemotherapy or immunotherapy, which can be given in either a concurrent or adjuvant fashion).[79] In early-stage cancer, the overall survival is equivalent when treated with radiation therapy or with surgery, so the treatment decision is made using patient factors (preference, anatomy that precludes endoscopic or robotic surgery, etc), as the secondary goal is to preserve a functional larynx.[11] 

Patients with advanced-stage cancer can achieve the same overall survival with either treatment regimen, with a few notable exceptions. If the larynx is nonfunctional, or if there is a high risk the larynx will be nonfunctional after nonsurgical treatment, then laryngectomy is the preferred treatment modality to prevent chronic aspiration and risk of pneumonia.[80] Also, if the patient has T4 laryngeal cancer or T3 due to cartilage invasion, the oncologic outcomes are superior with primary laryngectomy compared to nonsurgical treatment.[12]

Medical Oncology

Both chemotherapy and immunotherapy are used in combined-modality treatment for advanced-stage laryngeal cancer. Platinum-based chemotherapeutic agents (cisplatin, carboplatin) are first-line treatment for most laryngeal cancer, but these may be combined with additional agents such as 5-fluorouracil, paclitaxel, docitaxel, or methotrexate.[81] If patients are unable to receive chemotherapy (often due to comorbid medical conditions), then immunotherapy can potentially be used. Common immunotherapeutic agents include cetuximab, pembrolizumab, and nivolumab.[82] Neither chemotherapy nor immunotherapy are given as single-modality treatment with curative intent, though they can be used in this way for palliation.

Most chemotherapy and immunotherapy are given intravenously, and patients may require placement of long-term intravenous access, such as an indwelling port. The treating oncologist determines the timing of chemotherapy or immunotherapy administration and considers the patient's overall medical condition and other treatment modalities to be employed.[83]

Concurrent chemotherapy is chemotherapy given at the same time (concurrent with) radiation therapy. Typical schedules for cisplatin would include weekly infusions (cycles) for a total of 7 cycles or slightly higher doses given once every 3 weeks for a total of 3 cycles.[84] While concurrent chemoradiation therapy has been cited as having the best oncologic response, it also carries the most severe adverse-effect profile, and many patients struggle to complete concurrent treatment without a treatment break.[85]

Induction (neoadjuvant) chemotherapy is chemotherapy given prior to either surgery or definitive radiation therapy. The purpose is to assess the tumor response, either to shrink an unresectable tumor to render it resectable or to potentiate the effects of definitive radiation therapy. Some studies have suggested an overall survival benefit in induction chemotherapy for patients with resectable laryngeal cancer [86], while several clinical trials are ongoing using induction chemotherapy followed by combined chemoradiation therapy or radiation therapy in combination with a biologic agent.[87][88]

Adjuvant chemotherapy is chemotherapy given (typically in combination with radiation therapy) after surgical resection of the tumor. Adjuvant chemotherapy is given in advanced-stage laryngeal cancer with certain poor prognostic features seen on histology, including positive surgical margins, perineural invasion, lymphovascular invasion, and extracapsular spread or matted nodal disease based on comparative trials from the EORTC and RTOG.[89]

Staging

The staging of laryngeal cancer is crucial for determining prognosis and guiding treatment decisions. Staging also considers the specific subsite within the larynx affected, as each site carries distinct implications for prognosis and treatment options (see Image. Tumor and Nodal Staging of Laryngeal Cancer).

The American Joint Committee on Cancer (AJCC), 8th Edition Cancer Staging Manual bases primary tumor staging for glottic and supraglottic cancers on the local extent and the presence or absence of vocal cord fixation. With this staging, pathologic T staging is identical to clinical staging. Clinical and pathologic nodal staging is based on the size, number, laterality, and presence/absence of extranodal extension (ENE).

Stage groupings according to T, N, and M staging consider the size and extent of the tumor (T), involvement of regional lymph nodes (N), and the presence of distant metastasis (M). Laryngeal cancers are staged from I to IV, with higher stages indicating more advanced disease. Stage I tumors are limited to the larynx, while stage IV tumors have spread extensively. T3 to T4 disease or any nodal involvement is considered locally advanced for all subsites. 

Prognosis

The overall prognosis for laryngeal cancer is intimately linked to the stage of disease at the time of treatment. However, it is also affected by the patient's overall medical health and discontinuation of smoking. The overall 5-year survival for laryngeal cancer is 61% in the United States.[90]

If the cancer is confined to the larynx (stage I and II disease), the overall 5-year survival is 78%. Once positive nodal metastases are present (stage III disease), the 5-year survival drops to 46%, and if distant metastases are present, the 5-year survival is 34%.[91] Survivorship can be further examined by laryngeal subsite, with the overall prognosis being the best for glottic cancer, followed by supraglottic and then subglottic tumors.[92]

Glottis

Overall, 5-year survival for glottic SCC is 77%. If the disease is confined to the larynx (stage I and II), then 5-year overall survival is 84%, dropping to 52% if lymph node metastases are present (stage III disease), and further decreasing to 45% in the setting of distant metastases.[93]

Supraglottis

Overall, 5-year survival for supraglottic SCC is 45%. If the disease is confined to the larynx (stage I and II), then 5-year overall survival is 61%, dropping to 46% if lymph node metastases are present (stage III disease), and further decreasing to 30% in the setting of distant metastases.[94][95]

Subglottis

Overall, 5-year survival for subglottic SCC is 49%. If disease is confined to the larynx (stage I and II) then 5-year overall survival is 59%, dropping to 38% if lymph node metastases are present (stage III disease), and  44% in the setting of distant metastases.[96][97]

Complications

Complications of laryngeal cancer will depend upon the modality used to treat it and have been covered in more detail in the respective treatment sections of this review. Complications from radiation therapy for the treatment of laryngeal cancer are many and often include dysphonia, dysphagia, dysgeusia, mucositis, dermatitis, hypothyroidism, and persistent dry mouth. Complications from surgery will depend on the surgery performed and can include dysphonia, aphonia, aspiration, pharyngocutaneous fistula, shoulder weakness, bleeding, and infection.

Deterrence and Patient Education

Deterrence and prevention of laryngeal cancer primarily revolve around mitigating risk factors and promoting healthy lifestyle choices. Chief among these is the cessation of tobacco use, as smoking is the leading cause of laryngeal cancer. Encouraging smoking cessation programs and providing support for those looking to quit can significantly reduce the incidence of this disease. Similarly, limiting alcohol consumption, as well as avoiding excessive exposure to environmental carcinogens such as asbestos and certain industrial chemicals, can help decrease the risk of laryngeal cancer. Promoting a diet rich in fruits and vegetables, which are high in antioxidants and protective nutrients, may offer some protective benefits. Education campaigns highlighting the importance of regular screening and early detection can also aid in identifying precancerous lesions or early-stage tumors, potentially leading to more successful treatment outcomes. 

Enhancing Healthcare Team Outcomes

Managing laryngeal cancer is optimal with an interprofessional team that includes an ENT surgeon, oncologist, dietitian, pulmonologist, speech therapist, intensivist, radiation therapist, advanced care practitioner, nurses, pharmacists, and other healthcare professionals. The majority of patients first present with hoarseness, otalgia, dysphagia, and weight loss to the primary care clinician. Patients are typically male with a history of current or past tobacco smoking. A referral to an ENT surgeon should be made if the hoarseness is prolonged and associated with other features possibly indicating a malignancy. 

The most crucial physical examination component is an invasive assessment of the primary lesion, including indirect laryngoscopy, mirror exam, and often fiberoptic endoscopy. Due to the complexity of the disease, a multidisciplinary approach is warranted for evaluation and follow-up therapy. Collaborative strategic planning is essential to coordinate care effectively. Healthcare professionals must work together to develop comprehensive treatment plans tailored to each patient's unique needs and preferences. 

Post-treatment complications are common, and patients need close monitoring for airway patency. The outcomes for early-stage laryngeal cancer are good, but those with advanced cancer have a grim prognosis.[98][99] The patient and family require extensive education regarding procedures and follow-up care to obtain the best outcomes. Care coordination also involves connecting patients with support services, such as speech therapy, nutritional counseling, or palliative care, to address their holistic needs and improve overall quality of life.