Malignancies of the upper aero-digestive tract are a leading cause of death in the United States of America. Among all the cancers of the upper aero-digestive tract, squamous cell carcinoma is the most common. Approximately 40,000 new patients are diagnosed with squamous cell carcinoma of the head and neck each year in the United States. An estimated 12,260 men and women in the United States will be diagnosed with laryngeal squamous cell carcinoma in 2013.
Treatment of laryngeal carcinoma has changed over the past few decades. Until approximately 1990, therapy was surgically directed. Total and partial laryngectomy surgeries were and still are the mainstream surgical procedures to treat malignant tumors of the larynx. A paradigm change in treatment occurred in the early 1990s with the advent of organ preservation treatments using concurrent chemoradiation therapy. This treatment approach demonstrated survival rates similar to total laryngectomy plus radiation therapy, while preserving the larynx in 63% of the patients. In addition, new developments in endoscopic surgical techniques and laser equipment are opening a new era in the treatment of malignant tumor of the larynx.
An image depicting a tumor of the larynx can be seen in the image below.
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Axial view on CT scan of an advanced right laryngeal tumor invading through the thyroid cartilage.
Workup of malignant laryngeal tumors
Contrast-enhanced computed tomography (CT) scans obtained with appropriate section thickness (1-2 mm–thick sections through the larynx) aid in the evaluation of neck masses.
CT and magnetic resonance imaging (MRI) scans may demonstrate the extension of tumor into vital structures such as the surrounding soft tissue, the preepiglottic space. They may also show invasion though the thyrohyoid-ligament and cartilage invasion.
Positron emission tomography-CT (PET-CT) scanning is the most sensitive test available to detect metastasis or second primary tumors.
Direct laryngoscopy provides an opportunity for examination under general anesthesia, palpation and biopsy. Suspension laryngoscopy provides an excellent view of the extent of the tumor and the overall condition of the airway mucosa. When coupled with appropriate imaging such as a CT scan, the direct laryngoscopy provides the best information for tumor staging and surgical planning. The direct laryngoscopy also provides an opportunity for biopsies of the tumor to be obtained. Well-targeted biopsies will typically reveal the type and perhaps grade of the tumor.
Management of malignant laryngeal tumors
Early stage laryngeal carcinomas (stage I-II) are ideally treated with either radiation or surgical techniques (either endoscopic or open) that preserve laryngeal function. For carcinoma in situ or early stage invasive glottic or supraglottic cancer, endoscopic surgical excision or radiation therapy are both equally effective, with similar functional outcomes.
Historically, advanced-stage laryngeal carcinomas (stage III-IV) were treated with total laryngectomy, reconstruction, and adjuvant postoperative chemoradiation therapy. Although total laryngectomy is still required in cases of aggressive or extensive tumors, laryngeal preservation strategies using chemotherapy and radiation therapy protocols have now become the standard of care for many advanced laryngeal cancers.
In addition to total laryngectomy, other surgical techniques used in the treatment of malignant laryngeal tumors include transoral laser microsurgery (ideal for the management of early/intermediate glottic and supraglottic cancer), open supraglottic partial laryngectomy, and supracricoid partial laryngectomy.
The development of the technique of direct laryngoscopy by Manuel Garcia in 1855 provided the ability to examine the larynx in a living person for the first time. The first laryngofissure procedure for cancer was performed by Gurdon Buck in 1851, while Theodor Billroth is credited with the first laryngectomy in 1873. Postoperative mortality from this procedure was very high (around 40%), mainly due to aspiration and sepsis.
Constant improvement in technique and perioperative care led to improved outcomes. A standardized laryngectomy technique perfected by Gluck and Soerensen by 1922 yielded excellent surgical outcomes with few fatalities. Billroth and Gluck also described hemilaryngectomies, but these procedures resulted in high recurrence rates and intractable dysphagia. Partial laryngectomies gradually regained an important role as a therapeutic option for laryngeal cancer mainly through improved techniques and recognition of appropriate indications. In recent years, surgery of laryngeal cancer has evolved to refined endoscopic and laser techniques.
New strategies using chemotherapy, radiotherapy and surgery have not substantially changed the survival rate of patients with advanced malignant tumors of the larynx in the last 30 years. Tobacco and alcohol are recognized as the major risk factors for developing malignant tumors of the larynx. New efforts in understanding the molecular biology and carcinogenesis of laryngeal malignancies have given us knowledge in the evolution of this disease and have shown therapeutic potential. The main challenge in laryngeal cancer treatment is improving survival while preserving function by limiting treatment toxicities.
According to the SEER Cancer Statistics Review of the National Cancer Institute, an estimated 12,260 men and women will be diagnosed with cancer of the larynx in 2013; of those, 3,670 patients will die. The age-adjusted incidence is 3.6 per 100,000 with a mortality of 1.3 per 100,000.
Sex
A study by Marchiano et al indicated that subglottic squamous cell carcinoma cases have a male-to-female ratio of 3.83:1. The report included 889 cases from the National Cancer Institute’s Surveillance, Epidemiology, and End Results (SEER) program database.[1]
Age
According to the Marchiano study, subglottic squamous cell carcinoma predominantly occurs in the fifth to seventh decade of life.[1]
Until the complex molecular interactions of all associated etiologic agents for any cancer can be understood, these interactions are best thought of as associations. Thinking of intrinsic (eg, genetic) factors and/or extrinsic (eg, smoking) factors as causes is too simple.
To most people, a cause implies a condition that is both necessary and sufficient to produce a prespecified result. Laryngeal carcinomas have multiple associations.
The foremost risk factor for the development of laryngeal cancer is tobacco use. The risk of developing laryngeal cancer with tobacco increases with use and decreases after cessation. When associated with the intake of alcohol, a strong synergistic effect is created. However, whether or not alcohol alone is an independent risk factor is still unclear. Potential risk factors linked to the development of laryngeal cancer include:
Tobacco use
Excessive ethanol use
Male sex
Infection with human papillomavirus
Increasing age
Diets low in green leafy vegetables
Diets rich in salt preserved meats and dietary fats
Metal/plastic workers
Exposure to paint
Exposure to diesel and gasoline fumes
Exposure to asbestos
Exposure to radiation
Laryngopharyngeal reflux
A study by Zhao et al suggested that an association exists between overexpression of histone deacetylase 1 (HDAC1) and the clinical characteristics of laryngeal squamous cell carcinoma. A correlation was indicated, for example, between upregulation of HDAC1 expression and T classification, tumor clinical stage and location, lymph node metastases, and the cancer’s sensitivity to radiotherapy, with higher expression of HDAC1 found in the low-sensitivity squamous cell cancer samples. Patients in whom HDAC1 was overexpressed and with low sensitivity to radiotherapy had a poorer overall 5-year survival rate.[2]
The larynx is an essential organ that is responsible for the following vital functions:
Maintaining an open air way
Vocalizing
Protecting the lungs from direct exposure to noxious fumes and gases of unsuitable temperatures
Protecting the lungs from aspiration of solids and liquids
Allowing leverage, by closing the glottis during a Valsalva maneuver, to increase upper-body strength and to ease defecation
Malignant tumors of the larynx may affect laryngeal physiology depending on tumor location and size. Supraglottic tumors may not alter laryngeal function until they reach a relatively large size, at which time airway obstruction may be the first symptom. Conversely, glottic tumors alter voice quality early in their development and are thus often discovered at an early stage. In addition, malignant tumors of the larynx affect swallowing physiology. The mechanism of swallowing is altered when tumors invade and alter the physiology of the swallowing muscles. This may lead to either dysphagia or aspiration.
Development and progression of malignant tumors of the larynx occurs at the molecular and histologic level. The molecular steps involved in tumorigenesis have not been fully elucidated and likely vary from patient to patient. Histologic progression occurs from normal laryngeal mucosa to dysplastic mucosa to carcinoma in situ to invasive carcinoma. This progression is a multistep process of accumulated genetic events that lead to the development of larynx tumors.
Given the functions of the larynx mentioned above, one can easily imagine the consequences of a carcinoma destroying and/or obstructing the laryngeal structures and their functions (eg, vocal-cord movement). Symptoms vary with the structures involved by malignancy and its accompanying inflammatory reaction. Although the particular tumor, the site, and the patient's constitution all contribute to the spectrum of symptoms seen in any given individual, laryngeal cancers as a whole can cause any of the following findings, alone or in combination:
Dysphonia/aphonia
Dysphagia
Dyspnea
Aspiration
Blood-tinged sputum
Fatigue and weakness
Cachexia
Pain
Halitosis
Expectoration of tissue
Neck mass
Otalgia (Outside the field of otorhinolaryngology, many physicians do not realize that otalgia may be a sign of laryngeal cancer. This seems to be especially true if the arytenoids are involved.)
History
As in all clinical evaluations, the history is the first step in gathering the facts. Assess or inquire about the following:
Weight loss
Fatigue
Pain
Difficulty breathing or swallowing
Vocal changes noted by the patient and his or her family
Ear pain
Coughing up blood or solid material
Physical examination
The patient's general condition and nutritional status should be evaluated. A full head and neck examination should be completed. Head and neck examination includes inspection and palpation of the oral cavity and oropharynx to rule out second primary tumors or other lesions, as well as evaluation of dentition. Inspection of the larynx is best accomplished using a flexible laryngoscope. Flexible laryngoscopy allows the otolaryngologist to evaluate the function and anatomy of the entire larynx. Evaluation of vocal cord mobility and the location and extension of the tumor are crucial to stage the patient accurately. Palpation of the neck looking for enlarged lymph nodes is paramount in the patient's evaluation. Thorough evaluation of the cranial nerves should also be included in the physical examination.
Many laryngeal tumors may appear late with distant metastasis and near-total destruction of some neck structures. Others may appear early. Treatment is necessary for all tumors. Treatment may include single therapy or combinations of surgery, radiation therapy, and/or chemotherapy. In advanced metastatic tumors, treatment may be only palliative, but it should still be addressed because tumors of the larynx can cause severe misery for the patient and his or her loved ones. To select proper therapy, all of the necessary information must first be obtained before available options are discussed with the patient.
The anatomy of the larynx is complex and difficult to visualize. Nevertheless, the team caring for each patient must understand it. Specialists in the areas of head and neck surgery, pathology, radiation oncology, and radiology understand this anatomy well. For family members, patients, and clinicians who do not deal with anatomic detail in their daily practice, this is a complicated arena. The entire team must effectively understand each other and communicate with the family.
Entire books are written about gross and microscopic laryngeal anatomy. The discussion below is an abbreviated version of the relevant anatomy. It should provide the information any clinician needs to understand this anatomic region, and it should explain why different procedures are indicated in different areas. It also helps in clarifying the consequences of each procedure.
The larynx is divided into the supraglottic larynx, the glottis or glottic larynx, and the subglottic larynx. The supraglottic larynx includes the epiglottis, the preepiglottic space, the laryngeal aspects of the aryepiglottic folds, the false vocal cords, the arytenoids, and the ventricles. The inferior boundary is a horizontal plane drawn trough the apex of the laryngeal ventricles. This corresponds to the area of transition from squamous epithelium superiorly to respiratory epithelium inferiorly. The glottis consists of the true vocal cords extending to roughly 1 cm below the true cords, the paraglottic space, and the anterior and posterior commissures. The subglottic larynx has its superior border at the inferior border of the glottis, that is, approximately 1 cm below the true vocal cords and extending inferiorly to the trachea.
See the image below.
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Fiberoptic endolaryngeal view of an early glottic lesion of the right true vocal cord extending to the anterior commissure.
Therapy has no "contraindications." However, a multitude of issues must be discussed in deciding which therapy is best for each patient. These issues include such things as the tumor stage, the patient's co-morbid status, prior treatments, and, of course, the patient's desires. Even in the setting of tumor recurrence and incurability, the patient should be offered palliative care.
The patient's symptoms or clinical findings may indicate the need to obtain arterial blood gases.
This analysis may be performed preoperatively to provide a baseline to monitor the patient's course.
Blood studies for clotting parameters
These studies might be ordered when surgery is a consideration.
Include a platelet count.
Blood typing and cross matching are also prudent.
Every experienced head and neck surgeon or trauma physician is aware of the tremendous potential for hemorrhage in this area. Anomalous blood vessels often yield unexpected complications.
Thyroid function studies
These studies may be indicated, as may tests of serum calcium levels, because the results are occasionally anomalous after surgery. Having baseline data for reference is ideal.
In some cases, especially with cases of fibrosis, either radiation or tumor induced, the thyroid may be biopsied during laryngectomy to assess for occult carcinoma.
Studies of renal and hepatic function
These studies are necessary before any informed discussion of chemotherapeutic regimens can occur.
Many chemotherapeutic agents are metabolized by the liver and/or kidneys.
Nutrition studies: Albumin and transferrin serum levels are important to establish nutritional status.
Contrast-enhanced CT scans obtained with appropriate section thickness (1-2 mm–thick sections through the larynx) aid in the evaluation of neck masses.
CT and MRI scans may demonstrate the extension of tumor into vital structures such as the surrounding soft tissue, the preepiglottic space. They may also show invasion though the thyrohyoid-ligament and cartilage invasion. See the image below.
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Axial view on CT scan of an advanced right laryngeal tumor invading through the thyroid cartilage.
Plain radiography of the chest
See the list below:
Plain films of the chest may be useful in planning surgery.
If metastases are present in the chest, the therapeutic decision tree changes entirely. However, chest CT or PET-CT are more sensitive for metastasis that plain films
This is a radiologic tool that detects metabolic signals from cells with high metabolic activity like cancer cells. The patient intravenously receives a glucose analog called fluorodeoxyglucose (FDG) that is tagged with a radioisotope. This analog is taken up by cells with high metabolic activity, and the decay of the radioisotope is detected. A CT scanner is used to correlate the nuclear medicine image with anatomic abnormality.
This is the most sensitive test available to detect metastasis or second primary tumors. The clinician must be aware, however, that tumor FDG uptake may vary, normal tissues may display FDG avidity (eg, tonsillar tissue, active muscle tissue), and that PET cannot detect very small tumors (< 5 mm). See the image below.
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PET/CT image of a laryngeal cancer showing increased FDG avidity.
Pulmonary function tests are necessary before one decides whether the patient is a suitable candidate for radical surgery that involves airway function.
Direct laryngoscopy provides an opportunity for examination under general anesthesia, palpation and biopsy. Suspension laryngoscopy provides an excellent view of the extent of the tumor and the overall condition of the airway mucosa. When coupled with appropriate imaging such as a CT scan, the direct laryngoscopy provides the best information for tumor staging and surgical planning. The direct laryngoscopy also provides an opportunity for biopsies of the tumor to be obtained. Well-targeted biopsies will typically reveal the type and perhaps grade of the tumor. Multiple biopsies may also be used to map out the tumor extent in cases where the tumor margins are unclear; this may be important to optimally plan surgical treatment.
Fine needle aspiration (FNA) of a neck mass may be useful to diagnose malignant lymphadenopathy from a laryngeal tumor, and may be an alternative means of establishing a diagnosis rather than direct biopsy via direct laryngoscopy.
Reminders
The rationale behind the entire work-up is to have as much staging information available as possible to present to a tumor board in order to determine a treatment plan. Treatment options are frequently discussed in a multidisciplinary format called a tumor board. Although a tumor board may comprise only a few physicians, the ideal head and neck tumor board is a powerful ally. Diverse experts on these boards widely expand and exchange knowledge, such as awareness of new open clinical trials (on the part of radiation or medical oncologists); the patient in question may be ideal for such a trial.
Likewise, the surgeon may know of a new technique that may obviate postoperative therapy or considerably decrease disfigurement, and the pathologist may know that certain histologic features suggest an improved prognosis or a different response to therapy.
The value of this tumor board is greater than the sum of its parts. Therefore, the tumor board approach is strongly advocated. In the United States, such tumor boards may include the following members:
Surgeons
Anesthesiologists
Radiologists
Pathologists
Radiation oncologists
Medical oncologists
Psychiatrists and or the patients' spiritual advisors
The vast majority of laryngeal cancers are squamous cell carcinoma. Variations include standard squamous cell carcinoma (in situ or invasive, well, moderately or poorly differentiated), verrucous carcinoma, spindle cell carcinoma, basaloid-squamous cell carcinoma, and papillary squamous cell carcinoma. Other malignancies of the larynx are neuroendocrine carcinoma,[3] lymphoepitheliomatous carcinoma, adenocarcinoma, and rare tumors (including sarcomas, lymphomas, adenocarcinomas, and metastases).
Because 96% of laryngeal carcinomas in the United States are squamous cell carcinomas, the following discussion is limited to this neoplasm.
Laryngeal squamous cell carcinoma histology is similar in many ways to squamous cell carcinoma found elsewhere in the body. The spectrum ranges from hyperplasia, mild to severe dysplasia, in situ carcinoma, and invasive squamous cell carcinoma. At times, these stages cannot be observed in an invasive carcinoma. In addition, some squamous cell carcinomas of the larynx may arise de novo without an in situ stage. This process was demonstrated for oral tumors, and some indications suggest that this may be true in laryngeal tumors as well.
About 5-7 cell layers line the normal larynx. In some regions, this lining is stratified squamous epithelium, and in others (eg, ventricle, false cord, and subglottis), this is pseudostratified respiratory epithelium. The nuclei at the base are elongated, with their long axis perpendicular to the basement membrane. Normal mitotic figures are present in the basal layer, and should be absent above the second layer. As the cells move toward the surface, the nuclei become oval, then full circles. By the fourth to fifth layer from the bottom, all of the squamous cells should have circular nuclei. The nuclei then continue upward and elongate again, with the long axis parallel to the surface (parallel to the basement membrane). Surface keratinization may or may not be present.
Dysplasia is present when the ovoid, basal-appearing nuclei and mitotic figures persist higher in the epithelium, beyond the second layer. In mild dysplasia these atypical cells extend about one third of the way to the surface, in moderate dysplasia they reach two thirds of the way to the surface, and in severe dysplasia they encompass the entire thickness of the epithelium. Severe dysplasia is similar to carcinoma in situ, which is full-thickness atypia of the squamous cells with typical and atypical mitosis present. The individual cells themselves are bizarre in appearance, with angulated nuclei, multipoled mitotic figures, apoptotic cells (individually necrotic cells), hyperchromasia, and high nuclear-to-cytoplasmic ratios.
Invasive squamous cell carcinoma means that abnormal-appearing squamous cells, and often keratin, are beneath the area where the usual basement membrane lies. The cells may extend deeply into soft tissue, and they may invade cartilage, nerves, blood vessels, and lymphatics. They may invade as nests, broad and pushing fronts, as individual cells, or as any combination of these.
The pathologists classify the degree of atypicality as follows: well, moderately, or poorly differentiated or undifferentiated. Use of the undifferentiated classification is best avoided. The term undifferentiated carcinoma is an oxymoron in that an undifferentiated neoplasm cannot show any morphologic features of epithelium (ie, carcinoma). In addition, the pathologist may subtype the tumor according to the types of tumors listed at the beginning of this section (eg, papillary carcinoma or verrucous carcinoma).
The 2002 AJCC classification for laryngeal tumors is determined by the following 3 main factors[4] :
Number of subsites involved
Vocal fold mobility
Presence of cervical or distant metastases
Furthermore, one must pay attention to specific factors that are essential for initial staging and can help determine the optimal therapeutic option(s) for the patient. These factors are as follows:
Involvement of the base of tongue
Involvement of the preepiglottic space, ie, the tissue anterior to the epiglottis, posterior to the thyrohyoid membrane, superior to the petiole, and inferior to the hyoepiglottic ligament
Paraglottic space involvement
Thyroid cartilage invasion
Soft tissue invasion, including strap muscles
Carotid artery and sheath involvement
Esophageal invasion
Neck lymph nodes, their location, involvement (ipsilateral, bilateral, contralateral), size, and extranodal spread
Distant metastases and location
The American Joint Committee on Cancer Sixth Edition Larynx Staging Schema is discussed below.
Primary tumor (T)
Criteria for primary tumor staging depends on tumor location in either the supraglottis, glottis, or subglottis.
TX: Primary tumor cannot be assessed.
T0: No evidence of primary tumor
Tis is carcinoma in situ .
Supraglottis
T1: Tumor is limited to one subsite of supraglottis with normal vocal cord mobility.
T2: Tumor invades mucosa of more than one adjacent subsite of supraglottis or glottis or region outside the supraglottis (eg, mucosa of base of tongue, vallecula, medial wall of pyriform sinus) without fixation of the larynx.
T3: Tumor is limited to larynx with vocal cord fixation and/or invades any of the following: postcricoid area, pre-epiglottic tissues, paraglottic space, and/or minor thyroid cartilage erosion (eg, inner cortex).
T4a: Tumor invades through the thyroid cartilage and/or invades tissues beyond the larynx (eg, trachea, soft tissues of neck including deep extrinsic muscle of the tongue, strap muscles, thyroid, or esophagus).
T1: Tumor is limited to the vocal cord or cords (may involve anterior or posterior commissure) with normal mobility.
T1a: Tumor is limited to one vocal cord.
T1b: Tumor involves both vocal cords.
T2: Tumor extends to the supraglottis and/or subglottis, and/or with impaired vocal cord mobility.
T3: Tumor is limited to the larynx with vocal cord fixation and/or invades paraglottic space, and or minor thyroid cartilage erosion (eg, inner cortex).
T4a: Tumor invades through the thyroid cartilage and/or invades tissues beyond the larynx (eg, trachea, soft tissues of the neck including deep extrinsic muscle of the tongue, strap muscles, thyroid, or esophagus).
T2: Tumor extends to the vocal cord(s), with normal or impaired mobility.
T3: Tumor is limited to the larynx with vocal cord fixation.
T4a: Tumor invades the cricoid or thyroid cartilage and/or invades tissues beyond the larynx (eg, trachea, soft tissues of neck including deep extrinsic muscles of the tongue, strap muscles, thyroid, or esophagus).
T4b: Tumor invades the prevertebral space, encases carotid artery, or invades mediastinal structures.
Regional lymph nodes (N)
See the list below:
NX: Regional lymph nodes cannot be assessed.
N0: No regional lymph node metastasis exists.
N1: Metastasis is in a single ipsilateral lymph node, 3 cm or less in greatest dimension.
N2a: Metastasis is in a single ipsilateral lymph node, more than 3 cm but less than 6 cm in greatest dimension.
N2b: Metastasis is in multiple ipsilateral lymph nodes, none more than 6 cm in greatest dimension.
N2c: Metastasis is in bilateral or contralateral lymph nodes, none more than 6 cm in greatest dimension.
N3: Metastasis is in a lymph node, more than 6 cm in greatest dimension.
Distant Metastasis (M)
See the list below:
MX: Distant metastasis cannot be assessed.
M0: No distant metastasis.
M1: Distant metastasis.
Stage Grouping
Stage groupings can be seen in the table below.
Table 1. Stage Tumor, Node, and Metastasis Groupings
Treatment of patients with laryngeal carcinoma is complex because of the crucial functions of this anatomic area. If possible, the goal of treatment is to remove the tumor and prevent recurrence while maintaining laryngeal function. The ideal treatment varies for laryngeal cancer depending on the stage of the disease. Location of the primary tumor (ie, glottic, supraglottic or subglottic) is also an important consideration when selecting therapy.
Early stage laryngeal carcinomas (stage I-II) are ideally treated with either radiation or surgical techniques (either endoscopic or open) that preserve laryngeal function. For carcinoma in situ or early stage invasive glottic or supraglottic cancer, endoscopic surgical excision or radiation therapy are both equally effective, with similar functional outcomes. Certain early stage lesions, may require more extensive resection, in which case open partial laryngectomy options exist that provide good oncologic control, although usually with worse voice outcomes than endoscopic surgery or radiation.
Historically, advanced-stage laryngeal carcinomas (stage III-IV) were treated with total laryngectomy, reconstruction, and adjuvant postoperative chemoradiation therapy. However, remarkable progress has been made in the past 20 years in the management of laryngeal cancer. Although total laryngectomy is still required in cases of aggressive or extensive tumors, laryngeal preservation strategies using chemotherapy and radiation therapy protocols have now become the standard of care for many advanced laryngeal cancers.
Landmark studies such as The Veteran Affairs Laryngeal Cancer Study Group in 1991 and the RTOG 91-11 intergroup trial helped establish the basis of laryngeal preservation therapies using chemotherapy (cisplatinum and fluorouracil) and radiation therapy protocols.[5] . These trials established that chemoradiation provides equivalent oncologic control to surgery, while allowing a substantial number of patients to avoid the sequelae of laryngectomy. Support for chemotherapy as part of a multimodality approach has been strengthened by many subsequent clinical trials demonstrating the benefit of concurrent chemoradiation protocols.
Current recommendations of the NCCN Practice Guidelines in Oncology for achieving laryngeal preservation in cases of locally advanced laryngeal cancer are concurrent radiation therapy and cisplatin 100mg/m2 on days 1, 22, and 43.[6] Radiation therapy alone can be considered for patients who are medically unfit to undergo chemotherapy. Good evidence suggests that radiation efficacy is improved with accelerated and hyperfractionated treatment schemes.
Despite the increased use of chemoradiation in the treatment of advanced laryngeal cancer, surgery is still frequently required. Concurrent chemoradiotherapy protocols are associated with significant acute and late toxicities. Some patients remain with dysfunctional swallowing and life-threatening aspiration episodes that require total laryngectomy. Furthermore, total laryngectomy is required for chemoradiation treatment failures in up to one third of patients. Additionally, total laryngectomy is the best initial therapeutic option in certain situations.
Primary surgical treatment should be considered in patients with high volume disease, patients with T4a tumors, or patients with anticipated poor functional outcome (eg, poor laryngeal function, intractable aspiration). Significant early and late toxicities associated with concurrent chemoradiation protocols led to recent interest in targeted therapies such as monoclonal antibodies (eg, cetuximab). Cetuximab is presently used in many organ preservation protocols for laryngeal cancer following a landmark multicenter trial. Many other targeted therapies are under investigation. In summary, therapy for laryngeal cancer is predicated on the tumor type and staging, patient’s wishes and compliance, and the surgeon’s and institution’s preferences and experience. Treatment must be individualized to consider each patient and his or her social circumstances.
Although laryngeal preservation strategies using chemoradiation have taken a central role in the treatment of advanced laryngeal cancer, late toxicities have led us to rethink the paradigm of laryngeal cancer treatment. The refinement of laryngeal surgeries and the sophistication of endolaryngeal laser techniques offer a wide array of laryngeal preservation options that should be carefully considered by the multidisciplinary team. As described in the previous section, total laryngectomy must be considered in cases of bulky or advanced disease, clear cartilage invasion, and failures of larynx-sparing strategies. Although a full description of surgical techniques is beyond the scope of this article, the clinician should be familiar with the basic surgical options.
Transoral laser microsurgery
Popularized and legitimized by Steiner and Ambrosch, transoral laser microsurgery is ideal for the treatment of early/intermediate glottic and supraglottic cancer. It is performed under suspension micro-laryngoscopy with a CO2 laser. Adequate instrumentation and surgeon's experience are paramount.
The tumor is transected and removed piecemeal (which allows for precise tumor removal by margin visualization). The tumor must be well exposed through the laryngoscope.
This treatment has the same indications and contraindications as open partial laryngectomies. A functional cricoarytenoid unit must be preserved.
Survival and laryngeal preservation is comparable to other conventional treatments and results in excellent functional outcomes in appropriately selected patients.
In a study of patients with T1 glottic squamous cell carcinoma, Ahmed et al reported that primary transoral microsurgery with a potassium titanyl phosphate (KTP) laser resulted in similar outcomes to those from primary external beam radiation therapy. The average follow-up periods in the laser and radiation groups were 924 and 994 days, respectively, with the laser group achieving a 98% laryngeal preservation rate, compared with a 90% rate in the patients who received radiation. The laser group had disease-free and overall survival rates of 88% and 98%, respectively, while the rates in the radiation group were 85% and 95%, respectively.[7]
Open partial laryngectomy
Various partial laryngectomy procedures have been described. Many of these, such as vertical partial laryngectomy or near-total laryngectomy, are primarily of historical interest and are rarely used today. However, 2 procedures, supraglottic partial laryngectomy and supracricoid partial laryngectomy, have a role in the modern management of laryngeal cancer.
Open supraglottic partial laryngectomy involves resection of much or all of the supraglottis, with preservation of both true vocal cords and arytenoids. This thereby preserves laryngeal function and voice. While occasionally useful, this procedure may often be accomplished endoscopically with CO2 laser excision, thus open supraglottic partial laryngectomy is somewhat rare.
Supracricoid partial laryngectomy involves resection of the vocal fold, thyroid cartilage, and paraglottic space, as well supraglottic structures such as the epiglottis if needed.[8] The surgeon must preserve at least 1 functional cricoarytenoid unit (arytenoid and associated musculature, plus the superior and recurrent laryngeal nerve) for speech and swallowing. Open partial laryngectomy is useful for cancer involving the anterior commissure with or without spread onto the petiole of the epiglottis[9] and is a sound option for selected advanced tumors (T3 or early T4). Following resection, reconstruction is performed with cricohyoidoepiglottopexy (CHEP) or cricohyoidopexy (CHP) epiglottis preservation, depending on glottic or supraglottic involvement.
Contraindications include cartilage invasion, bilateral vocal fold fixation, interarytenoid involvement, significant tongue base involvement, transglottic lesion, or poor performance status.
Cure and organ preservation rates are comparable with chemoradiation. Decreased voice quality may result, but adequate swallowing can be achieved with rehabilitation.
Total laryngectomy
As previously discussed, total laryngectomy is the historical criterion standard for treatment of laryngeal cancer and is still widely used in the treatment of advanced or recurrent disease. This involves complete resection of the larynx, from the vallecula to the upper trachea. Additional resection of the pharynx, such as the piriform sinus or lateral pharyngeal wall, may be performed as needed due to tumor extension. The goal is complete, en bloc resection of the tumor. Selective neck dissection is usually performed along with this procedure, either to clear metastatic nodes or to detect occult metastasis.
Following resection, the proximal end of the trachea is sewn to the skin to create a permanent tracheostoma, and the pharyngeal mucosa is closed, thereby completely separating the airway from the upper digestive tract. Closure of the pharyngeal mucosa is either accomplished primarily, or with the use of a flap, either a regional flap (usually pectoralis flap) or free tissue transfer, depending on the size of the pharyngeal defect and the patient’s history of radiation therapy. A tracheoesophageal puncture is often performed in order to place a tracheoesophageal prosthesis (TEP) for voice rehabilitation.
A retrospective study by McGuire et al indicated that in patients with advanced laryngeal carcinoma, those in whom intraoperative evaluation reveals no extralaryngeal extension or in whom there is no concern regarding paratracheal nodal metastases, thyroid preservation in total laryngectomy does not increase the rate of local recurrence or negatively impact disease-free survival.[10]
When a patient is considering surgery, ascertaining that medical care is optimized is essential. Nutrition should be stable. Pain must be controlled. A tracheostomy may be needed at presentation in the case of a large obstructive lesion. A trip to the dentist is essential to be sure the dentition is free of active infection. Tobacco and alcohol are best avoided.Patients with severe lung disease may not be candidates for larynx-sparing surgery. Similarly, patients with compromised heart and renal disease may not be candidates for chemotherapy. The patient who has had prior irradiation to the head and neck area represents a special problem. Re-irradiation can be undertaken, sometimes with good results, but the risk of severe complications is increased.
This chapter does not allow for an in-depth discussion of operative technique. The author would refer the interested reader to an atlas where the various techniques are depicted.[11] For small endoscopic resections, many patients can be discharged on the day of the procedure. Extensive supraglottic resections do cause dysphagia and potentiate aspiration, so these patients require hospitalization and swallowing therapy. Open partial laryngeal resections are almost always accompanied by a temporary tracheotomy. Most patients are decannulated prior to or soon after discharge. The vocal result is generally reflective of the extent of surgery. Most patients have a dysphonic but serviceable voice. Following total laryngectomy, the authors recommend immediate insertion of a tracheoesophageal stent to accommodate a voice prosthesis. These patients may be speaking about 3 weeks after surgery.
See the image below.
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Tracheostoma and skin flap reconstruction following total laryngectomy for a locally advanced laryngeal cancer invading the skin of the neck.
Recovery from laryngeal surgery is reflective of the structures removed, the extent of the resection, and the patient's underlying cardio-pulmonary health. The patient who undergoes resection for a small tumor can be predicted to have excellent functional recovery with good voice. Treatment of advanced cancer always results in compromise of some quality of life and functional capabilities.
Follow-up care is necessary because second primary cancers, recurrences, and late metastases are all strong possibilities. In the course of a lifetime, one third of patients with head and neck cancer may develop another cancer.
The assistance of speech therapists, occupational therapists, and physical therapists with experience in swallowing or secretion control should also be considered.
The complications and consequences of surgery, radiation therapy, and chemotherapy are well known. However, in the larynx, unique or at least unusual complications must be considered. These are listed as follows:
Loss of upper body strength after laryngectomy
Psychosocial trauma from surgery and/or radiation therapy[12]
Outcomes in malignant tumor of the larynx are measured by 5-year survival rates. Data from the National Cancer Database based on patients diagnosed between 1998-1999 is as follows:
As demonstrated above, outcomes are highly dependent on the initial staging. In general, early stage disease is treated with single modality therapy, either surgery or radiation therapy. The outcomes in early disease are quite good, approaching over 90% 5-year survival rates with either modality of treatment in glottic cancer. Advanced disease (stage III-IV) is generally treated with multimodality therapy, concurrent chemoradiation therapy and surgery.
The 5-year survival rates vary depending on the treatment modality. The 5-year survival rate after concurrent chemoradiation therapy is 54% with preservation of 88% of the larynx at 2 years. The 5-year survival after endoscopic laser laryngeal surgery is 55%. Interestingly, laryngeal cancer is perhaps the only cancer to actually demonstrate a decrease in survival rates over the past few decades.[13] The increasing use of nonsurgical therapy has been implicated in this decrease. Quality of life is emerging as an outcome measure in the treatment of laryngeal carcinoma. New data are showing the functional outcomes and quality of life after different treatment modalities.[14]
The aforementioned study by Marchiano et al found the overall 5-year disease specific survival rate to be 53.7% for patients with subglottic squamous cell carcinoma; the rate was highest (62.4%) for those treated with surgery alone.[1]
Functional preservation of the larynx remains a challenging goal in the treatment of malignant laryngeal tumors. Organ-sparing chemoradiation protocols have become the standard of care for advanced laryngeal cancer. Although these strategies were proven effective in preserving the larynx, the may not necessarily preserve laryngeal function. Improving surgical techniques such as endolaryngeal lasers, sophistication of radiation techniques such as IMRT, and the development of novel targeting agents such as cetuximab will surely change the landscape of current trends in laryngeal cancer treatment. Novel work in tumor angiogenesis and immunotherapy also holds promise. In the near future, individualizing treatment through optimal patient selection and biomarker analysis will be an interesting challenge.
Head and neck cancer guidelines published in November 2017 by the Spanish Society of Medical Oncology included the following options for laryngeal cancer[15, 16] :
Surgical resection (total versus partial laryngectomy + neck dissection) followed by radiotherapy or chemoradiotherapy if pathologic factors have a high recurrence risk, particularly T4a; for the most part of subglottic tumors
If the patient refuses surgery, then concurrent chemoradiotherapy with thrice-weekly cisplatin; the use of cetuximab concurrent to radiotherapy is recommended if cisplatin cannot be administered
Induction chemotherapy with TPF (docetaxel/cisplatin/fluorouracil) schedule (except for subglottic tumors)
With the induction chemotherapy option, the guidelines recommend the following[15, 16] :
If complete response - Radiotherapy
If partial response - Concomitant radiotherapy (with cisplatin or cetuximab), or consider surgery followed by radiotherapy
If stable disease or progression - Surgery (including neck dissection) followed by radiotherapy or chemoradiotherapy
Jonas T Johnson, MD, FACS, Chairman, Department of Otolaryngology, The Eugene N Myers, MD, Distinguished Service Professor and Chairman of Otolaryngology, Professor, Department of Radiation Oncology, University of Pittsburgh School of Medicine; Professor, Department of Oral Maxillofacial Surgery, University of Pittsburgh School of Dental Medicine
Disclosure: Nothing to disclose.
Coauthor(s)
Daniel Clayburgh, MD, PhD, Clinical Instructor, Head and Neck Surgery Fellow, Department of Otolaryngology-Head and Neck Surgery, University of Pittsburgh Medical Center
Disclosure: Nothing to disclose.
Specialty Editors
Francisco Talavera, PharmD, PhD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference
Disclosure: Received salary from Medscape for employment. for: Medscape.
Karen H Calhoun, MD, FACS, FAAOA, Professor, Department of Otolaryngology-Head and Neck Surgery, Ohio State University College of Medicine
Disclosure: Nothing to disclose.
Chief Editor
Arlen D Meyers, MD, MBA, Professor of Otolaryngology, Dentistry, and Engineering, University of Colorado School of Medicine
Disclosure: Serve(d) as a director, officer, partner, employee, advisor, consultant or trustee for: Cerescan;RxRevu;Cliexa;The Physicians Edge;Sync-n-Scale;mCharts<br/>Received income in an amount equal to or greater than $250 from: The Physicians Edge, Cliexa<br/> Received stock from RxRevu; Received ownership interest from Cerescan for consulting; .
Additional Contributors
Jack A Coleman, MD, Consulting Staff, Franklin Surgical Associates
Disclosure: Received honoraria from Accarent, Inc. for speaking and teaching.
Acknowledgements
Emiro E Caicedo-Granados, MD Assistant Professor, Department of Otolaryngology, University of Minnesota Medical School
Emiro E Caicedo-Granados, MD is a member of the following medical societies: American Academy of Otolaryngology-Head and Neck Surgery
Disclosure: Nothing to disclose.
Apostolos Christopoulos, MD, MSc, FRCSC Assistant Professor of Otolaryngology-Head and Neck Surgery, Department of Surgery, Universite de Montreal Faculty of Medicine, Canada
Edge S, Byrd DR, Compton CC, Fritz AG, Greene FL, Trotti A. American Joint Comittee on Cancer - Head and Neck cancer staging 2007. 7th. Philadelphia: Springer; 2010.
NCCN Practice Guidelines in Oncology - v.2.2013 - Head and Neck Cancers. National Comprehensive Cancer Network. Available at http://www.nccn.org/professionals/physician_gls/PDF/head-and-neck.pdf. Accessed: 1/13/14.
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