Malignant Tumors of the Larynx
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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.
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.
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]
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
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.)
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
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.
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.
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Zhao R, Chen K, Cao J, Yu H, Tian L, Liu M. A correlation analysis between HDAC1 over-expression and clinical features of laryngeal squamous cell carcinoma. Acta Otolaryngol. 2015 Nov 20. 1-5. [Medline].
Angouridakis N, Goudakos J, Karayannopoulou G, Triaridis S, Nikolaou A, Markou K. Primary neuroendocrine neoplasms of the larynx. A series of 4 cases reported and a review of the literature. Head Neck. 2012 Feb 6. [Medline].
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Ahmed J, Ibrahim ASG, M Freedman L, Rosow DE. Oncologic outcomes of KTP laser surgery versus radiation for T1 glottic carcinoma. Laryngoscope. 2017 Sep 12. [Medline].
Laccourreye O, Ishoo E, de Mones E, Garcia D, Kania R, Hans S. Supracricoid hemilaryngopharyngectomy in patients with invasive squamous cell carcinoma of the pyriform sinus. Part I: Technique, complications, and long-term functional outcome. Ann Otol Rhinol Laryngol. 2005 Jan. 114(1 Pt 1):25-34. [Medline].
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Stage
Grouping
Stage 0
Tis
N0
M0
Stage I
T1
N0
M0
Stage II
T2
N0
M0
Stage III
T3
N0
M0
T1
N1
M0
T2
N1
M0
T3
N1
M0
Stage IVA
T4a
N0
M0
T4a
N1
M0
T1
N2
M0
T2
N2
M0
T3
N2
M0
T4a
N2
M0
Stage IV B
T4b
Any N
M0
Any T
N3
M0
Stage IV C
Any T
Any N
M1
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
Jonas T Johnson, MD, FACS is a member of the following medical societies: Allegheny County Medical Society, American Academy of Otolaryngology-Head and Neck Surgery, American Association for Cancer Research, American Bronchoesophagological Association, American College of Surgeons, American Head and Neck Society, American Laryngological Association, American Medical Association, American Rhinologic Society, American Society of Clinical Oncology, Pennsylvania Medical Society, Society of University Otolaryngologists-Head and Neck Surgeons, The Triological Society
Disclosure: Nothing to disclose.
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.
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
Karen H Calhoun, MD, FACS, FAAOA is a member of the following medical societies: American Academy of Facial Plastic and Reconstructive Surgery, American Head and Neck Society, Association for Research in Otolaryngology, Southern Medical Association, American Academy of Otolaryngic Allergy, American Academy of Otolaryngology-Head and Neck Surgery, American College of Surgeons, American Medical Association, American Rhinologic Society, Society of University Otolaryngologists-Head and Neck Surgeons, Texas Medical Association
Disclosure: Nothing to disclose.
Arlen D Meyers, MD, MBA Professor of Otolaryngology, Dentistry, and Engineering, University of Colorado School of Medicine
Arlen D Meyers, MD, MBA is a member of the following medical societies: American Academy of Facial Plastic and Reconstructive Surgery, American Academy of Otolaryngology-Head and Neck Surgery, American Head and Neck Society
Disclosure: Serve(d) as a director, officer, partner, employee, advisor, consultant or trustee for: Cerescan;RxRevu;Cliexa;Preacute Population Health Management;The Physicians Edge<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; for: Rxblockchain;Bridge Health.
Jack A Coleman, MD Consulting Staff, Franklin Surgical Associates
Jack A Coleman, MD is a member of the following medical societies: American Academy of Facial Plastic and Reconstructive Surgery, American Academy of Sleep Medicine, American Academy of Otolaryngic Allergy, American Academy of Otolaryngology-Head and Neck Surgery, American Bronchoesophagological Association, American College of Surgeons, The Triological Society, American Society for Laser Medicine and Surgery, Association of Military Surgeons of the US
Disclosure: Received honoraria from Accarent, Inc. for speaking and teaching.
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
Disclosure: Nothing to disclose.
Malignant Tumors of the Larynx
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