Laryngeal cancers represent one-third of all head and neck cancers and may be a significant source of morbidity and mortality. They are most often diagnosed in patients with significant smoking history, who are also at risk for cancers in the remainder of the aerodigestive tract. They can involve different subsites of the larynx, with different implications in symptomatic presentation, patterns of spread, and treatment paradigm. Early stage disease is highly curable with either surgical or radiation monotherapy, often larynx-preserving, whereas late-stage disease has a worse outcome, warrants multimodal therapy, and is less often larynx-preserving. For patient’s requiring laryngectomy, speech rehabilitation methods have improved in the modern era. 
Smoking is the most significant risk factor for cancers of the larynx, associated with an estimated 70% to 95% of all cases. 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 in younger patients. In contrast to other cancers of the head and neck, the role of human papillomavirus (HPV) as a causative agent has not been established. 
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 smoking. Approximately 98% of laryngeal cancers arise in either the supraglottic or glottic regions, with glottic cancers being three times more common that supraglottic cancers, and subglottic cancers representing approximately 2% of all cases. Early-stage cancers are highly curable, with local control rates ranging from 90% to 95% for T1 glottic cancers, and likewise 80% to 90% for early-stage supraglottic cancers. Furthermore, such early-stage cancers are generally amenable to vocal cord-sparing surgical therapy. In contrast, locally-advanced cancers demonstrate control rates ranging from 40% to 70%, with bulky and/or T4 disease often requiring laryngectomy. However, advances over the years have allowed increased laryngeal preservation, as well as improved speech rehabilitation in patients receiving laryngectomy.
The vast majority of laryngeal cancers are well-differentiated squamous cell carcinoma. A minority of cases represent squamous cell variants, including verrucous carcinoma, sarcomatoid carcinoma, and neuroendocrine carcinoma. Verrucous and sarcomatoid carcinomas historically were regarded as radioresistant, though recent experience contradicts this notion. Patterns of spread depend on the location of the primary mass, 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
The supraglottis is further subdivided into suprahyoid epiglottis, infrahyoid epiglottis, false vocal cords, aryepiglottic folds and the arytenoids. Suprahyoid epiglottic tumors may grow exophytically and superiorly, at times becoming quite large before inducing symptoms. In other cases, they may invade inferiorly into the tip of the epiglottis and destroy associated cartilage. Infrahyoid epiglottic tumors, on the other hand, tend to grow circumferentially, where they can involve 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.Lymphatic involvement is a pathologic hallmark of supraglottic cancers, in contrast to both glottic and subglottic cancers, with 55% of patients having clinical evidence of nodal metastasis at presentation, and 16% with contralateral involvement. In order of decreasing risk of involvement, cancer principally spreads to levels II, II, and IV of the cervical nodal chain. 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 tongue, vallecula, and pyriform sinus. Glottic
The apex of the ventricle represents the transition from supraglottic to the glottic larynx. The vocal cords themselves range from 3 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 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 one vocal cord. They can induce vocal cord fixation by pure bulk, involvement of intrinsic muscles and ligaments, or, more rarely, involvement of the recurrent laryngeal nerve. Subglottic
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. ,
Patients are typically male with a history of current or past tobacco smoking. Hoarseness is often an early presenting symptom of glottic cancers due to vocal cord immobility or fixation, with pain with swallowing and referred ear pain indicating advanced disease. In contrast, pain with swallowing is the most common early symptom of supraglottic cancer, with hoarseness indicating advanced disease extending into the glottis. Nodal metastases 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. The most crucial component of a physical examination is an invasive assessment of the primary lesion, including indirect laryngoscopy, mirror exam, and often fiberoptic endoscopy. The objective is to assess local extent of the tumor, noting size and involvement of adjacent structures, as well as assessing the mobility of the vocal cord. Direct laryngoscopy offers enhanced ability to delineate the extent of disease as well as the ability to obtain tissue specimens. Thorough neck examination is imperative, not only to assess for nodal metastasis but 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.
In addition to history, physical examination, and direct visualization of the larynx with tissue sampling as described above, other studies are necessary. Multiple methods of obtaining tissue are feasible. The most valuable are biopsy during direct laryngoscopy of the suspected primary lesion, and fine-needle aspiration (FNA) of any suspected nodal disease.For all laryngeal cancers, whether suspected to be early or late stage, imaging of the primary lesion and draining lymph nodes is indicated, usually with contrast-enhanced 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, as well as detect subtle signs of disease extension such as minor invasion into the thyroid cartilage, all of which are crucial for accurate staging.
Suspected locally advanced disease would prompt contrast-enhanced CT of the chest as well as PET/CT to rule out distant metastases. Suspected invasion into the hypopharynx may prompt esophagogastroduodenoscopy (EGD) and/or barium swallow, which may differentiate the correct aerodigestive tissue of cancer origin.
Early Stage Laryngeal Cancer
Early stage laryngeal cancers, inclusive of T1-2N0 disease, are treated successfully with a single, locally-directed treatment modality, whether local radiation therapy or surgery.
T1-2N0 Glottic Cancer
Local radiation therapy or surgery are 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 in that they only address the primary tumor. Level I data comparing the 2 approaches do not exist, but local control rates from retrospective experience are comparable between surgical approaches and RT. Voice-sparing surgery is an option in many, but not all, of these cancers. In one experience, total laryngectomy was the required surgical approach in 10% of T1 and 55% of T2 tumors. Other approaches include transoral laser excision, laryngofissure, and partial laryngectomy. Despite no randomized evidence comparing surgery and RT, there is randomized data demonstrating superior voice preservation with definitive RT versus transoral laser excision.
T1-2N0, Selected T1-2N1/T3N0-1 Supraglottic Cancer
Similar to early-stage glottic cancers, supraglottic cancers can be managed with either larynx-sparing surgical or RT monotherapy, with demonstrated overall comparable efficacy. The major difference versus glottic cancers is the management of the neck given the risk of nodal metastases. Surgical approaches include endoscopic resection or partial supraglottic laryngectomy for T1-2 and low-volume T3 disease, with neck dissection often indicated T2 or T3 lesions. Adjuvant RT is given to many patients, with common indications including positive nodal disease, extracapsular extension, and positive margins. Definitive RT often entails the inclusion of at-risk cervical nodal stations, generally levels II to IV.
Locally Advanced Laryngeal Cancers
Locally-advanced cancers, inclusive of T3-4N1-3 disease, are more difficult to treat and typically involve combination therapy. These cancers, if surgically resectable, are not 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 both improved locoregional control and larynx-preservation. In the context of T4 disease, laryngectomy, and adjuvant RT has demonstrated similar locoregional control rates compared to chemoradiation and salvage surgery. Larynx-preserving chemoradiation is not recommended for T4 disease and associated with inferior survival. ,,,
Post-operative RT is indicated in the case of emergent tracheostomy due to morbid tumor invasion (to reduce risk of tumor spread into the tracheostomy), advanced tumor and nodal stage on surgical pathology (pT3-4, pN2-3), as well as other high-risk pathologic features, including close margins (less than 5 mm), perineural invasion, lymphovascular space invasion, and extracapsular extension. Moreover, close or involved margins, multiple positive nodes, and extracapsular extension necessitate the addition of chemotherapy concurrent with RT.,,,,
The American Joint Committee on Cancer, 8th Edition Cancer Staging Manual (AJCC) bases primary tumor staging for glottic and supraglottic cancers on local extent as well as the presence or absence of vocal cord fixation.
Table 1: Tumor staging, based on local extent and presence/absence of vocal cord fixation. Pathologic T staging is identical to clinical staging.
Table 2: Clinical and pathologic nodal staging, based on size, number, laterality and presence/absence of extranodal extension (ENE).
Table 3: Stage groupings according to T, N, and M staging. For all subsites, T3-4 disease or any nodal involvement are considered locally advanced.
The management of laryngeal cancer is with a multidisciplinary team that includes an ENT surgeon, oncologist, dietitian, pulmonologist, speech therapist, intensivist and radiation therapist. The majority of patients first present with hoarseness, otalgia, dysphagia and weight loss to the nurse practitioner or primary care provider. 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 indicating a malignancy. The most crucial component of a physical examination is an invasive assessment of the primary lesion, including indirect laryngoscopy, mirror exam, and often fiberoptic endoscopy. The treatment of laryngeal cancer is surgery which is technically demanding and complex. Post operative 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. (Level V)
|||Mourad M,Jetmore T,Jategaonkar AA,Moubayed S,Moshier E,Urken ML, Epidemiological Trends of Head and Neck Cancer in the United States: A SEER Population Study. Journal of oral and maxillofacial surgery : official journal of the American Association of Oral and Maxillofacial Surgeons. 2017 Dec [PubMed PMID: 28618252]|
|||Bhattacharyya S,Mandal S,Banerjee S,Mandal GK,Bhowmick AK,Murmu N, Cannabis smoke can be a major risk factor for early-age laryngeal cancer--a molecular signaling-based approach. Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine. 2015 Aug [PubMed PMID: 25736926]|
|||O'Sullivan B,Warde P,Keane T,Irish J,Cummings B,Payne D, Outcome following radiotherapy in verrucous carcinoma of the larynx. International journal of radiation oncology, biology, physics. 1995 Jun 15 [PubMed PMID: 7790246]|
|||Ballo MT,Garden AS,El-Naggar AK,Gillenwater AM,Morrison WH,Goepfert H,Ang KK, Radiation therapy for early stage (T1-T2) sarcomatoid carcinoma of true vocal cords: outcomes and patterns of failure. The Laryngoscope. 1998 May [PubMed PMID: 9591559]|
|||Aaltonen LM,Rautiainen N,Sellman J,Saarilahti K,Mäkitie A,Rihkanen H,Laranne J,Kleemola L,Wigren T,Sala E,Lindholm P,Grenman R,Joensuu H, Voice quality after treatment of early vocal cord cancer: a randomized trial comparing laser surgery with radiation therapy. International journal of radiation oncology, biology, physics. 2014 Oct 1 [PubMed PMID: 25304787]|
|||Forastiere AA,Ismaila N,Lewin JS,Nathan CA,Adelstein DJ,Eisbruch A,Fass G,Fisher SG,Laurie SA,Le QT,O'Malley B,Mendenhall WM,Patel S,Pfister DG,Provenzano AF,Weber R,Weinstein GS,Wolf GT, Use of Larynx-Preservation Strategies in the Treatment of Laryngeal Cancer: American Society of Clinical Oncology Clinical Practice Guideline Update. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2018 Apr 10 [PubMed PMID: 29172863]|
|||Rosenthal DI,Mohamed AS,Weber RS,Garden AS,Sevak PR,Kies MS,Morrison WH,Lewin JS,El-Naggar AK,Ginsberg LE,Kocak-Uzel E,Ang KK,Fuller CD, Long-term outcomes after surgical or nonsurgical initial therapy for patients with T4 squamous cell carcinoma of the larynx: A 3-decade survey. Cancer. 2015 May 15 [PubMed PMID: 25586197]|
|||Ruytenberg T,Verbist BM,Vonk-Van Oosten J,Astreinidou E,Sjögren EV,Webb AG, Improvements in High Resolution Laryngeal Magnetic Resonance Imaging for Preoperative Transoral Laser Microsurgery and Radiotherapy Considerations in Early Lesions. Frontiers in oncology. 2018 [PubMed PMID: 29928638]|
|||Zhang MJ,Mu JW,Chen XR,Zhang X,Feng C, Effect of voice rehabilitation training on the patients with laryngeal cancer after radiotherapy. Medicine. 2018 Jun [PubMed PMID: 29953001]|
|||Dziegielewski PT,Reschly WJ,Morris CG,DeJesus RD,Silver N,Boyce BJ,Santiago I 3rd,Amdur RJ,Mendenhall WM, Tumor volume as a predictor of survival in T3 glottic carcinoma: A novel approach to patient selection. Oral oncology. 2018 Apr [PubMed PMID: 29598950]|
|||Yamazaki H,Suzuki G,Nakamura S,Yoshida K,Konishi K,Teshima T,Ogawa K, Radiotherapy for laryngeal cancer-technical aspects and alternate fractionation. Journal of radiation research. 2017 Jul 1 [PubMed PMID: 28898958]|
|||Dixon LM,Douglas CM,Shaukat SI,Garcez K,Lee LW,Sykes AJ,Thomson D,Slevin NJ, Conventional fractionation should not be the standard of care for T2 glottic cancer. Radiation oncology (London, England). 2017 Nov 14 [PubMed PMID: 29137654]|
|||Forastiere AA,Zhang Q,Weber RS,Maor MH,Goepfert H,Pajak TF,Morrison W,Glisson B,Trotti A,Ridge JA,Thorstad W,Wagner H,Ensley JF,Cooper JS, Long-term results of RTOG 91-11: a comparison of three nonsurgical treatment strategies to preserve the larynx in patients with locally advanced larynx cancer. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2013 Mar 1 [PubMed PMID: 23182993]|
|||Zhou J,Zhou L,Tao L,Zhang M,Wu H,Chen X,Li X,Li C,Gong H, Oncological outcomes of surgical treatment for T3 supraglottic laryngeal squamous cell carcinoma patients. Acta oto-laryngologica. 2019 Feb 8; [PubMed PMID: 30735065]|
|||Hay A,Simo R,Hall G,Tharavai S,Oakley R,Fry A,Cascarini L,Lei M,Guerro-Urbano T,Jeannon JP, Outcomes of salvage surgery for the oropharynx and larynx: a contemporary experience in a UK Cancer Centre. European archives of oto-rhino-laryngology : official journal of the European Federation of Oto-Rhino-Laryngological Societies (EUFOS) : affiliated with the German Society for Oto-Rhino-Laryngology - Head and Neck Surgery. 2019 Jan 21; [PubMed PMID: 30666441]|