Continuing Education Activity

Laryngeal cancers are one of the most common head and neck malignancies. Glottic cancers arise from true vocal cords and similarly to other laryngeal cancers linked with poorer outcomes to smoking and alcohol abuse. Management and involvement of a multi-disciplinary team can vary depending on the stage of the disease. This activity outlines the etiology, clinical history, and prognosis of glottic cancer, and highlights the role of the interprofessional healthcare team in investigating and managing patients with this condition.

Objectives:

• Identify the etiology of glottic cancer with related medical conditions and emergencies.
• Describe the appropriate evaluation of glottic cancer.
• Review the management options available for glottic cancer.
• Summarize the interprofessional team strategies for improving care coordination and communication to advance Glottic cancer and improve outcomes.

Introduction

Laryngeal cancers are one of the most common head and neck malignancies and thought to make up 1% of all cancers worldwide. Glottic cancer is defined as a malignancy arising from the true vocal cords and the anterior and posterior commissure of the larynx. Like other laryngeal cancers, smoking and alcohol abuse typically causes glottic cancer; however, tumors from this subsite have a better prognosis than other laryngeal cancers due to its reduced rate of local, nodal and distant invasion. The management of glottic cancers can vary significantly, from single modality transoral laser surgery or radiotherapy in early disease, through to chemoradiotherapy or total laryngectomy for more advanced disease. Providers, therefore, must have a thorough understanding of the anatomy and staging of glottic cancer to facilitate the most appropriate management plan for this disease.

Etiology

There has long been an association between the consumption of smoking and excessive alcohol consumption and the occurrence of glottic and laryngeal squamous cell carcinoma. Rates of laryngeal cancer are 15-30 times higher in smokers than non-smokers[1], with the inclusion of heavy alcohol intake having a multiplicative effect on the risk of malignancy.[2] Moreover, continued smoking following diagnosis and treatment is associated with poorer survival outcomes and a higher rate of recurrence.[3] 

Other proposed risk factors include gastroesophageal reflux, low socioeconomic status, opium use, red meat, and occupational exposure, with a healthy diet thought to have a minor protective effect.[4][5][6][7][8][9] Although the role of human papillomavirus (HPV) is now well established in many oropharyngeal tumors, this is less clear in laryngeal cancers. Several meta-analyses have suggested approximately 20-30% of laryngeal cancers may be associated with HPV. However, these rates vary considerably with geographical location, and further studies will be needed to establish a true causal link between the virus and glottic cancer.[10][11]

Epidemiology

Primary laryngeal and glottic cancers are uncommon, representing approximately 1% of all male and 0.3% of female cancers worldwide. The American Cancer Society estimates the diagnosis of 12370 new cases of laryngeal carcinoma in 2020, with approximately 60% arising primarily from the glottis. Of these new cases, 9820 will occur in men, and 3750 will die from the disease with a male to female ratio of 4 to 1. Reassuringly, these figures follow a 2 to 3% year on year reduction in overall cases. Rates of laryngeal cancer vary significantly with specific patient characteristics as male, low-income, and African-American patients have shown to present with higher rates of advanced disease.[12][13] Moreover, geographical location can influence rates of disease, with England exhibiting less than half the number of cases per 100,000 compared to Scotland and Northern Ireland (2 vs. 4.2 vs. 4.3).

Pathophysiology

Squamous cell carcinoma composes over 90% of all laryngeal malignancies. It is slow-growing and can appear as an exophytic or endophytic lesion. Glottic tumors typically arise from the free margin of the anterior 1/3rd of the vocal cords. Numerous anatomical boundaries can contain the lesion within the Reinke space for a significant period. Spread may occur locally across the anterior commissure (although the anterior commissure ligament provides a resilient barrier to the invasion) or posteriorly to the arytenoid cartilages.

Cancers may eventually breach the glottis through a direct invasion of the vocal ligament and vocalis muscles, causing vocal cord fixation via involvement of the thyroarytenoid muscle. From here, tumors gain access to the paraglottic space, facilitating cranial and caudal spread. Laryngeal cartilage is relatively resistant to direct tumor invasion, although invasion of the thyroid cartilage will often occur in advanced T4a disease. While supraglottic cancers often exhibit early bilateral nodal metastasis and subglottic cancers invade paratracheal and mediastinal nodes, carcinomas of the glottis have a low rate of lymphatic spread, attributed to an inadequate submucosal lymphatic supply. Nodal metastasis tends to occur when the tumor breaches the anterior commissure or invades another laryngeal subsite, most often spreading to levels 2, 3, 4, and 6.

Lymphoma is the second most common laryngeal malignancy; however, only thought to represent less than 1% of all cancers in this region. Nevertheless, it remains an important differential diagnosis, as it rarely requires surgical intervention beyond initial biopsy or tracheostomy in acute airway obstruction. It has a good prognosis when managed with chemoradiotherapy.[14][15] Other laryngeal cancer subtypes can arise from a large variety of cells, including chondrosarcoma, neuroendocrine tumors, and salivary gland cell type cancers; however, these tumors are vanishingly rare and are described only in a limited number of case reports and case series.[16][17][18]

History and Physical

Glottic cancers often present early, as even small lesions of the glottis can result in significant hoarseness. Resultantly, current American and British guidelines advise urgent referral to an otolaryngologist for persistent hoarseness lasting 4 and 6 weeks, respectively. However, there have been suggestions for referrals as early as three weeks from the onset of hoarseness.[19][20] Patients may also present with other head and neck red flag symptoms, including dysphagia, odynophagia, and referred otalgia. Though this typically occurs in advanced disease with tumor extension beyond the glottis. In more extreme cases, patients can present late as an emergency with stridor and acute airway compromise. Looking at the patient's past medical and drug history should be done to ascertain associated risk factors and assess the patient's fitness for oncological treatment or major surgery. Quantification of etiological risk factors, in particular, smoking and alcohol consumption status, must also be performed.

Patients require a full ear, nose, and throat examination by an experienced otolaryngologist, including palpation of the neck for cervical lymphadenopathy, as well as close inspection of the oral cavity and oropharynx to exclude an oropharyngeal malignancy and assess dentition. Flexible nasal endoscopy in the outpatient clinic is essential to evaluate the glottis with particular attention paid to the involvement of one or more cords, cord mobility, and invasion to other subsites in the supraglottis and subglottis. To assess subtle vocal cord immobility, video-stroboscopic equipment is available.

Evaluation

The initial investigation of choice for glottic cancer is a CT scan of neck and thorax to accurately assess local invasion, nodal disease, and distant metastasis. However, CT scans are unlikely to be of any diagnostic benefit in early T1 cancers that do not involve the anterior commissure, as both local and nodal disease in these cancers is exceedingly uncommon.[21] MRI scanning can offer superior soft tissue definition in the neck and thus used in some centers for assessment of direct invasion of the laryngeal cartilages.[22] PET-CT may be of use when the primary site is not detectable, and a 12-week post-treatment PET-CT is the current gold standard method of assessing response to treatment.[23] While considering patients for radiotherapy, the indication of an x-ray orthopantomogram is essential to reduce the risk of highly debilitating osteoradionecrosis.[24]

A definitive diagnosis is achieved with direct laryngoscopy and biopsy under general anesthetic. Assessment with 0, 30, and 70-degree rigid endoscopes can provide the most detailed evaluation of the primary tumor and its extension to other laryngeal subsites.

Treatment / Management

Early T1-T2a Glottic Cancers

Given the low incidence of nodal metastasis and the small, slow-growing nature of the primary lesion, early T1-2 glottic cancers can be managed very successfully with single-modality treatment. Transoral laser microsurgery (TLM) and radiotherapy are the most commonly employed treatments for early glottic cancer. Although there is no direct comparison in a randomized controlled trial, a Cochrane review has noted equivalent survival outcomes and local disease control in both methods.[25] Resultantly, the use of a particular method is often determined by tumor anatomy and resectability, perceived functional outcomes, patient preference, and departmental experience.

The fundamental principles of transoral laser microsurgery are the preservation of the cricoid cartilage and of at least a single crico-arytenoid joint, failure of which can result in a narrowed airway and a non-functional larynx respectively.[26] TLM is a day case done under general anesthesia with a CO2 laser. Risks of complications are low, and it avoids the morbidity, and repeated outpatient visits seen in radiotherapy, while also reserving radiotherapy as a second-line option should the tumor recur.[27] It has been well established that a 2 mm surgical margin must be achieved to ensure complete oncological resection.[28] This may prove to be technically challenging in bulky tumors, and risk causing poor voice outcomes secondary to laryngeal scarring in anterior commissure lesions. Resultantly, radiotherapy may be preferable in T1b-T2 lesions involving the anterior commissure and patients unsuitable for an endoscopic approach (e.g., restricted c-spine movement).[27][29]

Radiotherapy regimes for glottic cancers vary between centers. Usually, they range from 50–52 Gy in 16 fractions or 53–55 Gy in 20 fractions over three to four weeks, with a higher dose per fraction resulting in improved locoregional control for both T1 and T2 lesions.[30][31] In tumors involving the anterior commissure, augmentation of radiotherapy beams is essential to provide a bolus of radiation to the anterior neck, as this is a frequent site of post-treatment recurrence.[32] Unlike early to moderately advanced supraglottic cancers, there is no routine need for bilateral nodal irradiation for early glottic cancer. Although somewhat limited due to short-term radiation toxicity side effects, radiotherapy is said to have superior voice-related outcomes when compared to TLM.[33]

Partial laryngectomy is less commonly performed for primary early glottic cancers but offers a viable alternative to radiotherapy and TLM in experienced centers. Systematic reviews have demonstrated comparable oncological outcomes in both de novo and radio-recurrent cancers to radiotherapy and TLM.[34][35] However, appropriate patient selection is vital to achieving surgical clearance, as specific tumor characteristics such as subglottic or posterior commissure extension, cricoarytenoid complex fixation, or significant thyroid cartilage invasion are not appropriate candidates for partial laryngectomy.[36]

Moderately Advanced T2b-T3 Glottic Cancers

At present, UK and US guidelines advise organ preservation therapy for moderately advanced glottic cancer in the form of chemoradiotherapy.[27][29] Before the early 1990s, however, the treatment of choice for moderately advanced glottic cancer was total laryngectomy. The Veterans Affairs (VALCSG) study resulted in a paradigm shift in the management of these cancers, as they found equivalent two-year survival of induction chemotherapy and radiotherapy (68%) compared to laryngectomy and radiotherapy (64%), with a lower rate of salvage laryngectomy noted in T3 patients.[37] As a result, the management of moderately advanced glottic cancers now focuses on laryngeal preservation therapies, wherein radiotherapy and chemotherapy are employed to avoid the significant lifestyle change and long term morbidity associated with a laryngectomy. The RTOG 91-11 trial further built on this, establishing that concurrent platinum-based chemotherapy (cisplatin) with radiotherapy had higher 3-year survival compared to induction chemotherapy with radiotherapy or radiotherapy alone.[38]

Furthermore, a 10-year follow-up study confirmed the long term survival benefits of the concurrent chemotherapy group but did note a higher rate of non-cancer deaths in this treatment arm.[39] The addition of chemotherapy, however, can cause significant side effects with a severe impact on the patients' quality of life. This impact, combined with the reducing efficacy of chemotherapy in patients over the age of 70, means it is not routinely used in elderly patients with head and neck cancers.

Advanced T4 Glottic Cancer

Chemoradiotherapy may be used effectively in some advanced T4 cancers; however, the high rate of the thyroid cartilage and neck soft tissue invasion means many patients will be unsuitable for laryngeal preservation and will require surgery in the form of total laryngectomy. The Veterans affairs study noted T4 laryngeal tumors had a reduced response to chemotherapy and a higher rate of salvage surgery, suggesting organ preservation is not effective in advanced laryngeal cancer.[37] Additionally, epidemiological studies have shown improved survival in patients with locally advanced cancers undergoing total laryngectomy compared to chemoradiotherapy, strongly suggesting surgery is the treatment of choice for T4a glottic disease.[40][41] Total laryngectomy may also be considered in patients with significant laryngeal destruction, pre-laryngectomy tracheostomy, and non-functioning larynges.[29] T4b tumors are deemed inoperable due to the encasement of major vessels or the inability to achieve negative margins. Consideration of palliative treatment or chemoradiotherapy at this stage is feasible, and this has shown an association with a reduction of tumor progression and improved life expectancy.

Postoperative Treatment

Postoperative radiotherapy can improve locoregional outcomes in advanced head and neck cancer, and is therefore recommended in any T4 tumors, T2-3 lesions with significant nodal disease, and any patient with positive margins or extra-nodal extension.[42] The EORTC 22931 trial found that the addition of concurrent postoperative chemotherapy may further improve locoregional control and disease-free survival compared to radiotherapy alone.[42] RTOG 95-11 trial noted similar results in high-risk patients, but this stated a higher morbidity burden in the chemotherapy group. Thus postoperative chemotherapy may be used selectively in patients with a high risk of recurrence.[43]

Treatment of Nodal Disease

The rate of nodal disease in glottic cancer is considerably lower than the supraglottic disease, where bilateral elective neck dissection or nodal irradiation is advised even in clinically N0 necks.[44] Nevertheless, treatment with chemoradiotherapy has an excellent complete response rate in N1-3 disease, and many patients with advanced T3/4 glottic cancer will undergo ipsilateral or bilateral level 2-5 radiotherapy, regardless of pre-treatment nodal status.[45][46]

In patients undergoing total laryngectomy, elective bilateral neck dissection for staging purposes is essential, which may prevent the need for postoperative radiotherapy if no positive nodes are present. In patients who have failed to show a complete response following completion of treatment, or before chemoradiotherapy in patients with significant volume neck disease that are less likely to respond to primary oncological treatment, neck dissection is considered.[47]

Differential Diagnosis

The differential diagnosis of glottic cancer includes:

• Supraglottic, subglottic and transglottic laryngeal cancers
• Other head and neck cancers, including hypopharyngeal and upper esophageal
• Pre-malignant glottic lesions (leukoplakia, low and high-grade dysplasia)
• Vocal cord immobility
• Benign laryngeal lesions such as laryngeal papillomatosis, Reinke edema, vocal cord polyps, cysts, and nodules, granuloma, chronic laryngitis, hyperkeratosis, and functional dysphonia

Staging

The staging of glottic and other laryngeal cancers is according to the 2016 eighth edition of the AJCC TNM classification of malignant tumors. Unlike oral and oropharyngeal cancers, depth of invasion and p16 status does not have a role in staging glottic tumors. The extra-nodal extension is one of the most important predictors of clinical outcomes in head and neck cancers. To reflect this, TNM8 introduced the presence of extra-nodal extension into all laryngeal cancer staging, with its presence immediately classifying a patient as N3b regardless of nodal size, quantity, or location; to accurately reflect the negative impact this finding can have on prognosis.[48]

The TMN8 Tumour (T) staging is as follows:

• Tx: primary tumor cannot be assessed
• Tis: carcinoma in situ
• T1: tumor limited to the vocal cords (including the anterior and posterior commissure) with normal mobility
  • T1a: tumor limited to one vocal cord
  • T1b: tumor involving both vocal cords
• T2:
  • T2a: tumor extends to supraglottis and/or subglottis with normal vocal fold mobility
  • T2b: tumor extends to the supraglottis and/or subglottis, or with impaired vocal cord mobility
• T3: tumor limited to the larynx with vocal cord fixation or invasion of the paraglottic space or inner cortex of the thyroid cartilage
• T4: advanced disease
  • T4a: tumor invades through the outer cortex of the thyroid cartilage and/or invades tissues beyond the larynx (trachea, cricoid cartilage, tongue muscles, strap muscles, thyroid, or esophagus)
  • T4b: tumor invades prevertebral space, encases carotid artery, or invades mediastinal structures

The TNM 8 nodal (N) staging is as follows:

• Nx: nodes unable to be assessed
• N0: no regional lymph nodes
• N1: single ipsilateral lymph node ≤3cm and no extra-nodal extension
• N2
  • N2a: single ipsilateral lymph node >3cm but <6 cm in greatest dimension and no extra-nodal extension
  • N2b: multiple ipsilateral lymph nodes, none >6cm in greatest dimension and no extra-nodal extension
  • N2c: bilateral or contralateral lymph nodes, none >6cm in greatest dimension and extra-nodal extension
• N3
  • N3a: any lymph node >6cm and no-extra-nodal extension
  • N3b: any nodes with clinically overt extra-nodal extension

The TNM8 metastasis (M) staging is as follows:

• M0: no distant metastasis
• M1: distant metastasis

Prognosis

Overall, early laryngeal cancer carries a good prognosis, with 5-year survival outcomes, approximately 90% for stage 1 and 80% for stage 2 cancers when managed with single modality radiotherapy or laryngeal preserving surgery.[49] Survival outcomes are poorer for more advanced disease, with the 1990 Veterans Affairs study noting a 2-year survival of 68% and 64% for advanced disease treated with primary radiotherapy together with induction chemotherapy versus laryngectomy and postoperative radiotherapy.[37] Glottis cancer, however, carries a slightly better overall prognosis than other laryngeal sites, with 5-year survival rates of 83% for localized, 42% for advanced and 76% for all stages of the disease, compared to 61%, 30%, and 46% for supraglottic and 60%, 45%, and 52% for subglottic cancers, respectively. Unfortunately, between 1977 and 2002, the overall 5-year survival for regional and distant glottic cancer has fallen.[50]

Complications

Complications of Glottic Cancer

Compared to other laryngeal cancers, glottic cancer has a reduced propensity for regional and distant spread, but may still cause significant complications when left untreated. Dysphonia may occur through the direct invasion of the thyroarytenoid muscle and vocal ligament, progressing to dyspnoea, aspiration pneumonia, stridor, and acute airway emergencies necessitating tracheostomy in severe cases. Invasion of adjacent structures in the larynx and pharynx may also result in dysphagia and weight loss requiring nasogastric or gastrostomy feeding. The advanced local disease may encase and erode into the internal jugular vein and carotid artery, with the latter resulting in a carotid blowout and fatal hemorrhage.

Complications of Chemoradiotherapy

Despite its proven efficacy in the management of moderately advanced laryngeal cancer, chemoradiotherapy has a high rate of highly debilitating side effects and complications. Most commonly, patients will have complaints of xerostomia, mucositis, pain, and swallowing difficulty. These may manifest as late toxicity, resulting in gastrostomy support for nutritional intake in 13 to 14% of patients 1 to 2 years post-treatment.[51][52] Scarring, edema, and stenosis may also occur within the upper aerodigestive tract, necessitating recurrent endoscopic dilatation of pharyngeal strictures or tracheostomy in narrowed airways.[52] In the long term; depression, pain, dysphagia, and speech issues may have a significant effect on a patient's quality of life.[53] Further exacerbation of the rate of complications may occur due to numerous factors including advanced age and T-stage, site of primary disease, and neck dissection following oncological treatment.[51]

Complications of Surgery

Complications following transoral laser surgery are not infrequent, but are often minor and result in minimal morbidity for a patient. These can include local infection and bleeding, perforation and surgical emphysema, cutaneous fistula, dyspnoea, swallowing difficulties, and aspiration pneumonia.[54] Although uncommon, airway fires are a potentially devastating intra-operative complication of TLM, with potential sources of ignition, including the electrosurgical diathermy unit, light cords, and the CO2 laser.[55]

In more advanced cases, laryngectomy has a high rate of postoperative complications, with this rising further in salvage cases in previously irradiated patients. Pharyngocutaneous fistula remains one of the most common and challenging postoperative complications, frequently prolonging inpatient stay and delaying a return to an oral diet. Other potential complications include localized wound and lower respiratory tract infections, bleeding, damage to nerves (including the accessory, marginal mandibular and hypoglossal), and embolism.[56][57] Moreover, the long term quality of life impacts of a laryngectomy can be considerable, as patients have to re-adapt to even the most basic functions of eating, breathing, and speaking.[57]

Consultations

Management of glottic tumors requires the support of an interprofessional team. This team includes the following specialties:

• Otolaryngologists
• Maxillofacial and plastic surgeons
• Oncologists
• Radiologists
• Restorative dentists/oral surgeons
• Clinical nurse specialists
• Dieticians
• Speech and language therapists
• Palliative care

Deterrence and Patient Education

Excessive alcohol consumption and cigarette smoking are intrinsic to the development of glottic cancers, with the continuation of smoking resulting in poorer functional outcomes, reduced survival, and a higher rate of recurrence. Moreover, cessation of smoking after 1 to 4 years can result in a significant risk reduction in developing laryngeal cancer, reaching the level of never-smokers after 20 years.[58]

Enhancing Healthcare Team Outcomes

The variance in surgical and oncological management of glottic cancer across TNM stages highlights the importance of the multidisciplinary team. Invariably, there is an importance in performing an initial outpatient history and examination by an otolaryngologist. Subsequent initial investigations, including cross-sectional imaging and biopsy, radiologists, and pathologists, are essential in achieving definitive diagnosis and staging. Depending on the required treatment, otolaryngologists, and oncologists with a specialist interest in head and neck, cancer will be responsible for the provision of surgical, chemotherapy, and radiotherapy interventions. Given the myriad of complications and the often life-changing nature of these treatments, early involvement of associated specialists such as speech and language therapists, nurse specialists, dieticians and psychologists are essential in maintaining patients' quality of life and providing a patient-centered care approach.