Guidelines for the Surgical Management of Laryngeal Cancer: Korean Society of Thyroid-Head and Neck Surgery

A5-1. Assessment of patients who are eligible for laryngectomy

The workup required for a laryngectomy includes an anestheticrelated assessment of general health and specific tests relevant to laryngectomy [54-56].

Preoperative posteroanterior and lateral chest radiography of patient may be mandatory when planning laryngeal surgery [56]. In patients with additional risk factors, including COPD, age older than 60 years, ASA class II or greater (Table 5), functional dependence, and congestive heart failure, pulmonary function tests (spirometry and flow-volume loops) could be very useful [57]. The effectiveness of preoperative and surgical countermeasure can be assessed by quantitative measurement of ventilation. Spirometry data is used not only to distinguish restrictive from obstructive pulmonary disease but also to forecast perioperative pulmonary complications. Universally, less than 75% of forced expiratory volume in 1 second (FEV1)/vital capacity (VC) ratio is regarded abnormal, and less than 50% of the ratio indicates significantly increased risk of perioperative pulmonary morbidities [56].

Table 5.

American Society of Anesthesiologists physical status classification system

In patients with pulmonary disease, preoperative room air arterial blood gas analysis (ABGA) is recommended. Patients with less than 60 mmHg of arterial oxygen pressure or greater than 50 mmHg of carbon dioxide pressure are tend to develop pulmonary distress after surgery. Consecutive ABGA can also be used to validate the effectiveness of respiratory or medical intervention. In addition, preoperative ABGA as well as chest X-ray give a baseline for postoperative comparison [56].

The preoperative management of underlying pulmonary disease is critical and should consult to a pulmonologist. Smoking have to be prohibited for at least 1 week before surgery. Interventions such as preoperative incentive spirometry or deep-breathing exercises, and the use of intraoperative nasogastric tube decompression can successfully reduce pulmonary complications in high-risk patients. Acute exacerbation of pulmonary disease or infection should be cleared with antibiotics and chest physiotherapy before surgery [58].

If the patient is eligible for partial laryngectomy, a preoperative assessment of the pulmonary status and careful review of the patient’s exercise tolerance are especially important because the patient’s preoperative pulmonary reserve is an important indicator of how well the patient will tolerate postoperative aspiration [57,59].

Nevertheless, no existing objective standards can reliably distinguish which patients can tolerate the physiological changes that accompany conservation laryngeal surgery [57,60].

A5-2. Screening assessment of second primary cancers (synchronous and metachronous head and neck carcinomas)

Patients with HNSCC often have a history of alcohol and nicotine abuse and therefore have an elevated risk of developing synchronous and/or metachronous squamous cell carcinoma in other parts of the upper aerodigestive system [61]. The reported annual incidence of second primary malignancy (SPM) in HNSCC patients is approximately 3% to 7%, and patients with a previous history of HNSCC have an approximately 14% chance of developing a SPM. Patients with initial HNSCC also have a high rate of secondary cancer, with 41% and 59% developing synchronous and metachronous tumors, respectively. The potential to develop a secondary malignancies within 5 years after undergoing treatment for an initial HNSCC was 22%. Screening and chemoprevention programs should be recommended to the patients with initial HNSCC [62]. Generally, oral cavity and oropharyngeal squamous cell cancers are more frequently associated with head and neck region SPM, whereas laryngeal and hypopharyngeal cancers are more associated with lung SPM [61].

SPMs compromise overall survival of HNSCC patients. The survival of patients with HNSCC and SPM has been shown to be poorer than that of HNSCC patients without SPM (38% vs. 49% at 10 years). The early detection and staging of SPMs has an important impact on treatment and is therefore highly important. A majority of SPMs are detected at an early stage, when curative treatment is still an option. In particular, many patients have curable lung cancers. Taken together, patients with HNSCC, including laryngeal cancer, should undergo careful physical examinations and regular follow-ups to detect SPMs.

Routine workups for metastases of laryngeal carcinoma are essential. The lung is the most frequent site of distant metastasis, followed by the liver, and accordingly chest radiographs and laboratory investigations of liver function, with possible liver US, are the minimal standards at several institutions [63]. Patients with abnormal chest radiography findings and those with advanced disease or a strong clinical suspicion may warrant CT scanning of the chest or abdomen [61].

Recently, FDG-PET/CT is usually included in the initial staging work-up of a patient with laryngeal cancer [57]. FDG-PET/CT is quite better than morphological imaging modalities such as CT or MRI in terms of assessing the primary tumor, lymph nodes, potential distant metastases, and SPMs in a single examination. However, the method by which FDG-PET/CT should be integrated into the staging algorithms of the disease remains controversial [64]. FDG-PET/CT detects many synchronous primaries and seems to be an ideal tool for the guidance of metabolically active lesion biopsies; consequently, panendoscopy can be performed more sufficiently when using information gained from PET [65].

However, the limited spatial resolution of FDG-PET/CT may render small and superficially growing tumors of the aerodigestive system invisible [66]. Therefore, FDG-PET/CT will not substitute routine panendoscopy [65]. The use of panendoscopy for SPM surveillance has been reinforced by several studies. In a study of 200 patients with HNSCC, most metachronous tumors were found to involve the lung and esophagus, and index tumors were diagnosed within 1 to 3 years of therapy [67]. Haughey et al. [68] recommended endoscopic examinations at routine intervals within 2 years of head and neck treatment to ensure the optimal detection of SPMs, as half of all aerodigestive tract SPMs are detected within 2 years of the index tumor diagnosis.

Therefore, concurrent evaluation of FDG-PET/CT and PET/CT-guided endoscopic exam might be the most sensitive strategy for detecting synchronous tumors at early and curable condition. The efficacy of this tactic to improve outcomes with regard to oncologic outcome and cost-effectiveness must be evaluated in the future [61,65].

A5-3. Risk factors for laryngeal cancer

Laryngeal cancer is a multifactorial disease associated with a variety of lifestyle factors, environmental factors, and other host factors. Smoking is the predominant risk factor for laryngeal cancer [69]. The combined consumption of alcohol and tobacco increases the laryngeal cancer risk in a synergistic, rather than additive, way. Chronic alcohol consumption affects carcinogenesis through malnutrition and the depletion of vitamins and minerals that protect against cancer [69-73]. Tobacco and alcohol use deteriorate treatment efficacy for laryngeal cancer. The laryngeal cancer patients who maintain smoking and/or drinking are less likely to be cured and apt to develop a secondary malignancies [73]. Current smokers have a 10- to 20-fold increased risk of laryngeal cancer when compared with nonsmokers [74,75]. However, these risks decline after smoking cessation, although never to the same level as that of patients who have never smoked. There is an approximately 60% reduction in the relative risk at 10 to 15 years after smoking cessation [76].

Alcohol consumption can increase the risks of cancer of the mouth, throat, esophagus, larynx, liver, and breast. People who take 50 or more grams of alcohol per day (approximately 3.5 or more drinks per day) have at least a 2- to 3-fold greater risk of developing such cancers, compared with nondrinkers [77]. The risk of cancer is much higher for individuals who take both alcohol and tobacco. Moreover, the risks of these cancers are significantly higher among people who consume such high amounts of alcohol while using tobacco [78].

A lower socioeconomic status, which results in poor health care, smoking, drinking, and dietary habits, and exposure to environmental and occupational carcinogenic factors have been associated with cancer. All of these factors are possible explanations for the increased risk of laryngeal cancer [69-80].

Other risk factors include carcinogens in the workplace, such as asbestos, nickel compounds, wood dust, leather products, paint, diesel fume, and glass-wool [81]. A potential association with chronic gastroesophageal reflux disease or laryngopharyngeal reflux disease remains controversial [82,83].

Furthermore, the relationships between the increased incidence of SCC, laryngeal papillomatosis and human papilloma virus (HPV) remain controversial. Although good evidence supports a causal link between HPV subtypes 16 and 18 and oropharyngeal cancer, the association with laryngeal cancer is uncertain [84,85].

B1-1. Definition of a premalignant laryngeal lesion

The World Health Organization classifies premalignant laryngeal lesions as either hyperplasia; keratosis; mild, moderate, or severe dysplasia; or carcinoma in situ [86,87]. Very early lesions may exhibit hyperkeratosis or parakeratosis without cellular atypia or dysplasia. Squamous cell dysplasia is characterized by cellular atypia and a loss of normal maturation and stratification. Cellular abnormalities associated with mild dysplasia are limited to the basal third of the epithelium; whereas, moderate dysplasia shows marked cellular abnormalities involving up to two-thirds of the epithelium, and severe dysplasia is characterized by cellular abnormalities involving more than two-thirds of the epithelium. Carcinoma in situ is an intraepithelial neoplasm in which the full thickness of the squamous epithelium exhibits the cellular features of carcinoma without violation of the basement membrane.

B1-2. Diagnostic procedure for a premalignant laryngeal lesion

The visual appearance of a premalignant laryngeal lesion does not predict its histologic nature, nor does laryngeal videostroboscopy reliably differentiate premalignant from malignant lesions [88]. The use of vital dyes, including toluidine blue and methylene blue, has been explored [89,90]. Toluidine blue yielded a 91% sensitivity but only 52% specificity for the detection of dysplasia or malignant changes [90]. Contact endoscopy with methylene blue staining provides a magnified image with histologic information and an assessment of vascular patterns [91]. However, this technique is inadequate for characterizing thicker lesions. Regarding autofluorescence endoscopy, human tissues contain many compounds that fluoresce when exposed to blue light. The differing fluorescence of abnormal tissues has been exploited as a diagnostic aid for laryngeal malignancy. However, this technique is limited by the possibility of false-positive and false-negative examinations in cases involving scarring, hyperkeratotic lesions, and inflammation [92]. Optical and microscopic imaging is limited by an inability to evaluate the submucosal architecture below the first few layers of epithelial cells. In contrast, infrared light has increased tissue penetrance and can provide diagnostic information about subsurface tissues. Optical coherence tomography uses near-infrared light waves to examine the epithelial and subepithelial architecture waves [93]. Therefore, optical coherence tomography is a potentially useful tool in the management of laryngeal cancer.

NBI is a new technology that uses blue and green light (respective wavelengths: 415 and 540 nm) to observe the microvascular structure in the epithelium. Superficial mucosal lesions that cannot observed with white light endoscopy could be identified by their angiogenic patterns on NBI. Ni et al. [94] devised a five-type classification system of laryngeal leukoplakias that incorporated the vascular pattern of the intrapapillary capillary loop, and reported a correlation between their classification system and pathologic findings. Subsequently, Bertino et al. [14] analyzed premalignant laryngeal lesions using the Ni classification. In that study, NBI yielded a sensitivity, specificity, accuracy, PPV, and NPV of 97.4%, 84.6%, 92.7%, 91.6%, and 95.1%, respectively [14]. Compared with autofluorescence, NBI showed superior specificity for the detection of early neoplastic lesions [92,95-97]. However, endoscopic analyses should always be confirmed by histopathologic lesion analyses.

B1-3. Approach for a premalignant laryngeal lesion

As the lesions of moderate dysplasia progressed to invasive cancer in 0% to 45%, medical or surgical intervention was recommended in these cases [80,98-105]. Dysplastic lesions could be excised using microlaryngoscopic techniques to remove the visible lesion. Close follow-up is required because of the risk of recurrence of the lesion and possible malignant transformation. In patients with lesions of mild dysplasia, it progressed to invasive cancer in 0% to 11.5%. Therefore, a regular follow-up is usually recommended.

Severe dysplasia and carcinoma in situ have the similar high risk of progression to invasive carcinoma and they are considered as the same disease entity for clinical purposes [98]. Standard treatment strategies have not established in laryngeal lesions of severe dysplasia or carcinoma in situ yet. Practices implemented in different environments are likely based on consensus rather than on a high level of evidence from the literature [86,106]. In previous studies, watchful waiting policy has failed to manage the lesions of severe dysplasia/carcinoma in situ, because the lesions progressed to invasive cancer in most cases [99,100]. Therefore, medical or surgical treatment should be performed in all cases of severe dysplasia/carcinoma in situ. The treatment method of these lesions includes radiotherapy, CO₂ laser excision, vocal cord stripping, and so on [98]. Radiation therapy is generally not recommended for the treatment of premalignant lesions of the larynx. However, this modality is recommended on rare occasions for high grade dysplastic lesions with poor access [107].

B1-4. Follow-up of premalignant lesions

Patients with severe dysplasia and carcinoma in situ should be kept under surveillance in a manner similar to that for early laryngeal carcinoma: every 1 to 3 months for the first year, every 2 to 6 months for the second year, every 3 to 6 months during the third year, and every 6 months during years 4 and 5. Patients with mild or moderate dysplasia and risk factors (continued smoking, persistent hoarseness, and visible lesions) should also be observed for at least 6 months. Patients who have mild or moderate dysplasia without risk factors are considered as low-risk group. Opinions vary widely with regard to the duration of follow-up for these patients. Some clinicians recommend at least a 2-year follow-up. Others recommend early discharge from the clinic and an early return if symptoms develop [107].

C3-1. Management for clinically positive neck (N+) in patients with glottic cancer

Treatment of neck lymph node metastases should be performed according to the presence of clinically positive neck nodes [184]. Radical or modified radical neck dissection could be considered according to the lymph nodes metastasis status. Few studies have reported recommendations regarding the levels of neck dissection in clinically neck-positive glottic cancer, as the specifics of this procedure are normally determined according to disease involvement. Ipsilateral levels II, III, and IV are most frequently involved in the cervical metastasis of advanced glottic cancers [185]. Levels I (1.8% to 5%) and V (2% to 11%) are rarely involved [186-188]. However, the involvement of levels I and V is usually associated with metastases in levels II, III, or IV. Moreover, the involvement of level V increases along with the involvement of other levels in aerodigestive tract SCCs (0% to 15.8% for single-level involvement; 3.2% for two-level involvement; 15.3% for three-level involvement; 40.0% for four-level involvement) [189]. Therefore, dissection of neck level I or V may be considered according to the individual nodal status.

The clinical efficacy and safety of super-selective neck dissection have not yet been evaluated in the context of clinically N+ glottic cancer.

A few studies have evaluated contralateral neck dissection for glottic cancer. In advanced glottic cancer, most metastatic lymph nodes are located at ipsilateral levels II, II, and IV (87.5% to 95%) [185,190,191]. Among lateral glottic cancers, the rate of contralateral neck metastasis was very low (3.5%) [191]. Glottic cancers, including transglottic cases, are associated with a low prevalence of contralateral metastases, even if the primary tumor extends beyond the midline (4%) [192]. Therefore, contralateral neck dissection may not be considered [191,193].

C3-2. Management for clinically negative neck (N0) in patients with glottic cancer

Generally, elective treatment of the neck is justified if the risk of occult lymph node metastasis exceeds 15% [151]. In previous studies, the rates of occult lymph node metastasis in early glottic cancer (T1–T2) ranged from 0% to 8.6%, and nodal recurrence rarely occurred during follow-up [194-196]. Therefore, elective neck dissection is not recommended for early glottic cancer [110,197]. Among advanced N0 glottic cancers, the neck recurrence rate ranges from 14.3% to 23.4% [185,194,196,198]. Therefore, elective neck dissection is acceptable for advanced glottic cancers without clinical neck metastasis (T3N0 and T4N0) [166,199-203]. However, some studies reported that among patients with T3N0 glottic cancer, follow-up observation involving meticulous examinations and appropriate treatment for subsequent neck disease resulted in a similar survival rate as that of initial neck treatment (treated group 72%, observation group 70%) [166]. Other authors reported the survival rates of patients with T4N0 glottic cancer who underwent initial neck treatment versus those who remained under observation, with later treatment if necessary (5-year disease-specific survival, 31% vs. 44%) [204].

Ipsilateral selective neck dissection of levels II, III, and IV is sufficient for clinically node negative glottic cancer [200,201, 205,206], as the lymphatic spread of glottic cancer to the neck follows a predictable path along the jugular chain [207-209], and levels I and V are rarely involved in a clinically negative neck (level I, 0% to 14%; level V, 0% to 7%) [201,209,210]. This finding was proven by many studies, including well-controlled randomized prospective studies [196,211-213]. Contralateral neck dissection is not recommended for T3N0 and T4N0 glottic cancers, which have a very low contralateral neck metastasis rate [185].

Recently, super-selective neck dissection of levels IIa and III was suggested [184,214]. Sublevel IIb (0% to 9.5%) and level IV (3.4%) are rarely involved in clinically N0 glottic cancers [215-218]. Level IIb sparing could reduce morbidities such as spinal accessory nerve paralysis and injuries to the digastric and sternocladomastoid muscles [218]. Level IV sparing could reduce potential complications such as chylous fistula and phrenic nerve injury [219].

D1-1. Surgical treatment for T1/T2 supraglottic cancer

For patients with early supraglottic cancers (T1 and T2 tumors), successful disease control can be achieved by either traditional conservation surgical procedures, including open partial laryngectomy, or curative doses of irradiation [220,221]. Therefore, treatment modality can be decided according to the expected posttreatment functional outcome, the patient’s wishes and general medical condition, and reliability of follow-up. Open partial laryngectomy yields excellent local control of early supraglottic cancers, with reported rates ranging from 80% to 100% [222-225]. Despite the high rates of local tumor control with open partial laryngectomy, the possibility of lung complications by significant aspiration and postoperative dysphagia may frequently preclude the application of this procedure. Because open partial laryngectomy disrupts the pharyngeal muscles, strap muscles, and sensory innervation of the pharynx and larynx, swallowing is markedly impaired, especially in the early postoperative period. Moreover, the adjunctive use of a tracheostomy and feeding tubes is necessary during the early and intermediate postoperative period after open partial laryngectomy due to airway obstruction by laryngeal swelling [226].

With the wide acceptance of transoral laryngeal surgery, extrapolations of less invasive approaches to the supraglottic larynx have been described [227,228]. The oncologic results of transoral laryngeal surgery can be comparable to those of open partial laryngectomy if complete resection is achieved. Moreover, although open partial laryngectomy and radiotherapy yielded comparable functional outcomes [229], transoral laryngeal surgery is generally associated with a lower risk and shorter duration of postoperative morbidity [230-232]. The functional outcomes of transoral laryngeal surgery are superior to those achieved with a conventional open approach with regard to the duration of applying feeding tube and tracheostomy, incidence of pharyngocutaneous fistulae, and lengths of hospital stay [116].

In 1998, Ambrosch et al. [233] reported the outcomes of early (T1 and T2) supraglottic cancer who underwent transoral laryngeal surgery between 1979 and 1991. A 100% 5-year local control rate was achieved for pT1 cases, whereas a rate of 89% was achieved for pT2 cases. The 3-year recurrence-free was 83% and overall survival rates was 76%, respectively. This study revealed that local control and survival of transoral laryngeal surgery were comparable to those of conventional open partial laryngectomy in early supraglottic cancer. Other reports of transoral laryngeal surgery for supraglottic cancer also concluded that transoral laryngeal surgery is an excellent treatment for early supraglottic cancers including selected T3 lesions, if clear margins could be achieved [234,235]. In 2004, Davis et al. [227] reported the outcomes of T2 and T3 supraglottic cancers by laser resection, in which local control was achieved in 97% of patients receiving combined treatment with radiotherapy and in 100% among patients treated with surgery alone. In 2008, Cabanillas et al. [236] retrospectively compared the patients with supraglottic cancer treated by laser surgery and conventional open approaches. The laryngeal preservation rates were 86% and 80% in the laser group and transcervical group, respectively (P=0.6). The larynx was preserved in all patients classified as T1 and T2 who survived for 5 years after surgery. In 2006, Peretti et al. [230] performed study comparing the functional outcomes of transoral laryngeal surgery with conventional open approach. Significant differences were observed with respect to swallowing function (P=0.03), duration of hospital stay (P=0.0001) and feeding tube and tracheostomy duration (P=0.0001). The authors concluded that transoral laryngeal surgery had a significantly lower functional impact on swallowing, compared with the conventional open approaches, and was also associated with reduced postoperative morbidity and a shorter hospitalization duration. Recently, transoral laryngeal surgery via a robotic system was introduced. Several papers reported the comparable surgical and function outcomes of this procedure with those of conventional transoral laser surgery; however, a longer follow-up duration and larger observational cohort may be needed to establish the role of transoral laryngeal surgery in supraglottic cancer treatment [237,238].

One important consideration of transoral laryngeal surgery is that adequate exposure is necessary to ensure a proper resection [235,239]. Even with experienced hands, complete resection was impossible in approximately 8% to 10% of cases [235]. In addition, approximately 40% of patients in whom R1 and R2 resection were achieved with transoral laryngeal surgery failed to reach complete remission after initial treatment modalities and finally died by tumor progression. Therefore, if the surgical extent is inadequate, other treatment option including radiation therapy or open partial laryngectomy should be considered for proper tumor resection. A skilled surgical technique and experience are important factors in a successful resection, and the possibility of conversion to open partial laryngectomy or a change to postoperative radiotherapy should be addressed with the patient before surgery. In summary, early supraglottic cancer (T1/T2) can be managed via transoral laryngeal surgery (with adequate surgical exposure) with or without postoperative radiation therapy, and favorable local control and survival outcomes can be achieved. A majority of studies that compared transoral laryngeal surgery with open surgery for supraglottic cancer (mostly case series or case-control studies) demonstrated comparable oncological outcomes with superior functional results, especially with regard to swallowing.

D1-2. Surgical treatment for T3/T4 supraglottic cancer

Traditionally, survival has been used as the endpoint when assessing the best treatment option; however, consideration of several parameters including posttreatment functional status, organ preservation, treatment costs, and quality of life have been increasingly emphasized during the last two decades [240]. Until 1950, total laryngectomy and radical neck dissection and followed by radiotherapy was the only procedure accepted for the treatment of laryngeal cancer, and was associated with cure of disease by approximately 60% to 70% [240-242]. Today, however, the goal of treatment focuses not only on a cancer cure, but also on the preservation of laryngeal function [243].

Although the surgical excision of advanced primary tumors has traditionally been achieved via total laryngectomy, which remains the most commonly used procedure, conservative laryngeal resection may be used in selected cases. In 2007, a prospective study evaluated patients who underwent transoral laryngeal surgery for supraglottic cancer [244]. In addition to T1/T2 cases, this study included selected T3 and T4 cases (eight patients, 21%). The 2-year local control, loco-regional control, disease-specific survival, and overall survival were 97%, 94%, 80%, and 85%, respectively. In addition, 79% of the patients finally had overall functional laryngeal preservation. In addition, Canis et al. [245] also reported excellent oncologic outcomes with better functional outcomes of transoral laryngeal surgery for supraglottic cancer. These authors evaluated 277 patients and concluded that transoral laryngeal surgery yields a low rate of morbidity, fast recovery, and superior postoperative function when compared to standard therapy [245].

As described for early supraglottic cancer treatment, advanced supraglottic cancer (T3/T4) can be managed with supraglottic laryngectomy or SCL [246]. T3 tumors with pre-epiglottic space invasion but without transglottic spread may be good candidates for supraglottic partial laryngectomy (SPL). Cases requiring arytenoidectomy will also require extended SPL. However, this procedure is often associated with a longer recuperative duration and increased incidence of serious complications [247]. In addition, SCL may be another option for lesions with glottic extension. The oncologic results of SCL are excellent, with 5-year survival rates and local control rates of 67% to 95% and 88% to 95%, respectively [137]. SCL can be used for the following selected T2, T3, and T4 supraglottic and transglottic tumors: T2 tumors involving the true vocal cords or anterior commissure, extension to the floor of the ventricle, and/or impaired motion of the true vocal cord; T3 transglottic and supraglottic tumors with true vocal cord fixation and/or pre-epiglottic space invasion; and T4 transglottic and supraglottic tumors with limited invasion of the thyroid cartilage but without extension to the outer thyroid perichondrium, or extralaryngeal spread [248-250]. In summary, for T3 or T4a supraglottic tumors without extensive tongue base involvement or cartilage destruction, conservative laryngeal surgery may be used primarily for functional larynx preservation. For tumors with extensive tongue base invasion, bilateral cricoarytenoid unit impairment, or inferior extension to the cricoid cartilage, total laryngectomy remains the preferred initial treatment.

D2-1. Management for clinically positive neck (N+) in patients with supraglottic cancer

Neck management of supraglottic cancer requires a different philosophy than that of glottic cancer because in the former, the lymphatic system is involved at a much earlier disease phase and neck nodal metastases are much more common [251]. Appropriate cervical lymph node treatment is an important aspect of therapy for patients with supraglottic cancer, as the nodal status has prognostic significance [252-255]. The presence of clinically palpable cervical lymph node metastasis is associated with an approximately 50% reduction in overall survival [252-256]. The cervical metastasis sites are well-defined, and the most common nodal metastasis sites are cervical levels II, III, and IV. Candela et al. [188] retrospectively reviewed 247 consecutive patients with supraglottic cancer who underwent comprehensive neck dissection. An analysis of the lymph node metastasis distribution revealed a remarkable preference for levels II (62%), III (53%), and IV (31%). Levels I (5%) and V (6%) were rarely involved, and level V was never pathologically involved in the absence of nodal disease at other levels [188]. For patients in whom clinical nodal disease is evident on preoperative imaging, via nodal fine needle aspiration cytology, or at the time of surgery, surgical resection via comprehensive node dissection might reduce the risk of recurrence and, possibly, mortality. Some authors have attempted to evaluate the effectiveness of selective neck dissection in clinically N+ patients with laryngeal cancer [257-259]. Selective neck dissection (levels II–IV) could be considered for clinically N+ in some selected patients with supraglottic cancer. Selective neck dissection may be an appropriate treatment for patients with clinically N+ disease and nodal pathology limited to two or fewer neck levels [260].

D2-2. Management for clinically negative neck (N0) in patients with supraglottic cancer

The ideal management of the clinically N0 neck remains controversial. The main controversy surrounds the issue of whether steps should be taken to eradicate occult metastases in the clinically N0 neck. The incidence of nodal metastases varies widely from 10% to 50%, depending on the choices of clinical, imaging, and histopathological methods [207,261,262].

Elective ipsilateral neck dissection was previously recommended for all patients with supraglottic cancer [263,264]. The morbidity associated with selective neck dissection is very low. Djordjevic et al. [265] reported a statistically significant observed difference in the development of postoperative regional metastases in a prospective case-control study, with rates of 4.15% (eight cases) in the elective neck dissection group versus 11.8% (six cases) in the ‘wait and see’ group. Weber et al. [266] also showed a significant reduction in the incidence of cervical recurrent disease from 20% to 9%. These authors demonstrated that 38 of 39 recurrences among 202 patients with supraglottic cancer had developed in non-surgically treated necks. Redaelli de Zinis et al. [267] suggested elective neck dissection only for advanced-stage supraglottic cancers. In their study, occult metastases were observed in 0% of pT1, 26% of pT2, 46% of pT3, and 26% of pT4 cases. Some authors suggested considering elective neck dissection only when the tumor had spread into the vallecula, tongue base, or medial wall of the pyriform sinus, or when the tumor depth exceeded 1 mm [268-270]. However, the ‘wait and see’ policy has been proposed as an alternative to cN0 neck treatment in patients with supraglottic cancer [242,271-273]. In several studies, the neck disease-free survival rate did not differ significantly between patients with neck dissection and those subjected to a ‘wait and see’ evaluation [242,272,273]. In a study by Sessions et al. [242], survival rates of 75.5% and 79.9% were reported in the neck dissection and ‘wait and see’ groups, respectively; these rates were not significantly different.

Approximately 15% of the lymphatic circulation crosses the laryngeal midline and may lead to bilateral and contralateral metastases [274]. The contralateral undissected neck is the most common site of failure in cases of supraglottic cancer [275]. Lutz et al. [275] reported that the neck was the most common site for recurrent disease (39 of 47 patients), and such disease strongly tended to appear in the undissected, contralateral side (35 of 39 recurrent patients). Chiu et al. [276] also demonstrated that routine bilateral neck dissection reduced cervical recurrences and appeared to improve survival within the context of supraglottic cancer management. However, other authors preferred to perform ipsilateral neck dissection under the assumption of a higher risk of metastases according to the primary tumor site and extent or the ipsilateral nodal status [251,267,277]. Gallo et al. [207] demonstrated that supraglottic cancers involving or extending up to the midline had a higher risk of contralateral metastases when compared with well-lateralized tumors. Ozturkcan et al. [278] reported contralateral occult metastasis rates of 44% and 5% in patients with pathologically N+ and N0 ipsilateral necks, respectively. Routine bilateral neck dissection for the treatment of early-stage lateral supraglottic cancer with a clinically N0 neck might not be necessary because no significant improvements in regional control and survival have been observed with this technique relative to the use of ipsilateral neck dissection [272].

There is no general consensus regarding which type of neck dissection is more adequate in patients with cN0 supraglottic cancer. However, selective neck dissection of level II–IV has become the procedure of choice for the surgical treatment of clinically negative necks in patients with supraglottic cancer. In a prospective randomized trial that compared modified radical neck dissection with selective level II–IV neck dissection in 132 clinically N0 patients with supraglottic and transglottic carcinomas, no significant differences were observed in the incidence of neck recurrence (four in the modified radical neck dissection group and two in the selective neck dissection group) or survival (72.3% in the modified radical neck dissection group and 62.4% in the selective neck dissection group) [212]. Some authors showed that the level IIB and IV lymph nodes are rarely involved in cases of metastatic disease, and may be left in place during neck dissection in patients with N0 necks [215,279-281]. Superselective neck dissection to remove the level IIA and III lymph nodes could be considered for patients with SCC of the supraglottic larynx and a N0 neck [215,279,280].

E1-1. Postoperative management and complications

Postoperative management includes the monitoring of vital signs, fluid and electrolyte balances, oxygenation, wound drainage, neck flap viability, and respiratory (e.g., tracheostomy tube care, airway humidification) and nutritional care. Erythema and edema of the skin flaps, fever, foul odor, and an elevated leukocyte count imply wound infection.

Pharyngocutaneous fistula may be suspected in a patient with a spiking fever and tense, warm, erythematous skin flap in the suprastomal region after total laryngectomy. Many investigators have reported factors that predispose patients to pharyngocutaneous fistula. Comorbidities such as diabetes, hepatic disease, thyroid disease, anemia, peripheral vascular disease, COPD, and malnutrition, the use of immunosuppressive medication, and local factors such as the tumor location and stage, persistent disease, pre- or postoperative radiotherapy, preoperative tracheostomy, extent of neck dissection, method of pharyngeal closure, and early nasogastric tube removal are considered predisposing factors for pharyngocutaneous fistula [282-289]. Recent metaanalyses have reported that COPD, a previous hemoglobin level of less than 12.5 g/dL, blood transfusion, previous radiotherapy or chemoradiotherapy, advanced primary tumor, supraglottic subsite, hypopharyngeal tumor site, positive surgical margins, and neck dissection were risk factors for fistula, whereas the suture material was not a significant factor [285,290].

Prolonged aspiration is a major morbidity experienced after partial laryngectomy. Usually, the incidence and severity of this condition are related to the extent of resection. Great care must be taken after SCL or SPL, and even after transoral endoscopic resection or total laryngectomy as aspiration may occur via tracheoesophageal puncture. Dysphagia may also occur after total and partial laryngectomy. Dysphagia after total laryngectomy is mainly due to stenosis of the neopharynx as a result of a tight surgical closure or cicatricial scar formation.

Stomal stenosis is a slowly progressive complication after total laryngectomy. Predisposing factors for this condition include the presence of a tube that induces local inflammation and fibrosis, postoperative radiotherapy, tracheoesophageal puncture prosthesis, or tumor characteristics. Local infection, female sex, and diabetes were found to correlate with stomal stenosis in several multivariate analyses [291-293]. This complication can be quite severe and may require surgical correction. Long-term use of a stomal tube may be necessary.

Hypothyroidism was reported in 13% to 38% of patients after laryngeal cancer treatment [294-296]. Surgeons should keep in mind that the risk of hypothyroidism may persist for several years. Therefore, thyroid function tests should be performed regularly after treatment completion [297]. Radiation therapy, thyroid gland invasion, nodal metastasis, and postoperative fistula were found to correlate significantly with the development of hypoparathyroidism [296].

E1-2. Adjuvant treatment

Given the poor prognosis of stage III/IV HNSCC, a combination of radical surgery and postoperative radiation therapy has remained the standard treatment. Generally, a total dose of 60 to 66 Gy of conventional postoperative radiation is administered for resectable locally advanced HNSCC [298]. Radiotherapy should be initiated within 6 weeks after surgery [299]. However, local recurrence and distant failure rates are as high as 30% and 25% and the 5-year survival rate is as low as 40% after radical surgery with postoperative radiotherapy. Furthermore, pathologic findings of surgical specimen such as a positive surgical margin, vascular invasion, and extracapsular nodal extension (ECE) adversely affect the prognosis.

Several randomized trials have been conducted to clarify the role of adjuvant chemoradiotherapy in the postoperative management of patients with advanced resectable HNSCC and poor prognostic factors. The RTOG 9501 study included patients with advanced HNSCC and high risk factors, including multiple lymph node metastases (≥2), ECE, or microscopic surgical margin involvement. This study found that the chemoradiotherapy group had a higher locoregional control rate (82% vs. 72% for radiotherapy) and improved disease-free survival (hazard ratio for disease or death, 0.78 relative to radiotherapy; 95% CI, 0.61 to 0.99; P=0.04). However, overall survival was not significantly different (hazard ratio for death, 0.84; 95% CI, 0.65 to 1.09; P=0.19) [300]. Concurrently, the European Organization for Research and Treatment of Cancer (EORTC) suggested that stage III/IV disease, perineural infiltration, vascular tumor embolism in addition to ECE, and microscopic surgical margin involvement indicate candidates for chemoradiotherapy (EORTC 22931) [301]. That trial recruited 338 HNSCC patients with adverse features and found that the chemoradiotherapy group, when compared with the radiotherapy group, had better 5-year progression-free survival (47% vs. 36%) and overall survival rates (53% vs. 40%) and a lower recurrence rate (18% vs. 31%). To identify the most suitable patients for chemoradiotherapy, data from the two studies were subjected to a combined analysis [302]. Accordingly, ECE and microscopic margin involvement were found to be the most significant prognostic factors for loco-regional recurrence and survival. In contrast, chemoradiotherapy yielded no advantage over radiotherapy alone in patients with multiple lymph node metastases but without ECE. Long-term follow-up data from the RTOG 9501 trial also demonstrated the significance of ECE and microscopic margin involvement [303]. Among patients in that study with HNSCC and ECE or microscopic margin involvement, the chemoradiotherapy group had a lower 10-year locoregional recurrence rate (21.0% vs. 33.1%) and higher 10-year disease-free survival (18.4% vs. 12.3%) and overall survival rates (27.1% vs. 19.6%). However, there were no additional gains in locoregional control and disease-specific survival in the chemoradiotherapy group when compared with the radiotherapy only group among patients with multiple lymph node metastases.

E2-1. Swallowing rehabilitation

Laryngeal cancer patients often develop swallowing disorders that delay patient recovery after radiation therapy or laryngectomy; these disorders are often life-threatening.

In general, patients who undergo hemilaryngectomy have a relatively lower rate of aspiration and a more rapid return to a normal diet, compared to patients who undergo supraglottic laryngectomy [304,305]. However, a broader dissection site, which may include arytenoid cartilage, increases the risk of developing aspiration [306,307]. A brief change in swallowing, particularly liquids, will occur after surgery; within 1 to 2 weeks; however, recovery begins as the normal side of the larynx compensates for the damaged side [308].

Up to 74% of patients who underwent supraglottic laryngectomy reported postoperative aspiration, and approximately 4 to 6 weeks were required for these patients to achieve a safe and effective oral intake [308,309]. However, a longer period might be needed to recover normal swallowing once a large tongue base resection has been performed [304].

Although a high incidence of dysphagia was observed among patients who underwent SCL, good swallowing recovery rates were observed at 3 months after surgery [310]. Several studies observed better functional results after SCL-CHEP than after SCL-CHP [311-313].

Patients experience decreased pharyngeal wall contraction and pharyngoesophageal pressure after total laryngectomy, and these conditions affect the swallowing pattern; however, patients may return to a normal diet within a month [314].

Radiotherapy to the pharynx and larynx can damage the pharyngeal constrictor and trigger dysphagia. Fibrosis in the irradiated tissues can lead to dysfunctional movement in the oral tongue, tongue base, pharyngeal constrictor muscles, and larynx [315].

Useful diagnostic tests for dysphagia include the modified barium swallowing procedure under videofluorography and the swallowing examination via fiberoptic endoscopy. Of these, the modified barium swallow provides much of the information necessary to develop a swallowing rehabilitation plan [316-320].

Swallowing rehabilitation methods after treatment for laryngeal cancer include changes in the head or body posture, swallowing maneuvers, and modifications of the bolus size or consistency [321-323]. Changes in head or body postures, such as chin down, head back, head rotation, and lateral head tilt postures, are used in controlling the bolus flow and also in reducing or eliminating aspirations. The chin down posture carried out either alone or along with other postures or maneuvers, has been reported to yield successful results in postsurgical patients with head and neck cancer; specifically, aspiration was decreased or eliminated in 50% of patients with tongue base resection and 90% of patients with oral or laryngeal resection [321,324]. The head rotation posture induces compensatory movements in the healthy side of the arytenoid, which might effectively reduce aspiration in posthemilaryngectomy patients experiencing difficulties in closure of remaining vocal fold [325].

Swallowing maneuvers include the supraglottic swallow and super-supraglottic swallow maneuvers, effortful swallow maneuver, Mendelsohn maneuver, and tongue hold method [326,327]. Among the various methods, the supraglottic swallow and super-supraglottic swallow maneuvers are especially effective not only for reducing aspirations in supraglottic laryngectomy patients but also in patients who have received a full course of radiotherapy for head and neck [308,328].

Surgical excision of laryngeal cancer may have a significant impact on the swallowing function because of the following factors: tumor site, resected structures, and subsequent reconstruction. Dysphagia also occurs after radiation therapy. Therefore, diagnostic imaging procedures such as the modified barium swallow with videofluorography should be used along with various rehabilitation methods for successful swallowing rehabilitation.

E2-2. Voice rehabilitation methods after total laryngectomy

The loss of the laryngeal voice is the main consequence of total laryngectomy; accordingly, learning to use a new voice is the main objective of rehabilitation for these patients.

Commonly used voice rehabilitation methods include esophageal speech, electrolarynx usage, and tracheoesophageal puncture for tracheoesophageal speech, which can be performed primarily or secondarily [329].

There are distinctive advantages to using the esophageal voice method; for example, the patient’s hands remain free and the costs of the surgical procedure and/or a speaking device are not required. The acquisition of esophageal speech, however, requires 30 to 50 hours of intense speech therapy [330]. Furthermore, the rehabilitation success rate varies depending on the individual conditions [331]. Compared with lung-powered speech, patients can only speak short phrases and may not be satisfied with the voice quality [331]. The resulting voice is rough and breathy, with a low pitch and reduced loudness [332,333].

The electrolarynx method uses electromagnetically generated sound-producing vibrations; however, the substitute voice is monotonous and mechanical [332,334]. The electrolaryngeal voice can be used when other voice rehabilitation methods have failed, or even if other options are available [330,335-337]. According to related studies, more than 50% of patients who undergo total laryngectomy will continue to rely on the electrolarynx as their primary method of verbal communication at 2 years after surgery [338].

Recently, the use of tracheoesophageal speech vocalization with a voice prosthesis has increased among patients who have undergone total laryngectomy for laryngeal cancer [339]. The Provox voice (Atos Medical, Milwaukee, WI, USA) prosthesis, which was developed by the Netherlands Cancer Institute in 1988, is currently of the most widely used devices [340,341]. In several studies, tracheoesophageal speech with a voice prosthesis yields speech that is considered more normal than esophageal speech [342,343]. In addition, functional outcome analyses have found that tracheoesophageal speech with a voice prosthesis yields a good voice quality [344,345]. Voice prostheses may be inserted either at the time of total laryngectomy (primary) or at a later stage (secondary). A primary prosthesis provides almost immediate and satisfactory voice rehabilitation [346,347].

E2-3. Shoulder dysfunction after neck dissection

General complaints and functional impairment of shoulder are common sequelae after neck dissection. These complications may be attributable not only to nerve injury caused by traction or other surgical procedures but also to secondary effects such as adhesive capsulitis or myofascial pain [348]. Shoulder problems gained after the neck dissection are caused by the dysfunction of spinal accessory nerve. In addition, the secondary glenohumeral stiffness can be caused by weakness of the scapulohumeral girdle muscles and also by lack of postoperative mobility [349].

The accessory nerve can be found in levels II and V during neck dissection. In level V, the spinal accessory nerve is more superficial. Thus it is easy to be led to local iatrogenic surgical trauma or inadvertent division of the nerve [350].

Injury to the spinal accessory nerve, which provides motor innervation to the sternocleidomastoid and trapezius, results in pain, losses of mobility and strength, and deformity of the shoulder homolateral to the dissection [351,352].

Even if the spinal accessory nerve has not been injured, shoulder complaints can be detected commonly after the neck dissection. Several studies revealed that 31% to 60% of patients after modified radical neck dissection, and 29% to 39% of patients after selective neck dissection are found to be experiencing shoulder related symptoms [353,354].

Spinal accessory nerve sparing during neck dissection is associated with a significant reduction in long-term shoulder disability among 5-year survivors of head and neck cancer [355]. A number of studies have demonstrated that spinal accessory nerve-preserving neck dissection is associated with reduced shoulder pain, better shoulder function, and an improved overall quality of life, compared to radical neck dissection [356-360].

In addition, several studies have reported that neck dissection with level 2b preservation reduces spinal accessory nerve trauma [361]. During surgery, spinal accessory nerve neuromonitoring may be used to predict a patient’s postoperative shoulder function and activity restrictions [362].

Physical therapy is essential in dealing with shoulder complaints after neck dissection whether the spinal accessory nerve has been preserved or sacrificed [348]. This type of therapy is aimed at an early recovery of passive motion, and has been shown to be beneficial in preventing the occurrence of joint fibrosis. Physical therapy is very important for promoting functions and for reducing pains. This can be done by maintaining the lengths of muscles and ranges of movement and also by preventing secondary complications such as adhesive capsulitis [363]. In addition, several reports have recommended the early repair of iatrogenic spinal accessory nerve damage to avoid significant atrophy of the trapezius muscle and long-term functional deficits [364,365].

Progressive resistance exercise training, which can be done along with the standard physiotherapy, may improve scapular stability and strength of the upper extremity [366,367]. Moreover, physical therapy was found to have a significant positive effect on the patient’s quality of life after neck dissection [368].

The importance of a timely initiation of physical therapy has also been supported by epidemiologic studies of the clinical course of neck and shoulder symptoms after presentation. A Dutch study reported a low recovery rate after consultation for shoulder symptoms; 24% of patients reported recovery at their 3-month follow-up examinations, and 32% reported recovery at their 12-month follow-up examinations. Therefore, a timely initiation of physical therapy after neck dissection appears to be important because it is more difficult to treat already established shoulder complaints and disabilities [348].

E2-4. Counseling for smoking cessation

In general, smokers have higher infection and pulmonary complication rates. In addition, smokers have relatively longer postoperative hospital stays, compared with non-smokers [369,370]. Smoking leads to increases in all-cause mortality, cancer-specific mortality, and the risk of a second primary cancer. Furthermore, smoking is known to correlate with an increased rate of cancer recurrence, poor treatment responses, and increased treatment-related toxicity [371].

The risk of wound complications after reconstructive head and neck surgery is closely related to serum cotinine concentration [372]. Among patients receiving radiotherapy for head and neck cancer, smokers had a poorer locoregional control rate [373,374]. Patients with head and neck cancer who continue to smoke throughout radiotherapy experience relatively poorer therapeutic effects and a shorter survival time, compared with non-smoking patients and those who quit smoking before treatment [375].

Smoking affects the cytochrome P450 enzyme, which ultimately impacts the metabolism of chemotherapeutic and targeted therapeutic agents; specifically, the drug clearance times and plasma concentrations deviate from the normal values [376-378].

Smoking cessation immediately reduces the blood carbon monoxide level and respiratory irritation, and improves lung function. Over the long term, smoking cessation significantly reduces the incidence of smoking-related diseases and mortality [379]. Smoking cessation at or near the time of a cancer diagnosis reduces the risk of therapy-related complications and decreases the rate of second primary cancer onset, compared to smoking continuation [380-382]. Therefore, smokers with cancer must be educated about the specific risks of smoking during their particular anti-cancer treatments; specifically, smoking cessation before cancer treatment initiation would be the best option, if possible.

Pharmacotherapy is most effective when combined with behavioral therapy [383-385]. The recommended initial treatment durations are 12 weeks for varenicline and combination nicotine replacement therapy, and 7 to 12 weeks for bupropion [386]. Successful behavior therapy strategies employ practical counseling, which addresses problem solving and skill training, as well as social support and motivational interviewing [387].

E2-5. Psychiatric consultation

The diagnosis and subsequent treatment of head and neck cancer could have potentially devastating impacts on psychosocial functioning [388].

Cancer-related symptoms such as fatigue, pain, anxiety, and depression frequently interfere with patient’s activities of daily life [389-391]. A study of more than 5,000 patients found that 6% of patients with cancer experienced suicidal ideation [392]. Patients with uncontrolled mood and adjustment disorders have a high tendency to suicide [393-395]. Older patients and male patients with head and neck cancer or myeloma are reported to be at a higher risk of committing suicide [396].

Compared to those who have undergone partial laryngectomy, patients who have undergone total laryngectomy are known to experience more severe psychiatric stress as a result of permanent voice impairment and a reduced life expectancy [397,398]. A study of 74 patients subjected to total laryngectomy reported a significant degree of abnormal findings such as sexual dysfunction, depression, and decreased self-esteem [399].

Psychiatric mood disorders, such as depression, are usually managed with psychotherapy or psychotropic medication [400-406]. Otherwise, referrals to social work counseling and chaplaincy services could be considered. Patients who endanger themselves or the others should be considered for psychiatric consultation. These patients need close and increased monitoring and any dangerous objects near them should be removed. Psychiatric treatment and hospitalization can be considered if necessary [407].

E3-1. Long-term follow-up schedule

There are several reasons to subject patients with laryngeal cancer to a posttreatment follow-up, including the early identification of recurrent disease, early detection of new primary tumors, monitoring and management of complications, optimization of rehabilitation, promoting cessation of smoking and excessive alcohol consumption, providing support to patients and their families, and patient counseling and education.

Frequent posttreatment visits should be recommended to patients with head and neck cancer, including laryngeal cancer, especially during the first 2 years when the risk of locoregional recurrence is known to be high; the visit frequency may be reduced thereafter, and follow-up can be completed by year 5. Patients with high-risk disease or specific tumors, those who require continuous special rehabilitation, and those who prefer a longer period of follow-up may be examined for a longer period of time, and even the remainder of their lives [408-417].

The European Journal of Surgical Oncology advised a follow-up schedule comprising visits every 4 to 6 weeks during the first 2 years, every 3 months during year 3, twice yearly in years 4 and 5, and yearly thereafter [418].

Members of the American Society for Head and Neck Surgery reported 73% agreement in response to a schedule comprising monthly follow-up visits during the first year after surgery, visits every 2 to 3 months during year 2, and visits every 4 to 6 months during years 3 to 5 years after surgery [419].

The National Comprehensive Cancer Network guideline also recommends follow-up visits every 1 to 3 months during year 1, every 2 to 6 months during year 2, every 4 to 8 months during years 3 to 5, and annual follow-ups thereafter [420].

Many studies have shown that the first 2-year follow-up generally occurs between 4 and 8 weeks postoperatively, and subsequent visits occur every 3 to 6 months [408-413].

E3-2. Tests during the follow-up period

The first step in the posttreatment follow-up of a patient with laryngeal cancer involves educating the patient about the potential symptoms and signs of recurrence. This education should include tobacco smoking and alcohol cessation programs [409, 421,422].

During follow-up, a rigid telescope, transnasal video, or fibroscopy should be used for laryngeal inspection, and the neck should be palpated. According to the research, laryngoscopy and stroboscopy provide better accuracy (100% for both methods) than history taking and physical examination (33%) [10]. The use of a videostroboscope can provide valuable additional information [423].

Chest radiography is performed as a part of routine a head and neck cancer follow-up to detect lung metastasis and second primary tumors in the lung. According to de Visscher and Manni [424], yearly performed chest radiographies were only useful in patients with laryngeal index tumors; the incidence of secondary primary and metastatic tumors was higher in supraglottic cancer than in glottic cancer. Chest CT should be used instead of chest radiography to screen patients with advanced HNSCC [424-426].

Research conducted to evaluate how efficient the use of US and palpation are during follow-up revealed that US showed 97.5% of accuracy in successfully detecting enlarged lymph nodes, with an accuracy of 97.5% [427]. Other researchers have also reported that US and US-guided fine needle aspiration cytology provide information critical to the detection of cervical lymph node recurrences [428-430].

Baseline CT or MR, conducted between 3 to 6 months after the surgical, radiological, or combined treatment of high-risk HNC, can be compared with subsequent images for the earlier detection of abnormalities [431,432]. Patients who have undergone radiotherapy for laryngeal cancer require careful follow-up studies involving clinical examinations and CT imaging at 3- to 4-month intervals for a duration of 2 years after radiotherapy [432].

MR and PET-CT scanning exhibit superior performance for the detection of recurrences and second primary tumors. PET-CT is also advantageous as a systematic evaluation and has a reported sensitivity of 92% in detecting recurrent laryngeal cancer. PET-CT shows nearly 100% of accuracy in diagnosing distant metastasis in cancer patients [433-436].

In patients treated with primary radiation therapy alone, CT, MR and US cannot specifically differentiate postradiation edema from recurrence. Therefore, CT, MR, or PET-CT to obtain baseline images for later reference should be performed 3 to 6 months after treatment [434].

Patients who have undergone extended resection via transoral laser surgery require regular laryngeal examinations every 4 to 8 weeks during the first year after surgery, as the risk of locoregional recurrence remains high [408]. Second look microlaryngoscopy is still considered somewhat controversial, but may be adapted for uncertain (close or altered for iatrogenic artifacts) surgical margins, granulomas, web formation, other postexcision abnormal tissue growth at the level of the primary resection site (despite appropriate medical and voice therapy), or the involvement of certain laryngeal subsites (anterior commissure, ventricle, subglottis) [437-439].

For patients who have undergone open partial laryngectomy, a clinical laryngoscopic examination and CT scan of the primary site are recommended [408]. Although the optimal follow-up regimen after total or pharyngolaryngectomy remains under dispute, a clinical examination of the remaining upper aerodigestive track and neck should be performed, followed by contrast CT if the result is positive [409]. Follow-up PET-CT has been incorporated to screen for metastasis in patients who have undergone surgery accompanied by radiotherapy or chemoradiotherapy [434,435,440-442].

Patients treated with definitive chemoradiotherapy should undergo PET-CT at 3 months (12 weeks) after the completion of therapy to assess the primary and neck disease response and to plan salvage neck surgery if required [434,435,440-442].

NBI, which uses pathognomonic neoangiogenic patterns to detect abnormal lesions, reportedly has a true-positive laryngeal cancer lesion detection rate that is 18% higher than that of conventional white light endoscopy. Furthermore, NBI features both high accuracy as well as the ability to differentially diagnose abnormal regions from postradiotherapy or chemoradiotherapy inflammatory and/or cicatricial changes [443-445].

Tumor markers and gene expression profiling, which are poorly sensitive and have low cost-to-benefit ratios, have yet to be proven useful for the follow-up of laryngeal cancer [446,447].

E3-3. Thyroid function evaluation

Head and neck irradiation results in biochemical hypothyroidism in at least 50% of patients. Moreover, a definitive initial surgery that removes part of the thyroid gland can increase the risk of hypothyroidism [448]. Previous studies revealed that 10% to 70% of cases after head and neck cancer treatment suffer from thyroid dysfunction [294,449-451].

Thyroid function is determined by measuring the serum levels of thyroid stimulating hormone (TSH) and free thyroxine (FT4). Thyroid function is classified into three categories: firstly, euthyroidism, which is with normal TSH and FT4 levels; secondly, subclinical hypothyroidism, which has increased TSH and normal FT4 levels; and lastly, clinical hypothyroidism, which shows increased TSH and decreased FT4 levels [452].

Several pathophysiologic mechanisms, such as vascular supply, may give rise to hypothyroidism. It is because the vascular structure near the thyroid might be iatrogenically damaged or intentionally sacrificed during the course of neck dissection, which thus affect the blood supply and eventually the function of the thyroid. Furthermore, the thyroid gland itself may be subjected to partial or full resection for oncologic reasons. Radiotherapy-induced fibrosis may result in decrease of thyroid function not only be compromising the thyroid vascularity but also by causing fibrosis of the whole gland [294].

Increased TSH levels have been detected in 20% to 25% of patients who have received neck irradiation; accordingly, these patients are at an increased risk of hypothyroidism [453]. In a retrospective review of 147 total laryngectomy patients, 19.9% of patients developed hypothyroidism at year 3 of follow-up; at years 6 and 10, 38.6% and 93.3% had developed hypothyroidism, respectively [454]. Such reports support regular thyroid evaluations for a period of at least 10 years after receiving treatment for laryngeal cancer.

In conclusion, thyroid dysfunction is a frequently occurred complication in up to 50% of patients who have undergone laryngectomy and radiotherapy but tend to be unrecognized easily. Therefore, a regular thyroid function tests are recommended after treatment for laryngeal cancer [452].

F1-1. Salvage surgery for a local failure of non-surgical treatment

The use of salvage surgery for residual or recurrent cancer after non-surgical treatment has increased following the acceptance of organ preservation into mainstream laryngeal cancer treatment strategies. The reported recurrence rate after radiotherapy alone ranges from 32% to 58% [455-457]. Among early glottic cancers, the recurrence rate after radiotherapy ranges from 10.4% to 32% [456,458-462]. Among advanced cancers, concurrent chemoradiotherapy significantly decreases the incidence of locoregional failure; in the RTOG 91-11 trial, only 16% of patients required salvage total laryngectomy after concurrent chemoradiotherapy [463].

Total laryngectomy remains the mainstay of salvage treatment after radiotherapy, with or without chemotherapy, because many patients (up to 56% to 59%) present with more advanced-stage disease after radiotherapy [464,465]; in addition, there exists some concern about submucosal spread in cases of radiation failure [466]. The rate of total laryngectomy after radiation failure ranged from 44.8% to 92%, even for an initially early glottic cancer [461,464,465,467-470]. However, laryngeal preservation surgical techniques have improved, and good survival results have been reported. Vertical partial laryngectomy, frontolateral laryngectomy, supraglottic laryngectomy and, more recently, transoral laser microsurgery or SCL are frequently used laryngeal saving techniques used for salvage surgery [407,471-476]. The general contraindications for laryngeal preserving surgery may include the following: (1) arytenoid fixation; (2) invasion of the posterior commissure; (3) subglottic extension of more than 5 mm posteriorly and 5 to 10 mm anteriorly or to the upper border of the cricoid cartilage; (4) cricoid cartilage invasion and major thyroid cartilage invasion (T4); (5) massive pre-epiglottic space involvement; (6) positive margins in a frozen section; and (7) extralaryngeal spread. Transoral laser microsurgery may be preferred if the recurrent disease does not extend beyond the original site and the larynx is mobile. However, if the recurrent tumor has extended beyond its original site, has impaired vocal cord motion or caused fixation, and/or presents with pre-epiglottic space or thyroid cartilage invasion, then SCL should be strongly advocated [466,477].

The reported local control rate of transoral laser microsurgery ranges approximately from 57% to 65%, whereas that of external laryngeal preservation surgery, including SCL, ranges from 77% to 85% [473,478-480]. For rT1 or rT2 lesions, approximately 42% to 70.6% of patients can be treated with a single transoral laser surgical procedure [481-485]. In addition, the laryngeal preservation rate of transoral laser microsurgery ranges from 62.3% to 86% [483,484]. In one report, transoral laser microsurgery yielded good local control for rT1 lesions (87.5%), but unsatisfactory outcomes for rT2 lesions (16.6%). However, that report did not observe differences in overall or disease-specific survival after the second salvage [482]. In contrast, Steiner et al. [485] reported the use of transoral laser microsurgery in patients with rT4 disease. In other words, the surgeon’s level of expertise seems to be an important factor in laser microsurgery.

Complications of open surgery, including total laryngectomy, increase significantly after concurrent chemoradiotherapy, and the reported local complication rates range from 45% to 92% [486,487]. In particular, the risk of fistula development increases (23.5% to 68%) [486,488,489]. Accordingly, procedures such as a pectoralis major muscle flap overlay or the uses of other fresh tissues (e.g., free flap) have been attempted to prevent fistula formation. However, the data are not consistent. Some papers have reported a similar fistula rate even with a pectoralis major muscle flap; however, the effect was the prevention of large fistulas, thus reducing the rate of reoperation [420,490,491]. Others have reported the usefulness of a pectoralis major muscle flap for fistula prevention. These researchers reported that the fistula rate associated with primary closure (31% to 58%) could be reduced by using a pectoralis major muscle flap onlay reinforcement (10.5% to 22%) [492-497]. Therefore, pectoralis major muscle flap onlay reinforcement may play a role in fistula prevention, but the effect is remained uncertain.

F1-2. Management of the N0 neck during salvage surgery after nonsurgical treatment

Comprehensive neck dissection is recommended for regional failure, with a reported survival rate of approximately 61.2% [498]. Elective neck dissection is generally recommended for the salvage treatment of supraglottic or transglottic cancer, given the high rate of occult metastasis with these tumors (28% to 60%) [478-480,499,500]. In addition, elective neck dissection is considered suitable for advanced recurrent glottic cancer; a previous report described improved disease-free and overall survival in patients with locally advanced disease who had undergone elective neck dissection, but not in patients with limited disease [501]. Among patients with rT3 or higher disease, the reported occult metastasis rate is approximately 20%. Very few reports have discussed the rate of occult metastasis in the contralateral neck, and therefore it is difficult to draw conclusions regarding the need for elective neck dissection. Occult contralateral neck metastasis has been found in 0% to 6.4% of laryngeal cancer cases [502,503]. Accordingly, bilateral neck dissection at the time of laryngectomy cannot be recommended generally. However, for recurrent supraglottic cancers, the occult bilateral neck metastasis rate was as high as 15% in one report, and the authors recommended bilateral elective neck dissection for such patients [504].

However, the issue of elective neck dissection during salvage open laryngectomy remains controversial, especially for cases of early recurrent glottic cancer. The initial N stage before radiation therapy may correlate with occult metastasis during salvage surgery. The reported occult metastasis rates in initially N0 necks range from 7.7% to 10%, whereas the corresponding rate in initially N+ necks is 50% [503,504]. Other studies reported low occult metastasis rates (4% to 5%) but high complication rates after elective neck dissection, with overall complication rates of 42.2% in the neck dissection group and 21.3% in observation group, and corresponding fistula rates of 32% to 57.2% and 13.4% to 18%, respectively [505,506]. Furthermore, the complication rate increased to as high as 67% in cases involving bilateral neck dissection [507]. Therefore, the researchers concluded that the benefit of elective neck dissection, especially bilateral neck dissection, should be balanced against the increased risk of morbidity. Another paper that investigated the role of preoperative CT scanning suggested that among N0 patients the preoperative CT metastasis rate was only 3% [508]. Given these data, observation of the neck is suggested for some patients with rT1 or rT2 and clinically rN0 disease [509].

F1-3. Salvage surgery for recurrence after surgical therapy

The reported recurrence rates after initial transoral laser microsurgery were 13% for T1 disease and 15.4% for T2 [109]. Furthermore, the reported total laryngectomy rates among patients with recurrent disease after transoral laser microsurgery range from 40.9% to 45% [109,510]. However, other papers suggest repeated transoral microsurgery as a treatment option, with reported 5-year survival rates of 75.1% among early recurrent cases and 51.6% among advanced cases [511].

However, recurrence after an initial total laryngectomy was associated with a poor prognosis, and only 21% to 27.5% of such cases were eligible for surgical salvage [512,513]. Particularly for stomal recurrence, the reported overall 2-year survival rate ranges from 10% to 16% with a median survival range of 6 to 11 months, even after surgical salvage treatment [514-516]. The reported rates of stomal recurrence range from 1.2% to 10.8%, according to the literature [514,515,517-521].

Extensive studies of the risk factors for stomal recurrence have been conducted. Preoperative tracheostomy, subglottic involvement extent, advanced tumor, and paratracheal node metastasis were reported to correlate positively with stomal recurrence [515,519,521-531]. However, the risk of preoperative tracheostomy for stomal recurrence is controversial, with some papers reporting negative results [532,533].

Radiotherapy and chemotherapy provide only limited palliation, whereas extensive resection offers the best chance of a cure [523].