Diseases of the Larynx

From The University of California, San Francisco, School of Medicine’s Otolaryngology Update

Educational Objectives

The goal of this program is to improve the recognition and management of diseases of the larynx. After hearing and assimilating this program, the clinician will be better able to:

1.   Recognize the classic focal symptoms and inflammatory changes associated with laryngopharyngeal reflux (LPR).

2.   Discuss with patients the treatment options and lifestyle changes that are effective in the management of LPR.

3.   Avoid pitfalls that frequently cause clinicians to miss or delay the diagnosis of laryngeal cancer.

4.   Evaluate the indications and limitations of surgery, radiation therapy and chemotherapy for treatment of laryngeal cancer.

5.   Assess the indications for and results of endoscopic laryngectomy.

Faculty Disclosure

In adherence to ACCME Standards for Commercial Support, Audio-Digest requires all faculty and members of the plan­ning committee to disclose relevant financial relationships within the past 12 months that might create any personal con­flicts of interest. Any identified conflicts were resolved to ensure that this educational activity promotes quality in health care and not a proprietary business or commercial interest. For this program, Drs. Ford and Smith and the planning commit­tee reported nothing to disclose. In his lecture, Dr. Smith presents information related to off-label or investigational use of a therapy, product, or device.

Acknowledgements

Drs. Ford and Smith were recorded at the University of California, San Francisco, School of Medicine’s Otolaryngology Update 2009, held November 5-7, 2009, in San Francisco, CA. The Audio-Digest Foundation thanks the speakers and the UCSF School of Medicine for their cooperation in the production of this program.

Update on Laryngopharyngeal Reflux (LPR)

Charles N. Ford, MD, Professor Emeritus, Division of Otolaryngology – Head and Neck Surgery, University of Wisconsin School of Medicine and Public Health, Madison

Basics: retrograde movement of irritant from stomach to larynx; can indirectly stimulate tenth nerve, causing reflec­tive cough; classic focal symptoms  —  hoarseness, throat clearing, cough, postnasal drip sensation, dysphagia, and globus sensation; inflammatory changes  —  edema, posterior erythema, pseudosulcus, granuloma

Prevalence: because LPR ill-defined and controversial, questions remain about prevalence; reports indicate 86% of controls show signs of reflux; Merati showed 30% of asymptomatic controls have positive pH test (although def­inition of positive pH test not established)

Evolution: originally, clinicians unaware of diagnosis; even patients with numerous symptoms treated inappropri­ately, and many developed complications; over last 10 to 15 yr, clinicians became overly sensitized to LPR; too many patients with laryngeal symptoms categorized as having LPR, resulting in unnecessary treatment and costs

Diagnosis: look at symptoms, laryngoscopic findings, and response to medical treatments; symptoms  —  distinguishable from those of gastroesophageal reflux disease (GERD); heartburn and subjective sense of regur­gitation often absent; nonproductive cough; throat clearing; reflux symptom index  —  scoring system to determine whether LPR present; however, data show positive predictive value of index impaired by presence of psychologic disturbances, eg, depression, anxiety

Findings: posterior laryngitis, erythema in posterior glottis, contact granuloma, and pseudosulcus; reflux finding score (RFS) helpful; can combine with reflux symptom index

Algorithm: patients underwent initial assessment using symptoms and findings; if reflux suspected, patient put on trial of proton pump inhibitors (PPIs); patients who responded weaned off medication; nonresponsive patients or those who worsened underwent more definitive assessment; speaker recommends employing definitive assess­ment earlier in algorithm

Demonstrating reflux events: identify associated pathologies (eg, esophagitis); examine molecular and genetic changes in tissue; ambulatory multiprobe pH monitoring  —  former gold standard; what constitutes positive study controversial; generally drop to pH of 4 significant for lower esophageal events; for hypopharyngeal and upper esophageal events, pH of 5.5 may be significant; acid exposure time more important than number of episodes; impedance studies  —  multiple probes placed along length of esophagus to record flow of substances from stom­ach to hypopharynx; impedance decreased by liquid, increased by gas; synchronization with manometry allows for computer graphic displaying events and refluxate consistency; symptoms and damage may be caused by pep­sin and bile alkali agents rather than acid

Potential diagnostic markers: elevated pepsin; carbonic anhydrase  —  present throughout esophagus; increased in patients with GERD and moved to surface, where it neutralizes acid; absent or decreased in two-thirds of patients with LPR; decreases seen along with increase in pepsin level; breakdown of bacterial barriers  —  particularly barriers against Helicobacter pylori; mucin gene expression  —decreased levels of mucins may correlate with LPR; may be measurable; others  —  inflammatory markers; absence of epithelial growth markers

Treatment: behavioral management  —  weight loss and diet important; medical treatment  —  PPI should be given be­fore meals; surgery  —  Nissen fundoplication; advances in endoscopy; radiofrequency ablation; surgical option particularly suitable for patients with nonacidic reflux

PPIs: expensive; studies show long-term PPI use may increase risk for osteoporosis; 2006 Cochrane review of 300 studies found PPIs lacked efficacy; subsequent Class I studies had mixed results; studies had problematic inclu­sion and exclusion criteria, eg, patients with both GERD and LPR excluded but most likely to respond to PPIs

On Seeing the Trees And Missing Laryngeal Cancer

Dr. Ford

Causes of missed or delayed diagnosis: patient with formerly benign disease; patient with minimal early symptoms or delayed onset of symptoms (particularly hoarseness); hidden or difficult-to-see lesions; inadequate biopsies; findings with noncancerous explanations; focus on specific problem (particularly voice restoration) rather than un­derlying pathology

Red flags: progressive hoarseness, particularly after procedures; progressive stiffness on video stroboscopy; recalci­trant disease such as leukoplakia with progressive dysplastic change; recurrent respiratory papillomatosis (RRP) and human papillomavirus (HPV); history of smoking, reflux, or previous cancer; voice worse than endoscopic ap­pearance

Patient 1: history  —  several months of hoarseness; leukoplakia; biopsy negative; intensive voice therapy with initial improvement and later progression of hoarseness; video stroboscopy; subsequent negative biopsy; subsequent stro­boscopy revealed mass lesion, stiffness and impaired mobility on one side; computed tomography (CT) showed le­sion filling paraglottic space; involvement of arytenoid; at time of surgery, speaker confident of presence of cancer; surgical biopsy showed dysplasia but no obvious cancer; retracted false vocal fold, made incision into paraglottic space, and took deep biopsy which proved cancerous; reasons for delayed diagnosis  —  inadequate biopsy because of lesion location; initial positive response to voice therapy

Patient 2: history  —  years of hoarseness and voice problems; previous removal of vocal fold nodules and takedown of web; vocal fold granuloma; reflux; history of smoking; 3 yr later, speaker saw patient, found and lysed web, and inserted keel stent (no sign of tumor); small granuloma formed after removal of keel; hoarseness progressed; stro­boscopy showed stiffness; biopsy of granuloma showed squamous cell carcinoma (also documented radiographi­cally); reasons for delayed diagnosis  —  granulation tissue had reasonable noncancerous explanation; improvement of voice after lysis of web; reason to suspect cancer  —  patient had severe LPR

Correlation between reflux and cancer: years of studies show correlation, often in nonsmokers; reflux related to factors known to cause cancer, eg, smoking, ethanol use; basic science studies show impact of reflux on laryngeal defense mechanisms; observational study  —  found ³50% of nonsmoking patients with laryngeal cancer had docu­mented reflux or symptoms suggestive of reflux; reflux, smoking, and ethanol use  —  several reports associate GERD with smoking; studies show smoking decreases lower esophageal sphincter (LES) pressure, predisposing to reflux; studies show alcohol causes nocturnal reflux; studies show that combination of smoking and ethanol associ­ated with higher incidence of cancer; laryngeal defense mechanisms  —  recent studies show reflux reduces ability of mucosal barrier of larynx to resist irritants and bacteria; mechanisms include decreased salivary flow and impaired epithelial growth factor

Patient 3: history  —  elderly man; vocal folds appeared normal on endoscopy despite hoarseness; patient received conservative treatment from local otolaryngologist; hoarseness progressed; suspected mild leukoplakia; referred to speaker, who found infraglottic lesion on CT; vocal folds still appeared normal; reasons for delayed diagnosis  —delayed onset of hoarseness because vocal folds proper not primary problematic site; lesion difficult to see initially; reasons to suspect cancer  —  progressive hoarseness, presence of mass with stiffness, and LPR

Patient 4: history  —  referred from prominent center; history (many years) of progressive hoarseness; previous smoker; previous leukoplakia (biopsied and found to be benign); sulcus vocalis originally suspected; thyroplasty and revision thyroplasty performed at previous treatment center; patient referred to speaker, who performed biopsy that showed hyperkeratosis with some dysplasia; subsequent biopsy showed cancer; cancer resected with CO₂ la­ser; original thyroplasty removed and area rebuilt with pedicle flap; patient well 3 yr postoperatively; reasons for delayed diagnosis  —  misplaced focus; attention focused on voice, scarring, and sulcus vocalis; malignancy devel­oped gradually; reasons to suspect cancer  —  progressive hoarseness; stiffness beyond that anticipated from sulcus and scarring; history of smoking

Patient 5: woman with history of supraglottic cancer; suspected Reinke's edema and papilloma; suspicious reflux symptom index; smoker; at surgery, papilloma visible; contact endoscopy revealed typical vascular patterns; papil­loma removed with laser; Reinke’s edema decompressed; vocal folds appeared smooth; hoarseness appeared over following weeks; subsequent surgery revealed recurrence of cancer; take-home point  —  RRP deserves serious at­tention

Papilloma: recent study looked not only at HPV types 16 and 18, but also at 37 other subtypes; study found that among 38 early cancers of larynx, 6 had HPV; among HPV-negative group, only 22% nonsmokers; among HPV-positive, 66% nonsmokers

Management Of Larynx Cancer 2009

Richard V. Smith, MD, Professor and Vice Chair, Department of Otorhinolaryngology – Head and Neck Sur­gery, Professor of Clinical Surgery, Professor of Clinical Pathology, Albert Einstein College of Medicine, and Director, Head and Neck Service, Montefiore Medical Center, Bronx, NY

Background: overall 5-yr survival for all cancers improved from mid 1970s to late 1990s, but 5-yr survival (relative and observed) for laryngeal cancer decreased slightly; this period also saw move from primary surgical manage­ment to chemotherapy and radiation therapy for larynx cancer; data for this period show no difference in cancer stage, patient demographics, or socioeconomic status; only difference seen in expanded use of organ preservation

Staging: subcategories of T4 resectable and unresectable; biologic data missing (eg, no information on HPV, Bcl, P53); in general, single-modality therapy for early-stage (T1, T2) glottic cancer; multimodality therapy for ad­vanced disease

Modalities: surgery, chemotherapy, and radiation therapy; each has benefits and drawbacks; chemotherapy and radi­ation therapy may result in decreased distant metastases, but affect mucositis rates; all can result in dysphagia; all can be used in late-stage disease; survival rates comparable; treatment with surgery shorter; chemotherapy and radi­ation therapy contraindicated in elderly or debilitated patients

Radiation therapy: used for early- or late-stage disease; generally indicated to reduce tumor bulk; good responses seen with 15- to 20-cm³ tumors; poorer responses with smaller or larger tumors

Transoral laser microsurgery (TLM) vs open surgery: data from 1950s to 1970s supported efficacy of open sur­gery for partial laryngectomy; require similar amount of operating time; both can be used for primary therapy or ir­radiation failure; tumor margins still important, even with transoral approach; open technique results in higher rates of fistula and permanent need for tracheotomy or gastrostomy tube; concept of maximal resection for good postop­erative function; TLM  —  better preservation of anatomic structures results in better function for swallowing and phonation; swallowing function excellent; tracheotomy rarely needed; cost of TLM equipment high (»$10,000 at outset)

Preoperative evaluation: evaluate lesions carefully; define tumor location endoscopically and plan resection accord­ingly; anatomic location critical; radiographic imaging useful for late-stage tumors and tumors with possible para­glottic or subglottic extension; consider patient physiology (eg, is larynx particularly anterior?)

TLM technique: usually not en bloc resection; make perpendicular cuts behind tumor first, then directly through tu­mor to assess depth; cut then made at that depth to remove tumor completely; degree of resection  —  1 to 5, based on cordotomy; for early-stage disease, 1 to 3; 4 or 5 when paraglottic space involved

TLM vs radiation therapy: disease-free survival excellent for carcinoma in situ with any treatment modality; similar disease-free survival for T1 glottic cancer with surgery or irradiation; local control slightly better with TLM; case  —  large T1 lesion of anterior glottis with some changes in posterior mucosa, extension on superior vocal fold; approach  —  anterior vestibulotomy, involving removal of anterior portion of false vocal fold; allows view of anterior commissure; remaining vocal ligament and vocalis muscle left intact with appropriate resection; tu­mor removed successfully and patient vocalization excellent

Vocalization: past belief that TLM more detrimental for vocalization unfounded; numerous studies comparing TLM and radiation therapy, but with varying data and indices; universal finding that outcome related to extent of resection; excellent results for small cordotomies, with TLM either superior or equal to irradiation; voice quality declines with larger resections

Higher-stage glottic carcinomas: T2 carcinoma  —  local control and disease-free survival better with TLM than with radiation therapy alone; studies on TLM vs radiation therapy for T3 and T4 carcinomas not definitive, but may favor TLM

Chemotherapy and radiation therapy: Radiation Therapy Oncology Group Trial 91-11 compared induction che­motherapy and radiation therapy with concurrent chemotherapy and radiation therapy or radiation therapy alone; local and regional control and preservation of larynx better with concurrent chemotherapy and radiation; survival comparable for all 3 approaches; mucositis rates higher in concomitant chemotherapy and radiation group; primary chemotherapy and radiation therapy appropriate for patients with T3 or small T4 tumors; survival better with total laryngectomy as primary therapy for T4 tumors

Suggested Readings

Altman KW et al: Unexpected consequences of proton pump inhibitor use. Otolaryngol Head Neck Surg 141:564, 2009; Baumann JL et al: Human papillomavirus in early laryngeal carcinoma. Laryngoscope 119:1531, 2009; Hafidh M et al: Radiotherapy for T1 and T2 laryngeal cancer: the Dalhousie University experience. J Otolaryngol Head Neck Surg 38:434, 2009; Hartl DM et al: Chemotherapy alone for glottic carcinoma: a need for higher-level evidence. Ann Otol Rhinol Laryn­gol 118:543, 2009; Johnston N et al: Pepsin in nonacidic refluxate can damage hypopharyngeal epithelial cells. Ann Otol Rhinol Laryngol 118:677, 2009; Johnston N et al: Receptor-mediated uptake of pepsin by laryngeal epithelial cells. Ann Otol Rhinol Laryngol 116:934, 2007; Merati AL et al: Meta-analysis of upper probe measurements in normal subjects and patients with laryngopharyngeal reflux.Ann Otol Rhinol Laryngol 114:177, 2005; Papadas TA et al: Survival after laryn­gectomy: a review of 133 patients with laryngeal carcinoma. Eur Arch Otorhinolaryngol Nov 18, 2009 [Epub ahead of print]; Papakonstantinou L et al: Laryngopharyngeal reflux: a prospective analysis of a 34 item symptom questionnaire. Clin Otolaryngol 34:455, 2009; Starmer HM et al: Complications that affect postlaryngectomy voice restoration: primary surgery vs salvage surgery. Arch Otolaryngol Head Neck Surg 135:1165, 2009; Varghese BT et al: Treatment outcome in patients undergoing surgery for carcinoma larynx and hypopharynx: a follow-up study. Acta Otolaryngol 129:1480, 2009; Wolf GT: Reexamining the treatment of advanced laryngeal cancer: The VA laryngeal cancer study revisited. Head Neck 32:7, 2010