Bobby R. Alford Department of
Otolaryngology-Head and Neck Surgery
Disclaimer: The information contained within the Grand Rounds Archive is intended for use by doctors and other health care professionals. These documents were prepared by resident physicians for presentation and discussion at a conference held at Baylor College of Medicine in Houston, Texas. No guarantees are made with respect to accuracy or timeliness of this material. This material should not be used as a basis for treatment decisions, and is not a substitute for professional consultation and/or peer-reviewed medical literature.
Early Stage Glottic Carcinoma
Mark Zafereo, M.D.
October 25, 2007
This morning’s topic is early glottic carcinoma. We will discuss the anatomy, staging and management, looking predominantly at transoral and external surgery and radiotherapy and comparing these treatment modalities in terms of local control, laryngeal preservation, and vocal quality.
First a few points concerning laryngeal anatomy. The glottic larynx extends from the junction between the respiratory and the squamous epithelium on the floor of the ventricle to the junction of the squamous and respiratory epithelium on the undersurface of the true vocal folds, which has arbitrarily been defined as a point 5mm below the free edge of the vocal folds. The vocal ligaments along with the vocalis muscle and vocal cover make up the anterior two-third of the vocal folds, also called the musculomembranous vocal fold. The posterior one-third of the fold is called the cartilaginous cord as it is made up of the arytenoid cartilages and the posterior interarytenoid soft tissue and muscle. The pre-epiglottic space lies between the thyrohyoid membrane anteriorly and the epiglottis posteriorly. Superiorly it is bound by the hyoepiglottic ligament and inferiorly by the thyroepiglottic ligament. The intrinsic muscles of larynx (i.e., the thyroarytenoid, the thyroepiglottic, and aryepiglottic muscles), make up the quadrangular membrane.
Looking more closely at the membranes of the larynx. The elastic membrane of larynx is divided into upper and lower parts by the ventricles. The quadrangular membrane is a fold of connective tissue that extends from the lateral portion of the epiglottic cartilage to the corniculate and arytenoid cartilages. This membrane forms the aryepiglottic folds as well as the vestibular or false vocal folds. The conus elasticus, also called the triangular membrane, cricovocal membrane, or lateral cricothyroid membrane, is a fold of connective tissue that extends from the cricoid cartilage to the inner surface of the thyroid cartilage anteriorly and the vocal process of the arytenoid posteriorly, thickens between these to form the projecting edges of the vocal ligament and then with its covering stratified squamous epithelium is called the vocal fold. The quadrangular and triangular membranes act as barriers to extraglottic and extralaryngeal spread.
The paraglottic space is bounded anteriorly and laterally by the inner perichondrium of the thyroid cartilage, posteriorly by the mucosa of the piriform sinus, medially by the ventricle, superiorly by the quadrangular membrane, and inferiorly by the triangular membrane. Most of the mucosal cover of the upper respiratory tract is respiratory epithelium, i.e., ciliated pseudostratified columnar epithelium. However, glottic epithelium is non-keratinized, stratified squamous epithelium with no mucous glands. The junction of the two is illustrated here to the right. The highly specialized lamina propria, illustrated on the left, separates the epithelium from the underlying vocalis muscle. Reinke’s space is the most superficial layer of the lamina propria, and the deep and intermediate layers of the lamina propria make up the vocal ligament.
Glottic cancer is staged according to the AJCC staging system. Tis includes carcinoma in situ or lesions that do not invade the basement membrane. T1 is limited to the vocal fold with normal mobility, T1a is limited to one vocal fold and T1b involves both vocal folds. T2 extends to the supra- or subglottis or has impaired vocal fold mobility. Some will further classify these T2s into favorable and non-favorable T2s: the unfavorable being more deeply invasive with impaired vocal fold mobility. The T3 is characterized by vocal fold fixation or invading the paraglottic space or with minor thyroid cartilage erosion. The left paraglottic space is invaded here. Vocal cord fixation is caused by invasion of the thyroarytenoid muscle and correlates with the degree of invasion. Invasions of less than 25% do not produce disturbance in mobility, 25% to 75% result in impaired mobility and greater than 75% causes fixation of the cord. T4a invades through the thyroid cartilage or beyond the tissues of the larynx. T4b invades the prevertebral space, mediastinal structures, or encases the carotid.
Early glottic carcinoma includes stage I and II tumors with no vocal fold fixation, no nodal involvement, and no extralaryngeal extension. Within this broad category or early stage tumors, there is a range from epithelial abnormalities involving a segment of the true vocal fold to large, bulky tumors extending to the anterior commissure, contralateral cord, supraglottis, or subglottis. The overall cure rate for glottic cancers is around 60% to 70%, but exceeds 90% for early stage lesions. The focus of this presentation will be the early stage lesions, mostly the T1’s. The goal of treatment for early stage lesions is first and foremost oncologic cure followed by preserving and optimizing voice and then other considerations such as swallowing, and minimizing cost and complications.
Treatment options include radiotherapy, partial laryngectomy via an external approach, and transoral endoscopic cordectomy with cold instruments or laser resection. There has been lot of evidence showing single modality therapy to be adequate in the treatment of early glottic cancer. Initially, early laryngeal cancers were managed through the laryngofissure approach with vocal excisions. Gordon Buck, a surgeon at the New York Hospital and a pioneer military surgeon during the civil war, first described this procedure in 1853. Then Dr. Theodore Billroth, a famous German surgeon, was the first to perform a total laryngectomy for laryngeal cancer in Vienna in 1873. The history of radiotherapy dates back to 1895 when William Conrad Roentgen discovered the x-ray, for which he was awarded the first Nobel prize in physics. Radioactive cobalt was introduced in the 1940s and applied to cancer therapy in the 1950s and since that time radiotherapy has been applied in varying protocols to the treatment of laryngeal cancer. However, over the last several decades, there have been many published case series showing comparable survival and voice outcomes with endolaryngeal resection. Despite the fact that endolaryngeal surgery and radiotherapy a have been equally effective in curing early disease, XRT has been considered the mainstay of therapy through the latter part of the 20th century because XRT is generally thought to provide the greatest likelihood of voice conservation and optimization.
Many factors make it difficult to compare nonrandomized data, including selection bias, use of pathologic versus clinical staging, and different staging methods for patients undergoing different treatments. For example, pathologic staging cannot be performed in patients undergoing radiotherapy. There are several multi-center randomized clinical trials underway, one by Dr. Coman in Queensland, Australia, in which Dr. Holsinger will be participating, which is comparing effectiveness of radiotherapy versus laser surgery in early glottic carcinoma. However, for now, the quality of evidence comparing treatment modalities for this disease remains either retrospective double-arm cohort studies or prospective single-arm studies.
Conventional open surgery in the treatment of laryngeal cancer has been increasingly replaced by transoral endoscopic surgery for many early stage lesions, and in the interest of time I only speak briefly about this. The advantages of the open surgical approach are good visualization and better assessment of the extent of the tumor as well as with low local recurrence rates. Thomas and others reported in 1994 on a cohort of 159 patients who underwent conventional open procedures for early glottic cancer, reporting a 93% local control rate at five years and 94% laryngeal preservation. However, with high morbidity and poorer voice results than with either endoscopic surgery or radiation, these procedures are now less commonly used for early glottic cancer.
I will spend the remainder of the time discussing transoral endoscopic cordectomy, radiotherapy and then compare the two in terms of local control and voice quality. The transoral endoscopic cordectomy is ideally for carcinoma in situ or isolated T1 lesions of the musculomembranous fold. This slide is an overview of some of the advantages and disadvantages of transoral endoscopic resection. Proponents of transoral endoscopic resection will argue that there are comparable control rates, radiation therapy can be reserved for second primary or salvage, and that there are potentially lower costs in view of fewer long-term complications. But there is ongoing debate about whether equivalent voice quality can be achieved with endolaryngeal resection. There is also a steep learning curve, with those who advocate this approach generally having a high level of experience and expertise.
While I’ll speak mostly about transoral endoscopic laser resection, there are minority of surgeons who perform the transoral resection with cold instruments with good results. Cold instruments avoid heat injury, but do not provide hemostasis when dissecting within the vocalis muscle. These pictures are from Dr. Zeitels, who is one of the biggest proponents of cold instrument resection. He most recently published a case series of 32 patients, mostly T1a. He reported only one local recurrence, which was salvaged with a second transoral surgery. He also reported good voice results. These pictures illustrate the point that although the staging for laryngeal cancer does not take into account the depth of invasion, the depth of invasion does become important when considering surgical treatment as deeper resections sequentially involves more layers of the vocal fold and will have more adverse effects on the voice.
The laser, specifically the carbon dioxide laser, is the most commonly used instrument for transoral endoscopic resection. Laser is just a focused beam of light. The CO2 laser has a longer wavelength than other lasers, 10,500nm, which is absorbed by water, and has minimal depth of penetration. The CO2 laser has both cutting and hemostatic properties in the focused and defocused modes, respectively. Although the CO2 laser itself is invisible, there is coincidental delivery of the visible helium neon beam that allows it to be visible to the naked eye.
In 1917, Einstein described the basic physics of stimulated emission of radiation. However, it was not until 1954 that Townes and Gordon built a microwave laser called the maser. Many other have contributed to the development of the laser and then specifically, the carbon dioxide laser, which was first used in ophthalmology during the 1960s. A group of otolaryngologists in Boston led by M. Stuart Strong and Gezo Jako introduced the C02 laser to our specialty, publishing the initial clinical report on the use of the C02 laser in otolaryngology in 1972.
Laser resection was propagated more recently and predominantly in Europe by Remacle and others. This is a laser cordectomy classification based on the 2000 European Laryngological Society Working Committee proposed by Dr. Remacle and others. A type I cordectomy represents epithelium only; type II includes Reinke’s space and the vocal ligament; and type III includes part of the vocalis muscle, demonstrated in the picture to the right. A type IV is a total cordectomy and type V is an extended cordectomy, which can encompass the contralateral true vocal fold, the arytenoid, ventricular fold, or subglottic tissue.
Since with early laryngeal lesions, spread to regional nodes or distant sites is rare, control of the primary lesion is usually equivalent to a cure. So, it is helpful to look at studies in terms of local control and laryngeal preservation, which indicates what percentage of patients did not end up with a total laryngectomy. Steiner treated 159 patients in Gottingen, Germany over a 12-year period. He performed excisional biopsies for most of his carcinoma in situ, partial cordectomies for T1s, and complete cordectomies for most of his T2s. The T2s he operated on were small with freely mobile cords. He achieved 94% local control and 99% laryngeal preservation with more than 90% of his patients having slight or no dysphonia following surgery. Motta and others treated 479 patients over a 15-year period in Naples, Italy. Most of these were T1, for which he performed unilateral cordectomies for the T1a’s and bilateral cordectomies for the T1b’s. He achieved 82% local control and 89% laryngeal preservation. He performed a bilateral cordectomy for the T2s with 60% local control and ultimately preserved the larynx in 2/3rds of these patients. Peretti and others treated 140 patients over an 8-year period in Italy, two-thirds of whom were T1s. He was very selective, excluding patients with extraglottic extension. Local control was about 80% and very few required salvage radiation or total laryngectomy. In fifty percent of cases which required retreatment, the second laser surgery was successful. Gallo and others treated 156 patients in Italy over a 14-year period. He operated only on T1s, performing more extensive types 3, 4, and 5 cordectomies. He did not operate on tumors with deep involvement of the anterior commissure. He reported excellent results in terms of high local control and 100% laryngeal preservation.
This is a case illustrating pre- and postoperative stroboscopies in a 51-year-old gentleman who presented to the M.D. Anderson Cancer Center with a primary T1b glottic carcinoma. He underwent laser cordectomy by Dr. Christopher Holsinger. This tumor involves the left cord as well as the commissure and the anterior right cord. The postoperative videostroboscopy, several months after endoscopic laser excision, is shown here. We see the left true vocal fold has lost much of its mucosal vibratory wave.
Now to shift gears and talk about radiotherapy. For all other laryngeal cancer including supraglottic, subglottic, and late stage glottic cancer, the cervical lymph nodes must be included in the radiation field. However, regional lymph node metastases are rare in early glottis cancer, occurring in only about 2% to 7%. Therefore, the neck is generally not radiated with early glottic carcinomas. In speaking with Dr. Giri, who is the chief of radiation oncology at the VA and Dr. Garden, one of the radiation oncologists at MDA, both institutions are generally still using conventional opposed lateral fields for early stage larynx, though some places are using more IMRT. The thought is that with very small fields (5cm squared), there is extremely low morbidity and it is hard to justify the cost and complexity associated with IMRT. There is also the possibility of missing the tumor with IMRT.
The T1s are pretty clear-cut. At the VA, they are generally using 70Gy in 35 fractions of once daily dosing and at MDA, 66 Gy in 33 fractions, once daily dosing. With the T2s there is more variation. This is a study by Trotti and others presented at the 2006 ASTRO meeting. T2s were randomly assigned to receive either hyperfractionation to 79.2 Gy in 66 fractions of 1.2 Gy given twice a day, or standard fractionation (SFX) to 70 Gy in 35 fractions given once a day. The results here are not quite statistically significant, but there was a trend toward higher local control and survival in the hyperfractionated group, although they were modestly higher rates of acute skin, mucosal and laryngeal toxicity associated with this group.
Based on this and similar data, MDA is using some altered fractionation, either a twice daily regimen or once daily with concomitant boost, in unfavorable T2 lesions. For very aggressive T2s, they are also using some IMRT and, in some cases, chemotherapy. The major potential advantage of radiotherapy over surgical resection is better voice results. However, there are also higher complication rates if the cancer has to be surgically salvaged, as well as limited ability to reirradiate for second primary laryngeal tumors.
These are few studies of radiotherapy for early glottic cancer. Warde and others looked at 735 patients over a 6.8-year period. Local control was 91% for T1a’s, 82% for T1bs and 69% for T2s. Mendenhall treated 519 patients with local control in the mid-90% for T1s and about 70% to 80% for favorable and unfavorable T2s, respectively. The laryngeal preservation rates were only marginally higher indicating that the patients who recur often had to undergo a total laryngectomy. Four patients, which is less than 1% of the total patients in this study, experienced late radiation complications, three of whom required tracheostomies, and there was only one pharyngocutaneous fistula. Garden, at MD Anderson, treated 230 patients with T2 with local control in the mid to low 70 percent range. There were 4% severe complications, including 5 patients who had chondroradionecrosis requiring tracheostomy. There were two perioperative deaths with attempted surgical salvage procedures, and one pharyngocutaneous fistula in this study. Cellai treated 831 patients with T1s in Italy with an 83% local control at 10 year. Six percent had significant edema and mucositis, which extended at least six months beyond treatment. Five ended up with tracheostomies and one had pharyngocutaneous fistula. Of these 831 patients, 68, which represent 8%, eventually had to undergo total laryngectomy.
These are some pre and postoperative stroboscopies with radiotherapy courtesy of Dr. Richard Stasney. This is a 49-year-old gentleman with a very thickened right vocal cord and a lesion that extends to the anterior left cord, making it a T1b. He also had invasion at the level of the vocal ligament on biopsy. There is normal fold mobility, but complete loss of the mucosal wave on the right side. Six weeks after completion of 64 cGy of radiotherapy at The Methodist, this is his stroboscopy. The right mucosal wave does not recover after radiotherapy. However, he has no evidence of disease. This is a second patient who is a 65-year-old gentleman who presented with hoarseness and a left true vocal cord exophytic lesion extending to the anterior commissure, the ventricle and subglottis. Dr. Stasney surgically debulked 80% of this tumor when taken to the OR for biopsy and then the patient received 74 cGy of radiation. This is the post-treatment stroboscopy. He has some slight preservation of the mucosal wave.
So, summarizing local control and laryngeal preservation. For radiotherapy, 5-year local control ranges from 85-95% for T1 and 70-80% for T2. The rates of laryngeal preservation with radiotherapy are only marginally higher than the local control rates; meaning that those patients who recurred often required total laryngectomy. The local control for the transoral endoscopic resection ranges from 80-90% for T1 disease and laryngeal preservation that usually exceeds 90-95%. For T2s, local control falls to 70-85%, with laryngeal preservation in the 70-90% range.
Moving on to voice. Speech consists of phonation, which is the generation of sound by vibration of the vocal folds; resonance to the throat, oral cavity, and nasal cavity; and, articulation with the tongue and soft palate. This is an illustration of the Bernoulli effect where short puffs of air at high speed push open the vocal folds leaving behind areas of low pressure in their wake. The area of low pressure causes the vocal folds to shut, and this closure releases a pulse of air.
The capacity of vocal folds to vibrate depends on the homogeneity and the flexibility of the mucosa and the lamina propria. With surgical resection, the epithelium will regenerate, but will assume the viscoelastic properties of the soft tissue underlying it. The tethering of the epithelium to the underlying muscle due to scarring after surgery blocks the normal propagation of mucosal waves. When the lesion is superficial, a normal postoperative voice can be achieved if the dissection is confined to Reinke’s space. However, with more invasive lesions, resection may result in permanent dysphonia, because deep resections result in a healed neocord that is concave, resulting in incomplete glottic closure. On the other hand, if the glottic closure is maintained with a straight postoperative cold, the vocal system can usually compensate by increasing subglottic pressure, along with intact vibration from the contralateral cord, to achieve a normal or near normal conversational voice.
Radiation also causes scarring and changes of the elastic properties of the vocal folds, most importantly the superficial lamina propria, which is the main vibrating layer of the vocal fold, and both the vocal folds are always irradiated. The most common complication is edema, which increases the impedance of the submucosa and impairs vibration, causing a hoarse or raspy voice. But there are more serious, though rare, complications including chondroradionecrosis in 1% to 5% of patients.
So, how does this translate to patients who have been treated with radiation therapy or surgery? It can be difficult to compare studies because of differences in the extent of surgery or radiotherapy, differences in patient selection, and differences in the actual assessment of vocal quality. These are couple of studies from the mid 1990s that are still often cited. They use both objective, acoustic measures and subjective assessments by patients and speech pathologists. McGuirt and others evaluated voice outcomes for 24 T1a glottic carcinomas with about a dozen patients undergoing radiotherapy and a dozen undergoing transoral laser endoscopic resection. This was a joint effort by the Otolaryngology and Radiotherapy Departments at North Carolina. There was mild dysphonia in both groups with no statistically significant difference between groups. Rydell and others published a paper from Sweden in the mid 1990’s, and the voice quality at 3 months and 2 years was significantly better with the radiotherapy group. They also used both objective and subjective measures. Both improved voice quality with EBRT and similar outcomes regardless of treatment continue to be described in the literature.
Dr. Cohen, Dr. Osoff, and others published a meta-analysis in August 2006, a review over the last 40 years for studies in which the Voice Handicap Index (VHI) was assessed at least three months after treatment for T1 glottic cancers. The VHI is a detailed voice-related questionnaire which the patient answers with a range from 0 to 120, with 0 to 30 representing minimal voice handicap, the lower the score the better. A VHI score of 30 to 50 is common with vocal cord nodules, polyps, and cysts and a VHI index of 60 to 70 is common with neurologic voice disorders. The overall average VHI for laser surgery in this analysis was around 13, whereas that for EBRT was around 19. There was no statistically significant difference between the groups. The authors argue that both perceptual and acoustic voice evaluation correlate poorly with the patient’s own evaluation of their voice and so cite this as most pertinent to treatment options.
A couple of quality of life studies were done by the senior Dr. Myers and others in a 1994 study. They looked at total treatment cost among patients with T1 glottic cancers undergoing transoral endoscopic surgery, radiotherapy, or open conservation surgery, including the cost of salvage for treatment failure. Then, in 2003, Dr. Myers again looked at the quality of life based on patient questionnaires for patients undergoing only transoral endoscopic resection or XRT for T1 lesions. The findings from these studies were that XRT and open conservation surgery were cost equivalent, with XRT two to three times more expensive than endoscopic transoral surgery. In addition, they noted significant difference in hidden costs with radiotherapy, such as days of treatment and missed work time.
Dr. Gary Clayman was one of the authors of these guidelines published in 2006 from the American Cancer Society of Clinical Oncology. For T1 glottic cancers, the recommendation is endoscopic resection for selected patients or radiation therapy. Other options include open organ preservation surgery. For favorable T2 glottic cancers, i.e., lesions that are more superficial on radiographic imaging and do not involve impaired vocal cord mobility, open organ preservation surgery or radiation therapy is primarily recommended. Other options include endoscopic resection in selected patients. For unfavorable T2 glottic cancer, open organ preservation surgery or concurrent chemoradiotherapy is recommended. These are lesions that they more deeply invasive on imaging, causing impaired mobility of the cord.
So, back to the case presentation, this is a 64-year-old gentleman, who had fairly diffuse thickening and erythema of the right fold, which came back invasive squamous cell carcinoma. He also had erythema of the left fold, which was high grade dysplasia. The diffuse cancerous and dysplastic changes to both of the folds without obvious exophytic lesions made him an ideal candidate for radiotherapy, which he is currently undergoing. He will be treated with laterally opposed field radiation to a total of 70 cGy in 35 fractions of 2 Gy/fraction.
Looking at the patients at the Michael E. Debakey VAMC who presented with larynx cancer in 2005 and 2006, there were 13 patients who had follow-up of at least one year. Two patients with carcinoma in situ were treated surgically, one with an excisional biopsy and another with a vocal cord stripping, both with no evidence of disease. Nine patients with T1s were treated with XRT. One has recurrent disease, and he is currently being worked up for a total laryngectomy. The other eight had no evidence of disease. In two patients with T2, both were treated with XRT, one who died of other cause and one with no evidence of disease. So, overall good results with the understanding that these patients have only been followed for an average of a year-and-half following treatment.
In summary, patient preference; patient physical condition; lesion characteristics including location, size, the tumor biology; vocal function and occupation; cost-effectiveness; and local facilities and expertise are all important management considerations. For example, for a patient with a T1a tumor, if the voice outcome is predicted to be good, as with a superficial lesion located in the middle third of the cord, then endoscopic laser resection may be more efficient and the preferred method of treatment. However, with indistinct lesions, especially widespread abnormal appearing mucosa, radiation therapy may be more suitable.
Case Presentation:
W.A. is a 64-year-old gentleman with no significant past medical history who presented to the Michael E. Debakey VA Medical Center otolaryngology-head and neck surgery clinic with a six month history of hoarseness. He described a gradual onset of hoarseness that began six months previously. He denied recent upper respiratory infection or trauma. He is a retired carpenter and denied voice abuse or previous episodes of hoarseness. He had no dysphagia, odynophagia, otalgia, neck pain, cough, hemoptysis, dyspnea, or weight loss. He had no known history of GERD and denied heartburn, globus sensation, subjective reflux, frequent throat clearing, and food/mucus sticking in his throat. He had no allergies or allergic symptoms and no known history of thyroid or neurologic disorders. He had a 40 pack year smoking history, but had quit smoking cigarettes thirty years previously.
Physical examination revealed a gentleman in no acute distress and without stridor or stertor. He had a raspy voice without significant straining or breathiness. The ears, nasal cavity, and oral cavity were without abnormality. The neck was without masses or palpable lymphadenopathy. The laryngeal cartilages were intact, and the thyroid gland was normal in size and without palpable nodularity. Flexible fiberoptic examination revealed no abnormalities of the nasopharynx, oropharynx, or hypopharynx. The right true vocal fold was irregularly thickened and erythematous diffusely, most predominantly in the middle third of the fold, but without any exophytic lesions or ulceration. The left true vocal fold was slightly erythematous with several polyps projecting from the middle third of the fold. The true vocal folds were fully mobile bilaterally.
The patient was placed on a twice-daily proton pump inhibitor and referred to speech therapy. A microsuspension direct laryngoscopy was performed with pathology from biopsies significant for left true vocal fold high grade dyplasia and right true vocal fold moderately differentiated squamous cell carcinoma. Other than a thickened right true vocal fold, a CAT scan showed no abnormality. The patient’s glottic cancer was staged T1N0M0.
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Bobby R. Alford Department of Otolaryngology-Head and Neck Surgery
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Last modified: Dec. 04, 2007