clinical and histologic predictors of voice and disease outcome in patients with early glottic...

The LaryngoscopeVC 2012 The American Laryngological,Rhinological and Otological Society, Inc.

Clinical and Histologic Predictors of Voice and Disease Outcome inPatients With Early Glottic Cancer

Joseph Chang; Tuan-Jen Fang, MD; Katherine Yung, MD; Annemieke van Zante, MD, PhD;

Theodore Miller, MD; Soha Al-Jurf, MA, CCC-SLP; Sarah Schneider, MS, CCC-SLP; Mark S. Courey, MD

Objectives/Hypothesis: To determine preliminarily if clinical or histological features of patients with laryngealdysplasia/early carcinoma correlate with voice and disease outcomes.

Study Design: Retrospective case series.Methods: All UCSF Voice Center patients treated with endoscopic surgery for severe dysplasia or early laryngeal cancer

between 2004 and 2010 were identified. Preoperative stroboscopy, intraoperative appearance, and histologic characteristics(pattern of invasion, degree of inflammation, and degree of keratinization) of the neoplastic lesions were compared with cor-dectomy type and the outcomes of voice quality and disease-free interval.

Results: Eighteen patients were evaluated. Increased stromal chronic inflammation correlated with longer disease-freeinterval (r(2) ¼ 0.38). Cordectomy type correlated with both preoperative and postoperative voice parameters (r(2) ¼ 0.42–0.68 and 0.33–0.39).

Conclusion: Increased stromal chronic inflammation correlates with improved disease outcome. Voice outcome corre-lates with the amount of tissue removed. The clinical appearance of the lesion did not correlate with disease or voiceoutcome.

Key Words: cancer, early glottic, larynx, head and neck, voice, histology.Level of Evidence: 4.

Laryngoscope, 122:2240–2247, 2012

INTRODUCTIONIn the United States, glottic squamous cell carcino-

mas account for approximately half of all laryngealcancers.1 Of these glottic cancers, approximately 60%are detected as early stage tumors defined as TisN0M0,T1N0M0, and T2N0M0.1 In spite of all these lesions,Tis–T2, being described as early stage, patients canpresent with vastly different symptoms. Specifically,patients with bulky exophytic tumors with absent tominimal invasion may have marked dysphonia or othersymptoms of glottic dysfunction, while patients withwidely superficially spreading disease or those with alimited surface extension but deep invasion, approaching

T2 size, may have minimal vocal change or signs of glot-tal dysfunction, yet not respond as well to therapy.

Historically these early stage tumors have beentreated with either radiation therapy or surgical exci-sion. While slightly controversial, the rate of control andmorbidity, in terms of voice and swallowing, by eithermodality, are reported as similar.2,3 Due to earlieradvances in radiation therapy techniques, radiationtherapy has become the more common method of treat-ment for these lesions. However, with the recentgrowing expertise in endoscopic management techni-ques, the paradigm of RT as the most effective and leastmorbid modality of treatment is being challenged.

In the currently used TNM classification system theT stage of early glottic cancers is determined solely bythe number of laryngeal sub sites involved. Specifictumor characteristics such as size, location, depth ofinvasion, and pattern of invasion—as well as associatedpatient symptoms at presentation—are not required forT stage determination and are not routinely evaluatedand categorized by the treating physicians. These fac-tors, which currently are not routinely evaluated orrecorded, may affect management choices and overalltreatment outcomes. Therefore, due to this lack of infor-mation it is difficult to adequately compare the truemorbidity of our treatment choices. Specifically, we fre-quently cannot determine if the failure of treatment orthe posttreatment morbidity to voice and swallowingwere due to disease characteristics at presentation orentirely a result of the method of treatment.

From the School of Medicine (J.C.) University of California, SanFrancisco, San Francisco, California, U.S.A; School of Medicine (T-J.F.)Chang Gung University, Taoyuan, Taiwan; Chang Gung MemorialHospital (T-J.F.), Taipei, Taiwan; Department of Otolaryngology–Headand Neck Surgery (K.Y., S.A-.J, S.S., M.C.) University of California, SanFrancisco, San Francisco, California, U.S.A; Department of Pathology,(A.VZ., T.M.) University of California, San Francisco, San Francisco,California.

Editor’s Note: This Manuscript was accepted for publication May9, 2012.

Presented at the 133nd Annual Meeting of the American Laryngo-logical Association in San Diego, California, on April 18–19, 2012.

The authors have no funding, financial relationships, or conflictsof interest to disclose.

Send correspondence to Mark S. Courey, UCSF Voice and Swallow-ing Center, 2330 Post Street, 5th Floor, San Francisco, CA 94115.E-mail: [email protected]

DOI: 10.1002/lary.23501

Laryngoscope 122: October 2012 Chang et al.: Predictors of Voice and Disease Outcome in Early Glottic Cancer

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In an attempt to establish a better system withwhich to assess surgical outcomes, the European Laryn-gological Society proposed that endoscopic surgeries forthe resection of these early laryngeal cancers be catego-rized into six cordectomy types based on location, type,and amount of laryngeal tissue removed.4,5 Using thiscategorization system, the vocal outcome has been showto correlate with the quantity of tissue remove.6 However,while this system can provide information on outcomebased on the amount of tissue removed, it does not providepredictive information to aid us in counseling our patientsbased on their clinical picture at presentation.

The purpose of this project is to determine if clinicalfeatures and clinical appearance of the lesions at presen-tation, as well as information from histologic examinationfrom the initial biopsy correlate with outcomes of treat-ment in terms of cure rate and voice outcome. The overallpurpose of this pilot study is to develop a reproduciblemethod to accurately classify glottic dysplasia and earlyglottic cancer based on patients’ clinical presentation andhistologic features at the time of biopsy and resection. Toevaluate these specific aims, we correlated clinical andhistologic characteristics of patients and lesions at presen-tation with the type of transoral resection, disease-freeinterval, and voice outcome in patients who underwentendoscopic resection for management of their disease. Inaddition, to determine if the measures we evaluated werereliable, ratings were made by multiple observers trainedon the rating systems.

MATERIALS AND METHODSA retrospective series of patients treated with endoscopic

surgery between 2004 and 2010 for severe dysplasia or early la-

ryngeal cancer at the UCSF Voice and Swallowing Center wasassessed. Subjects were included if they underwent eitherprimary surgery or surgical resection for recurrence (greaterthan 1 year) after completion of definitive RT (Table 1). Clinicalcharacteristics of the lesion as well as laryngeal vibratory char-acteristics and cordectomy types were correlated with measuresof pre- and postsurgical vocal quality and disease recurrence.Clinical data was gathered from electronic patient records aswell as pre- and postoperative videostroboscopy recordings,intraoperative imaging captured at the time of direct laryngos-copy, and archived tissue biopsies.

Clinical lesion appearance was evaluated by intraoperativeimages taken immediately before excisional biopsy. Images wereevaluated for location of the lesion in the larynx (anterior com-missure or right or left true vocal fold) and lesion location onthe true vocal fold (dorsolateral or medial surface), growth type(exophytic or endophytic), erythema (present or not present),and lesion border definition (well- or ill-defined). Two laryngolo-gists blinded to patient identity and treatment outcome gradedeach image independently. Interrater, but not intrarater, reli-ability was calculated for this data.

Archived tissue biopsies were evaluated for keratinization,pattern of invasion, severity of dysplasia/cancer, and the degreeof acute (neutrophilic) and chronic (lymphocytic) inflammationwithin the surrounding stroma and within the tumor itself(Table 2). Keratinization and pattern of invasion were scoredbased on a system devised by Bryne et al.7 All biopsies wereindependently evaluated by two pathologists blinded to treat-ment outcome. Interrater, but not intrarater, reliability wascalculated for this data.

Pre- and postoperative laryngeal vibratory characteristicswere evaluated based on recorded stroboscopy videos taken1–42 days before and 7–11 months after surgical treatmentrespectively. Mucosal wave and vertical phase were graded asnormal, reduced, or absent. Glottic closure was graded as nor-mal, or mild, moderate, or severe impairment (< 1/3, 1/3–2/3,and > 2/3 the width of one true vocal fold respectively). Two

TABLE I.Patient Demographics.

Patient Gender Age Cancer Stage Cordectomy Surgical Type Treatment Result

1 M 61 Severe Dysplasia I Primary NED

2 M 74 Severe Dysplasia I Salvage Recurrence

3 M 52 Cis I Primary Recurrence

4 M 65 Cis V Primary NED

5 M 43 T1a I Primary NED



8 M 65 T1a I Primary Recurrence

9 M 65 T1a I Primary Recurrence

10 M 77 T1a II Salvage NED

11 M 67 T1a III Primary NED

12 M 71 T1a III Primary NED

13 M 59 T1a III Salvage Recurrence

14 M 44 T1a V Salvage NED

15 M 66 T1b I Primary Recurrence

16 M 50 T1b V Salvage NED

17 M 74 T2 II Primary NED

18 M 81 T2 V Salvage NED

NED ¼ No evidence of Disease.


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laryngologists blinded to patient identity and treatment out-come graded each video independently. Ten percent of the videosamples were graded twice to allow calculation of both intra-and interrater reliability.

Voice quality was evaluated from recorded voice samplesof patients reading the Rainbow Passage. Overall severity,roughness, breathiness, strain, pitch, and loudness were eval-uated on a visual analog scale. Scores ranged from 0 to 100,with higher scores indicating greater impairment. Pre- andpostoperative vocal qualities were determined from samplestaken 1–42 days before and 7–11 months after surgery. Twospeech-language pathologists blinded to patient identity andtreatment outcome graded each sample independently. Ten per-cent of the voice samples were graded twice to allow calculationof both intra- and interrater reliability.

Cordectomy type, as defined by the European Laryngologi-cal Society guidelines,4,5 was recorded by a laryngologist afterreview of intraoperative images and operative reports.

Interrater reliability was calculated using kappa, intra-class correlation (ICC) coefficients, and proportion of agreement.Quadratically weighted kappa was used to assess reliability ofvibration characteristics, unweighted kappa to assess lesionappearance, and ICC to assess vocal quality parameters. ICCcalculations assumed that judges were randomly drawn from alarger population and that each judge rated each one of thesamples.8 Proportion of agreement was used to assess interraterreliability for all variables except voice quality. This was calcu-lated in two ways, using grades from all vocal cords (composite)and using grades from all vocal cords excluding those deemednormal by both graders (non-normal). Non-normal proportion ofagreement more accurately determines reliability in distin-guishing between different degrees of abnormality.

Intrarater reliability was calculated for vibration charac-teristics and vocal quality using slope, Pearson’s coefficient andSpearman’s coefficient. Slope was calculated from linear regres-sion of samples evaluated twice by graders. Pearson’s coefficientwas used for vibration characteristics and Spearman’s coeffi-cient for vocal quality.

Parameters with poor inter- or intrarater values wereexcluded from analysis; this includes ICC coefficients below0.4,9 Kappa values below 0.4,10 proportion of agreement below0.65, Pearson’s or Spearman’s coefficients below 0.5,11 and slopevalues below 0.75 or above 1.25. Individual data points onwhich raters disagreed were excluded. Raters were consideredin disagreement for voice parameters when scores differed bygreater than 18 points. Correlation was determined using R2values. Statistical significance was determined using Student’st and ANOVA tests with a ¼ 0.05.

RESULTS

Reliability Assessments (Table 3)Interrater reliability for the vibratory parameters,

mucosal wave, vertical phase, and glottic closure rangedfrom 0.56 to 0.74 for kappa, from 0.59 to 0.76 for com-posite proportion of agreement, and from 0.50 to 0.72 fornon-normal proportion of agreement. Only mucosal wavemet the kappa and proportion of agreement cutoffs of0.4 and 0.65 respectively.

Interrater reliability for the lesion appearance pa-rameters was evaluated using unweighted kappa andproportion of agreement. Unweighted kappas rangedfrom 0.25 to 0.85 for lesion appearance evaluated by vid-eostroboscopy and from 0.35 to 0.70 when evaluated byintraoperative imaging. Composite proportions of agree-ment ranged from 0.53 to 0.90 for parameters evaluatedby videostroboscopy and from 0.60 to 0.80 when eval-uated by intraoperative imaging. Non-normal proportionof agreement ranged from 0.22 to 0.85 and from 0.30 to0.70 for parameters evaluated by videostroboscopy andintraoperative imaging respectively. When evaluated byvideostroboscopy, surface location, erythema, and defini-tion of lesion borders met the 0.4 kappa cutoff and the0.65 proportion of agreement cutoff. When evaluated byintraoperative imaging, surface location, true vocal cordgrowth type, and definition of lesion borders met kappaand proportion of agreement cutoffs.

Interrater reliability for histological parameterswas evaluated using kappa and proportion of agreement.Unweighted kappa was used to evaluate pattern of inva-sion and was calculated to be 0.50. Quadratic weightedkappa was used to evaluate all other histological param-eters and ranged from 0.13 to 0.78. Composite and non-normal proportions of agreement ranged from 0.38 to0.89 and from 0.17 to 0.89 respectively. Evaluation ofdysplasia/cancer scale and stromal chronic inflammationmet the kappa and proportion of agreement cutoffs.

Voice quality interrater reliability was evaluatedusing ICC coefficients. ICC values for the six voice qual-ity parameters ranged from 0.60 to 0.87. All parametersexceeded the 0.4 ICC coefficient cutoff.

Intrarater reliability was evaluated for vibratorycharacteristic and voice quality assessments using

TABLE II.Histological Grading Scale.

Score

0 1 2 3

Dysplasia/Cancer Moderate Dysplasia Severe Dysplasia Carcinoma in situ Invasive Carcinoma

Keratinization None (0–5% of cells) Minimal (5–20%) Moderate (20–50%) Marked (> 50%)

Acute (Neutrophilic)Inflammation

None Mild Moderate Severe

Chronic (Lymphocytic)Inflammation

None Mild Moderate Severe

Pattern of Invasion: ‘‘Pushing, well delineated,infiltration borders’’

‘‘Infiltrating, solid cords,bands, and/or strands’’

‘‘Small groups or cordsof infiltrating cells (n > 15)’’

‘‘Marked and widespreadcellular dissociation in small

groups and/or insingle cells (n < 15)’’

Keratinization and Pattern of Invasion were adapted from Bryne et al.7. Inf ¼ Infiltration.


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Spearman’s rho and slope, and Pearson’s correlationcoefficient and slope respectively. Spearman’s rho valuesfor vibratory characteristics ranged from 0.17 to 0.96and slope values ranged from 0.17 to 0.95. Pearson’s cor-relation coefficients for voice quality ranged from 0.27 to0.98 and slope values ranged from 0.24 to 1.14. One ofthe vibratory characteristics, vertical phase, and fourvoice quality parameters, overall quality, roughness,strain, and pitch exceeded the intrarater reliability cut-off values.

Clinical and Histologic Features (Table 4, Table 5)Increased stromal chronic inflammation correlated

weakly with longer disease-free interval with an R2

value of 0.38 (Fig. 1). At 1 year, patients with scores of1, 2, and 3 had mean disease-free intervals of 5.9months, 7.7 months, and 11.7 months respectively. Thisresult was not statistically significant.

Cordectomy type correlated with both pre- and post-

operative voice quality, but not disease-free interval.

More extensive cordectomy procedures correlated with

increasing preoperative overall dysphonia grade (R2 ¼0.42), roughness (R2 ¼ 0.68), and strain scores (R2 ¼0.47) (Table 6), and increasing postoperative pitch (R2 ¼0.39) and strain (R2 ¼ 0.33) scores (Fig. 2). None of these

cordectomy associations were statistically significant.Preoperative voice quality also correlated with post-

operative voice quality, but not disease-free interval.

TABLE III.Interrater and Intrarater Reliability.

Kappa/ICC

Proportion of Agreement

r SlopeComposite Non-normal

Videostroboscopy

Vibratory Parameters1,4

Mucosal Wave 0.56 0.76 0.72 0.69, 0.70 0.64, 0.77

Vertical Phase 0.58 0.66 0.61 0.92, 0.96 0.79, 0.95

Glottic Closure 0.74 0.59 0.50 0.17, 0.61 0.17, 0.75

Lesion Appearance2

*Surface 0.85 0.90 0.85 – –

Growth Type (TVF) 0.62 0.73 0.60 – –

Growth Type (AC) 0.25 0.53 0.22 – –

*Border Type 0.67 0.80 0.70 – –

*Erythema 0.82 0.90 0.85 – –

Intraoperative Imaging –

Lesion Appearance2 – –

*Surface 0.70 0.80 0.70 – –

*Growth Type (TVF) 0.67 0.78 0.67 – –

Growth Type (AC) 0.35 0.65 0.30 – –

*Border Type 0.70 0.80 0.70 – –

Erythema 0.45 0.60 0.41 – –

Histology –

*Dysplasia/Cancer1 0.78 0.89 0.89 – –

Keratin1 0.42 0.56 0.56 – –

Stromal Acute Inf1 0.58 0.65 0.45 – –

*Stromal Chronic Inf1 0.77 0.65 0.65 – –

Epithelial Acute Inf1 0.13 0.69 0.17 – –

Epithelial Chronic Inf1 - 0.38 0.29 – –

Pattern of Invasion2 0.50 0.61 0.42 – –

Voice Quality3,5

*Overall Dysfunction 0.84 – – 0.92, 0.96 1.05, 0.77

*Roughness 0.60 – – 0.93, 0.95 0.98, 1.14

Breathiness 0.80 – – 0.89, 0.95 0.37, 0.47

*Strain 0.81 – – 0.96, 0.98 0.83, 0.93

*Pitch 0.72 - - 0.94, 0.97 1.05, 1.08

Loudness 0.87 - - 0.27, 0.45 0.24, 0.37

*Parameter met kappa/ICC, proportion of agreement, r, and slope cut-offs (>0.4, >0.65, >0.5, and within 0.75–1.25 respectively), — Value could not becalculated, 1Quadratic weighted kappa, 2Unweighted kappa, 3ICC, 4Spearman’s rho, 5Pearson’s coefficient.

TVF ¼ True Vocal Fold, AC ¼ Anterior Commissure, Inf ¼ Inflammation, ICC ¼ Interclass Correlation Coefficient, r ¼ Intrarater Correlation Coefficients.


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Severe preoperative voice dysfunction correlated withsevere postoperative voice dysfunction when comparingpreoperative overall dysfunction with postoperative over-all dysfunction (R2 ¼ 0.93) and strain (R2 ¼ 0.80);preoperative roughness with postoperative overall score(R2 ¼ 0.82); preoperative strain with postoperative over-all dysfunction (R2 ¼ 0.37), strain (R2 ¼ 0.76), and pitch(R2 ¼ 0.74); and preoperative pitch with postoperativeoverall dysfunction (R2 ¼ 0.37), strain (R2 ¼ 0.79), andpitch (R2 ¼ 0.92) (Fig. 3). No statistical tests were per-formed on pre- and postoperative voice comparisons.

There were no statistical differences or strong cor-relations between the vibratory and clinical lesionappearance parameters and disease and vocal outcomes.

DISCUSSIONThe purpose of this pilot study was to identify clini-

cal and histological parameters which may be betterable to predict outcomes of early glottic cancers treatedwith transoral resection than the current TNM clinicalstaging system alone. The current TNM system is inad-equate in part because it does not take into accountclinical symptoms, exact tumor location and tumor char-acteristics at presentation which may affect treatmentchoices and treatment outcomes. This ‘‘lack of informa-tion’’ makes it difficult to compare results of differenttreatment modalities in terms of disease-free intervaland post-treatment morbidity.

Our results from this preliminary evaluation indi-cate that the clinical appearance of the lesion atpresentation, as judged on either still light endoscopy orstroboscopy, did not correlate with disease-free interval.Specifically, the lesion appearance on still light endos-copy, exact lesion location, appearance of associatedinflammation, and vibrational characteristics on strobo-scopy did not correlate with disease-free interval, norvoice outcome after endoscopic resection. There are twopossible reasons for this. First, due to our limited samplesize (n ¼ 18), only very large effects could be expected to

TABLE IV.P-values for Predictors and Outcomes.

0DFI

Postoperative Voice Quality

Overall Roughness Strain Pitch

Histology

Dysplasia/CancerScale

0.72 0.57 0.64 0.94 —

Stromal ChronicInflammation

0.23 0.68 — 0.41 0.78

Cordectomy Type 0.40 0.06 0.45 0.16 0.12

Lesion Appearance

Videostroboscopy

Surface 0.50 0.96 0.57 0.92 0.70

Border Type — — — — —

Erythema — — — — —

Intraoperative Imaging

Surface 0.85 0.31 0.87 — 0.48

Growth Type (TVF) 0.45 0.17 0.90 0.50 0.68

Border Type 0.78 0.97 0.28 0.55 0.59

P-values for all predictors that met inter- and intrarater reliability cut-offs. Results were not statistically significant (a ¼ 0.05). 0Disease Free Inter-val in the first year after surgery, — p value not able to be calculated dueto insufficient n in each group.

DFI ¼ Disease Free Interval.

TABLE V.R2 values for Continuous Predictors and Outcomes.

0DFI

Postoperative Voice Quality


Histology

Dysplasia/Cancer Scale 0.09 0.06 0.03 < 0.01 —

Stromal ChronicInflammation

*0.38 0.09 — 0.13 —

Cordectomy Type 0.14 0.20 0.06 *0.33 *0.39

Preoperative Voice Quality

Overall 0.18 *0.93 0.09 *0.80 —

Roughness <0.01 *0.82 — — —

Strain — *0.50 0.05 *0.76 *0.74

Pitch 0.12 *0.37 0.11 *0.79 *0.92

R2 values for continuous predictors that met inter- and intrarater reli-ability cut-offs. 0Disease Free Interval in the first year after surgery, — n <7 or p value not able to be calculated due to insufficient n in each group,*R2 value � 0.33.

DFI ¼ Disease Free Interval.

TABLE VI.Cordectomy Type vs. Preoperative Voice Quality.


R2 value *0.42 *0.68 *0.47 0.19

P value 0.34 0.19 0.09 0.30

More extensive cordectomy procedures correlated with increasingpreoperative voice dysfunction. Results were not statistically significant(a ¼ 0.05).

*R2 value > 0.33.

Fig. 1. Increased stromal chronic inflammation correlates withincreased disease free interval in the first year following surgery.Results are not statistically significant (ANOVA, a < 0.05, n ¼ 9).[Color figure can be viewed in the online issue, which is availableat wileyonlinelibrary.com.]


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be significant. Second we had low inter- and intraraterreliability on many of our measures. This was surprisinggiven that these measures were evaluated by two fellow-ship-trained laryngologists who have worked with eachother in daily contact for over 3 years. We were able toobtain moderate interrater reliability with regard togross lesion appearance parameters for surface location(dorsolateral or medial) and border type rated on eitherpreoperative stroboscopic light examination or intraoper-ative imaging, erythema rated on only stroboscopicexamination, and growth type rated on only intraopera-

tive imaging. Other parameters such as anteriorcommissure involvement did not have significant reli-ability. With regard to preoperative stroboscopicevaluation, despite using commonly evaluated parame-ters such as mucosal wave, vertical phase, and glotticclosure and a simple three-point scale for grading, all ofthe vibratory parameters had either poor intrarater reli-ability, poor interrater reliability, or both. When ourraters did not agree on the evaluation scale, the individ-ual data point could not be used to determine correlationor statistical significant. This further reduced our

Fig. 2. Cordectomy types correlates with both postoperative voice quality parameters, a) pitch (n ¼ 11) and b) strain (n ¼ 12), and preoper-ative voice quality parameters, c) overall quality (n ¼ 8), d) strain (n ¼ 11), and e) roughness (n ¼ 7) with R2 � 0.33. These results are notstatistically significant (ANOVA, a ¼ 0.05)


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sample size. The clinical measures with the acceptableinter- and intrarater reliability as determined by our apriori analysis plan included vocal cord surface involve-ment, lesion border definition, erythema (assessed onlyby stroboscopy), and growth type on the true vocal fold(assessed only by intraoperative imaging).

With regard to clinical voice parameters as judgedby trained speech language pathologists, we found thatpreoperative voice dysfunction correlated with post-operative voice outcome and cordectomy type. Thisimplies that patients who present with significant vocaldysfunction will likely need an extended cordectomy.Additionally we found that preoperative voice qualityparameters tend to correlate with multiple postoperativevoice parameters, most likely because multiple voicequality measures tend to present together in similarranges of dysfunction. As a result, patients might bescreened by assessment of a single voice parameter, suchas overall dysfunction or pitch, instead of the full set ofparameters evaluated in this study. In general, meas-ures of voice dysfunction had good interrater reliabilityfor all parameters and poor intrarater reliability for onlybreathiness and loudness. This is most likely secondaryto the recording of the examinations which were done atinconsistent mouth to microphone distances and underpoor ambient noise control. The voice parameters with

acceptable inter- and intrarater reliability included over-all quality, roughness, strain, and pitch.

With regard to histologic parameters, we found thatincreased stromal chronic inflammation scores correlatedwith longer disease-free interval after endoscopic resec-tion. We adopted a histologic grading system similar tothat published by Bryne et al.7 for early glottic cancerstreated with radiation therapy and found that one histo-logic predictor of disease outcome was similar in ourstudy. Specifically, increased stromal chronic inflamma-tion, measured by lymphocytic infiltration in this study,and increased host response, defined as leukocyte infil-tration in the Bryne article7, correlated with improvedlocal control. While the positive correlation existed, thisresult was not statistically significant. It should be notedthat the parameters graded in the Bryne article are notroutinely assessed by pathologists evaluating such sam-ples. Pathologists would need to be educated regardingthe grading system and utility of making this assess-ment. Additionally, of all the parameters measured onlythe dysplasia/cancer scale and stromal chronic inflam-mation had good interrater reliability as judged bytrained pathologists. All other histological parametershad poor interrater reliability. The histological parameterswith acceptable inter- and intrarater reliability includeddysplasia/cancer scale and stromal chronic inflammation.

Fig. 3. Preoperative voice parameters, a) overall quality (n ¼ 7), b) strain (n ¼ 10), and c) pitch (n ¼ 9), correlate with their correspondingpostoperative voice parameters (R2 � 0.33).


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CONCLUSIONSDue to the increasing application of transoral resec-

tion for early laryngeal cancers, understanding clinicaland disease factors that are associated with increaseddisease-free survival could provide significant advancesin treatment for patients. In this pilot study weattempted to develop a reproducible method for assess-ment of clinical and histological features to predictoutcomes in patients with glottic dysplasia and earlyglottic cancer. First we found that many of our measureschosen from our routine clinical practice patterns didnot exhibit adequate inter- and intrarater reliability.Clinical measures of lesion appearance that were reli-able included our rating of the vocal fold surfaceinvolved, the definition of the border of the lesion, thepresence of erythema assessed on stroboscopic lightsource, and the exophytic or endophytic nature of thelesion as assessed by methods of direct visualization.Again, while these measures of clinical lesion appear-ance showed good rater reliability, they did not correlatewith disease-free interval or post-treatment morbidity.Clinical assessment of preoperative voice dysfunctioncorrelated with postoperative voice dysfunction and thetype of cordectomy necessary to excise the lesion. Clini-cal voice measures of overall quality, roughness, pitchand strain, as rated by trained speech-language patholo-gists were reliable. Finally, increased inflammation onhistologic evaluation correlated with increased diseas-

free interval. While the dysplasia/cancer scale was a reli-able measure, it did not correlate with disease-freeinterval. These findings were not statistically significantmost likely secondary to our small size and difficultywith reliability of our measures.

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clinical and histologic predictors of voice and disease outcome in patients with early glottic...

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