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ORIGINAL ARTICLE

EFFECTIVENESS OF NARROW BAND IMAGING IN PATIENTSWITH ORAL SQUAMOUS CELL CARCINOMA AFTERTREATMENT

Pen-Yuan Chu, MD, Tung-Lung Tsai, MD, Shyh-Kuan Tai, MD, Shyue-Yih Chang, MD

Department of Otolaryngology, Taipei Veterans General Hospital, and National Yang-Ming University,Taipei, Taiwan. E-mail: [email protected]

Accepted 26 October 2010Published online 14 February 2011 in Wiley Online Library (wileyonlinelibrary.com). DOI: 10.1002/hed.21704

Abstract: Background. We evaluated the effectiveness of

narrow band imaging (NBI) in patients with oral squamous cell

carcinoma (OSCC) after treatment.

Methods. In all, 101 consecutive OSCC patients underwent

NBI examination for posttreatment follow-up. Four patients had

local recurrence. Twenty-six second primary malignancies were

found in 18 patients; 6 patients (33%) had more than 1 lesion.

Seventeen lesions (65%) were carcinoma in situ or severe dys-

plasia. Most of them occurred in the oral cavity (77%).

Results. A higher incidence (18% vs 9%, p ¼ .037) and

less-advanced stage (4% vs 37%, p ¼ .0005) of second

primary malignancies were found among the NBI group com-

pared with a previous cohort without NBI examination, and

fewer patients needed postoperative adjuvant therapy (12% vs

50%, p ¼ .0005).

Conclusions. NBI is an effective method to identify early

lesions in the head and neck area, especially the oral cavity,

among patients with OSCC after treatment. VVC 2011 Wiley

Periodicals, Inc. Head Neck 34: 155–161, 2012

Keywords: narrow band imaging; oral cavity; squamous cell

carcinoma

Oral squamous cell carcinoma (OSCC) is the fifthmost common cancer in the world.1 More than 90% ofthe patients with OSCC have a history of tobacco andalcohol consumption. Therefore, there is a high risk ofdeveloping second primary malignancy in the mucousmembranes of the aerodigestive tract.2

In Taiwan, OSCC is the fourth most common cancerand the most common cancer among men between 30and 49 years of age.3 In addition to tobacco and alcoholexposure, betel quid chewing is another common risk fac-tor. An epidemiologic study has computed the incidenceof OSCC to be 123-fold higher in patients who smoked,drank alcohol, and chewed betel quid than inabstainers.4

Although the locoregional control of head and necksquamous cell carcinoma (HNSCC) has improved inthe past decades, only minimal improvement in sur-vival has been achieved because of the development ofdistant metastasis and second primary malignan-cies.5,6 In early-stage cancer, second primary malig-nancy is still the main cause of treatment failure.Therefore, prevention and early diagnosis of secondprimary malignancy has become essential to improv-ing survival after treatment.

Narrow band imaging (NBI) is a novel techniquethat has been proven effective in detecting earlymalignancies in the gastrointestinal (GI) tract.7–9 It isalso useful for identifying early lesions in the orophar-ynx and hypopharynx.10–12 However, very littleresearch has focused on the oral cavity.13

The purpose of this study was to present our expe-rience with the application of NBI among patientswith OSCC after treatment and to evaluate its effec-tiveness for early detection of oral lesions.

MATERIALS AND METHODS

Between September 2008 and August 2009, 101 con-secutive patients with OSCC who had been treatedsurgically with or without postoperative adjuvanttherapy for >3 months were included in this study.The study was conducted in accord with the princi-ples stated in the Declaration of Helsinki (1964), andits design was approved by the hospital InstitutionalReview Board.

The NBI system is equipped with a rhinolaryngovi-deoscope (ENF-V2), light source (CLV-160B), and videosystem center (CV-160B) from Olympus Medical Sys-tems (Tokyo, Japan). The optical filter for NBI isinserted into the optical axis of the light source whenthe observation mode is NBI. A button on the controlsection of the scope allows switching between the con-ventional view and the NBI view.

During outpatient follow-up, a complete head andneck examination was performed first, and then theNBI examination was performed. The patient wasseated in the ear/nose/throat examination chair.

Correspondence to: P.-Y. ChuContract grant sponsor: Taipei Veterans General Hospital; contractgrant number: V96C1-068; contract grant sponsor: National ScienceCouncil, Taiwan; contract grant number: 97-2314-B-075-024-MY3.VVC 2011 Wiley Periodicals, Inc.

Narrow Band Imaging in Patients with OSCC after Treatment HEAD & NECK—DOI 10.1002/hed February 2012 155

Topical anesthesia with 4% xylocaine was sprayedinto the nose and oral cavity. Before introducing thescope, the patient was asked to drink a small cup ofwater to wash away saliva throughout the oral cavityand pharynx. The sequence of tissues examined inthe oral cavity was as follows: from the left buccalmucosa, retromolar trigone, anterior tonsillar pillar,hard and soft palate, to the upper and lower gingiva;and then the sequence was repeated on the rightside. The scope was then moved to the oral tongueand floor of the mouth. The oral tongue was directedupward, right, and then left to examine the ventraltongue and floor of the mouth. The scope was thenintroduced through the nasal floor, nasopharynx, oro-pharynx, hypopharynx, and larynx. During examina-tion, the white light and NBI light were exchangedalternatively. The patient was asked to swallow if sa-liva was pooling over the pyriform sinus, which wasnoted to improve the examination view. The criteriafor diagnosing a cancerous lesion with conventionalwhite-light endoscopic imaging included the presenceof demarcated red lesions, white lesions, elevatedlesions, and ulcerative lesions. The criterion for classi-fying a lesion as malignant using the NBI system wasthe presence of a well-demarcated brownish area withthick dark spots and/or winding vessels. The secondprimary malignancy was defined by the criteria ofWarren and Gates14 and modified by Hong et al,15

including when both tumors were malignant withhistological confirmation; the 2 tumors were requiredto be geographically distinct (at least 2 cm of normalmucosa between them) or separated in time for �3years. Otherwise, it was classified as a local recur-rence. If any suspicious lesion >5 mm was found, bi-opsy and excision were then performed.

The results were compared with those of a cohortof patients with oral cancer treated in our hospitaland followed up without NBI examination.16 The sta-tistical analysis was performed using commerciallyavailable computer software (JMP 4.0; SAS InstituteInc., Cary, NC). Nonparametric qualitative and quan-titative comparisons were performed using Pearson’schi-square or Fisher’s exact test. A value of p < .05was considered statistically significant.

RESULTS

Characteristics of the 101 patients are shown in Table1. Most patients had a history of exposure to carcino-gens, including tobacco consumption, alcohol con-sumption, and betel quid chewing. Most of theprimary tumors were located in the oral tongue, andthe buccal mucosa was the next most common site. Inaccord with the American Joint Committee on Cancer(AJCC) 2002 classification, most patients had classifi-cations of T1 and T2, most patients did not have cer-vical lymph node metastasis, and most had TNMstage I and stage II disease. All of the patients under-went surgical treatment, and 28 patients (28%) had

postoperative radiotherapy or concurrent chemoradia-tion therapy. The time interval between finishing thetreatment and NBI examination ranged from 3 to 176months, with a median of 30 months.

The entire NBI examination could be completedwithin 3 minutes. None of the patients had complica-tions after examination. The findings of the NBIexaminations are summarized in Table 2. Twenty-twopatients (22%) had positive findings, including secondprimary malignancy (squamous cell carcinoma, carci-noma in situ, and severe dysplasia), or localrecurrence.

Among the 18 patients with second primarymalignancy, a total of 26 lesions were found. The sitesof the second primary malignancy included the oralcavity, the oropharynx, the hypopharynx, and the lar-ynx. The lesions detected by NBI are shown in Fig-ures 1, 2, and 3. Six of them were difficult to identifyby direct vision or conventional endoscopy. All of thepatients received peroral excision or transoral lasermicrosurgery. The pathologic examinations showedthe lesions included severe dysplasia, carcinoma insitu, and squamous cell carcinoma. Only 3 patientshad postoperative radiotherapy because of a positivedeep margin in 1 and cervical lymph node metastasis

Table 1. Demographic data of the patients.

Factor No. (%)

Age, y

Range 36–85

Median 52

Sex

Male 92 (91)

Female 9 (9)

Tobacco consumption

Yes 71 (70)

No 30 (30)

Alcohol consumption

Yes 36 (36)

No 75 (75)

Betel quid chewing

Yes 55 (54)

No 46 (46)

Sites of primary tumor

Oral tongue 51 (50)

Buccal mucosa 32 (31)

Mouth floor 7 (7)

Retromolar trigone 4 (4)

Hard palate 4 (4)

Low gingival 2 (2)

Lip 1 (1)

Pathologic T classification

T1 þ T2 73 (72)

T3 þ T4 28 (28)

Pathologic N classification

N0 76 (75)

Nþ 25 (25)

Pathologic TNM stage

Stages I þ II 60 (60)

Stages III þ IV 41 (40)

Treatment

Surgery alone 73 (72)

Surgery þ adjuvant therapy 28 (28)

156 Narrow Band Imaging in Patients with OSCC after Treatment HEAD & NECK—DOI 10.1002/hed February 2012

in 2. Two of the 3 patients were alive without diseaseafter salvage treatment. The 4 cases of local recur-rence occurred in the oral tongue, the mouth floor,the hard palate, and the tongue base, as presented indetail in Table 2. Two of 3 cases of recurrence in theoral cavity were difficult to find without NBI exami-nation. Both patients were still alive without diseaseafter salvage surgery and postoperative chemoradia-tion therapy.

Of the 101 patients, 1 patient had a false negativebecause of a hyperkeratotic lesion with underlying ma-lignant change and 2 patients had a false positivebecause of chronic inflammation of dental irritation inthe NBI examination. Eight patients had false nega-tives in the conventional endoscopic examination,including 6 second primary malignancies and 2 localrecurrences. The sensitivity, specificity, positive predic-tive value, negative predictive value, and accuracy fordetecting malignancy by NBI were 95%, 97%, 91%,99%, and 97%. In contract, those by white light were64%, 96%, 82%, 90%, and 89%.

The results of a comparison of the patient character-istics and incidence and stage of second primary malig-nancy between the between patients with NBIexamination and those from a previous cohort who didnot undergo follow-up NBI examination are shown in Ta-ble 3. The patient characteristics were similar betweenthese 2 groups, including sex, age, carcinogen exposure,treatment, and pathologic TNM classification. Only thesubsites of the primary tumors were different. Half of thepatients in the NBI group had tongue cancer, whereasthe patients in the previous cohort all had tongue cancer.Although there was no statistically significant differencein the overall incidence of second primary malignancybetween the 2 groups, the incidence detected in the head

and neck area was higher in the NBI group than that inthe previous cohort (18% vs 9%, p ¼ .037). The stage ofsecond primary malignancy was also significantly differ-ent between these 2 groups. Most of the second primarymalignancies were early-stage lesions (96%) in the NBIgroup compared with only 63% in the previous cohort (p¼ .0005). The number of patients who needed toundergo adjuvant radiotherapy or chemoradiation ther-apy after salvage surgery was also significantly higheramong the previous cohort than that among the NBIgroup (50% vs 12%, p ¼ .0005).

Table 2. Results of NBI examination (n ¼ 101).

Factor All SPM LR

Positive exam 22 18 4

Total number of positive exam 30 26 4

Number of positive sites

One 16 12 4

Two 4 4 0

Three 2 2 0

Sites of positive legion

Oral cavity 23 20 3

Oropharynx 4 3 1

Hypopharynx 2 2 0

Larynx 1 1 0

Pathology

Severe dysplasia 13 13 0

Carcinoma in situ 4 4 0

Squamous cell carcinoma 13 9 4

Pathologic T classification

Tis 4 4 0

T1 8 7 1

T2 2 1 1

T3 1 0 1

T4 2 1 1

Abbreviations: NBI, narrow band imaging; SPM, second primary malignancy; LR,local recurrence.

FIGURE 1. Squamous cell carcinoma of oral tongue. (A)

Conventional endoscopic view. (B) NBI endoscopic view. [Color

figure can be viewed in the online issue, which is available at

wileyonlinelibrary.com.]


DISCUSSION

In our study, NBI was proven to be an effective toolto detect early precancerous or cancerous lesions inthe oral cavity of patients with OSCC after surgery.Seventy-seven percent of the second primary malig-nancies (20/26) occurred in the oral cavity in thisstudy. When the rate of detection was compared withthat among patients in a previous cohort who did notreceive NBI examinations, NBI diagnosed more sec-ond primary malignancies in the head and neck area.Among the NBI group, one third of the patientshad >1 second primary malignancies and two thirdsof the patients were diagnosed with severe dysplasia

or carcinoma in situ. It is valuable to detect theselesions in the preinvasive stage, in which there is alow incidence of cervical lymph node metastasis.Because most of the cases of second primary malig-nancies were diagnosed at an early stage among thepatients in the NBI group, fewer of them needed radi-cal surgery and postoperative adjuvant therapy. It isstill too early to tell whether the early diagnosis ofsecond primary malignancy with NBI will increasesurvival, but we are certain that the functional out-comes will improve if second primary malignancy isdiagnosed early.

FIGURE 2. Squamous cell carcinoma in situ of hard palate. (A)

Conventional endoscopic view. (B) NBI endoscopic view. [Color

figure can be viewed in the online issue, which is available at


FIGURE 3. Severe dysplasia of floor of mouth. (A) Conventional

endoscopic view. (B) NBI endoscopic view. [Color figure can

be viewed in the online issue, which is available at



The occurrence of second primary malignancy is acrucial problem in treating patients with HNSCC. Thereported incidence of second primary malignancy inHNSCC is around 10% to 40%, with a 4% to 6% an-nual rate of development.5,17–19 The presence of secondprimary malignancy has been reported to have a nega-tive impact on long-term survival.5,20,21

Unlike other regions in which tobacco and alcoholare primary contributors to the development ofOSCC, betel quid chewing is an important etiologycausing OSCC in Taiwan. The synergistic effects ofalcohol, tobacco, and betel quid in OSCC have beenclearly demonstrated, as has a significant associationbetween OSCC and betel quid chewing alone.4 Inaddition to increasing the incidence of OSCC, devel-opment of second primary malignancy after treatmentalso increased significantly in patients with betel quidchewing compared with those without (20.8% vs11.7%, p ¼ .0123).22

Because second primary malignancy is a majorcause of morbidity and mortality among patients withHNSCC after treatment, identifying ways to reducethe incidence of second primary malignancy hasbecome the main goal of head and neck oncologists.

Animal and clinical studies have shown that treat-ment with retinoids is effective in reversing premalig-nant lesions of oral cancer.23,24 A preliminary study ofchemoprevention with high-dose isotretinoin alsodemonstrated an encouraging result by decreasingthe incidence of second primary malignancy.15 How-ever, isotretinoin has high toxicity, and most of thepatients required a dose reduction for long-term use.A recently published randomized phase III trial oflow-dose isotretinoin for prevention of second primarymalignancy in stage I and stage II HNSCC showedthe disappointing result that low-dose isotretinoinwas not effective in reducing the rate of developmentof second primary malignancy.25 Therefore, at pres-ent, regular follow-up for early diagnosis and treat-ment is still the best way to manage the secondprimary malignancy in patients with HNSCC.

Most oncologists agree that follow-up evaluationsaid in early diagnosis of locoregional recurrences, dis-tant metastasis, and second primary malignancy. Themain theory supporting follow-up after treatment isthat early lesions that are identified promptly can betreated easily and often with curative intent.26 Inresponse to a survey,27 most head and neck surgeonsused directed history, physical examination at regularintervals, and annual chest radiographs for posttreat-ment follow-up. Some authors have recommendedroutine triple endoscopy to detect early second pri-mary malignancy28,29; however, there is still a diver-sity of opinions regarding the usefulness of searchingfor second primary malignancy.30 In our experience,patients with OSCC still have a high incidence ofdeveloping second primary malignancy after surgicaltreatment.16 Because of the submucosal fibrosis afterlong-term betel quid chewing, most of these patientshave different degrees of trismus after treatment.Sometimes, it is difficult for the patient or primaryphysician to examine the oral cavity. Once a patienthas symptoms of tumor recurrence or second primarymalignancy, it is usually already at an advancedstage, which makes salvage treatment more difficult.Therefore, routine endoscopic examination is recom-mended in our clinical practice for patients withOSCC after treatment.

NBI is a novel optical technique that can visualizethe microvascular structures of the superficial mu-cosa.31 This technique has been proven more effectivethan traditional endoscopy in the detection of high-grade dysplasia and early cancer in various anatomicregions, such as the esophagus, stomach, and colo-rectal region.7–9 Muto et al12 first used an NBI GI en-doscopy system for screening lesions in the oropharynxand hypopharynx in patients with esophageal cancer.Watanabe et al11 further investigated the efficiency ofan NBI rhinolaryngoscopy system in screening the oro-pharynx and hypopharynx in patients with esophagealcancer. These studies had shown the effectiveness ofNBI for the diagnosis of early lesions in the orophar-ynx and hypopharynx.10–12

Table 3. Comparison of the incidence and classification of second

primary malignancy in patients with or without NBI examination.

Factor

NBI examination

p value

Yes

(n ¼ 101)

No

(n ¼ 146)

Median age, y 52 51 .800

Sex

Male 92 (91%) 121 (83%) .065

Female 9 (9%) 25 (17%)

Tumor subsites

Oral tongue 51 (50%) 146 (100%) <.0001

Others 50 (50%) 0 (0%)

Carcinogen exposure 80 (79%) 111 (76%) .557

Treatment of primary tumor

Surgery alone 75 (72%) 118 (81%) .114

Surgery þ RT or CCRT 28 (28%) 28 (19%)

Pathologic primary T classification

T1 þ T2 73 (72%) 117 (80%) .149

T3 þ T4 28 (28%) 29 (20%)

Pathologic primary N classification

N0 76 (75%) 112 (77%) .790

Nþ 25 (25%) 34 (23%)

Pathologic primary TNM stage

Stage I þ Stage II 60 (59%) 101 (69%) .113

Stage III þ Stage IV 41 (41%) 45 (31%)

Time of median follow-up, mo 30 48 .003

Incidence of SPM 18 (18%) 18 (12%) .229

SPM in head and neck area 18 (18%) 13 (9%) .037

SPM in head and neck

area, total number

26 (26%) 16 (11%) .002

Stage of SPM

Precancer 13 (50%) 0 (0%) .0005

Tis þ T1 þ T2 12 (46%) 10 (63%)

T3 þ T4 1 (4%) 6 (38%)

Adjuvant therapy 3 (12%) 8 (50%) .0005

Abbreviations: NBI, narrow band imaging; RT, radiotherapy; CCRT, chemoradiationtherapy; SPM, second primary malignancy.


Although NBI GI endoscopy or rhinolaryngoscopysystems are essential examinations for diagnosingpharyngeal, esophageal, and gastroesophageallesions, the oral cavity is not meticulously evaluatedduring examination unless the tumor is quite obvious.To our knowledge, this study is the first to evaluatethe effectiveness of NBI in conducting endoscopicscreening in the oral cavity.

Although NBI is an effective method for earlydetection of second primary malignancy in the headand neck area, this technique still has some limita-tions when used in the oral cavity. It is difficult todiagnose hyperkeratotic lesions, which may have

underlying malignant changes. The malignant cellsmay hide below the lesion and appear benign. Chronicinflammation arising from dental irritation or postop-erative radiation may result in a false-positive finding.Coloration or staining of the oral mucosa from betelquit chewing (see Figure 4) or other food materialsmay also interfere with the diagnostic judgment. It isalso difficult to early diagnose the tumors arising fromtongue base or recurrence after previous surgicaltreatment. This can explain why 5 of the 13 malignantlesions were classified as T2 or greater in our study.However, we still think NBI is a powerful toolto detect early lesions in the oral cavity. Routine fol-low-up within a 6-month interval is recommended.

In conclusion, NBI is an effective method of iden-tifying early lesions in the head and neck area, espe-cially the oral cavity, in patients with OSCC aftertreatment. Routine follow-up with NBI is recom-mended for such patients.

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FIGURE 4. Color stain (betel quid) in the oral mucosa may

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(B) NBI endoscopic view. [Color figure can be viewed in the

online issue, which is available at wileyonlinelibrary.com.]


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