NBI utility in the pre-operative and intra-operative assessment of oral cavity and oropharyngeal carcinoma

Abstract

Purpose

Despite advances in the surgical management of head and neck squamous cell carcinoma, the identification of synchronous lesions, precancerous lesions around the main tumor, or the unknown primary in the case of neck metastasis remains a problem, as these lesions may be invisible to the naked eye or with standard white light (WL) endoscopy. However, the advent of tools such as narrow-band imaging (NBI) could help the clinician. The purpose of this study was to assess the impact of NBI during the pre-operative and intra-operative stages of management of oral and oropharyngeal cancers.

Materials and methods

NBI was used pre-operatively in 47 patients with oral or oropharyngeal squamous cell carcinoma to identify the involvement of adjacent subsites, multifocality, synchronous lesions or an unknown primary. NBI was used intra-operatively in 30 patients to better define the tumor limits and guide the resection. The advantage of NBI versus WL endoscopy was analyzed by calculating the true and false positive rate pre-operatively, and the need for resection enlargements, histology of the enlargement, and the rate of clear margins at definitive histology, intra-operatively.

Results

Pre-operatively, the diagnostic gain of NBI was 8.5%, allowing identification of three synchronous tumors and one unknown primary. Intra-operatively, NBI improved the definition of tumor limits in 67.7% of cases, with resection enlargements showing dysplasia and carcinoma in 8 and 12 patients, respectively; we obtained 74.2% negative margins at histology.

Conclusions

NBI could represent an added value in the pre-operative and intra-operative assessment of oral cavity and oropharyngeal carcinoma.

1 Introduction

Head and neck cancers are the sixth most common cancer worldwide, with squamous cell carcinoma (SCC) representing the vast majority . Their incidence is also high in Italy, with 4500 new cases diagnosed each year and 3000 deaths . Smoking and drinking alcohol are well-known risk factors for the development of these cancers ; extended areas of oral and oropharyngeal mucosa are exposed to their carcinogenic effect, which explains the possible development of multifocal primary cancers according to the “field cancerization” phenomenon proposed by Slaugher et al. .

The prevalence of a second SCC in cadaver dissection studies ranges between 3.7% and 15.5%, while panendoscopy studies have shown the prevalence of synchronous primary SCC to range from 1.4% to 17% . An early diagnosis is essential for guaranteeing a radical resection with minimal morbidity, but it could prove difficult because radiologic examinations such as computed tomography (CT) and magnetic resonance imaging (MRI) are able to detect only larger lesions . A late diagnosis may therefore account for the lack of improvement in survival rates over the past 30 years despite advances in the treatment of these tumors .

Another problem is the presence of cervical node metastases from unknown primary tumors; though rare, this event represents a major challenge in head and neck oncology ; if these lesions are superficial SCC, they may be difficult to identify using CT, MRI, or even fluorodeoxyglucose-positron emission tomography/CT (FDG-PET/CT) given the limited resolution of the technique and the insufficient FDG uptake by superficial SCC .

Moreover, according to the concept of “field cancerization” , multiple, unrelated, precancerous lesions may exist adjacent to the original tumor mass, each one bearing the potential to develop a new tumor. Their identification and removal with the main tumor mass during the first surgical treatment could help to obtain clear surgical margins at histology; this is essential because the presence of dysplasia or carcinoma following resection of head and neck cancers has been shown to be associated with a higher incidence of local recurrence .

Endoscopy is still considered to have a pivotal role in the evaluation of head and neck cancer, and the surgeon is required to perform it correctly . However, conventional white light (WL) endoscopy, irrespective of the endoscopist’s experience, may overlook superficial mucosal cancers and precancerous lesions because of the limited resolution and contrast .

In the light of the problems outlined above, the use of new technologies to help in the identification of early mucosal changes is therefore crucial.

Narrow-band imaging (NBI), first introduced for the early detection of gastrointestinal tumors, has also demonstrated its value in the early identification of SCC of the head and neck region . The NBI system is an advanced optical image enhancement technology that magnifies mucosal surface patterns and vessels by employing the characteristics of light spectrum . The wavelength of light determines its depth of penetration , thus NBI uses an optical filter that allows for the passage of only two specific wavelengths (415 nm and 540 nm) highlighting the capillary bed and intrapapillary capillary loop (IPCL) pattern in the superficial mucosa and the thicker blood vessels in the deeper mucosa and submucosa. Observing the mucosal microvascular architecture and its changes can help to determine the nature of the lesions .

The purpose of this study was to evaluate the impact of NBI in oral and oropharyngeal tumor assessment during the pre-operative and intra-operative stages of management, with particular attention paid to its ability to identify synchronous lesions and unknown primaries and to better define the surgical resection margins.

2 Materials and methods

This prospective, nonrandomized, unblinded study was conducted at the ENT Department of Trieste in accordance with the principles stated in the Declaration of Helsinki (1964), and its design was approved by the University of Trieste Review Board.

2.1 NBI in pre-operative assessment

Between June 2013 and June 2015, NBI was used during the pre-operative assessment of oral and oropharyngeal cancers. Patients were selected according to the following inclusion criteria: patients aged between 18 and 90, with a biopsy-proven oral squamous cell carcinoma (OSCC) or oropharyngeal squamous cell carcinoma (OPSCC) or with the presence of a neck metastasis from an unknown SCC primary, undergoing a pre-treatment endoscopic evaluation with WL and NBI. Patients who had undergone oral or oropharyngeal surgery or radiotherapy were excluded, as these areas can appear falsely positive on NBI in the early stage of the learning curve . A total of 47 patients (28 males, 19 females, mean age 69 years, range 44–89) were enrolled.

Patients were evaluated using a Visera Elite system OTV-S190 videoprocessor and CLV-S190 light source, CH-S190-XZ high definition television (HDTV) camera, OEV261H 26″ LCD HD monitor (Olympus Medical Systems Corp, Tokyo, Japan) with rigid endoscopes with a viewing angle of 0° for the oral cavity and 70° for the oropharynx. Patients were assessed for the presence of synchronous lesions such as different grades of dysplasia or carcinoma or an unknown primary tumor, thus all of the oral and oropharyngeal subsites were analyzed.

Topical anesthesia with lidocaine spray 10 g/100 ml was used only if necessary to reduce patient discomfort. If mobile dental prostheses were present, the patient was asked to remove them during the examination. Each examination was carried out as follows: right buccal mucosa, retromolar superior and inferior trigones, upper and lower gingiva; the sequence was repeated on the left side; then, the anterior and posterior tonsillar pillar, tonsils, lateral and posterior pharyngeal walls were visualized bilaterally. The scope was then moved to the oral tongue and floor of the mouth. The oral tongue was directed upward, to the left, and then to the right to examine the ventral tongue, the floor of the mouth and the tongue margins. Finally the hard and soft palate were evaluated. The complete examination took an average of 10 min.

During the examination, the system was switched between WL and NBI light by pressing a button on the camera.

All NBI examinations were performed by two physicians experienced in the use of NBI. Photographs of all examinations were recorded and saved on a computer for further evaluation. Conventional WL examination was considered “positive” in the presence of persistent and demarcated red lesions, white lesions, elevated lesions, and ulcerative lesions. NBI was classified as “positive” in the presence of the known alterations of the intrapapillary capillary loop (IPCL), such as dilatation and crossing, elongation and meandering or pattern destruction and angiogenesis , or the presence of brown dots which can reflect histological changes. Histology was “positive” if it revealed the presence of different grades of dysplasia (mild, moderate or severe) or carcinoma (in situ or invasive); other histological responses, such as dyskeratosis or hyperplasia were considered “negative” at histology.

If more than one IPCL type was seen, the most advanced type detected was determined as the IPCL type of the lesion. If more than one histological alteration was present, the most advanced type detected was determined as the histology of the lesion.

If an NBI positive finding was revealed, an NBI-guided incisional biopsy was performed. NBI endoscopic evaluations were assessed in relation to the definitive histopathological report in order to calculate the number of true positive (TP) and false positive (FP) lesions. For NBI, a true positive lesion (TP) was defined as an area considered NBI-positive and with the presence of dysplasia or cancer at histology. A false positive lesion (FP) was defined as an area considered NBI-positive but which presented no histological alterations. True positive lesions were resected under general anesthesia.

The NBI ability to detect synchronous lesions such as different grades of dysplasia or carcinoma or an unknown primary tumor was analyzed; we then verified whether the positive lesions at histology had been detected with WL alone during the standard outpatient visits in order to calculate the diagnostic advantage of NBI.

Because ethical reasons prevented us from obtaining histological confirmation for patients without suspicious lesions on NBI, we were unable to calculate the number of true negative (TN) and false negative (FN) findings and consequently to evaluate the sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV) and accuracy of the technique.

2.2 NBI in intra-operative assessment

Between January 2014 and June 2015, NBI was used intra-operatively to identify the possible presence of suspicious areas beyond the resection line made by the surgeon based on clinical observation (i.e., visual and tactile examination) in order to better define the real superficial extension of the known primary tumor. Patients were selected according to the following inclusion criteria: age between 18 and 90, with a biopsy proven OSCC or OPSCC, undergoing a transoral surgical resection. Patients who had undergone oral or oropharyngeal surgery or radiotherapy were excluded, as these areas can appear falsely positive on NBI in the early stage of the learning curve . Thirty patients (18 males, 12 females, mean age 69 years, range 44–85) for a total of 31 tumors, (20 OSCC ad 11 OPSCC) were considered; all the surgical resections were performed by a single operator (G.T.).

As described in our previous pilot study , a few days before surgery two physicians experienced in the use of NBI carried out a preliminary evaluation focusing on the clinically negative areas around the tumor that had a suspicious appearance on NBI: this step served only the practical purpose of reducing the intra-operative time required for defining the resection margins.

On the day of surgery a first definition of the resection margins was obtained with an electric scalpel, using a ruler to help maintain a distance of 1.5 cm from the macroscopic lesion boundaries defined visually and by palpation. Then, NBI was used to assess the superficial extension of the lesion for the known IPCL alterations and for the presence of brown dots , which can reflect histological changes. This evaluation increased the operating time by an average of 5 min. The different steps were videorecorded. If the use of NBI revealed one or more positive areas not included within the previously drawn WL tattoo, these were outlined and included in the resection. The distance between the two templates was measured. After tumor resection, extemporaneous examinations of superficial and deep margins were performed; if they were positive for cancer or dysplasia (mild/moderate/severe) the resection was immediately enlarged, if they were negative, closure of the surgical defect was started. The resected specimen was fixed onto a piece of cork with insulin needles to minimize shrinkage ; sutures of different lengths were placed for correct orientation and to indicate the NBI-guided enlargement; an explanatory drawing with specific notes, was prepared for the pathologist. The specimen was then sent to a dedicated pathologist for histological evaluation. Our pathology department classifies margins as “clear” when >3 mm, “close” when 0.1–3 mm, and “involved” only when clearly infiltrated by neoplastic cells. In the case of close or positive margins, a margin-widening operation was planned or, if this was precluded by patient factors or particularly difficult anatomical sites, the patient was referred for adjuvant treatments.

In the intra-operative group, we recorded the need for a resection enlargement owing to the presence of NBI-positive areas around the first drawing, the histological findings on the enlargement areas, and the rate of negative margins at definitive histological examination.