Photodiagnosis and Photodynamic Therapy (2006) 3, 259—265
DAFE autofluorescence assessment of oral cavity, larynx and bronchus in head and neck cancer patients David Fielding FRACP, MD a,∗, Julie Agnew b, David Wright b, Robert Hodge b a
Department of Thoracic Medicine, Royal Brisbane and Women’s Hospital, Herston Rd., Herston 4029, Australia b Department of ENT Surgery, Royal Brisbane and Women’s Hospital, Herston Rd., Herston 4029, Australia Available online 28 August 2006 KEYWORDS Autofluorescence bronchoscopy; Lung cancer; Panendoscopy; Larynx cancer
∗
Summary Head and neck (H&N) cancer patients have a high incidence of local field change as well as second primary lung tumours. We have applied the Wolf Diagnostic Autofluorescence Endoscopy (DAFE) system in a novel way, combining autofluorescence evaluation of both H&N region and bronchial. New H&N cases as well as ‘‘old’’ cases with symptoms were included. The DAFE procedure was done separate to panendoscopy. The H&N region was examined first; images were recorded of the known primary with reference to subsequent resection margins, as well as of adjacent mucosa inspecting for additional abnormal sites. Then autofluorescence bronchoscopy was performed. Changes in management were only on the basis of histology taken because of abnormal autofluorescence. One hundred and seven cases were referred, including 96 new cases and 11 old cases. Autofluorescence examination of H&N detected sites which led to change of management in 11 patients. This included additional sites in nine patients (which then either had extra surgery or radiotherapy as a result) and wider resection margins were made possible in two patients. In the bronchus there were 21 significant lesions in 16 patients. Immediate management change occurred in one invasive cancer, two microinvasive carcinomas and three carcinomas in situ (in four patients). There were 15 sites of severe and moderate dysplasia in 12 patients. None of these bronchoscopic lesions were detectable on CT chest. Therefore, overall an immediate change in management occurred in 15 of 107 patients (14% of patients). This combined procedure yielded a significant number of lesions particularly as a simple addition to preoperative workup in new H&N cancer cases. © 2006 Elsevier B.V. All rights reserved.
Corresponding author. Tel.: +61 7 36367631; fax: +61 7 36365651. E-mail address: david fi[email protected] (D. Fielding).
1572-1000/$ — see front matter © 2006 Elsevier B.V. All rights reserved. doi:10.1016/j.pdpdt.2006.07.004
260
Introduction Tissue autofluorescence is an established mode of detecting preneoplasia and in situ carcinoma in mucosal surfaces [1,2]. The most common application of fluorescence detection is in the bronchial tree [3—6]. Patients with squamous carcinoma of the head and neck are well known to have high risk of synchronous and metachronous carcinomas in the lung and other areas of the upper aerodigestive tract [7—9]. For this reason patients are usually referred for pan-endoscopy prior to definitive treatment [10]. The upper aerodigestive tract is easily accessible to flexible and rigid optics used in autofluorescence diagnosis. Because of the common occurrence of field change disease in these regions, there is potential for fluorescence detection of additional significant lesions within the oral cavity, oropharynx and glottic regions. Fluorescence bronchoscopy has been used in head and neck patients but usually as surveillance rather than to detect synchronous primaries at the time of initial diagnosis [11]. The potential exists for the clinical application of using autofluorence to inspect the upper airway as well as the bronchial tree at panendoscopy. Tissue auto fluorescence has been investigated in the oral cavity as reported by Arens et al. [12], Svistun et al. [13], and Onizawa et al. [14]. In these studies known tumours were assessed for a fluorescence difference from the adjacent normal mucosa; there was correlation between increasing degrees of fluorescence abnormality and increasing degrees of epithelial malignancy. Arens showed lesions of the larynx to have diminished fluorescence using the filtered blue light (375—440 nm) of the Storz D Light system [12]. Generally specificity was high at 84% for high grade dysplasia and malignancy. Causes for false positive results were marked hyperkeratosis, scarring and inflammation, although generally these were an uncommon finding and did not limit the overall utility of the technique. Autofluorescence of freshly resected oral tissue has shown best specificity for discriminating malignant from benign tissue when incident light is 400 nm and observation is at 530 nm [14]. Despite this potential application, autofluorescence is not widely used to detect synchronous disease at panendososcopy in these patients, and has not been reported in terms of its ability to change management. Our study looked at clinical aspects of the potential application of autofluorescence at panendoscopy. Some data exists for the application of tissue fluorescence using the topical photosensitizer aminolaevulinic acid (ALA) in the oral cavity [15] however in this study we only used auto fluorescence. The aims were firstly to define margins
D. Fielding et al. of known or small localized primary tumours in the head and neck to assist with local excisions such as laser excision. Secondly we looked for additional sites of in situ carcinoma and dysplasia within these regions which might alter surgical management. Finally, as part of the same procedure autofluorescence bronchoscopy was performed with the usual aim of detecting preneoplastic and in situ lesions. We sought to determine whether the addition of fluorescence to standard work-up would have the potential to change management.
Methods Patients were selected for this procedure from a large multi-disciplinary Head and neck cancer clinic in a prospective fashion. Patients were either newly diagnosed with a head and neck cancer which was in the process of being worked up for a definitive local treatment including surgery or radiotherapy, or were in a follow-up phase having received prior curative treatment for a head and neck cancer. Patients had usually undergone biopsy to confirm the primary head and neck cancer under standard white light conditions. They were at the point of referral for pan endoscopy. Patients who had bulky tumours (T3 or T 4) were not included as the finding of additional small sites of tissue abnormality was thought unlikely to change management. All patients had chest X-ray and chest CT scan in addition to other CT scans in workup of the head and neck primary. Patients undergoing fluorescence bronchoscopy did not have radiological evidence of lung cancer. Procedures were performed in a bronchoscopy suite under standard conscious sedation. Local anaesthetic was applied to the oral cavity with mist spray of 2 ml 2% lignocaine. Auto fluorescence was performed using the Diagnostic Autofluorescence Endoscopy (DAFE) system (Wolf) [16]. This utilises a detachable camera for attachment to either a fiberoptic bronchoscope or a rigid optic. The camera receives the autofluorescence signal which is displayed in real time on the monitor, with red indicating neoplasia and green or light pink or white representing non malignant tissue. The camera also provides feedback to the light source such that overall light intensity is maintained; in more voluminous parts of the airway therefore greater light output from the light source occurs. Only additional sites of AF abnormality were acted upon, not the abnormal fluorescence of the known primary tumour. The procedures were performed in two parts; the first part was assessment of the floor of mouth, buccal mucosa, and tonsil regions in patients known to
DAFE autofluorescence assessment of oral cavity, larynx and bronchus in head and neck cancer Table 1
261
Site of new head and neck tumours
Site of head and neck primary
Number of cases
Larynx Supraglottis Floor of mouth, alveolus Oropharynx Unknown primary
36 12 22 17 9
Total
96
have tumours in these regions. This was done in a sitting position without administration of sedation. A rigid optic specific to the Wolf system was used in this location. Secondly with the patient supine the dedicated 4.5 mm diameter flexible fluorescence bronchoscope was used to inspect the oropharynx, supraglottis and glottis, then the bronchoscopy was performed in standard fashion. Where abnormalities were detected in the head and neck region digital video images were recorded so that at the time biopsy could be performed subsequently. Some of the oral cavity assessments were performed using a dedicated rigid 4 mm fluorescence optic (Wolf). Changes in management were considered only on the basis of biopsy histology taken as a result of abnormal tissue autofluorescence rather than the images themselves.
Results There were 96 new cases who had both head and neck fluorescence inspection, and 11 cases with prior definitive treatment of H&N carcinoma who had only fluorescence bronchoscopy. There were 90 males and 17 females with a mean age of 62 ± 9.1 years. Table 1 lists the site of the primary carcinoma in the newly diagnosed head and neck cancer patients. The mean time for a procedures including both head and neck and bronchus was 16 ± 6 min. There were no side-effects. Known primary sites clearly showed marked autofluorescence abnormalities (Fig. 1). The DAFE system provided excellent images even in more open parts of the oral cavity because of the camera automatically adjusting incident light intensity. DAFE detected significant sites in the H&N region which led to change of management in 11 patients. Additional sites were found in nine patients and wider resection margins were made possible in two patients. Table 2 lists the location of these sites. There were five cases of additional sites detected around the larynx. One of these cases was a 65-year-old man who had previously been diagnosed with a Right vocal cord squamous cell
Figure 1 White light (a) and fluorescence (b) image of a known squamous cell carcinoma of floor of mouth. The fluorescence image is bright and clear demarcation of normal and abnormal mucosa is possible. Note in the left of the fluorescence image a red fluorescence point due to salivary gland opening.
carcinoma. This patient had undergone two white light assessments by ENT surgeons prior to referral for the fluorescence procedure. The DAFE examination revealed an additional lesion on the Left false cord, approximately 3 mm in diameter (Fig. 2). Therefore, in the subsequent ENT procedure, this additional tumour was biopsied and frozen section revealed microinvasive squamous cell carcinoma. This was treated by laser excision along with the planned laser of the known of tumour on the right vocal cord. Another of these cases was a 70-year-old lady who had contralateral vocal
262 Table 2
D. Fielding et al. Sites of additional H&N tumour found with DAFE inspection of H&N region
Primary site
Additional disease
Number of patients
Histology of additional site
Larynx
Contralateral cord or supraglottis
5
Carcinoma (3) CIS (1) Severe dysplasia (1)
Pyriform fossa Floor of mouth Soft palate Unknown primary
Local field change Tongue base, alveolus Local field change Tongue base, tonsil
1 2 1 2
Carcinoma Severe dysplasia (2) Carcinoma Carcinoma (2)
cord carcinoma found by fluorescence which meant that radiotherapy was given rather than the previously planned surgery. Another case was a patient who had previously had laser excision on Left vocal cord who had a Right cord carcinoma identified by fluorescence amongst non specific post radiotherapy inflammation; this patient had laryngectomy. A fourth case had a biopsy proven carcinoma of
Figure 2 (a) White light appearance of larynx showing R cord tumour. (b) DAFE appearance showing the abnormal R cord as well as an additional lesion anteriorly on L false cord. Frozen section biopsy of this additional site showed in situ carcinoma; both sites were treated with laser excision.
right arytenoid after a standard white light H&N assessment. Subsequent fluorescence assessment showed widespread disease of contralateral supraglottic region; biopsies showed invasive carcinoma in these regions. Radiotherapy was therefore given instead of surgery which had been planned. In the
Figure 3 Case of unknown primary of head and neck. Subtle changes in R tonsil on white light (a) are clearly shown as abnormal on fluorescence image (b).
DAFE autofluorescence assessment of oral cavity, larynx and bronchus in head and neck cancer
263
tongue base and alveolus there were two cases where biopsies showed severe dysplasia. One case was therefore treated with radiotherapy rather than surgery due to contralateral disease. The second had an abnormal PET scan showing diffuse right alveolar disease, and fluorescence was able to localise this abnormality, clarifying the reasons for the PET change, and allowing an observation approach rather than repeat treatment to an area of local recurrence. Two cases of unknown primary disease had prior standard white light H&N examination (Fig. 3). In both cases fluorescence was readily able to identify the subsequent histological site
Figure 5 Example of moderate-severe dysplasia detected by fluorescence examination (b) after prior standard white light examination only showed the macroscopic R vocal cord tumour.
Figure 4 Squamous cell carcinoma in the right Pyriform fossa which was assessed prior to laser excision. The autofluorescence pictures demonstrate the margins to the approximately 2—3 mm greater than can be seen under standard white light conditions. This directed the laser excision to take a wider margin.
of tumour. Biopsies could be directed to these sites immediately. There were two cases where laser excision was to be performed (Fig. 4). The margins of the tumour were clearly seen to extend further away from the subtle white light abnormalities, allowing the surgeon to extend the resection margins further. In both cases resection margins were clear on final histology. Not included in this list is an example of moderate-severe dysplasia seen on the L vocal cord in a patient with histologically proven R vocal cord squamous cell carcinoma (Fig. 5). This patient was to receive radiotherapy as part of a clinical study and as such management was not altered. Had this patient been sent for laser resection this lesion would have required careful surveillance.
264
D. Fielding et al.
Table 3 Significant histology results of DAFE fluorescence bronchoscopic biopsies Histology
Number of lesions
Moderate—severe dysplasia Carcinoma in situ Micronvasive carcinoma Carcinoma
15 3 2 1
With respect to fluorescence bronchoscopy, in total from all patients there were 124 biopsies at an average of 1.2 ± 1.2 biopsies per patient. Table 3 lists the biopsies from fluorescence bronchoscopy which had moderate dysplasia or worse on histology; (the remaining histologies were mild dysplasia, metaplasia, inflammation or normal). In the bronchus there were 21 significant lesions in 16 patients. All were not detectable on CT chest. Four patients had six lesions showing carcinoma or carcinoma in situ. Of these four patients, all received radiotherapy either in combination with treatment of the new head and neck primary, or as sole treatment. In addition one of these four had endobronchial electrocautery to a contrateral carcinoma-in-situ lesion. The other 12 patients are having repeat DAFE biopsies of the known moderate to severe dysplasias, as are those with mild dysplasia at a longer interval. Therefore, overall an immediate change in management occurred in 15 patients (14% of cases) with a further 12 cases still under review. The best sites for H&N fluorescence assessment were the floor of mouth, epiglottis, larynx and false cord regions, and pyriform fossae. False positive biopsies were obtained in five cases where fluorescence was positive but biopsies showed no malignancy. These were in the base of tongue region, and the tonsils, presumably due to strong fluorescence changes in lymphoid tissue in these regions. As listed in Table 2 fluorescence could provide useful information from these sites where there was a clear difference in fluorescence signal when comparing the two sides; that is there was a clear change compared to the background signal. One other artefact of note was the salivary gland openings in the floor of mouth. Fig. 1 shows an example of the bright fluorescence as obtained from these ducts. On occasion only the opening of the duct was seen on tissue auto fluorescence whereas in other cases the length of the duct traversing the flora of mouth could be seen. The surface of the tongue generally fluoresced very strongly and evaluation of tongue tumour margins was difficult. This was presumably due to an abundance of fluophores
in the actively dividing cells on the tongue surface mucosa.
Discussion We have demonstrated that autofluorescence can be simply used in the oral cavity and larynx to change management in head and neck cancer patients. We have also shown that the addition of autofluorescence bronchoscopy allows simultaneous inspection of the other region commonly involved by second primary disease in these patients, the bronchus. Panendoscopy with conventional white light has been reported to show asymptomatic synchronous primary disease in up to 3% of cases of new head and neck cancer, including both the head and neck region and the bronchus [10]. Our results are a proof of principle which suggest the possible benefits of adding fluorescence examination to a panendoscopy. They allow us to plan a detailed randomised study to determine the overall benefits of adding autofluorescence to a panendoscopy. This will include the use of a dedicated 70◦ fluorescence rigid pharyngoscope for the initial part of the assessment. As expected it a significant number of patients had radiologically occult but significant bronchial mucosal lesions. Detection of these lesions is clearly important in these head and neck cancer patients, as up to 30% higher can eventually succumb to second primary lung cancer having being cured of the original primary tumour. Studies have already shown benefits of fluorescence bronchoscopy in these patients. We found it easiest to image the larynx, supraglottic region, pyriform fossae, and floor of mouth. The larynx is particularly suited to this technique, not only because of the ease of inspecting this region given the strong normal autofluorescence signals from the laryngeal tissue, but also because regional sites of dysplasia are common. The tonsil and tongue base were more difficult to inspect because of background strong autofluorescence due to lymphoid tissue. None the less it was still be possible to detect relative differences in local tissue auto fluorescence. We consider this technique to have potential in assisting ENT surgeons in detection of unknown primaries. In the two cases with this was useful in our series one case had been identified by the ENT surgeon as a possible site prior to referral. Clearly a detailed blinded randomised study is in these types of patients is required before it can be recommended as a tool in this setting. It may be that fluorescence could limit the number of sites requiring biopsy around the upper aerodigestive tract.
DAFE autofluorescence assessment of oral cavity, larynx and bronchus in head and neck cancer In conclusion this simple addition to the work up of cases of head and neck carcinoma can change management.
References [1] Hung J, Lam S, LeRiche JC, et al. Autofluorescence of normal and malignant bronchial tissue. Laser Surg Med 1991;11:99—105. [2] Ikeda N, Hiyoshi T, Kakihana M, Honda H, Kato Y. Histopathological evaluation of fluorescence bronchoscopy using resected lungs in cases of lung cancer. Lung Cancer 2003;41:303—9. [3] Lam S, Kennedy T, Unger M, et al. Localization of bronchial intraepithelial neoplastic lesions by fluorescence bronchoscopy. Chest 1998;113:696—702. [4] Kennedy T-C, Lam S, Hirsch F-R. Review of recent advances in fluorescence bronchoscopy in early localization of central airway lung cancer. Oncologist 2001;6:257—62. [5] Weigel TL, Kosco PJ, Dacic S, Rusch VW, Ginsberg RJ, Luketich JD. Postoperative fluorescence bronchoscopic surveillance in non-small cell lung cancer patients. Ann Thorac Surg 2001;71:967—70. [6] Weigel TL, Yousem S, Dacic S, Kosco PJ, Siegfried J, Luketich JD. Fluorescence bronchoscopic surveillance after curative surgical resection for non small cell lung cancer. Ann Surg Oncol 2000;7:176—80. [7] Laccorreye O, Vievers FD, Hans S, Brasnu FD, Garcia D, Laccourreye FL. Metachronous second primary cancers after partial laryngectomy for invasive sqaumous cell carcinoma of the true vocal cord. Ann Otol Rhinol Laryngol 2002;111(3 Pt 1):204—9.
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[8] Morita M, Araki K, Saeki H, et al. Risk factors for multicentric occurrence of carcinoma in the upper aerodigestive tract-analysis with a serial histologic evaluation of the whole resected-esophagus including carcinoma. J Surg Oncol 2003;83:216—21. [9] Tabor MP, Brakenhoff RH, van-Houten VM, et al. Persistence of genetically altered fields in head and neck cancer patients: biological and clinical implications. Clin Cancer Res 2001;7(6):1523—32. [10] Stoeckli SJ, Zimmerman R, Schmid S. Role of routine panendoscopy in cancer of the upper aerodigestive tract. Otolaryngol Head Neck Surg 2001;124:208—12. [11] Venmans B, Ton JM, van Boxem Smit EF, Postmus PE, Sutedja T. Bronchial intraepithelial neoplastic lesions in head and neck cancer patients. Ann Otol Rhinol Laryngol 2001;110:635—8. [12] Arens C, Glanz H, Dreyer T, Malzahn K. Compact endoscopy of the larynx. Ann Otol Rhinol Laryngol 2003;112: 113—9. [13] Svistun E, Alizadeh Naderi R, El Naggar A, Jacob R, Gillenwater A, Richards Kortum R. Vision enhancement system for detection of oral cavity neoplasia based on autofluorescence. Head Neck 2004;26:205—15. [14] Onizawa K, Okamurab N, Saginoyac H, Yoshidaa H. Characterization of autofluorescence in oral squamous cell carcinoma. Oral Oncol 2003;69:150—6. [15] Betz CS, Stepp H, Janda P, et al. A comparative study of normal inspection, autofluorescence and 5ALA induced PPIX fluorescence for oral cancer diagnosis. Int J Cancer 2002;97:245—52. [16] Goujon D, Glanzmann T, Gabrecht T, et al. Detection of early bronchial carcinoma by imaging of the tissue autofluorescence. Proc SPIE 2001;4432:131—8.
DAFE autofluorescence assessment of oral cavity, larynx and bronchus in head and neck cancer patients David Fielding FRACP, MD a,∗, Julie Agnew b, David Wright b, Robert Hodge b a
Department of Thoracic Medicine, Royal Brisbane and Women’s Hospital, Herston Rd., Herston 4029, Australia b Department of ENT Surgery, Royal Brisbane and Women’s Hospital, Herston Rd., Herston 4029, Australia Available online 28 August 2006 KEYWORDS Autofluorescence bronchoscopy; Lung cancer; Panendoscopy; Larynx cancer
∗
Summary Head and neck (H&N) cancer patients have a high incidence of local field change as well as second primary lung tumours. We have applied the Wolf Diagnostic Autofluorescence Endoscopy (DAFE) system in a novel way, combining autofluorescence evaluation of both H&N region and bronchial. New H&N cases as well as ‘‘old’’ cases with symptoms were included. The DAFE procedure was done separate to panendoscopy. The H&N region was examined first; images were recorded of the known primary with reference to subsequent resection margins, as well as of adjacent mucosa inspecting for additional abnormal sites. Then autofluorescence bronchoscopy was performed. Changes in management were only on the basis of histology taken because of abnormal autofluorescence. One hundred and seven cases were referred, including 96 new cases and 11 old cases. Autofluorescence examination of H&N detected sites which led to change of management in 11 patients. This included additional sites in nine patients (which then either had extra surgery or radiotherapy as a result) and wider resection margins were made possible in two patients. In the bronchus there were 21 significant lesions in 16 patients. Immediate management change occurred in one invasive cancer, two microinvasive carcinomas and three carcinomas in situ (in four patients). There were 15 sites of severe and moderate dysplasia in 12 patients. None of these bronchoscopic lesions were detectable on CT chest. Therefore, overall an immediate change in management occurred in 15 of 107 patients (14% of patients). This combined procedure yielded a significant number of lesions particularly as a simple addition to preoperative workup in new H&N cancer cases. © 2006 Elsevier B.V. All rights reserved.
Corresponding author. Tel.: +61 7 36367631; fax: +61 7 36365651. E-mail address: david fi[email protected] (D. Fielding).
1572-1000/$ — see front matter © 2006 Elsevier B.V. All rights reserved. doi:10.1016/j.pdpdt.2006.07.004
260
Introduction Tissue autofluorescence is an established mode of detecting preneoplasia and in situ carcinoma in mucosal surfaces [1,2]. The most common application of fluorescence detection is in the bronchial tree [3—6]. Patients with squamous carcinoma of the head and neck are well known to have high risk of synchronous and metachronous carcinomas in the lung and other areas of the upper aerodigestive tract [7—9]. For this reason patients are usually referred for pan-endoscopy prior to definitive treatment [10]. The upper aerodigestive tract is easily accessible to flexible and rigid optics used in autofluorescence diagnosis. Because of the common occurrence of field change disease in these regions, there is potential for fluorescence detection of additional significant lesions within the oral cavity, oropharynx and glottic regions. Fluorescence bronchoscopy has been used in head and neck patients but usually as surveillance rather than to detect synchronous primaries at the time of initial diagnosis [11]. The potential exists for the clinical application of using autofluorence to inspect the upper airway as well as the bronchial tree at panendoscopy. Tissue auto fluorescence has been investigated in the oral cavity as reported by Arens et al. [12], Svistun et al. [13], and Onizawa et al. [14]. In these studies known tumours were assessed for a fluorescence difference from the adjacent normal mucosa; there was correlation between increasing degrees of fluorescence abnormality and increasing degrees of epithelial malignancy. Arens showed lesions of the larynx to have diminished fluorescence using the filtered blue light (375—440 nm) of the Storz D Light system [12]. Generally specificity was high at 84% for high grade dysplasia and malignancy. Causes for false positive results were marked hyperkeratosis, scarring and inflammation, although generally these were an uncommon finding and did not limit the overall utility of the technique. Autofluorescence of freshly resected oral tissue has shown best specificity for discriminating malignant from benign tissue when incident light is 400 nm and observation is at 530 nm [14]. Despite this potential application, autofluorescence is not widely used to detect synchronous disease at panendososcopy in these patients, and has not been reported in terms of its ability to change management. Our study looked at clinical aspects of the potential application of autofluorescence at panendoscopy. Some data exists for the application of tissue fluorescence using the topical photosensitizer aminolaevulinic acid (ALA) in the oral cavity [15] however in this study we only used auto fluorescence. The aims were firstly to define margins
D. Fielding et al. of known or small localized primary tumours in the head and neck to assist with local excisions such as laser excision. Secondly we looked for additional sites of in situ carcinoma and dysplasia within these regions which might alter surgical management. Finally, as part of the same procedure autofluorescence bronchoscopy was performed with the usual aim of detecting preneoplastic and in situ lesions. We sought to determine whether the addition of fluorescence to standard work-up would have the potential to change management.
Methods Patients were selected for this procedure from a large multi-disciplinary Head and neck cancer clinic in a prospective fashion. Patients were either newly diagnosed with a head and neck cancer which was in the process of being worked up for a definitive local treatment including surgery or radiotherapy, or were in a follow-up phase having received prior curative treatment for a head and neck cancer. Patients had usually undergone biopsy to confirm the primary head and neck cancer under standard white light conditions. They were at the point of referral for pan endoscopy. Patients who had bulky tumours (T3 or T 4) were not included as the finding of additional small sites of tissue abnormality was thought unlikely to change management. All patients had chest X-ray and chest CT scan in addition to other CT scans in workup of the head and neck primary. Patients undergoing fluorescence bronchoscopy did not have radiological evidence of lung cancer. Procedures were performed in a bronchoscopy suite under standard conscious sedation. Local anaesthetic was applied to the oral cavity with mist spray of 2 ml 2% lignocaine. Auto fluorescence was performed using the Diagnostic Autofluorescence Endoscopy (DAFE) system (Wolf) [16]. This utilises a detachable camera for attachment to either a fiberoptic bronchoscope or a rigid optic. The camera receives the autofluorescence signal which is displayed in real time on the monitor, with red indicating neoplasia and green or light pink or white representing non malignant tissue. The camera also provides feedback to the light source such that overall light intensity is maintained; in more voluminous parts of the airway therefore greater light output from the light source occurs. Only additional sites of AF abnormality were acted upon, not the abnormal fluorescence of the known primary tumour. The procedures were performed in two parts; the first part was assessment of the floor of mouth, buccal mucosa, and tonsil regions in patients known to
DAFE autofluorescence assessment of oral cavity, larynx and bronchus in head and neck cancer Table 1
261
Site of new head and neck tumours
Site of head and neck primary
Number of cases
Larynx Supraglottis Floor of mouth, alveolus Oropharynx Unknown primary
36 12 22 17 9
Total
96
have tumours in these regions. This was done in a sitting position without administration of sedation. A rigid optic specific to the Wolf system was used in this location. Secondly with the patient supine the dedicated 4.5 mm diameter flexible fluorescence bronchoscope was used to inspect the oropharynx, supraglottis and glottis, then the bronchoscopy was performed in standard fashion. Where abnormalities were detected in the head and neck region digital video images were recorded so that at the time biopsy could be performed subsequently. Some of the oral cavity assessments were performed using a dedicated rigid 4 mm fluorescence optic (Wolf). Changes in management were considered only on the basis of biopsy histology taken as a result of abnormal tissue autofluorescence rather than the images themselves.
Results There were 96 new cases who had both head and neck fluorescence inspection, and 11 cases with prior definitive treatment of H&N carcinoma who had only fluorescence bronchoscopy. There were 90 males and 17 females with a mean age of 62 ± 9.1 years. Table 1 lists the site of the primary carcinoma in the newly diagnosed head and neck cancer patients. The mean time for a procedures including both head and neck and bronchus was 16 ± 6 min. There were no side-effects. Known primary sites clearly showed marked autofluorescence abnormalities (Fig. 1). The DAFE system provided excellent images even in more open parts of the oral cavity because of the camera automatically adjusting incident light intensity. DAFE detected significant sites in the H&N region which led to change of management in 11 patients. Additional sites were found in nine patients and wider resection margins were made possible in two patients. Table 2 lists the location of these sites. There were five cases of additional sites detected around the larynx. One of these cases was a 65-year-old man who had previously been diagnosed with a Right vocal cord squamous cell
Figure 1 White light (a) and fluorescence (b) image of a known squamous cell carcinoma of floor of mouth. The fluorescence image is bright and clear demarcation of normal and abnormal mucosa is possible. Note in the left of the fluorescence image a red fluorescence point due to salivary gland opening.
carcinoma. This patient had undergone two white light assessments by ENT surgeons prior to referral for the fluorescence procedure. The DAFE examination revealed an additional lesion on the Left false cord, approximately 3 mm in diameter (Fig. 2). Therefore, in the subsequent ENT procedure, this additional tumour was biopsied and frozen section revealed microinvasive squamous cell carcinoma. This was treated by laser excision along with the planned laser of the known of tumour on the right vocal cord. Another of these cases was a 70-year-old lady who had contralateral vocal
262 Table 2
D. Fielding et al. Sites of additional H&N tumour found with DAFE inspection of H&N region
Primary site
Additional disease
Number of patients
Histology of additional site
Larynx
Contralateral cord or supraglottis
5
Carcinoma (3) CIS (1) Severe dysplasia (1)
Pyriform fossa Floor of mouth Soft palate Unknown primary
Local field change Tongue base, alveolus Local field change Tongue base, tonsil
1 2 1 2
Carcinoma Severe dysplasia (2) Carcinoma Carcinoma (2)
cord carcinoma found by fluorescence which meant that radiotherapy was given rather than the previously planned surgery. Another case was a patient who had previously had laser excision on Left vocal cord who had a Right cord carcinoma identified by fluorescence amongst non specific post radiotherapy inflammation; this patient had laryngectomy. A fourth case had a biopsy proven carcinoma of
Figure 2 (a) White light appearance of larynx showing R cord tumour. (b) DAFE appearance showing the abnormal R cord as well as an additional lesion anteriorly on L false cord. Frozen section biopsy of this additional site showed in situ carcinoma; both sites were treated with laser excision.
right arytenoid after a standard white light H&N assessment. Subsequent fluorescence assessment showed widespread disease of contralateral supraglottic region; biopsies showed invasive carcinoma in these regions. Radiotherapy was therefore given instead of surgery which had been planned. In the
Figure 3 Case of unknown primary of head and neck. Subtle changes in R tonsil on white light (a) are clearly shown as abnormal on fluorescence image (b).
DAFE autofluorescence assessment of oral cavity, larynx and bronchus in head and neck cancer
263
tongue base and alveolus there were two cases where biopsies showed severe dysplasia. One case was therefore treated with radiotherapy rather than surgery due to contralateral disease. The second had an abnormal PET scan showing diffuse right alveolar disease, and fluorescence was able to localise this abnormality, clarifying the reasons for the PET change, and allowing an observation approach rather than repeat treatment to an area of local recurrence. Two cases of unknown primary disease had prior standard white light H&N examination (Fig. 3). In both cases fluorescence was readily able to identify the subsequent histological site
Figure 5 Example of moderate-severe dysplasia detected by fluorescence examination (b) after prior standard white light examination only showed the macroscopic R vocal cord tumour.
Figure 4 Squamous cell carcinoma in the right Pyriform fossa which was assessed prior to laser excision. The autofluorescence pictures demonstrate the margins to the approximately 2—3 mm greater than can be seen under standard white light conditions. This directed the laser excision to take a wider margin.
of tumour. Biopsies could be directed to these sites immediately. There were two cases where laser excision was to be performed (Fig. 4). The margins of the tumour were clearly seen to extend further away from the subtle white light abnormalities, allowing the surgeon to extend the resection margins further. In both cases resection margins were clear on final histology. Not included in this list is an example of moderate-severe dysplasia seen on the L vocal cord in a patient with histologically proven R vocal cord squamous cell carcinoma (Fig. 5). This patient was to receive radiotherapy as part of a clinical study and as such management was not altered. Had this patient been sent for laser resection this lesion would have required careful surveillance.
264
D. Fielding et al.
Table 3 Significant histology results of DAFE fluorescence bronchoscopic biopsies Histology
Number of lesions
Moderate—severe dysplasia Carcinoma in situ Micronvasive carcinoma Carcinoma
15 3 2 1
With respect to fluorescence bronchoscopy, in total from all patients there were 124 biopsies at an average of 1.2 ± 1.2 biopsies per patient. Table 3 lists the biopsies from fluorescence bronchoscopy which had moderate dysplasia or worse on histology; (the remaining histologies were mild dysplasia, metaplasia, inflammation or normal). In the bronchus there were 21 significant lesions in 16 patients. All were not detectable on CT chest. Four patients had six lesions showing carcinoma or carcinoma in situ. Of these four patients, all received radiotherapy either in combination with treatment of the new head and neck primary, or as sole treatment. In addition one of these four had endobronchial electrocautery to a contrateral carcinoma-in-situ lesion. The other 12 patients are having repeat DAFE biopsies of the known moderate to severe dysplasias, as are those with mild dysplasia at a longer interval. Therefore, overall an immediate change in management occurred in 15 patients (14% of cases) with a further 12 cases still under review. The best sites for H&N fluorescence assessment were the floor of mouth, epiglottis, larynx and false cord regions, and pyriform fossae. False positive biopsies were obtained in five cases where fluorescence was positive but biopsies showed no malignancy. These were in the base of tongue region, and the tonsils, presumably due to strong fluorescence changes in lymphoid tissue in these regions. As listed in Table 2 fluorescence could provide useful information from these sites where there was a clear difference in fluorescence signal when comparing the two sides; that is there was a clear change compared to the background signal. One other artefact of note was the salivary gland openings in the floor of mouth. Fig. 1 shows an example of the bright fluorescence as obtained from these ducts. On occasion only the opening of the duct was seen on tissue auto fluorescence whereas in other cases the length of the duct traversing the flora of mouth could be seen. The surface of the tongue generally fluoresced very strongly and evaluation of tongue tumour margins was difficult. This was presumably due to an abundance of fluophores
in the actively dividing cells on the tongue surface mucosa.
Discussion We have demonstrated that autofluorescence can be simply used in the oral cavity and larynx to change management in head and neck cancer patients. We have also shown that the addition of autofluorescence bronchoscopy allows simultaneous inspection of the other region commonly involved by second primary disease in these patients, the bronchus. Panendoscopy with conventional white light has been reported to show asymptomatic synchronous primary disease in up to 3% of cases of new head and neck cancer, including both the head and neck region and the bronchus [10]. Our results are a proof of principle which suggest the possible benefits of adding fluorescence examination to a panendoscopy. They allow us to plan a detailed randomised study to determine the overall benefits of adding autofluorescence to a panendoscopy. This will include the use of a dedicated 70◦ fluorescence rigid pharyngoscope for the initial part of the assessment. As expected it a significant number of patients had radiologically occult but significant bronchial mucosal lesions. Detection of these lesions is clearly important in these head and neck cancer patients, as up to 30% higher can eventually succumb to second primary lung cancer having being cured of the original primary tumour. Studies have already shown benefits of fluorescence bronchoscopy in these patients. We found it easiest to image the larynx, supraglottic region, pyriform fossae, and floor of mouth. The larynx is particularly suited to this technique, not only because of the ease of inspecting this region given the strong normal autofluorescence signals from the laryngeal tissue, but also because regional sites of dysplasia are common. The tonsil and tongue base were more difficult to inspect because of background strong autofluorescence due to lymphoid tissue. None the less it was still be possible to detect relative differences in local tissue auto fluorescence. We consider this technique to have potential in assisting ENT surgeons in detection of unknown primaries. In the two cases with this was useful in our series one case had been identified by the ENT surgeon as a possible site prior to referral. Clearly a detailed blinded randomised study is in these types of patients is required before it can be recommended as a tool in this setting. It may be that fluorescence could limit the number of sites requiring biopsy around the upper aerodigestive tract.
DAFE autofluorescence assessment of oral cavity, larynx and bronchus in head and neck cancer In conclusion this simple addition to the work up of cases of head and neck carcinoma can change management.
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