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Autofluorescence/a clinical trial: a new hope for early detection of oral cancer & oral potentially malignant disorders.

Byline: UMAIR KHAN ANUM AZIZ MYRA AHMED MARIAM RABIA BUSHRA MAZHAR HURIYA IFTIKHAR ZAINAB RIZVI HAJRA IMTIAZ MAHAM CHEEMA and FATIMA KHALID

In conclusion although all 22 patients showed loss of fluorescence/fluorescence visualization loss (FVL) i.e. producing a black shadow on autofluores- cence the sensitivity of VELscope for the detection of dysplastic lesions was found to be 86%.

In Group II (Oral potentially malignant disorders group) patients who showed no clinical sign of speckling (mixed red and white patches or clinical indication of histopathological presence of dysplasia) or neo- plastic changes none of them showed fluorescence visualization loss (FVL) or a black shadow on VEL- scope examination thus confirming the certainty of autofluorescence with its relation to absence of dys- plasia of clinical non-neoplastic lesions by giving the result of FVR (fluorescence visualization retained hence concluding its sensitivity for non-dysplastic lesions or for oral potentially malignant disorders having no clinically visible neoplastic change at the time of patient's registration into the clinical trial (patient's initial acquaintance) to be 100%.

3 out of a total of 13 patients (3/13=23%) of Group II agreed to undergo biopsy for histopathology in order to detect any neoplastic transformation (dysplasia CIS and OSCC) histopathologically and none of the patients showed presence of dysplasia or neoplasia on H and E staining thus further supporting the spectroscopic tissue fluorescence imaging results of VELscope in relation to oral potentially malignant disorders having no clinical sign of neoplasia. In Group III (benign lesions/conditions group) neither did the patients show any clinical sign of malignancy nor did the VELscope (Autofluorescence) show FVL. Thus concluding the sensitivity of autofluorescence

TABLE 6: DISEASE SPECIFIC PROFILE OF THE PATIENTS

Total number of patients = 92

No. of###Disease###Gender###Mean

patients###Age

###(years)

15###Lichen pla-###3 Males and 12###43

###nus###Females

9###Oral submu- 4Males and 5 Fe-###37

###cous fibrosis males

2###Chronic hy- 2 Males###48.5

###perplastic

###candidosis

4###Oral squa- 3 Males and 1###40.2

###mous cell car- Female

###cinoma

3###Oral trauma 2 Males and 1###44.5

###Female

1###Haematinic 1 Female###42

###deficiency

1###Smokeless###1 Male###47

###tobacco kera-

###tosis

16###Coated###6 Males and 10 405

###tongue (Bac- Females

###teria and Can-

###dida)

4###Frictional###I Male and 3 Fe-###35.6

###keratosis###males

1###Telangiecta- 1 Female###33

###sia

3###Mucositis###3 Females###35

1###Geographic###1 Male###27

###tongue

1###Median###1 Male###33

###rhom-

###boid glossitis

1###Pyostomati- 1 Female###24

###tis vegetans

###Idiopathic OSCC

TABLE 7: AUTOFLUORESCENCE RESULTS IN RELATION TO FOUR GROUPS OF THE PATIENT

Group 1###Diagnosis###Cases###Clinical Ex-###Histopatho-###Autofluorescence

###(n)###amination###logical Assess-###FVL###FVR###Se###Sp

###ment

Dysplasia/ Neo-###Oral lichen###7###All +ve for###6 +ve and 1 ve###7###0###86%###--

plasia group###planus###speckling###for neoplasia

###Oral submucous###4###All +ve for###All +ve for###4###0###100%###--

###fibrosis###speckling###neoplasia

###Chronic hyper-###2###All +ve for###All +ve for###2###0###100%###--

###plastic candi-###speckling###neoplasia

###dosis

###Oral squamous###4###All +ve for###2 +ve and 2 ve###4###0###50%###--

###cell carcinoma###speckling###for neoplasia

###(Idiopathic)

###Oral trauma###3###All +ve for###All +ve for###2###1###67%###33%

###speckling###neoplasia

###Haematinic###1###+ve for speck- +ve for neopla-###1###0###100%###--

###deficiency###ling###sia

###Smokeless to-###1###+ve for speck- +ve for neopla-###1###0###100%###--

###bacco keratosis###ling###sia

Group 2###Diagnosis###Cases###Clinical Ex-###Histopatho-###FVL###FVR###Se###Sp

###(n)###amination###logical Assess-

###ment

Oral potentially###Oral lichen###8###All -ve for###Only 2 pa-###1 with###7###100%###88%

malignant disor-###planus###speckling###tients' biopsy white

ders group###done (Both ve###hue

###for neoplasia) (plaque)

###Oral submucous###5###All ve for###Only 1 pa-###5 (with###0###100%###0%

###fibrosis###speckling###tient's biopsy###bright

###done (ve for###white

###neoplasia)###hue)

Group 3###Diagnosis###Cases###Clinical Ex-###Histopatho-###FVL###FVR###Se###Sp

###(n)###amination###logical Assess-

###ment

Benign lesions/ Coated tongue###9###Classical###--###9###0###100%###--

conditions group (Bacteria) Coat-###7###Classical###--###7###0###100%###--

###ed tongue (Can-###4###3 Plaque and 1###--###4###0###100%###--

###dida) Frictional###linear

###keratosis

###Geographic###1###Classical###--###1###0###0%###--

###tongue Me-###1###Classical###--###1###0###0%###--

###dian rhom-

###boid glossitis

###Mucositis###3###Classical###--###3###0###100%###--

###Pyostomatitis###1###Classical###--###1###0###100%###--

###vegetans Tel-###1###Prominent###--###1###0###0%###--

###angiectasia

Group 4###Clinically nor-###30###Thorough In-###--###0###30###0%###100%

###mal oral mu-###troral exam-

Control group

###cous membrane###ination

for benign lesions to be 62.5% (Table 7). In Group IV (Control group) all patients showed FVR (fluorescence visualization retained) on VELscope hence the speci- ficity of autofluorescence for the controls was 100%.

DISCUSSION

Five-year survival rates for oral cancer have not changed for several decades. Poor survival is at least in part due to the failure in early detection of oral potentially malignant disorders (OPMDs) and oral cancers. To this end improving diagnostic abilities of primary care dentists via specialists (such as Oral Physicians) and also facilitating less interventional investigations in secondary care units remain import- ant cornerstones in the research agenda. This clinical trial was based on the investigation of the utility of autofluorescence as a diagnostic test to evaluate its accuracy in the detection of early stage oral squamous cell carcinomas oral potentially malignant disorders and benign conditions.

TABLE 8: FORMULAS FOR CALCULATING SENSITIVITY AND SPECIFICITY VALUES OF AUTOFLUORESCENCE

Sensitivity = No. of true positives

###Total number of patients in the particular

group

OR

Sensitivity =###No. of true positives

###No. of true positives + No. of false negatives

Specificity =###No. of true negatives

###Total number of patients in the particular

group

OR

Specificity =###No. of true negatives

###No. of true negatives + No. of false positives

Note:-In case of Group III since the conditions

like Median rhomboid glossitis Geographic

tongue and Telangiectasia produce black shad-

ow on autofluorescence which is not indicative

of dysplasia as these lesions are never cancerous

hence the sensitivity is 0% for them but in case of

frictional keratosis mucositis and coated tongue;

autofluorescence does not produce black shadow

and neither show FVR therefore the FVL values

for these lesions is the same but sensitivity values

are 100%.

Fluorescence visualization loss (FVL) was observed in majority of the patients especially for Group 1 pa- tients in which FVL was observed in all the 22 patients though 3 of them came out to be false positive hence winding up the sensitivity of VELscope to be 86%.

These results notably demonstrate the ability of the technique to detect high risk lesions. Sensitivity and specificity of autofluorescence as shown in Table 7 was calculated by using the formulas shown in Table 8.

As discussed earlier tissue fluorescence imaging or Autofluorescence does not only aid in detecting the presence of dysplasia but also can help Oral Surgeons to identify diseased tissue around a clinically apparent lesion and thus aid in determining the appropriate margins for surgical excision.1213 Such an example is shown in the photographs of one of the patients enrolled in the study (Fig 3 and Fig 4).

Comparison of the results of the recent study with published data proved to be difficult due to limited number of studies in the literature reporting sensi- tivity and specificity of the device. Only two previous studies appear to have employed autofluorescence in a systemic examination on a cohort of patients. One of the studies was conducted at the British Columbia Cancer Agency (BCCA) where a prototype of the VELscope was investigated by the group.13 Using the blue-excitation light 50 lesions were examined which included 33 oral cancers 11 severe dysplasia and carcinoma-in-situ and 6 with no oral mucosal lesions. The authors reported a sensitivity of 98% and specificity of 100% against the gold standard (histology). However the data of the current clinical trial/research shows a moderately low specificity (74%) for the technique.

It became possible to demonstrate this by the inclusion of several benign disorders thus reducing the spectrum bias' encoun- tered in published studies a desirable feature of this study/clinical research. In this clinical trial it was also found that certain manifestations of particular dis- eases behave in a strange fashion when viewed by the VELscope. For instance the reticular pattern/variant of oral lichen planus even when clinically very prominent and extensive somehow disappears completely when viewed by VELscope the phenomena of which is hard to explain. Similarly the fibrotic lesions such as in oral submucous fibrosis mucositis and others appear bright white in auto-fluorescence (Fig 13 and 14). The bacteria and candida in a coated tongue appear red (Fig 15 and 16) and yellow (Fig 17) respectively in VELscope and orange (Fig 15 and 16) in the presence of both at the same site.

Other spectroscopic features of VELscope that should be taken into account are shown in Table 9. Two studies on VELscope reported contrasting results on its utility. Huber et al.24 reported that VELscope failed to detect any additional suspicious lesions not identified by conventional oral examination and Huff et al.25 reported an increase in prevalence of mucosal disorders in a second cohort subjected to VELscope compared with an earlier cohort examined visually only. Their research was seriously flawed as they did not consider alternative possible reasons for a true increased prevalence of disorders in the later cohort. As sufficient studies had not examined sensitivity and specificity of the VELscope system this clinical trial data need to be discussed against the backdrop of sensitivity and specificity reported for clinical visual screening.

This study should not be seen as a screening study as the data are specific to a hospital population referred following the detection of a range of mucosal abnormalities by primary care practitioners/dentists. So far no studies have been reported for evaluating VELscope for screening the population.

To have an impact on the incidence of oral cancer a broad range of stakeholders must be involved including (but not limited to) professional societies educational institutions health care facilities government and the public. A combined effort will guide the evolution of oral cancer screening toward population-based coverage (Fig 27).

TABLE 9: FLUORESCENCE VISUALIZATION IN THE NORMAL MOUTH

###Understand what a normal oral cavity looks like

###under VELscope to best appreciate what may be

###abnormal.

###(i) The attached gingiva and anterior tonsillar

###pillars for example often have a naturally

###darker appearance (Figures 18 and 19)

###(ii) Pigmented tissue appearing dark under white

###light usually also looks dark under VELscope

###Vx (Figures 20 and 21)

###Inflammation typically appears darker under

###VELscope due to the excess blood content.

###The oral cavity is naturally exposed to varying

###degrees of chronic irritation and mild inflammation

###(Figures 22 and 23)

###(i) Due to inflammation the buccal mucosa

###lateral surfaces of the tongue and hard palate

###may sometimes show darker areas typically

###characterized by poorly-defined borders.

###Hyperkeratosis may often appear bright under

###VELscope because of strong keratin fluorescence

###(Figures 24 and 25)

CONCLUSION

In conclusion this study demonstrated a relatively high sensitivity (86%) and a moderately low specificity (74%) in discriminating high-risk (dysplasias) from be- nign lesions. Further well designed multi-institutional national- based studies are needed to examine the role of VELscope as an oral examination system in primary care.

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Author:Khan, Umair; Aziz, Anum; Ahmed, Myra; Rabia, Mariam; Mazhar, Bushra; Iftikhar, Huriya; Rizvi, Zainab
Publication:Pakistan Oral and Dental Journal
Date:Jun 30, 2014
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