Non-invasive visual tools for diagnosis of oral cancer and dysplasia: A systematic review

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Med Oral Patol Oral Cir Bucal. 2016 May 1;21 (3):e305-15. Diagnostic tools for oral cancer

Journal section: Oral Medicine and Pathology Publication Types: Review

Non-invasive visual tools for diagnosis of oral cancer and dysplasia: A systematic review

Ilaria Giovannacci 1, Paolo Vescovi 1, Maddalena Manfredi 2, Marco Meleti 2

1 DDS, Msci. Department of Biomedical, Biotechnological and Translational Science-Center of Oral Laser Surgery and Oral Pathology, Dental School, University of Parma, Parma, Italy

2 DDS, PhD. Department of Biomedical, Biotechnological and Translational Science-Center of Oral Laser Surgery and Oral Pathology, Dental School, University of Parma, Parma, Italy


Center of Oral Laser Surgery and Oral Medicine Dental School. Department of Biomedical Biotechnological and Translational Sciences Via Gramsci, 14 - 43125 Parma, Italy

Received: 11/08/2015 Accepted: 14/10/2015


Background: Gold standard for the diagnosis of oral dysplasia (OD) oral squamous cell carcinoma (OSCC) and malignant lesions is the histological examination.

Several adjunctive diagnostic techniques have been proposed in order to increase the sensitivity (SE) and specifi- city (SP) of conventional oral examination and to improve the diagnostic first level accuracy.

The aim of this study is to perform a systematic review on non-invasive tools for diagnosis of OD and early OSCC.

Material and Methods: Medline, Scopus, Web of Knowledge databases were searched, using as entry terms “oral dysplasia AND diagnosis” / ”oral cancer AND diagnosis”. Data extracted from each study included number of lesions evaluated, histopathological diagnosis, SE, SP, positive and negative predictive values (PPV and NPV), diagnostic accuracy (DA) and the main conclusions.

Results: After title and abstract scanning of 11.080 records, we selected 35 articles for full text evaluation. Most evaluated tools were autofluorescence (AF), chemiluminescence (CL), toluidine blu (TL) and chemiluminescence associated with toluidine blue (CLTB).

Conclusions: There is a great inhomogeneity of the reported values and there is no significant evidence of supe- riority of one tool over the other. Further clinical trials with a higher level of evidence are necessary in order to assess the real usefulness visual diagnostic tools.

Key words:Oral dysplasia, oral cancer, diagnosis, visual diagnostic tool, systematic review.

Giovannacci I, Vescovi P, Manfredi M, Meleti M. Non-invasive visual tools for diagnosis of oral cancer and dysplasia: A systematic review. Med Oral Patol Oral Cir Bucal. 2016 May 1;21 (3):e305-15. Article Number: 20996

© Medicina Oral S. L. C.I.F. B 96689336 - pISSN 1698-4447 - eISSN: 1698-6946 eMail:

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Oral squamous cell carcinoma (OSCC) is the sixth most common malignant tumour, with an incidence of more than 500.000 cases per year (1).

The most important prognostic factor influencing the disease-specific survival rate is the tumour stage at diagnosis. Patients with stage I tumours have a 5-year survival rate of 75%, which dramatically decreases in patients with tumours in stage III or IV, being 49% and 30%, respectively (1,2).

The diagnostic pathway for oral suspicious lesions usu- ally starts with the conventional objective examination (COE) based on inspection and palpation of the oral mu- cosa with the support of an incandescent light available on the dental chair. It is well known that COE mainly depends on a subjective interpretation, which is a conse- quence of the experience of the operator. Moreover, oral epithelial dysplasia (OED) and early OSCC may already be present within areas of oral mucosa macroscopically normal, as well as within the context of oral potentially malignant disorders such as leukoplakia, erythroplakia, submucous fibrosis and oral lichen planus (3).

The gold standard for the diagnosis of oral dysplastic and neoplastic malignant lesions is the histological ex- amination (4). Incisional or excisional biopsy techniques are the most reliable methods to collect a surgical speci- men suitable for microscopic evaluation. However, de- spite the little invasivity of such techniques, they still have some disadvantages in terms of morbidity and pos- sible artifacts induced by the method of collection.

In a recent paper, Mehrotra et al. indicated that there are two approaches for detection of oral dysplasia and cancer:

1) oral cancer screening programs that identify asympto- matic patients with suspicious lesions and 2) specific di- agnostic tools to identify dysplasia and early oral cancers in asymptomatic patients with an oral abnormality (5).

Several visual diagnostic aids have been developed as adjunctive tools in order to increase the diagnostic ac- curacy (DA) and enhance the specificity (SP) and sen- sitivity (SE) of the conventional diagnostic pathway.

However, results of studies on the usefulness of such tools show impressive discrepancies with regard to val- ues such as the positive or negative predictive values (PPV, NPV), when the same tools is evaluated by dif- ferent researchers.

The aim of this study is to perform a systematic review on non-invasive tools for the diagnosis of OED and OSCC, taking into account factors as SE, SP, PPV, NPV and DA.

Material and Methods

The databases Medline, Scopus and Web of Knowledge were searched, using as entry terms “oral dysplasia AND diagnosis” / ”oral cancer AND diagnosis”. No time limits were specified in the present research.

Search flow is shown in figure 1. Papers with abstract unavailable were excluded for further evaluation.

Titles and abstract were screened and the following ex- clusion criteria were applied:

- papers not in English.

- studies ex vivo or based on animal models.

- typology of the study: case reports, case series with less than 10 patients, conference proceedings, personal communications, editorials, descriptive studies and re- views.

- studies that analyse COE, invasive diagnostic tools (e.g. scalpel biopsy) or minimally invasive diagnostic tools (e.g. brush biopsy, exfoliative cytology) alone.

- studies that analyse salivary biomarkers.

- studies including also tumours of other head and neck regions (e.g. oropharynx).

Papers with equivocal abstracts were included for full- text evaluation. Further studies were excluded after full-text reading, if not pertinent with aim of the present review.

Data extracted from each study included authors and publication year, typology of the study, diagnostic tool analysed, number of lesions evaluated, (if present) his- topathological diagnosis, (if present) SE, SP, PPV, NPV, DA and the main conclusions of the study (Tables 1 and 1 continue,2).

SE and SP measure the accuracy of a test without any relation to the disease or population, whereas PPV and NPV measure the proportion of people whose test results reflect their health status. DA is the proportion of true positive results (both true positive and true negative) in a selected population, with regard to a specific disease.

The mean value of each variable analysed was calcu- lated; range and standard deviation (SD) were indicated for samples having > 2 values.

Level of evidence of each study was assessed according to the Oxford Evidence-based Medicine (OEBM) Lev- els for Diagnosis updated in March 2009.


Twenty-three papers were eventually selected for the present systematic review when using “oral dysplasia AND diagnosis” as entry terms. The use of “oral cancer AND diagnosis” as entry terms allowed the identifica- tion of further 25 full-text manuscripts (6-39).

Twenty-three studies were perspective (OEBM level: 2b), 4 studies were pilot (OEBM level: 3b), 3 studies were case-control (OEBM level: 4), 4 studies were cross-sec- tional (OEBM level: 2b). Only one study was a perspec- tive randomized clinical trial (RCT) (OEBM level: 1b).

Eight typologies of non-invasive visual diagnostic tools were identified (Table 3).

Mean SE and SP (with SD) are shown in figures 2,3.

1. Auto fluorescence (AF) - Direct visual fluorescence examination (DVFE)


Med Oral Patol Oral Cir Bucal. 2016 May 1;21 (3):e305-15. Diagnostic tools for oral cancer

Among 12 studies evaluating AF/DVFE, 8 were per- spective (OEBM level: 2b), 2 were cross-sectional (OEBM level: 2b), 1 was a pilot study (OEBM level:

3b) and 1 was a perspective RCT (OEBM level: 1b) (6,10,13,14,16-18,24,29,32,33,35).

Data on SE were reported in 10 studies, while informa- tion on SP was available in 11 studies. Mean SE was 72.4% ranging from 20% to 100% (SD = 27.1). Mean SP was 63.79% ranging from 15.3% to 100% (SD = 28.17).

Data on PPV were available in 5 studies (mean: 55.74%,

ranging from 15.1% to 92%, SD = 36.71); data on NPV were available in 5 studies (mean: 79.76%, ranging from 61% to 100%, SD = 15.99); DA was reported in 1 study (55%).

2. Chemiluminescence (CL)

Among 5 studies evaluating CL, 4 were perspective (OEBM level: 2b) and 1 was observational cross-sec- tional (OEBM level: 2b) (7,15,38).

Data on SE and SP were reported in 4 studies. Mean SE was 86.72%, ranging from 69.6% to 100% (SD = 15.65).

Fig. 1. Flow-chart diagram for the selection of the 35 studies included in the present analysis.


Authors and year (ref)Typology of the studyDiagnostic tools analysedNumber of lesionsHistopathologic diagnosis ResultsMain authors conclusions 1 Petruzzi M et al. 2014 (6) Double centre cross sectional studyDVFE vs TB 56


DVFE SE: 70%, SP: 57.7%, PPV: 65.6%, NPV: 70.6% (mild dysplasia positive) DVFE and TB are both sensitive but not specific in OSCC and dysplasia diagnosis. TB SE: 80%, SP: 61.5%, PPV: 62.5%, 72.7% 2 mmerer PW et al. 2013 (7) Perspective studyCL; CLTB 50Reactive lesions (40), dysplastic lesions (3), OSCC (7)

CL SE: 100%, SP: 30%. PPV: 26%, NPV: 100% The adjunct of TB to CL reduces the number of false positives without increasing the rate of false negatives. CLTB SE: 80%, SP: 97.5%, PPV: 90%, NPV: 95% 3 Pallagatti et al. 2013 (8) Perspective studyTB37Benign lesions (14), dysplastic lesions (23) SE: 95%, SP: 71.45%, PPV: 84.6%, NPV: 90.9%, DA: 86.48% The use of TB staining was taken into consideration to identify clinically doubtful oro-pharyngeal lesions. 4 Mittal et al. 2012 (9)Pilot studyBR20Dysplastic lesions (17), Verrucous Ca (1), OSCC (3)SE and DA: 90%BR staining can be used as a valuable diagnostic test in the detection of oral potentially malignant and malignant disorders. 5 McNamara KK et al. 2012 (10) Perspective studyDVFE vs COE95Benign lesions (50), premalignant lesions (2), malignant (1) – 52 no f/u DVFE was statistically different from scalpel biopsy (P=0.0001) COE is more valid than DVFE at discriminating benign mucosal alterations from premalignancy and do not support the use of DVFE as oral cancer screening adjunct. 6 Awan KH et al. 2012 (11) Perspective studyTB92Benign lesions (51), Dysplastic lesions (41) SE: 56.1%, SP: 56.9% TB is a useful adjunct to clinical visual examination by aiding in the visualization of lesions. 7 Mojsa et al. 2012 (12) Perspective studyCLTB 41Benign lesions (34), Dysplastic lesions (6), OSCC (1)SE: 81.8%, SP: 37.5%, PPV: 84.4%, NPV: 33.3% CLTB may help to visualize oral pathologic lesions that are not readily detectable with conventional operatory lighting. 8 Farah et al. 2011 (13) Perspective studyDVFE118 Non dysplastic lesions (91), dysplastic lesions (24), OSCC (3)SE: 30%, SP: 63%, PPV: 19%, NPV: 75%, DA: 55%DVFE cannot provide a definitive diagnosis regarding the presence of epithelial dysplasia. 9 Paderni C et al. 2011 (14) Perspective studyDVFE175 Benign lesions, dysplastic lesions, OSCC SE (OSCC): 96.4%, dysplasia (60%), no dysplasia (71%) The device was found to not replace the histopathology procedure. However, it is useful for oral tissue examination. 10Awan KH et al. 2011 (15) Perspective studyCL126 Non dysplastic lesions (82), dysplastic lesions (44) SE: 77.3%, SP: 27.8% CL does not have the ability to accurately classify PMD by discriminating between high-risk and low- risk lesions and therefore should be used with caution. 11Awan KH et al. 2011 (16) Perspective studyDVFE126 Non dysplastic lesions (82), dysplastic lesions (44) SE: 84.1%, SP: 15.3% The device was unable to discriminate high-risk from low-risk lesions. 12Moro A et al. 2010 (17) Perspective studyDVFE32Non dysplastic lesions (20), dysplastic lesions (6), OSCC (6)SE: 100%, SP: 95%, PPV: 92%, NPV: 100% Preliminary results seem to indicate that autofluorescence is a high-performing test for the individuation of oral cancer in populations at risk

Table 1. Studies identified using as entry terms “oral dysplasia AND diagnosis”.


Med Oral Patol Oral Cir Bucal. 2016 May 1;21 (3):e305-15. Diagnostic tools for oral cancer

13Koch FP et al. 2010 (18)Perspective blinded CT DVFE78Non dysplastic lesions, dysplastic lesions, OSCC SE: 20%, SP: 98%, PPV: 87%, NPV: 61% (OSCC/dysplasia)Red autofluorescence should be an indication for scalpel biopsy due to a high PPV for cancer. 14Sieroń A et al. 2008 (19)Perspective studyLIFE14Inflammatory lesions, dysplastic lesions, OSCC This study demonstrate a dependence of numerical color value (NCV) on histopathological grade

Diagnostics using white-light imaging with LIFE imaging is not only a significant faster method and a better diagnostics of pre-neoplastic and neoplastic lesions, but also there is a correlation between NCV and histopathological grade. 15Schwarz RA et al. 2009 (20)Case-control studyDSOS154 Non dysplastic lesions (66), dysplastic lesions (44), OSCC (44)SE and SP comparable to expert COEDSOS has potential to augment oral cancer screening efforts in community settings. 16Mallia RJ et al. 2008 (21)Case-control studyLIFE44Hyperplastic lesions, dysplastic lesions, OSCCSE: 100%, SP:96 % (hyperplastic vs dysplastic) SE: 95%, SP: 86% (dysplastic vs OSCC)

This methodology could act as an adjunct for early discrimination of oral dysplasias and hyperplasias. 17Epstein JB et al. 2007 (22)Perspective studyCLTB 97Non dysplastic lesions (43), dysplastic lesions (41), OSCC (13)SP: 55.26%, NPV: 100%The results suggest that use of this technology will facilitate identification of oral mucosal lesions that require follow-up 18Du GF et al. 2007 (23)Pilot studyBR128 Non dysplastic lesions (95), dysplastic lesions/OSCC (33)SE: 93.9%, SP: 73.7%BR staining may be a valuable diagnostic test in detection of PMD and malignant lesions. 19Lane PM et al. 2006 (24)Pilot studyDVFE44NSSE: 98%, SP: 100%This device is a suitable adjunct for oral cancer screening, biopsy guidance and margin delineation. 20Sharwani A et al. 2006 (25)Perspective studyESS 25Non dysplastic lesions (14), dysplastic lesions (10), OSCC (1) SE: 72%, SP: 75%ESS may be able to identify dysplasia in oral tissues. 21Onofre MA et al. 2001 (26)Perspective studyTB50Non dysplastic lesions (37), dysplastic lesions (6), OSCC (7) SE: 77%, SP: 67%, PPV: 43.5%, NPV: 88.9% TB staining is an adjunct to clinical judgment and not a substitute for either judgment or biopsy. 22Leunig A et al. 2000 (27)Perspective study5-ALA induced PPIX fluorescence58NSSE: 99%, SP: 60%PPIX could represent a possible new diagnostic tool to detect early malignant and secondary lesions in the oral cavity. 23Martin IC et al. 1999 (28)Perspective studyTB14Displastic lesions/OSCCFalse negative rates: 42%(Ca in situ), 58% (moderate dysplasia)This study suggests restricting the use of TB in high-risk patients and in cases of suspicious oral lesions.

Table 1 Continue. Studies identified using as entry terms “oral dysplasia AND diagnosis”. Abbreviations: BR=Bengal Rose; CL= Chemiluminescence; Chemiluminescence associated with Toluidine Blue (CLTB); COE=conventional objective examination; DA=diagnostic accuracy; DSOS= depth-sensitive optical spectroscopy; DVFE=direct visual fluorescence examination; ESS=elastic scattering spectroscopy; LIFE=laser induced fluorescence examination; NPV=negative prognostic value; NS=not specified; OSCC=oral squamous cell carcinoma; PMD= potentially malignant disorders; PPV=positive prognostic value; PPIX=protoporphyrin IX; SE=sensitivity; SP=specificity; TB=toluidine blue; 5-ALA=5-aminolevulinic acid.




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