Risk of oral squamous cell carcinoma in 402patients with oral lichen planus: a follow-up studyin an Italian population

S. Gandolfoa,*, L. Richiardic, M. Carrozzoa, R. Broccolettia, M. Carbonea,M. Paganob, C. Vestitaa, S. Rossod, F. Merlettic

aDepartment of Biomedical Sciences and Oncology, Section of Oral Medicine, School of Medicine andDentistry, University of Turin, Turin, ItalybDepartment of Biomedical Sciences and Oncology, Section of Human Pathology, School of Medicine andDentistry, University of Turin, Turin, ItalycDepartment of Biomedical Sciences and Oncology, Section of Cancer Epidemiology, School of Medicine andDentistry, University of Turin, Turin, ItalydCPO, Piedmont Cancer Registry, City of Turin, Italy

Received 5 May 2003; accepted 6 June 2003

Summary The most important complication of oral lichen planus (OLP) is the devel-opment of oral squamous cell carcinoma (OSCC) but this is a very controversial matter.The aim of the study was to estimate in a Northern Italian cohort of OLP patients therisk for OSCC. Four hundred and two patients with histologically confirmed OLP diag-nosed from January 1988 to July 1999, were followed-up to the end of February 2001.The standardized incidence ratio (SIR) of OSCC was calculated for the entire cohort andspecific for gender, type of OLP, therapy for OLP and hepatitis C virus (HCV) infection.The relative risk (RR) of OSCC according to HCV infection was also estimated in thecohort. During the follow-up period, two men (1.3%) and seven women (2.9%) devel-oped an OSCC. The SIR was 44.9 (95% CI: 20.5—85.2), being higher among women, butstatistically significant in both genders. The RR of OSCC for patients with HCV as com-pared with those without HCV infection was 3.16 (0.8—12.5). Patients with OLP had asignificantly increased risk of OSCC, irrespective of the clinical type of OLP and ther-apy. HCV infection apparently increased the risk for OSCC although this result couldreflect the role of confounders, such as liver cirrhosis.# 2003 Elsevier Ltd. All rights reserved.

KEYWORDSLichen planus;

Oral;

Oral cancer;

Standardized incidence

ratio;

Hepatitis C virus

1. Introduction

The most important complication of oral lichenplanus (OLP) is the development of an oral squa-mous cell carcinoma, although this is a very con-troversial matter.1 Results from previous studies

1368-8375/$ - see front matter # 2003 Elsevier Ltd. All rights reserved.doi:10.1016/S1368-8375(03)00139-8

Oral Oncology (2004) 40 77–83

www.elsevier.com/locate/oraloncology

* Corresponding author at present address: Ospedale Molin-ette, Clinica Odontostomatologica, C.so Dogliotti 14, I-10136Torino, Italy. Tel.: +39-011-633-4047; fax: +39-011-663-6489.

E-mail address: sergio.gandolfo@unito.it (S. Gandolfo).

show a large heterogeneity and the estimates ofthe frequency of malignant evolution vary between0% and 12.5%.2�4 Meta-analysis of published data isdifficult because of differences in diagnostic cri-teria, time of follow-up and information on expo-sure to known oral carcinogens. The diagnosticcriteria are a major problem as there is not anaccepted standard.4 Thus, results from some stud-ies are biased by the inclusion of OLPs with histo-logical signs of epithelial dysplasia with lichenoidappearance (lichenoid dysplasias), which is a wellestablished premalignant entity.5 The lack of well-defined objective criteria of epithelial dysplasia,mainly when there is abundant inflammation, alsoadds inconsistency between studies.1

Results of studies conducted in the 1980s onwardshowever report more consistent estimates, suggest-ing that OLP may be a premalignant condition.3,7�16

Nevertheless, according to a recent review,4 theavailable evidence is not yet sufficient to reach aconclusion. Moreover, only minimal loss of hetero-zygosis in OLP lesions has been found, suggestingthat OLP is not a lesion inherently at risk for malig-nant trasformation.17 On the other hand a significantalteration in the expression of p53 and c-erbB-2 hasbeen found by two independent studies that ana-lyzed cases of OLP evolving toward oral cancer.18,19

The association between OLP and the hepatitis Cvirus (HCV) is also controversial. An increased pre-valence of HCV infection in patients with OLP hasbeen described, mainly in southern Europe andJapan,20 and oral verrucous and squamous cellcarcinomas have been reported in HCV-infectedpatients.3,21�23 HCV infection may thus increasethe risk of oral cancer among OLP patients whocould be already at high risk.The aim of our study is to estimate the risk for

oral cancer in a northern Italian cohort of patientsdiagnosed with OLP by the use of strict diagnosticcriteria. The role in OLP transformation of HCVinfection and other factors, such as clinical form ofOLP, are also investigated.

2. Subjects and methods

Patients diagnosed with OLP at the Oral Medicinesection of the Department of Biomedical Scienceand Human Oncology of the main hospital of thecity of Turin, Italy, from January 1988 to July 1999were selected for the present study. According toKrutchkoff,2 the diagnosis of OLP was based on thefollowing criteria:

A. Presence of characteristic bilateral clinical

signs of OLP [papular and/or reticular lesions

(Wickham striae) alone or in association withatrophic or erosive lesions];

B. Histologic confirmation of clinical diagnosis

through incisional biopsy demonstrating thefollowing microscopic characteristic:1. Ipercheratosis of the superficial epithe-

lial layers2. Vacuolar degeneration of the germina-

tive layer of the epithelium3. Band-like sub-epithelial lymphocytic

inflammatory infiltrateC. Absence of signs of dysplasia at the moment

of first diagnosis;D. Absence of suspicion that lichenoid lesions

maybe related to anydrug or oral restoration.

Subjects were resident in Piedmont region,north-west Italy. At the time of the diagnosis ofOLP, they were selected for the study and includedin a computerized clinical file, which recordedinformation on smoking habit, status of the liver(according to a diagnostic protocol publishedbefore),20 and clinical aspect of the lesions.The clinical forms of OLP were gathered in two

categories: (a) white lichen, which included thepapular, reticular and plaque forms; (b) red lichen,which included all the atrophic-erosive forms,irrespective of a contemporaneous presence of awhite form. Presence of any systemic disease anduse of any drug were also recorded. Patients werere-contacted by telephone to revise and completethe information obtained at the first visit.For patients presenting symptomatic OLP, a pro-

tocol of topical or systemic corticosteroids therapyin association with antimycotics therapy was car-ried out, as previously described in detail.24 Thelong-lasting (more than 6 months) lesions withaspect of plaque or atrophic/erosive located in thelingual pelvis and the oral floor were removed sur-gically, usually by scalpel. Periodical visits of fol-low-up were conducted for all patients, with afrequency established on the basis of the clinicalfeature and the need for therapy. In general,patients were seen at least once a year. Whenevera malignant evolution was suspected, an incisionalbiopsy was performed, usually preceded by tolui-dine blue staining. Additional information, includ-ing alcohol consumption, was obtained for subjectswho were diagnosed with oral cancer.

2.1. Follow-up and statistical analysis

The cohort was followed-up to 28 February 2001,death or the date of diagnosis of an oral squamouscell carcinoma, whichever occurred first. Some 105patients (42 males and 63 females) were lost to

78 S. Gandolfo et al.

follow-up because of complete remission of symp-toms or unavailability of the subject. A latencytime of at least 6 months between the diagnosis ofOLP and the diagnosis of the oral carcinoma wasconsidered to exclude concomitant presentations.Thus, the actual follow-up started 6 months afterthe diagnosis of OLP. We estimated standardizedincidence ratio (SIR) of oral carcinoma with corre-sponding 95% confidence intervals by using the sta-tistical software STATA.25 SIRs were obtained bycomparison of the observed number of mouth andtongue tumors with the expected number of casesin our cohort. The latter was calculated using thesex and 5-years age class specific incidence rate ofmouth and tongue cancers (code 01-06 in theInternational Classification of Diseases 10th Revi-sion) provided by the Piedmont Cancer Registry,city of Turin for the period 1993—1998.26

We assessed SIRs for the overall cohort as well asfor specific subgroups, according to gender, type ofOLP, therapy for OLP and positivity for HCV infec-tion. In addition, a Cox proportional-hazard modelwas used to estimate in our cohort the relative risk(RR) of oral cell carcinoma according to positivityto HCV infection.27 This model was adjusted for age(temporal scale), gender, smoking habit, clinicalform of OLP and therapy for OLP. Variables werecategorized as reported in Table 1. Smokers inclu-ded subjects who either were active smokers orquitted smoking less than 10 years before the

interview. Information on HCV infection was notavailable for 45 patients (20 men and 25 women),who were excluded from the multivariable model.

3. Results

The cohort included 402 patients with OLP, whowere followed-up for 4.9 years on average. Maincharacteristics of subjects at the time of enrol-ment in the cohort are summarized in Table 1. Mostof the patients were non-smokers (72.8%) and19.3% were HCV infected. The red form of OLP wasmore frequent than the white one among bothgenders.During the follow-up period two men (1.3%) and

seven women (2.9%) developed an oral squamouscell carcinoma. The clinical features of the tumorsand some lifestyle characteristics of these subjectsare reported in Table 2. Eight patients had aninvasive squamous cell carcinoma whereas one hada verrucous carcinoma. The latter (patient no. 5,Table 2) has been described before as a casereport.21 Only three patients had the carcinoma inthe same site of the initial biopsy.Table 3 presents the number of observed and

expected cancer cases and the corresponding SIRs.The overall SIR was 44.9 (95% CI: 20.5—85.2), beinghigher among women rather than among men, butstatistically significant for both genders. Neither

Table 1 Characteristics of the study subjects

Characteristic

All patients Men (N=156) Women (N=246)

N

% N % N %

Age

Mean (S.D.) 56.7 (11.8) 58.8 (10.8) 53.5 (12.4)

Smoking

No 268 (72.8) 89 (61.0) 179 (80.6) Yes 100 (27.2) 57 (39.0) 43 (19.4) Missing 34 10 24

HCV

Negative 288 (80.7) 114 (83.8) 174 (78.7) Positive 69 (19.3) 22 (16.2) 47 (21.3) Missing 45 20 25

Type of OLP

White 162 (40.3) 68 (43.6) 94 (38.2) Red 240 (59.7) 88 (56.4) 152 (61.8)

Therapy for OLP

Yes 219 (54.4) 96 (61.5) 123 (56.2) No 183 (45.5) 60 (38.5) 123 (67.2)

Risk of oral squamous cell carcinoma in 402 patients with oral lichen planus 79

ttorh

2 Characteristics of oral lichen planus (OLP) patients with malignant development

ex Agea OLP clinicalformb

Biopsy sitefor diagnosisb

OLPtherapy

Generaldisease

OLP clinicalforma

Site ofcarcinoma

Histologicaltype ofcarcinoma

TN Smoke Alcohol Latencytime(months)f

54 Reticular andplaque-type

Left buccalmucosa

No HypertensionHCV+

Reticular-atrophic

Right dorsumof the tongue

Squamous T1 No >500ml/day

85

64 Atrophic-erosive

Left buccalmucosa

No Chronicbronchitis

Reticular andplaque-type

Right buccalmucosa

Squamous T2 25cig/day

>500ml/day

17

67 Reticularand atrophic

Right buccalmucosa

No None Atrophic Left borderof tongue

Squamous T1 No No 8

67 Reticularand atrophic

Right buccalmucosa

Cc HypertensionHCV+

Atrophic-erosive

Left buccalmucosa

Squamous T2 No No 37

69 Plaque-typeand atrophic

Right borderof tongue

C HCV+ Plaquetypeand atrophic

Right borderof tongue

Verrucous T1 No No 10

71 Atrophic-erosive

Right buccalmucosa

No Arthritis Atropbicerosive

Right buccalmucosa

Squamous T2 3—4cig/day

No 62

73 Reticular Right buccalmucosa

No Diabetes,hypertensionHCV+

Plaque-typeand atrophic

Left buccalmucosa

Squamous T2 25cig/day

No 12

52 Reticularand atrophic

Right borderof tongue

C Hypertensionglaucoma

Atrophic Right borderof tongue

Squamous T1 20cig/day

No 62

80 Atrophic-erosive

Right borderof tongue

Pr, Cyd None Atrophicerosive

Buccalvestibule

Squamous T4 No No 108

malignant development.time of OLP original diagnosis.pical clobetasol plus antimycotics.ednisone, cyclosporine.e clinical staging was defined on the basis of the International Union Against Cancer TNM classification.38

cluding the first 6 months of follow-up.

80S.

Gan

dolfo

etal.

Table

Pt S

1 M

2 M

3 F

4 F

5 F

6 F

7 F

8 F

9 F

a Ab Ac Td Pe Tf Ex

Me

N0M0

N0M0

N0M0

N0M0

N0M0

N0M0

N0M0

N0M0

N1M0

therapy for OLP and form of OLP changed themagnitude of the SIRs more than marginally. Con-versely, the SIR for oral carcinoma was particularlyelevated among HCV infected subjects (SIR: 125.0,95% CI: 34.1—320.0). In the cohort, the age-adjus-ted RR of oral carcinoma for patients positive forHCV infection compared to those negative for HCVinfection was 3.05 (95% CI: 0.80—11.6), whichincreased to 3.16 (95% CI: 0.80—12.5) whenadjusting for age, gender, smoking, form of lichenand therapy for lichen (data not shown in tables).Some sensitivity analyses were performed.

Firstly, under the most conservative scenario, sub-jects lost to follow-up were considered to be aliveand without a diagnosis of oral carcinoma at 28February 2001, when the study ended. The overallSIR decreased to 35.4 (95% CI: 16.2—67.2) andremained statistically significant among both gen-ders. Secondly, we changed from at least 6 monthsto at least 2 years the definition of the latencyperiod between the diagnosis of OLP and the diag-nosis of oral carcinoma necessary to avoid con-comitant presentations. According to this strictercriteria suggested by Krutchkoff,2 355 subjectsremained for analysis and four oral carcinoma wereidentified versus 0.1479 expected. The correspond-ing SIR was 27.0 (95% CI: 7.4—69.2). Krutchkoff 2 alsosuggested to restrict the analyses to non-smokers.Our cohort included 268 non-smokers with fourdiagnoses of oral cancer compared to 0.1615expected during the period of follow-up. The SIRamong non-smokers was 24.8 (95% CI: 6.8—63.4).Finally, we included also the oropharynx as a pos-sible site at increased incidence of cancer (ICD-10code: 9-10) among patients with OLP. The expec-ted number of oral cancers increased to 0.2870,

whereas no oropharingeal tumors were observed,resulting in a SIR of 31.4 (95% CI: 14.3—59.5).

4. Discussion

There are two critical variables for the estimateof malignant development of OLP: the originaldiagnosis of OLP and the time from diagnosis tomalignant development. The diagnosis of OLP isbased on the contemporaneous presence of severalclinical and histopathological criteria, but it stillrelies on a important amount of subjectivity.1

Thus, some previous findings could have been dis-torted by the inclusion of dysplastic lichenoidlesions that are well established premalignantentities.5 Furthermore, in some reported cases thetime interval between OLP and oral carcinoma wassmall and it is likely that the two diseases weresynchronous.4 This pattern could be a consequenceof the cancer (due for example, to a cell-mediatedresponse to tumor antigens28) rather than the evo-lution of an OLP. In our study, we applied the strictcriteria proposed by Krutchkoff2 both to select thepatients and to define the occurrence of a malig-nant evolution. These criteria have been previouslyused to deny the possibility that OLP represents apotentially premalignant lesion. In fact, Krutch-koff’s criteria also imply the exclusion of tobaccousers, who were instead included in our analyses toavoid a biased comparison between a cohort ofnon-smokers and the general population thatincludes both smokers and non-smokers. However,when analyses were restricted to non-smokers, theSIR was still high and statistically significant. Theproportion of smokers in our cohort was lower than

Table 3 Standardized incidence ratios (SIR) and 0.5% confidence intervals for squamous cell carcinoma

A

ll M en Women

O

bSa Expa SIR 95% CI O bs Exp SIR 95% CI Obs Exp SIR 95% CI

All patients 9

0.2005 44.9 (20.5—85.2) 2 0.1306 15.3 (1.9—55.3) 7 0.0699 100.1 (40.2—206.3)

HCV

Negative 5 0.1427 35.0 (11.4—81.8) 1 0.0957 10.4 (0.3—58.2) 4 0.0470 85.1 (23.2—217.9) Positive 4 0.0320 125.0 (34.1—320.0) 1 0.0176 56.9 (1.4—316.6) 3 0.0143 209.8 (43.3—613.0)

Type of OLP

White 2 0.0635 31.5 (3.8—113.7) 1 0.0468 21.4 (0.5—119.1) 1 0.0167 60.0 (1.5—333.6) Red 7 0.1370 51.1 (20.5—105.3) 1 0.0838 11.9 (0.3—66.5) 6 0.0532 112.8 (41.4—245.5)

Therapy for OLP

No 5 0.1045 47.8 (15.5—111.7) 2 0.0768 26.04 (3.2—94.0) 3 0.0277 108.3 (22.3—316.4) Yes 4 0.0961 41.6 (11.3—106.6) 0 0.0538 — 4 0.0422 94.8 (25.8—242.7)

a Obs, observed; Exp, expected.

Risk of oral squamous cell carcinoma in 402 patients with oral lichen planus 81

expected in the population of Turin,29 possiblybecause of an association between having symp-toms related to OLP and deciding to quit smoking.Only two out of nine of the tumors occurred amongalcohol consumers and only one among subjectswho were both alcohol drinkers and smokers, sug-gesting that the effect of alcohol and of the inter-action between alcohol and tobacco cannot explainthe excess risk for oral cancer that we found in ourcohort.We found that 2.23% of the subjects in the cohort

developed an oral carcinoma during the period offollow-up and this proportion decreased to 1.13%when a latency of 2 years was applied, in accor-dance with Krutchkoff’s criteria. Similar malignanttransformation rates have been recently reportedby large Danish, American and Greek studies (1.5%,1.2% and 1.3%, respectively),6,8,14 which used strictcriteria, but did not fully apply the Krutchoff’sones. The OLP patients in our cohort had a greaterrate of malignant evolution in comparison to theexpected in the general population, being themagnitude of the SIR consistent with a previousDanish study.8 In our study, as well as in the Danishone, the risk of oral cancer was higher in womenthan in men. However, in the general populationfrom which the patients originated, the incidenceof oral carcinoma is higher among men than amongwomen,26 as the former smoke more. Thus, theSIRs gender-specific, which are calculated usinggender-specific incidence data in the generalpopulation, are not entirely comparable.A secondary aim of the study was to investigate

factors that could modify the risk of oral canceramong OLP patients. This issue has not been inves-tigated in details so far, although non reticularvarieties6,7,10,12 smoking and alcohol consumptionand therapy with immunosuppressive drugs andmouthwashes30 have been suggested to increasethe risk of transformation in uncontrolled clinicalstudies or case-reports. The present study does notsupport that non-reticular OLP are more predis-posed to malignant change. Moreover, immuno-suppressive therapy did not influence the risk fororal cancer. Since most of the patients were trea-ted with topical and sometime systemic steroidsplus antimycotics, our study suggests that thesetherapeutic modalities do not affect the risk ofmalignant transformation of OLP. However, othertreatments such as PUVA could theoreticallyincrease the risk of oral cancer and would need in-depth investigation.1

Oral verrucous and squamous cell carcinomashave been reported in HCV-infected patients, irre-spective of OLP,21�23 and positive HCV-RNA strandshave been detected both in oral cancer tissues31

and in OLP tissues.32 Some HCV proteins, namelythe core and the non-structural 3 protein, mayderegulate the cell cycle in vitro.33,34 We have,therefore, analyzed the role of HCV infection onOLP outcome. Although four out of nine patientswith oral cancer were HCV infected, the increasedrisk was not significant, possibly because of lowstatistical power. This result is difficult to inter-pret, because HCV is a common cause of liver cir-rhosis which may represent itself an independentrisk factor for the development of oral cancer.35

We were not able to disentangle between theeffect of HCV and the effect of cirrhosis, as onlyfew patients had a liver biopsy or were screenedfor liver cirrhosis.We did not directly address other suggested risk

factors for oral cancer in OLP patients as diet andcandida infection. Because of the pain, patientswith atrophic-erosive OLP could modify their dietby decreasing the consumption of fresh fruit andthey may thus increase their risk for oral cancer.36

Nevertheless, our study did not find an excess ofrisk for the atrophic-erosive form (red lichen) ascompared to white lichen, which is less frequentlyassociated with pain. Candida albicans has beenassociated with malignant development of oraldysplastic lesions and yeasts have also been iden-tified in OLP patients but not invariably.37 Morethan half of the patients in our cohort were treatedwith antimycotic drugs to prevent candidiasis butthe treatment did not influence significantly theonset of malignancy.In conclusion, the northern Italian patients with

OLP have a significantly increased risk of oral can-cer in comparison to the general population. Therisk applies to carriers of reticular-plaque OLP andatrophic-erosive forms invariably, and is not influ-enced by corticosteroids and anti-mycotic therapy.As a result, patients with OLP lesions should becarefully followed up to allow early detection ofthe onset of oral cancer irrespective of clinicalpresentation and other risk factors for oral cancer.

References

1. Scully C, Eisen D, Carrozzo M. Management of oral lichenplanus. Am J Clin Dermatol 2000;1:287—306.

2. Krutchkoff D, Cutler L, Laskowski S. Oral lichen planus: theevidence regarding potential malignant transformation.J Oral Pathol 1978;7:1—7.

3. Lo Muzio L, Mignogna MD, Favia G, Procaccini M, Testa NF,Bucci E. The possible association between oral lichen pla-nus and oral squamous cell carcinoma: a clinical evaluta-tion on 14 cases and a review of the literature. Oral Oncol1997;34:239—246.

4. Van der Meij EH, Schepman KP, Smeele LE, van der Vaal JE,Bezemer PD, van derWaal I. A review of the recent literature

82 S. Gandolfo et al.

regarding malignant trasformation of oral lichen planus.Oral Surg, Oral Med, Oral Pathol, Oral Radiol Endod 1999;88:307—310.

5. Krutchkoff DJ, Eisenberg E. Lichenoid dysplasia: a distincthistopathologic entity. Oral Surg Oral Med Oral Pathol1985;60:308—315.

6. Silverman Jr S, Gorsky M Lozada-Nur F. A prospective fol-low-up study of 570 patients with oral lichen planus: per-sistence, remission, and malignant association. Oral SurgOral Med Oral Pathol 1985;60:30—34.

7. Murti PR, Daftary DK, Bhonsle RB, Gupta PC, Mehta FS,Pindborg JJ. Malignant potential of oral lichen planus:observations in 722 patients from India. J Oral Pathol 1986;15:71—77.

8. Holmstrup P, Thorn JJ, Rindum J, Pindborg JJ. Malignantdevelopment of lichen planus-affected oral mucosa. J OralPathol 1988;17:219—225.

9. Salem G. Oral lichen planus among 4277 patients fromGizan. Saudi Arabia Community Dent Oral Epidemiol 1989;b7:322—324.

10. Silverman S, Gorsky M, Lozada-Nur F, Giannotti K. A pro-spective study of findings and management in 214 patientswith oral lichen planus. Oral Surg, Oral Med, Oral Pathol1991;72:665—670.

11. Voute AB, de Jong WF, Schulten EA, Snow GB, van der WaalI. Possible premalignant character of oral lichen planus.The Amsterdam experience. J Oral Pathol Med 1992;2b:326—369.

12. Barnard A, Scully C, Eveson W, Cunningham S, Porter R.Oral cancer development in patients with oral lichen pla-nus. J Oral Pathol Med 1993;22:421 -424.

13. Moncarz V, Ulniansky M, Lustmann J. Lichen planus:exploring its malignant potential. J Am Dent Assoc 1993;124:102—108.

14. Markopoulos AK, Antoniades D, Papanayotu P, Trigonidis O.Malignant potential of oral lichen planus: a follow-up studyof 326 patients. Oral Oncol 1997;33:263—269.

15. Silverman Jr S, Bahl S. Oral lichen planus update: clinicalcharacteristics, treatment responses, and malignant trans-formation. Am J Dent 1997;10:259—263.

16. Rajentheran R, McLean NR, Kelly CG, Reed MF, Nolan A.Malignant transformation of oral lichen planus. Eur J SurgOncol 1999;25:520—523.

17. Thang L, Michelsen C, Cheng X, Zeng T, Priddy R, Rosin MP.Molecular analysis of oral lichen planusA premalignantlesion? Am J Pathol 1997;151:323—327.

18. Kilpi A, Rich AM, Konttinen YT, Reade PC. The expression ofc-erbB-2 protein in the keratinocytes of oral mucosal lichenplanus. Br J Dermatol 1995;b33:847—852.

19. Valente O, Pagano M, Carrozzo M, et al. Sequential immu-noistochemical p53 expression in oral lichen lichen planusbiopsies undergoing malignant evolution. J Oral Pathol Med2001;30:135—140.

20. Carrozzo M, Gandolfo S, Carbone M, et al. Hepatits C virusinfection in Italian patients with oral lichen planus: a pro-spective case-control study. J Oral Pathol Med 1996;25:527—533.

21. Carrozzo M, Gandolfo S, Carbone M, Colombatto P, Olivieri

F. An atipical verrucous carcinoma of the tongue arising in apazient with oral lichen planus and hepatitis C virus infec-tion. Oral Oncol 1997;33:220—225.

22. Porter SR, Lodi O, Chandler K, Kumar N. Development ofsquamous cell carcinoma in hepatitis C virus-associatedlichen planus. Oral Oncol 1997;33:58—59.

23. Nagao Y, Sata M, Tanikawa K, Itoh K, Kameyama T. Highprevalence of hepatitis C virus antibody and RNA in patientswith oral cancer. J Oral Pathol Med 1995;24:354—360.

24. Carbone M, Conrotto D, Carrozzo M, Broccoletti R, GandolfoS, Scully C. Topical corticosteroids in association withmiconazole and chlorhexidine in the long-term manage-ment of atrophic-erosive oral lichen planus: a placebo-con-trolled and comparative study between clobetasol andfluocinonide. Oral Dis 1999;5:44—49.

25. Stata. Stata statistical software 6.0. College Station (TX):Stata Corporation; 1999.

26. Zanetti R, Gala L, Pannelli F, Conti E, Rosso S. Cancer inItaly. Incidence data from cancer registries 3rd vol. 1993—1998. Roma: II Pensiero Scientffico Editore; 2000.

27. Cox DR, Oakes D. Analysi of survival data. New York: Chap-man and Hall; 1984.

28. Helm TN, Camisa C, Liu AY, Valenzuela R, Bergfeld WF.Lichen planus associated with neoplasia: a cell-mediatedimmune response to tumor antigens? J Am Acad Dermatol1994;30:219—224.

29. Simonato L, Agudo A, Abrens W, et al. Lung cancer andcigarette smoking in Europe: an update of risk estimatesand an assessment of inter-country heterogeneity. Int JCancer 2001;91:876—878.

30. Lind PO, Koppang HS, Aas E. Malignant transformation inoral lichen planus Int J Oral Surg 1985;14:509—516.

31. Nagao Y, Sata M, Noguchi S, Seno’o T, Kinoshita M,Kameyama T, Ueno T. Detection of hepatitis C virus RNA inoral lichen planus and oral cancer tissues. J Oral PatholMed 2000;29:259—266.

32. Carrozzo M, Quadri R, Latorre P, et al. Molecular evidencethat the hepatitis C virus replicates in the oral mucosa. JHepatol 2002;37:364—369.

33. Sakainuro D, Furukawa T, Takegami T. Hepatitis C virusnonstructural protein NS3 transforms NIH 3T3 cells. J Virol1995;69:3893—3896.

34. Ray RB, Lagging LM, Meyer K, Ray R. Hepatitis C virus coreprotein cooperates with ras and transforms primary ratembryo fibroblasts to tumorigenic phenotype. J Virol 1996;70:4438—4443.

35. Sorensen HT, Friis S, Olsen JH, et al. Risk of liver andother types of cancer in patients with cirrhosis: a nation-wide cohort study in Denmark. Hepatology 1998;28:921—925.

36. McLaughlin JK, Gridley G, Block G, et al. Dietary factors inoral and pharyngeal cancer. J Natl Cancer Inst 1988;5:801237-1243.

37. Barrett AW, Kingsmill VJ, Speight PM. The frequency offungal infection in biopsies of oral mucosal lesions. Oral Dis1998;4:26—31.

38. International Union Against Cancer. TNM classification ofmalignant tumours. 5th ed. New York: Wiley-Liss; 1997.

Risk of oral squamous cell carcinoma in 402 patients with oral lichen planus 83