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Clinical guidelines in early detection of oral squamous cell carcinoma arising in oral lichen planus: a 5-year experience
Oral Oncology 37 (2001) 262±267
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Clinical guidelines in early detection of oral squamous cell carcinoma arising in oral lichen planus: a 5-year experience M.D. Mignogna *, L. Lo Muzio, L. Lo Russo, S. Fedele, E. Ruoppo, E. Bucci Department of Oral Medicine and Pathology, Faculty of Medicine, School of Dentistry, University of Naples Federico II, Via Domenico Fontana 81 pal. 10, 80128 Naples, Italy Received 21 June 2000; accepted 2 August 2000
Abstract In recent years, studies on the malignant potential of oral lichen planus (OLP) provided clinical evidence that patients aected by OLP have an increased risk to develop oral squamous cell carcinoma (OSCC); nevertheless, controversies still exist as to whether OLP has inherent predisposition to become malignant, or not. We believe extremely careful management of OLP patient is mandatory, and the aim of this paper is to illustrate our clinical guidelines in evaluating the possible risk of transformation in OLP lesions. Five-hundred and two patients (311 women and 191 men) aected by OLP regularly undergo follow-up examination in our Department. Patients' ages range from 18 to 83 years, with a mean of 55.4 years (57.5 for women and 53.9 for men); minimal follow-up period is 4 months, with a maximum of 12 years. In our group of OLP patients in the past 5 years we detected 24 carcinomas: excluding three cases in which diagnoses of OLP and OSCC were synchronous and three patients who had a history of tobacco use, thus possible malignant transformation of OLP would appear to be 3.7%. Clinical criteria used in our follow-up allowed us to detect 28.5% of tumours as in situ OSCC, 38% as microinvasive OSCC, 28.5% as stage I OSCC and 4.7% as stage II OSCC, with a remarkable improvement in prognosis compared to our previous study in which we adopted dierent criteria. # 2001 Elsevier Science Ltd. All rights reserved. Keywords: Oral lichen planus; Squamous cell carcinoma; Follow-up
1. Introduction Lichen planus is a chronic in¯ammatory mucocutaneous disease that frequently involves the oral mucosa. The disease aects 0.5±2% of the population with a predilection for females and a mean age at onset in the fourth to ®fth decade [1±3]. Since the turn of the century, numerous theories concerning its premalignant potential have been postuled; in fact, in 1910 Hallopeau reported a case of oral lichen planus (OLP) with malignant degeneration [4]. From that date, many sporadic cases of transformation have been reported in the literature [5±7], and many retrospective studies have been performed in several countries [8], showing a frequency of malignant transformation in OLP ranging from 0 to 10% [9±15]. An increased risk of oral cancer development for patients with OLP is now generally accepted, diagnosed * Corresponding author. Tel.: +39-81-7701718. E-mail address: [email protected] (M.D. Mignogna).
on the basis of clinical and histological manifestations [8,13,15±19], ful®lling uniformly accepted criteria [11,20], though necessity of a prospective multicentre case-control study has been pointed out [21]. Of course an early diagnosis is mandatory, also because of our suspicion of a high lymph nodal metastases rate (unpublished data), and reports of a rather poor prognosis [22]. So in this study, based on the past 5 years clinical experience, we analyse clinical aspects and criteria useful in early detection of malignant transformation of OLP. 2. Patients and methods To date, in the Division of Oral Medicine of the University of Naples ``Federico II'', 502 patients (311 women and 191 men) aected by OLP regularly undergo follow-up examination. Patients' ages range from 18 to 83 years, with a mean of 55.4 years (57.5 for women and 53.9 for men); minimal follow-up period is
1368-8375/01/$ - see front matter # 2001 Elsevier Science Ltd. All rights reserved. PII: S1368-8375(00)00096-8
M.D. Mignogna et al. / Oral Oncology 37 (2001) 262±267
4 months, with a maximum of 12 years. In all patients OLP diagnosis was con®rmed by oral biopsy and histological hallmarks used as diagnostic criteria, in haematoxilin±eosin-stained sections obtained from 10% neutral-buered formalin-®xed specimens, were hyperortho-hyperparakeratosis, varying thickness of the epithelium, focal signs of basal cell liquefaction degeneration, and a well-de®ned band-like in®ltrate of mononuclear cells adjacent to the basement membrane. Furthermore, testing for liver disease was performed by evaluation of serum levels of hepatic enzymes, and bilirubin following standard methods, and, in addition, serum antibodies to hepatitis C virus (HCV) were detected by second generation ELISA and con®rmed by second generation RIBA. Clinically, patients were categorised into six forms of OLP [3]: reticular (also including the papular form), plaque, atrophic, erosive, bullous and mixed (in which both reticular±plaque and atrophic±erosive lesions coexist). The categorisation was based on the prevalent clinical morphology of the lesions, and was extremely meticulous. In fact, we previously removed all clinical factors that could modify the clinical features of OLP, some of which represent, at the same time, a risk factor for oral cancer. So, we detected Candida infection and, when positive, we treated the patient topically with miconazole; as necessary, we removed calculus only by mechanical scaling, smoothed or extracted teeth in wrong position, recti®ed ill-®tting dentures, and made sure that patients did not use any drug locally and/ or perform incorrect oral care. No patients was suspected to have drug- or restoration-related lichenoid reaction; in addition, each patient was evaluated and OLP was morphologically classi®ed before therapy, and location of lesions was carefully recorded. During the follow-up, which implies clinical examination every 4 months, we analysed morphology, location, extent, and homogeneity of lesions, and whenever suspicious signs of malignant transformation were found we increased, as necessary, frequency of followup examination, or directly performed an additional oral biopsy. 3. Results In a previous paper [8] we reported a clinical evaluation on 14 cases of oral squamous cell carcinoma (OSCC) in OLP on patients that were followed with annual visits: half of them were stage II tumours, three were diagnosed in stage III and only four (about onethird) in stage I. In those 14 patients, morphological pictures of OLP were generally mixed, but the majority of carcinomas arose in a pre-existing plaque OLP lesion. In the past 5 years 24 new cases of OSCC occurred and all of them were located in an area of pre-existing OLP; 20 were women with a mean age of 52.05 years
263
(range 35±74) and four were men whose age ranged between 48 and 78 years with a mean of 66.75 years. Clinical features and location of OLP lesions in these patients are detailed in Table 1. The most commonly involved site was the buccal mucosa bilaterally, prevalently with keratotic features. Monolateral involvement was never found in men, whereas it was relatively uncommon in women, but with a predominant mixed morphology. The tongue was aected in 54.1% of cases, with a strong predilection for women. Unusually, involvement of palatal arch was found in 25% of cases and labial mucosa in 16.6%, with predominant keratotic lesions. Only one woman had a plaque lesion on the ¯oor of the mouth, whereas gingival location was found in 29.1% of patients. Morphological pictures of OLP were principally mixed (14 patients), although keratotic lesions had generally a wider extent; 10 patients had almost only keratotic lesions. Moreover, only two carcinomas arose in areas with atrophic±erosive lesions, while the others occurred in plaque±reticular ones. Clinically, OSCC were exophitic lesions with keratotic masses (eight cases: 33.3%), or indurated, non-healing ulcers (11 cases: 45.8%) with elevated margins; less frequently (®ve cases: 20.8%) the neoplasms showed clinical appearance of a red lesion, often speckled, and we noted this aspect particularly in in situ carcinomas or in OSCC localised on keratinized mucosa of the attached gingiva. This site and the tuber were involved in six cases (25%), buccal mucosa in eight patients, while the tongue was the most common location (nine cases: 37.5%) of OSCC. Histopathologically, almost all carcinomas were well dierentiated, only two were moderately dierentiated. Furthermore, as shown in Table 2, six (25%) were in situ carcinomas, in eight (33.3%) was found a microinvasive pattern of in®ltration (Fig. 1), one (4.1%) was a stage II tumour and the remaining (nine cases: 37.5%) were stage I tumours, except three of them classi®ed as stage IV tumours, which were new patients, whose diagnosis of OLP was synchronous to that of OSCC; unfortunately, these three patients died because of their oral cancer. Three patients (12.5%) developed OSCC in dierent sites during the follow-up period, whereas in three patients (12.5%) were found recidives near the site of the primary tumour, even if in two of them histopathological examination of the specimens of the primary tumours revealed margin of resection free of tumour and/or displasia, while only one case showed a mild displasia in one margin of resection. In addition, in ®ve cases lymph nodal metastases were detected by FNAC after clinical examination and imaging techniques revealed nodal enlargement; in one of these cases nodal metastases occurred in a 74year-old female aected by a stage II OSCC diagnosed after the patient had given up 4 years of follow-up examinations. Apart from this, it is of great interest to note that in the others four cases nodal metastases
1 ± ± ± ± ± 1
100 ± ± ± ± ± 100
2 ± ± ± ± 1 3
66.6 ± ± ± ± 33.3 100
± ± ± ± ± ± 3 50 ± ± 1 16.6 1 100 1 16.6 ± ± ± ± ± ± 1 16.6 1 100 6 100
occurred in microinvasive carcinomas, with a mean thickness of 1.75 mm, in a mean time of 4.75 months after diagnosis of OSCC was made. None of the patients drink alcohol and only three (two women and one man) smoked about 15 cigarettes a day; none of the other common predisposing factors to oral cancer could be encountered. As regards HCV antibodies, positivity was found in ®ve patients (20.8%): one man and four women. OLP lesions were completely asymptomatic in 15 cases (62.4%); three patients had only non-speci®c discomfort, whose therapy was deemed unnecessary, whilst the remaining patients had moderate (four cases: 16.6%) or severe pain (two cases: 8.3%), that required therapy with topical steroids (Clobetasol ointment 0.05% mixed 1:1 in orabase). Remission of symptoms was obtained, so all 24 patients were able to maintain a normal diet including fresh fruit and/or vegetables.
± 1 ± ± ± ± 1 ± ± ± ± ± ± ±
4. Discussion
Mixed=erosive/atrophic+plaque/reticular. a
41.7 100
Reticular Plaque Atrophic Erosive Bullous Mixeda Total
1 2 ± ± ± 1 4
25 50 ± ± ± 25 100
3 3 ± 1 ± 5 12
25 25 ± 8.3
± ± ± ± ± ± ±
± ± ± ± ± ± ±
1 ± ± ± ± 3 4
25 ± ± ± ± 75 100
± 1 ± ± ± ± 1
± 100 ± ± ± ± 100
2 5 ± ± ± 5 12
16.7 41.6 ± ± ± 41.6 100
1 ± ± ± ± ± 1
100 ± ± ± ± ± 100
3 1 ± ± ± 1 5
60 20 ± ± ± 20 100
± ± ± ± ± ± ±
± 100 ± ± ± ± 100
n % % n % n % n % n n % n % n %
%
n
%
n
% n n
Women Men Women Men
Men
Women
Men
%
Women
Women
%
n
Men2 Women Men Men
Gingiva Labial mucosa Floor of mouth Palatal arch Tongue Buccal mucosa monolaterally Buccal mucosa bilaterally
Table 1 Clinical features and sites of oral lichen planus lesions in oral squamous cell carcinoma patients
n %
M.D. Mignogna et al. / Oral Oncology 37 (2001) 262±267 Women
264
In recent years, studies on malignant potential of OLP knew a great ferment. From many of these studies came clinical evidence that patients aected by OLP have an increased risk to developing oral cancer. This concept is generally accepted [8,13,15±19] and OLP is classi®ed among precancerous conditions [23]; nevertheless, controversies still exist as to whether OLP has inherent predisposition to become malignant or not [24±26]. As clinicians, we think that OLP cannot be considered an entity unto itself, but there are patients aected by OLP and in these patients the action of various factors cannot be evaluated singularly. For this reason, though controversy still rages, we cannot disregard clinical evidence of an increased, even if small, risk of oral cancer development in OLP. So, according to us, extremely careful management of an OLP patient is mandatory, and the aim of this paper is to illustrate our clinical guidelines in evaluating the possible risk of malignant transformation in OLP lesions. In our series, location of OLP in patients with OSCC does not dier so much from other patients; however, it is interesting to note we found an unusual as much signi®cative higher frequency of involvement of midline structures such as palatal arch, labial mucosa and gingiva. Keratotic forms of OLP need particular care, both when they exist alone and when associated with atrophic±erosive ones into mixed form; in fact, all, except two of the 24 carcinomas arose in pre-existing keratotic (plaque and reticular) OLP lesions. So, classi®cation of the clinical form of OLP is a very important step in order to programme the followup, and necessarily requires removing all clinical factors that could modify clinical features of OLP, as described above. Regular follow-up must be performed at least three times a year. Every time an extremely meticulous
M.D. Mignogna et al. / Oral Oncology 37 (2001) 262±267
265
Table 2 Clinical data of carcinomas arising in patients with oral lichen planus (OLP) Case
Sex
Agea
Site of SCC
Type of OLP in area with SCC
Grading
Staging
Follow-up (years)b
Recidives
1 2 3 4 5 6 7
F F F F F F F
52 65 40 50 70 70 45 40 72 35 36 70
± G1 ± G2 G1
I (T1N0M0) I (T1N0M0) In situ I (T1N0M0) Microinvasive I (T1N0M0) In situ In situ In situ IV (T2N2M0) In situ IV (T2N2M0) Microinvasive
3 3 3 2 2 2 3 4 2 ± 2 ± 2
No SCC No SCC No SCC No SCC No SCC No SCC Yes SCC (after 1 year)
F F F F M
Reticular/plaque Reticular/plaque Plaque/reticular Plaque/reticular Reticular/plaque Reticular/plaque Reticular/plaque Atrophic/erosive Reticular/plaque Plaque/reticular Reticular/plaque Plaque/reticular Atrophic/erosive
G2 G1 ± G1 G1 G1 ±
8 9 10 11 12 13 14
F M
74 48
Margin of tongue (left) Gingiva Tongue Gingiva Tongue Tuber (right) Buccal mucosa (left) Buccal mucosa (right) Buccal mucosa (left) Tongue Buccal mucosa (right) Tuber (left) Buccal mucosa (left) Buccal mucosa (right) Tongue Tongue
Reticular/plaque Plaque/reticular
G1 G1
II (T2N0M0) Microinvasive
5 2
15
M
71
Buccal mucosa (right)
Plaque/reticular
G1
Microinvasive
2
16
F
72
Buccal mucosa (right)
Reticular/plaque
G2
I (T1N0M0)
2
17
F
59
Gingiva (left) Tuber (left)
Reticular/plaque Reticular/plaque
G1 G1
Microinvasive Microinvasive
2 2
18 19 20 21 22 23 24
M F F F F F F
78 72 71 46 61 54 74
Buccal mucosa (right) Tongue Tongue Tongue Gingiva (right) Palate Buccal mucosa (left)
Plaque/reticular Plaque/reticular Plaque/reticular Plaque/reticular Reticular/plaque Plaque/reticular Reticular/plaque
G1 G1 G1 G1 G1 ± ±
Microinvasive IV (T2N2M0) Microinvasive Microinvasive I (T1N0M0) In situ In situ
3 ± 2 3 4 3 4
a b
Yes SCC (after 1year) Died No SCC Died Yes SCC (after 7 months) Nodal metastases Nodal metastases (after 3 months) Nodal metastases (after 6 months) Nodal metastases (after 4 months) Yes SCC (after 4 months) Nodal metastases (after 6 months) Yes SCC (after 9 months) Died No SCC No SCC No SCC No SCC No SCC
Age at time of diagnosis of squamous cell carcinoma (SCC). Time from diagnosis of OLP.
Fig. 1. Case 21, microinvasive oral squamous cell carcinoma (OSCC): note the islands of neoplastic cells surrounded by a lymphocytic in®ltrate (haematoxylin±eosin, 100).
266
M.D. Mignogna et al. / Oral Oncology 37 (2001) 262±267
Fig. 2. Case 21, oral squamous cell carcinoma (OSCC) localised on right margin of the tongue arised in oral lichen planus: note the lack of homogeneity in the keratotic area.
clinical examination is required in order to evaluate both modi®cations of OLP lesions and suspicious signs of transformation. In the former eventuality the presence of local causes must be excluded; in the latter, care must be taken on various factors. First of all, neither the extent nor the degree of symptoms of lesions are useful indicators, whereas the most important factor is homogeneity of lesions in relation to the single site. In fact, loss of homogeneity in a site, clinically, expresses an alteration of epithelium biology and this is suspicious, especially when the involved area is small, because modi®cations due to disease activity generally involve the whole site or more than a site (Fig. 2). When clinical examination suggests disease progression or otherwise suspicious behaviour, the follow-up period must be halved to 2 months or an additional biopsy and careful histologic analysis can be directly performed. Choice should be guided only by clinical suspicion, because, according to our experience, toluidine blue is not dependable and sometimes (10% of cases) goes astray. In the past 5 years, in our group of OLP patients, incidence of oral cancer was 4.9%; excluding three cases in which diagnoses of OLP and OSCC were synchronous and three patients that had a history of tobacco use, possible malignant transformation of OLP could be estimated near 3.7%. The aforementioned criteria, applied on diagnosis of 21 OSCC, since the remaining three cases were stage IV tumours, referred to us for the ®rst time, allowed us to detect 28.5% of tumours as in situ OSCC, 38% as microinvasive OSCC, 28.5% as stage I OSCC and 4.7% as stage II OSCC. Conversely, in a
previous study [8], in a group of patients homogeneous to the present one for age, gender and HCV antibodies positivity, adopting an annual follow-up examination and giving major importance to atrophic±erosive forms of OLP, as literature reported [13,27], we were able to diagnose only 28.5% of tumours in stage I, 50% in stage II and 21.4% in stage III. Obvious are implications and the role of the described approach in prognosis of patients. So, these data stress the importance of a regular follow-up for OLP patients, at least three times a year, with an extremely meticulous clinical examination, especially in keratotic forms. Acknowledgements We thanks Mrs. Caterina BonavolontaÁ for clinical assistance to patients. References [1] Scully C, El-Korm M. Lichen planus. A review and update on pathogenesis. J Oral Pathol 1985;14:431±58. [2] Durke JJ, Frick WG. Lichen planus. Oral manifestation and suggested treatments. J Oral Maxillofac Surg 1982;40:240±4. [3] Andreasen JO. Oral lichen planus. A clinical evaluation of 115 cases. Oral Surg Oral Med Oral Pathol 1968;25:31±41. [4] Hallopeau H. Sur un cas de lichen de Wilson gingival avec neoplasie voisine dans la region maxillaire. Bull Soc Fr Derm Syph 1910;17:33. [5] Massa MC, et al. Malignant transformation of oral lichen planus: case report and review of the literature. Cutis 1990;45:45±7.
M.D. Mignogna et al. / Oral Oncology 37 (2001) 262±267 [6] Katz RW, et al. Oral squamous cell carcinoma arising in a patient with long standing lichen planus. A case report. Oral Surg Oral Med Oral Pathol 1990;70:282±5. [7] Tovaru S, et al. Lichen planus buccal et cancer. A propos de deux cas. Rev Stomatol Chir Maxillofac 1993;94:46±50. [8] Lo Muzio L, Mignogna MD, Favia G, Procaccini M, Testa NF, Bucci E. The possible association between oral lichen planus and oral squamous cell carcinoma: a clinical evaluation on 14 cases and a review of literature. Oral Oncology 1998;34:239±46. [9] Shklar G. Lichen planus as an oral ulcerative disease. Oral Surg Oral Med Oral Pathol 1972;33:376±88. [10] Reisman RJ, et al. The malignant potential of oral lichen planus: diagnostic pitfalls. Oral Surg Oral Med Oral Pathol 1974;38:227± 32. [11] Krutchko DJ, Cutler L, Laskowski S. Oral lichen planus: the evidence regarding potential malignant transformation. J Oral Pathol 1978;7:1±7. [12] Brabant P, Bossuyt M. Oral lichen planus. Acta Stomatol Belg 1990;87:233±9. [13] Barnard NA, Scully C, Eveson JW, Cunningham S, Porter SR. Oral cancer development in patients with oral lichen planus. J Oral Pathol Med 1993;22:421±4. [14] White FH, Jin Y, Yang L. Quantitative cellular and nuclear volumetric alterations in epithelium from lichen planus lesions of human buccal mucosa. J Oral Pathol Med 1994;23:205±8. [15] Duey DC, Eversole LR, Abemayor E. Oral lichen planus and its association with squamous cell carcinoma: an update on pathogenesis and treatment implications. Laryngoscope 1996; 106:357. [16] Holmstrup P. The controversy of a premalignant potential of oral lichen planus is over. Oral Surg Oral Med Oral Pathol 1992; 73(6):704±6. [17] Eversole LR. Editorial. Oral Surg Oral Med Oral Pathol 1992; 73:707.
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[18] Scully C, Beyli M, Ferreiro MC, Ficarra G, Gill Y, Griths M, et al. Update on oral lichen planus: etiopathogenesis and management. Crit Rev Oral Biol Med 1998;9(1):86±122. [19] Rajentheran R, McLean NR, Kelly CG, Reed MF, Nolan A. Malignant transformation of oral lichen planus. Eur J Surg Oncol 1999;25(5):520±3. [20] Van der Meij EH, Schepman KP, Smeele LE, Van der Wal JE, Bezemer PD, Van der Waal I. A review of recent literature regarding malignant trasformation of oral lichen planus. Oral Surg Oral Med Oral Pathol 1999;88:307±10. [21] Lozada-Nur F. Oral lichen planus and oral cancer: is there enough epidemiologic evidence? Oral Surg Oral Med Oral Pathol 2000;89(3):265±6. [22] Hietanen J, Paasonen M-R, Kuhlefelt M, Malmstrom M. A retrospective study of oral lichen planus patients with concurrent or subsequent development of malignancy. Oral Oncology 1999; 35:278±82. [23] Pindborg JJ, Reichart PA, Smith CJ, Van der Waal I. Histological typing of cancer and precancer of the oral mucosa. 2nd ed. Berlin: Springer, 1997. p. 30 [24] Eisenberg E, Krutchko DJ. Lichenoid lesions of oral mucosa. Diagnostic criteria and their importance in the alleged relationship to oral cancer. Oral Surg Oral Med Oral Pathol 1992; 73:699±704. [25] Zhang L, Michelsen C, Cheng X, Zeng T, Priddy R, Rosin MP. Molecular analysis of oral lichen planus: is this a premalignant lesion? Am J Pathol 1997;151:323±7. [26] Kilpi A, Rich AM, Konttinen YT, Reade PC. The expression of c-erbB-2 protein in keratinocytes of oral mucosal lichen planus. Br J Dermatol 1995;133:847±52. [27] Silverman SJ, Gorsky M, Lozada-Nur F. A prospective followup study of 570 patients with oral lichen planus: persistence, remission, and malignant association. Oral Surg Oral Med Oral Pathol 1985;60:30±4.
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Clinical guidelines in early detection of oral squamous cell carcinoma arising in oral lichen planus: a 5-year experience M.D. Mignogna *, L. Lo Muzio, L. Lo Russo, S. Fedele, E. Ruoppo, E. Bucci Department of Oral Medicine and Pathology, Faculty of Medicine, School of Dentistry, University of Naples Federico II, Via Domenico Fontana 81 pal. 10, 80128 Naples, Italy Received 21 June 2000; accepted 2 August 2000
Abstract In recent years, studies on the malignant potential of oral lichen planus (OLP) provided clinical evidence that patients aected by OLP have an increased risk to develop oral squamous cell carcinoma (OSCC); nevertheless, controversies still exist as to whether OLP has inherent predisposition to become malignant, or not. We believe extremely careful management of OLP patient is mandatory, and the aim of this paper is to illustrate our clinical guidelines in evaluating the possible risk of transformation in OLP lesions. Five-hundred and two patients (311 women and 191 men) aected by OLP regularly undergo follow-up examination in our Department. Patients' ages range from 18 to 83 years, with a mean of 55.4 years (57.5 for women and 53.9 for men); minimal follow-up period is 4 months, with a maximum of 12 years. In our group of OLP patients in the past 5 years we detected 24 carcinomas: excluding three cases in which diagnoses of OLP and OSCC were synchronous and three patients who had a history of tobacco use, thus possible malignant transformation of OLP would appear to be 3.7%. Clinical criteria used in our follow-up allowed us to detect 28.5% of tumours as in situ OSCC, 38% as microinvasive OSCC, 28.5% as stage I OSCC and 4.7% as stage II OSCC, with a remarkable improvement in prognosis compared to our previous study in which we adopted dierent criteria. # 2001 Elsevier Science Ltd. All rights reserved. Keywords: Oral lichen planus; Squamous cell carcinoma; Follow-up
1. Introduction Lichen planus is a chronic in¯ammatory mucocutaneous disease that frequently involves the oral mucosa. The disease aects 0.5±2% of the population with a predilection for females and a mean age at onset in the fourth to ®fth decade [1±3]. Since the turn of the century, numerous theories concerning its premalignant potential have been postuled; in fact, in 1910 Hallopeau reported a case of oral lichen planus (OLP) with malignant degeneration [4]. From that date, many sporadic cases of transformation have been reported in the literature [5±7], and many retrospective studies have been performed in several countries [8], showing a frequency of malignant transformation in OLP ranging from 0 to 10% [9±15]. An increased risk of oral cancer development for patients with OLP is now generally accepted, diagnosed * Corresponding author. Tel.: +39-81-7701718. E-mail address: [email protected] (M.D. Mignogna).
on the basis of clinical and histological manifestations [8,13,15±19], ful®lling uniformly accepted criteria [11,20], though necessity of a prospective multicentre case-control study has been pointed out [21]. Of course an early diagnosis is mandatory, also because of our suspicion of a high lymph nodal metastases rate (unpublished data), and reports of a rather poor prognosis [22]. So in this study, based on the past 5 years clinical experience, we analyse clinical aspects and criteria useful in early detection of malignant transformation of OLP. 2. Patients and methods To date, in the Division of Oral Medicine of the University of Naples ``Federico II'', 502 patients (311 women and 191 men) aected by OLP regularly undergo follow-up examination. Patients' ages range from 18 to 83 years, with a mean of 55.4 years (57.5 for women and 53.9 for men); minimal follow-up period is
1368-8375/01/$ - see front matter # 2001 Elsevier Science Ltd. All rights reserved. PII: S1368-8375(00)00096-8
M.D. Mignogna et al. / Oral Oncology 37 (2001) 262±267
4 months, with a maximum of 12 years. In all patients OLP diagnosis was con®rmed by oral biopsy and histological hallmarks used as diagnostic criteria, in haematoxilin±eosin-stained sections obtained from 10% neutral-buered formalin-®xed specimens, were hyperortho-hyperparakeratosis, varying thickness of the epithelium, focal signs of basal cell liquefaction degeneration, and a well-de®ned band-like in®ltrate of mononuclear cells adjacent to the basement membrane. Furthermore, testing for liver disease was performed by evaluation of serum levels of hepatic enzymes, and bilirubin following standard methods, and, in addition, serum antibodies to hepatitis C virus (HCV) were detected by second generation ELISA and con®rmed by second generation RIBA. Clinically, patients were categorised into six forms of OLP [3]: reticular (also including the papular form), plaque, atrophic, erosive, bullous and mixed (in which both reticular±plaque and atrophic±erosive lesions coexist). The categorisation was based on the prevalent clinical morphology of the lesions, and was extremely meticulous. In fact, we previously removed all clinical factors that could modify the clinical features of OLP, some of which represent, at the same time, a risk factor for oral cancer. So, we detected Candida infection and, when positive, we treated the patient topically with miconazole; as necessary, we removed calculus only by mechanical scaling, smoothed or extracted teeth in wrong position, recti®ed ill-®tting dentures, and made sure that patients did not use any drug locally and/ or perform incorrect oral care. No patients was suspected to have drug- or restoration-related lichenoid reaction; in addition, each patient was evaluated and OLP was morphologically classi®ed before therapy, and location of lesions was carefully recorded. During the follow-up, which implies clinical examination every 4 months, we analysed morphology, location, extent, and homogeneity of lesions, and whenever suspicious signs of malignant transformation were found we increased, as necessary, frequency of followup examination, or directly performed an additional oral biopsy. 3. Results In a previous paper [8] we reported a clinical evaluation on 14 cases of oral squamous cell carcinoma (OSCC) in OLP on patients that were followed with annual visits: half of them were stage II tumours, three were diagnosed in stage III and only four (about onethird) in stage I. In those 14 patients, morphological pictures of OLP were generally mixed, but the majority of carcinomas arose in a pre-existing plaque OLP lesion. In the past 5 years 24 new cases of OSCC occurred and all of them were located in an area of pre-existing OLP; 20 were women with a mean age of 52.05 years
263
(range 35±74) and four were men whose age ranged between 48 and 78 years with a mean of 66.75 years. Clinical features and location of OLP lesions in these patients are detailed in Table 1. The most commonly involved site was the buccal mucosa bilaterally, prevalently with keratotic features. Monolateral involvement was never found in men, whereas it was relatively uncommon in women, but with a predominant mixed morphology. The tongue was aected in 54.1% of cases, with a strong predilection for women. Unusually, involvement of palatal arch was found in 25% of cases and labial mucosa in 16.6%, with predominant keratotic lesions. Only one woman had a plaque lesion on the ¯oor of the mouth, whereas gingival location was found in 29.1% of patients. Morphological pictures of OLP were principally mixed (14 patients), although keratotic lesions had generally a wider extent; 10 patients had almost only keratotic lesions. Moreover, only two carcinomas arose in areas with atrophic±erosive lesions, while the others occurred in plaque±reticular ones. Clinically, OSCC were exophitic lesions with keratotic masses (eight cases: 33.3%), or indurated, non-healing ulcers (11 cases: 45.8%) with elevated margins; less frequently (®ve cases: 20.8%) the neoplasms showed clinical appearance of a red lesion, often speckled, and we noted this aspect particularly in in situ carcinomas or in OSCC localised on keratinized mucosa of the attached gingiva. This site and the tuber were involved in six cases (25%), buccal mucosa in eight patients, while the tongue was the most common location (nine cases: 37.5%) of OSCC. Histopathologically, almost all carcinomas were well dierentiated, only two were moderately dierentiated. Furthermore, as shown in Table 2, six (25%) were in situ carcinomas, in eight (33.3%) was found a microinvasive pattern of in®ltration (Fig. 1), one (4.1%) was a stage II tumour and the remaining (nine cases: 37.5%) were stage I tumours, except three of them classi®ed as stage IV tumours, which were new patients, whose diagnosis of OLP was synchronous to that of OSCC; unfortunately, these three patients died because of their oral cancer. Three patients (12.5%) developed OSCC in dierent sites during the follow-up period, whereas in three patients (12.5%) were found recidives near the site of the primary tumour, even if in two of them histopathological examination of the specimens of the primary tumours revealed margin of resection free of tumour and/or displasia, while only one case showed a mild displasia in one margin of resection. In addition, in ®ve cases lymph nodal metastases were detected by FNAC after clinical examination and imaging techniques revealed nodal enlargement; in one of these cases nodal metastases occurred in a 74year-old female aected by a stage II OSCC diagnosed after the patient had given up 4 years of follow-up examinations. Apart from this, it is of great interest to note that in the others four cases nodal metastases
1 ± ± ± ± ± 1
100 ± ± ± ± ± 100
2 ± ± ± ± 1 3
66.6 ± ± ± ± 33.3 100
± ± ± ± ± ± 3 50 ± ± 1 16.6 1 100 1 16.6 ± ± ± ± ± ± 1 16.6 1 100 6 100
occurred in microinvasive carcinomas, with a mean thickness of 1.75 mm, in a mean time of 4.75 months after diagnosis of OSCC was made. None of the patients drink alcohol and only three (two women and one man) smoked about 15 cigarettes a day; none of the other common predisposing factors to oral cancer could be encountered. As regards HCV antibodies, positivity was found in ®ve patients (20.8%): one man and four women. OLP lesions were completely asymptomatic in 15 cases (62.4%); three patients had only non-speci®c discomfort, whose therapy was deemed unnecessary, whilst the remaining patients had moderate (four cases: 16.6%) or severe pain (two cases: 8.3%), that required therapy with topical steroids (Clobetasol ointment 0.05% mixed 1:1 in orabase). Remission of symptoms was obtained, so all 24 patients were able to maintain a normal diet including fresh fruit and/or vegetables.
± 1 ± ± ± ± 1 ± ± ± ± ± ± ±
4. Discussion
Mixed=erosive/atrophic+plaque/reticular. a
41.7 100
Reticular Plaque Atrophic Erosive Bullous Mixeda Total
1 2 ± ± ± 1 4
25 50 ± ± ± 25 100
3 3 ± 1 ± 5 12
25 25 ± 8.3
± ± ± ± ± ± ±
± ± ± ± ± ± ±
1 ± ± ± ± 3 4
25 ± ± ± ± 75 100
± 1 ± ± ± ± 1
± 100 ± ± ± ± 100
2 5 ± ± ± 5 12
16.7 41.6 ± ± ± 41.6 100
1 ± ± ± ± ± 1
100 ± ± ± ± ± 100
3 1 ± ± ± 1 5
60 20 ± ± ± 20 100
± ± ± ± ± ± ±
± 100 ± ± ± ± 100
n % % n % n % n % n n % n % n %
%
n
%
n
% n n
Women Men Women Men
Men
Women
Men
%
Women
Women
%
n
Men2 Women Men Men
Gingiva Labial mucosa Floor of mouth Palatal arch Tongue Buccal mucosa monolaterally Buccal mucosa bilaterally
Table 1 Clinical features and sites of oral lichen planus lesions in oral squamous cell carcinoma patients
n %
M.D. Mignogna et al. / Oral Oncology 37 (2001) 262±267 Women
264
In recent years, studies on malignant potential of OLP knew a great ferment. From many of these studies came clinical evidence that patients aected by OLP have an increased risk to developing oral cancer. This concept is generally accepted [8,13,15±19] and OLP is classi®ed among precancerous conditions [23]; nevertheless, controversies still exist as to whether OLP has inherent predisposition to become malignant or not [24±26]. As clinicians, we think that OLP cannot be considered an entity unto itself, but there are patients aected by OLP and in these patients the action of various factors cannot be evaluated singularly. For this reason, though controversy still rages, we cannot disregard clinical evidence of an increased, even if small, risk of oral cancer development in OLP. So, according to us, extremely careful management of an OLP patient is mandatory, and the aim of this paper is to illustrate our clinical guidelines in evaluating the possible risk of malignant transformation in OLP lesions. In our series, location of OLP in patients with OSCC does not dier so much from other patients; however, it is interesting to note we found an unusual as much signi®cative higher frequency of involvement of midline structures such as palatal arch, labial mucosa and gingiva. Keratotic forms of OLP need particular care, both when they exist alone and when associated with atrophic±erosive ones into mixed form; in fact, all, except two of the 24 carcinomas arose in pre-existing keratotic (plaque and reticular) OLP lesions. So, classi®cation of the clinical form of OLP is a very important step in order to programme the followup, and necessarily requires removing all clinical factors that could modify clinical features of OLP, as described above. Regular follow-up must be performed at least three times a year. Every time an extremely meticulous
M.D. Mignogna et al. / Oral Oncology 37 (2001) 262±267
265
Table 2 Clinical data of carcinomas arising in patients with oral lichen planus (OLP) Case
Sex
Agea
Site of SCC
Type of OLP in area with SCC
Grading
Staging
Follow-up (years)b
Recidives
1 2 3 4 5 6 7
F F F F F F F
52 65 40 50 70 70 45 40 72 35 36 70
± G1 ± G2 G1
I (T1N0M0) I (T1N0M0) In situ I (T1N0M0) Microinvasive I (T1N0M0) In situ In situ In situ IV (T2N2M0) In situ IV (T2N2M0) Microinvasive
3 3 3 2 2 2 3 4 2 ± 2 ± 2
No SCC No SCC No SCC No SCC No SCC No SCC Yes SCC (after 1 year)
F F F F M
Reticular/plaque Reticular/plaque Plaque/reticular Plaque/reticular Reticular/plaque Reticular/plaque Reticular/plaque Atrophic/erosive Reticular/plaque Plaque/reticular Reticular/plaque Plaque/reticular Atrophic/erosive
G2 G1 ± G1 G1 G1 ±
8 9 10 11 12 13 14
F M
74 48
Margin of tongue (left) Gingiva Tongue Gingiva Tongue Tuber (right) Buccal mucosa (left) Buccal mucosa (right) Buccal mucosa (left) Tongue Buccal mucosa (right) Tuber (left) Buccal mucosa (left) Buccal mucosa (right) Tongue Tongue
Reticular/plaque Plaque/reticular
G1 G1
II (T2N0M0) Microinvasive
5 2
15
M
71
Buccal mucosa (right)
Plaque/reticular
G1
Microinvasive
2
16
F
72
Buccal mucosa (right)
Reticular/plaque
G2
I (T1N0M0)
2
17
F
59
Gingiva (left) Tuber (left)
Reticular/plaque Reticular/plaque
G1 G1
Microinvasive Microinvasive
2 2
18 19 20 21 22 23 24
M F F F F F F
78 72 71 46 61 54 74
Buccal mucosa (right) Tongue Tongue Tongue Gingiva (right) Palate Buccal mucosa (left)
Plaque/reticular Plaque/reticular Plaque/reticular Plaque/reticular Reticular/plaque Plaque/reticular Reticular/plaque
G1 G1 G1 G1 G1 ± ±
Microinvasive IV (T2N2M0) Microinvasive Microinvasive I (T1N0M0) In situ In situ
3 ± 2 3 4 3 4
a b
Yes SCC (after 1year) Died No SCC Died Yes SCC (after 7 months) Nodal metastases Nodal metastases (after 3 months) Nodal metastases (after 6 months) Nodal metastases (after 4 months) Yes SCC (after 4 months) Nodal metastases (after 6 months) Yes SCC (after 9 months) Died No SCC No SCC No SCC No SCC No SCC
Age at time of diagnosis of squamous cell carcinoma (SCC). Time from diagnosis of OLP.
Fig. 1. Case 21, microinvasive oral squamous cell carcinoma (OSCC): note the islands of neoplastic cells surrounded by a lymphocytic in®ltrate (haematoxylin±eosin, 100).
266
M.D. Mignogna et al. / Oral Oncology 37 (2001) 262±267
Fig. 2. Case 21, oral squamous cell carcinoma (OSCC) localised on right margin of the tongue arised in oral lichen planus: note the lack of homogeneity in the keratotic area.
clinical examination is required in order to evaluate both modi®cations of OLP lesions and suspicious signs of transformation. In the former eventuality the presence of local causes must be excluded; in the latter, care must be taken on various factors. First of all, neither the extent nor the degree of symptoms of lesions are useful indicators, whereas the most important factor is homogeneity of lesions in relation to the single site. In fact, loss of homogeneity in a site, clinically, expresses an alteration of epithelium biology and this is suspicious, especially when the involved area is small, because modi®cations due to disease activity generally involve the whole site or more than a site (Fig. 2). When clinical examination suggests disease progression or otherwise suspicious behaviour, the follow-up period must be halved to 2 months or an additional biopsy and careful histologic analysis can be directly performed. Choice should be guided only by clinical suspicion, because, according to our experience, toluidine blue is not dependable and sometimes (10% of cases) goes astray. In the past 5 years, in our group of OLP patients, incidence of oral cancer was 4.9%; excluding three cases in which diagnoses of OLP and OSCC were synchronous and three patients that had a history of tobacco use, possible malignant transformation of OLP could be estimated near 3.7%. The aforementioned criteria, applied on diagnosis of 21 OSCC, since the remaining three cases were stage IV tumours, referred to us for the ®rst time, allowed us to detect 28.5% of tumours as in situ OSCC, 38% as microinvasive OSCC, 28.5% as stage I OSCC and 4.7% as stage II OSCC. Conversely, in a
previous study [8], in a group of patients homogeneous to the present one for age, gender and HCV antibodies positivity, adopting an annual follow-up examination and giving major importance to atrophic±erosive forms of OLP, as literature reported [13,27], we were able to diagnose only 28.5% of tumours in stage I, 50% in stage II and 21.4% in stage III. Obvious are implications and the role of the described approach in prognosis of patients. So, these data stress the importance of a regular follow-up for OLP patients, at least three times a year, with an extremely meticulous clinical examination, especially in keratotic forms. Acknowledgements We thanks Mrs. Caterina BonavolontaÁ for clinical assistance to patients. References [1] Scully C, El-Korm M. Lichen planus. A review and update on pathogenesis. J Oral Pathol 1985;14:431±58. [2] Durke JJ, Frick WG. Lichen planus. Oral manifestation and suggested treatments. J Oral Maxillofac Surg 1982;40:240±4. [3] Andreasen JO. Oral lichen planus. A clinical evaluation of 115 cases. Oral Surg Oral Med Oral Pathol 1968;25:31±41. [4] Hallopeau H. Sur un cas de lichen de Wilson gingival avec neoplasie voisine dans la region maxillaire. Bull Soc Fr Derm Syph 1910;17:33. [5] Massa MC, et al. Malignant transformation of oral lichen planus: case report and review of the literature. Cutis 1990;45:45±7.
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