Transformation of proliferative verrucous leukoplakia to oral carcinoma: a ten years follow-up

NAVARRO CM, SPOSTO MR, SGAVIOLI-MASSUCATO EM, ONOFRE MA. TRANSFORMATION OF PROLIFERATIVE VERRUCOUS LEUKOPLAKIA TO ORAL CARCINOMA: A TEN YEARS FOLLOW-UP. MED ORAL 2004;9:229-33.

SUMMARY

The authors present a case of proliferative verrucous leukoplakia (PVL) in a 78-year-old man. It was initially presented as leukoplakia on the tongue but a microscopic investigation in 1991 revealed it to be a mild epithelial dysplasia. After 5 years of follow-up, the lesion presented changes in size and location, and a recidivant behavior. In 1996, a red granular and indurated area that appeared on the tongue was found to be a microinvasive squamous cell carcinoma when microscopically investigated. After a review of the clinicopathologic behavior of this entity, the authors concluded that it was a typical PVL, whose diagnosis is difficult and retrospective, as indicated by others. The authors emphasize the importance of periodic detailed clinical and histological examination of this type of lesions in order to detect early signs of malignancy.

Key Words: Proliferative verrucous leukoplakia, papilloma-tosis, squamous cell carcinoma, epithelial hyperplasia, dysplasia.

INTRODUCTION

In a retrospective study, Hansen et al. (1985) (1) reported that 26 of the 30 lesions initially diagnosed as leukoplakia became oral carcinomas in patients followed for 1 to 20 years (average, 6.1 years). After this study, these lesions were named proliferative verrucous leukoplakia (PVL). The term PVL is used for lesions initially presenting homogeneous white appearance with changes in clinical and microscopic aspects during their natural history. Variation in diagnosis and clinical management can occur according to the stage in which PVL is observed in the first examination. Therefore, clinical follow-up of the patient is essential because PVL is a clinicopathologic disease with high potential for malignancy whose diagnosis is retrospective. According to Silverman and Gorsky (1997) (2), 70.3% of the patients studied developed a squamous cell carcinoma at a PVL site, most frequently at the gingiva and tongue, over a mean time of 7.7 years. Thus, the PVL must be considered aggressive. It has been shown that almost all lesions occur bilaterally in elderly women, mainly affecting the lower alveolar ridge and buccal mucosa (1-4). In the 54 patients studied (2) the most common sites involved were buccal mucosa in women and tongue in men. There is significant evidence of PVL infection with type 16 HPV (5).

We report here a patient with multiple white lesions on the tongue compatible with PVL which was transformed into oral carcinoma after 5 years of clinical and microscopic follow-up.

CASE REPORT

In November 1991, a 78-year-old white man was admitted to the Oral Medicine Service of the Dental School of Araraquara, UNESP, Brazil, referred by a dermatologist who had made a diagnosis of oral leukoplakia. The medical history revealed that the patient had been a smoker for 40 years and had stopped smoking 17 years before. His brother died of oral squamous cell carcinoma on the lateral border of the tongue. The patient reported that the white lesions had appeared 3 years before. 

The first oral examination (November 1991) showed asymptomatic white patches with the aspect of verrucous leukoplakia on the borders of the tongue spreading to the floor of the mouth. On the left side of the tongue there was a nodular and indurated area (Figure 1a). The Toluidine blue staining used as routine staining (6) was positive in this area, which was completely removed. Microscopic investigation showed mild epithelial dysplasia with papillomatous aspect [stage 2 - Axéll (7)] Numerous eosinophils were found in the subepithelial connective tissue. The microscopic pattern was compatible with the clinical diagnosis of verrucous leukoplakia [Figure 1b - Hansen (1) microscopic grade 1 - 4]. The second oral examination (November 1992) revealed at the same site, homogeneous leukoplakia on the left ventral surface of the tongue and extending to the floor of the mouth. Although Toluidine blue staining had negative results, the clinical decision was a complete surgical excision. Microscopic investigation showed mild dysplastic epithelium [stage 1 - Axéll (7)] with hyperplasia, intense hyperparakeratosis and the presence of several coilocytes on the superficial layers of the oral epithelium. 

Fig. 1 a). Nodular white plaque with a verrucous surface on the left border of 
the tongue (toluidine blue stain positive). b) Epithelium showing mild 
hyperkeratosis (H/E - 25X).

1a). Placa blanca nodular con superficie verrugosa sobre el borde izquierdo lingual
(tinción positiva con azul de toluidina). b) Epitelio mostrando ligera 
hiperqueratosis (H/E - 25X)

 

Numerous eosinophils were also found in connective tissue. The microscopic pattern was in agreement with the clinical diagnosis of homogeneous leukoplakia. The third oral examination (October 1994) showed a verrucous leukoplakia with superficial roughness and an indurated and raised circumscribed region similar to the first lesion (November 1991). In spite of negative results showed by Toluidine blue staining (6), the clinical decision was to remove the lesion completely. The microscopic investigation showed moderate epithelial dysplasia [stage 3 - Axéll (7)] associated with hyperplasia of papillomatous appearance and eosinophils in connective tissue [Hansen (1) microscopic grade 4 - 5]. The fourth oral examination (May 1996) presented an oral leukoplakia with a verrucous surface on the left border of the tongue in three areas, i.e., anterior, middle and posterior (Figure 2a). The anterior and middle regions presented a nodular and indurated area of verrucous texture, both proved negative by Toluidine blue staining. The microscopic investigation of the anterior and middle area of the tongue revealed moderate dysplasia [stage 3 - Axéll (7)] associated with papillomatous hyperplastic epithelium, and sparse eosinophils in connective tissue. This pattern was compatible with the clinical diagnosis of verrucous leukoplakia. The posterior area was verrucous, slightly raised and indurated, with a granular texture and a red discoloration probably corresponding to an area of epithelial erosion. This area was considered positive by Toluidine blue stain. A fissure was also observed in the lower edge of the lesion. The microscopic examination of the incisional biopsy revealed moderately differentiated microinvasive squamous cell carcinoma with the neoplastic cells close to the epithelium without muscular involvement [Figure 2b - Hansen (1) microscopic grade 9 - 10]. Finally, all the lesion on the left lateral border of the tongue was surgically excised. The postoperative evolution has been satisfactory and the patient is still under periodic follow-up at his 88 years of age.

 

Fig. 2 a). Verrucous white plaque on the left side of the tongue, posterior region 
presenting erosive surface. b) Epithelium showing hyperkeratosis, severe dysplasia, and an 
island of epithelial cell in connective tissue. Microinvasive squamous cell carcinoma (H/E - 25X).

2 a). Placa blanca verrugosa en el lado izquierdo lingual, en la zona posterior presenta
una superficie erosiva. b) El epitelio muestra hiperqueratosis, severa displasia así como nidos 
de células epiteliales en el tejido conectivo. Carcinoma de células escamosas microinvasor (H/E - 25X).

 

A total of 4 biopsies and 4 surgical excisions were performed during the follow-up period (10 years). The patient has been examined periodically according to his complaints. The lesions presented changes in the intensity of the papillomatous aspect, presence of red areas, size and location. Based on this clinical evolution with a recidivant aspect, and on the review of the clinical and microscopic diagnosis associated with malignant transformation to a squamous cell carcinoma after 5 years of follow-up, we conclude that this disease is a PVL retrospectively diagnosed (1-3).

DISCUSSION

The follow-up of the leukoplakias is important due to the evolutional aspects involved in this lesion. The objective of the authors is to demonstrate the importance of a periodic and detailed clinical examination in attempt to detect areas suggesting oral carcinomas in the early stages. In the present case we observed a strong recidivant pattern as well as changes in size, clinical appearance and location of the lesion indicating a clinically aggressive evolution making periodic recall mandatory.

The patient reported here initially presented an oral verrucous leukoplakia with mild dysplasia which presented malignant transformation after 5 years in an area whose initial clinical and microscopic appearance were not serious, in agreement with reports (1-3).

The appearance of mild erythematous discoloration and the granular texture suggesting epithelial erosion proved to be more effective indicators of malignancy than indurated or nodular aspects (8). This observation supports the common sense approach that, if a leukoplakia presents a red component, this area of the lesion should be investigated due to the high risk for malignant transformation (9). This is particularly true for verrucous leukoplakias located on the lateral border or ventral surface of the tongue.

In fact, techniques for advanced diagnosis of the oncogenic potential of potentially malignant epithelial oral lesions (PMEOL) such as in situ hybridization or PCR are available to identify HPV infection, but these techniques are not always available in the routine care of patients with leukoplakias or others PMEOL. Besides, according to Silverman and Gorsky (1997) (2), careful clinical and microscopic assessment combined with surgical intervention, clinical judgement, and close follow-up offers the best approach to management and control of leukoplakia.

With this report we illustrate the relevance of periodic and detailed examination mainly in cases of suspected PVL. In fact, the diagnosis of PVL is based on the biological behavior of the lesion during a long period of time according to the evolution. PVL has almost 100% rate of malignant transformation, mainly over an extended follow-up period (1,2,4). On the other hand, it is accepted that approximately 5% of all non-PVL leukoplakias will become cancer over an average period of 5 years (10).

This report presents the PVL as an aggressive clinicopathologic entity whose diagnosis was based on a 10 years retrospective analysis. Finally, it is necessary to remind that the diagnosis of PVL requires a comprehensive re-evaluation of the case. This must be based on the clinicopathologic evolution and it requires a reformulation of our own clinical concepts and ideas, always considering that this lesion is progressive.

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