Study of persistence and recurrence rates in 106 patients with condyloma and intraepithelial neoplasia after CO2 laser treatment

ARTICLE

Auteur(s) : Olivier Aynaud¹, Marc Buffet¹, Philippe Roman¹, Françoise Plantier², Nicolas Dupin¹

¹Department of Dermatology and Venereology, Pavillon Tarnier, Hôpital Cochin, APHP, 89 rue d’Assas, 75006 Paris, France
²Department of Pathology, Pavillon Tarnier, Hôpital Cochin, APHP, 89 rue d’Assas, 75006 Paris, France

accepté le 6 Octobre 2007

Human papillomavirus (HPV)-induced anogenital lesions are the expression of one of the most common sexually transmitted infections (STI). In the United Kingdom, the prevalence of anogenital condylamatosis is estimated at between 4% and 13% among patients attending venereal disease clinics [1], with a consistently increasing annual incidence [2]. In the USA in 1997, the prevalence of HPV-induced clinical lesions was approximately 1% in sexually active adults, and 15% of adults suffered from an infra-clinical infection detected by DNA screening for HPV [2].

In the United States, the incidence of high-grade vulvar intraepithelial neoplasia (VIN III) is estimated at 4.5 per 100,000 women aged 35 to 54 years [3]. In the Ile-de-France region around Paris, the incidence of high-grade penile intraepithelial neoplasia (PIN III) is estimated at 3.3 per 100,000 in the male population aged 20 to 60 years, and 3.9 per 100,000 for VIN in females in the same age group [4]. These epidemiological evaluations demonstrate the importance of efficiently treating HPV-induced anogenital lesions.

Numerous therapeutic methods have been proposed, adapted either as a function of the clinical appearance of lesions, or their surface area, or their site. No method can achieve a cure in 100% of cases. Of these treatments, CO2 laser is proposed with a remission rate which ranges from 27% to 94%, and a relapse rate of between 7% and 72% [5-8]. Other treatments comprised self-application of podophyllotoxine, application of imiquimod, trichloacetic acid, cryotherapy, electrocoagulation and surgery, with a relapse rate between 15 to 65% [8, 9].

During this study, we assessed the results obtained with CO2 laser treatment under colposcopic guidance, in all immunocompetent and non-immunocompetent patients treated for HPV-induced anogenital lesions. We sought to determine the factors associated with a persistence or recurrence of HPV-induced lesions.

Methods

Patients

Of the 106 patients, 27 (25.5%) had been previously treated. Seventeen patients had been treated by imiquimod, 7 patients treated by application of liquid nitrogen and 3 patients had already been treated by CO2 laser.

Treatment

The patients were treated with a CO laser (CM-500, 50 watts), under colposcopic guidance (Zeiss colposcope, OPMI-9FC, focal distance: 250 mm). We used a displayed power of 30 watts at the cutaneo-mucosal level, in continuous mode, with a focal distance of 125 mm and a spot at 0.5 mm. The average lateral margins applied were 5 millimetres. Treatments were performed in an outpatient setting: 62 patients (58.5%) under local anaesthesia, and the 44 others under general anaesthesia (Diprivan^®).

The surface area for laser lesion excision was quantified by S1 ≤ 4 cm², 4 cm²  ≤ S2 ≤ 8 cm² and S3 > 8 cm². We also quantified the number of sites in the anogenital region (1 to 3 sites) where HPV-induced lesions had developed. In patients who had undergone several treatments (either because of a relapse, or because of several scheduled appointments), we counted the number of CO2 laser sessions. During each post-operative consultation, an anogenital examination was performed under colposcopy (vulvar colposcopy, peniscopy, anuscopy, meatoscopy).

Patients attended control visits at M1 (30 days), M3 (90 days) and M6 (180 days).

In order to evaluate relapses, we introduced the notion of recurrence and persistence to enable discussion of the efficacy of CO2 laser treatment. The recurrence of an HPV-induced anogenital lesion was defined by the onset after its treatment of a new lesion at distance from the treated zone, whatever the time elapsing and the site. The recurrent lesion originated from a current or latent zone of HPV infection. Persistence of a lesion was the development of a new HPV-induced lesion after treatment in the treated zone, thus suggesting either insufficient or ineffective treatment. Thus relapse was the clinical appearance of an HPV-induced lesion, after treatment, of either type: persistent or recurrent.

The results were studied as a function of immune status. The study population was thus divided into three groups: an HIV(+) group, a group receiving immunosuppressant therapy (ImST) and an immunocompetent group (ImC). Statistical analyses were performed using the χ² and Fisher tests.

Results

HPV-induced intraepithelial neoplasms affecting the anogenital organs were significantly more frequent in the HIV(+) group of patients (47.4%) than in the ImC group (20.2%) (p = 0.015, χ²). In contrast, this difference was not significant between ImST and IC patients (p = 0.79, Fisher test).

Whatever the immune status of patients, we saw no significant difference between groups with respect to the surface area affected (Fisher test).

A significant difference could be seen (p < 0.05) between the risk of developing high-grade intraepithelial neoplasms at several sites in HIV+ patients (67%, 6/9) and in ImC patients (43.7%, 7/16). In contrast, there was no significant difference (p = 0.79, Fisher test) between the three groups regarding the development of condylomas as a function of the number of sites on the body.

Post-laser control visits (M1) after the initial treatment revealed relapses in 20 cases (18.8%), including 13 cases of recurrence (12.6%) and 7 of persistence (6.6%), while in 86 cases (81.2%) there were no clinical HPV-induced lesions (table 2). The remission rate at one month did not differ significantly in the three groups (Fisher test, 2 ddl), but immunocompetent patients exhibited a higher remission rate than those with therapeutic or viral immunodepression (83.5% versus 74%, ns). There was no significant difference between remission and relapse in terms of the histological type of the lesions treated.

The results at 6 months are summarised in table 3, although 13 patients (12.3%) were lost to follow-up. 93% of patients in remission at 1 month were also in remission at 3 months, and 65% of relapses at 1 month were in remission at 3 months (67% persisting cases, 57% recurrences). Intraepithelial neoplasms in remission at 1 month were always still in remission at 6 months, but 50% and 70% respectively of patients with persistence and recurrence at 1 month were in remission at 6 months. ImC and ImST patients presented more frequently with recurrence than persistence when compared with HIV(+) patients, who presented with identical recurrence and persistence rates.

Patients presenting with recurrence underwent 2.25 laser treatments each, and the mean interval to the onset of recurrence was 74 days. Patients presenting with persistence underwent 1.95 laser treatments per patient and the mean interval to persistence was 112 days. In total, out of 93 patients, at 6 months, 87 (83%, 87/106) were in remission after a total number of 1.4 laser sessions per patient. The principal post-operative incidents were two cases of dyschromia on the genital zones treated, and two patients presenting with anogenital pain requiring major analgesia. We did not observe any cases of urethral narrowing, phimosis or paraphimosis. One female patient experienced a tear to the vulvar interlabial frenum, requiring a perineotomy. No post-treatment infections were reported.

Statistical analysis of the entire population demonstrated a lack of any significant difference between men and women regarding lesion type (p = 0.79), the topography of lesions and the number of remissions.

Prior to CO2 laser treatment, lesions in patients with a recurrence had been developing on average for more than 10 months, versus 29 months for persistent lesions. More than half (10/19, 52.6%) of HIV(+) patients relapsed, compared with ImST patients (3/8, 37.5%) and ImC patients (18/79, 22.8%). There was no significant difference between the three groups with respect to recurrence. However, there was a significant difference between ImC and HIV(+) patients with respect to relapse (table 4). Recurrence in HIV(+) patients was more frequently associated with intraepithelial neoplasms (80%) versus ImC patients (29.4%) (p = 0.01).
Table 1 Topography and histology of HPV-induced lesions responding to CO2 laser treatment

Discussion

Krebs et al. saw a 79% success rate after the first session of laser treatment, which reached 87% after a second session [13]. Similarly, Lassus et al. showed that in patients suffering from an infection due to HPV which was resistant to conventional therapy, laser treatment was effective in treating macroscopically visible lesions, but the HPV genome was not eradicated. They also demonstrated that CO2 laser treatment reduced the relapse rate in patients with bowenoid papulosis [14].

Furthermore, relapses of condylomas appear to be linked to a persistence of HPV DNA in an epithelium of normal appearance [10]. In healthy skin, taken 5 to 15 mm from the zone treated with laser sequences, Ferenczy et al. demonstrated the presence of HPV in 45% of these biopsies, suggesting that HPV could be clinically and histologically latent close to the treated area [15].

In our study population, we saw a higher incidence of the development of HPV-induced lesions affecting the urethra in men (14%) than in women (5%). In contrast, there was an identical incidence of localisation in the anal sphere: 44% of cases in men involved the anal margin versus 50% of cases in women, and 33% of cases in men involved the anal canal, versus 26% of cases in women. However, the development of a lesion more frequently unique in the anal sphere in men (41.3% of cases versus 34.9% in women) was due to a recruitment bias concerning homosexual men. Little reference is made to these data in the literature. Krebs found 12% of urethral (meatus and peri-meatic) and 3% of anal cases, this bias arising from the recruitment of patients amongst the partners of women infected by HPV [16]. More than one-third of these patients had several affected sites. It is therefore necessary to screen for HPV-induced lesions throughout the anogenital region, and ensure the global management of these lesions.

Among the different types of lesions diagnosed, our study differed in that it found 25% of high-grade intraepithelial neoplasms. The figures in the literature suggest a rate of between 10 and 15% [2, 16]. It is currently acknowledged that patients with an immune deficit have a higher risk of developing dysplastic anogenital lesions [17, 18], and our patient series contained a high proportion of individuals with therapeutic or viral immunodeficiency (25.5% of cases), which might explain this incidence of anogenital intraepithelial neoplasms.

The remission rate at 6 months among patients followed after the laser treatment of HPV-induced anogenital lesions was 93.5%, but 12.3% of patients had been lost to follow-up by that stage; if the latter were considered as failures, the remission rate we achieved reached 83%. On average, we performed 1.4 CO2 laser sessions per patient to achieve a remission, or 1.95 laser sessions for patients presenting with persistent lesions versus 2.25 sessions in each patient with a recurrence.

Following the first session of laser treatment, we observed a remission rate of 81.2%, all types of immune status taken together. This result was comparable to the majority of the findings published in the literature, which refer to remission rates of between 34 and 100% [16]. On the other hand, we achieved a slightly higher remission rate in immunocompetent patients (83.5%) versus 75% in the group with therapeutic immunodepression and 73.7% in HIV+ patients, although these differences were not significant.

Furthermore, it is necessary to follow patients for up to 6 months, because although 93% of patients in remission at 1 month remain so at 3 months, this figure only reaches 87% at 6 months. In most cases, relapses took the form of recurrences, thus confirming the importance of patient follow-up, including a clinical anogenital examination, particularly since the median intervals for the detection of relapses were 74 days and 128 days, for recurrence and persistence, respectively.

The prognosis for remission was more favourable with lesions limited to one or two sites on the body (73% of remissions) than in patients with more than two affected sites (50% of remissions). The surface area of the lesion was also a factor in favour of early remission, as 40.7% of patients in remission had lesions ≤ 4 cm², versus 10% in the other group.

Individuals presenting with anogenital intraepithelial neoplasms experienced recurrence (37.5%) more frequently than persistence (20%). This suggests that intraepithelial neoplasms may be diseases which initially develop infra-clinically, the lesions tending to develop at several sites (as is the case in bowenoid papulosis), and more frequently in immunodeficient individuals, particularly since the mean age of this population is 36 years.

During this study, we did not demonstrate any significant difference with respect to the surface area of lesion development between the three groups (HIV(+), ImST, ImC). This was probably linked to the fact that in the patients recruited, the indication for laser treatment was made because of a marked development of lesions and/or their resistance to other therapies. In contrast, intraepithelial neoplasms were significantly more common in HIV(+) patients (47.4% versus 20.2%), and lesions covered a larger surface area (p < 0.05). In these patients, relapses more frequently took the form of recurrence, which could correspond to the mode of expression of the evolving primary HPV infection, in the context of cellular immune deficiency [17, 19].

The excision of HPV-induced anogenital lesions by CO2 laser remains an effective treatment when compared with the other therapeutic options proposed for this type of disorder. After the initial lesions have been diagnosed and treated by laser, HPV infection may continue to develop around the lesion and at other sites which favour recurrence. This type of relapse is more easily treated again using CO2 excision. It is therefore possible to consider the possibility of adapting the management of patients as a function of persistence or recurrence. Among proposed treatments, podophyllotoxine gave the best results on mucosal lesions with a relapse rate between 30 to 45% with no distinction between persistence or recurrence. The rate of relapse with imiquimod was comprised between 20% to 60% and in most of the cases it was described as a persistence [9, 20].

Human papillomaviruses are the cause of frequent, transmissible and often unpleasant conditions, some of which may evolve towards invasive carcinoma. Their treatment is necessary to reduce the discomfort caused to the patient, to limit transmission and to prevent a malignant outcome. At present, no treatment is able to eliminate HPV with certainty. In this patient series, the treatment with CO2 laser, under colposcopic guidance, of HPV-induced anogenital lesions, achieved satisfactory results in patients with longstanding lesions resistant to other treatments, as well as in immunodeficient patients, with good post-operative tolerance. However, it may be possible to couple immunomodulating therapies with laser excision in order to accelerate the host response and reduce the relapse rate in patients.

Acknowledgments

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