M Lebreton

I Carton

S Brousse

V Lavoué

G Body

Jean Levêque
email: jean.leveque@chu-rennes.fr

K Nyangoh-Timoh

Vulvar intraepithelial neoplasia: classification

Keywords: Vulvar intraepithelial neoplasia: Classification, epidemiology, diagnosis, and management, epidemiology, diagnosis, and management classification, epidemiology, diagnosis, and management vulvar intraepithelial neoplasia, human papilloma virus (HPV), therapy, vulvar high

Littérature review

We conducted an open-ended literature review by searching Pubmed and Cochrane Library using the PRISMA method. The key words were: vulvar intraepithelial neoplasia, vulvar neoplasm AND surgical treatment, vulvar neoplasm AND imiquimod, vulvar neoplasm AND cidofovir, vulvar neoplasm AND laser CO2, vulvar neoplasm AND electrosurgical excision, vulvar neoplasm AND cavitron ultrasonic surgical aspiration, vulvar neoplasm AND photodynamic therapy, vulvar neoplasm AND indole 3 carbinol, vulvar neoplasm AND therapeutic vaccination, vulvar neoplasm AND prevention, vulvar neoplasm AND follow up.

The search of these databases was supplemented by the review of references contained in meta-analyses, systematic reviews and original articles. Articles published in English and French were included.

The oldest article dates back to 1953 and the last bibliographic search was conducted in September 2019. 4303 articles were reviewed, of which 61 were selected by title and abstract on Pubmed and 11 articles were added from bibliographies. (Fig. 1).

Classification

Vulvar intraepithelial neoplasia (VIN) has come under different names since it was first described almost 100 years ago. The current Lower Anogenital Squamous Terminology (LAST) classification developed by the International Society for the Study of Vulvar Diseases (ISSVD) relating to human papillomavirus (HPV)-associated squamous lesions of the anogenital tract [START_REF] Bornstein | The 2015 International Society for the Study of Vulvovaginal Disease (ISSVD) Terminology of Vulvar Squamous Intraepithelial Lesions[END_REF][START_REF] Yang | Vulvar and Anal Intraepithelial Neoplasia: Terminology, Diagnosis, and Ancillary Studies[END_REF]distinguishes between:

-Low-grade vulvar lesions, referred to as vulvar low-grade squamous intraepithelial lesions (vL-SIL). These are benign lesions (flat condyloma or HPV effect) associated with low-risk HPV infection.

-High-grade vulvar lesions, which affect between 2.5 and 8.8 of every 100,000 women and are further classified into:

Vulvar high-grade squamous intraepithelial lesions (vH-SIL), formerly known as VIN usual type. These account for 86.7% of all VIN cases based on data from Scandinavian series [START_REF] Nygård | Targeting human papillomavirus to reduce the burden of cervical, vulvar and vaginal cancer and pre-invasive neoplasia: establishing the baseline for surveillance[END_REF], are associated with high-risk HPV infection, and can progress to invasive vulvar cancer. Differentiated VIN lesions (dVIN), develop in chronic skin lesions (lichen), and have a greater potential for malignant transformation.

Epidemiology

Clinically, there are two types of vL-SIL: anogenital warts (condyloma acuminatum) and Buschke-Lowenstein tumor (Fig. 2), which is a rare entity that can invade local structures.

Anogenital warts do not progress to invasive cancer and are associated with HPV 6 or 11 infection in almost 90% of cases [START_REF] Léonard | A clinical and pathological overview of vulvar condyloma acuminatum, intraepithelial neoplasia, and squamous cell carcinoma[END_REF]. HPV is spread through direct contact: infectious contact is responsible for 60% to 70% of all cases of anogenital warts [START_REF] Handsfield | Clinical presentation and natural course of anogenital warts[END_REF]. Co-risk factors include smoking and immunosuppression (CD4 + T cells < 200/mm 3 ) [START_REF] Madsen | Risk factors for invasive squamous cell carcinoma of the vulva and vagina--population-based casecontrol study in Denmark[END_REF][START_REF] Mcintyre-Seltman | Smoking is a risk factor for cervical intraepithelial neoplasia grade 3 among oncogenic human papillomavirus DNA-positive women with equivocal or mildly abnormal cytology[END_REF][START_REF] Krogh | Management of anogenital warts (condylomata acuminata)[END_REF]. vL-SIL is common in France, with prevalence rates ranging from 107 cases per 100,000 women seen by general physicians [START_REF] Lukasiewicz | Incidence and management of condylomata acuminata by French general physicians[END_REF] to 229 cases per 100,000 adolescents and women aged 15 to 65 years seen by gynecologists [START_REF] Monsonégo | Incidence, prise en charge et coût des condylomes acuminés anogénitaux chez les femmes consultant leur gynécologue en France[END_REF]. vH-SIL (Fig. 3) is directly linked to high-risk HPV infection. In an international study by Sanjose et al [START_REF] De Sanjosé | Worldwide human papillomavirus genotype attribution in over 2000 cases of intraepithelial and invasive lesions of the vulva[END_REF], HPV-DNA was detected in 509 of 587 VIN lesions (86.7%) and was more common in younger patients (prevalence of 93.0% in women aged < 37 years vs. 76.7% in those aged > 62 years). The most common HPV types were HPV 16 (77.2%), HPV 33 (10.6%), HPV 18 (2.6%), and HPV 31 (1.2%). A recent meta-analysis reported an HPV prevalence of 86.2% (95% CI 73.5-95.5] for vH-SIL (356 cases from 10 studies) compared with just 2.0% (95% CI 0-10.0) for dVIN; the distribution of genotypes is similar in both groups [START_REF] Faber | Prevalence and type distribution of human papillomavirus in squamous cell carcinoma and intraepithelial neoplasia of the vulva: Prevalence and type distribution of HPV in SCC and VIN[END_REF]. The risk factors for vH-SIL are the classic factors linked to HPV-related lesions in the NIH-AARP Diet and Health Study [START_REF] Brinton | Epidemiology of vulvar neoplasia in the NIH-AARP Study[END_REF]: marital status with a hazard ratio (HR) of 1.77 Non-HPV-related squamous lesions (dVIN) (Fig. 4) develop in existing lichen sclerosus and therefore typically affect older women (60-80 years vs. 30-50 years for vH-SIL). Mechanisms described to date include chronic inflammation, ischemic and oxidative stress [START_REF] Preti | Vulvar intraepithelial neoplasia[END_REF], and p53 mutations [START_REF] Pinto | Differentiated vulvar intraepithelial neoplasia contains Tp53 mutations and is genetically linked to vulvar squamous cell carcinoma[END_REF]. Concomitant HPV infection is not associated with dVIN and its prevalence in this setting is comparable to that in the general population of a similar age [START_REF] Faber | Prevalence and type distribution of human papillomavirus in squamous cell carcinoma and intraepithelial neoplasia of the vulva: Prevalence and type distribution of HPV in SCC and VIN[END_REF].

A landmark Dutch cohort study involving 3038 women with lichen sclerosus followed between 1991 and 2001 [START_REF] Bleeker | Lichen Sclerosus: Incidence and Risk of Vulvar Squamous Cell Carcinoma[END_REF] found that:

the mean incidence of lichen sclerosus was 10.4 cases per 100,000 women-years (with a peak of 28.6 cases in the 65-69 year group), -2.6% of women with lichen sclerosus developed invasive squamous carcinoma within a median of 3.3 years; time-specific incidence rates were 2.1% (95% CI 1.5-2.7) at 5 years, 3.3% (95% CI 2.5-4.1) at 10 years, 4.1% (95% CI 3.2-5.1) at 15 years, and 6.7% (95% CI 4.0-9.4) at 20 years.

the risk of vulvar squamous carcinoma was considerably higher in women with lichen sclerosus and VIN (10-year cumulative incidence of 18.8% [95% CI 9.2-28.4] in women with concomitant lichen sclerosus and VIN vs. 2.8% [95% CI 2.0-3.6] in women with lichen sclerosus only.

The above findings were corroborated in an Italian study of 976 women with lichen sclerosus (mean age, 60 years) who were followed for a mean of 52 months; 34 of the women developed vulvar neoplasia (14 premalignant lesions and 20 invasive cancers), which represents an overall incidence of 3.5% (8.1 cases per 1000 women-years). The cumulative probability of progression to neoplasia (dVIN or invasive cancer) was 1.2% at 2 years and 36.8% at 25 years [START_REF] Micheletti | Vulvar Lichen Sclerosus and Neoplastic Transformation: A Retrospective Study of 976 Cases[END_REF].

Lichen planus is a chronic autoimmune disorder that affects genital and extragenital skin. It has a prevalence of between 1% and 2% in the general population. The largest series of squamous invasive vulvar cancer associated with lichen planus to date is from a single-center Austrian study involving 38 women [START_REF] Regauer | Vulvar cancers in women with vulvar lichen planus: a clinicopathological study[END_REF] who overall developed particularly severe forms of cancer with poor prognosis: 42% of the women had inguinal metastasis at presentation, 30% died of the disease, and 40% experienced recurrence. In a later study of 584 women with lichen planus (Fig. 5), the same team detected just 16 cases of dVIN (3%) and concluded that "simple" lichen planus (without dysplasia) was associated with a low risk of progression [START_REF] Regauer | Human Papillomavirus-Induced Squamous Intraepithelial Lesions in Vulvar Lichen Planus[END_REF].

More recently, an Australian team challenged the purported association between lichen planus and HPV-negative invasive vulvar squamous cell carcinoma (SCC), as they detected no cases of lichen planus in a group of 43 women with vulvar SCC [START_REF] Day | Is Vulvovaginal Lichen Planus Associated With Squamous Cell Carcinoma?[END_REF]. They also stressed the difficulty of differentiating between dVIN and erosive and hypertrophic lichen planus [START_REF] Day | Is Vulvovaginal Lichen Planus Associated With Squamous Cell Carcinoma?[END_REF].

Progression of vH-SIL and dVIN. dVIN has a greater potential for malignant transformation than vH-SIL, which has been found to progress to SCC in just 3% to 5% of patients who receive treatment and in 10% of those who do not [START_REF] Allbritton | Vulvar Neoplasms, Benign and Malignant[END_REF].

In a small series comparing disease course in patients with dVIN and vH-SIL, six out of seven patients with dVIN developed invasive carcinoma (median time to progression, 1.9 years) compared with none of the 18 patients with vH-SIL [START_REF] Mcalpine | HPV-independent Differentiated Vulvar Intraepithelial Neoplasia (dVIN) is Associated With an Aggressive Clinical Course[END_REF]. Recurrence was almost identical in the two groups. Another study that analyzed data from the Dutch Histopathology and Cytology Database found that patients with dVIN were much more likely to develop vulvar SCC than those with vH-SIL (32.8% vs. 5.7%) [START_REF] Van De Nieuwenhof | Vulvar squamous cell carcinoma development after diagnosis of VIN increases with age[END_REF]. They also found that vH-SIL incidence increased with age. In a more recent study of 318 patients with vulvar SCC, another group of Dutch authors found that HPV-independent tumors were associated with a worse prognosis than HPV-related tumors (respective recurrence and disease-specific mortality rates of 36% vs. 20% and 72% vs. 50%). The worse outcomes in the HPV-independent group were associated with an accumulation of unfavorable histological features [START_REF] Hinten | Vulvar cancer: Two pathways with different localization and prognosis[END_REF].

Clinical presentation

History taking can reveal nonspecific warning signs, such as itching, vulvar pain (especially superficial dyspareunia), burning, and provoked bleeding (potentially indicative of invasion) and leakages, particularly in the perianal region. Symptom intensity is correlated with lesion severity; 30% of patients with low-grade lesions are asymptomatic. Chronic symptoms are more indicative of HPV-independent lesions occurring in lichen sclerosus, while intermittent signs suggest an associated HPV infection.

An exhaustive clinical examination of the vulvar region is essential and should include the vulvar and anal regions, the lymph nodes, and the pubis. Gynecological examination of the vagina and cervix is also essential and is particularly important in patients with a viral infection. Cervical and anal pap smears should be performed and cervical lesions examined, particularly in women aged over 45 years with HPV 16 infection [START_REF] Lin | Cervical determinants of anal HPV infection and high-grade anal lesions in women: a collaborative pooled analysis[END_REF]. All suspicious lesions should be biopsied. A general physical examination, with careful attention paid to the extremities, is also necessary, and depending on the patient's sexual practices, an ear, nose, and throat examination may be warranted.

Vulvoscopy is a useful diagnostic tool in patients with multifocal lesions and symptomatic patients without clinically evident lesions. Vulvoscopy has a similar diagnostic yield to colposcopy for cervical lesions. According to one US study of 344 women, vulvoscopy had very high sensitivity (97%), moderate specificity (40%), and a positive predictive value of 37% [START_REF] Santoso | Colposcopic acetowhitening of vulvar lesion: a validity study[END_REF]. One drawback of this test is that it may detect subclinical lesions, although it remains to be determined whether or not treatment is indicated in such cases.

The main clinical features of dVIN and vH-SIL are compared in Table 1 [START_REF] Preti | Vulvar intraepithelial neoplasia[END_REF][START_REF] Allbritton | Vulvar Neoplasms, Benign and Malignant[END_REF][START_REF] Van Der Meijden | European guideline for the management of vulval conditions[END_REF][START_REF] Hoang | Squamous precursor lesions of the vulva: current classification and diagnostic challenges[END_REF].

Biopsy is key to diagnosis in all cases.

Risk factors for recurrence

The risk factors for the recurrence of high-grade VIN, regardless of treatment, are an age of over 50 years, immunosuppression, metasynchronous H-SIL (vaginal, anal, or cervical lesions) [START_REF] Satmary | Vulvar intraepithelial neoplasia: Risk factors for recurrence[END_REF] and multifocal lesions [START_REF] Gentile | Adjuvant topical treatment with imiquimod 5% after excisional surgery for VIN 2/3[END_REF][START_REF] Van Esch | Clinical characteristics associated with development of recurrence and progression in usual-type vulvar intraepithelial neoplasia[END_REF][START_REF] Hillemanns | Evaluation of different treatment modalities for vulvar intraepithelial neoplasia (VIN): CO(2) laser vaporization, photodynamic therapy, excision and vulvectomy[END_REF][START_REF] Lawrie | Medical and surgical interventions for the treatment of usual-type vulval intraepithelial neoplasia[END_REF]. Multifocal lesions pose greater therapeutic dilemmas than unifocal lesions.

Risk factors for recurrence after surgery include positive margins, underlying lichen sclerosus, persistent HPV infection, and immunosuppression [START_REF] Satmary | Vulvar intraepithelial neoplasia: Risk factors for recurrence[END_REF].

Management

Treatment of VIN is typically dictated by lesion characteristics (size, location, multifocality, multicentricity, possible signs of occult invasion), patient characteristics (age, general health, symptoms, comorbidities, reliability of follow-up), and availability of medical resources and expertise.

The goals of treatment are secondary prevention of invasive vulvar cancer, prevention of recurrence, symptom relief, and preservation of vulvar anatomy and function and quality of life [START_REF] Preti | Vulvar intraepithelial neoplasia[END_REF].

There is little agreement in the literature on the optimal management of vulvar intraepithelial lesions.

Surgery

The classic treatment for high-grade VIN is surgical excision and, in the case of multifocal lesions, vulvectomy [START_REF] Hillemanns | Evaluation of different treatment modalities for vulvar intraepithelial neoplasia (VIN): CO(2) laser vaporization, photodynamic therapy, excision and vulvectomy[END_REF]. With the growing incidence of VIN among young women and recurrence rates ranging between 10% and 50% after radical treatment, conservative treatment is now the preferred approach.

Surgical excision is the first-choice treatment when histology shows the slightest signs of invasion [START_REF] Kaufman | Intraepithelial neoplasia of the vulva[END_REF][START_REF]American College of Obstetricians and Gynecologists' Committee on Gynecologic Practice, American Society for Colposcopy and Cervical Pathology (ASCCP)[END_REF]. Cosmetic and functional vulvo-perineal reconstruction is an integral part of surgery [START_REF] Preti | Vulvar intraepithelial neoplasia[END_REF]. Flap repair may be needed for certain surgical defects. Flaps used in this setting include skin flaps (Z-plasty with V-Y advancement flaps, rotation flaps, transposition flaps, Dufourmentel rhombic [LLL transposition] flaps), perforator flaps (anterolateral thigh flaps, superior or inferior gluteal artery perforator flaps), and, in the case of wide excision, splitthickness skin grafts. Superficial vulvectomy with a split-skin graft offers good outcomes in terms of quality of life and sexual function, particularly in patients with posterolateral [START_REF] Lavoué | Quality of life and female sexual function after skinning vulvectomy with split-thickness skin graft in women with vulvar intraepithelial neoplasia or vulvar Paget disease[END_REF] and clitoral [START_REF] Terlou | Skinning clitorectomy and skin replacement in women with vulvar intra-epithelial neoplasia[END_REF] lesions. In a retrospective study of the recurrence and progression of vH-SIL in 73 patients treated with surgery, laser CO2 or imiquimod, Van Esch et al. showed an increased recurrence free survival for these treatments. Progression of vH-SIL to carcinoma was accelerated and increased in patients with immunosuppression [START_REF] Van Esch | Clinical characteristics associated with development of recurrence and progression in usual-type vulvar intraepithelial neoplasia[END_REF].

The loop electrosurgical excision procedure (LEEP) can be considered for small lesions. In a retrospective study of 62 patients with VIN treated for the first time, Vlastos et al [START_REF] Vlastos | Loop electrosurgical excision procedure in vulvar intraepithelial neoplasia treatment[END_REF] found comparable recurrence-free rates in patients treated with LEEP, CO2 laser vaporization, and wide local excision.

No differences in quality of life or adverse effects have been found following treatment with cold knife excision and LEEP [START_REF]American College of Obstetricians and Gynecologists' Committee on Gynecologic Practice, American Society for Colposcopy and Cervical Pathology (ASCCP)[END_REF].

There is currently a lack of consensus about the optional size of lateral margins during the excision of VIN. Several authors agree that in the absence of invasive disease, superficial excision is sufficient if it removes the diseased skin and the first 5 mm of underlying fat; the margins must also extend to the base of any hair follicles. Lateral margins of at least 5 mm are recommended [START_REF] Preti | Vulvar intraepithelial neoplasia[END_REF][START_REF] Ahr | Risk factors for recurrence of vulvar intraepithelial neoplasia III (VIN III)][END_REF]. Ioffe et al [START_REF] Ioffe | Low yield of residual vulvar carcinoma and dysplasia upon re-excision for close or positive margins[END_REF] recommend follow-up rather than re-excision for patients with clear margins. This recommendation is justified considering the higher risk associated with positive margins [START_REF] Satmary | Vulvar intraepithelial neoplasia: Risk factors for recurrence[END_REF]. According to Jones et al [START_REF] Jones | Vulvar intraepithelial neoplasia: aspects of the natural history and outcome in 405 women[END_REF], 50% of women with involved margins will need repeat treatment versus 15% of those with negative margins.

Surgical treatment of vH-SIL

According to the 2016 recommendations for the management of vH-SIL published by the American College of Obstetricians and Gynecologists (ACOG) and the American Society for Colposcopy and Cervical Pathology, vH-SIL can be treated with surgical excision, laser ablation, or topical imiquimod when there are no signs of occult invasion [START_REF]American College of Obstetricians and Gynecologists' Committee on Gynecologic Practice, American Society for Colposcopy and Cervical Pathology (ASCCP)[END_REF]. When deciding on an initial treatment for young women (who frequently have multifocal lesions), the treatment of choice should be one with minimal psychosexual impact (e.g., a topical treatment) [START_REF] Lawrie | Medical and surgical interventions for the treatment of usual-type vulval intraepithelial neoplasia[END_REF][START_REF] Westermann | Treatment of vulvar intraepithelial neoplasia with topical 5% imiquimod cream[END_REF]. In a 2016 Cochrane review of medical and surgical interventions for the treatment of VIN, Lawrie et al [START_REF] Lawrie | Medical and surgical interventions for the treatment of usual-type vulval intraepithelial neoplasia[END_REF] recommended surgical excision as second-line therapy for patients who fail to respond to medical treatment. That said, first-line surgical excision (preferably superficial vulvectomy) of small, well-circumscribed lesions would probably not affect vulvar function.

Surgical treatment of dVIN. The 2016 European guideline for the management of vulval conditions recommends surgical excision as the treatment of choice for dVIN [START_REF] Van Der Meijden | European guideline for the management of vulval conditions[END_REF]. Diagnosis must always be confirmed by biopsy as these lesions can progress to invasive cancer [START_REF] Preti | Vulvar intraepithelial neoplasia[END_REF].

Ablative treatments

The 2016 European guideline describes CO2 laser therapy as an alternative to surgery for vH-SIL [START_REF] Van Der Meijden | European guideline for the management of vulval conditions[END_REF]. In a retrospective study of 73 patients with vH-SIL, Van Esch et al found no differences in recurrence-free survival between patients treated with CO2 laser, excision, and imiquimod. A Cochrane review concluded that their findings were supported by a good level of evidence [START_REF] Lawrie | Medical and surgical interventions for the treatment of usual-type vulval intraepithelial neoplasia[END_REF]. Choice of technique has not been found to have any bearing on disease progression rates in vH-SIL [START_REF] Van Esch | Clinical characteristics associated with development of recurrence and progression in usual-type vulvar intraepithelial neoplasia[END_REF][START_REF] Leufflen | Treatment of vulvar intraepithelial neoplasia with CO(2) laser vaporization and excision surgery[END_REF]. Leufflen et al. found (in a retrospective study of 50 patients treated by surgery or laser CO2) in univariate analysis that tobacco (p=0,03), VIN unicentric (p= 0,02) and laser CO2 treatment (p= 0,01) was a factor with a negative impact on recurrence free survival [START_REF] Leufflen | Treatment of vulvar intraepithelial neoplasia with CO(2) laser vaporization and excision surgery[END_REF].

In principle, CO2 laser therapy should only be applied to non-hair-bearing skin (with a superficial penetration depth of 2 mm). One disadvantage of laser ablation is that it causes postoperative pain and requires longer wound care management than surgery. Lawrie et al. Cochrane review concluded that women who undergo surgical treatment for vH-SIL have about a 50% chance of the condition recurring one year later, irrespective of whether treatment is by surgical excision or laser vaporisation [START_REF] Lawrie | Medical and surgical interventions for the treatment of usual-type vulval intraepithelial neoplasia[END_REF].

CO2 laser therapy can be considered as an alternative to imiquimod for vH-SIL without histologic signs of occult invasion in young women for whom surgical excision would cause excessive disfigurement. Laser ablation, however, is not recommended for dVIN, as it does not provide a surgical specimen for examination and this is particularly important considering the malignant potential and worse prognosis of these lesions.

Cavitron ultrasonic surgical aspiration (CUSA) is a more recent technique and consists of a vibrating handpiece with a separate irrigator and aspirator. It generates ultrasonic waves that break down diseased tissue in the reticular dermis that is then suctioned out via the aspirator. This selective targeting of diseased tissue spares healthy surrounding tissue and provides a sample that can be sent for histological examination. CUSA has shown promising results in several studies, including a randomized clinical trial (RCT) by Von Gruenigen et al [START_REF] Von Gruenigen | Surgical treatments for vulvar and vaginal dysplasia: a randomized controlled trial[END_REF] in which it was compared with CO2 laser therapy. In this RCT, younger age (p<0,01) and current smokers (p= 0,01) where factors associated with recurrence. Similar 1-year recurrence rates (ranging from 22%-35%) have been reported for the two techniques [START_REF] Von Gruenigen | Surgical treatments for vulvar and vaginal dysplasia: a randomized controlled trial[END_REF][START_REF] Miller | Vulvar intraepithelial neoplasia treated with cavitational ultrasonic surgical aspiration[END_REF][START_REF] Robinson | Cavitational ultrasonic surgical aspiration for the treatment of vaginal intraepithelial neoplasia[END_REF]. In the RCT by Von Gruenigen, patients in the CUSA arm had significantly fewer post-procedural adverse effects and less scarring than those in the laser arm. Nonetheless, a 2014 Cochrane review concluded that the trial lacked statistical power and consequently that definitive guidance or recommendations for clinical practice cannot be made [START_REF] Kaushik | Surgical interventions for high-grade vulval intraepithelial neoplasia[END_REF]. Miller et al. showed in a retrospective study that recurrence were significantly more frequent for VIN involved hairbearing tissues (p=0,04) [START_REF] Miller | Vulvar intraepithelial neoplasia treated with cavitational ultrasonic surgical aspiration[END_REF]. This treatment, like the laser, should not be used in hair-bearing tissues.

Medical treatment

Imiquimod (Aldara®, MYLAN Paris) is a topical immunomodulator that does not have direct antiviral activity but acts by inducing a local in vivo immune response that enhances the ability of natural killer cells to target and eradicate HPV-infected cells, inducing lasting antiviral immunity [START_REF] De Witte | Imiquimod in cervical, vaginal and vulvar intraepithelial neoplasia: a review[END_REF]. Imiquimod is authorized for the treatment of external HPV-related genital and perianal warts, but not for VIN.

Most studies of imiquimod continue to use the VIN 1, 2, and 3 classification system dating from 1986 rather than the more recent ISSVD LAST classification.

The dosing regimen recommended by the ACOG is three times weekly application to affected areas for 12 to 20 weeks with vulvoscopic assessment every 4 to 6 weeks during treatment [START_REF]American College of Obstetricians and Gynecologists' Committee on Gynecologic Practice, American Society for Colposcopy and Cervical Pathology (ASCCP)[END_REF].

Even though imiquimod is not indicated for the treatment of vH-SIL, both the US [START_REF]American College of Obstetricians and Gynecologists' Committee on Gynecologic Practice, American Society for Colposcopy and Cervical Pathology (ASCCP)[END_REF] and European [START_REF] Van Der Meijden | European guideline for the management of vulval conditions[END_REF] guidelines recommend it as first-line therapy in this setting and suggest it be followed by surgical excision in nonresponders or in patients with residual or progressive disease. Compared with the more aggressive option of surgical excision, it is a particularly interesting option in this setting as vH-SIL lesions are often multifocal and affect young women.

Local adverse effects of imiquimod treatment include a burning sensation following application, pain, erythema, erosion, edema, pruritus, and general effects, such as headache, apathy, asthenia, and myalgia [START_REF] Van Seters | Treatment of vulvar intraepithelial neoplasia with topical imiquimod[END_REF]. These effects have been linked to poor adherence and early discontinuation of treatment [START_REF] De Witte | Imiquimod in cervical, vaginal and vulvar intraepithelial neoplasia: a review[END_REF]. A group of German authors reported a positive correlation between an inflammatory reaction to topical imiquimod and treatment success [START_REF] Westermann | Treatment of vulvar intraepithelial neoplasia with topical 5% imiquimod cream[END_REF]. Imiquimod can be combined with nonsteroidal anti-inflammatory drugs [START_REF] Terlou | Nonsteroidal anti-inflammatory drugs do not interfere with imiquimod treatment for usual type vulvar intraepithelial neoplasia[END_REF] or alternated with other local topical treatments (containing hyaluronic acid or weak estrogens).

A Greek team led by Iavazzo et al [START_REF] Iavazzo | Imiquimod for treatment of vulvar and vaginal intraepithelial neoplasia[END_REF] published a literature review on the effectiveness and safety of imiquimod for the treatment of VIN in 2008. On analyzing 17 studies conducted between 2001 and 2007, they found complete and partial regression rates ranging from 26% to 100% and 0% to 60%, respectively. Recurrence rates of between 0% and 37% were observed during follow-up. In another literature review of the use of imiquimod in high-grade VIN published in 2015, De Witte et al [START_REF] De Witte | Imiquimod in cervical, vaginal and vulvar intraepithelial neoplasia: a review[END_REF] observed a complete histologic regression rate of 5% to 88% in 13 of 14 studies featuring 780 women analyzed. The studies included two placebo-controlled RTCs, eight prospective studies, and four retrospective studies. The two placebo-controlled RCTs by Van Seters et al [START_REF] Van Seters | Treatment of vulvar intraepithelial neoplasia with topical imiquimod[END_REF] and Mathiesen et al [START_REF] Mathiesen | Topical imiquimod can reverse vulvar intraepithelial neoplasia: a randomised, double-blinded study[END_REF] showed complete histologic regression rates of 31% and 81% respectively for patients treated with imiquimod.

None of the patients in the placebo groups showed histologic regression. HPV clearance rates following treatment with imiquimod ranged from 33% to 85% according to a review of six studies by De Witte et al [START_REF] De Witte | Imiquimod in cervical, vaginal and vulvar intraepithelial neoplasia: a review[END_REF]. Van Seters et al [START_REF] Van Seters | Treatment of vulvar intraepithelial neoplasia with topical imiquimod[END_REF], by contrast, reported clearance rates of 60% for patients treated with imiquimod and 8% for those treated with placebo. In 2013, a German study published by Westermann et al [START_REF] Westermann | Treatment of vulvar intraepithelial neoplasia with topical 5% imiquimod cream[END_REF] on the use of imiquimod to treat VIN in 62 women reported a regression rate of 76% and a recurrence rate of 27%. Recurrence was less common in HPV-positive patients (11% vs 38% for HPV-negative patients).

Few studies have analyzed the long-term effects of imiquimod and most of these were small series with short follow-up times. A Dutch team led by Terlou et al [START_REF] Terlou | Treatment of vulvar intraepithelial neoplasia with topical imiquimod: seven years median follow-up of a randomized clinical trial[END_REF] analyzed the longterm effects of treatment in patients treated with imiquimod in the RCT by Van Seters et al (n = 26) [START_REF] Van Seters | Treatment of vulvar intraepithelial neoplasia with topical imiquimod[END_REF]. Eight of the nine patients who had shown complete response after 20 weeks of treatment remained disease-free at 5 years and had shown no signs of recurrence. Two of the 12 patients with partial response in the original trial had undergone additional imiquimod treatment and were disease-free after more than 5 years' follow-up. HPV clearance had been observed 20 weeks after treatment initiation in all the complete responders (12/26), highlighting the powerful immunomodulatory effect exerted by imiquimod against HPV [START_REF] Paternotte | Traitement des néoplasies vulvaires intra-épithéliales par imiquimod[END_REF].

The 2016 Cochrane review of the medical and surgical treatment of vH-SIL by Lawrie et al [START_REF] Lawrie | Medical and surgical interventions for the treatment of usual-type vulval intraepithelial neoplasia[END_REF] found that small lesions were predictive of good response to imiquimod while multifocal lesions were a risk factor for recurrence. Van Peolgeest et al [START_REF] Van Poelgeest | Detection of human papillomavirus (HPV) 16specific CD4+ T-cell immunity in patients with persistent HPV16-induced vulvar intraepithelial neoplasia in relation to clinical impact of imiquimod treatment[END_REF], in turn, found that detection of HPV 16-specific cells predicted a stronger clinical response in patients with vH-SIL treated with imiquimod.

No studies have analyzed imiquimod in the setting of dVIN, although it has been analyzed in studies and ongoing trials of basal cell carcinoma [START_REF] Tanese | Diagnosis and Management of Basal Cell Carcinoma[END_REF] and Paget disease [START_REF] Van Der Linden | Paget disease of the vulva[END_REF]. Nevertheless, reports in the literature seem to indicate that imiquimod is less effective in HPV-independent lesions [START_REF] Westermann | Treatment of vulvar intraepithelial neoplasia with topical 5% imiquimod cream[END_REF], which, as should be recalled, require rigorous histological examination. Cidofovir and imiquimod applied three times weekly for a maximum of 12 weeks were compared in a phase 2 trial of patients with VIN 3 in the United Kingdom [START_REF] Tristram | Activity, safety, and feasibility of cidofovir and imiquimod for treatment of vulval intraepithelial neoplasia (RT3VIN): a multicentre, open-label, randomised, phase 2 trial[END_REF]. There was no difference in complete response rates (around 46%, 95% CI 0.73-1.18) between the groups after 6 months of treatment. At the 12-month follow-up point, complete response rates were 87% for cidofovir and 78% for imiquimod. The frequency of adverse effects was similar in the two groups, except for fatigue and headache, which were more common in patients treated with imiquimod. The authors present a per protocole analysis of predictors of treatment response, HPV status, disease locality, disease recurrence, smoking status, immune status.

None of these factors were found to be predictive of a response to treatment. In the perprotocol population, two patients allocated cidofovir had previously been immunocompromised: one responded to treatment and one did not. Six individuals assigned imiquimod has also been immunocompromised, of whom two responded and four did not.

A 2016 Cochrane review of medical interventions for high-grade VIN by Pepas et al [START_REF] Pepas | Medical interventions for highgrade vulval intraepithelial neoplasia[END_REF] concluded that cidofovir was a good alternative to imiquimod for the topical treatment of vH-SIL, although long-term outcomes have yet to be analyzed.

Results of literature review for imiquimod and cidofovir are resumed in Table 2.

Other treatments

Photodynamic therapy (PDT) has been used to treat skin disorders for many years. Its mechanism of action is based on the toxic activity of an exogenous porphyrin (5aminolevulinic acid [5-ALA], which is the methyl ester of ALA) that penetrates the skin, where it preferentially accumulates in cells with high metabolic activity and is then activated by appropriate long-wavelength light. In the presence of oxygen, photoactivation triggers the formation of cytotoxic oxygen species and free radicals. In the absence of light excitation, 5-ALA and its precursors are metabolized in 24 to 48 hours. PDT offers very good cosmetic results with minimal destruction of diseased tissue and sparing of healthy tissue. Its main drawback is pain, which may lead to early discontinuation and consequently reduced effectiveness [START_REF] Ang | Photodynamic therapy and pain: A systematic review[END_REF].

The studies that have analyzed PDT in the treatment of VIN have used different methodologies and their findings are supported by a low level of evidence. In a literature review of the role of PDT in the treatment of VIN published in 2018, the Italian team led by Tosti et al [START_REF] Tosti | The Role of Photodynamic Therapy in the Treatment of Vulvar Intraepithelial Neoplasia[END_REF] reported complete histological response rates ranging from 20% to 67% and symptom relief rates in the range of 52% to 89%. Hillemans et al [START_REF] Hillemanns | Photodynamic therapy of vulvar intraepithelial neoplasia using 5-aminolevulinic acid[END_REF], in turn, reported a complete histological response rate of 52% in a retrospective study of patients with VIN 1-3 treated with PDT. All the patients with VIN 1, or mono-or bifocal VIN 2/3 showed complete response. Their findings, however, showed that multifocal lesions were much more difficult to treat, as only 27% of patients with these lesions achieved complete remission. In 2001, Fehr et al [START_REF] Fehr | Photodynamic therapy of vulvar intraepithelial neoplasia III using topically applied 5-aminolevulinic acid[END_REF] published the results of a study comparing treatment outcomes in 72 patients with high-grade VIN treated with PDT (n = 15), CO2 laser therapy (n = 30), and surgical excision (n = 27). At the 1-year evaluation, there were no significant differences in disease-free survival between the groups. Several studies have shown that monofocal lesions are more reactive to PDT than multifocal pigmented lesions [START_REF] Hillemanns | Photodynamic therapy of vulvar intraepithelial neoplasia using 5-aminolevulinic acid[END_REF][START_REF] Fehr | Photodynamic therapy of vulvar intraepithelial neoplasia III using topically applied 5-aminolevulinic acid[END_REF][START_REF] Es | Immunological and viral factors associated with the response of vulval intraepithelial neoplasia to photodynamic therapy[END_REF].

PDT is an alternative for treating small, solitary VIN lesions, but it requires special equipment and trained personnel. Consensus is lacking among expert bodies about when PDT should be used in VIN.

Indole-3-carbinol (I3C) is a natural compound present in large concentrations in cruciferous vegetables. A small RCT published in 2006 compared the efficacy of two doses of I3C for the treatment of high-grade VIN [START_REF] Naik | A randomized phase II trial of indole-3-carbinol in the treatment of vulvar intraepithelial neoplasia[END_REF]. The Cochrane review published by Pepas et al in 2015 concluded that the trial did not demonstrate the compound's efficacy in this setting [START_REF] Pepas | Medical interventions for highgrade vulval intraepithelial neoplasia[END_REF].

The aim of therapeutic vaccination is to enhance HPV-specific CD4 + and CD8 + T cell responses to vH-SIL lesions [START_REF] Van Esch | Expression of coinhibitory receptors on T cells in the microenvironment of usual vulvar intraepithelial neoplasia is related to proinflammatory effector T cells and an increased recurrence-free survival: T-cell expressed receptors predict recurrences[END_REF]. Most vaccines induce specific immunity against HPV oncogenic proteins E6 and E7 [START_REF] Preti | VIN usual type-from the past to the future[END_REF]. Two studies have analyzed the effectiveness of a combination of two vaccines (TA-HPV and TA-CIN) in women with HPV 16-associated VIN [START_REF] Smyth | Immunological responses in women with human papillomavirus type 16 (HPV-16)associated anogenital intraepithelial neoplasia induced by heterologous prime-boost HPV-16 oncogene vaccination[END_REF][START_REF] Davidson | Effect of TA-CIN (HPV 16 L2E6E7) booster immunisation in vulval intraepithelial neoplasia patients previously vaccinated with TA-HPV (vaccinia virus encoding HPV 16/18 E6E7)[END_REF]. Of the 39 patients treated, nine patients showed lesion shrinkage, 25 remained stable, and five experienced disease progression. Although this combined therapeutic vaccine proved to be immunogenic, no association was observed between induced HPV-specific immunity and clinical outcomes. Kenter et al [START_REF] Kenter | Vaccination against HPV-16 oncoproteins for vulvar intraepithelial neoplasia[END_REF] tested a synthetic long-peptide vaccine derived from HPV 16 oncogenic proteins E6 and E7 in 20 patients with vH-SIL. After 12 months of follow-up, 15 patients showed a clinical response that persisted up to 24 months (there were nine complete responses). The study demonstrated that the vaccine induced an HPV 16-specific immune response. Therapeutic vaccines, however, are still at the research stage and are expensive to develop. In addition, the focus is still very much on prophylactic rather than therapeutic vaccines.

The 2016 European guideline proposes follow-up without treatment as an alternative to the medical or surgical management of vH-SIL [START_REF] Van Der Meijden | European guideline for the management of vulval conditions[END_REF]. There have been reports of spontaneous regression in this setting, particularly among young patients [START_REF] Jones | Vulvar intraepithelial neoplasia: aspects of the natural history and outcome in 405 women[END_REF]. Spontaneous remission, however, cannot be predicted and close follow-up is therefore advised in patients who do not receive treatment [START_REF] Preti | Vulvar intraepithelial neoplasia[END_REF].

Results of literature review for surgical excision, LEEP, laser CO2, CUSA, PDT, indol-3carbinol and therapeutic vaccination is resume in Table 3.

Prevention

In France, HPV vaccination (Gardasil9 ® , MSD Lyon France) is recommended for all girls aged 11 to 14 years. The recommended regimen is a 2-dose series administered at 6-month intervals, with a catch-up 3-dose series available for girls up to the age of 19. HPV vaccine coverage in France, however, remains insufficient. According to the 2017 report from the French Public Health Council (HCSP), just 20.4% of girls born in 2000 had been vaccinated as of December 31, 2015. In a study of the impact of prophylactic vaccination against HPV types 11, 16, and 18 on HPV-associated genital disease, Muñoz et al [START_REF] Muñoz | Impact of human papillomavirus (HPV)-6/11/16/18 vaccine on all HPV-associated genital diseases in young women[END_REF] showed an efficacy of 94.9% in women who had never been infected by HPV and of 75.6% in a mixed group of HPV-exposed and -unexposed women (intention-to-treat group). A reduction in the incidence of vH-SIL among vaccinated patients is likely to reduce the incidence of vulvar cancer [START_REF] Jemal | Annual Report to the Nation on the Status of Cancer, 1975-2009, featuring the burden and trends in human papillomavirus(HPV)-associated cancers and HPV vaccination coverage levels[END_REF].

In 2018, the World Health Organization called for greater HPV vaccine worldwide.

According to data from March 31, 2017, just 37% of countries (n = 71) had included HPV shots for girls in their national vaccination programs and even fewer (n = 11, 6%) had done so for boys. Results from countries with exemplary coverage levels (> 85%), such as Australia and New Zealand, should inspire more countries to follow suit, as these countries have seen a dramatic increase in HPV infection rates and cervical cancer is on track to being eliminated.

Follow-up

According to the ACOG, women with a complete response to therapy and no new lesions at follow-up visits scheduled 6 months and 12 months after initial treatment should be monitored by visual inspection of the vulva annually thereafter" [START_REF]American College of Obstetricians and Gynecologists' Committee on Gynecologic Practice, American Society for Colposcopy and Cervical Pathology (ASCCP)[END_REF]. The 2016 European guideline recommends a follow-up examination every 6 to 12 months with annual cervical smear for patients with vH-SIL and every 6 months for those with dVIN [START_REF] Van Der Meijden | European guideline for the management of vulval conditions[END_REF]. Close follow-up is mandatory, life long.

Long-term follow-up [START_REF] Satmary | Vulvar intraepithelial neoplasia: Risk factors for recurrence[END_REF] including examination of the vulva and other anogenital tissues targeted by HPV is essential considering that over 25% of patients experience late recurrence.

A proposed algorithm for guiding treatment decisions is presented in Fig. 6.

Conclusions

dVIN affects older women, typically develops as a solitary lesion on existing lichen sclerosus, and has greater potential for serious invasion. The primary treatment of choice is therefore surgical excision (cold knife excision or LEEP).

vH-SIL are HPV-associated lesions that affect younger women, are preferentially multifocal and extensive, and are less likely to cause invasive cancer. Alternatives to surgery, which can cause unnecessary disfigurement in young women, are topical imiquimod and cidofovir.

Other options include ablation and a watch-and-wait approach. Diagnosis should be confirmed by biopsy before any treatment is started.

  Topical 1% cidofovir cream (Vistide®) is a nucleotide analog of cytosine that inhibits viral replication by inhibiting viral DNA polymerases, effectively blocking DNA synthesis. It has been granted temporary authorization for use in VIN in France.

Fig 1 .Fig. 2

 12 Fig 1. Flow chart of literature review (PRISMA)

Fig. 3

 3 Fig. 3 High-grade vulvar squamous intraepithelial lesion.

Fig. 4

 4 Fig. 4 Differentiated vulvar intraepithelial neoplasia.

Fig. 5 Fig 6 .

 56 Fig. 5 Lichen planus.

-

  Vestibular mucosa: shiny, slightly raised, extensive red plaque -Border of mucous membrane: thick, carcinoma dVIN: differentiated vulvar intraepithelial neoplasia; HPV: human papillomavirus; LAST: Low Anogenital Squamous Terminology; vH-SIL: vulvar high-grade squamous intraepithelial lesion.

Table 1 .

 1 Comparison between vH-SIL and dVIN

		vH-SIL	dVIN
	Age, years	30-50	60-80
	Relative proportion of VIN	95%	5%
	Focality	Multifocal	Unifocal

LEEP: loop electrosurgical excision procedure; CUSA: cavitron ultrasonic aspiration,; PDT: photodynamic therapy


E Lecarpentier

MD Bassam Haddad
email: bassam.haddad@chicreteil.fr

ASPIRIN FOR THE PREVENTION OF PLACENTA-MEDIATED COMPLICATIONS IN PREGNANT WOMEN WITH CHRONIC HYPERTENSION

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INTRODUCTION

During pregnancy, chronic hypertension (CHTN) is defined by the existence of pre-existing hypertension before the onset of the pregnancy (with or without treatment), or the finding of a hypertension before 20 weeks of gestation. CHTN affects 1-5% of women of childbearing age [START_REF] Haddad | Chronic hypertension in pregnancy[END_REF][START_REF] Roberts | The accuracy of reporting of the hypertensive disorders of pregnancy in population health data[END_REF][START_REF] Bateman | Prevalence, trends, and outcomes of chronic hypertension: a nationwide sample of delivery admissions[END_REF][START_REF] Bramham | Chronic hypertension and pregnancy outcomes: systematic review and meta-analysis[END_REF].

Its prevalence increased in US between 1995 and 2008 from 0.97% to 1.76% [START_REF] Rey | The prognosis of pregnancy in women with chronic hypertension[END_REF]. However, this prevalence is relatively stable in France ; the French national perinatal survey reports CHTN prevalence before pregnancy of 1% in 2010 and 0.7% in 2016.

Several risk factors for CHTN are described in the literature: ethnic origin (Black African or Caribbean) [START_REF] Caughey | Maternal ethnicity, paternal ethnicity, and parental ethnic discordance: predictors of preeclampsia[END_REF], age of women > 35 years [START_REF] Mathews | Mean Age of Mothers is on the Rise: United States, 2000-2014[END_REF][START_REF] Yoder | Hypertension in pregnancy and women of childbearing age[END_REF], and obesity [START_REF] Rey | The prognosis of pregnancy in women with chronic hypertension[END_REF]. The objectives of this article is first to detail the complications of chronic hypertension during pregnancy, then to review the expected benefits of low dose aspirin in prevention of preeclampsia during pregnancy and more specifically in patients with chronic arterial hypertension. Finally, we will present a summary of the main national recommendations, and we will present the French randomized controlled trial CHASAP (Chronic Hypertension and Acetyl Salicylic Acid in Pregnancy).

METHODS

The PubMed database has been systematically consulted with an appropriate search strategy. We did not place any restrictions on the year of publication. We only took acount the articles or reports published in English or French. Additionally, we hand searched the cross-references of the included studies.

COMPLICATIONS OF CHRONIC HYPERTENSION DURING PREGNANCY

In women with CHTN, the risk of both preterm and term preeclampsia (PE) is 5-6 times higher than in women without this medical disorder [START_REF] Panaitescu | Chronic hypertension and adverse pregnancy outcome: a cohort study[END_REF]. The risk of superimposed preeclampsia is estimated at 25.9% (95% CI: 21% -31.5%) in a recent meta-analysis [START_REF] Bramham | Chronic hypertension and pregnancy outcomes: systematic review and meta-analysis[END_REF]. In this same meta-analysis, the studies from the United States were reviewed separately: they show a risk of superimposed PE at 29.2% (95% CI: 21.6% -38.2%). Our team published a retrospective study of 211 patients with CHTN from the Paris region. Our results, included in the meta-analysis (4), found a risk of 23% [START_REF] Lecarpentier | Risk factors of superimposed preeclampsia in women with essential chronic hypertension treated before pregnancy[END_REF].

Recently, the CHIPS (Control of Hypertension in Pregnancy Study) trial, a large multicenter international study including 981 participants (75% of whom had CHTN) found a risk of PE to almost 28% [START_REF] Magee | Less-tight versus tight control of hypertension in pregnancy[END_REF]. In this latter study, the authors also analyzed the occurrence of PE according to the new definition of preeclampsia(12); the risk of PE raised at 47.3% [START_REF] Magee | Less-tight versus tight control of hypertension in pregnancy[END_REF]. One feature of superimposed preeclampsia on CHTN is its early onset. Indeed, in a prospective study of 861 patients, superimposed PE that occurred before 37 weeks was observed in 51% of the cases of preeclampsia [START_REF] Chappell | Adverse perinatal outcomes and risk factors for preeclampsia in women with chronic hypertension: a prospective study[END_REF].

The incidence of Intra-Uterine Growth Restriction (IUGR) below the 10th percentile is higher in patients with CHTN when compared to the general population (RR: 2.4, 95% CI: 1.7 -3.6) (8). In addition, compared with non-hypertensive patients, its frequency is multiplied by 5.5 for premature IUGR and 1.5 for term IUGR [START_REF] Catov | Chronic hypertension related to risk for preterm and term small for gestational age births[END_REF]. In recent studies, this risk is found between 17.9% and 27.2% [START_REF] Magee | Less-tight versus tight control of hypertension in pregnancy[END_REF][START_REF] Chappell | Adverse perinatal outcomes and risk factors for preeclampsia in women with chronic hypertension: a prospective study[END_REF].

Preterm delivery is also found to be very high in patients with CHTN. In a recent meta-analysis (4), preterm birth at less than 37 weeks of gestation complicates 28.1% of pregnancies in chronic hypertensive women (95% CI: 22.5% -34.4%). In addition, the authors were able to compare the CHTN-induced prematurity with that of the general American population in the studies included in the meta-analysis, which is found to be 33% in chronic hypertensive versus 12% in the general population (RR: 2.7, 95% CI: 1.9-3.6). Importantly, prematurity at less than 37 weeks of gestation remains elevated in chronic hypertensive patients even without superimposed PE; in the study published by our team it is found at 19.8% [START_REF] Lecarpentier | Risk factors of superimposed preeclampsia in women with essential chronic hypertension treated before pregnancy[END_REF].

Placental abruption is observed in 1.5% of women with chronic hypertension [START_REF] Sibai | Risk factors for preeclampsia, abruptio placentae, and adverse neonatal outcomes among women with chronic hypertension. National Institute of Child Health and Human Development Network of Maternal-Fetal Medicine Units[END_REF], and compared to the general population the relative risk is 2.4 (95% CI: 2.3 -2.5) [START_REF] Ananth | Chronic hypertension and risk of placental abruption: is the association modified by ischemic placental disease?[END_REF].

In a a longitudinal cohort study, the perinatal death rate in chronic hypertensive patients was found at 4.5% compared to 1.2% found in non-hypertensive patients (relative risk: 3.2, 95% CI: 1.8 -5.5) [START_REF] Rey | The prognosis of pregnancy in women with chronic hypertension[END_REF].

In the same study, the authors found that superimposed PE in chronic hypertensive women was associated with a significantly higher perinatal death rate compared to patients with chronic hypertension without superimposed PE (10.8% vs 2.9%, relative risk: 3.6, 95% CI: 1.4-9.2).

Importantly in this study, almost a third of perinatal deaths occurred outside of superimposed PE. In a meta analysis encompassing 795 221 pregnancies, Bramham et al report in chronic hypertensive patients, a perinatal death of 3.99% (95% CI: 2.95% -5.38%) (4), in agreement with our results (3.79%) [START_REF] Lecarpentier | Risk factors of superimposed preeclampsia in women with essential chronic hypertension treated before pregnancy[END_REF].

PREVENTION OF PREGNANCY COMPLICATIONS WITH LOW DOSES ASPIRIN

The first evidence of the obstetrical efficacy of aspirin was noted in 1985 by Beaufils et al [START_REF] Beaufils | Prevention of pre-eclampsia by early antiplatelet therapy[END_REF], in an open label randomized trial which studied the preventive treatment with aspirin (aspirin 150 mg + dipyridamole 300mg vs placebo) in 102 patients at high risk of preeclampsia and/or intrauterine growth restriction. The prevalence of preeclampsia was significantly reduced in the aspirin group compared with the control group (0/48 vs 6/45 p<0.05). In 1991, the same team published the randomized, double-blind EPREDA trial which showed a beneficial effect of aspirin (150 mg) in the secondary prevention of intrauterine growth restriction [START_REF] Uzan | Prevention of fetal growth retardation with low-dose aspirin: findings of the EPREDA trial[END_REF]. Thereafter the majority of the studies were designed to analyze the effectiveness of aspirin in preventing preeclampsia in patients at high risk and low risk. Most of these studies, used doses of aspirin < 75 mg and inclusion gestational age > 15SA [START_REF] Uzan | Prevention of fetal growth retardation with low-dose aspirin: findings of the EPREDA trial[END_REF][START_REF] Viinikka | Low dose aspirin in hypertensive pregnant women: effect on pregnancy outcome and prostacyclin-thromboxane balance in mother and newborn[END_REF][START_REF]CLASP: a randomised trial of low-dose aspirin for the prevention and treatment of preeclampsia among 9364 pregnant women. CLASP (Collaborative Low-dose Aspirin Study in Pregnancy) Collaborative Group[END_REF][START_REF] Caritis | Low-dose aspirin to prevent preeclampsia in women at high risk. National Institute of Child Health and Human Development Network of Maternal-Fetal Medicine Units[END_REF][START_REF]ECPPA: randomised trial of low dose aspirin for the prevention of maternal and fetal complications in high risk pregnant women. ECPPA (Estudo Colaborativo para Prevenção da Préeclampsia com Aspirina) Collaborative Group[END_REF]. The results of many of these studies have been grouped into meta-analyzes that suggest a rather moderate efficacy of low-dose aspirin in the prevention of PE (10 to 15% decrease of the occurrence of PE) [START_REF] Duley | Antiplatelet drugs for prevention of preeclampsia and its consequences: systematic review[END_REF].

Several meta-analyzes published by Roberge et al showed a greater decreased risk of PE by up to 40% (relative risk: 0.57, 95% CI: 0.43 -0.75, P <0.001) and also a decreased risk of intrauterine growth retardation (relative risk: 0.56, 95% CI: 0.44 -0.70, P <0.001) when the dose of aspirin was ≥ 100 mg and the introduction ≤ 16 weeks of gestation [START_REF] Roberge | Prevention of perinatal death and adverse perinatal outcome using low-dose aspirin: a meta-analysis[END_REF][START_REF] Roberge | Aspirin for the prevention of preterm and term preeclampsia: systematic review and metaanalysis[END_REF][START_REF] Roberge | Early administration of low-dose aspirin for the prevention of severe and mild preeclampsia: a systematic review and metaanalysis[END_REF][START_REF] Roberge | The role of aspirin dose on the prevention of preeclampsia and fetal growth restriction: systematic review and meta-analysis[END_REF]. The preventive effect of aspirin depending on the dose and the gestational age at introduction, however, is disputed by other authors [START_REF] Askie | Antiplatelet agents for prevention of pre-eclampsia: a meta-analysis of individual patient data[END_REF][START_REF] Meher | Antiplatelet therapy before or after 16 weeks' gestation for preventing preeclampsia: an individual participant data meta-analysis[END_REF].

PREVENTION OF COMPLICATIONS OF CHRONIC HYPERTENSION IN PREGNANCY WITH LOW DOSES ASPIRIN

Low-dose aspirin for the prevention of placenta-mediated complications in chronic hypertensive pregnant women has been poorly studied [START_REF] Caritis | Low-dose aspirin to prevent preeclampsia in women at high risk. National Institute of Child Health and Human Development Network of Maternal-Fetal Medicine Units[END_REF][START_REF]ECPPA: randomised trial of low dose aspirin for the prevention of maternal and fetal complications in high risk pregnant women. ECPPA (Estudo Colaborativo para Prevenção da Préeclampsia com Aspirina) Collaborative Group[END_REF]. Viinika et al conducted a randomised multicentre trial on the effect of daily treatment with 50 mg of aspirin from the 16th week of pregnancy to term in 208 women. Among these women, 89% (n=185/208) had pre-existing arterial hypertension [START_REF] Viinikka | Low dose aspirin in hypertensive pregnant women: effect on pregnancy outcome and prostacyclin-thromboxane balance in mother and newborn[END_REF]. No significant difference was seen in exacerbation of hypertension with new onset proteinuria (9/97 in the aspirin group vs 11/100 in the placebo group) or without proteinuria (12/97 in the aspirin group vs 14/100 in the placebo group). No significant difference was seen in the birthweights of the newborns, although those of aspirin group tended to weigh more (3348±707g in the aspirin group vs 3170±665g in the placebo group, p=0.07), and IUGR was twice as common (4/97 in the aspirin group vs 9/100 in the placebo group).

Caritis et al conducted a double-blind, randomized, placebo-controlled trial in four groups of pregnant women at high risk for preeclampsia, including 471 women with pregestational insulin-treated diabetes mellitus, 774 women with chronic hypertension, 688 women with multifetal gestations, and 606 women who had had preeclampsia during a previous pregnancy [START_REF] Caritis | Low-dose aspirin to prevent preeclampsia in women at high risk. National Institute of Child Health and Human Development Network of Maternal-Fetal Medicine Units[END_REF]. Women were enrolled between the 13 th and the 26 th weeks of pregnancy. In the group of women with chronic hypertension the mean gestational age of enrollement was 20±4 weeks. Their results showed that aspirin (60 mg) was ineffective in preventing preeclampsia in all four risk groups, regardless of parity, race, base-line blood pressure, gestational age at base line or delivery, or degree of compliance. In the group of women with chronic hypertension (n=763), the incidence of preeclampsia was 26% in the aspirin group and 25 % in the placebo group (RR CI 95% 1.1 [0.8, 1.4]).

The American College of Cardiology/American Heart Association (ACC/AHA) Task Force on Clinical Practice Guidelines have revised the recommendations for diagnosis of chronic hypertension in adults based on compelling evidence that incremental increases in blood pressure (BP) impact the risk of future cardiovascular disease, as well as clinical complications and death. Formerly classified as prehypertension, the new parameters now consider stage 1 hypertension as systolic BP measurement between 130 and 139 mmHg or diastolic BP measurement between 80 and 89 mmHg [START_REF] Whelton | ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA Guideline for the Prevention, Detection, Evaluation, and Management of High Blood Pressure in Adults: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines[END_REF]. Hauspurg et al performed a secondary analysis of the high-risk aspirin trial [START_REF] Caritis | Low-dose aspirin to prevent preeclampsia in women at high risk. National Institute of Child Health and Human Development Network of Maternal-Fetal Medicine Units[END_REF][START_REF] Hauspurg | Aspirin Effect on Adverse Pregnancy Outcomes Associated With Stage 1 Hypertension in a High-Risk Cohort[END_REF]. Among these women, 827 (81%) were classified as normotensive, whereas 193 (19%) were classified as stage 1 hypertensive (systolic pressure ranging from 130 to 139 mm Hg or a diastolic pressure ranging from 80 to 89 mm Hg). In this high-risk population, the authors showed that entering pregnancy with stage 1 hypertension was associated with a >2-fold increased risk of preeclampsia (RR, 2.49; 95% CI, 1.74-3.55) compared with normotensive women. In women with stage 1 hypertension, low-dose aspirin was associated with a 39% reduction of pre-eclampsia (RR, 0.61; 95% CI, 0.39-0.94) compared with stage 1 hypertensive women receiving placebo, with a 45% reduction in mild disease (RR, 0.55; 95% CI, 0.31-0.97).

In a meta-analysis of individual patient data from 32 217 women recruited to 31 trials on the use of antiplatelet agents, for prevention of PE, Askie et al reported a subgroup analysis according to preexisting hypertension [START_REF] Askie | Antiplatelet agents for prevention of pre-eclampsia: a meta-analysis of individual patient data[END_REF]. The relative risk (with 95% CI) for all women was 0.90 (0.84-0.97); in the subgroup of women with preexisting hypertension (aspirin : 293/1678, control : 295/1625) it was 0.97 (0.84 -1.12) ; and in those without preexisting hypertension (aspirin : 849/11641 , control : 958/11603) it was 0.88 (0.81-0.96).

In 2009, Poon et al proposed an algorithm for estimation of the risk of preeclampsia on the basis of maternal demographics, medical and obstetrical history, pulsatility index of the uterine arteries, mean blood pressure, maternal serum levels of PlGF and pregnancy associated plasma protein A (PAPP-A) between 11 and 13 weeks of gestation [START_REF] Poon | First-trimester prediction of hypertensive disorders in pregnancy[END_REF]. In this algorithm the regression coefficient for « chronic hypertension » is relatively important (-7.2897) in the calcul of the risk. This test identified 91% cases of early and severe preeclampsia, with a 10% false-positive rate and became the algorithm of the Fetal Medicine Foundation (FMF). The ASPRE trial was designed to propose aspirin as a treatment for primary prevention of preeclampsia in all patients considered to be at high risk following firsttrimester combined screening the FMF algorithm. This multicenter, double-blind, randomized, placebo-controlled trial evaluated the effect of aspirin (150 mg) administered in the first trimester of pregnancy on the incidence of delivery with preeclampsia before 37 weeks of gestation in patients at high risk [START_REF] Rolnik | Aspirin versus Placebo in Pregnancies at High Risk for Preterm Preeclampsia[END_REF]. The secondary objectives were to study the effects of aspirin on the incidence of early (delivery before 34 weeks of gestation) preeclampsia, the incidence of intrauterine growth restriction, fetal death, perinatal death, admission to neonatal intensive care, a composite measure of neonatal morbidity and mortality and placental abruption. A total of 26,941 pregnant women were screened, 2,641were at high risk of preeclampsia and eligible for inclusion. Among the patients included, 1,776 were randomized to aspirin or a placebo. The occurrence of preterm preeclampsia (<37 weeks) was significantly reduced by aspirin (0.38; 95% CI 0.20-0.74; p = 0.004). Preterm preeclampsia occurred in 13 of 798 participants (1.6%) in the aspirin group, as compared with 35 of 822 (4.3%) in the placebo group.

In a secondary analysis, the authors showed that the beneficial effect of aspirin in the prevention of preterm preeclampsia may not apply in pregnancies with chronic hypertension [START_REF] Poon | Aspirin for Evidence-Based Preeclampsia Prevention trial: effect of aspirin in prevention of preterm preeclampsia in subgroups of women according to their characteristics and medical and obstetrical history[END_REF]. In participants with chronic hypertension preterm preeclampsia occurred in 10.2% (5/49) in the aspirin group and 8.2% (5/61) in the placebo group (adjusted odds ratio, 1.29; 95% confidence interval, 0.33-5.12). In the subgroup with chronic hypertension the OR for preterm preeclampsia was 2.06 (95% confidence interval, 0.40-10.71); and in those without chronic hypertension it was 0.05 (95% confidence interval, 0.01-0.41).

IATROGENIC FETAL AND MATERNAL EFFECTS OF ASPIRIN TREATMENT

The principal studies of fetal and maternal iatrogenesis are reassuring ; low doses of aspirin administered during the first trimester do not seem to constitute a teratogenic risk [START_REF] Slone | Aspirin and congenital malformations[END_REF][START_REF] Klebanoff | Aspirin exposure during the first 20 weeks of gestation and IQ at four years of age[END_REF][START_REF] Werler | The relation of aspirin use during the first trimester of pregnancy to congenital cardiac defects[END_REF][START_REF] Nørgård | Aspirin use during early pregnancy and the risk of congenital abnormalities: a population-based case-control study[END_REF].

Teratogenicity associated with aspirin concerns only patients exposed to doses of between 650 and 2600 mg/day, with variable clinical expression including cardiopathies and limb anomalies. Such events are not seen at lower doses. Low-dose aspirin seems not to influence birth-weight or the duration of pregnancy [START_REF] Hertz-Picciotto | The risks and benefits of taking aspirin during pregnancy[END_REF]. At the 150 mg daily dose, there does not appear to be an increased risk of maternal bleeding [START_REF] Caritis | Low-dose aspirin to prevent preeclampsia in women at high risk. National Institute of Child Health and Human Development Network of Maternal-Fetal Medicine Units[END_REF].

RECOMMENDATIONS AND NATIONAL GUIDELINES

Due to the very high risk of superimposed preeclampsia in chronic hypertensive women and despite the lack of objective evidence of the effectiveness of low-dose aspirin in the prevention of superimposed preeclampsia in this population, the National Institute for Health and Clinical Excellence (NICE) associated with the Royal College of Gynecology-Obstetrics recommends to women with chronic hypertension to take 75 mg of aspirin daily from 12 weeks until the birth of the baby [START_REF]Hypertension in pregnancy: diagnosis and management | Guidance | NICE[END_REF]. Then it was followed by the "U.S. Preventive Services Task Force (USPTF)" in 2014 (41).

The American College of Obstetrics and Gynecology (ACOG) adopted the suggestions of the USPTF in 2018 [START_REF]No. 743 Summary: Low-Dose Aspirin Use During Pregnancy[END_REF]. The ACOG and the Society of Maternal-Fetal Medicine (SMFM) recommand for women with chronic hypertension, low dose aspirin (81mg) initiated between 12 and 28 weeks of gestation (optimally before 16 weeks) continued daily until delivery.

In a retrospective cohort study Banala et al evaluated the implementation of 2016 ACOG guidelines recommending low dose aspirin in high-risk patients over time and the effectiveness of aspirin in preventing superimposed preeclampsia and adverse maternal and neonatal outcomes in women with chronic hypertension [START_REF] Banala | Impact of the ACOG guideline regarding low dose aspirin for prevention of superimposed preeclampsia in women with chronic hypertension[END_REF]. They identified 457 pregnant women with chronic hypertension, 254 in the pre-ACOG group and 203 in the post-ACOG group. Aspirin 81 mg was offered to 18/254 (7%) pre-ACOG and 142/203 (70%) women post-ACOG. Implementation of the guideline increased over time from 24.2% in 2016 to 82.6% in 2018. The overall incidence of superimposed preeclampsia was not significantly different: 87 (34.3%) vs. 72 (35.5%), p=0.79 in the pre and post ACOG guideline groups, respectively.

The French college of Obstetrics and Gynecology (CNGOF) and the French Society of Hypertension (SFHTA) do not recommend the use of low-dose aspirin in pregnant chronic hypertensive women with no history of preeclampsia because of insufficient data (44).

CHASAP trial (Chronic Hypertension and Acetyl Salicylic Acid in Pregnancy)

The main objective of the CHASAP trial (NCT04356326)( 45) is to compare, in pregnant women with chronic hypertension, the efficacy of Aspirin (acetylsalicylic acid) at a dose of 150 mg / day with a placebo, in the prevention of maternal-fetal morbidity and mortality (preeclampsia, placental abruption, IUGR, perinatal death, maternal death, and preterm delivery). This is a prospective multicentric randomized double-blind superiority trial, placebo-controlled, on two parallel arms. The randomization at 1:1 ratio, will be stratified by center and ethnic origin of mother (Black African-Antilles) and delivered centrally by a web server. The pregnant women with chronic hypertension (treated or not) and singleton pregnancy will be included between 10 weeks and 14 weeks + 6 days.

To show a 33% relative reduction in the incidence of maternal-fetal morbidity and mortality (from 45% to 30%) (alpha risk: 5%, power: 90%, continuity correction) the inclusion of 230 women in each arm will be needed. The provision of 10% for non-evaluable data gives a total of 500 patients.

Secondary objectives are:

-To estimate this preventive effect on each of the following: the severity of PE, IUGR, and preterm delivery; the risks of miscarriage, fetal death, neonatal death; the neonatal morbidity (stay in neonatal intensive care unit, assisted ventilation > 24 hours, hyaline membrane disease, stage III or IV intraventricular hemorrhage), -To evaluate the potential toxicity of the active treatment: major maternal hemorrhagic event (externalized active bleeding, intracranial, intraocular, retroperitoneal, or articular bleeding), or minor, -To analyze patients' compliance with treatment and its relation to treatment efficacy in its preventive action on the main endpoint, -The constitution of a biological collection. Blood and urine samples performed every month for all included patients will allow us to analyze the impact of aspirin on circulating levels of angiogenic factors (sFLT-1 and PlGF) and to study the predictive performance of these angiogenic factors in this high-risk population.

There are three main reasons for conducting the CHASAP trial: 1-Studies that analyzed the effectiveness of low-dose aspirin in the prevention of preeclampsia in patients with chronic hypertension used doses that were too low (< 75 mg) and inclusion gestational ages too advanced to find an efficacy, 2-None was specifically dedicated to the analysis of the efficacy of low-dose aspirin in the prevention of intrauterine growth retardation or other complications of chronic hypertension during pregnancy, 3-Finally, none has addressed the effectiveness of low-dose aspirin in the prevention of composite maternal and perinatal complications.

CONCLUSION

The ASPRE study raises several questions. Is screening of preeclampsia based on the FMF algorithm more effective than current national guidelines? Prospective trials are still necessary to compare these two strategies, with evaluation of medical and medico-economics outcomes. In France, low dose aspirin is not recommended for all pregnant women with chronic hypertension, and the systematic first trimester screening for preeclampsia risk is neither recommended nor performed routinely. The CHASAP trial will specifically evaluate the interest of low dose aspirin (150 mg) in the population of pregnant women with CHTN and no indication of aspirin for obstetric or medical history.


Mélanie Pons
email: mpons@chu-besancon.fr.

Jean-Christophe Lutz
email: jean-christophe.lutz@chru-strasbourg.fr.

Nicolas Sigaux
email: nicolas.sigaux@chu-lyon.fr.

Laurent Tavernier
email: ltavernier@chu-besancon.fr.

Nicolas Graillon
email: nicolas.graillon@ap-hm.fr.

Surgical reconstruction of the foramen tympanicum: what is known and how we do it

Keywords: Foramen tympanicum, foramen of Huschke, tinnitus, surgery, iliac crest graft, temporomandibular joint

Defects affecting the anterior wall of the tympanal bone can result from trauma, infection, neoplasm or previous local surgery. An anatomic variation, namely the persistence of the foramen tympanicum, can also be encountered. When symptomatic, surgical reconstruction may be indicated. The aim of this study was to identify the surgical treatments of symptomatic foramen tympanicum found in the literature and detail our innovative reconstruction technique. A bibliographic research was conducted in PubMed database in March 2020, without time limitation. Papers dealing with surgical management of a foramen tympanicum were included. Data collected were the publication date, the number of patients, their age and gender, the symptoms and the surgical treatment performed. We report, in addition, the case of a symptomatic persistent foramen tympanicum in a 30-year-old man with a follow-up of 18-months. A total of 17 studies (n=23 patients) were included for analysis. The main reconstruction techniques were, in equal proportion, cartilage graft (30%) and insertion of a titanium mesh (30%). We carried out an iliac crest bone graft using a preauricular approach on a patient suffering from chronic tinnitus and fullness in the left ear resulting from a persistent foramen tympanicum, confirmed by clinical and radiological examinations. It allowed the complete resolution of symptoms and no complication such as temporomandibular ankylosis occurred. Based on the review of the literature, we believe this technique has the advantage of providing durable reconstruction thanks to osseointegration.

Introduction

The temporomandibular joint (TMJ) is in close proximity to the external auditory canal (EAC). Anterior tympanal wall defects mostly result from injuries and cholesteatoma [START_REF] Park | Temporomandibular joint herniation into the external auditory canal[END_REF]. Infection, neoplasms or perforation during TMJ arthroscopy have also been previously reported [START_REF] Van Sickels | Middle ear injury resulting from temporomandibular joint arthroscopy[END_REF] as a cause of TMJ herniation into the EAC. The tympanal bone is formed by an anterior and a posterior prominence growing towards each other and merging during the first year of life, thereby delineating the foramen tympanicum (FT). During growth, the FT becomes smaller and is usually closed by ossification before the age of five [START_REF] Anand | Defects of the external auditory canal: a new reconstruction technique[END_REF][START_REF] Akcam | Temporomandibular joint herniation into the external ear canal through foramen of Huschke[END_REF][START_REF] Shin | Temporomandibular Joint Herniation Into the External Auditory Canal: Two Cases Involving a Persistent Foramen Tympanicum[END_REF][START_REF] Humphrey | Age of closure of the foramen of Huschke: an osteological study [Internet][END_REF]. Failure of fusion of the FT is a congenital condition of dehiscence of the EAC, also known as Huschke's foramen [START_REF] Hawke | Spontaneous temporomandibular joint fistula into the external auditory canal[END_REF]. Over time, the mechanical influence of masticatory movements may enlarge the defect [START_REF] Moriyama | Spontaneous temporomandibular joint herniation into the external auditory canal: a case report and review of the literature[END_REF]. This could explain why such a congenital condition only reveals in adults. Subsequent symptoms are nonspecific, including either TMJ or otologic patterns such as tinnitus, otalgia, otorrhea, hearing loss and aural fullness [START_REF] Li | Spontaneous temporomandibular joint herniation into the external auditory canal[END_REF]. In symptomatic patients, surgery may be required to close the defect. The aim of this study was to report the surgical treatments of the FT found in the literature and detail our innovative reconstruction technique of this defect.

Material and methods

A bibliographic research was conducted in March 2020 in PubMed, without time limitation, employing "foramen tympanicum" or "foramen of Huschke" and "surgery" as search terms. Papers written in English as the language of publication, dealing with surgical management of a FT were included. Articles without available on-line abstracts were excluded. References of included studies were also searched to identify any relevant articles. For each selected article, we recorded the publication date, the number of patients, their age and gender, the symptoms and the surgical procedure. We report the case of a symptomatic persistent FT in a 30-year-old man with a follow-up of 18-months. This retrospective study was granted an exemption from the local institutional review board. The patient gave written informed consent for the publication of his case in agreement with the Declaration of Helsinki.

Results

Review of the literature

The study identification process is summarized in Figure 1. Through the research on Pubmed, 53 articles were initially identified. After screening of the abstracts, 31 were selected, and 13 met the inclusion criteria after full text reading. A further 4 articles were identified through references of these papers. Thus, a total of 17 studies were included for analysis. The characteristics of the included studies are presented in Table 1. The dates of publication ranged from 2000 (3) to 2019 [START_REF] Lim | Temporomandibular joint herniation through the foramen of Huschke with clicking tinnitus[END_REF]. Overall, 23 patients (16 males and 7 females) were treated. The average age of patients was 53 years (ranging from 35 to 73 years). Surgical approach used was: preauricular in 61% of the cases (n=14) [START_REF] Park | Temporomandibular joint herniation into the external auditory canal[END_REF][START_REF] Anand | Defects of the external auditory canal: a new reconstruction technique[END_REF][START_REF] Akcam | Temporomandibular joint herniation into the external ear canal through foramen of Huschke[END_REF][START_REF] Lim | Temporomandibular joint herniation through the foramen of Huschke with clicking tinnitus[END_REF][START_REF] Ajduk | Temporomandibular joint fistula into the external ear canal[END_REF][START_REF] Bernstein | Spontaneous Temporomandibular Joint Herniation into the External Auditory Canal through a Persistent Foramen Tympanicum (Huschke): Otologic Features[END_REF][START_REF] Rushton | Salivary otorrhoea: a case report and a review of the literature[END_REF][START_REF] Ryu | Spontaneous temporomandibular joint herniation into the external auditory canal through a patent foramen of Huschke: A case report[END_REF][START_REF] Shapiro | Temporoparietal fascia flap and total temporomandibular joint replacement for the management of patent foramen of Huschke[END_REF][START_REF] Singh | Spontaneous temporomandibular joint herniation: a rare case[END_REF], endaural in 26% (n=6) [START_REF] Park | Temporomandibular joint herniation into the external auditory canal[END_REF][START_REF] Moriyama | Spontaneous temporomandibular joint herniation into the external auditory canal: a case report and review of the literature[END_REF][START_REF] Yoo | Repair of the foramen of Huschke using an extended endaural approach[END_REF][START_REF] Williams | Benign Temporomandibular Joint Lesions Presenting as Masses in the External Auditory Canal[END_REF], postauricular in 9% (n=2) [START_REF] Kaftan | Herniation of the soft tissue of the temporomandibular joint into the external auditory canal[END_REF][START_REF] Burlak | Foramen tympanicum with symptomatic temporomandibular joint herniation[END_REF] and was not documented in one case [START_REF] Nakasato | Spontaneous temporomandibular joint herniation into the external auditory canal through a persistent foramen tympanicum (Huschke): radiographic features[END_REF].

The two main surgical reconstruction techniques were cartilage graft (tragal or conchal cartilages) in 30% (n=7) [START_REF] Akcam | Temporomandibular joint herniation into the external ear canal through foramen of Huschke[END_REF][START_REF] Moriyama | Spontaneous temporomandibular joint herniation into the external auditory canal: a case report and review of the literature[END_REF][START_REF] Ajduk | Temporomandibular joint fistula into the external ear canal[END_REF][START_REF] Bernstein | Spontaneous Temporomandibular Joint Herniation into the External Auditory Canal through a Persistent Foramen Tympanicum (Huschke): Otologic Features[END_REF][START_REF] Williams | Benign Temporomandibular Joint Lesions Presenting as Masses in the External Auditory Canal[END_REF][START_REF] Kaftan | Herniation of the soft tissue of the temporomandibular joint into the external auditory canal[END_REF][START_REF] Burlak | Foramen tympanicum with symptomatic temporomandibular joint herniation[END_REF] as well as insertion of a titanium mesh (30%, n=7) [START_REF] Park | Temporomandibular joint herniation into the external auditory canal[END_REF][START_REF] Ryu | Spontaneous temporomandibular joint herniation into the external auditory canal through a patent foramen of Huschke: A case report[END_REF][START_REF] Yoo | Repair of the foramen of Huschke using an extended endaural approach[END_REF]. To a lesser extent, collagen mesh was used in 1 case [START_REF] Singh | Spontaneous temporomandibular joint herniation: a rare case[END_REF], isolated temporoparietal fascia flap in 1 case [START_REF] Shapiro | Temporoparietal fascia flap and total temporomandibular joint replacement for the management of patent foramen of Huschke[END_REF], and skin graft in 2 cases [START_REF] Park | Temporomandibular joint herniation into the external auditory canal[END_REF]. Combined techniques were also used as follow: cartilage graft and temporoparietal fascia flap in 2 cases [START_REF] Rushton | Salivary otorrhoea: a case report and a review of the literature[END_REF][START_REF] Nakasato | Spontaneous temporomandibular joint herniation into the external auditory canal through a persistent foramen tympanicum (Huschke): radiographic features[END_REF], polypropylene implant and titanium miniplate in 2 cases (3), polypropylene implant with cartilage graft and titanium mesh in 1 case [START_REF] Lim | Temporomandibular joint herniation through the foramen of Huschke with clicking tinnitus[END_REF].

Illustrative case

A 30-year-old man was referred to our department for chronic tinnitus and aural fullness of the left ear. The symptoms, worsened by mouth opening, had increased over the previous two years, causing daily discomfort, and therefore becoming unbearable for the patient. He denied other otologic or facial symptoms and medical history found no trauma, ear infection, surgery or neoplastic disease. On the left side, otoscopic examination found a mobility of the anterior wall of the EAC in relation to mouth opening and closing. A CT scan was performed with 0.6 mm slice thickness and showed a tympanal bone defect between the EAC and the TMJ measuring 3.4 x 3.6 mm, respectively in the axial (Fig. 2A) and sagittal planes (Fig. 2B) attributed to a persistent FT.

The surgical procedure was carried out under general anesthesia. A preauricular approach, assisted by intraoperative tympanoscopy (Hopkins ® Telescope, Storz, Tuttlingen, Germany), allowed accurate localization of the bone defect on the anterior wall of the EAC. The TMJ capsule was detached from the zygomatic arch in order to expose the superior compartment of the TMJ and to identify the tympanal bone defect avoiding injury of the disc and the mandibular condyle.

An iliac crest bone graft was harvested using a piezoelectric device (Piezosurgery ® plus, Mectron, Loreto, Italia) with a minimally invasive surgical approach which preserves the surrounding tissues and minimizes scarring. The bone graft was contoured to perfectly fit the tympanal bone defect, taking into account the concavity of the recipient site (Fig. 3A).

In order to prevent displacement, the graft was held in place by an absorbable thread (Vicryl ® 3.0, Ethicon Inc., Johnson & Johnson, NE, USA) tied through a hole drilled with the piezoelectric device in the bony EAC of the tympanal bone (Fig. 3B). Closure was performed after attaching the articular capsule to the periosteum of the zygomatic arch, on a suction drain placed above the capsular plane.

The otologic symptoms resolved immediately after surgery. No malocclusion was noted. Maximum inter-incisal opening was temporarily reduced (27 mm for 3 months) and progressively returned to normal (48 mm at 6 months) with physical therapy. A CT scan, at 3 months postoperatively, showed a complete osseointegration of the bone graft with no sign of TMJ ankylosis (Fig. 4A andB). No recurrence was observed after an 18-month follow-up.

Discussion

Our study highlighted the role of bone grafts in FT closure, which promote a durable and stable reconstruction due to osseointegration, contrary to cartilage grafts and alloplastic materials which are, however, still more used.

Tympanal bone defects can be diagnosed from otoscopic or radiological findings [START_REF] Ryu | Spontaneous temporomandibular joint herniation into the external auditory canal through a patent foramen of Huschke: A case report[END_REF]. Symptoms are non-specific and the most commonly reported are otalgia (32%), otorrhea (32%), clicking tinnitus (20%), hearing loss (20%) and aural fullness (10%). Ten percent remain asymptomatic [START_REF] Li | Spontaneous temporomandibular joint herniation into the external auditory canal[END_REF]. Examination of the EAC during mouth movement is helpful because the herniation retracts with mouth opening. TMJ herniation is noted in 27% of the persistent FT (1) and is correlated with the size of the defect. According to the review of 985 CT scans, the mean size of the bony defect was 3.1

x 2.7 mm [START_REF] Park | Temporomandibular joint herniation into the external auditory canal[END_REF]. Radiologic investigations should also look for salivary fistula, because communication between the parotid gland and the EAC through a persistent FT has been reported [START_REF] Rana | Bilateral spontaneous salivary otorrhoea: Case report and a review of the literature[END_REF][START_REF] Fusconi | Foramen of Huschke: case report and experimental procedure for diagnosis of spontaneous salivary fistula[END_REF]. The prevalence of persistent FT is estimated at 9% in radiologic studies [START_REF] Pękala | Incidence of Foramen Tympanicum (of Huschke): Comparing Cadaveric and Radiologic Studies[END_REF]. A recent meta-analysis showed a higher prevalence in cadaveric studies with a 21% rate (24), suggesting a variable percentage of undetectable persistent FT on imaging techniques.

According to literature [START_REF] Shin | Temporomandibular Joint Herniation Into the External Auditory Canal: Two Cases Involving a Persistent Foramen Tympanicum[END_REF][START_REF] Singh | Spontaneous temporomandibular joint herniation: a rare case[END_REF], treatment depends on the severity of the symptoms. A conservative strategy is often considered when symptoms are trivial. It consists of anxiolytic medication, muscle relaxant and a soft diet [START_REF] Shin | Temporomandibular Joint Herniation Into the External Auditory Canal: Two Cases Involving a Persistent Foramen Tympanicum[END_REF][START_REF] Kim | A Case of Spontaneous Temporomandibular Joint Herniation into the External Auditory Canal with Clicking Sound[END_REF][START_REF] Ertugrul | Rare Cause of Tinnitus: Spontaneous Temporomandibular Joint Herniation Into the External Auditory Canal[END_REF]. Surgical closure of the defect is required when significant symptoms appear. The aim of the surgical treatment is to restore the integrity of the EAC in order to preserve hearing and TMJ functions.

Two kinds of surgical approaches are mainly used; a preauricular approach providing access to the TMJ and an endaural approach exposing the anterior aspect of the temporal bone [START_REF] Kim | A Case of Spontaneous Temporomandibular Joint Herniation into the External Auditory Canal with Clicking Sound[END_REF]. The latter is usually preferred by ENT surgeons who harvest autologous cartilage from the same incision and use it as a reconstructive graft [START_REF] Moriyama | Spontaneous temporomandibular joint herniation into the external auditory canal: a case report and review of the literature[END_REF]. It only allows small reconstructions because the material must be small enough to be inserted through the defect. According to Yoo et al. [START_REF] Yoo | Repair of the foramen of Huschke using an extended endaural approach[END_REF], an extended endaural approach allows an easy separation of the canal skin from the joint capsule, and a correct exposure of both the TMJ capsule and the EAC through a single surgical field. It allows the insertion of a small titanium mesh but leaves a postoperative external scar. In the present case, we performed a conventional preauricular approach, which is widely used according to literature [START_REF] Park | Temporomandibular joint herniation into the external auditory canal[END_REF][START_REF] Anand | Defects of the external auditory canal: a new reconstruction technique[END_REF][START_REF] Akcam | Temporomandibular joint herniation into the external ear canal through foramen of Huschke[END_REF][START_REF] Lim | Temporomandibular joint herniation through the foramen of Huschke with clicking tinnitus[END_REF][START_REF] Ajduk | Temporomandibular joint fistula into the external ear canal[END_REF][START_REF] Bernstein | Spontaneous Temporomandibular Joint Herniation into the External Auditory Canal through a Persistent Foramen Tympanicum (Huschke): Otologic Features[END_REF][START_REF] Shapiro | Temporoparietal fascia flap and total temporomandibular joint replacement for the management of patent foramen of Huschke[END_REF][START_REF] Singh | Spontaneous temporomandibular joint herniation: a rare case[END_REF]. It provided an easy, quick, and wide access to the bony defect with an inconspicuous residual scar.

Various materials, such as tragal cartilage, temporoparietal fascia, polypropylene implant, collagen or titanium mesh, are used to repair the defect. Although cartilage allows autologous reconstruction, the surgical repair can be compromised by graft displacement [START_REF] Singh | Spontaneous temporomandibular joint herniation: a rare case[END_REF] or its resorption over time [START_REF] Akcam | Temporomandibular joint herniation into the external ear canal through foramen of Huschke[END_REF][START_REF] Moriyama | Spontaneous temporomandibular joint herniation into the external auditory canal: a case report and review of the literature[END_REF]. A temporoparietal fascia flap seems to ensure a more reliable surgical outcome, especially when alloplastic reconstruction of the TMJ is associated [START_REF] Shapiro | Temporoparietal fascia flap and total temporomandibular joint replacement for the management of patent foramen of Huschke[END_REF]. Recent alloplastic materials have become popular because they do not require tissue from a donor site. However, inert implants (such as Silastic ® ) do not allow a vascular growth and increase the risks of displacement and infection [START_REF] Rojas | Facial Implants: Controversies and Criticism. A Comprehensive Review of the Current Literature[END_REF]. High density porous polyethylene implants (Medpor ® ) may improve tissue ingrowth (3), but have a higher extrusion rate [START_REF] Rojas | Facial Implants: Controversies and Criticism. A Comprehensive Review of the Current Literature[END_REF]. In several cases, thin titanium meshes were used because they combine easy material management and sufficient solidity to prevent recurrence [START_REF] Park | Temporomandibular joint herniation into the external auditory canal[END_REF]. In cases of salivary fistula, surgery should include the ligature of the fistula and the closure of the bony defect [START_REF] Rana | Bilateral spontaneous salivary otorrhoea: Case report and a review of the literature[END_REF]; without bone reconstruction, recurrence may occur [START_REF] Williams | Benign Temporomandibular Joint Lesions Presenting as Masses in the External Auditory Canal[END_REF]. According to Gillies principle of "replacing like with like" (28), we used an iliac crest bone graft, to avoid a foreign body reaction with a minimal donor site morbidity. Reconstruction of the TMJ after traumatic injuries is a common cause of temporomandibular ankylosis. However, a recent review by Monteira et al. [START_REF] Monteiro | Updated Review of Traumatic Dislocation of the Mandibular Condyle Into the Middle Cranial Fossa[END_REF] showed that bony reconstruction of the glenoid fossa was not responsible for ankylosis. The surgical procedure must be carried out in the upper compartment of the TMJ and respect the integrity of the articular disc as well as the condylar head. Vigorous physical therapy, aimed at rehabilitating the TMJ functions, probably help to prevent temporomandibular ankylosis. Such a bone graft ensures a solid and durable reconstruction because of optimal osseointegration, as shown by radiological control in our case.

Conclusion

Considered as an anatomic variation, the persistence of the FT is responsible for a communication between the TMJ and the EAC. In symptomatic patients, surgical reconstruction mainly involves cartilage grafts or alloplastic materials. We described an original surgical treatment of a symptomatic persistent FT using an iliac crest bone graft. This procedure resulted in the complete resolution of all the symptoms with an uneventful postoperative course and no recurrence after an 18-month follow-up. The main advantage of this autologous correction is the osseointegration of the graft, which considerably lowers the risks of displacement and infection encountered when using exogenous materials.

Figure 2 .Figure 3 .

 23 Figure 2. Preoperative CT scan (0.6 mm slice thickness) of the left external auditory canal demonstrating the bony defect (red arrow) measuring 3.4 x 3.6 mm. Axial view (A). Sagittal view (B).

Figure 4 .

 4 Figure 4. Postoperative CT scan (0.6 mm slice thickness) of the left external auditory canal demonstrating the closure of the foramen tympanicum by the osseointegrated iliac crest bone graft (red arrow). Axial view (A). Sagittal view (B).

Table 1 .

 1 Symptomatology and surgical treatment of foramen tympanicum in the literature.M: male, F: female, PeA: Preauricular approach, PoA: Postauricular approach, EA: Endaural approach, ND: Non documented.

	Authors	Age	Gender Symptoms	Treatment
	Anand,	51	F	Hearing loss, painful clicking	Polypropylene implant (Medpor®) fixed by a
	2000 (3)	46	F	Pain, noises	titanium miniplate via PeA
	Kaftan,	64	F	Otorrhea	Conchal cartilage graft via PoA
	2004 (19)
	Rushton,	59	M	Ear discharge	Temporalis fascia and tragal cartilage graft via PeA
	2005 (13)
	Moriyama,	41	M	Tinnitus, crunching sound	Tragal cartilage graft fixed with fibrin glue via EA
	2005 (8)
	Park, 2010	54	M	Aural fullness, clicking tinnitus	Titanium mesh via PeA
	(1)	48	M	Aural fullness, clicking tinnitus, hearing	"
				loss
		50	M	Aural fullness, clicking tinnitus, hearing	"
				loss
		73	F	Tinnitus, hearing loss	"
		56	M	Otalgia, otorrhea	Skin graft via EA
		61	M	Aural fullness, hearing loss, otorrhea	"
	Akcam,	48	F	Clicking sound, aural fullness	Tragal cartilage graft via PeA
	2011 (4)
	Ajduk,	53	F	Otorrhea	Tragal cartilage graft via PeA
	2012 (11)
	Nakasato,	61	M	Crunching sound	Auricular cartilage graft fixed by fibrin glue and
	2013 (21)				temporalis fascia flap, approach ND
	Bernstein,	58	F	Aural fullness, otorrhea	Conchal cartilage graft via PeA
	2015 (12)
	Shapiro,	54	M	Otalgia, tinnitus	Discectomy, alloplastic reconstruction of the
	2016 (15)				condyle, temporoparietal fascia flap via PeA
	Yoo, 2015	66	M	Otalgia	Titanium mesh via EA
	(17)	47	M	Otalgia	"
	Singh, 2017	35	M	Otorrhea, aural fullness	Collagen mesh via PeA
	(16)
	Ryu, 2017	46	M	Mastication induced tinnitus	Titanium mesh via PeA
	(14)
	Williams,	46	M	Otorrhea	Tragal cartilage graft via EA
	2017 (18)
	Burlak,	52	M	Otorrhea	Tragal cartilage graft via PoA
	2018 (20)
	Lim, 2019	55	M	Otorrhea, tinnitus	Polypropylene implant (Medpor®), titanium mesh
	(10)				and tragal cartilage graft via PeA
	Mean	53	16M
			7F

grant from funding agencies in the public, commercial, or not-for-profit sectors.