Review of squamous premalignant vulvar lesions
Introduction
Vulvar squamous cell carcinoma (SCC) accounts for approximately 3–5% of all gynaecological malignancies and 1% of all carcinomas in women, with an incidence rate of 1–2/100,000 [1]. In the Netherlands (16 million inhabitants) about 230 new patients with vulvar cancer are diagnosed [1], [2]. Typically these cancers occur in the seventh decade when comorbidity is common. A rise in absolute numbers of vulvar SCC is expected because of the proportional increase in the average age of the population. Squamous cell carcinomas (SCCs) are the most common vulvar carcinomas. The cornerstone of treatment of SCC of the vulva is surgery [3].
There are two different types of vulvar SCC with their own associated premalignant lesions (see Fig. 1 for an overview). The most common type occurs in elderly women and leads to mostly differentiated keratinising SCC, in a background of lichen sclerosis (LS) and often differentiated vulvar intraepithelial neoplasia (VIN) [4]. There is no association with high-risk human papilloma virus (HPV) infection. Differentiated VIN is underreported, has a relatively brief intraepithelial phase before progression to invasive carcinoma, and is a difficult histological diagnosis [5], [6]. The oncogenesis of LS to SCC and its connection with differentiated VIN is not exactly known.
The second type of vulvar SCC consists of mainly non-keratinising carcinomas and primarily affects younger women. This type of vulvar SCC is caused by an infection with high-risk HPV, predominantly HPV 16 and 18 [4], [7]. This type of carcinoma is associated with warty and/or basaloid VIN (together grouped as usual VIN). These HPV-associated usual VIN lesions are seen adjacent to approximately 30% of the vulvar SCCs. In the processes associated with both progression to invasive disease and spontaneous regression of usual VIN the immune system seems to play an important role [8]. Multicentric HPV infections affecting both cervix, vagina and/or anus have been described. Twenty-two percent of usual VIN patients has a concurrent cervical intraepithelial neoplasia (CIN) [9] and up to 71% of usual VIN patients had a previous, concomitant or subsequent history of vaginal intraepithelial neoplasia (VAIN), CIN or cervical carcinoma [10], [11], [12]. Despite a stable pattern in the incidence of vulvar carcinoma [13], [14], the incidence of usual VIN and vulvar carcinoma is increasing in women aged 50 years and younger [13], [15], [16], [17], [18]. This might be due to a higher incidence of HPV infection of the genital tract and/or to an increased awareness of usual VIN.
In this review an outline is given on vulvar premalignant lesions. For an overview of vulvar carcinomas we refer to the review of de Hullu et al., published in this journal in 2006 [3]. Clinical and histopathological characteristics, the different treatment modalities and malignant potential of premalignant vulvar lesions are described.
Relevant studies were identified by a computer search in the Pubmed database (last date of search February 4th 2008). We searched the medical literature using combinations of the following terms: vulvar intraepithelial neoplasia, simplex, differentiated, usual, classic, VIN, Lichen Sclerosus, HPV, incidence, vaccines, vaccination, treatment, surgery, steroids, ointments, imiquimod, interferon, photodynamic therapy, 5-fluorouracil, cidofovir, recurrence, progression, oncogenesis and malignant potential. With the button ‘related articles’ in Pubmed, additional papers were identified. The reference lists from the selected articles were used in order to identify other relevant publications. Also gynaecologic oncology handbooks and relevant theses were used.
Vulvar biopsy is the only method to get a histopathological diagnosis when there is a vulvar lesion of uncertain significance, or in the presence of persisting symptoms, such as vulvar irritation or itching. The optimal biopsy is a punch or small incision biopsy, preferably taken from the edge of the lesion, including a small piece of normal tissue (see Fig. 2). In case of a suspected malignancy, the biopsy should be taken from the most suspicious part of the lesion. A punch biopsy will produce a core-shaped specimen that is very small, but descends through the full thickness of the epithelium. It can be performed under local, topical anaesthesia. Infiltration anaesthesia, using lidocaine 1% (which may be combined with adrenalin), may be preceded by the application of EMLA® spray or cream, which contains lidocaine and prilocaine as a surface anaesthetic. Disposable punch biopsy devices are available, and a minimal size of 4 mm is advisable for a reliable diagnosis.
After taking the biopsy, pressure should be applied to the biopsy site, and when necessary for haemostasis, the wound can be closed by one or two approximating resolvable stitches or by using a silver nitrate stick. When the lesion is multifocal, the most divergent lesions should be biopsied to obtain the diagnoses of the entire vulvar area. Obtaining the right diagnosis is greatly helped by providing the pathologist with a description of the clinical picture and providing a differential diagnosis. When the results of a punch biopsy are inconclusive, an incision or excision (especially in unifocal lesions that cause symptoms) biopsy can be an attractive alternative.
A photograph can be taken for consultation with other medical specialties, to note the localisations of the biopsies that were taken, and to document changes during follow-up (see Fig. 6B).
Vulvoscopy consists of careful observation and the possible use of a 5% acetic acid solution the entire vulvar area to facilitate examination of the vulva by the colposcope. It may result in identification of previously unidentified, subclinical lesions and better define the distribution of clinically evident disease [19]. After application of acetic acid solution clearly demarcated, dense acetowhite areas in the epithelium and abnormal vascular patterns, like mosaicism and punctuation (which reflect the underlying capillary distribution) can be seen [19]. However, acetowhitening has low sensitivity as a predictor of HPV infections [20], [21] although it can be used to determine the extent of the VIN lesion. Another disadvantage is the use of acetic acid, which can be very painful on ulcerative or de-epithialised lesions. In conclusion, vulvoscopy gives limited additional information in the diagnostics of vulvar disease and the painful experience make that there is only a limited role for vulvoscopy. Moreover, performance of a biopsy remains required to establish the diagnosis.
The effect of vulvar lesions on quality of life is unmistakable.
Many LS patients feel embarrassed and have sexual problems [22], [23]. Some psychological disturbance has been noted in surveys of women with LS, but this disturbance is thought to be a consequence rather than a cause of the disease [24], [25]. Patients may be embarrassed by the disfiguring changes that may occur and avoid sexual intimacy. Limited data that focus on the effect of LS on sexual function are available. A study regarding the impact of LS on women's sexual satisfaction showed that women with LS were less likely to be sexually active (vaginal intercourse, oral intercourse, and masturbation) than controls [26]. The majority of women with LS reported dyspareunia, apareunia and difficulty achieving orgasms and 71% of the patients with a reduced frequency of intercourse experienced an improvement in sexual functioning after treatment with topical steroids [27]. Introital dyspareunia in patients with LS may be related to three different causes; dryness of the vulvar mucosa, posterior synechiae of the labia minora and rarely introital stenosis. The dryness can be treated with topical steroids and lubricants. The synechiae of the labia minora and the introital stenosis may require limited surgical intervention [28].
Also the diagnosis VIN can have a great impact on the quality of life. In a review of eight studies on the sexual function for patients treated for VIN, only a small number of women had chronic vulvar pain after vulvar excision, however the majority of women did not return to baseline sexual function [29]. The type of surgery significantly correlates with the magnitude of sexual difficulties, with greater sexual problems among those who underwent radical vulvectomy than among patients treated with wide local excision (WLE) [30], [31], [32]. However, in the study of Green et al. the sexual dysfunction after vulvectomy did not correlate with the extent of surgery or type of vulvectomy [33]. Not all changes in sexual functioning after cancer treatment automatically lead to sexual dysfunctioning. In patients treated for a gynaecological malignancy, sexual dysfunctioning depended on personal and social factors, and the context in which changes in sexual functioning occurred [34]. It is likely that this mechanism can also be applied to patients suffering from a vulvar premalignancy.
Most studies focused on surgically treated patients; less information is available about the initial effect of pain and pruritus, the two main complaints in patients with LS and VIN lesions. Sargeant and O’Callaghan report that patients with vulvar pain have a significantly worse health-related quality of life in comparison with women without vulvar pain. Moreover, women without vulvar pain were significantly happier in their relationships than those with pain. In addition, women with vulvar pain reported significantly higher levels of distress related to sexual activities. It is important to teach a couple to broaden their sexual repertoire, such that intercourse does not become the major part of sexual activities. Assisting couples dealing with vulvar conditions may lead to an increase in couple happiness and a decrease in sex-related distress [35].
In conclusion, the number of studies regarding sexuality and LS and/or VIN is very limited. This important aspect of care for patients with LS and/or VIN deserves clinical and scientific attention.
Section snippets
History
Over the years, a variety of names and descriptions have been used for the disease that is currently named lichen sclerosus (LS). In 1892, Darier was the first to describe the histological features of the disease [36], [37]. Lichen sclerosus et atrophicans has been an often used term for a long time. In 1975, the removal of “et atrophicans” was proposed by the Terminology Committee of the International Society for the Study of Vulvar Disease (ISSVD, later the name was changed to International
History
Differentiated VIN was first described in the 1960s by Abell as a highly differentiated form of vulvar carcinoma in situ (CIS) and designated ‘intraepithelial carcinoma of simplex type’ to distinguish it from ‘intraepithelial carcinoma of Bowen's type’ (which nowadays would be called usual VIN). In 1977, the term ‘differentiated’ was introduced to highlight the marked differentiated morphologic features of this entity [113]. In the subsequent ISSVD revisions of the classification that followed,
History
Historically, various terms have been used to define vulvar cancer precursors. In 1912, Bowen described ‘squamous intraepithelial lesions’ (also referred to as Bowen's disease) and since then a myriad of clinical and histopathological terms have been employed to describe what is currently known as usual VIN [114]. The first series of Bowen's disease of the vulva was described in 1943 by Knight et al. referred to in [125]. In 1965, Kaufman separated non-neoplastic from neoplastic vulvar lesions.
Conclusion
In the absence of HPV, vulvar squamous cell carcinoma can develop in a background of LS, differentiated VIN or both. A variety of medical treatments for LS exist, with dermatocorticosteroids as the treatment option of first choice. It is unknown whether the medical treatment of LS decreases the risk on development of vulvar cancer. Patients with LS should be followed at least once a year. In case of difficulty with symptom control, clinical evidence of localised skin thickening or uncertainty
Reviewers
Mario Preti, MD, University of Turin, St. Anna Hospital, Department of Obstetrics and Gynecology, Via Ventiniglia 3, I-10126 Turin, Italy.
Ronald W. Jones, MD, Consultant Gynecological Oncologist, National Womens Hospital, Department of Gynecologic Oncology, Claude Road, Epson, Auckland, 1003, New Zealand.
James Scurry, MD, Nextpath, Suite 1, 24 Brown Road, Broadmeadow, NSW 2292, Australia.
David M. Luesley, MD, City Hospital, Pan-Birmingham Gynecological Cancer Centre, Dudley Road, Birmingham,
Conflict of interest statement
None.
Hedwig P. van de Nieuwenhof attended Medical School at the Radboud University in Nijmegen, the Netherlands. After her graduation in 2006, she started working as a PhD-student at the Department of Obstetrics and Gynaecology (subdivision Gynaecologic Oncology) of the Radboud University Nijmegen Medical Centre in Nijmegen, the Netherlands.
References (211)
- et al.
Surgery and radiotherapy in vulvar cancer
Crit Rev Oncol Hematol
(2006) - et al.
Prognostic significance of human papillomavirus DNA in vulvar carcinoma
Obstet Gynecol
(1995) - et al.
Vulvar intraepithelial neoplasia in adolescents with abnormal Pap smear results: a series report
J Pediatr Adolesc Gynecol
(2004) - et al.
In situ and invasive vulvar cancer incidence trends (1973 to 1987)
Am J Obstet Gynecol
(1992) - et al.
Vulvar squamous cell carcinoma in young women: a clinicopathologic study of 21 cases
Gynecol Oncol
(2002) - et al.
Trends in squamous cell carcinoma of the vulva: the influence of vulvar intraepithelial neoplasia
Obstet Gynecol
(1997) - et al.
Vulvar neoplasia in young women
Gynecol Oncol
(1999) - et al.
Carcinoma of the vulva in young women
Obstet Gynecol
(1995) - et al.
Acetowhitening of the cervix and vulva as a predictor of subclinical human papillomavirus infection: sensitivity and specificity in a population-based study
Obstet Gynecol
(1997) - et al.
Perineoplasty for the treatment of introital stenosis related to vulvar lichen sclerosus
Am J Obstet Gynecol
(2002)
Correlates of sexual function following vulvar excision
Gynecol Oncol
Sexual dysfunction following vulvectomy
Gynecol Oncol
Lichen sclerosus
J Am Acad Dermatol
Lichen sclerosus
Lancet
Childhood vulvar lichen sclerosus: an increasingly common problem
J Am Acad Dermatol
Risk factors for vulvar lichen sclerosus
Am J Obstet Gynecol
Early onset vulvar lichen sclerosus in premenopausal women and oral contraceptives
Eur J Obstet Gynecol Reprod Biol
Vulvovaginal examinations in elderly nursing home women residents
Arch Gerontol Geriatr
Penile cancer among patients with genital lichen sclerosus
J Am Acad Dermatol
Guidelines for the follow-up of women with vulvar lichen sclerosus in specialist clinics
Am J Obstet Gynecol
Short-term effects of topical testosterone in vulvar lichen sclerosus
Obstet Gynecol
Topical testosterone in the treatment of vulvar lichen sclerosus
Int J Gynaecol Obstet
Topical testosterone versus clobetasol for vulvar lichen sclerosus
Int J Gynaecol Obstet
Clobetasol dipropionate 0.05% versus testosterone propionate 2% topical application for severe vulvar lichen sclerosus
Am J Obstet Gynecol
Vulvar cancer
Incidence of cancer in the Netherlands
Vulvar squamous cell carcinoma is a multifactorial disease following two separate and independent pathways
Int J Gynecol Pathol
Recent advances in the pathology of the vulva
Histopathology
Squamous vulvar intraepithelial neoplasia: 2004 modified terminology, ISSVD Vulvar Oncology Subcommittee
J Reprod Med
Immunological and clinical responses in women with vulval intraepithelial neoplasia vaccinated with a vaccinia virus encoding human papillomavirus 16/18 oncoproteins
Cancer Res
Multifocal vulvar intraepithelial neoplasia grade III and multicentric lower genital tract neoplasia is associated with transcriptionally active human papillomavirus
Cancer
High-risk human papillomavirus infection of the genital tract of women with a previous history or current high-grade vulvar intraepithelial neoplasia
J Med Virol
Effect of human papillomavirus vaccines on vulvar, vaginal, and anal intraepithelial lesions and vulvar cancer
Obstet Gynecol
Trends in vulvar neoplasia. Increasing incidence of vulvar intraepithelial neoplasia and squamous cell carcinoma of the vulva in young women
J Reprod Med
Premalignant and malignant tumors of the vulva
Blaustein's pathology of the female genital tract
Subclinical manifestations of vulvar human papillomavirus infection
Int J Gynecol Pathol
Guidelines for the management of lichen sclerosus
Br J Dermatol
Lichen sclerosus
Clin Exp Dermatol
Serum levels of sex hormones in vulvar lichen sclerosus, and the effect of topical testosterone
N Engl J Med
Psychological distress in women with nonneoplastic epithelial disorders of the vulva
J Reprod Med
Vulvar pain and sexual function in patients with lichen sclerosis.
J Reprod Med
Effect of lichen sclerosus on sexual function and parturition
J Reprod Med
Use of the female sexual function index in women with vulvar intraepithelial neoplasia
J Sex Marital Ther
Sexual functioning after treatment of in situ vulvar cancer: preliminary report
Obstet Gynecol
Sexual function and somatopsychic reactions after local excision of vulvar intra-epithelial neoplasia
Acta Obstet Gynecol Scand
Sexuality, intimacy, and gynecological cancer
J Sex Marital Ther
The impact of chronic vulval pain on quality of life and psychosocial well-being
Aust NZ J Obstet Gynaecol
New nomenclature for vulvar disease—report of the committee on terminology
Obstet Gynecol
International Society for the study of vulvar disease—progress report
Br J Dermatol
Prevalence of vulvar lichen sclerosus in a general gynecology practice
J Reprod Med
Cited by (161)
Superficial versus deep inguinal nodal dissection for vulvar cancer staging
2022, Gynecologic OncologyAdjuvant radiotherapy and local recurrence in vulvar cancer – a subset analysis of the AGO-CaRE-1 study
2022, Gynecologic OncologyTopical therapies for the treatment of cervical intraepithelial neoplasia (CIN) 2–3: A narrative review
2020, Gynecologic Oncology ReportsPrecursor lesions of vulvar squamous cell carcinoma – histology and biomarkers: A systematic review
2020, Critical Reviews in Oncology/Hematology
Hedwig P. van de Nieuwenhof attended Medical School at the Radboud University in Nijmegen, the Netherlands. After her graduation in 2006, she started working as a PhD-student at the Department of Obstetrics and Gynaecology (subdivision Gynaecologic Oncology) of the Radboud University Nijmegen Medical Centre in Nijmegen, the Netherlands.
Irene A.M. van der Avoort finished a Master of Science (Biomedical Health Sciences, major in epidemiology) in 2000, and Medical School in 2004, both at the Radboud University in Nijmegen, the Netherlands. In 2004 she started working as a PhD-student at the Department of Obstetrics and Gynaecology (subdivision Gynaecologic Oncology) of the Radboud University Nijmegen Medical Centre in Nijmegen, the Netherlands. In April 2008 she started training as a gynaecologist.
Joanne A. de Hullu attended Medical School at the State University in Groningen, the Netherlands. After finishing her training as a gynaecologist in 1998, she followed a fellowship in gynaecologic oncology at the Department of Gynaecologic Oncology of the University Medical Centre Groningen, the Netherlands and the Royal Adelaide Hospital, Australia (Dr. M. Davy). In 2002 she successfully defended her thesis “Innovations in treatment of vulvar cancer”. Until 2003 she worked as a gynaecologic oncologist at the Department of Gynaecologic Oncology of the University Medical Centre Groningen. From 2003 onwards, she is working as a gynaecologic oncologist at the Department of Obstetrics and Gynaecology (subdivision Gynaecologic Oncology) of the Radboud University Nijmegen Medical Centre in Nijmegen, the Netherlands. She has published over 40 articles in peer-reviewed journals. Her fields of interest are vulvar cancer, vulvar premalignancies and hereditary cancer.
- 1
Both authors equally contributed to the manuscript.