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Non-Cervical-Human-Papillomavirus-Related-Disease-Prometric-Note.pdf
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DOI: 10.1111/tog.12049 2013;15:221–6The Obstetrician & Gynaecologist
Review
http://onlinetog.org
Non-cervical human papillomavirus-related disease
a, b c
Jonathan Lippiatt MD MRCOG, * Ned Powell PhD, Amanda Tristram MD MRCOG
a
Subspecialty Trainee in Gynaecological Oncology, South East Wales Gynaecological Oncology Centre, University Hospital Llandough, Cardiff
CF64 2XX, UK
b
Senior Lecturer, HPV Research Group, Institute of Cancer and Genetics, Cardiff University School of Medicine, University Hospital of Wales,
Cardiff CF14 4XN, UK
c
Senior Clinical Lecturer, Institute of Cancer and Genetics, Cardiff University School of Medicine, University Hospital of Wales, Cardiff CF14 4XN,
UK
*Correspondence: Jonathan Lippiatt. Email: jalippiatt@doctors.org.uk
Accepted on 31 January 2013
Key content To review the management of HPV-associated disease in
Human papillomavirus (HPV) is associated with neoplastic disease pregnancy.
at sites other than the cervix. To be aware that future research into HPV-related disease may
Cancer caused by HPV may behave differently to other cancers at alter management.
the same site.
Ethical issues
The presence of HPV alone is not sufficient to demonstrate a
What advice should women be given regarding their sexual
causal association.
HPV vaccination has the potential to impact on disease burden
partners?
Should boys be offered HPV vaccination?
beyond cervical cancer.
Keywords: genital warts / human papillomavirus / intraepithelial
Learning objectives
neoplasia / vaccination / vulval cancer
To understand the spectrum of disease caused by HPV.
Please cite this paper as: Lippiatt J, Powell N, Tristram A. Non-cervical human papillomavirus-related disease. The Obstetrician & Gynaecologist 2013;15:221–6.
increasingly recognised and this review will summarise the
Introduction evidence available.
The recent Nobel Prize winner in Physiology or Medicine, HPV is species- and tissue-specific (Table 1). There are
Harald zur Hausen, first hypothesised a role for human approximately 40 types that affect human mucocutaneous
papillomavirus (HPV) in the development of cervical tissue, such as those found in the anal, genital and oral tracts.
cancer.1 Since the 1970s HPV has been proposed as a In addition, they can be divided between those of malignant
causative factor in a variety of benign and malignant diseases. potential (high risk) and those associated with benign
HPV is a non-enveloped double-stranded DNA virus that conditions (low risk). Although the focus of this article is
infects the epithelial basal layer. The majority of HPV on HPV-associated neoplastic disease, there is reference to
infections occur without symptoms and are cleared by the benign conditions affecting the anogenital site, with
host over 8–12 months. However, infection may persist, particular emphasis on their management in pregnancy.
resulting in intraepithelial neoplasia and, over time,
progression to invasive carcinoma.
One hundred and twenty different types of HPV affecting
Anogenital tract
humans have now been described.2 HPV has been identified Vulval cancer
in various benign and malignant lesions within anogenital In 2010, 1172 women were diagnosed with vulval cancer in
sites, the aerodigestive tract, skin and conjunctiva.3 There the UK. When coupled with cancer of the vagina, it
are extensive data in the literature regarding HPV and accounts for 8% of gynaecological cancers in the UK.5 The
cervical disease. Walboomers et al.4 reported that the incidence of both vulval cancer and its precursor, vulval
worldwide prevalence of HPV in cervical carcinomas is intraepithelial neoplasia (VIN), are increasing, especially in
99.7%. The burden of HPV in non-cervical disease has been women below the age of 50 years.6–8 In the UK, the
ª 2013 Royal College of Obstetricians and Gynaecologists 221
, Non-cervical HPV-related disease
presenting symptom of VIN is pruritus, however, this is also
Table 1. Diseases commonly associated with individual HPV types
a common symptom found in many benign conditions and
HPV type Disease therefore may not be recognised as serious. Clinical
examination is essential and in order to make an accurate
1, 2 Verruca vulgaris diagnosis a biopsy is always recommended.14 VIN lesions in
1, 2 & 4 Plantar warts
3, 10 Flat cutaneous warts
particular can vary in size, shape, regularity, pigmentation
5, 8 Carcinogenesis in epidermodysplasia verruciformis and location on the vulva and, without a biopsy,
6, 11 Anogenital warts, respiratory papillomatosis misdiagnosis is common.
16, 18 Anogenital neoplasia, oropharyngeal cancers
Vaginal cancer
Primary cancer of the vagina is rare. The most common
proportion of vulval cancer diagnosed in women under the causes of squamous cell vaginal cancer are HPV and
age of 50 rose from 6% in 1975 to 14% in 2008.5 Vulval irradiation. There were 281 cases of vaginal cancer in the
squamous cell carcinoma (VSCC) accounts for over 90% UK in 2010.15 There are a limited number of studies looking
of vulval cancers. There appear to be at least two distinct at HPV prevalence in vaginal cancer and its precursor, vaginal
pathways for the development of vulval cancer and VIN intraepithelial neoplasia (VAIN). The combined overall HPV
(Figure 1). Usual type VIN is most common and is prevalence from a total of 15 studies has been reported as
associated with HPV, younger patients, multifocal lesions 100% in VAIN 1, 90.1% in VAIN 2/3 and 69.9% in vaginal
and other anogenital intraepithelial neoplasia.9 It generally carcinomas.16 HPV 16 is responsible for the majority of the
gives rise to warty/basaloid VSCC. Differentiated VIN is HPV-related vaginal disease. VAIN may be responsible for
usually found adjacent to invasive keratinising VSCC. It is abnormal cervical smears. Careful vaginal examination is,
typically HPV-negative and is seen most frequently in older therefore, mandatory when a cervical cause for the abnormal
women with other epithelial disorders such as lichen smear cannot be found. Vaginal lesions may also coexist with
sclerosus or lichen simplex chronicus.10 cervical or vulval lesions and may not, therefore, be recorded
Most of the studies looking at HPV prevalence in vulval as a separate entity, leading to underreporting.
cancer and VIN have been small and results vary
considerably. A meta-analysis carried out in 200911 Anal cancer
reported HPV prevalence in vulval cancer, high-grade VIN The incidence of anal cancer is approximately 1100 new
and low-grade VIN to be 40.4%, 85.3% and 67.8%, diagnoses each year in the UK.17 Although a relatively
respectively. HPV 16 is by far the most commonly found uncommon malignancy, studies have shown an increase in
type accounting for 67.5% of VIN and 32.2% of vulval incidence over the last few decades.18,19 Both anal cancer and
cancer. The study demonstrates the paucity of data regarding anal intraepithelial neoplasia have been linked to HPV
vulval neoplasia. HPV positivity in VSCC varies widely infection. Overall HPV prevalence has been reported as
between populations, from 34.7% in some European 91.5%, 93.9% and 84.3% in anal intraepithelial neoplasia
countries to 63.2% in the USA.12 (AIN) 1, AIN 2 and AIN 3, and anal carcinomas, respectively.11
The symptoms associated with VIN and vulval cancer can HPV 16 is responsible for 68–76% of anal cancers.3,11,20
be quite distressing and embarrassing.13 However, the However, in immunocompromised individuals with anal
diagnosis of vulval cancer is often delayed. A Dutch study12 cancers or AIN 2/3, several studies have shown proportionally
found that out of all the gynaecological malignancies, vulval higher rates of infection with other genotypes, and they are
cancer had the longest delay in diagnosis. The most common often multi-type infections.3,11,20 In the absence of any effective
prevention or screening, the current trends of increasing
incidence appear unlikely to change until the effects of HPV
prophylactic vaccination become apparent in 10–30 years.
Penile cancer
Penile cancer is rare in the UK, with approximately 520 cases
diagnosed each year.21 It appears that, like vulval neoplasia,
the prevalence of HPV in penile cancer varies with
histological type.3,22 The review by Backes et al.22 reported
the overall prevalence of HPV in penile cancer to be 47.9%.
Basaloid and warty subtypes are far more consistently
Figure 1. There are two distinct pathways in the development of associated with HPV infection than verrucous penile
vulval cancer cancers (66.3% versus 22.4%).22 HPV 16 is again the most
222 ª 2013 Royal College of Obstetricians and Gynaecologists
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