s10 Lower Genital Tract

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SECTION TEN

LOWER GENITAL
TRACT

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Chapter 104  Benign vulval problems
Lubna Haque and Margaret Cruickshank

3
MRCOG standards 2 4
1
Theoretical skills
• Revise your knowledge of vulva anatomy and
physiology. 10
5

Practical skills 9 6
• Take a vulvar history.
• Counsel patient on the use of topical steroids/
emollients on the vulva.
• Interpret histopathological reports and ask a histo- 8
pathologist if needed.
7
• Take a vulva biopsy under local anaesthetic.
• Be able to perform excision biopsy of a benign
vulva lesion under local or general anaesthetic.

INTRODUCTION
Benign vulval skin disorders are common. Vulval itch, pain or Fig. 104.1  Anatomical landmarks of the vulva: 1, clitoris; 2, mons pubis;
skin changes are commonly experienced. Community-based 3, clitoral hood; 4, urethral meatus; 5, vestibule; 6, hymen (torn); 7,
surveys indicate that about 20 per cent of women have sig- perineum; 8, labia majora; 9, vaginal opening; 10, labia minora
nificant vulval symptoms. Of women who are referred on to a
gynaecology clinic, the most common causes seen are derma- ●● the urinary meatus;
titis, lichen simplex, vulval candidiasis, lichen sclerosus and ●● the vaginal orifice;
lichen planus. This chapter relates to the initial assessment and ●● the hymen.
care of women with vulval disorders expected in the RCOG
core curriculum by the general gynaecologist. The mons pubis is the soft mound of the anterior vulva
formed by fatty tissue covering the pubic bone. This s­ eparates
into two folds known as the labia majora. Between the labia
ANATOMY majora is the pudendal cleft and posteriorly between the
pudendal cleft and the anus is the flat hairless area of the peri-
neum. The labia minora are two folds of skin within the
The vulva consists of the external genital organs of the female
labia majora which originate with the covering of the clito-
(Fig. 104.1).
ris, the clitoral hood. Between the labia minora is the vesti-
Major structures of the vulva are:
bule which contains the urethral and vaginal openings. The
●● the mons pubis; opening of the vagina is known as the introitus. This may
●● the labia, consisting of the labia majora and the labia be partly covered by the hymen, a mucosal membrane or,
minora; more ­commonly, its remnants known as c­ arunculae myr-
●● the external portion of the clitoris, consisting of the clito- tiformes which can be mistaken for skin tags or p ­ olyps.
ral glans and the clitoral hood; Posteriolateral on the left and right of the introitus are two

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840  Benign vulval problems

Bartholin glands and the ducts from these open into the lower, Selectiveness in the use of skin biopsy is advised as a diag-
posterior vagina. nosis can usually be made on clinical examination. Many vul-
val dermatoses can be recognised from history and classical
features on examination. Biopsy is required if the woman fails
ASSESSMENT to respond to treatment, there is diagnostic uncertainty of
skin changes or there is clinical suspicion of VIN or cancer [E].
A standard gynaecological history will not identify all relevant
symptoms and potential causes of vulva skin disorders. In General measures
addition to factors that relate to the presenting vulval symp-
toms, the patient should be asked specifically about symptoms General measures are a key component of the management
at other skin sites, other medical problems, and recent or cur- of vulval dermatoses in addition to condition-specific man-
rent drug history and family history. agement. Emollients protect the skin and restore skin bar-
rier function. General vulval care includes avoiding potential
irritants that may worsen vulval symptoms, reducing symp-
History toms and resolving contact dermatitis and lichen simplex.
Non-specific symptoms such as pruritus and pain are the Avoiding soap and detergents and using soap substitutes
common presenting symptoms in vulval skin disorders but instead can be soothing and protective to the skin. The com-
they are not diagnostic. The pattern of intensity and flare-up bined use of emollients and soap substitutes helps maintain
of symptoms should be explored during the day and over the symptom relief3 and reduce use of topical steroids making this
menstrual cycle, and aggravating and relieving factors such as approach safe and inexpensive [C]. (See Box 104.1 on general
urinary or faecal incontinence. The use of self-medication or measures.)
previous inadequate or inappropriate treatments may con-
tribute to symptoms. It is not unusual for vulval skin to come Box 104.1  General measures for vulval care
into contact with potential allergens and irritants such as sani- General measures which can help improve symptoms of vulval
tary products, textile dyes, perfumes and preservatives. discomfort and irritation.
●● Use a soap substitute to clean the vulva area. Water on its
Examination own tends to cause dry skin and lead to soreness.

It is important to examine the vulva with an adequate light ●● Shower rather than bathe and clean the vulval area only once
source and a systematic approach. Colposcopy is not neces- a day. Overwashing can aggravate vulva symptoms.
sary as the use of a gynaecology couch allows visualisation of ●● Wear loose-fitting natural fabric (silk/cotton) underwear.
the whole anogenital region. It is important to ask the patient ●● Sleep without underwear.
to identify the symptomatic area. If vulval intraepithelial neo- ●● Avoid fabric conditioners and biological washing powders.
plasia (VIN) is suspected, it is important to examine other
●● Avoid soaps, shower gel, scrubs, bubble baths, deodorants,
lower genital tract sites including the vagina, cervix and peri-
baby wipes or douches in the vulval area.
anal skin. Consider examination of other skin sites including
the mouth for signs of lichen planus or ulcers and the scalp, ●● Some over-the-counter creams including baby or nappy
elbows, knees and nails for psoriasis. Eczema can involve creams, herbal creams (e.g. tea tree oil/aloe vera) and
any site but is more commonly found on the scalp, neck, and ‘thrush’ treatments may include possible irritants.
elbow and knee flexor surfaces. ●● Avoid wearing panty liners or sanitary towels on a regular
basis.
Investigations ●● Avoid antiseptic (as a cream or added to bath water) in the
vulval area.
Routine investigations in the initial assessment of women ●● Wear white or light colours of underwear. Dark textile dyes
with vulval symptoms should only be performed if clinically (black, navy) may irritate sensitive skin.
indicated. These include thyroid function tests and random
●● Use white or pastel toilet paper and avoid strong colours such
blood glucose,1 a vulval skin swab for culture or an STI screen
as blue, green and peach.
[D]. In addition, serum ferritin and skin patch testing should
be considered in women with vulval dermatitis [D].2 Specific
LOWER GENITAL TRACT

allergic reactions are often identified in women with pruritus


vulvae. The most common relevant allergens are cosmetics,
medicaments and preservatives. Others include fragrances, DERMATOSES
preservatives in topical treatments, rubber and textile dyes.
Washing powder, fabric conditioners, sanitary towels or panty The term ‘dermatosis’ covers any skin disorder and those
liners and synthetic underwear may also be irritants and sec- most commonly seen in anogenital skin are covered below
ondary sensitisation to multiple products is common. but the complete classification has been developed by the

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Dermatoses 841

Box 104.2  Summary of 2011 ISSVD clinical classification of vulvar International Society for the Study of Vulvovaginal Disease
dermatological disorders5 (ISSVD).5 The ISSVD terminology was designed to enable
clinicians to describe skin features in a consistent and system-
1. Skin-coloured lesions
atic way with the intention of aiding the diagnosis and care of
A. Skin-coloured papules and nodules women (Box 104.2).
e.g. Bartholin gland cyst, warts, skin tags
B. Skin-coloured plaques Lichen sclerosus
1. Lichen simplex chronicus (LSC) Lichen sclerosus (LS) is a chronic inflammatory dermatosis
2. Vulvar intraepithelial neoplasia that is commonly seen in post-menopausal women but can
2. Red lesions: patches and plaques present at any age. Women complain bitterly of severe pruri-
tus that often follows a fluctuating pattern of symptoms but
A. Eczematous and lichenified diseases
may be worse at night. The vulval and perianal area is usu-
e.g. dermatitis, lichen simplex ally affected in a typical figure-of-eight distribution although
B. Red patches and plaques occasionally it can be localised. Scratching causes skin trauma
e.g. candidiasis, psoriasis, plasma cell (Zoon’s) vulvitis, with symptoms of discomfort, pain and dyspareunia.
extramammary Paget’s disease Pruritus is related to active inflammation with erythema
and keratinisation of the skin. The skin is often atrophic and
3. Red lesions: papules and nodules
erythematous, classically demonstrating sub-epithelial haem-
A. Red papules orrhages (ecchymoses), and fissuring. Hyperkeratosis may be
e.g. hidradenitis suppurativa marked with thickened white skin. Continuing inflammation
B. Red nodules results in inflammatory adhesions. Lateral fusion of the labia
minora starts with adherence to the outer mucosa and increas-
e.g. urethral caruncle, Bartholin’s abscess
ing agglutination can eventually result in complete reabsorp-
4. White lesions tion. The hood of the clitoris and its lateral margins may fuse,
A. White papules and nodules burying the clitoris. The accumulation of ­underlying skin
e.g. warts, scars debris and secretions can form a painful retention cyst often
described as the sensation of ‘walking on a pebble’. Midline
B. White patches and plaques
fusion produces webbing at the fourchette and narrowing of
e.g. lichen sclerosus, lichen planus, VIN, vitiligo the introitus, making intercourse ­painful and eventually pene-
5. Dark coloured lesions tration impossible. Occasionally the labia minora fuse together
A. Dark coloured patches medially causing difficulty with micturition, ­dribbling incon-
tinence and eventually acute ­urinary retention.
e.g. melanocytic naevus
B. Dark coloured papules and nodules Aetiology
e.g. VIN, melanoma The aetiology of LS is unknown but it does not appear to be
6. Blisters linked to female hormone changes, contraceptives, HRT or
A. Vesicles and bullae the menopause. Evidence suggests that it is an autoimmune
condition with around 40 per cent of women with LS having
e.g. herpes simplex, pemphigoid or going on to develop another autoimmune condition.6
B. Pustules
e.g. candidiasis, folliculitis Prognosis
7. Erosions and ulcers Prepubescent LS often improves at puberty but can recur in
adulthood. It is a lifelong condition but good symptom con-
A. Erosions trol and prevention of tissue destruction can be achieved with
e.g. erosive lichen planus ultrapotent topical steroids. LS is associated with a 4 per cent
B. Ulcers lifetime risk of squamous cell carcinoma (SCC) of the vulva7
e.g. chancre, Beçhet’s and women need to know the signs or symptoms of malignant
change to look out for.
8. Oedema
LOWER GENITAL TRACT

A. Skin coloured oedema Management


e.g. Crohn’s disease, post-radiation lymphatic obstruction The treatment of LS should control symptoms, prevent fur-
B. Pink or red oedema ther skin damage and reduce the risk of developing cancer.
Ultrapotent corticosteroids are the cornerstone of treatment
e.g. cellulitis, Bartholin’s abscess
for most women with LS. Clobetasol propionate is the most

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842  Benign vulval problems

potent topical corticosteroid available and recommended as s­ econd-line treatment is topical tacrolimus under the super-
first-line treatment. Response rates are high with either com- vision of a specialist clinic.9 Tacrolimus and ­pimicrolimus
plete or partial resolution of symptoms [A].8 Relapse of symp- belong to the class of immunosuppressant drugs known as
toms is common although improved response rates are seen calcineurin inhibitors. Their mode of action differs from
with longer regular use on an ultrapotent steroid, usually on a ­corticosteroids, mainly reducing inflammation by suppress-
reducing regime before returning to ‘as required’ use. Lower- ing the T-lymphocyte responses. Tacrolimus and pimicroli-
potency steroids and topical testosterone are not advocated. mus have both been shown to be effective in controlling the
The British Association of Dermatology has detailed guide- symptoms of LS8 although less effective in reversing changes
lines based on the best available evidence for the management in the skin appearance [A]. In a phase II study, maximal effects
of LS (see Box 104.3 for summary points) [A].9 Women need were seen after 10–24 weeks of treatment and 77 per cent of
clear information and directions on the use of their medica- women had a full or partial response.10 Calcineurin inhibi-
ments. Underuse of topical steroids is a more common prob- tors are well tolerated and avoid steroid side effects. However
lem than overuse. However there are no RCTS to support the use in LS is off licence and should be monitored in a special-
frequency and duration of use of topical steroids. A widely ist clinic. Local side effects such as burning are usually short
used regime is daily clobetasol propionate for one month fol- lived. They may also cause heat sensitivity and increase the
lowed by a gradual reducing regime [E].4 risk of herpes. Tacrolimus cannot be used in pregnancy due to
teratogenic effects. The long-term safety of topical calcineu-
rin inhibitors is not established although based on reports
Box 104.3  British Association of Dermatologists’ guidelines for from extensive use, this would appear to be low. Whilst long-
the management of lichen sclerosus 2010:9 Recommendations and term data are awaited, use for longer than two years is not
conclusions recommended due to c­ oncerns about potential malignant
transformation [E].
1. An ultrapotent topical corticosteroid is the first-line treatment
It is important to consider other factors which may con-
for LS in either sex or age group, at any site, but there are no
tribute to failure to respond to first-line treatment: poor com-
RCTs comparing steroid potency, frequency of application and
pliance with treatment; inability to comply e.g. due to poor
duration of treatment.
eyesight or mobility problems; superimposed secondary
2. Asymptomatic patients with evidence of clinically active LS condition such as infection; contact allergy to medicaments;
(ecchymosis, hyperkeratosis and progressing atrophy) should urinary or faecal incontinence; development of vulvodynia
be treated. secondary to tissue damage.9
3. Anogenital LS is associated with SCC but the development
of this complication is rare in clinical practice, <5%. It is not
yet known whether treatment lessens the long-term risk of Surgery
malignant change. Surgery and CO 2 laser vaporisation do not relieve the
­symptoms of LS but have a role in restoring function impaired
4. Long-term follow-up in a specialised clinic is unnecessary for
by agglutination and adhesion of vulva skin or mucosal
uncomplicated disease that is well-controlled clinically using
­surfaces. This can result in partial or complete urinary
small amounts of a topical corticosteroid i.e. <60 g in 12
­retention or narrowing of the vaginal introitus with altered
months.
body image or impaired sexual function. Prior to surgery, the
5. Secondary care follow-up should be reserved for patients skin should be pre-treated with daily clobetasol propionate
with complicated LS that is unresponsive to treatment and to ensure that there is no active inflammation at the time of
those patients who have persistent disease with a history of a ­surgery. Simple procedures such as modified Fenton’s proce-
previous SCC. dure can be effective in releasing webbing to allow restoration
6. A dermatology opinion should be sought in any patient with of sexual ­function [D].11
atypical or poorly controlled LS.
7. Surgical intervention is only indicated in women for the
Follow-up
complications of scarring, premalignant change or an invasive
Women who achieve good symptom control on ‘as
SCC.
required’ regimes of topical ultrapotent steroids do not
8. If psychosexual issues arise, these should be addressed and, require follow-up at a gynaecology clinic. They should
if appropriate, referral made to a practitioner experienced in have information on suspicious symptoms and continue
this field.
LOWER GENITAL TRACT

to use general measures to improve skin care. There are


no clinical trials on self-examination or the frequency or
duration of monitoring. However patient support groups
Second-line treatment and specialist societies do advocate self-examination
Approximately 5–10 per cent of women with LS will have to detect any suspicious areas. 12 Self-examination tech-
symptoms that do not improve with topical ultrapotent niques are provided by these groups and may have a role in
steroids (steroid-resistant disease). The recommended follow-up [E].

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Dermatoses 843

Lichen planus Lichen simplex


Lichen planus (LP) is a common dermatosis which may affect Women with sensitive skin, dermatitis or eczema can present
the skin anywhere on the body. LP usually affects mucosal with vulval symptoms of dermatitis which can result in lichen
surfaces and is more commonly seen in oral mucosa. LP pre- simplex, a common chronic inflammatory skin ­condition.
sents with polygonal purple plaques and papules with a fine This presents with severe intractable pruritus, especially at
white reticular pattern (Wickham’s striae). However, in the night. Non-specific inflammation often involves the labia
vulva it is more likely to be erosive LP and associated with pain majora but can extend to the mons pubis and inner thighs.
rather than pruritus. Erosive LP appears as a well demarcated, There may be erythema and oedmatous swelling with dis-
glazed erythema around the introitus. It can extend into the crete areas of thickening and lichenification often secondary
vagina as a painful desquamative vaginitis13 which can cause to scratching. This can be exacerbated by chemical or contact
dyspareunia and apareunia from stenosis and even vaginal dermatitis and is sometimes linked to stress or low body iron
obliteration. stores.

Aetiology Management
The aetiology of LP is unknown but it may be an autoim- The mainstay of treatment is general care of the vulva avoid-
mune condition. It can affect all ages, although it is more ing potential irritants and use of emollients and soap substi-
common after the menopause, and is not linked to hormonal tutes. Antihistamines or other antipruritics may be helpful,
status.6 especially if sleep is disturbed. However, moderate or ultra-
potent topical steroids may be necessary to break the itch–
Prognosis scratch cycle.
Like LS, LP is thought to have a small lifetime risk of SCC of
the vulva, but the small number of reported cases makes the
level of risk unclear. A UK-wide audit suggests a similar rate Vulval candidiasis
to LS of 2.3 per cent although this may be confounded by case
collection from specialist centres.13 Vulval candidiasis tends to present with irritation and soreness
of the vulva and anus rather than discharge. Diabetes, obesity
and antibiotic use may be contributory factors. Vulval can-
Management didiasis may become chronic. On examination, a leading edge
High-potency topical corticosteroids are first-line therapy of inflammation with satellite lesions may be seen extending
for all forms of LP although there have been no RCTs to sup- out from the labia majora to the inner thighs or mons pubis.
port this widely accepted practice which include anogenital There may be oedema, fissuring and excoriation from inflam-
LP [A].15 It needs to be recognised that this is indirect evi- mation and scratching.
dence as this systematic review identified only RCTs of the
management of LP in oral disease. In addition to clobetasol,
topical tacrolimus appears to be an effective treatment for vul- Management
vovaginal LP. A number of different treatments are reported Prolonged topical antifungal therapy may be necessary to clear
for women when LP does not respond to topical treatment, a skin infection with oral or topical preparations. A small pro-
or symptoms are severe or widespread. The most common spective case series suggests that a combined approach with
is oral steroids until disease remission is reached.14 Evidence oral fluconazole and topical antifungal cream may increase
is limited for vulval LP refractory to topical steriods but a clearance and reduce recurrence [D].17 In non-responsive
multicentre UK CRS trial completed recruitment in July cases, identification of the candida type and sensitivity may
2015 and is still to report. The hELP study (systemic therapy help to guide treatment.
for vulval erosive lichen planus) compares methotrexate,
hydoxychloroquine and mycophenolate mofetil16 along with
general supportive measures and topical ultrapotent ster- Extramammary Paget’s disease
oids and oral steroids if required. (Further information can
be found at http://public.ukcrn.org.uk/search/StudyDetail. Extramammary Paget’s disease of the vulva is a rare condi-
aspx?StudyID=16788) tion seen in post-menopausal women. The main symptom is
pruritus. On examination, discrete lesions usually affect hair-
LOWER GENITAL TRACT

bearing skin and not the mucosa, and have a florid eczematous
Prognosis appearance with lichenification, erythema and excoriation.
LP may resolve spontaneously within one to two years, Extramammary Paget’s disease can be associated with an
although recurrences are common. However, LP involving underlying adenocarcinoma. Imaging is recommended for
mucous membranes may be more persistent and resistant to the GI and urinary tracts and breasts but there is insufficient
treatment. evidence to advocate best practice.

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844  Benign vulval problems

Management Beçhet’s disease


Surgical excision is recommended to exclude adenocarcinoma Beçhet’s disease is a chronic multisystem disease character-
arising locally from a skin appendage and a case series of 76 ised by recurrent oral and genital ulcers. In women, ulcers can
cases pooled by BSSVD18-19 indicated that this is the treat- involve the cervix, vulva or vagina. These are usually recur-
ment option of choice. Photodynamic therapy, radiotherapy rent, painful and can leave scarring. Treatment to control
and topical imiquimod have been used with some success in flare-ups and reduce symptoms is based on topical or systemic
case reports [D]. Despite what appear to be obvious clini- immunosuppressants.
cal features, surgical margins are difficult to achieve due to
subclinical disease and recurrence is common. However the Vulval Crohn’s disease
margin status and lesion size did not appear to correlate with Crohn’s disease is a chronic inflammatory bowel disorder.
progression-free interval in a retrospective cohort study from It can involve the vulva by direct extension from involved
a single institution.19 bowel or ‘metastatic’ granulomas. Rarely it is seen with-
out known bowel disease or preceding the presentation of
bowel disease. The vulva is often swollen and oedematous
Psoriasis with granulomas, abscesses, draining sinuses and ulceration.
Psoriasis can involve the skin of the vulva but not vagi- Surgery can result in sinus and fistula formation and tissue
nal mucosa. The appearance differs from the typical scale ­breakdown and ­therefore should be avoided. Treatments
of non-genital sites. It often appears as smooth, non-scaly include m­ etronidazole and oral immunomodulators and so
red or pink discrete lesions. Scratching may cause infec- care needs to involve liaison with medical and surgical gastro-
tion, d­ ryness and skin thickening. Examination of other intestinal specialists.
sites including nails and scalp may be helpful in making a
diagnosis. Pemphigoid and pemphigus
Pemphigoid is a rare blistering disorder which usually occurs
in later life, the average age of onset for vulval disease being
Management over 70 years. Pemphigoid is classified as a connective tissue
Emollients, soap substitutes, topical steroids and calcipot- autoimmune disease. Prior to blister development or with
riene are useful for symptom control but cold tar preparations atypical disease, there may be non-specific pruritic papules,
should not be used in genital sites. eczematous or urticarial rash with marked itch. The blisters
are large tense fluid-filled bullae.
Pemphigus vulgaris is a rare autoimmune disease that
Plasma cell vulvitis (Zoon’s vulvitis) causes severe blistering of the skin and of the mucous mem-
Zoon’s vulvitis is a rare benign chronic inflammatory condi- branes lining the mouth, nose, throat and genitals. The fragile
tion of the vulva which presents with symptoms of pruritus, blisters break down to painful ulcers and itching is unusual.
burning, dyspareunia and dysuria. It usually presents in post- Treatment is with topical or oral steroids. Vulval rather than
menopausal women and its appearance is similar to erosive vaginal involvement is more common and is almost always
LP with glazed erythema often involving the introitus and associated with mouth and skin lesions. The bullae are usu-
labia minora. Zoon’s vulvitis is diagnosed histologically and ally large and tense. Treatment is important because second-
is characterised by dermal infiltration with plasma cells, vessel ary infection can lead to sepsis. Pemphigus vulgaris is usually
dilatation and haemosiderin deposition. The aetiology of this treated with oral corticosteroids.
condition is unknown; one theory is that it is an autoimmune If pemphigoid or pemphigus is suspected, the diagnosis
disorder. There have been case reports favouring success- can usually be made on the clinical appearance of the preced-
ful treatment with topical ultrapotent steroids and surgical ing rash or large fluid-filled bullae. Biopsies of the blister and
excision.20 adjacent normal skin should be taken for histological exami-
nation and a fresh sample in 0.9% saline for direct immuno-
fluorescence. Dermatological opinion on atypical blistering
Blistering and ulcerative conditions rashes and the treatment is essential.

Herpes Vulva lumps and bumps


Genital herpes usually presents with acute vulva pain and
asymptomatic episodes with genital blisters or ulcers are Lumps and bumps are common in the vulva area and normal
LOWER GENITAL TRACT

more likely to be seen with recurrence than primary infection. anatomical features such as carunculae myrtiformes or papil-
Swabs should be taken for confirmation and typing when her- lomatosis may be mistaken by the patient (or their doctor) for
pes infection is suspected as it is essential to have an accurate pathology. Vulval cysts are usually benign and can be treated
diagnosis. conservatively.

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Dermatoses 845

Sebaceous cyst pedunculated. Dermatofibromas cause little or no discomfort.


Sebaceous cysts are generally mobile masses that can consist On the shin, they are thought to arise from ­reaction to previ-
of fibrous tissue filled with inspissated sebaceous material. ous injuries such as shaving but trauma is less often related
They are more common in hair-bearing areas, are smooth in to vulva lesions. They tend to recur and should be managed
appearance and to the touch, and vary greatly in size. They conservatively.
can be multiple and widespread involving the labia majora.
Infection is uncommon but can recur. Excision of a sebaceous Lipoma
cyst scan be done under local anaesthetic. It is important to Vulvar lipomas are uncommon and benign consisting of
remove the central punctum to prevent recurrence. With ­lobulated fat enclosed by a thin fibrous capsule. They can
multiple cysts, it is possible to treat by laser ablation to avoid occur anywhere and in the anogenital area they usually involve
scarring and extensive skin excision.21 the labia majora or buttock. They tend to be slow growing and
are usually asymptomatic. They are more commonly seen in
Epithelial inclusion cyst the third and fourth decades of life. Treatment of vulval lipo-
This benign cyst is usually found on the skin of the labia majora mas should be conservative as surgery can cause scarring and
or minora. The appearance is similar to a sebaceous cyst. The disfigurement from removing subcutaneous fat which can
cyst may be asymptomatic but can also become infected. The extend deeply.
management is the same as for a sebaceous cyst.
Hidradenatis suppurativa
Bartholin’s cyst Hidradenitis suppurativa (HS) is a chronic skin disorder
A Bartholin’s cyst is formed when the duct from the Bartholin’s ­characterised by skin abscesses, fistulas and scarring, gener-
gland to the vaginal opening becomes blocked, causing a ally affecting the anogenital and axillary areas. It is a com-
fluid-filled cyst to develop. Infection of the duct and/or gland mon disease with an estimated prevalence of 1 per cent.23
results in a Bartholin’s abscess. Bartholin’s cysts are most likely The aetiology is unknown although it appears on histologi-
to occur in women of child-bearing age and can grow from the cal ­examination to be a disease of hair follicles rather than
size of a pea to the size of a golf ball. This is ­usually smooth and ­apocrine sweat glands. Recurrent and multiple boils and
well localised but when infected, there may be s­ urrounding scarring makes this condition embarrassing and distress-
oedema and induration. Marsupialisation is more effective ing. Treatment options are limited. First-line treatment
than simple incision and drainage for cysts and abscesses as it includes topical antibiotics (e.g. metronidazole gel) or sys-
allows the gland to drain and reduces the risk of r­ ecurrence. temic a­ ntibiotics (e.g. low-dose minocycline). Second-line
A cruciate incision is performed over the dome of the abscess, treatment with retinoids and immunosuppressive drugs may
the cavity drained and the wound edges are sutured apart have limited response and should involve collaboration with
to ensure drainage. An alternative ­procedure is to insert a dermatology.
­balloon catheter under local anaesthetic. The catheter stays in
place using a saline-filled balloon, usually for up to 4 weeks. Hidradenoma
This is to allow epithelialisation of the tract, after which it is Hidradenoma papilliferum (HP) is a rare, benign, cystic, pap-
deflated and removed if it has not fallen out s­ pontaneously. illary tumour. It is a sharply circumscribed nodule of ectopic
This procedure is recommended by a NICE review22 which breast tissue usually found on the labia majora or interlabial
identified from a small number of case series that insertion folds. It is often confused clinically with carcinoma of the
is almost always successful, most women find this procedure vulva as it often ulcerates. Histologically, it is identical to an
acceptable and the recurrence rate is 3–17 per cent [C] even if intraductal papilloma of the breast.
the catheter falls out in a shorter time [D].

Papillomatosis EBM
Papillomatosis describes a benign epithelial tumour, g­ rowing
exophytically with often finger-like fronds. Vulvar ­vestibular The supporting evidence for the management of common
papillomatosis is considered an anatomical variant of the vulva disorders is limited mostly to uncontrolled observational
vulva, characterised by pink, asymptomatic, fine ­projections.9 studies or case series.
Recognition of this condition is important to distinguish
it from warts and therefore avoid unnecessary biopsy or
LOWER GENITAL TRACT

­treatment. Papillomatosis may be more pronounced with


inflammation of the vulval mucosa. Vulval varicosities
Vulval varicosities are rare outwith pregnancy. They may
Dermatofibroma ­present with pain, dyspareunia or general discomfort, espe-
Dermatofibromas are classed as benign, often pigmented, skin cially when standing or later in day. Varicose swellings are
lesions forming firm solitary papules. They can be e­ levated or most likely to involve the labia majora. An MRI scan of the

K22970_C104.indd 845 17/12/15 3:49 PM


846  Benign vulval problems

pelvis may identify pelvic varicosities, local venous malforma- of the vulva and autoimmune disease. Arch Dermatol
tions of the vulva or vagina or arteriovenous malformations 2008;1449(11):1432–5.
of the leg or ovarian vessels or other pelvic organs.24 Isolated 7. Carli P, Cattaneo A, de Magnis A, Biggeri A, Taddei G,
varicosities are managed conservatively in pregnancy but Giannotti B. Squamous cell carcinoma arising in vulval
when symptomatic in non-pregnant women may be treated lichen sclerosus: a longitudinal cohort study. European
by incision and ligation or by sclerotherapy [D]. Journal of Cancer Prevention 1995;4:491–5.
8. Chi CC, Kirtschig G, Baldo M, Lewis F, Wojnarowska F.
Systematic review and meta-analysis of randomized con-
KEY POINTS trolled trials on topical interventions for genital lichen
sclerosus. J Am Acad Dermatol 2012;67:305–12.
●● Vulval itch is a very common complaint. 9. Neill SM, Lewis FM, Tatnall FM, Cox NH. British
●● The history required for vulva skin disorders differs from a Association of Dermatologists’ guidelines for the
standard gynaecological history to include information on management of lichen sclerosus 2010. Br J Dermatol
other skin disorders and related factors. 2010;163(4):672–82.
●● Examination requires good positioning of the patient with a 10. Hengge UR, Krause W, Hofmann H et al. Multicentre,
good light source and a systematic approach to examining phase II trial on the safety and efficacy of topical tac-
the whole ano-genital region. rolimus ointment for the treatment of lichen sclerosus.
●● Skin biopsy is not always necessary unless you suspect British Journal of Dermatology 2006;155(5):1021–1028.
malignant disease or the condition does not improve with 11. Gurumurthy M, Cruickshank ME. The surgical man-
first-line therapy. agement of complications of vulval lichen sclerosus.
●● Advice on general care of vulva skin and avoiding irritants European Journal of Obstetrics and Gynaecology and
often benefits women with vulva skin disorders in addition to Reproductive Biology 2012;162(1):79–82.
specific therapies. 12. http://lichensclerosus.org/check-your-vulva/ (accessed
●● Lichen sclerosus is a lifelong condition but good symptom 12/2/2014).
control and prevention of tissue destruction can be achieved 13. Helgesen AL, Gjersvik P, Jebsen P, Kirschner R, Tanbo
with topical ultrapotent steroids. T. Vaginal involvement in genital erosive lichen
●● LS is associated with a 4 per cent risk of squamous cell planus. Acta Obstetricia et Gynecologica Scandinavica
cancer of the vulva and women should be aware of the signs 2010;89(7):966–70.
or symptoms of malignant change. 14. Simpson E, Littlewood S, Cooper S et al. Real life expe-
●● Surgery is rarely required for LS except to correct the effects rience from UK multi-centre case-note audit of erosive
of scarring such as apareunia or urinary retention. vulval lichen planus. British Journal of Dermatology
●● Lumps and bumps are common in the vulva area and can 2012;167(1):85–91.
often be managed conservatively. 15. Cheng S, Kirtchig G, Cooper S. Interventions for erosive
lichen planus affecting mucosal sites. Cochrane Library of
Systematic Reviews 2012;CD008092.
16. Personal communication Dr Ruth Murphy and Dr
References Rosalind Simpson, 2014.
17. Beikert FC, Le MT, Koeninger A, Technau K, Clad A.
1. Crone AM, Stewart EJ, Wojnarowska F, Powell SM. Recurrent vulvovaginal candidosis: focus on the vulva.
Aetiological factors in vulvar dermatitis. Journal of Mycoses 2011;54(6):e807–10.
the European Academy of Dermatology & Venereology 18. MacLean AB, Makwana M, Ellis PE, Cunnington F.
2000;14(3):181–6. Management of Paget’s disease of the vulva. Journal of
2. Utas S, Ferahbas A, Yildez. Patients with vulvar pruritus; Obstetrics & Gynaecology 2004;24(2):124–8.
patch test results. Contact Dermatitis 2008;58:296–8. 19. Mendivil AA, Abaid L, Epstein HD et al. Paget’s dis-
3. Simonart T et al. Vulvar lichen sclerosus: effect of main- ease of the vulva: a clinicopathologic institutional
tenance treatment with a moisturizer on the course of the review. International Journal of Clinical Oncology 2012;
disease. Menopause 2008;15:74–7. 17(6):569–74.
4. Cruickshank ME, Hay I. The management of vulva skin 20. Gurumurthy M, Cairns M, Cruickshank ME. A case
disorders. RCOG Green-top Guideline No 58, 2011. series of Zoon’s vulvitis. Journal of Lower Genital Tract
5. Lynch PJ, Moyal-Barracco M, Scurry J, Stockdale C. 2011 Disease 2010;14(1):56–8.
LOWER GENITAL TRACT

ISSVD terminology and classification of vulvar derma- 21. Wu H, Wang S, Wu L, Zheng S. A new procedure
tological disorders: an approach to clinical diagnosis. for treating sebaceous cyst. Aesthetic Plastic Surgery
JLGTD 2012;16(4):339–44. 2009;33(4):597–9.
6. Cooper SM, Ali I, Baldo M, Wojnarowska F. The asso- 22. http://www.nice.org.uk/nicemedia/live/12140/
ciation of lichen sclerosus and erosive lichen planus 46577/46577.pdf

K22970_C104.indd 846 17/12/15 3:49 PM


Dermatoses 847

23. Nazary M, van der Zee HH, Prens EP, Folkerts G, Boer 24. Bell D, Kane PB, Liang S, Conway C, Tornos C. Vulvar
J. Pathogenesis and pharmacotherapy of hidrad- varices: an uncommon entity in surgical pathol-
enitis suppurativa. European Journal of Pharmacology ogy. International Journal of Gynecological Pathology
2011;672(1–3):1–8. 2007;26(1):99–101.

LOWER GENITAL TRACT

K22970_C104.indd 847 17/12/15 3:49 PM


Chapter 105  Vulvodynia
Shuchi Dixit and David Nunns

Box 105.1  ISSVD classification of vulval pain


MRCOG standards
Vulval pain related to a specific disorder
The established standards relevant for this topic are: 1. Infectious (e.g. candidiasis, herpes, etc.)
2. Inflammatory (e.g. lichen planus, lichen sclerosus,
Theoretical skills ­immunobullous disorders, etc.)
• Understand and distinguish between the different
3. Neoplastic (e.g.Paget’s disease, squamous cell
subgroups of vulvodynia.
­carcinoma,  etc.)

Practical skills 4. Neurologic (e.g. herpes neuralgia, spinal nerve


­compression,  etc.)
• Be able to clinically assess patients presenting with
superficial dyspareunia and vulval pain. Vulvodynia
• Be able to plan appropriate management and 1. Generalised
understand when to involve other disciplines. i. Provoked (sexual, non-sexual or both)
ii. Unprovoked
iii. Mixed (provoked and unprovoked)
INTRODUCTION 2. Localised (vestibulodynia – previously known as vulval
­vestibulitis, clitorodynia, hemivulvodynia, etc.)
Vulvodynia has been defined by the ISSVD as vulval discom- i. Provoked (sexual, non-sexual or both)
fort, most often described as a burning pain, occurring in the ii. Unprovoked
absence of relevant visible findings or a specific, clinically
identifiable, neurological disorder.1 Patients can be further iii. Mixed (provoked and unprovoked
classified by the anatomical site of the pain (e.g. general-
ised vulvodynia, hemivulvodynia, clitorodynia) and also by the production of pain by stimuli that do not usually cause
whether pain is provoked or unprovoked. Patients previously pain, by a reduction in the sensory threshold of ­neurons. Hence,
given a diagnosis of vestibulitis should now be diagnosed inflammatory pain seen with vestibulodynia is associated with
with vestibulodynia (localised provoked vulvodynia) (see Box pain on light touch and is usually localised. Neuropathic pain
105.1). Some patients may have a combination of vulvodynia is usually caused by damage to either the central or peripheral
with another vulval problem e.g. herpes or thrush, and both nervous system and produces a diffuse burning, aching pain
conditions may require treatment. with intermittent flare-ups. Hyperalgesia and allodynia may
Before a diagnosis of vulval pain syndrome can be made, not necessarily be present.
infections and vulval dermatoses should be excluded.

ASSESSMENT
PAIN PATHOPHYSIOLOGY
History
Clinical pain can either be inflammatory or neuropathic in
origin. Inflammatory pain is associated with tissue damage or An accurate pain history is essential to differentiate between
injury and clinically exhibits sensory hypersensitivity, which the different subtypes. In addition to the nature of the pain,
is characterised by hyperalgesia and allodynia. Hyperalgesia one should record any aggravating and relieving factors,
is the exaggerated response to noxious substances through a with particular reference to sexual intercourse. Any past
general increase in the responsiveness of tissues. Allodynia is treatments should also be recorded to avoid duplication.

K22970_C105.indd 848 17/12/15 3:52 PM


Vestibulodynia (localised provoked vulvodynia – formerly vulval vestibulitis)  849

A psychosexual history is essential, as many women have elicited by a partner) have all been described in vestibulo-
­significant ­dysfunction and may require a psychosexual dynia. These are all risk factors for significant psychosexual
­referral [II].2 ­dysfunction such as vaginismus and anorgasmia, the man-
agement of which usually requires psychosexual input [III]
(see Chapter xx).
Examination Clinically, simply using a Q-tip applicator can identify
Identifying sites of vulval tenderness and discomfort can ­vestibular tenderness. A defining feature of vestibulodynia
help in making a diagnosis. Clinical examination should is that the labial skin is non-tender. Vestibular erythema is
also exclude other vulval conditions that can produce simi- a subjective finding that is often present on normal exami-
lar symptoms. Inflammatory vulval diseases such as lichen nation and is usually not helpful in making the diagnosis of
sclerosus and seborrhoeic dermatitis can cause vulval pain vestibulodynia or in planning management.9 The application
and soreness through excoriation, splitting and fissuring of of diluted acetic acid to the vulva does not assist in making a
the vulval skin, as well as itching. Some conditions may not diagnosis [II].
be manifest at the time of examination, such as a tight poste-
rior fourchette and the vulval fissuring.3 Symptomatic der- Incidence
mographism is a rare cause of vulval pain, but this may be
suggested by dermographism evident at other body sites. 4 The incidence within gynaecology clinics in the UK remains
Other less common causes of vulval pain are worth consider- unknown. However, the prevalence of vestibulodynia was
ing, including aphthous ulceration, erosive lichen planus and 1.3 per cent of women attending a Central London GUM
genital herpes simplex These conditions are less common but clinic.10 Misdiagnosis is common.
should be ruled out by adequate examination and investiga-
tion. Where diagnosis is unclear patients should be referred to
a vulval service or clinic. Aetiology/risk factors
This remains unknown, but is likely to be multifactorial. It is
often difficult to identify a cause, as symptoms usually develop
VESTIBULODYNIA (LOCALISED insidiously. Recurrent attacks of vaginal candidiasis are
­frequently cited, but this may be due to initial misdiagnosis.
PROVOKED VULVODYNIA – FORMERLY
VULVAL VESTIBULITIS) Prognosis
Definition Up to 30 per cent of women with vestibulodynia may
­experience resolution of their symptoms without treat-
Vestibulodynia is a cause of superficial dyspareunia and is ment and in 50 per cent of these, resolution can occur within
characterised by vestibular tenderness on light touch.5 This 12 months [II].6
hyperaesthesia can be generalised throughout the vestibule or
can be more focal, involving the opening of the ducts of the
major vestibular glands or the posterior fourchette.6 Management
The aims of management are to reduce vestibular t­ enderness
Clinical features and to identify the potential need for input from other
­disciplines, for example psychosexual counsellors.
Affected women are usually Caucasian, aged between 20 and
40 years, and present with a history of provoked pain such as
superficial dyspareunia, tampon intolerance and pain during
General measures
Reassurance and an explanation of the condition are essential,
gynaecological examinations.5,7 There is often a delay between
and providing written information is helpful [II].11 Strict vul-
the onset of symptoms and receiving a diagnosis, which var-
val hygiene measures should be practised to reduce the chance
ies from months to years. A 6-month period of time has been
of contact sensitivity [III].
arbitrarily suggested from the onset of symptoms to making a
Only one RCT addresses surgery, group therapy and bio-
diagnosis of vestibulodynia so as to exclude women recover-
feedback.12 Good evidence for effective treatment is lacking.
ing from acute vulval inflammation from other causes.6
Many studies are methodologically flawed, for example low
LOWER GENITAL TRACT

As the condition is frequently chronic, a high level of


study numbers and short follow-up times.
­p sychological morbidity is common. Some patients are
prone to stress and anxiety, which may play a role in devel-
oping symptoms [III].2 Sexual dysfunction is common and Topical agents and vaginal dilators
­frequently reported.8 Reduced sexual arousal, more nega- No RCTs have compared topical agents. Local anaesthetic gel/
tive sexual feelings and less spontaneous interest in sex (not ointment prior to sex and emollients are worthy of mention

K22970_C105.indd 849 17/12/15 3:52 PM


850 Vulvodynia

as first-line treatment [III]. Lidocaine gel together with the Surgery


use of vaginal dilators can help desensitise the pelvic floor The modified vestibulectomy is the procedure of choice, involv-
for patients who are fearful of sex and where secondary ing excision of a horseshoe-shaped area of the vestibule and
­vaginismus may exist [II].13 inner labial fold followed by dissection of the posterior vaginal
Other topical agents include steroids and antifungal wall [II]. The vaginal tissue is then advanced to cover the skin
creams, which have been used with variable results, but no defect. The complete response rate is around 60 per cent. Women
control arm existed in these studies.14 Long-term empiri- who respond to lidocaine gel prior to sex have a more success-
cal prescribing of topical treatments should be discouraged, ful outcome.15 The response rate can be f­ urther improved with
as it places the woman at unnecessary risk of developing post-operative psychosexual counselling, which is likely to help
irritant dermatitis and contact allergy. Irritant dermatitis is overcome the fear of sex after surgery [II].13
common on the vulva and in essence is a chemical irritation In an RCT, 78 women with vestibulodynia were randomised
to a topical treatment. It usually resolves when the irritant to one of three arms: (1) group cognitive–behavioural therapy
is removed. (12 weeks’ duration), (2) pelvic floor biofeedback therapy
(12 weeks’ duration), and (3) vestibulectomy.12 At follow-up at
Pain management and psychosexual counselling 6 months, all patients reported significant improvements in pain
A cognitive–behavioural assessment has been suggested to scoring. Sexual functioning with surgery had the highest suc-
complement the physical treatments [Ib].12 Over a series of cess rates; however, one concern was the high number of partici-
sessions, a clinical psychologist can teach patients c­ oping pants randomised to surgery who declined to be included in the
mechanisms and pain management strategies such as the study. The study did support both non-surgical treatments for
pain-gate theory, and can address the patient’s e­ xpectations vestibulodynia and suggested that patients prefer a behavioural
of treatment, which might not necessarily be a cure for approach to treatment than a surgical one.
pain, but rather the ability to have penetrative sex. Fig.
105.1 o­ utlines a connection between the psychological and
psychosexual aspects of vulval pain connecting thoughts, Other treatments
emotions, behaviours and symptoms. Hence there is an Biofeedback therapy using surface electromyographic (sEMG)
important role that psychological therapies play in the signals from the pelvic floor has been used successfully to help
overall management of vulval pain. For many women with overcome pelvic floor muscle dysfunction in women with vesti-
vestibulodynia, sexual rehabilitation may be required and bulodynia [II].16 Using portable home machines with a special
this can be structured over several sessions with a psycho- vaginal skin sensor, 78 per cent of patients with apareunia had
sexual counsellor, preferably with the woman’s partner. It is resumed penetrative sex and there was an objective improve-
important to stress that a referral for therapy does not mean ment in the sEMG reading of the pelvic floor; however, many of
that the pain is all in the mind.21 Improving physical non- these patients were also treated with amitriptyline. The system is
coital sexual contact, h­ elping to o
­ vercome pelvic floor mus- not routinely available and experience in the UK is lacking. It is
cle hypertonia using sensate focus therapy, and addressing likely that patients may benefit from desensitising the vulval area
secondary psychosexual d ­ ysfunction such as low libido and using a variety of techniques; the optimal technique is not clear.
anorgasmia will be of help to many.8 Biofeedback or vaginal dilators may all work in a similar way.

Behaviours
Avoid intimacy
Becomes withdrawn emotionally
Push self to make up for it

Thoughts Physical sensations


I’m less of a woman Muscle tension = Further pain
I better not lead my partner on Headaches
He might find someone else Irritable bowel symptoms
I’ll try & make up for it in other ways Sinking feeling in stomach
LOWER GENITAL TRACT

Emotions
Fear / Anxiety
Stress
Guilt
Depression

Fig. 105.1  Psychological and psychosexual therapy aspect of sexual pain

K22970_C105.indd 850 17/12/15 3:52 PM


Conclusion 851

General measures
KEY POINTS Reassurance and an explanation of the condition are essential,
Vestibulodynia and providing written information is helpful.11 Strict vulval
●● Topical agents are commonly used, but the evidence hygiene measures should be practised to reduce the chance of
supporting a specific application is lacking. contact sensitivity.
●● Surgery is of benefit in well-selected patients. No RCTs have been carried out to assess the management
●● One RCT showed a benefit of vestibulectomy above of this group of patients, and only case-controlled studies
biofeedback therapy and group cognitive–behavioural therapy. exist, which frequently contain small numbers of women.
●● Biofeedback is effective, but UK experience is limited and
requires further evidence of benefit. Physiotherapy referral for Tricyclic antidepressants and neuroleptics
pelvic floor assessment and treatment can be considered. Amitriptyline (a tricyclic antidepressant) is of benefit
and addresses the central and peripheral components of
­neuropathic pain seen in unprovoked vulvodynia [II]. 16
No evidence exists that dietary manipulations can improve
A dose of 10 mg/day, increasing every week until the pain
outcome in vestibulodynia.
is ­controlled, has been suggested. The average dosage is
60 mg/day, although up to 150 mg/day can be used. Side
effects may affect c­ ompliance. The duration of treatment
UNPROVOKED VULVODYNIA is ­debatable, but 3–6 months has been suggested. Patients
­intolerant of the side effects can try dothiepin or nortriptyl-
Definition ine. The n­ euroleptic gabapentin can be used as a second-line
agent. In the only series to date of 17 patients with unpro-
Unprovoked vulvodynia is a cutaneous dysaesthesia causing voked vulvodynia, the complete response rate was 41 per cent
non-localised vulval pain. Unlike with provoked pain, unpro- for ­treatment with gabapentin with a follow-up period of
voked vulvodynia gives more constant neuropathic-type pain 26 months [II].19
in the vulva and occasionally the perianal area.17
Surgery
Clinical features Surgery is contraindicated in this group.
The affected women are typically perimenopausal or
­post-menopausal and, like women with vestibulodynia, can Other treatments
present with a long history of multiple, inappropriate use of Acupuncture has shown limited promise in cases ­refractory
topical agents prior to a diagnosis.18 Superficial dyspareunia to standard medical treatments. In one study comprising only
is not consistently reported, as many women are less ­sexually 12 patients with unprovoked vulvodynia, two were c­ ompletely
active.5 In addition, many experience rectal, perineal and cured [II].20
­urethral discomfort and there may be an overlap with other
perineal pain syndromes.17 Psychological morbidity is likely
to be high as a consequence of chronic pain. KEY POINTS
Clinical examination of the vulva is normal.
Unprovoked vulvodynia
Incidence ●● Tricyclic antidepressants and gabapentin are of benefit.
●● Surgery is contraindicated.
The incidence is unknown, but, as with vestibulodynia,
­misdiagnosis is likely.

Aetiology/risk factors CONCLUSION


These remain unknown.
Women with vulvodynia form a heterogeneous group, with
Prognosis the clinical presentation reflecting physical, psychological
and psychosexual factors. As with other chronic pain syn-
dromes, a specific cause remains elusive and is probably
LOWER GENITAL TRACT

The prognosis also remains unknown.


­multifactorial. A multidisciplinary approach to symptoms
Management is likely to be of benefit to address the many complex issues
­surrounding v­ ulval pain (Table 105.1). For some women
The aims of treatment are pain relief and identification of the who fail to respond to treatment, living and coping with
potential need for input from other disciplines. pain become key issues in management. (Fig. 105.2.)

K22970_C105.indd 851 17/12/15 3:52 PM


852 Vulvodynia

Table 105.1  The multidisciplinary approach to vulval pain syndromes


KEY POINTS
Health professional Treatments offered
●● A good history and clinical examination are essential
Clinician Topical agents to distinguish between different vulvodynia
Tricyclic antidepressants/neuroleptics subgroups.
●● Surgery is only suitable for well-selected patients with
Modified vestibulectomy
vestibulodynia.
Clinical psychologist Cognitive–behavioural therapy ●● Amitriptyline/gabapentin are treatments for unprovoked
Pain management vulvodynia.
Coping strategies ●● A multidisciplinary approach can be helpful.
●● Good evidence for effectiveness is lacking.
Psychosexual Treatment of secondary sexual
●● It is important to escalate patients to senior colleagues
counsellors dysfunction
for ongoing referral if 1) the patient has not responded to
Sensate focus therapy treatment, 2) the diagnosis is unclear, or 3) the
Increasing non-coital sexual activity symptoms are severe and there is a significant impact on
Physiotherapist Biofeedback function.

Pelvic floor muscle rehabilitation and


desensitisation Key References
1. Haefner HK. Report of the International Society for
The role of the general gynaecologist is assessment and the Study of Vulvovaginal Disease terminology and
then triage of the patient to the correct health professional classification of vulvodynia. J Low Genit Tract Dis
­depending on the needs of the patients. If the clinician is 2007;11(1):48–9.
unsure of management or the patient does not respond to 2. Nunns D, Mandal D. Psychological and ­psychosexual
treatment then the patient should be referred to the local vul- aspects of vulval vestibulitis. Genitourinary Med
val service. 1997;73(6):541–4.
3. Harrington C. Presidential address. In: Proceedings of
the British Society for the Study of Vulval Disease Biennial
Algorithm for Managing Vulvodynia Meeting, 1999; Oxford, UK.
4. Lambiris A, Greaves MW. Urticaria: increasingly
Diagnosis of vulvodynia ­recognised but not adequately highlighted cause of
­dyspareunia and vulvodynia. Acta Derm Venereol (Stockh)
1996;77:160–1.
Explanation of symptoms 5. Friedrich EG. Vulvar vestibulitis syndrome. J Reprod Med
reassurance/leaflet information 1987;32:110–14.
6. Peckham BM, Mak DG, Patterson JJ. Focal vulvitis:
a characteristic syndrome and a cause of dyspareunia. Am
Unprovoked
Vestibulodynia
vulvodynia J Obstet Gynecol 1986;154(4):855–64.
7. Marinnoff SC, Turner MLC. Vulvar vestibulitis syndrome:
an overview. Am J Obstet Gynecol 1991;165:1228–33.
Topical agents - Psychosexual Tricyclic
anaesthetics counselling* antidepressants
8. Schover LR, Youngs DD, Cannata RN. Psychosexual
aspects of the evaluation and management of vulval ves-
tibulitis. Am J Obstet Gynecol 1991;167(3):630–6.
Desensitisation Pain management
vaginal dilators Gabapentin 9. Van Beurden W, van der Vange N, de Craen AJM et al.
team
massage Normal findings in vulvar examination and vulvoscopy.
Br J Obstet Gynaecol 1997;104:320–4.
Pelvic floor muscle 10. Denbow ML, Byrne MA. Prevalence, causes and outcome
rehabilitation
of vulval pain in a genitourinary medicine clinic popula-
* Cognitive Behavioral Therapy
* Sensate Focus therapy
tion. Int J STI AIDS 1998;9:88–91.
LOWER GENITAL TRACT

Biofeedback 11. The Vulval Pain Society, PO Box 7804, Nottingham, NG3
therapy 5ZQ (send an s.a.e.).
12. Bergeron S, Binik YM, Khalife S, Pagidas K et al. A ran-
Surgery - modified domised comparison of group cognitive–behavioural
vestibulectomy therapy, surface electromyographic biofeedback and
vestibulectomy in the treatment of dyspareunia resulting
from vulvar vestibulitis. Pain 2001;91:297–306.
Fig. 105.2  Algorithm for managing Vulvodynia

K22970_C105.indd 852 17/12/15 3:52 PM


Conclusion 853

13. Abramov L, Wolman I, David MP. Vaginismus: an 17. McKay M. Dysaesthetic vulvodynia. J Reprod Med
important factor in the evaluation and management 1993;38(1):9–13.
of vulvar vestibulitis syndrome. Gynaecol Obstet Inv 18. McKay M. Subsets of vulvodynia. J Reprod Med
1994;38:194–7. 1987;32:110–14.
14. Friedrich EG. Therapeutic studies on vulval vestibulitis. 19. Ben-David B, Friedman M. Gabapentin therapy for vul-
J Reprod Med 1988:33(6):515–18. vodynia. Anesth Analg 1999;89:1459–60.
15. Kehoe S, Leusley D. An evaluation of modified vestibulec- 20. Powell J, Wojnarowska F. Acupuncture for vulvodynia.
tomy in the treatment of vulvar vestibulitis: preliminary J R Soc Med 1999;92:579–81.
results. Acta Obstet Gynecol Scand 1996;75:676–7. 21. Woolf J. Too sore for sex: the mind–body interface. IPM
16. Glazer HI. Treatment of vulval vestibulitis syndrome J 2007;26:4–10.
with electromyographic biofeedback of pelvic floor mus-
culature. J Reprod Med 1995;40(4):283–90.

LOWER GENITAL TRACT

K22970_C105.indd 853 17/12/15 3:52 PM


Chapter 106  Pre-invasive disease
Nirmala Rai and Gabrielle Downey

MRCOG standards and treatment in the pre-malignant phase is highly effective.


The accessibility of the cervix and the availability of a simple
The established standards relevant for this topic are: test for the presence of pre-malignancy make it suitable for
mass screening. Other malignancies and pre-malignancies of
Theoretical skills the lower genital tract are much less common and therefore
• Understand the central role of human papilloma- most of this chapter focuses on the cervix. A causal relation-
virus in the aetiology of cervical intraepithelial ship has been established beyond reasonable doubt between
neoplasia. cervical cancer and infection with human papillomavirus
• Understand the principles of organising popula- (HPV). The association has been seen in virtually all cases
worldwide, paving the way for tests based on viral detection to
tion screening, the current NHS cervical screening
be integrally linked with screening.
programme and the implications of HPV positivity.
• Be confident about interpreting cervical cytology
reports and counselling women accordingly.
• Be aware of the new changes to the cervical CERVICAL INTRAEPITHELIAL
screening programme including HPV triage and NEOPLASIA, ITS PATHOGENESIS AND
‘test of cure’.
• Understand the principles and application of the
THE ROLE OF HPV INFECTION
national HPV vaccination programme.
• Be aware of the controversies in both screening Definitions
and vaccination. Pre-cancer of the cervix was first described at the end of the
nineteenth century. Histologically areas were described where
Practical skills neoplastic cells replaced the entire thickness of the epithelium
• Recognise pre-malignant conditions and cancer of without breaching the basement membrane. This was referred
cervix. to as carcinoma in situ (CIS). Retrospective studies found CIS
• Be able to counsel patients with abnormal cervical lesions in women who subsequently went on to develop cer-
cytology/HPV tests. vical cancer, and so the precursor nature of CIS came to be
• Understand indications and limitations of screen- established. Subsequent prospective studies have confirmed
ing and investigative techniques of cytology, HPV these findings.1,2 After exfoliative cytology was introduced,
testing and colposcopy. lesser degrees of change, not amounting to CIS, were recog-
nised and termed ‘dysplasia’. In order to rationalise the clas-
sification to encompass all degrees of change, the term cervical
intraepithelial neoplasia (CIN) was introduced.3 Pre-invasive
INTRODUCTION changes were divided into grades 1, 2 and 3. Grades 1 and 2 cor-
responded to mild and moderate dysplasia respectively, and
Worldwide, cervical cancer is the third most common cancer grade 3 combined severe dysplasia and CIS into one category.
affecting women. Of the estimated 530,000 new cases in 2008, The definition implied a continuum of change from CIN-1
more than 85 per cent were in developing countries; in the through to CIN-3 and invasive cancer. As knowledge of the
same year 275,000 women died from it, about 88 per cent of natural history of pre-malignancy has grown, the concept of a
whom were in the developing world. In developed nations, continuum of change has been challenged. For practical pur-
the figures for invasive cervical cancer are much lower. The poses, there is now a two-stage grading, with CIN-1 becom-
disease has a relatively long natural history, and intervention ing low-grade CIN (in which there is a significant chance of

K22970_C106.indd 854 17/12/15 3:54 PM


Cervical intraepithelial neoplasia, its pathogenesis and the role of HPV infection 855

regression), and CIN-2 and CIN-3 being grouped together as Incidence


high-grade CIN (Table 106.1). In North American and some
European countries, this grouping has been formalised as the The UK has the second highest recorded incidence of CIN in
Bethesda Classification for cytological changes, consisting of the European Community. In 2010 in the UK there were 2900
low-grade squamous intraepithelial lesions (LSIL) and high- new cases of invasive cervical cancer and 940 deaths, which
grade squamous intraepithelial lesions (HSIL). equates to 8 women per day being diagnosed with cervical
cancer and over 2 women per day dying of it.4,5 The major-
ity of deaths are in women aged over 50. There has been an
Table 106.1  Glossary of terms increase in incidence rates of 60 per cent for women aged
25–34 years of age since 2002, which previously had seen a fall
Term Explanation until then. This is attributed perhaps to an increase in HPV
CIN Cervical intraepithelial neoplasia, graded 1–3 infection because of the increased proportion of women initi-
depending on severity ating sexual activity before the age of 16. Changes in smoking
behaviour in women born after the 1970s are also proposed
VAIN Vaginal intraepithelial neoplasia, graded 1–3
to be a factor contributing to the raised incidence. Another
depending on severity
contributory factor is an increasing number of migrants from
VIN Vulval intraepithelial neoplasia, graded 1–3 other countries without a screening programme being diag-
depending on severity nosed with cervical disease after arrival in UK. There was an
AIS Adenocarcinoma in situ, pre-invasive disease increase in incidence in 2009 across the UK which was attrib-
of glandular tissue uted to the raised awareness brought on by the high-profile
CIGN Cervical intraepithelial glandular neoplasia, death of a young reality TV star; incidence has subsequently
pre-invasive disease of glandular tissue dropped below the rates for 2008. There has also been a statis-
graded low and high; high-grade CIGN = AIS tically significant increase in the age-standardised incidence
by 17 per cent for all ages in the UK.4 Statistical modelling
Pap smear Cervical smear – cytological test described by
performed by the Imperial Cancer Research Fund (now a part
Papanicolaou
of Cancer Research UK) has extrapolated that the current
ASCUS Atypical squamous cells of uncertain screening programme prevents around 3900–4500 deaths
significance – Bethesda system grade from cervical cancer per annum.6,7
equating to borderline nuclear abnormalities It is difficult to estimate the total number of cases of CIN,
LSIL Low-grade squamous intraepithelial lesion as cancer registries only record cases of CIN-3, but there were
– Bethesda system grade equating to mild around 24,070 cases of CIN-3 in England, Scotland and Wales
dyskaryosis/CIN-1 registered in 2010 with the peak incidence being between
HSIL High-grade squamous intraepithelial lesion – 25 and 29 years of age.8
Bethesda system grade equating to moderate
and severe dyskaryosis/CIN-2 and CIN-3
Dyskaryosis A cytological term describing the nuclear
Aetiology
abnormalities – not synonymous with HPV infection is the essential prerequisite for the develop-
dysplasia ment of cervical malignancy. The most recent data on Dutch
Squamo- Where squamous and columnar tissue meet; archived cervical cancer specimens, using sensitive methods
columnar this is not fixed, but is affected by metaplasia of detecting HPV DNA, call into question whether HPV-
junction (SCJ) negative cervical cancers actually exist: the estimated preva-
Metaplasia A physiological process whereby columnar lence of HPV in cervical cancers is 99.7 per cent.9 On the
epithelium is replaced by squamous tissue other hand, population-based studies have shown that genital
in response to the acid environment of the HPV infection is extremely common with up to 80 per cent
vagina of sexually active women being HPV positive at some point
during their lifetime. Using the incidence of genital warts as
Transformation That area on the cervix that has undergone
a marker the incidence appears to be rising five-fold in the
zone metaplasia; it is bounded by the original SCJ
female population and eight-fold in the male population, with
and the present SCJ
approximately 15 per cent prevalence of the oncogenic HPV
Dysplasia A histological term describing architectural types 16 and 18.
LOWER GENITAL TRACT

abnormalities within tissue While the likelihood of acquiring the infection is high, most
LLETZ Large loop excision of the transformation zone infections are usually transient with 90 per cent of women
LEEP Loop electrosurgical excision procedure clearing the infection within two years. Thus, the overwhelm-
ing majority of HPV infections will not lead to the develop-
DLE Diathermy loop excision: taking a cone biopsy ment of cancer. Progression or regression depends on several
with an electrosurgical loop factors that interfere with the host’s ability to clear the virus.

K22970_C106.indd 855 17/12/15 3:54 PM


856  Pre-invasive disease

The cell-mediated arm of the adaptive immune response the cervix. Although the test has been a significant factor in
is responsible for clearing HPV. If cell-mediated immunity is the reduction of the incidence of cervical cancer by the detec-
impaired, such as in transplant patients or in HIV-positive tion of pre-malignant cells the drive to improve the screen-
women, the virus will not be cleared and abnormalities may ing test has led to the development of liquid-based cytology.
develop. How the virus results in cancer has now largely been Traditionally, the cytology sample from the cervix was spread
defined. The virus lives in epithelial cells and is species specific. on a glass slide at the time of collection. Each slide would
Genital infection with HPV can only be acquired through sex- therefore have only a proportion of the cells collected from
ual contact. It is thought that the virus enters the epithelium the cervix (around 20 per cent). In October 2003 liquid-based
through a breach in the skin integrity caused by microtrauma. cytology (LBC) was introduced following a recommendation
The virus can remain and replicate within the cytoplasm (epi- from NICE. LBC collects the whole sample from the sam-
somal) of the cell and is often cleared by the host immune sys- pling device in a liquid medium that is sent to a laboratory
tem. Occasionally, the virus enters the cell’s nucleus and this for processing. Cells are transferred from the transport liq-
step towards oncogenesis is termed ‘integration’. The cell no uid to a slide as a monolayer for examination. This technique
longer undergoes programmed cell death after 40–60 cycles reduces the proportion of inadequate smears and increases
but now becomes immortalised. The E6 and E7 oncoproteins the detection of true dyskaryosis and improved recall rates.
are necessary for this, but vary in their ability to do so accord- This also resulted in improved efficiency by laboratories as
ing to HPV type; E6 binds to the p53 cellular protein and E7 it improved the quality of the sample and reduced the work-
to the RB cellular protein, both of which are cell cycle regula- load per lab. It also reduced anxiety in women by reducing
tors.10,11 Interfering with the cell cycle allows DNA damage to recall and giving quicker results. LBC is now the standard test
accumulate, which may result in genetic instability and trans- used for the NHS cervical screening programme. There are
formation of the cell into a malignant cell line. This process two main types in use, Surepath™ and Thinprep®. The evalu-
may be accelerated by cofactors. ation of the sentinel sites for the transport medium suggested
Why persistent infection happens in what appears to be a that both mediums were equally efficient for HPV testing.
healthy individual is largely unknown. Smoking is a recog- An additional advantage of the new transport media is that
nised cofactor for the development of disease: local immu- they also allow screening for sexually transmitted infections
nity within the cervix appears to be suppressed in women who if required.
smoke. Women who smoke and have pre-invasive disease of HPV testing for triage of low-grade abnormal cytology and
the lower genital tract should be advised to stop smoking and ‘test of cure’ following treatment was incorporated in January
offered smoking cessation support. The major histocompat- 2011 into the NHS cervical screening programme following
ibility complex is responsible for presenting viral antigen to the evaluation of the pilot studies conducted in six sentinel
the host’s immune system and there is limited evidence to sites in England. It was concluded that the introduction of
suggest that women with particular human leukocyte antigen HPV testing for triage and ‘test of cure’ is not only feasible
(HLA) types may have increased susceptibility to disease. The but also acceptable and cost effective and it was rolled out in
majority of HPV infections result in CIN-1 and 60 per cent England in 2012.14
of these will regress without the need for treatment, while More than 90 per cent of cervical cancers develop within
approximately 10 per cent will progress to high-grade lesions. the transformation zone, the upper limit of which is the
However, it should be noted that women with mild dyskaryo- squamo-columnar junction. It is therefore important that this
sis have a 16–47 times increased incidence of invasive disease area is adequately sampled by direct visualisation of the cervix.
compared with the general female population.12,13 In order to quality assure the screening programme, all cytol-
Cervical pre-cancer has a long natural history, which is ogy samplers have a unique identification code.
one of the reasons why it is a suitable condition for screen-
ing. If a cancer is going to develop at all, it will take several
years to do so, even from a CIN-3 lesion. It is unclear why
Test performance
Cervical cytology is not a perfect test: there are false-positive
some CIN-3 lesions become invasive, while others stay as
results (i.e. no disease is actually present) and false-negative
intraepithelial disease, and it is not known how many CIN-3
results (i.e. genuine disease is missed). False-positive rates
lesions will become invasive, as prospective studies are uneth-
vary from 7 to 27 per cent (high specificity) and false-negative
ical. However, the best prospective data suggest that at least
rates from 20 to 50 per cent (low sensitivity). HPV testing has
36 per cent of women with CIN-3 would develop invasive can-
higher sensitivity for detecting CIN-2 or worse compared to
cer if left untreated.2
cytology. Therefore HPV triage was introduced along with
LOWER GENITAL TRACT

cytology with intent to improve outcomes and screening effi-


Screening for cervical intraepithelial ciency. About 98 per cent of the smears taken are adequate for
neoplasia diagnosis, and just under 10 per cent of adequate smears are
‘not normal’. Most smear abnormalities are at the minor end
The test of the spectrum.
The traditional Papanicolaou (Pap) smear test is used According to the NHS cervical screening programme
­worldwide to screen for pre-cancerous cellular changes from (2011–2012) (comparable with new British Society for Cervical

K22970_C106.indd 856 17/12/15 3:54 PM


Cervical intraepithelial neoplasia, its pathogenesis and the role of HPV infection 857

Cytology classifications), cervical smear ­abnormalities can differed from those that preceded it in that it incorporated all
be broken down as in Table 106.2. the available evidence and used this information to define a
In general, the proportion of normal smears increases in minimum standard and what was ‘best practice’. There were
older women, but so does the proportion of abnormalities significant changes to 1) the age to commence screening,
representing invasive cancer. Borderline changes and mild dys- 2) the screening interval, 3) actions to be taken following a
karyosis are very common in young women; the proportion of mildly abnormal smear and 4) follow-up of both treated and
moderate dyskaryosis is highest for women aged 20–29 years; untreated women. There were also guidelines dealing with
and the proportion of severe ­d yskaryosis is ­h ighest immune-suppressed and HIV-positive women. In general,
in women aged 25–34 years.13 the principle of management was to keep ‘low-risk’ women in
the community and ‘high-risk’ women in the colposcopy ser-
Table 106.2  Breakdown of cervical smear abnormalities vice. There were further changes introduced into the national
screening programme i.e. HPV testing to triage low-grade
Type (new BSCC classification in brackets) Per cent
(borderline and mild) abnormalities and test of cure follow-
Borderline nuclear abnormalities (borderline 3.4 ing treatment which were rolled out from March 2012.There
change, squamous, and borderline change in were regional variations within the UK in the commencement
endocervical cells) and cessation of screening which will be dealt with later in this
Mild dyskaryosis (low-grade dyskaryosis) 1.8 chapter.
Moderate dyskaryosis (high-grade dyskaryosis 0.5
– moderate) Main changes to the programme
Severe dyskaryosis (high-grade dyskaryosis – 0.6 The screening interval
severe) The screening interval changed from 3- to 5-yearly to be
? Invasive or glandular abnormalities 0.0 defined as:
(? invasive or ? glandular neoplasia
●● 3-yearly to 49 years;
endocervical non-cervical)
●● 5-yearly thereafter to 64 years.
Evidence shows that a 3-yearly screening programme could
The programme prevent substantially more cancers than a 5-yearly programme
By definition, a screening test is not diagnostic, but ­identifies in the younger woman with little extra cost.17,18
a subgroup of the reference population at increased risk of the If maximum coverage for a 3-yearly programme is
disease for which further tests should be carried out. Screening 91 per cent and the incremental gains become less and less
is always a trade-off between sensitivity and specificity. In thereafter with increasing screening frequency, therefore, in
this case, the reference population being screened comprises terms of cost–benefit, there is little justification for reducing
healthy, asymptomatic women. the screening interval to less than 3 years in the younger age
No randomised trials have been undertaken to establish group.
whether screening actually reduces mortality from cervical
cancer. Evidence in support of screening has been extrapo- The age to commence and stop screening
lated from reducing trends in incidence and mortality in those In England, Wales and Northern Ireland, screening begins at
areas where screening has been introduced. This is most strik- 25 years while it has been 20 years in Scotland. The incidence
ingly illustrated by considering data from Northern Europe: of cervical cancer in the under-25-year group is low and the
Iceland, Finland, Sweden and Denmark noted reductions incidence of transient infection and low-grade CIN is high. A
in incidence and mortality soon after their screening pro- recent review of the age to commence screening in England
grammes achieved target coverage of the population in the was undertaken as a result of media pressure following the
1960s. Norway, on the other hand, with no organised pro- death of a high-profile TV personality. The group concluded
gramme in the 1960s, continued to show increasing incidence there was no new evidence to justify lowering the age of screen-
rates into the 1970s.15 ing and good evidence to support the current policy of start-
A nationwide, organised (as opposed to opportunistic) cer- ing to screen at 25 years of age. Since 1 September 2013 Wales
vical screening programme was introduced in England and no longer invites women until they reach 25 and Scotland
Wales in 1988 with a national computerised call-and-recall will change from 2015 onwards. Thus 25 will be the age to
system. The regions still have a degree of autonomy in plan- commence cervical screening throughout the UK. Cervical
LOWER GENITAL TRACT

ning their screening programme, but there is now a national screening before 25 years of age may detect an abnormality
coordinating network to ensure the adoption of common that would resolve spontaneously, thus screening such young
standards and working practices. The whole NHS cervical women could result in both physical and psychological mor-
screening programme was rewritten in 2004 and a revised bidity with little evidence of benefit.
edition is available with new evidence (at present this is only There are conflicting reports on the effect of large-loop
available on the (BSCCP website).16 This new programme excision of the transformation zone (LLETZ) on preterm

K22970_C106.indd 857 17/12/15 3:54 PM


858  Pre-invasive disease

delivery. A systematic review and meta-analysis by Kyrigou 40 per cent.24 The difference in guidelines and in management
et al.19 reported an increase in preterm delivery following was also influenced by availability of services and variable evi-
LLETZ. Since then more studies have been published which dence regarding the risk of underlying high-grade disease.
have suggested that the risk of preterm delivery may not be The high-risk (HR) HPV-positive rate in borderline and
related to LLETZ but may be due to other confounding factors mild dyskaryosis was 53.7 per cent and 83.9 per cent respec-
like smoking and socioeconomic status20 and may be influ- tively in the sentinel site studies;14 they also reported the posi-
enced by repeated LLETZ21 or depth and volume of LLETZ.22 tive predictive value of the HPV testing was 16.3 per cent and
The reduction in mortality from cervical cancer in women 6.1 per cent for CIN-2 or worse and CIN-3 or worse respec-
over the age of 50 years is thought to be unrelated to the cervical tively. Studies have shown that HPV testing is acceptable
screening process. Cervical screening is less effective in detect- to women. It also reduces anxiety in women because of the
ing CIN-3 in older women and the incidence of both CIN and reduced number of repeat smears. Triage reduces require-
cervical cancer over the age of 50 is low: 11/100,000 in well- ment for repeat cytology and improves effective use of colpos-
screened women compared to 59/100,000 women in the popu- copy services. However the overall referral rate to colposcopy
lation as a whole.23 Women over the age of 50 who are diagnosed is higher: hence it also increases pressure on the workforce
with cervical cancer usually have not fully participated in the because of increased colposcopy workload. Following the
cervical screening programme. The exit age of 65 years has been ­sentinel studies the operating framework for the NHS in
questioned, particularly on reducing the age of screening to 50 England recommended implementation of HPV testing as
in women who have been well screened with a satisfactory nega- triage for borderline and mild dyskaryosis for more patient-
tive history. The effectiveness of cervical screening in reducing centred and cost-effective services.
invasive cancer varies with age, being greatest in younger age Inclusion of HPV testing as a triage tool has introduced
groups and least in women aged over 70 years. Age-specific uniformity to the referral system of the screening programme.
declines in cervical cancer were confined to women aged 30 to This has also reduced the time period of treatment and sur-
70 years with a nadir around ages 45–50 years. veillance from a period of average 12 years to 9 months.25
All smears reported as low-grade dyskaryosis (borderline/
mild) are checked for HR-HPV DNA. This is called reflex
HPV TRIAGE HPV testing. HPV testing is done on the same sample that
is taken for cytology. Women who are HR-HPV positive will
Previous guidance recommended that women with 2 or 3 bor- be referred to colposcopy and women who are HPV negative
derline dyskaryosis and 1 or 2 mild dyskaryosis cytology samples will be returned to routine recall as women who are negative
be referred for colposcopy. The reason was an underlying risk of for HR-HPV are unlikely to develop cancer. If HPV testing is
high-grade lesions detected on biopsies in a significant num- negative women are returned to routine recall as per national
ber of women with low-grade smears. The risk of high-grade guidelines. Fig. 106.1 shows the HPV Triage protocol of the
disease in low-grade dyskaryosis was reported to be as high as NHS cervical screening programme.

Screening test result

Inadequate ?Glandular neoplasia Borderline-Squamous/Borderline-Endocervical High grade dyskaryosis or worse


Repeat at 3 months (non cx) or Negative or low grade dyskaryosis or other indication for referral
1R(3) Routine Recall HPV tested Colposcopy referral
ØA, 2A ØS, 1S, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S

HPV Negative HPV test inadequate or unreliable HPV test inadequate or unreliable HPV Positive <CIN1 or Untreated CIN
Routine Recall Cytology = Borderline (2) Cytology = Low grade dyskaryosis Colposcopy Referral Cytology Follow-up
BØA, EØA, MØA Repeat in 6m with HPV Colposcopy Referral B9S, E9S, M9S or Recall
test only if Neg/Bord/Low grade MUS *Set NTDD= 6-12m
BUR(6), EUR(6) or as appropriate

Repeat test result

Cytology Neg (2)/Borderline (2)/ Cytology Neg (2)/Borderline (2)/ Cytology High grade or worse
LOWER GENITAL TRACT

Low grade dyskaryosis; Low grade dyskaryosis; (no HPV test required)
HPV Negative HPV Positive Colposcopy Referral
Routine Recall Colposcopy Referral 4S, 5S, 6S, 7S
GØA, NØA, BØA, EØA, MØA G9S, N9S, B9S, E9S, M9S

<CIN 1 Untreated CIN 1 CIN 1/2/3-> Treatment CGIN-> Treatment


Cytology Neg(2)/Bord(2)/ Cytology Follow-up Invite for 6m test of cure Invite for 6m test
Low grade dyskaryosis *Set NTDD = 12m *Set NTDD = 6m *Set NTDD = 6m
Routine Recall Continued on page 2 Continued on page 3 Continued on page 4
*Set NTDD = 36/60m

K22970_C106.indd 858 17/12/15 3:54 PM


HPV triage  859

Untreated CIN 1
Cytology Follow-up
*Set NTDD = 12m

Follow-up test

Cytology Bord (2)/ Cytology Bord (2)/


Cytology Neg (2) Cytology
Cytology Bord (2)/ Low grade Low grade
(no HPV test High grade
Low grade dyskaryosis; dyskaryosis; dyskaryosis;
required) dyskaryosis or worse
HPV test inadequate HPV Negative HPV Positive
Repeat at 12 (No HPV test)
Repeat at 3 months 3 Year Recall Colposcopy
months Colposcopy Referral
BUR(3), EUR(3), MUR(3), BØR36, EØR36, Referral
Ø-R12, 2-R12 4S, 5S, 6S, 7S
MØR36 B9S, E9S, M9S

Follow-up test (i) Follow-up test

Cytology Neg (2) Restart screening


(no HPV test protocol algorithm
required)
Routine Recall
ØA, 2A

(i) The management of women with abnormal cytology at this second 12-month follow-up test will mirror that at the first 12-month repeat test.

Fig. 106.1  Flowchart for HPV-based triage (from reference 26, with permission)

The negative predictive value of the HR-HPV test is An economic model suggested that HPV triage is more cost
9­ 3.8–99.7 per cent. 27 In a recent meta-analysis which effective compared to cytology.
­evaluated the accuracy of hybrid capture assay (HC2) and
other HR-HPV DNA assays for high grade CIN in ASCUS
­(atypical squamous cells of undetermined significance) triage Follow-up of treated and untreated
­(equivalent to borderline dyskaryosis), the pooled sensitivity women
was >90 per cent and significantly higher than that of repeat
cytology; pooled specificity was >50 per cent and equivalent to Test of cure
cytology. The meta-analysis also found that other HPV DNA The NHS Cervical Screening Programme follow-up protocols
tests are comparable to HC2. The APTIMA mRNA test for are shown in Fig. 106.2.
five HPV types is not only equally sensitive but more ­specific High-risk HPV testing is used to predict residual or recur-
too for detection of CIN-2+ in comparison to HC2.28 rent disease more quickly and accurately. After treatment for
On the other hand for LSIL (equivalent to mild dyskaryosis) either high-grade or low-grade disease women are tested for
though the pooled specificity for HPV triage in comparison to HR-HPV. Women with negative result have a very low risk of
repeat cytology showed higher sensitivity, the specificity was residual disease and can be followed up as per routine 3/5-
significantly and substantially lower; similarly to ASCUS, test- year follow-up.29 Pooled sensitivity in a meta-analysis showed
ing with APTIMA viral mRNA is more specific without losing HR-HPV to be more sensitive than cytology (93% vs 72%).
sensitivity.28 The specificity in comparison to cytology was no better.28
There is no clear evidence suggesting that the diagnostic
performance of cytology in combination with colposcopy for
Referral to colposcopy the detection of persistent disease after treatment for CIN is
LOWER GENITAL TRACT

superior to cytology alone. However women treated for cervi-


The referral system to colposcopy in England and Northern cal glandular intraepithelial neoplasia (CGIN; see below) are
Ireland has changed significantly and is based on HPV reflex at somewhat higher risk of developing recurrent disease than
testing for triage. Women with low-grade dyskaryosis (bor- those with high-grade CIN.30 In addition, recurrent CGIN is
derline and mild) with HR-HPV positive and one mod- more difficult to detect by cytology. Smears should be taken for
erate or severe dyskaryosis will be referred to colposcopy. the same duration with the same frequency as after treatment

K22970_C106.indd 859 17/12/15 3:55 PM


860  Pre-invasive disease

CIN 1/2/3 ->Treatment


Invite for 6m test of cure
*Set NTDD = 6m

Test of cure

Cytology Neg (2)/Bord (2)/ Cytology Neg (2)/Bord (2)/ Cytology


Cytology Neg (2)/Bord (2)/
Low grade dyskaryosis; Low grade dyskaryosis; High grade
Low grade dyskaryosis;
HPV test inadequate HPV Negative dyskaryosis or worse
HPV Positive
Repeat at 3 months 3 Year Recall (No HPV test)
Colposcopy Referral
GUR(3), NUR(3), BUR(3), GØR36, NØR36, BØR36, Colposcopy Referral
G9S, N9S, B9S, E9S, M9S
EUR(3), MUR(3) EØR36, MØR36 4S, 5S, 6S, 7S

Follow-up test See note (ii)

Restart screening protocol


algorithm

(ii) Women referred back to colposcopy (at TOC following treatment for CIN) due to borderline, low-grade dyskaryosis or negative cytology, who are HR-HPV
positive, and who then have a satisfactory and negative colposcopy, can be recalled in 3 years.

of CIN-2/3 (minimum standard). Ideally, six-monthly smears will appear as varying degrees of whiteness. This is termed
would be taken for five years followed by annual smears for a ‘acetowhiteness’, in contrast to areas of hyperkeratosis or
further five years. leukoplakia, which appear white before application of ace-
tic acid. The exact reason why CIN tissue turns white with
acetic acid is not fully understood. The cytoplasm becomes
Management dehydrated so in areas of abnormality, where there is a high
nuclear:cytoplasmic ratio in the cells, the nuclei become
Colposcopy crowded and the light from the colposcope is reflected back.
Further investigation of smear abnormalities is by colposcopy. Such areas will therefore appear white. However, not all areas
A colposcope is a low-power binocular microscope that allows of high nuclear density are abnormal and so not all aceto-
magnification from around ×4 to ×25. In the UK, colposcopy is whiteness necessarily correlates with CIN: areas of regener-
a secondary investigation; in other countries that do not have ating epithelium, subclinical papillomavirus infection and
organised cytological screening, it may be used as a primary tool. immature metaplasia may also appear acetowhite. One of the
It is important to recognise that the screening programme challenges facing the colposcopist is to decide which areas of
has the ability to generate considerable psychological mor- acetowhiteness truly represent pre-malignancy and to avoid
bidity.31 Appropriate counselling at the time of or before col- treating benign conditions. The classical vessel patterns of
poscopy is important, and the vast majority of women can CIN are punctation and mosaicism. Bizarre-shaped vessels
be reassured prior to the examination that they are extremely suggest cancer.
unlikely to have cancer. This is very important to emphasise. Another test used in colposcopy involves the application
The cervix is first examined at low magnification ­(×4–6). of Lugol’s iodine solution to the cervix. Normal squamous
A saline-soaked cotton wool ball is then applied, which mois- epithelium contains glycogen and stains dark brown when
LOWER GENITAL TRACT

tens the epithelium, allowing the underlying blood v­ essels to Lugol’s iodine is applied. Conversely, pre-malignant and
be examined under higher magnification (preferably ×16 or malignant squamous tissue contains little or no glycogen and
even ×25). A green filter may be used as it makes the cap- does not stain with iodine. This is Schiller’s test: areas that are
illaries stand out more clearly. The shapes of the capillaries non-staining with iodine are referred to as Schiller-positive
are studied and the intercapillary distances estimated. Acetic and those that take up iodine as Schiller-negative. The test may
acid (3 or 5%) is then applied to the cervix. Areas of CIN be used following acetic acid colposcopy.

K22970_C106.indd 860 17/12/15 3:55 PM


HPV triage  861

CGIN-> Treatment (iii)


Invite for 6m test
*Set NTDD = 6m

Test of cure
with or without colposcopy
(local preference)

Cytology Neg (2); Cytology Neg (2), HPV Positive Cytology Neg (2), Cytology abnormal
HPV test inadequate Colposcopy referral if not HPV Negative Colposcopy referral if not
Repeat at 3 months already performed. Repeat at 12 already performed.
GUR(3), NUR(3) Normal colposcopy – repeat months 3S, 4S, 5S, 6S, 7S, 8S, 9S
test at 12 months N0R12, G0R12 Complete 10-year cytology
N9S, G9S or N9R12, G9R12 follow-up

Test of cure

Cytology Neg (2); Cytology Neg (2), HPV Positive Cytology Neg (2), Cytology abnormal
HPV test inadequate Colposcopy referral if not HPV Negative Colposcopy referral if not
Repeat at 3 months already performed. 3 year recall already performed.
GUR(3), NUR(3) Normal colposcopy – repeat N0R36, G0R36 3S, 4S, 5S, 6S, 7S, 8S, 9S
test at 12 months Complete 10-year cytology
N9S, G9S or N9R12, G9R12 follow-up

(iii) Women who have been adequately treated (complete excision margins)
for CGIN or SMILE will follow the management in this protocol algorithm. Follow-up test
Women receiving annual surveillance tests following treatment for CGIN or
SMILE in the past may also be tested in line with this policy at their next two
tests. Woman treated for cervical cancer are excluded from this management Restart screening protocol
policy. algorithm

Fig. 106.2  Follow-up protocols based on HPV test of cure (from reference 26 with permission)

Dynamic Spectral Imaging System (DySIS) and Niris are treated, as a large proportion (60 per cent) will resolve spon-
adjunctive colposcopic imaging systems that are newly avail- taneously. If it is decided that treatment is needed, there are
able for examination of the cervix. DySIS uses photonics and several options. Abnormal tissue can be removed (excisional
computer-assisted methods to map and provide quantitative techniques) or it can be destroyed (ablative techniques)
assessment of acetowhite areas. It is an objective assessment (Table 106.3). Removing the entire transformation zone has
and identifies abnormal lesions to guide biopsy. It shows the advantage of allowing a large specimen to be examined:
higher sensitivity to identify high grade lesions and NICE the pathologist can comment on the most severe abnormal-
guidance recommends that DySIS should be considered when ity and can assess whether all the abnormal tissue has been
new colposcopic equipment is bought by the NHS as it is cost removed. Destroying the transformation zone does not allow
effective and works well. Niris uses near-infrared light to scan this, so it is mandatory to establish the diagnosis by taking a
LOWER GENITAL TRACT

epithelial tissue and the rebound scattered optical light is ana- small biopsy before treatment. However, punch biopsy has
lysed to provide an image data in real time. NICE does not been shown to be an inaccurate investigation when compared
recommend Niris as it is not cost effective.32 with subsequent loop excision from the same cervix.33
Randomised trial data on the different methods of treating
Treatment CIN do not point to one overwhelmingly superior technique.
High-grade lesions (CIN-2/3) should be treated, but there Cryotherapy is cheap and easy to use, with low mor-
is some debate about whether and when CIN-1 should be bidity. It should be used as a double freeze–thaw–freeze

K22970_C106.indd 861 17/12/15 3:55 PM


862  Pre-invasive disease

Table 106.3  Treatment modalities for cervical intraepithelial neoplasia

Excisional techniques Ablative techniques


LLETZ – removal of the transformation zone using an electrodiathermy Radical electrodiathermy – burning the transformation zone; usually
loop; requires local, regional or general anaesthesia requires regional or general anaesthesia
Laser cone – removal of the transformation zone using the laser; Cold coagulation – destroying the transformation zone by applying a
requires local, regional or general anaesthesia probe heated to 100–120°C; usually requires local anaesthesia
Knife cone biopsy – taking a cone with a knife; usually requires Cryocautery – freezing the tissue; does not require any anaesthesia
regional or general anaesthesia
Hysterectomy – may be suitable if the woman has other Laser – vaporising the tissue; requires local, regional or general
gynaecological problems anaesthesia

technique. Success rates for treating CIN-3 vary between HPV-Proofer38 mRNA testing has been shown to be more spe-
77 and 93 per cent. Cryotherapy is a reasonable option for the cific without compromising sensitivity but these markers’ cur-
treatment of low-grade disease, but not of high-grade disease. rent ranges are lower than the full range of HR-HPV t­ esting.
It may be suitable in resource-poor situations. All of the other Quantitative HPV estimation has been suggested as being
ablative and excisional methods achieve cure (or success) rates more discriminatory than qualitative estimation. Methods
of 90–98 per cent.34 Women who are treated should be fol- of quantification vary and have limited reproducibility.
lowed as per test-of-cure protocol. Furthermore, data suggest that viral load varies in the natural
Current treatments rely on the destruction or excision of history of disease and may be of limited predictive value.39
affected tissue. However, with expanding knowledge about Increasing knowledge of HPV and improvement in HPV-
the role of HPV and the body’s immune response to it, new related assays have prompted consideration of using the HPV
immunological methods of disease prevention and therapy test as the primary screening method instead of the adjunct
have been proposed. These aim to address the cause of the dis- to cytology as it used now. In December 2012 a pilot study of
ease (i.e. HPV infection) and to either prevent (prophylactic screening using HPV as the primary tool was announced for
vaccination) or treat (therapeutic vaccination) it. Prophylactic England. The screening algorithm is detailed below. It included
vaccination targets the viral capsid and aims to prevent infec- all women aged 25–64 on routine call/recall and early recall.
tion or the early spread of infection through the ­production The recall was 3 years for age 25–49 years and 5 years for women
of n­ eutralising antibody (see section on the vaccination >/= 50 years. The routine recall was extended to 6 years for all
programme and the potential for prevention). Therapeutic age groups in the second year of the pilot. Fig. 106.4 shows the
vaccines aim to boost the host’s cell-mediated immune arm NHS HPV primary screening algorithm.
to attack established infection and have not shown efficacy New data are available from a population-based cohort
to date. study using HPV testing as the primary test for cervical screen-
ing. Participation was higher in all age groups and detection
Screening for HPV infection rates were reported to be three times higher than cytology. The
overall rate of referral to immediate colposcopy was similar
As HPV infection is strongly implicated in the genesis of CIN to cytology, but increased by 4.6 per cent when considered
and cervical cancer, it is logical to ask whether viral detec- together with the 1-year repeat that was done for women who
tion could improve the screening process. Two methods of were cytology negative in the first round. The 1-year repeat also
detecting HPV that have been commonly used for population contributed to 23 per cent of the CIN-2+ cases, underlying the
screening are the PCR and the hybrid capture system. Data importance of the need for high compliance with the screen-
from studies using earlier methodology can be disregarded. ing algorithm. A higher specificity for CIN-2+ was reported
Applications of HPV testing can be at a primary or secondary with cut-offs of greater than 1.00 Relative Light Units/Positive
level. Most published data refer to HPV testing as an adjunct to Controls ratio (RLU/PC) for HC2 positivity. The benefits
cytology and test the hypothesis that HPV detection improves are the earlier detection of CIN and reduced need for repeat
the accuracy of cytology alone.35,36 Qualitative identifica- testing. An important concern to consider is the response of
tion of HPV in women presenting with a high-grade smear is women to HPV testing and a perceived association by the pub-
pointless, as the vast majority will be HR-HPV-positive any- lic of HPV positivity with sexually transmitted infection.
LOWER GENITAL TRACT

way. It is becoming apparent that the same is true for women Whilst HPV testing for primary screening may improve
who have mild dyskaryosis (or LSIL). However, in women with cost effectiveness and effectiveness of the colposcopy ser-
a borderline smear, it may be more discriminatory. This is par- vice in general one must bear in mind whether it would lead
ticularly so in situations in which the background prevalence to unnecessary colposcopy and possible overdiagnosis and
of infection is lower (such as in women over 30 or 35 years psychological stress. HPV screening is not recommended in
of age). Testing with mRNA assays in research trials has also women under the age of 30 due to high clearance of infection.
been used in search of a better test. The APTIMA37 and Pretect Over 35 years HR-HPV testing mostly detects high-grade

K22970_C106.indd 862 17/12/15 3:55 PM


Hpv triage  863

HR-HPV Test

HR-HPV –ve HR-HPV +ve

Routine recall 3y(25–49) 5y(>50) Cytology triage

Cytology normal Cytology abnormal –


borderline or worse

Re-screen in 12m Colposcopy referral

HR-HPV –ve HR-HPV +ve

Cytology abnormal –
Routine recall Cytology normal
borderline or worse
3y(25–49) 5y(>50)

Re-screen in 12m Colposcopy referral

HR-HPV –ve HR-HPV +ve

Routine recall
Colposcopy referral
3y(25–49) 5y(>50)

Fig. 106.3  NHS cervical screening programme: HPV primary screening algorithm (from reference 40 with permission)

non-regressive lesions and makes it beneficial. HPV testing to community and may lead to over-interpretation of mildly
between 30 and 35 is debatable but evidence suggests detec- abnormal colposcopies resulting in more negative biopsies
tion of more high-grade non-regressive lesions compared to being taken.
cytology and hence HPV testing is being considered as ben- Other tests like HPV genotyping, viral load analysis,
eficial.41 A systematic review of the surveys undertaken to ­p16-INK4A staining, E6/E7 expression analysis and promotor
find out if women were ready for the new screening protocol methylation analysis of tumour supression genes have been
reported women to have concerns about HPV diagnosis and proposed as triage tools but so far cytology remains the best
associated problems of disclosure of STIs and its impact on available triage tool.43-46 A promising alternative to cytology is
relationships. However despite the negative concerns repeat p16-INK4A staining but for further confirmation larger stud-
LOWER GENITAL TRACT

HPV testing was a preferable alternative to repeat cytol- ies are required.47
ogy. It also highlighted the fact that much more needs to Results are awaited from the various trials and pilot stud-
be done to educate women regarding HPV and improved ies but it seems likely that cervical screening in future may be
information had a more positive impact.42 There also may more HPV based than cytology. Education of women and cli-
be an interpretation bias of cytology as the cytologists would nicians, training, quality assurance, programme management
be aware of HR-HPV-positive results. There also may be a and audits to maintain standards will all be crucial in main-
reluctance on the part of the clinicians to discharge patients taining the success of the cervical programme.

K22970_C106.indd 863 17/12/15 3:55 PM


864  Pre-invasive disease

GLANDULAR PRE-INVASIVE DISEASE in preventing and eradicating infection. It was therefore


inevitable that attempts would be made to exploit the virus’s
immunogenicity and develop vaccines to prevent infection.
Adenocarcinoma in situ (AIS), or high-grade cervical intraep-
There are now two commercially available vaccines, one
ithelial glandular neoplasia (CIGN) of the cervix, is a rare con-
a quadrivalent vaccine (Gardasil™) directed against HPV-6,
dition. It presents a particular challenge to the colposcopist,
-11, -16 and -18; the second is a bivalent vaccine (Cervarix™)
who may only see a few cases per year. Cytology screening for
directed against HPV-16 and -18. The design of both vaccines
this condition is unsatisfactory, and the disease has no reli-
uses the ability of viral capsid proteins to self-assemble into
able colposcopic features. Diagnosis is often made by chance
virus-like particles (VLPs). The VLPs present the same anti-
during the treatment of squamous pre-invasive disease,
genic signature to the host’s immune system as a ‘real’ virus,
which commonly (30 per cent) coexists with AIS. Although
but as they do not contain any internal DNA they are biologi-
the entire endocervical canal can be the site of disease, most
cally non-infective and non-transforming.
lesions lie within 1 cm of the squamo-columnar junction. Skip
Several large randomised studies have now been completed
lesions are rare, making fertility-sparing surgery a ­possibility,
and published and they have shown that both types of vaccine
­provided that endocervical margins are clear of disease.
effectively increase specific IgG, reduce or eliminate infection
Recurrent disease occurs in 14 per cent of cases when cone
with type-specific virus and effectively eliminate pre-invasive
margins are free of disease and rises to more than 50 per cent if
disease related to the vaccinated subtypes.49,50 As we believe
the margins are involved. The method of conisation is imma-
that up to 70 per cent of cervical cancers are the result of infec-
terial provided that a large enough specimen is taken and
tions caused by either HPV-16 or -18, there is an expectation
that the pathologist can evaluate the endocervical and lateral
that a vaccination programme, if systematically applied, will
margins. There are no guidelines on the optimal follow-up of
result in a significant reduction in the burden of invasive and
conservatively managed women; however, most would rec-
pre-invasive disease.
ommend that regular endocervical cytology be performed in
There are, however, some unanswered questions. The dura-
addition to conventional cytology and colposcopy.48
tion of the effect is unknown; although it would appear that
it is at least 5 years.51 Recent modelling of long-term antibody
persistence predicted that anti-HPV-16 and anti-HPV-18 will
KEY POINTS remain detectable for at least 20 years.52 An immunological-
based study reported anti-HPV-16 antibodies to be persistent
●● Virtually all cervical cancer is related to HPV infection [B]. above those induced from natural infection for at least 12 years
●● Cervical sampling now utilises liquid-based cytology. or potentially even for a lifetime.53 These studies suggest that a
●● The treatment methods (other than cryotherapy) to eradicate booster dose may be not required. However, there is no guid-
CIN are all equally effective [A]. ance as yet as to when and how often, if any, booster vaccina-
●● HPV is an extremely common infection that rarely causes tions may be required. Although there is some evidence that
cancer [C]. vaccinating against one subtype may provide cross-resistance
●● Organised cervical cytology with HPV testing programmes has with other subtypes, we must still accept that up to 30 per cent
been shown to reduce the incidence of invasive cancer [C]. of oncogenic subtypes remain potential threats to carcino-
●● HR-HPV testing detects 30% more CIN-2+ and 22% more genesis and thus it is strongly recommended that despite the
CIN-3+ in women over 30 years with 4–6% lower specifity. introduction of a vaccination programme, women should still
●● Negative HR-HPV test offers 50% better protection against be enrolled into the cervical screening programme.54 Whether
CIN-3+ in comparison to a negative cytology. the natural spectrum of HPVs will be altered by widespread
●● The screening of teenagers cannot be justified [E]. introduction of the vaccines is also unknown. There does not
●● Screening for HPV infection is not yet routinely recommended. appear to be any evidence as yet of an increasing prevalence of
●● Neither cytology nor colposcopy is a reliable method for non-16/18 HPV, although this effect will probably take dec-
detecting glandular disease [D]. ades to become noticeable.
The vaccines have not been shown to confer any signifi-
cant benefit to those who have already been exposed to HPV
and the current focus is schoolgirls aged 12 to 13 years with
­retrograde catch-up of older groups. The vaccination pro-
THE VACCINATION PROGRAMME AND gramme c­ ommenced in 2008 and is organised through
schools. The NHS initially opted for the bivalent vaccine
LOWER GENITAL TRACT

THE POTENTIAL FOR PREVENTION (Cervarix) and the quadrivalent vaccine (Gardasil) was avail-
able only on a private basis. The quadrivalent vaccine offers
Most, if not all, would now accept the central role played by the advantage of additional protection against vulvovaginal
oncogenic human papillomaviruses in the development of warts. The q ­ uadrivalent vaccine, as well as protection against
CIN and cervical cancer. Furthermore, there is also some 16 and 18, also offers protection against HPV-6 and -11 that are
understanding of the role played by the host’s immune ­system ­responsible for causing 90 per cent of vulvovaginal warts. In

K22970_C106.indd 864 17/12/15 3:55 PM


Vulval intraepithelial neoplasia  865

November 2011, the Department of Health (DH) announced


that the UK HPV immunisation programme would switch KEY POINTS
to Gardasil. Since September 2012 the NHS has adopted ●● VAIN is uncommon and there is little evidence base on the
Gardasil in line with DH recommendations. However, there subject.
is no e­ vidence to s­ uggest vaccinating boys alters CIN or HPV ●● It usually coexists with CIN [D].
infection rates. ●● The risk factors are similar to those for CIN [D].
Prevention of HPV infection is a desirable goal and now, ●● In-utero diethylstilboestrol exposure increases the risk of VAIN
for the first time, there is clear evidence that at least some cer- and vaginal adenocarcinoma [D].
vical cancer can be prevented. Further developments can be
expected in this field and trials are underway to explore the
therapeutic benefits of the vaccine. Further developments
could develop, particularly in the immunological interven- VULVAL INTRAEPITHELIAL NEOPLASIA
tions. This may provide benefit to women already exposed and
at risk of developing persistent disease. Pre-malignant disease of the vulva is much less common
than its cervical counterpart. HPV infection is recognised as
a major factor in the aetiology of some, though not all, vul-
VAGINAL INTRAEPITHELIAL NEOPLASIA val intraepithelial neoplasia. The HPV types most commonly
associated with VIN are HPV-16 and -33. HPV-associated VIN
Pre-invasive disease of the vagina is extremely uncommon is increasing in incidence, particularly in younger women.56
(about 150 times less common than CIN). In 70 per cent of This increase may be explained by a number of factors, such as
cases of vaginal intraepithelial neoplasia (VAIN), there will increased awareness amongst medical practitioners leading to
be associated CIN. The average age of the woman with VAIN improved detection, increased smoking by younger women,
tends to be higher than for CIN. The major predisposing or changing sexual attitudes and increased exposure to HPV.
­factor is the same, namely oncogenic HPV, but the reason These women should be examined for other intraepithelial
for the lower incidence is the relative stability of the epi- neoplasia of the anogenital tract.
thelium compared with the metaplastic cervical epithelium. The pre-malignant potential of VIN has been estimated
Women exposed to diethylstilboestrol in utero have a higher to range from 4 per cent for treated cases to 80 per cent for
incidence of VAIN and clear cell carcinoma of the vagina untreated cases.57,58 Most published series estimate a risk of
as here the areas of metaplastic transformation extend on 10 per cent or less.
to the vagina. Around 25 per cent of women with VAIN VIN affects mainly the labia minora and the perineum. It
will have had a hysterectomy previously, for either CIN or can take a variety of forms and can be difficult to diagnose.
a benign condition. Like CIN, VAIN is graded 1–3, but in Up to 60 per cent of affected women may complain of itch-
common with vulval intraepithelial neoplasia (VIN), the ing, soreness and burning, but many are asymptomatic and
invasive potential is less than for CIN. Treatment of VAIN-3 the abnormality can be a chance finding on examination.59
is by surgical excision; it is usually best removed vaginally. The lesions may extend to the perianal and anal mucosa.
Small areas of VAIN can be removed with local excision Diagnosis is made by examining the vulva with a good light
or laser ablation. Prior to ­destructive treatment it is essen- source, such as the colposcope at low magnification, and by
tial that invasion has been ruled out and it is best suited in taking representative biopsies. Like CIN, VIN is graded 1–3 in
patients where the entire lesion is visible. Medical treatment increasing severity of abnormal cell maturation and stratifi-
with 5-fluorouracil and imiquimod has also been described cation. However, there are some striking differences between
as an effective treatment.55 Treatment of multiple lesions or VIN and CIN (Table 106.4).
involvement of the upper vaginal wall or following hysterec- Current treatments for VIN are suboptimal in terms of
tomy (in the vault i­ nvolving suture line or dimples) may be their poor clinical response rates, high relapse rates and asso-
difficult and a m ­ ultimodal approach may be necessary and ciated physical and psychological morbidities. The high recur-
may even necessitate a vaginectomy which may be best per- rence rates following many therapies may reflect that they fail
formed by a combined abdomino-vaginal approach and an to remove the reservoir of HPV present in the vulval skin.
experienced surgeon. Chemosurgery using 5­ -fluorouracil Low-grade VIN should be observed. VIN-3 lesions can be
prior to ­diathermy ­ablation is an ­experimental treatment treated by local excision or laser vaporisation. Recurrences of
that has shown some promising results. Radiotherapy 39 and 70 per cent have been described after surgical excision
­( brachytherapy) is an ­a lternative treatment for women and laser ablation, respectively.60,61
LOWER GENITAL TRACT

who may not be suitable for surgery. Lower grades of dis- A topical immunomodulator called imiquimod may be
ease can be observed. For women who have had a hysterec- of use in the management of women with VIN, although it
tomy in which VAIN is seen at the ­vaginal vault, there may remains experimental at present. Cidofovir is also shown to
still be ­disease buried above the vault in the cuff that was have a clinical and histological response in the treatment of
closed over at ­hysterectomy. In view of this, if high-grade VIN and promises benefit.62 A randomised multicentre clini-
VAIN is detected at the vault of the vagina, it should be cal trial (RT3 VIN) examines cidofovir and imiquimod in the
treated by e­ xcision rather than destruction. treatment of VIN.63

K22970_C106.indd 865 17/12/15 3:55 PM


866  Pre-invasive disease

Table 106.4  Comparison of characteristics of vulval intraepithelial MIN may be detected in a woman who has repeated
neoplasia grade 3 (VIN-3) and cervical intraepithelial neoplasia grade a­ bnormal smears despite treatment for CIN, or in a woman
3 (CIN-3) being assessed for VIN. Genito-urinary physicians who
­perform colposcopy may also encounter MIN in HIV-positive
VIN-3 CIN-3
women under their care.
Proportion of cases of 25% 90% At the time of writing, there are no national guidelines for
disease adjacent to the management of women with MIN. Such cases are often
malignancy complex and become chronic, with women sometimes having
Invasive potential Low (<10%) Significant (40%) repeated surgery over several years. It is therefore important to
be aware that these women may suffer adverse psychological
Time to progress to 20–30 10–15 years
sequelae as a result of their condition. As their numbers are
invasion years
small, women with MIN should be managed in large centres
Spontaneous Up to 40% Low to concentrate experience and expertise. Investigations should
regression be individualised, but may include multiple colposcopically
directed biopsies, HPV typing, HIV testing and tests of T-cell
Non-HPV intraepithelial neoplasia is termed ‘differenti- function. Management aims to exclude invasive cancer and
ated VIN’ and oncogenesis involves alternative pathways to control symptoms while preserving anatomical and func-
the HPV model. There appears to be an association with some tional integrity where possible. The treatments of lesions of
inflammatory vulval epithelial disorders, such as lichen scle- the vagina and vulva are described above. Lesions of the peri-
rosus, but the condition is poorly understood. neum and anal canal may require an initial colostomy prior
to skin grafting. Such cases require a multidisciplinary team
comprising a gynaecologist, colorectal surgeon, plastic sur-
KEY POINTS geon, stoma nurse and possibly a psychologist.
New immunomodulating therapies currently under inves-
●● VIN is uncommon and there is little evidence base on the tigation, such as therapeutic vaccination and imiquimod, hold
subject. out some hope for women affected with MIN. Research to date
●● VIN in younger women is strongly associated with HPV [C]. suggests that they are suitable for around 30 per cent of cases
●● The most common presenting symptom is pruritus [D]. and thus upholds the theory that MIN has varied causes.
●● Lesions may be multifocal and have a variety of
appearances.
●● Multicentric disease should be considered when VIN is
diagnosed. KEY POINTS
●● Conservative surgery is currently the basis of treatment [E]. ●● MIN is a rare condition and there is no evidence base.
●● Long-term follow-up is essential as recurrence is ●● There is an association with conditions in which cell-
common [D]. mediated immunity is impaired [D].
●● It is often a chronic, relapsing condition [D].
●● The key aim of management is to do the least required to
exclude invasion and control symptoms [E].
MULTICENTRIC INTRAEPITHELIAL
NEOPLASIA
There is a small group of women in whom intraepithelial neo- SUMMARY
plastic changes can be detected at more than one site in the
lower genital tract. The sites involved are the cervix, vagina, Lower genital tract pre-malignancy is an important area of
vulva, perineum, anal canal and natal cleft. Although the gynaecology. Most of the pre-cancers in this area have an asso-
number of women affected by multicentric intraepithelial ciation with HPV, but HPV infection is extremely common
neoplasia (MIN) is small, the number appears to be increas- and causes no problems in the majority of individuals affected.
ing, which may be a true reflection of more disease or it may Organised national screening seems to have been effective in
be a result of increased awareness and detection. The aetiology reducing the incidence of, and mortality from, cervical cancer,
LOWER GENITAL TRACT

of MIN is a combination of HPV infection and host immuno- but there has been a cost to pay in terms of over-investiga-
suppression of varying degrees. Patients with compromised tion and treatment of women who have very minor changes
cell-mediated immunity, such as women who have had organ that are unlikely ever to progress to cancer. Pre-cancers of
transplantation or who carry HIV, often have recognisable the vagina, vulva and perineum are much less common, but
HPV-associated changes in numerous sites in the lower genital require specialised skills for accurate diagnosis and appropri-
tract. Conversely, women with humoral immunodeficiency ate management. Current treatment modalities for the pre-
do not have an increased risk of HPV-associated lesions. cancers involve ablation or excision. As our knowledge of the

K22970_C106.indd 866 17/12/15 3:55 PM


Summary 867

aetiology of lower genital tract pre-malignancy expands, it 13. Soutter WP. The management of a mildly dyskaryotic
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