The terminology of cervical premalignancy

Most cervical cancers are squamous in origin, but a significant, and increasing, proportion arise from cervical glandular epithelium (estimates ranging from 5% to 30% of the precancerous lesions found on the cervix). Both cancer types have premalignant lesions.

The premise that cervical squamous premalignancy was a continuum underpinned the concept of cervical intraepithelial neoplasia (CIN), which was suggested by Richart (1967). The usefulness of this system was limited by significant interobserver variability in the diagnosis and grading of CIN, particularly in differentiating CIN1 from human papilloma virus (HPV) lesions, and separating CIN1 from CIN2 lesions. Furthermore, there is no clear evidence that CIN3 arises from earlier lesions.

These considerations were addressed by the Bethesda classification which was initially introduced as a cervical cytological grading system. Cervical lesions are classified into high- and low-grade squamous intraepithelial lesions; the latter group includes HPV lesions. This has the potential advantage of simplicity and tends to reflect the way in which clinicians practise, in that high-grade lesions are thought to be genuinely premalignant and should be treated.

Currently, whilst CIN terminology is used in the UK, clinical practice reflects the Bethesda classification in that CIN1 is regarded as a low-grade lesion, which tends to be managed conservatively, and CIN2 and CIN3 are regarded as high-grade lesions which are treated.

Attempts to classify premalignant glandular lesions have been bedevilled by a number of problems. In the UK, they are termed ‘cervical glandular intraepithelial neoplasia’ (CGIN) and are classified as high- or low-grade lesions. Low-grade CGIN lesions are difficult to distinguish from a number of benign and reactive changes. The biological behaviour of low-grade CGIN is not understood.

Pathology of cervical premalignancy

Cervical intraepithelial neoplasia

CIN relates to lesions that are confined to the squamous epithelium. The diagnosis of CIN is based upon the architectural and cytological appearances of the squamous epithelium. It is characterized by abnormal cellular proliferation, abnormal epithelial maturation and cytological atypia. Grading depends on the level in the epithelium to which abnormal changes extend.

The proportion of the thickness of the epithelium showing differentiation is a useful feature to be taken into account when deciding the severity of a CIN; roughly lower-, middle- and upper-third involvement equate to CIN1, CIN2 and 3, respectively. It is not the most important criterion despite the fact that it is one of the easiest to assess. In CIN1, at least the upper half of the epithelium usually shows good differentiation and stratification, whereas in CIN3, differentiation may be very slight or even absent.

CIN may affect the gland crypts as well as the surface epithelium (Figure 38.1). It is recognized that the degree and depth of crypt involvement increases with the grade of CIN. Histological assessment of crypt involvement in women with CIN3 has shown a mean depth of 1–2 mm, with a maximum of 5.22 mm and a mean ±3 standard deviations (99.7%) of 3.8 mm (Anderson and Hartley 1980). These figures suggested that treatment of ectocervical lesions to a depth of 7 mm should be sufficient to eradicate most CIN.

Figure 38.1 The cervical transformation zone shows the metaplastic squamous epithelium replaced by full-thickness lack of maturation amounting to cervical intraepithelial neoplasia 3 (long arrow). This is seen extending down the gland cleft (block arrow). The inset shows brisk epithelial mitotic activity. Original magnification ×100, inset ×200.

Cervical glandular intraepithelial neoplasia

CGIN is characterized by columnar cells with hyperchromatic nuclei and stippled chromatin (Figure 38.2). The nuclei show increased stratification and abnormal mitotic figures with loss of normal mucin. In some cases, the whole of a gland may be involved, but the lesion often occurs as a sharply demarcated area. It may be multifocal. CGIN is often associated with goblet cells or intestinal metaplasia of the endocervical cells. In two-thirds of cases, there are associated squamous abnormalities, and CGIN is often serendipitously discovered in the management of these abnormalities.

Figure 38.2 High-grade cervical glandular intraepithelial neoplasia, characterized by hyperchromatic glandular cells with pseudostratification, relative paucity of mucin, brisk mitotic activity and abrupt junction with normal epithelium (long arrow). Intestinal metaplasia (short arrow) is noted. Original magnification ×40.

Pathogenesis of cervical premalignancy

The development of squamous precancerous abnormalities is intimately associated with the region of the cervical squamocolumnar junction (SCJ) and the changes that occur at puberty and adolescence.

The position of the SCJ is influenced by the hormonal changes that occur during a woman’s life (Figure 38.3). With the onset of puberty, the uterus enlarges and the cervix swells with a resultant eversion, exposing columnar epithelium to the acid environment of the vagina. This induces metaplasia in the exposed columnar epithelium, resulting in the development of metaplastic squamous epithelium. This area of transformation is termed the ‘cervical transformation zone’ (cervical TZ), and it is within this area that preneoplastic changes can occur with the development of CIN. It is thought that these dysplastic changes occur at the time of metaplasia, indicating that this is the time when the cervix is most vulnerable to potential carcinogenic factors, such as HPV and other cofactors.

Figure 38.3 The different stages in the development and involution of the cervix. (A) Before puberty, the ectocervix is covered with squamous epithelium, and columnar epithelium is usually confined to the endocervical canal. (B) The cervix enlarges and everts when oestrogen levels rise. This exposes columnar epithelium on the ectocervix. (C) The columnar epithelium on the ectocervix is replaced with squamous epithelium by a process of metaplasia. (D) Following the climacteric when oestrogen levels fall, the cervix shrinks, drawing the squamocolumnar junction up the canal.

These considerations have important clinical significance with regards to detecting and treating CIN, as these changes occur within the cervical TZ and it is accessible. Furthermore, the recognition that the development of precancerous changes can occur early in a woman’s sexual and reproductive life provided some indication that these events were potentially associated with some form of environmental exposure related to sexual activity. In other words, most of the identified risk factors for CIN are thought to be largely surrogate markers of HPV infection (Table 38.1).

Table 38.1 Risk factors for cervical intraepithelial neoplasia

Malignant potential of cervical premalignant lesions

Aetiology of cervical premalignancy

The epidemiological risk factors for both squamous and glandular cervical premalignant lesions are similar and include young age at first intercourse and multiple sexual partners. It is now well established that infection with oncogenic high-risk HPV types is the central causal factor in the development of cervical neoplasia (Walboomers et al 1999).

The fact that virtually all cervical malignancies contain HPV DNA illustrates the central role of HPV in cervical carcinogenesis. It has now been proven beyond reasonable doubt that HPV infection is a necessary prerequisite for cervical carcinogenesis.

HPVs are small double-stranded DNA viruses which have an icosahedral protein capsid (Figure 38.4). They are typed according to the DNA sequence homology in particular genes, specifically L1 (which codes for the viral capsid) and E6 and E7 (which have important carcinogenic functions). Nearly 30 HPV types can infect the genital tract and can be classified into high-, intermediate- and low-risk oncogenic types. HPV types 16 and 18 are by far the most common high-risk types, accounting for 60% of HPV-positive invasive cervical cancers.

Figure 38.4 Model of human papilloma virus showing the arrangement of capsid proteins.

Copyright © 2009, Re-used with the permission of The Health and Social Care Information Centre. All rights reserved.

HPV infection can lead to integration of viral DNA into the host’s genome, with expression of the viral oncogenes E6 and E7 which produce proteins that interfere with tumour-suppression genes controlling the cell cycle. As a result, the cell loses the ability to repair DNA damage and to undergo apoptosis, becoming susceptible to additional mutations and genomic instability. It is therefore postulated that HPV integration can lead to carcinogenesis.

HPV infection is very common. It can be detected in up to 20% of sexually active women in the reproductive age group, and approximately 80% of women will, at some point, be infected. In most cases, genital HPV infections are transient with only a small proportion developing persistent infection, but the risk of subsequent development of CIN increases substantially in this group. HPV alone is not thought to lead to neoplastic change, and other cofactors are thought to be involved, such as smoking-related carcinogens, and dietary and hormonal factors.

Prevention of cervical premalignancy

The recognition that risk factors for cervical neoplasia were sexually related suggested the potential for a number of primary preventive strategies.

Detection of cervical premalignancy

Population-based screening should be conducted using well-organized and high-quality programmes with high coverage, as well as providing adequate treatment for detected lesions.

In the developed world, cervical cytology has formed the basis of screening programmes, but the resources and infrastructure required have precluded its use in poorer countries. Current debate concerns the use of the HPV detection assay as a screening tool, whereas in poorer countries, attention has focused on cheaper screening techniques that involve visually assessing the cervix, such as cervicography and visual inspection with acetic acid.

Cervical cytology

The recognition that cervical cytology could be used to detect precancerous change led to the introduction of cervical cytology as a screening test (Figure 38.5). Early detection and treatment can prevent the development of 75% of cancers. Whilst cytology is used to detect women at risk of having cervical premalignancy, most abnormalities are not precancerous. Only a small proportion of women with abnormal smears would develop cancer, although these women are high risk compared with the normal population. There is therefore huge potential for overtreatment unless one can accurately select which lesions require treatment.

Figure 38.5 (A) Dyskaryotic squamous cells showing mild and moderate dyskaryosis. There is cytoplasmic clearing resulting in a clear area around the nucleus indicative of koilocytosis, which is a papilloma-virus-related cytopathic change (Sure Path, original magnification ×60). (B) Glandular cells show disturbance in the normal honeycomb architecture. There is nuclear hyperchromasia, crowding of cells and ‘feathering’ of outline. These are features of glandular dyskaryosis (Thin Prep, original magnification ×60).

Images courtesy of Dr C.A. Waddell, Birmingham Cytology Training Centre.

In the UK, the incidence of cervical cancers has halved since the National Health Service’s (NHS) cervical screening programme was introduced in 1988. The NHS cervical screening programme is highly organized. In the UK, women aged 25–65 years are invited for screening every 3 or 5 years. It is thought that screening under the age of 25 years may do more harm than good as cervical cancer is rare in this age group (Sasieni and Adams 1999). There are clear service guidelines, effective data collection systems using a number of mandatory returns from cytological laboratories, and internal and external quality assurance systems. Target population coverage is the key to success. The programme aims for coverage of over 80% of the target population, but there has been a worrying fall in levels in recent years, falling as low as 66% in women aged 25–30 years (Figure 38.6).

Figure 38.6 Cervical screening: coverage by age, England, 2003 and 2008, showing the fall in screening uptake in younger women.

Source: Health and Social Care Information Centre, 2009. Cervical Screening Programme 2007/2008. The Health and Social Care Information Centre, Sheffield.

In spite of the success achieved by cervical cytology, it is not without its shortcomings. The assessment and definition of cytological abnormality are subjective with considerable interobserver variation. The process is laborious and tiring with considerable scope for operator error, especially when the workload is high. Furthermore, cytology screening has little effect on the incidence of adenocarcinoma of the cervix.

False-negative results have been variously estimated as being between 2.4% and 26% in various types of study. False-negative results can occur because of inadequate sampling, incorrect laboratory processing, or detection and interpretative errors of the cell samples. This type of error is potentially serious, as a falsely reassuring result may result in no further investigation for 3–5 years, but it is relatively uncommon. There is a need for less labour-intensive and more reliable screening methods.

Colposcopy

Colposcopy should not be regarded as an effective primary screening tool, but is essential for diagnosing and treating premalignant lesions detected by either cytology or HPV testing.

Colposcopy involves the visual examination of the cervix under magnification and with enhancement from dilute acetic acid. It is usually performed in women with abnormal smears or an abnormal-looking cervix. It aims to detect macroscopic changes in tissue features such as colour and morphology which are used to classify the lesion.

Colposcopy aims primarily to examine the whole of the cervical TZ, extending from its innermost margin at the SCJ to the outer margin where the metaplastic squamous epithelium adjoins native squamous epithelium.

Colposcopic examination

Women are examined in a modified lithotomy position, often using a colposcopy couch which facilitates easy adjustment of height and position. A bivalve speculum is then introduced and the cervix visualized.

At the initial examination, obvious macroscopic abnormality is sought, including leukoplakia, viral condylomata and invasion. Invasion is associated with the surface of the cervix appearing raised or ulcerated (Figure 38.7). Atypical vessels seen on invasive lesions run a bizarre course and are often corkscrew- or comma-shaped (Figure 38.8). Condylomata are usually obvious from their regular frond-like surface (Figure 38.9).

Figure 38.7 Colpophotograph of a stage Ib cervical cancer showing the irregular surface.

Image courtesy of Dr Lázló Szalay, Györ, Hungary.

Figure 38.8 Colpophotograph showing abnormal vessels.

Image courtesy of Dr Lázló Szalay, Györ, Hungary.

Figure 38.9 Colpophotograph of a cervical condylomata.

Image courtesy of Dr Lázló Szalay, Györ, Hungary.

Having completed the initial inspection of the cervix, 5% acetic acid is applied liberally and gently. This turns abnormal epithelium white, producing the so-called ‘acetowhite’ changes of CIN. The position of the SCJ must then be ascertained to define the upper limits of the abnormality. On the basis of these findings, the cervical TZ can be classified into one of three types (Figure 38.10). In a type III TZ, the SCJ is not visible and the examination cannot be regarded as satisfactory. This has important management implications.

Figure 38.10 Types of cervical transformation zone. (A) Type I, (B) type II, (C) type III.

Images courtesy of Professor Walter Prenderville, Coombe Women’s Hospital, Dublin.

Colposcopic abnormalities

The key colposcopic features of suspected abnormalities are acetowhitening, abnormal vasculature and topography. Acetowhite change is the most important of all colposcopic features. Its actual mechanism is uncertain, but it is a reversible reaction which has an association with the activity of the epithelium and results in a temporarily increased reflection of light (Figure 38.11). These changes are non-specific. There is a spectrum of change from low- to high-density acetowhitening which corresponds with an increasing likelihood of high-grade CIN.

Figure 38.11 Tissue basis for colposcopy. (A) Normal epithelium, (B) abnormal (atypical) epithelium.

Source: Singer A, Monaghan J 2000. Lower Genital Tract Precancer. Blackwell Science, Oxford, p 10.

Abnormal vascular patterns comprise punctuation, mosaicism (Figure 38.12) and abnormal vessels. In general terms, the coarser the vascular pattern, the greater the likelihood of high-grade change. Abnormal vessels are typically irregular in size, shape and arrangement, and can suggest the presence of invasion.

Figure 38.12 Colpophotograph showing coarse mosaicism.

Image courtesy of Dr Lázló Szalay, Györ, Hungary.

CIN is usually a distinct acetowhite lesion with sharp margins. It often shows a mosaic vascular pattern with patches of acetowhite separated by vessels like red weeds between white flagstones. Where the vessels run perpendicular to the surface, punctation is seen as the vessels are viewed end-on. This appears as red spots on a white background. In general, the more quickly and strongly the acetowhite changes develop, the clearer and more regular the margins of the lesion, and the more pronounced the mosaic or punctation, the more severe the lesion is likely to be.

Colposcopic diagnosis

Colposcopic diagnosis is multifaceted. In part, it involves comparing the visual findings with the established patterns of disease as described above. These skills and abilities require training and experience. In addition, there are other important factors that a colposcopist uses to make a diagnostic decision, and these include the referring cytology, patient’s age and parity, and smoking history. These other factors are, on occasions, at least as important as the colposcopic image in making a diagnosis, especially when the colposcopic features are low grade or normal. This observation has led to the use of a number of scoring systems to facilitate diagnosis (Table 38.2), although these are not recommended for routine clinical use.

Table 38.2 Clinicocolposcopic index

Colposcopy is not reliable when the SCJ cannot be seen, when glandular lesions are suspected, and when there has been previous treatment. In these circumstances, if a high-grade lesion is suspected, an excisional biopsy of the cervix should be performed.

As with any subjective test, a high variation in colposcopic performance has been reported in terms of specificity, sensitivity, and inter- and intraobserver variability. The sensitivity of colposcopy to distinguish normal from abnormal tissue is relatively high, but it is less good at differentiating low-grade lesions from high-grade lesions. The sensitivity of colposcopy for detecting high-grade disease is approximately 50%. Women undergoing colposcopy are therefore at risk from both overtreatment and underdiagnosis.

Colposcopic diagnostic performance might be improved using some technological innovations such as digital image enhancement (Figure 38.13), and reflective and impedance spectroscopy (Louwers et al 2008). Despite a number of promising initial reports, these newer techniques have not been adopted, principally because of expense, inconvenience and insufficient high-quality evidence.

Figure 38.13 Dynamic Spectral Imaging System (DySIS; Forth Phototonics, Athens, Greece) is a colposcope that measures the acetowhitening of every image pixel of the cervix after the application of acetic acid.

Colposcopic biopsy

Colposcopy is often viewed as a means of deciding whether or not to take a biopsy and where to take it from. Colposcopic biopsies can be classified as in Figure 38.14. An extended excisional biopsy aims to sample most of the endocervical canal and can be performed when the SCJ is not visible or a glandular lesion is suspected. It is accepted that excisional biopsy is the gold standard for histological diagnosis, but this is best avoided when low-grade lesions are suspected.

Figure 38.14 Classification of cervical biopsies.

The colposcopically-directed punch biopsy (CDB) is often used, but the reliability and validity of this test is questionable for a variety of reasons. Few studies have been performed that have assessed the reliability of CDB, and these have been of poor quality. CDB should be avoided when the TZ cannot be fully seen, or when glandular lesions or high-grade lesions are suspected. If CDB is to be used, multiple biopsies must be taken.

Treatment of cervical premalignancy

Effective treatment involves striking a balance between the risks of persistent and recurrent disease from undertreatment and excessive damage due to overtreatment. This is particularly pertinent in the management of cervical precancerous change, as many women undergoing treatment will not have started or completed their child bearing.

A failure to appreciate the nature and behaviour of cervical premalignancy has bedevilled its treatment. In the past, CIN was treated by radical hysterectomy but it soon became evident that this was unnecessary, and simple hysterectomy became the method of choice. In time, it was realized that cone biopsy was just as effective, and hysterectomy is now reserved for women with difficult-to-treat recurrent disease or who have additional indications for hysterectomy. The introduction of colposcopy and a better appreciation of the limited location of CIN led to the introduction of more conservative methods of treatment (Soutter and Fletcher 1994).

There is no doubt that high-grade CIN (CIN2/3) and high-grade CGIN should be treated, but there is uncertainty about the therapeutic value of treating CIN1. Whilst conservative treatment is increasingly adopted, follow-up should be performed until spontaneous regression or treatment is performed.

The treatment morbidity is a function of the amount of tissue removed or destroyed. The potential complications are:

With the exception of radical diathermy, ablative treatments were not associated with a significantly increased risk of serious adverse pregnancy outcomes. However, all excisional procedures used to treat CIN seem to be associated with adverse obstetric morbidity, but among these, only cold knife conization is associated with a significantly increased rate of severe outcomes (Kyrgiou et al 2006). The risk of serious obstetric morbidity has not been confirmed with the use of loop excision, but excisions that remove large amounts of cervical tissue probably have the same effect as knife cone biopsies. Most loop excisions in young women with fully visible transformation zones only need to be 1 cm deep, and this should protect against serious obstetric outcomes.

Terminology and pathology of vaginal intraepithelial neoplasia

The terminology and pathology of vaginal intraepithelial neoplasia (VAIN) is analogous to that of CIN (VAIN1–3). The main difference is that vaginal epithelium does not normally have crypts so the epithelial abnormality remains superficial until invasion occurs. The common exception to this is found following surgery (usually hysterectomy) when abnormal epithelium can be buried below the suture line or in suture tracks.

Natural history of vaginal intraepithelial neoplasia

VAIN is seldom seen as an isolated vaginal lesion. It is more usual for it to be coexistent with CIN. In most cases, it is diagnosed colposcopically prior to any treatment during the investigation of an abnormal smear. However, it may not be recognized until after a hysterectomy has been performed. When this happens, abnormal epithelium is likely to be buried behind the sutures used to close the vault and cannot be assessed (Figure 38.15). Untreated or inadequately treated VAIN may progress to frank invasive cancer. Very rarely, VAIN may be seen many years after radiotherapy for cervical carcinoma, when it is probably a new lesion. Care must be taken in these women to ensure that postradiotherapy changes are not being misinterpreted as VAIN.

Figure 38.15 Sutures in the vaginal vault isolate a cuff of the vagina above the suture line.

Assessment of vaginal intraepithelial neoplasia

VAIN is often detected by abnormal cytology following hysterectomy. Colposcopy of the vagina is more difficult than that of the cervix, particularly if the patient has had a hysterectomy, as it is very difficult to see into the angles of the vagina, and impossible to visualize epithelium that lies above the suture line or vaginal adhesions. The colposcopic features of VAIN are very similar to those of CIN, except that mosaic is seen less often. Punch biopsy can indicate whether or not there is an abnormality, but assessment short of complete excision must be regarded as suboptimal.

Treatment of vaginal intraepithelial neoplasia

As with the cervix, excision avoids suboptimal assessment and inadvertent inadequate management of invasive lesions. Ablative treatments appeal because of their apparent simplicity, but they can be associated with morbidity as well as compounding the dangers of undertreatment with future difficulties in assessment.

In the past, a number of ablative techniques such as carbon dioxide laser, topical 5-fluorouracil and radiotherapy have been used, but surgical excision gives better results and is the only effective option available to patients previously treated with radiotherapy. Following hysterectomy, an abdominal or combined abdominal and vaginal approach is preferable to vaginal excision (Ireland and Monaghan 1988).

Pathology of premalignant disease of the vulva

Premalignant squamous lesions of the vulva are labelled ‘vulvar intraepithelial neoplasia’ (VIN). This term has been adopted by the International Society for the Study of Vulvar Disease and the International Society for Gynecologic Pathologists. This replaces previous terminology such as ‘hyperplastic dystrophy’, ‘Bowen’s disease’, ‘squamous dysplasia’ and ‘carcinoma in situ’.

VIN is classified into two distinct clinicopathological subtypes: classic (Bowenoid, usual type) and simplex (differentiated). Classic VIN is seen in younger women and is associated with HPV. Multifocal involvement of the vulva occurs in more than 40% of cases, and multicentric involvement affecting the vagina, cervix and perianal region occurs in 18–52% of patients. Approximately 50% of women with VIN present with symptoms of pruritus, irritation or a mass lesion, and in the remainder it is an incidental finding. Local recurrence or persistence has been noted in 7–32% of patients following therapy. Occult areas of invasive carcinoma are seen in approximately 6–18% of patients treated surgically for VIN. Histologically, classic VIN may have a warty pattern with an undulating surface, and frequent koilocytosis or multinucleation or a basaloid pattern with a relatively flat lesion where the normal epithelium is replaced by a fairly homogeneous proliferation of abnormal cells. Both types can coexist. Classic VIN is graded depending on the level of involvement of the affected epithelium by abnormal cells. This grading scheme is similar to that used in CIN: VIN1, when the lowest third is involved; VIN2, when the lower two-thirds are involved; and VIN3, when the abnormality extends to the upper third of epithelium. VIN1 is uncommon.

Simplex (differentiated) VIN is much less common and accounts for less than 10% of VIN cases. It occurs in postmenopausal women and is associated with lichen sclerosis. HPV is uncommon with differentiated VIN; however, it has a strong association with vulvar squamous cell carcinoma. Histologically, simplex VIN is a subtle lesion with a generally well-preserved architecture, thickened epidermis, abnormal basal keratinocytes and deeply situated abnormal individual cell keratinization.

Vulvar Paget’s disease is said to represent adenocarcinoma in situ and is very rare. The histological appearance of Paget’s disease is similar to the lesion seen in the breast. In one-third of cases of Paget’s disease, there is an associated invasive cancer, often an adenocarcinoma, in underlying apocrine glands and these carry an especially poor prognosis

Natural history of vulvar intraepithelial neoplasia

Forty per cent of women with VIN are under 41 years of age. Although histologically very similar to CIN and often occurring in association with it, VIN does not seem to have the same malignant potential. However, this opinion is based largely on studies of women who have been treated by excision biopsy or vulvectomy.

Diagnosis and assessment of vulvar intraepithelial neoplasia

VIN often presents with itching, but 20–45% are asymptomatic and are frequently found after treatment of preinvasive or invasive disease at other sites in the lower genital tract, particularly the cervix.

These lesions are often raised above the surrounding skin and have a rough surface. The colour is variable: white, due to hyperkeratinization; red, due to thinness of the epithelium; or dark brown, due to increased melanin deposition in the epithelial cells. They are very often multifocal.

Adequate biopsies must be taken from abnormal areas to rule out invasive disease. This can usually be done under local anaesthesia in the outpatient clinic using a disposable 4-mm Stiefel biopsy punch or a Keyes punch.

Treatment of vulvar intraepithelial neoplasia

Treatment of VIN is difficult. Uncertainty about the malignant potential, the multifocal nature of the disorder, and the discomfort and mutilation resulting from therapy suggest that recommendations should be cautious and conservative in order to avoid making the treatment worse than the disease. The youth of many of these patients is a further important consideration. In view of the mutilating nature of treatment, the high recurrence rate and the uncertainty about the risk of invasion, there is a place for careful observation, especially of young women without severe symptoms.

The documented progression of untreated cases of VIN3 to invasive cancer underlines the potential importance of these lesions. If the patient has presented with symptoms, therapy is required. Asymptomatic patients, particularly those under 50 years of age, may be observed closely with biopsies repeated if there are any suspicious changes.

Paget’s disease

This is an uncommon condition and is similar to that found in the breast. It is characterized by large malignant cells arranged singly and in clusters. The typical Paget’s cell has a vesicular nucleus and abundant cytoplasm which contains demonstrable mucin (Figure 38.16). The cells of primary Paget’s disease are characteristically positive with cytokeratin 7, carcinoembryonic antigen, CAM 5.2, androgen receptor, gross cystic disease fluid protein 15 and human epidermal growth factor receptor 2 (HER 2) (Goldblum and Hart 1997).

Figure 38.16 Single and nested Paget cells showing characteristic abundant cytoplasm and vesicular nuclei (block arrow). The inset shows the cells highlighted by cytoplasmic and membranous staining with cytokeratin 7 (arrowed). Original magnification x100.

The disease is often extensive or multifocal, so clinically unsuspected positive resection margins are not uncommon. No underlying regional malignancy is identified in the majority of cases, but up to 30% of cases have invasion of the dermis, microscopically noted but often clinically unsuspected. The main differential diagnosis of Paget’s disease is superficial spreading malignant melanoma which will, in contrast to Paget’s disease, show positivity for S100, HMB45 and Melan A. Concomitant genital malignancies are found in 15–25% of women with Paget’s disease of the vulva; these are most commonly vulval or cervical, but transitional cell carcinoma of the bladder (or kidney), and ovarian, endometrial, vaginal and urethral carcinomas have all been reported.

Pruritis is the presenting complaint and it often presents as a red, crusted plaque with sharp edges (Figure 38.17), sometimes with multiple erosions. The diagnosis is made histologically on biopsy.

Figure 38.17 Paget’s disease of the vulva. Note the crusted surface and clear margins.

The treatment of Paget’s disease is very wide local excision, usually involving total vulvectomy because of the propensity of this condition to involve apparently normal skin. The specimen must be examined histologically with great care to exclude an apocrine adenocarcinoma.

Introduction

The concept of premalignancy in the uterine corpus is confined to the endometrium. Myometrial neoplasms, such as leiomyomas, leiomyosarcomas and endometrial stromal sarcomas, do not have a recognized preneoplastic phase.

Terminology of endometrial premalignancy

Endometrial carcinoma is the most common malignancy of the female genital tract in the Western world. Simplistically and conceptually, there are two types of endometrial carcinomas: type 1, oestrogen-related, endometrioid carcinoma; and type 2, non-oestrogen-related, prototypically serous carcinomas. Type 1 carcinoma is more common and has a precursor termed ‘endometrial hyperplasia’. Endometrial hyperplasia is best described as a non-physiological, non-invasive proliferation of glands visibly resulting in an increase in the volume of endometrial glands relative to the stroma. The precursor of type 2 carcinoma is termed ‘endometrial intraepithelial carcinoma’ (EIC).

The World Health Organization (WHO) classification of endometrial hyperplasia is into simple and complex hyperplasia. Both simple and complex hyperplasia can be associated with cellular atypia. Simple atypical hyperplasia is exceedingly rare. Complex atypical hyperplasia is commonly termed ‘atypical hyperplasia’, and is closely related to progression or coexistence of endometrial carcinoma. In women who undergo hysterectomy soon after a biopsy that shows atypical hyperplasia, the uterus shows an established endometrioid adenocarcinoma in 17–45% of cases in various series reported in the literature. When such a cancer is discovered, it is almost always a low-grade, low-stage carcinoma.

Histopathology of endometrial premalignancy

On histopathological examination, all forms of hyperplasia show an increase in the number of glands in comparison with the stroma. Simple and complex forms of hyperplasia are distinguished by the gland morphology. Simple hyperplasia is characterized by variably sized cystically dilated glands. The stroma is abundant relative to the lesser volumes of stroma seen in complex hyperplasia. The latter shows more densely crowded glands with irregular outlines, and outpouching and infoldings of the lumen. The glands are closely packed, although stroma is consistently identified between the glands. In any sample of endometrium, a combination of simple and complex hyperplasia may be seen. Cellular atypia is identified by nuclear enlargement, rounded outlines and irregularity of nuclear chromatin.

The diagnosis of endometrial hyperplasia has been shown in several studies to be an area of gynaecological pathology with low diagnostic reproducibility. Even after accounting for extrinsic factors such as scanty sample or low volume changes, there is disagreement amongst general and specialist pathologists in the diagnosis of complex hyperplasia and cytological atypia. These difficulties in reproducibility of diagnosis are likely to be secondary to lack of strict definition and objective criteria in the present WHO classification. There is a proposal from Mutter and colleagues from Boston to use more specific diagnostic criteria for precancerous changes in the endometrium termed ‘endometrial intraepithelial neoplasia’. This classification is currently under discussion and has not replaced the current WHO classification.

EIC represents the precursor lesion of type 2 endometrial carcinoma. This lesion occurs in a background of atrophic endometrium, and has cells with pleomorphic nuclei that are immunoreactive for p53. By definition, EIC does not show myometrial invasion. Biologically, however, EIC can be aggressive with extrauterine spread noted at the time of diagnosis. This diagnosis of EIC can trigger management as carcinoma.

Aetiology and molecular pathology of endometrial premalignancy

Type 1 endometrial carcinoma is associated with hyperoestrinism. The development of endometrial hyperplasia is strongly influenced by steroid hormones; oestrogen induces glandular proliferation leading to thickening of the uterine lining, whereas growth is suppressed by progesterone. This is reflected by the risk factors for endometrial hyperplasia, including obesity, nulliparity and oestrogen-only hormone replacement therapy, which are associated with states of prolonged unopposed oestrogen. Hyperoestrogenic states such as polycystic ovary syndrome have a greater incidence of endometrial hyperplasia, as do patients taking the partial oestrogen agonist tamoxifen for breast cancer. Although there is no association with hyperoestrinism, hereditary non-polyposis colonic cancer is known to have an increased incidence of hyperplasia.

The most frequently altered gene in type 1 carcinoma is PTEN, located on chromosome 10. Up to 55% of preneoplastic lesions reveal loss of PTEN expression. This loss of PTEN is an early event in endometrial tumorigenesis. Mutations of p53 are found in approximately 80% of precursors of type 2 carcinoma.

Screening for endometrial premalignancy

Endometrial hyperplasia is typically diagnosed in perimenopausal women. There are few data in the literature regarding screening of asymptomatic women for endometrial hyperplasia. Both ultrasonography for endometrial thickness and outpatient endometrial biopsy have yields too low to justify investigation of asymptomatic women.

Clinical presentation of endometrial hyperplasia

Endometrial hyperplasia usually presents with abnormal uterine bleeding. This includes menorrhagia, intermenstrual bleeding, postcoital bleeding and postmenopausal bleeding. Occasionally, endometrial hyperplasia might be detected in asymptomatic women being investigated for smears containing atypical endometrial cells. Endometrial hyperplasia can occur in both pre- and postmenopausal women, accounting for approximately 15% of women presenting with postmenopausal bleeding.

Investigation of endometrial hyperplasia

In the UK, the cancer waiting time and 18-week waiting time initiatives have increasingly focused attention on one-stop assessment and diagnosis. Women over the age of 45 years with irregular bleeding or postmenopausal women are referred on the cancer pathway and seen within 14 days. Transvaginal ultrasound (TVS) is the primary investigation of choice in postmenopausal women as it can assess the endometrium and detect other relevant pelvic pathologies. The endometrial thickness is measured and, using a cut-off of more than 5 mm, has a high sensitivity and specificity for detecting endometrial pathology, as well as a true negative predictive value approaching 100% (Smith-Bindman et al 1998). If the endometrial thickness exceeds 5 mm, endometrial assessment is required. Whilst the diagnostic gold standard is hysteroscopy, blind endometrial sampling using tests such as Pipelle (Punimar, Wilton, Connecticut, USA) are frequently used and are cost-effective. When outpatient sampling is not feasible or is unsatisfactory, or in the context of the patient being on tamoxifen or in whom symptoms have persisted despite negative findings on initial assessment, hysteroscopy should be undertaken. Hysteroscopy allows the whole surface of the uterine cavity to be inspected and facilitates targeted biopsy or curettage. Hysteroscopy with biopsy has an excellent sensitivity and specificity for detecting endometrial pathology in women aged less than 45 years who have symptoms of irregular and/or heavy bleeding that is non-responsive to first-line management. In this clinical scenario, an endometrial sample should be the primary test, as TVS is less specific. Notwithstanding the above, TVS should always be considered when clinical findings are abnormal or examination is suboptimal.

Management of endometrial hyperplasia

The management will depend upon the nature of the abnormality and upon the patient’s wishes for further children. As most types of endometrial hyperplasia do not progress to endometrial cancer, treatment regimens should be individualized; hysterectomy is unnecessary in the majority of cases. On the other hand, the presence of cytological atypia with its risk of concomitant cancer or risk of progressing to endometrial cancer should be managed as if cancer was there, unless there are powerful considerations to do otherwise, such as fertility issues or significant medical comorbidity.

Introduction

Ovarian cancer is a heterogeneous disease including epithelial neoplasms, germ cell and stromal tumours, and metastatic malignancies. The concept of ovarian premalignant disease is currently confined to epithelial neoplasms; however, its clinical usefulness has been limited by the diverse histological subtypes and the lack of an obvious precursor.

As a result, attention has focused on the detection of small early-stage cancers in certain situations, such as the need for careful examination of ovaries and fallopian tubes removed at prophylactic surgery in patients with BRCA1 or BRCA2 mutations since small areas of malignant change can easily be missed. Similarly, it is recognized that endometriosis can be coexistent in up to 25–40% of cases of endometrioid and clear cell ovarian cancers (Fukunaga et al 1997), and consequentially all endometriotic cysts must be sampled optimally, especially to include any solid or suspicious areas. Only a small percentage of women with endometriosis will develop an ovarian cancer, and the mechanisms responsible for the malignant transformation have still to be elucidated. However, evidence is emerging of genetic mutations common to both ovarian endometriosis and endometriosis-associated ovarian cancer (Prowse et al 2006).

Ovarian carcinogenesis

Based on morphological and molecular genetic studies, a dualistic model has been suggested (Shih and Kurman 2004) in which ovarian cancers can be divided into two broad categories: type I and II tumours (Figure 38.18). The type I pathway resembles the adenoma–carcinoma pathway in colorectal cancer and is characterized by clearly recognized precursor lesions, namely cystadenoma and borderline lesions. Type I tumours evolve slowly in a stepwise fashion and are associated with distinct molecular changes that are not shared by the more common type II tumours. Type II tumours comprise high-grade tumours, such as poorly differentiated serous lesions and mixed mesodermal tumours, which arise and metastasize early.

Figure 38.18 The dualistic model of ovarian cancer pathogenesis.

Adapted from Kurman RJ, Shih IM 2008 International Journal of Gynecological Pathology 27: 151–160.

The pathological evidence for the progression of type I tumours arises from studies which have shown the frequent occurrence of a transition or coexistence between malignant and benign areas in mucinous ovarian cancers, and between low-grade serous cancers and areas of borderline change (Malpica et al 2004). Also, borderline serous tumours typically recur as low-grade serous cancers (Crispens et al 2002).

The significance of this dualistic theory is that it provides a basis for further morphological and molecular genetic studies that might help to explain ovarian carcinogenesis.

Prevention of premalignancy of the ovary

Due to the lack of a clearly identifiable premalignant phase, prevention strategies have concentrated on either trying to identify early-stage lesions or removing the ovaries before disease develops, thereby aiming to impact on disease-associated morbidity and mortality. Various approaches have been tried in order to achieve this aim, including clinical, chemoprevention and prophylactic surgery.

The clinical approach has been predominantly aimed at screening with the serum tumour marker CA125, pelvic ultrasound or a combination of both modalities. Large clinical trials are currently underway, investigating the potential of such screening programmes in both low- and high-risk populations (i.e. UK Collaborative Trial of Ovarian Cancer Screening, UK Familial Ovarian Cancer Screening Study).

Chemoprevention has particularly focused on the use of the oral contraceptive pill, which has been shown to reduce the risk of ovarian cancer in both low- and high-risk populations (Hankinson et al 1992, McLaughlin et al 2007). The use of oral contraceptives in BRCA mutation carriers is currently not advised due to an apparent increase in the rate of breast cancer, although the data on this are limited.

Bilateral salpingo-oophorectomy has also been shown to reduce the risk of ovarian and fallopian tube cancer in BRCA1 or BRCA2 mutation carriers (Rebbeck et al 2009). The timing of surgery is dependent on the individual, their fertility requirements, the potential surgical morbidity and long-term hormonal sequelae. The current advice is that surgery should be considered once a woman reaches 35 years of age. Prophylactic surgery, however, does not completely remove the risk of malignancy since women in some high-risk populations are still at risk of developing primary peritoneal carcinoma (Finch et al 2006).