Gynaecological oncology





Learning outcomes


After studying this chapter you should be able to:


Knowledge criteria





  • Understand the epidemiology, aetiology, diagnosis, management and prognosis of gynaecological cancer



  • Describe the aetiology, epidemiology and presentation of the common neoplasms of the female genital tract including:




    • Vulval and cervical intraepithelial neoplasia



    • Vulval and vaginal carcinoma



    • Cervical carcinoma



    • Endometrial hyperplasia



    • Endometrial adenocarcinoma



    • Ovarian epithelial and germ cell tumours




  • Discuss the role of minor procedures and diagnostic imaging procedures in the management of gynaecological cancers including:




    • Cervical and endometrial sampling



    • Ultrasound



    • Laparoscopy



    • Hysteroscopy



    • Magnetic resonance imaging and computerized tomography




  • List the short- and long-term complications of medical and surgical therapies for gynaecological cancer



  • Discuss the role of screening and immunization in the prevention of female genital tract malignancy



Clinical competencies





  • Counsel a woman about screening for the preclinical phase of squamous cell carcinoma of the cervix



  • Plan initial investigation of women presenting with symptoms of genital tract malignancy



  • Communicate sensitively with a woman and her family about the diagnosis of gynaecological cancer



Professional skills and attitudes





  • Discuss the principles of palliative care in gynaecological cancers





Lesions of the vulva


Vulval intraepithelial neoplasia


Vulval intraepithelial neoplasia (VIN) is a condition characterized by disorientation and loss of epithelial architecture extending through the full thickness of the epithelium. In the past, the World Health Organization classified VIN into VIN-1, 2 and 3 based on the extent to which normal epithelium is replaced by abnormal dysplastic cells. However, since VIN-1 mainly corresponds with condyloma that is not a precancerous lesion, the term VIN-1 has been abandoned and VIN now refers to the previous VIN-2 and 3 in the latest classification of the International Society for the Study of Vulvar Disease.


VIN is categorized into usual VIN (classic VIN or Bowen’s disease) and differentiated VIN (d-VIN) based on the distinctive pathological features ( Box 20.1 ). Usual VIN often occurs in young women between 30–50 years and is associated with cigarette smoking and human papilloma virus (HPV) infection. Patients can be asymptomatic, or they may complain of pruritus, pain, dysuria and ulceration. Lesions can be white, pink or pigmented, in the forms of plaques or papules. They are most frequently found in labia and posterior fourchette; 3–4% of usual VIN may progress to invasive disease.



Box 20.1

Vulval intra-epithelial neoplasia (VIN)





  • Squamous VIN




    • Usual VIN (formerly classic VIN or Bowen’s disease)



    • Differentiated VIN (formerly ‘simplex’ VIN)




  • Non-squamous VIN




    • Paget’s disease





d-VIN occurs in post-menopausal women and accounts for only 2–10% of all VIN. It is associated with squamous hyperplasia, lichen sclerosus and lichen simplex chronicus, and is considered as the precursor of most HPV-negative invasive keratinizing squamous cell carcinomas. Patients have similar symptoms as for lichen sclerosus. Grey, white, red nodules, plaques or ulcers may be found. It is found in up to 70–80% of adjacent cancer, and has a higher malignant potential than usual VIN. It is hence important to exclude malignancy when d-VIN is found.


Unlike VIN, which arises from squamous epithelium, extramammary Paget’s disease arises from apocrine glandular epithelium. The appearance of the lesions is variable, but they are papular and raised, may be white, grey, dull red or various shades of brown, and may be localized or widespread. These conditions are rare, with an incidence of 0.53/100 000, and commonly occur in women over the age of 50 years. Paget’s disease is associated with underlying adenocarcinoma or primary malignancy elsewhere in 20% of cases, mainly breast and bowel.


Management


It is important to establish the diagnosis by biopsy ( Fig. 20.1 ) and to search for intraepithelial neoplasia in other sites like the cervix and vagina, particularly when usual VIN is found. Treatment of usual VIN includes imiquimod, an immune modifier, laser therapy, and superficial excision of the skin lesion. There is no role for medical treatment in d-VIN, and surgical excision tends to be more radical than that for usual VIN. Recurrence is common and because there is a risk of malignant progression especially in d-VIN, long-term follow-up is essential.




Fig. 20.1


Diagnosis of vulval skin lesions using Keye’s punch biopsy under local anaesthetic.


Cancers of the vulva


Carcinoma of the vulva accounts for 1–4% of female malignancies: 90% of the lesions are squamous cell carcinomas, 5% are adenocarcinomas, 1% are basal carcinomas and 0.5% are malignant melanomas. Carcinoma of the vulva most commonly occurs in the sixth and seventh decades.


Vulvar cancer has two distinct histological patterns with two different risk factors. The more common basoloid/warty types occur mainly in younger women and are associated with usual VIN and HPV infection sharing similar risk factors as cervical cancer. The keratinizing types occur in older women and are associated with lichen sclerosus. As noted above, there may be foci of d-VIN adjacent to the main tumour.


Symptoms


The patient with vulval carcinoma experiences pruritus and notices a raised lesion on the vulva, which may ulcerate and bleed ( Fig. 20.2 ). Malignant melanomas are usually single, hyperpigmented and ulcerated. Vulval carcinoma most frequently develops on the labia majora (50% of cases) but may also grow on the prepuce of the clitoris, the labia minora, Bartholin’s glands and in the vestibule of the vagina.




Fig. 20.2


Ulcerative squamous cell carcinoma of the vulva.


Mode of spread


Spread occurs both locally and through the lymphatic system. The lymph nodes involved are the superficial and deep inguinal nodes and the femoral nodes ( Fig. 20.3 ). Pelvic lymph nodes, except in primary lesions involving the clitoris, have usually only secondary involvement. Vascular spread is late and rare. The disease usually progresses slowly and the terminal stages are accompanied by extensive ulceration, infection, haemorrhage and remote metastatic disease. In some 30% of cases, lymph nodes are involved on both sides. Stages are defined by the International Federation of Obstetrics and Gynaecology (FIGO) on the basis of surgical rather than clinical findings ( Table 20.1 ).




Fig. 20.3


Lymphatic drainage of the vulva.


Table 20.1

FIGO staging of vulval cancer (2009)















Stage I Tumour confined to the vulva:



  • Stage IA : Lesions ≤2 cm in size, confined to the vulva or perineum and with stromal invasion ≤1.0 mm * , no nodal metastasis



  • Stage IB : Lesions >2 cm in size or with stromal invasion >1.0 mm * , confined to the vulva or perineum, with negative nodes

Stage II Tumour of any size with extension to adjacent perineal structures (lower third of urethra, lower third of vagina, anus) with negative nodes
Stage III Tumour of any size with or without extension to adjacent perineal structures (lower third of urethra, lower third of vagina, anus) with positive inguinofemoral lymph nodes:



  • Stage IIIA : (i) With 1 lymph node metastasis (≥5 mm), or (ii) 1–2 lymph node metastasis(es) (<5 mm)



  • Stage IIIB : (i) With 2 or more lymph node metastases (≥5 mm), or (ii) 3 or more lymph node metastases (<5 mm)



  • Stage IIIC : With positive nodes with extracapsular spread

Stage IV Tumour invades other regional (upper two-thirds of urethra, upper two-thirds of vagina), or distant structures:



  • Stage IVA: Tumour invades any of the following: (i) upper urethral and/or vaginal mucosa, bladder mucosa, rectal mucosa, or fixed to pelvic bone, or (ii) fixed or ulcerated inguinofemoral lymph nodes



  • Stage IVB: Any distant metastasis including pelvic lymph nodes


* The depth of invasion is defined as the measurement of the tumour from the epithelial stromal junction of the adjacent most superficial dermal papilla to the deepest point of invasion.



Treatment


Stage IA disease can be treated by wide local excision. Stage IB lesions that are at least 2 cm lateral to the midline are treated by wide local excision and unilateral groin node dissection. All other stages are treated by wide radical local excisions or radical vulvectomy and bilateral groin node dissection ( Fig. 20.4 ). Sentinel node dissection may replace conventional node dissection in future. Postoperative radiotherapy has a role in patients where the tumour extends close to the excision margin or there is involvement of the groin nodes. Preoperative radiotherapy may be used in cases of extensive disease to reduce the tumour volume. Complications of radical vulvectomy and groin node dissection include wound breakdown, lymphocyst and lymphoedema (30%), secondary bleeding, thromboembolism, sexual dysfunction and psychological morbidity. Response to chemotherapy (bleomycin) is generally poor. Patients are followed up at intervals of 3–6 months for 5 years.




Fig. 20.4


Block dissection of the lymph nodes in surgical treatment of malignant disease of the vulva.


Prognosis


Prognosis is determined by the size of the primary lesion and lymph node involvement. The overall survival rate in operable cases without lymph node involvement is 90% and is up to 98% where the primary lesion is less than 2 cm in size. This falls to 50–60% with node involvement and is less than 30% in patients with bilateral lymph node involvement. Malignant melanoma and adenocarcinoma have a poor prognosis, with a 5-year survival of 5%.




Neoplastic lesions of the vaginal epithelium


Vaginal intraepithelial neoplasia


Vaginal intraepithelial neoplasia (VAIN) is usually multicentric and tends to be multifocal and associated with similar lesions of the cervix. The condition is asymptomatic and tends to be discovered because of a positive smear test or during colposcopy for abnormal cytology, often after hysterectomy. There is a risk of progression to invasive carcinoma, but the disease remains superficial until then and can be treated by surgical excision, laser ablation or cryosurgery.


Vaginal adenosis


This is the presence of columnar epithelium in the vaginal epithelium and has been found in adult females whose mothers received treatment with diethylstilboestrol during pregnancy. The condition commonly reverts to normal squamous epithelium, but in about 4% of cases the lesion progresses to vaginal adenocarcinoma. It is therefore important to follow these women carefully with serial cytology.


Vaginal malignancy


Invasive carcinoma of the vagina may be a squamous carcinoma or, occasionally, an adenocarcinoma. Primary lesions arise in the sixth and seventh decades, but are rare in the UK. The incidence of adenocarcinoma, typically clear cell, associated with in utero exposure of diethylstilboestrol has declined since this drug was withdrawn from use in pregnancy.


Secondary deposits from cervical carcinoma and endometrial carcinoma are relatively common in the upper third of the vagina and can sometimes occur in the lower vagina through lymphatic spread.


Symptoms


The symptoms include irregular vaginal bleeding and offensive vaginal discharge when the tumour becomes necrotic and infection supervenes. Local spread into the rectum, bladder or urethra may result in fistula formation. The tumour may appear as an exophytic lesion or as an ulcerated, indurated mass.


Method of spread


Tumour spread, as previously stated, occurs by direct infiltration or by lymphatic extension. Lesions involving the upper half of the vagina follow a pattern of spread similar to that of carcinoma of the cervix. Tumours of the lower half of the vagina follow a similar pattern of spread to that of carcinoma of the vulva.


Treatment


The diagnosis is established by biopsy of the tumour. Staging is made before commencing treatment ( Table 20.2 ).



Table 20.2

Clinical staging of vaginal carcinoma


















Stage 0 Intraepithelial carcinoma
Stage I Limited to the vaginal walls
Stage II Involves the subvaginal tissue but has not extended to the pelvic wall
Stage III The tumour has extended to the lateral pelvic wall
Stage IV The lesion has extended to involve adjacent organs (IVA) or has spread to distant organs (IVB)


The primary method of treatment is by radiotherapy – both by external beam therapy and brachytherapy.


Surgical treatment can also be considered in selected patients. For example, radical hysterectomy or vaginectomy and pelvic lymph node dissection can be considered in patients with stage I disease in the upper vagina, radical vulvectomy may be needed in stage I disease in the lower vagina, and pelvic exenteration may be considered in patients with localized metastatic disease to the bladder or rectum without parametrial or lymph node metastasis.


Prognosis


Results of treatment depend on the initial staging and on the method of therapy. Stages I and II have a 5-year survival of around 60% but this figure falls to 30–40% for stages III and IV. Adenocarcinoma of the vagina, which often occurs in young females, also responds well to irradiation.




Lesions of the cervix


Screening for cervical cancer


The aim of cervical screening programmes is to detect the non-invasive precursor of cervical cancer, cervical intraepithelial neoplasia (CIN), in the asymptomatic population in order to reduce mortality and morbidity. The NHS national cervical screening programme was introduced in England and Wales in 1988, and by 1991 80% of all women between the ages of 20 and 65 were being tested on a 5-yearly basis. Since then mortality from cervical cancer has fallen by 7% a year. Currently all women aged between 25 and 65 are invited for screening every 3–5 years. In Australia screening commences at the age of 18 or 2 years after the start of sexual activity and takes place every 2 years. In taking a cervical cytology, the speculum should be introduced with a minimum of artificial lubricant. Cells are taken from around the cervix from the whole of the transformation zone with a 360° sweep using an Ayres or Aylesbury spatula or a plastic cervical brush and fixed in an appropriate manner (see Chapter 15 ). Cervical cytology ( Figs 20.5 and 20.7 ) is primarily for screening for squamous lesions and cannot reliably exclude endocervical disease.




Fig. 20.5


Normal cervical smear showing superficial (pink) and intermediate (blue/green) exfoliated cervical cells (low power magnification).



Fig. 20.7


Moderate dyskaryosis. The cells are smaller and the nuclear:cytoplasmic ratio higher when compared with normal cells.


Classification of cervical cytology


The terminology used in the UK for reporting cervical smears was introduced by The British Society for Clinical Cytology in 1986 ( Table 20.3 ).



Table 20.3

Classification of cervical smears


































UK system US Bethesda system
Negative Within normal limits
Borderline nuclear change ASCUS/ASC-H/possible low-grade SIL
Wart virus change Low-grade SIL
Mild dyskaryosis Low-grade SIL
Moderate dyskaryosis High-grade SIL
Severe dyskaryosis High-grade SIL
Glandular neoplasia
Possible invasive cancer Invasive cancer
Inadequate samples

ASCUS, atypical squamous cells of undetermined significance; ASC-H, atypical squamous cells (high-grade), SIL, squamous intraepithelial lesion.


The term dyskaryosis is used to describe those cells that lie between normal squamous and frankly malignant cells




Fig. 20.6


Cell layers in the stratified squamous epithelium of the cervix and vagina.
and exhibit degrees of nuclear changes before malignancy ( Fig. 20.7 ). Cells showing abnormalities that fall short of dyskaryosis are described as borderline. Atypical glandular cells may represent premalignant disease of the endocervix or endometrium.


Malignant cells show nuclear enlargement at the expense of cytoplasmic mass ( Fig. 20.8 ). The nuclei may assume a lobulated outline. There is increased intensity of staining of the nucleus and an increase in the number of mitotic figures.




Fig. 20.8


Carcinoma cells. Note the large nuclei and abnormal distribution of chromatin.


The Bethesda system of classification used in the US ( Table 20.3 ) differs by combining moderate and severe dyskaryosis as high-grade squamous intraepithelial lesions (HSIL) and using the term atypical squamous cells of undetermined significance (ASCUS) instead of borderline. In the current edition of the classification system, the emphasis is to try and separate out borderline cases that may potentially be a high-grade lesion. This group of borderline lesion is called atypical squamous cells, cannot exclude high-grade intraepithelial lesion (ASC-H). A modified version of this classification is used in Australia and New Zealand with HSIL and low-grade squamous intraepithelial lesions (LSIL) but the term possible low-grade squamous intraepithelial lesions (PLSIL) and possible high-grade squamous intraepithelial lesions (PHSIL) being used instead of ASCUS and ASC-H, respectively.


The correlation between cytology and histological changes in the cervix is poor, with 30–40% of women with mild dyskaryosis having CIN-2 or greater. The overall false-negative rate varies from 2–26%. CIN will be detected in 2–3% of the screened population.


Colposcopy


In the UK the presence of dyskaryosis or malignant cells on cytology is an indication for examination by colposcopy. A borderline smear will be repeated after 6 months, and if borderline changes persist in three consecutive tests or if high risk HPV test is positive, colposcopy is required. Women should be referred for colposcopy after one mild dyskaryosis, but it is acceptable to repeat the smear. Women with a test reported as borderline nuclear change in endocervical cells should have colposcopy. In addition, women should have colposcopy if they have one report as moderate or severe dyskaryosis, possible invasion or possible glandular neoplasia. Those with three consecutive inadequate samples should also be referred for colposcopy.




Protocols for referral after Pap smears vary from country to country. In Australia women are referred after a single HSIL or PHSIL or following a LSIL if they are over the age of 35 and have not had a normal smear within the previous 2 years. Women with LSIL or PLSIL will otherwise have a repeat smear after 12 months and be referred only if the second smear is also abnormal.

Colposcopy is inspection of the cervix using a binocular microscope with a light source. It is usually an outpatient procedure performed using a speculum to expose the cervix. Squamous neoplasia most often occurs in the areas adjacent to the junction of the columnar (velvety red) and squamous (smooth pink) epithelium or the squamo–columnar junction (SCJ). If this cannot be seen in its entirety, CIN cannot be excluded by colposcopic examination and a cone biopsy will be required.


Pathophysiology


The SCJ moves in relation to the anatomical external cervical os. Changes in oestrogen during puberty, pregnancy or while on the combined oral contraceptive pills move the SCJ outwards, exposing columnar epithelium to the lower pH of the vagina. This reacts by undergoing transformation back to squamous epithelium by a process of squamous metaplasia. The area that lies between the current SCJ and that reached as it moves outwards across the ectocervix is the transformation zone and it is here that most preinvasive lesions occur.


Colposcopic appearances


Neoplastic cells have an increased amount of nuclear material in relation to cytoplasm and less surface glycogen than normal squamous epithelium. They are associated with a degree of hypertrophy of the underlying vasculature. When exposed to 5% acetic acid the nuclear protein will be coagulated, giving the neoplastic cells a characteristic white appearance ( Fig. 20.9 ). Small blood vessels beneath the epithelium may be seen as dots (punctation) or a crazy paving pattern (mosaicism) due to the increased capillary vasculature. The neoplastic cells do not react with Lugol’s iodine (Schiller’s test), unlike the normal squamous epithelium that will stain dark brown ( Fig. 20.10 ). The diagnosis is confirmed by biopsies taken from the most abnormal-looking areas. Early invasive cancer is characterized by a raised or ulcerated area with abnormal vessels, friable tissue and coarse punctation with marked mosaicism. It feels hard on palpation and often bleeds on contact. In more advanced disease the cervix becomes fixed or replaced by a friable warty looking mass ( Fig. 20.11 ).




Fig. 20.9


Colposcopy of CIN-1. The acetowhite appearance of the anterior lip of the cervix indicates the presence of CIN.



Fig. 20.10


Colposcopic appearances of CIN-2. The abnormal epithelium fails to stain with iodine.



Fig. 20.11


Colposcopic appearance of invasive carcinoma of the cervix.


Human papilloma virus


Certain types of HPV are found in association with neoplastic changes in the cervix. Types 6 and 11 are associated with low-grade CIN and condylomata, whereas 14 high-risk serotypes including the more common 16 and 18 are associated with high grades of CIN and carcinoma of the cervix. HPV is considered as the necessary though not sole cause of cervical cancer. It is present in 95% of squamous cell cervical cancers and 60% of adenocarcinomas, but it must be remembered that 10–30% of normal subjects will also be found to have HPV DNA present in cervical epithelium.


The role of testing for high-risk HPV serotypes in cervical screening has been extensively studied. The sensitivity of these tests for cervical neoplasia is much higher than that for conventional cytology, but not all women with high-risk HPV will develop clinical disease. High-risk HPV testing has been used in triaging borderline cytology for colposcopy referral, in the follow-up assessment after treatment of high-grade cervical dysplasia and is being explored as a primary screening tool on its own or as an adjunct to cervical cytology. However, its cost-effectiveness is still under investigation and therefore HPV testing is not routinely performed in the UK and is used only in follow up after treatment in Australia.


In theory, cervical cancer could be reduced by immunization against HPV as the prevention of infection of specific high risk HPV types could prevent development of cervical cancer from those particular types. The prevention of HPV-16 and 18 infections could theoretically prevent more than 70% cervical cancer. National vaccination programmes against HPV-16 and 18 infections were introduced in the late 2000s offering vaccination to girls aged 12–13 years old, but it will be several years before any decrease in incidence of cervical cancer is likely to be observed.


Cervical intraepithelial neoplasia


This is a histological diagnosis, usually made from colposcopic-directed biopsy, of changes in the squamous epithelium characterized by varying degrees of loss of differentiation and stratification and nuclear atypia ( Fig. 20.12 ). It may extend up to 5 mm below the surface of the cervix by involvement of crypt epithelium in the transformation zone, but does not extend beyond the basement membrane. The aetiology is the same as that of invasive disease but with a peak incidence 10 years earlier. In the UK CIN is graded as mild (CIN-1), moderate (CIN-2) or severe (CIN-3) depending on the proportion of the epithelium replaced by abnormal cells. Twenty-five per cent of CIN 1 will progress to higher grade lesions over 2 years, and 30–40% of CIN-3 to carcinoma over 20 years. Around 40% of low-grade lesions (CIN-1) will regress to normal within 6 months without treatment especially in the younger age group.




Fig. 20.12


Histological appearance of CIN-3.


Cervical glandular intraepithelial neoplasia is the equivalent change occurring in the columnar epithelium and is associated with the development of adenocarcinoma of the cervix. Two-thirds of cases coexist with CIN. Cervical cytology cannot be used reliably to detect adenocarcinoma of the cervix or CGIN and screening has had no impact on its incidence.


Treatment


Low-grade CIN can be managed by cytological and colposcopic surveillance at 6 monthly intervals as progress to invasive disease does not occur within 6 months, or it can be treated as for higher grade lesions (see below).


Higher grade lesions (CIN-2 and 3 and dyskaryotic glandular cells) are an indication for immediate treatment either by excision or destruction of the affected area (usually the whole of the transformation zone).


Destructive therapies include LASER ablation, cryocautery and coagulation diathermy. Ablative techniques are only suitable when the entire transformation zone can be visualized, there is no evidence of glandular abnormality or invasive disease, and there is no major discrepancy between the cytology and histology results. Excision can be carried out using scalpel, LASER or using a diathermy loop wire (large loop excision of the transformation zone, LLETZ; Fig. 20.13 ). LASER and LLETZ can be carried out under local anaesthetic. Ectocervical lesions can be adequately treated by removing tissue to a depth greater than 7 mm. When the SCJ cannot be seen or a lesion of the glandular epithelium is suspected, a deeper ‘cone’ biopsy is required to ensure that all of the endocervix is sampled ( Fig. 20.14 ). Patients are advised to abstain from intercourse and not to use tampons for 4 weeks after treatment to reduce the risk of infection. Hysterectomy is rarely indicated for treatment of CIN but may be used if indicated for another reason such as heavy periods.


Mar 2, 2019 | Posted by in OBSTETRICS | Comments Off on Gynaecological oncology
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