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.

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.

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).

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

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.

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).

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

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.

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.

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).

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.

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.

Complications of cone biopsy

The commonest complication is haemorrhage. This may be primary, i.e. within 12 hours of operation, or secondary, usually between 5 days and 12 days after the operation. Haemorrhage may be profuse but can be controlled by compression with vaginal packing, cauterization or resuturing the cervix. Secondary haemorrhage is commonly associated with infection and the management therefore includes blood transfusion and antibiotic therapy.

Later complications include cervical stenosis with dysmenorrhoea and haematometra. Cone or LLETZ biopsy may also cause cervical incompetence and subsequent second trimester miscarriage, preterm labour or premature preterm rupture of membranes.

Follow-up

Approximately 5% of women will have persistent or recurrent disease following treatment. Cervical cytology is used to carry out follow-up. In the UK those who have treatment for CIN-2 or III or glandular intraepithelial neoplasia (GIN) should have cervical smears at 6 and 12 months after treatment and then annually for the subsequent 9 years before returning to the normal 3-yearly screening programme. Patients in Australia can return to normal testing once they have had normal cytology and negative tests for high-risk HPV on two successive occasions a year apart. If the high-grade lesion persists during the follow-up a further excisional treatment is warranted. Those having treatment for low-grade disease require cytology follow up after 6, 12 and 24 months before returning to the routine screening programme. If the low-grade lesion persists within 2 years after the first colposcopy referral, at least a biopsy is required.

Cervical cancer

Cervical cancer is the second commonest female cancer worldwide. In many countries this is the most common cause of death from cancer in women. In the UK the annual incidence in 2007 was 9.1/100 000 women with 2276 new cases in 2007 and 759 deaths in 2008. Cervical cancer has a direct relationship to sexual activity. Associated risk factors are early age of first intercourse, number of partners, smoking, low socioeconomic status, infection with HPV and immunosuppression.

In contrast to other gynaecological cancers, cervical cancer affects young women, with a peak incidence at 35–39 years.

Pathology

There are two types of invasive carcinoma of the cervix. Approximately 70–80% of lesions are squamous cell carcinoma and 20–30% adenocarcinomas. Histologically, the degree of invasion determines the stage of the disease (Table 20.4).

Table 20.4

FIGO classification of cervical cancer (2009)

Stage I

Carcinoma is strictly confined to the cervix (extension to the corpus would be disregarded): Stage IA: Invasive carcinoma that can be diagnosed only by microscopy, with deepest invasion ≤5 mm and largest extension ≤7 mm Stage IA1: Measured stromal invasion of ≤3.0 mm in depth and extension of ≤7.0 mm Stage IA2: Measured stromal invasion of >3.0 mm and not >5.0 mm with an extension of not >7.0 mm Stage IB: Clinically visible lesions limited to the cervix uteri or preclinical cancers greater than IA* Stage IB1: Clinically visible lesion ≤4.0 cm in greatest dimension Stage IB2: Clinically visible lesion >4.0 cm in greatest dimension

Stage II Cervical carcinoma invades beyond the uterus, but not to the pelvic wall or to the lower third of the vagina:

Stage IIA: Without parametrial invasion

Stage IIA1: Clinically visible lesion ≤4.0 cm in greatest dimension

Stage IIA2: Clinically visible lesion >4.0 cm in greatest dimension

Stage IIB: With obvious parametrial invasion

Stage III The tumour extends to the pelvic wall and/or involves lower third of the vagina and/or causes hydronephrosis or non-functioning kidney:**

Stage IV The carcinoma has extended beyond the true pelvis or has involved (biopsy proven) the mucosa of the bladder or rectum. A bullous oedema, as such, does not permit a case to be allotted to stage IV:

Surgery – radical hysterectomy and pelvic lymph node dissection

Radical hysterectomy (Fig. 20.15) includes removal of the uterus, parametrium, and the upper third of the vagina. The ovaries may be conserved. This method of treatment, together with internal and external iliac and obturator lymph node dissection, is appropriate for patients with stage IB1 and early stage IIA1 diseases. Complications include haemorrhage, infection, pelvic haematomas, lymphocyst/lymphoedema, bladder dysfunction and damage to the ureters or bladder, which may result in fistula formation in 2–5% of cases. However, the incidence of vaginal stenosis is less than after radiotherapy, and so coital function is better preserved, making it the treatment of choice in the younger woman. Radical trachelectomy with pelvic lymph node dissection and prophylactic cervical cerclage can be considered in small stage IB1 tumour (less than 2 cm) if preservation of fertility is wished.

Radiotherapy/Chemoradiation

This is to treat other stages of cervical cancer and those patients with bulky stage IB disease or who are unfit for surgery. Survival stage-for-stage in early forms of the disease is similar to that for surgery. Adjuvant chemoradiotherapy is also used for those patients who have been found to have lymph node involvement at the time of surgery.

Chemotherapy is platinum based and given weekly in conjunction with radiotherapy.

Radiotherapy is administered by local insertion of a source of radium, caesium or cobalt-60 into the uterine cavity and the vaginal vault and external beam radiation to the pelvic side wall. Complications include the effects of excessive radiation on normal tissues, and may lead to radiation cystitis or proctitis, as well as fistula formation and vaginal stenosis.

Symptoms

The commonest symptom is postmenopausal bleeding. However, in the premenopausal woman, endometrial carcinoma is associated with irregular vaginal bleeding and increasingly heavy menses. Endometrial cancer should also be suspected in elderly patients with pyometra. These women usually present with purulent vaginal discharge.

Pathology

Endometrial carcinoma can be divided into two types. Type I refers to endometrioid adenocarcinoma. This type is related to the hyperoestrogenic state and hence all the risk factors associated with hyperoestrogenism, such as obesity, diabetes, unopposed oestrogen, etc. Type II represents other histological types, such as serous papillary and clear cell subtypes. These tend to be aggressive tumours with poorer prognosis.

Most endometrial cancer is endometrioid (type I) cancer. The microscopic appearances include changes in the architecture with the development of closely packed polyhedral cells with dark-staining nuclei and considerable numbers of mitoses.

Endometrial cancer grows locally (Fig. 20.16). The tumour spreads by direct invasion into the myometrium and then transcervically, transtubally and by spillage of carcinomatous material. There can also be lymphatic spread to the pelvic and para-aortic nodes

Investigations

Initial investigations include a transvaginal ultrasound scan to assess the endometrial thickness and an endometrial aspirate to obtain endometrial tissue for histological assessment. An endometrial thickness of less than 5 mm on transvaginal ultrasound in a postmenopausal woman indicates a very low risk of endometrial cancer. However, using endometrial thickness is less reliable in a pre- or perimenopausal women because the endometrial thickness varies with the menstrual cycle. In women over 40 years old who have abnormal vaginal bleeding, an endometrial aspirate should be the first line investigation to assess the endometrium. Endometrial aspirate can be done with various endometrial samplers such as the Pipelle sampler. The Pipelle is a transparent plastic cannula with a very small diameter, e.g. 3 mm that can be passed through the cervical os without dilation and can be done in the office without anaesthesia. However, if the endometrial aspirate is unsuccessful or inconclusive or symptoms persist despite a negative endometrial aspirate result, a diagnostic hysteroscopy and biopsy is required. This can be carried out as an outpatient procedure or under general anaesthesia. During a diagnostic hysteroscopy, a hysteroscope, which is a narrow rigid telescope, is passed through the cervical os and the uterine cavity is distended by either gas or fluid. This allows direct visualization of the uterine cavity and directed biopsies of any endometrial lesions can be taken. The risk of this procedure is small but complications can occur such as uterine perforation, cervical laceration, pelvic infection and reaction to distension media. The diagnosis of endometrial cancer is established histologically by endometrial biopsy result.

Treatment

The mainstay of treatment is total hysterectomy and bilateral salpingo-oophorectomy. The value of routine pelvic and para-aortic lymphadenectomy for all patients is controversial. Preoperative investigations include full blood count, renal and liver function test, a chest X-Ray as well as any additional investigations depending on individual health status such as ECG, blood sugar levels, etc. Cancer (or carbohydrate) antigen 125 (CA-125) may be raised in advanced disease and a preoperative baseline value can be useful for subsequent disease monitoring. Risk of extrauterine disease can be assessed preoperatively. These include high-grade lesions, unfavourable histological subtypes, e.g. serous or clear cell histology, tumour size and depth of myometrial invasion. The grading and histological subtypes can be assessed by endometrial biopsy. The tumour size and myometrial invasion can be assessed by preoperative imaging such as ultrasound, CT or MRI. Currently, MRI is the most widely used technique. It helps to assess myometrial invasion, cervical invasion and lymph node involvement. Nonetheless, MRI has limited accuracy and may not be cost-effective for all patients. Total hysterectomy can be done by open laparotomy, laparoscopically or vaginally. Patients should be individually assessed to determine the best route.

Adjuvant radiotherapy is often given to patients with high risk of recurrence. Vaginal brachytherapy can reduce local vault recurrence. Although this has not been shown to improve long-term survival in these patients, it does reduce the risk of vaginal and pelvic recurrence. Patients with advanced disease are treated by debulking the tumour followed by chemotherapy with or without radiotherapy. Cytotoxic drugs such as carboplatin and doxorubicin are used in the treatment of recurrent disease but response rates are low (20%).

Prognosis

Endometrial cancer is surgically staged (Table 20.5). Prognosis largely depends on the stage of the disease as well as other prognostic factors that include age, histological subtype and grading. For stage I grade A, the 5-year survival can be over 90% for those with superficial myometrial invasion, but for those with deep myometrial invasion and grade III disease, the 5-year survival is only about 60% even if the disease is still confined to the uterus. For stage II, III and IV diseases, the 5-year survival is about 70–80%, 40–50% and 20%, respectively. Serous papillary and clear cell carcinomas have poorer prognosis, with 5-year survival rates of 50% and 35%, respectively.

Stage II* Tumour invades cervical stroma, but does not extend beyond the uterus** Stage III* Local and/or regional spread of the tumour:

Stage IV* Tumour invades bladder and/or bowel mucosa, and/or distant metastases:

Stromal sarcomas

These tumours, arising from the stroma of the endometrium, account for 15% of uterine sarcomas. They tend to present in a younger age group (45–50 years) than other uterine tumours with vaginal discharge and bleeding. Endometrial stromal sarcoma is found in association with adenomyosis and endometriosis. It can be classified as low or high grade, depending on the number of mitotic figures and similarity to the non-glandular elements of the endometrium. Malignant mixed mesodermal sarcomas contain elements of both smooth muscle and stroma.

Mixed müllerian tumours (carcinosarcomas)

These tumours (Fig. 20.17) consist of both epithelial and mesenchymal elements. The epithelial elements are usually endometrioid but can be squamous or a mixture. The stromal elements are either heterologous (chondroblastoma, osteosarcoma, fibrosarcoma) or homologous (leiomyosarcoma, presarcoma). The mean age at presentation is 65 years. An enlarged, irregular uterus with tumour protruding through the cervical os is a common finding at examination. Extrauterine spread occurs early and only 25% of patients have disease limited to the endometrium at the time of diagnosis.

Leiomyosarcoma

These smooth muscle tumours arise in the myometrium of the uterus and account for only 1.3% of uterine malignancies. They are uncommon (0.7/100 000), with a peak incidence at the age of 52 years, about 10 years later than the peak incidence for fibroids. Between 5% and 10% arise in existing fibroids, although the risk of malignant change occurring in a fibroid is small (0.3–0.8%). Leiomyosarcomas are classified according to the degree of differentiation. They may present with pain, postmenopausal bleeding or a rapidly growing ‘fibroid’, but are often asymptomatic and diagnosed following hysterectomy for fibroids. Treatment is by hysterectomy and bilateral salpingo-oophorectomy. Adjuvant radiotherapy and chemotherapy reduces the risk of local recurrence but does not improve long-term survival.

Treatment

This is by hysterectomy, with removal of as much macroscopic disease as possible, followed by radiotherapy. Prognosis for low-grade stromal sarcomas is similar to that for endometrioid tumours, but poor for others, with a 20–40% 5-year survival.

Symptoms

Tumours of the ovary that are less than 10 cm in diameter rarely produce symptoms. The common presenting symptoms include:

Signs

On examination, the abdomen may be visibly enlarged. Percussion over the swelling will demonstrate central dullness and resonance in the flanks. These signs may be obscured by gross ascites. Small tumours can be detected on pelvic examination and will be found by palpation in one or both fornices. However, as the tumour enlarges, it assumes a more central position and, in the case of dermoid cysts, is often anterior to the uterus. Most ovarian tumours are not tender to palpation; if they are painful the presence of infection or torsion should be suspected. Benign ovarian tumours are palpable separately from the uterine body and are usually freely mobile.

Follicular cysts

Follicular cysts (Fig. 20.19) are the commonest functional cysts in the ovary and may be multiple and bilateral. The cysts rarely exceed 4 cm in diameter, the walls consisting of layers of granulosa cells and the contents of clear fluid, which is rich in sex steroids. These cysts commonly occur during treatment with clomiphene or human menopausal gonadotrophin (Fig. 20.20). They may produce prolonged unopposed oestrogen effects on the endometrium, resulting in cystic glandular hyperplasia of the endometrium.

Management

These cysts regress spontaneously but if they have not involuted after 60 days the diagnosis should be revised. The size and growth of the cysts can be monitored by ultrasound scans.

The prolonged and heavy menstrual loss caused by unopposed oestrogen action can be offset by the administration of a progestogen for 1 week followed by ‘medical curettage’, or through surgical intervention by cervical dilatation and uterine curettage.

Lutein cysts

There are two types of luteinized ovarian cyst:

Benign neoplastic cysts

These tumours may be cystic or solid and arise from specific cell lines in the ovary. The full World Health Organization classification of ovarian tumours illustrates the complexity of tumours arising from the ovary; only the commoner ones will be discussed in this section.

Epithelial tumours

Serous cystadenomas

These cysts, in conjunction with mucinous cystadenomas, form the commonest group of cystic ovarian tumours. The cysts may be unilocular, lined by a layer of cuboidal epithelium, or multilocular with papillary growths extending from both internal and external surfaces of the tumour. It is often difficult to differentiate between benign and malignant appearances. The wall of the tumour sometimes contains calcified granules known as psammoma bodies. The growths may be bilateral and may be large enough to fill the peritoneal cavity.

The tumours often replace all normal ovarian tissue; if this is the case, the whole ovary should be removed. If the tumour is small, it may be possible to perform a local resection and to conserve ovarian tissue. If both ovaries are extensively involved or there is reason to believe that the tumours are malignant, it is better to perform bilateral oophorectomy and hysterectomy.

Mucinous cystadenomas

These tumours are multilocular and often reach enormous dimensions, with tumours weighing in excess of 100 kg recorded in the literature. The fluid content consists of mucin, and the epithelium lining the cysts presents a characteristic appearance of a secretory epithelium of tall columnar cells with a pseudostratified appearance. This appearance is similar to the epithelium lining the endocervix. The demarcation between epithelial cells and stroma is sharply defined. There is little tendency to form papillae. These tumours are less likely to become malignant than the serous variety.

The only treatment is to remove the tumour surgically.

Care should be taken to avoid rupture of the cysts because mucinous epithelium may implant in the peritoneal cavity, giving rise to a condition known as pseudomyxoma peritonei. Huge amounts of gelatinous material may accumulate in the peritoneal cavity.

Brenner cell tumours

Brenner cell tumours are commonly solid and occur in women after the age of 50 years. They are only rarely malignant. The histological features of these tumours include nests of epithelial cells surrounded by fibromatous connective tissue groundwork.

The cut surface of the tumour is similar to that of an ovarian fibroma apart from a rather yellowish tinge. The tumours are occasionally bilateral and can be safely treated by local excision.

Sex cord stromal tumours

Hormone-secreting tumours of the ovary are a small but important group.

Granulosa cell tumours

Arising from ovarian granulosa cells, these tumours (Fig. 20.21) produce oestrogens and constitute some 3% of all solid ovarian tumours. Approximately 25% exhibit the characteristics of malignancy. As granulosa cell tumours can present at any age, the symptoms depend on the age of occurrence. Tumours arising before puberty produce precocious sexual development, and in women of the reproductive age, prolonged oestrogen stimulation results in cystic glandular hyperplasia and irregular and prolonged vaginal bleeding. Around 50% of cases occur after the menopause and present with postmenopausal bleeding. If the tumour is histologically benign, the surgery should be limited to oophorectomy. If there is evidence of malignancy, pelvic clearance is indicated.

Thecomas or theca cell tumours arise from the spindle-shaped thecal cells, but are often mixed with granulosa cells and are oestrogen secreting. The presence of a thecoma in one ovary is commonly associated with diffuse thecomatosis in the contralateral ovary.

Arrhenoblastomas or androblastomas

These are tumours of Sertoli–Leydig cells. They are rare androgen-secreting tumours that occur most frequently in the decade between 20 and 30 years of age. The clinical manifestations include the onset of amenorrhoea, loss of breast tissue, increasing facial and body hirsutism, deepening of the voice and enlargement of the clitoris. The diagnosis is established by the exclusion of virilizing adrenal tumours and the identification of a tumour in one ovary. The condition is treated by excision of the affected ovary. Approximately 25% of these tumours are malignant.

Germ cell tumours

Tumours of germ cell origin may replicate stages resembling the early embryo.

Mature cystic teratoma (dermoid cyst)

Benign cystic teratomas account for 12–15% of true ovarian neoplasms. They contain a large number of embryonic elements such as skin, hair, adipose and muscle tissue, bone, teeth and cartilage (Fig. 20.22). Some of the components can be recognized on radiography.

These tumours are often chance findings as they are commonly asymptomatic unless they undergo torsion or rupture, when the release of sebaceous material causes an acute chemical peritonitis. Dermoid cysts tend to be anterior to the uterus. They are bilateral in 12% of cases, and, although usually benign, become malignant in approximately 2%. Some specialized elements in these tumours become predominant. The growth of thyroid tissue (struma ovarii) may induce a state of hyperthyroidism.

These cysts should be excised from the ovary with conservation of ovarian tissue. They are frequently bilateral and it is important to examine both ovaries before proceeding to surgical excision.

Dermoid cysts are the commonest solid ovarian neoplasm found in young women.

Fibromas

These solid tumours of the ovary are rare. They may be associated with the presence of ascites or hydrothorax – a condition known as Meigs’ syndrome.

Tumour-like conditions

This group includes endometriotic cysts, pregnancy luteomas and germinal cell cysts. The treatment depends on the nature of the tumour and normally involves simple excision of the cysts.

Endometriotic cysts

Endometriomas contain chocolate-coloured fluid representing the accumulation of altered blood, and have a thick fibrous capsule (see Fig. 16. 13). The lining may consist of endometrial cells but in old cysts these may disappear. Management is discussed below.

Aetiology

Although the cause of ovarian cancer remains unknown, there are well defined risk factors.

Genetic

About 1% of cases of ovarian cancer occur in women whose families show an autosomal dominant pattern of inheritance of breast and ovarian cancer. Female members of these families have a 40% lifetime risk of developing the disease. Many of these women have been shown to have defects in the BRCA1or BRCA2 genes

Parity and fertility

Multiparous women are at 40% less risk than nulliparous women of developing ovarian cancer, whereas women who have had unsuccessful treatment for infertility seem to be at increased risk. The use of the contraceptive pill may produce up to a 60% reduction in the incidence of the disease

Pathology

Primary ovarian carcinoma

The distribution of histological types of ovarian cancers is as follows.

Epithelial type

This makes up 85% of cases of ovarian malignancy. Epithelial tumours include the following subtypes:

• Serous cystadenocarcinoma is the most common histological type of ovarian carcinoma (40%) and is usually unilocular. They may be bilateral. These tumours are more likely to contain solid areas than their benign counterparts.

• Mucinous cystadenocarcinomas: These multicystic tumours (Fig. 20.23) are characterized by mucin-filled cysts lined by columnar glandular cells, and may be associated with tumours of the appendix.

• Endometrioid cystadenocarcinomas resemble endometrial adenocarcinomas and are associated with uterine carcinomas in 20% of cases.

• Clear-cell cystadenocarcinoma is the most common ovarian malignancy found in association with ovarian endometriosis. The unilocular thin-walled cysts are lined by epithelium with a typical hobnail appearance and clear cytoplasm.

• Brenner or transitional cell cystadenocarcinoma is often found in association with mucinous tumours but has a better prognosis than similar tumours arising from the bladder.

Tumours of low malignant or borderline potential account for 10–15% of primary epithelial carcinomas. They are commonly serous or mucinous tumours. There are cytological changes of malignancy including cellular atypia with increased mitosis and multilayering but without invasion. They have a significantly better prognosis than invasive disease, with a 5-year survival of more than 95% for stage I lesions but there is a 10–15% incidence of late recurrence.

Sex cord stromal tumours

These tumours are relatively rare as they make up only 6% of primary ovarian cancers.

• Granulosa cell tumours: These solid, unilateral, haemorrhagic tumours are the most common oestrogen-secreting lesions. They are characterized histologically by the presence of Call–Exner bodies.

• Sertoli–Leydig cell tumours: Approximately 25% of these are malignant, and may present with signs and symptoms of androgen excess.

Germ cell tumours

• Dysgerminomas: These solid tumours may be small or large enough to fill the abdominal cavity. The cut surface of the tumour has a greyish-pink colour and the microscopically, the tumour consists of large polygonal cells arranged in alveoli or nests separated by septa of fibrous tissue.

• Teratomas: The malignant or immature form of teratoma is most commonly solid, unilateral and heterogenous with multiple tissue elements. These tumours may produce human chorionic gonadotrophin, alpha-fetoprotein or thyroxine.

• Endodermal sinus or yolk sac tumours. Although these tumours make up only 10–15% of germ cell tumours, they are the most common germ cell tumour in children. They are solid, encapsulated tumours containing microcysts lined by flat mesothelial cells.

Secondary ovarian carcinomas

The ovaries are a common site for secondary deposits from primary malignancies in the breast, genital tract, gastrointestinal system and haematopoietic system.

Krukenberg’s tumours are metastatic deposits from the gastrointestinal system. They are solid growths that are almost always bilateral. The stroma is often richly cellular and may appear to be myomatous. The epithelial elements occur as clusters of well-marked acini with cells exhibiting mucoid change, known as signet ring cells.

Staging of ovarian carcinoma

Spread of primary ovarian tumours can be by direct extension, lymphatics or via the bloodstream. Staging of ovarian carcinoma (Table 20.6) is important in determining both prognosis and the management. Ideally, it should be staged at the time of laparotomy with inspection and biopsy of the peritoneum and diaphragm, cytological examination of peritoneal fluid and pelvic and para-aortic lymph nodes dissection.

Stage II Growth involving one or both ovaries with pelvic extension:

Chemotherapy

Patients with high risk for recurrence, e.g. those with high grade, poor histological subtypes or stage IC or above, are often given adjuvant chemotherapy. The platinum-based drugs cisplatin and carboplatin are currently the mainstay of treatment. The main side effects are marrow suppression, neurotoxicity and renal toxicity. Carboplatin has now largely replaced cisplatin due to its better side effect profile and it is often combined with paclitaxel, another active agent for ovarian cancer. The overall response rate is up to 80%

Borderline tumours

These can be treated by unilateral oophorectomy in young women wishing to preserve their reproductive capacity, although careful, long-term follow-up is required.

Germ cell tumours

These are more common in young women, and chemotherapy may be curative without hysterectomy.

Follow-up and treatment of recurrence

Patients are followed up for any symptoms such as abdominal discomfort, tumour markers and clinical examination. Imaging can be arranged if there is suspicion of recurrence. Chemotherapy is the main-stay of treatment for recurrence. Debulking of the tumour may be feasible if it is localized and there is a long time interval to recurrence. In platinum-sensitive patients, i.e. those that recur after at least 12 months from completion of primary treatment, rechallenge with first-line chemotherapy (carboplatin and paclitaxel) is recommended. Otherwise, there are wide ranges of second-line chemotherapy agents such as liposomal doxorubicin, gemcitabine, etc. but their response rates are only about 20–30%.