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The waiting game

Gynaecological cancers: endometrial cancer, ovarian lesions and HPV vaccination

Consultant gynaecologist Mr Martin Lamb and associate colposcopy specialist Dr Beth Devonald answer questions from GP Dr Pam Brown

Consultant gynaecologist Mr Martin Lamb and associate colposcopy specialist Dr Beth Devonald answer questions from GP Dr Pam Brown

1 Is human papilloma virus (HPV) infection implicated in the aetiology of all cervical cancers?

Yes. HPV has been isolated in 99.7% of cervical cancers and probably exists in the rest, but has not been detected. HPV exists in more than 100 different types and only some of them are linked with cancer. There are about 12 of the so-called highly oncogenic types, which include HPV 16, HPV 18, HPV 31, HPV 33, HPV 35 and HPV 45. About 70% of all cervical cancers are caused by HPV 16 and 18.

The majority of sexually active women will come into contact with high-risk HPV types. In most, their body's immune system will get rid of the infection without them ever knowing it was there. Only a minority who are positive for high-risk HPV types will develop cervical abnormalities (CIN) that could develop into cervical cancer if left untreated.

2 If an HPV vaccination programme is implemented in the UK, how would this affect the national cervical cytology screening programme? How many women spontaneously clear oncogenic HPV and over what time period?

It will be many years before there is any noticeable effect on cervical screening. The aim of screening is to detect a premalignant change that can be treated and prevent cancer. This is often detected in women in their 30s, although it does occur in younger women.

Cancer of the cervix is most common in women over 50 but the age at which it occurs does seem to be coming down. Many women who are already sexually active will have had contact with HPV 16 and 18 so the screening programme will need to continue for them. The intention is to vaccinate girls aged 10 to 12 before they are sexually active. It will take some years before they reach the age when abnormal smears might be expected.

It is hoped the vaccination will prevent 75% of all CIN. Eventually this may mean that the detection rate of smears will become so low that it is no longer cost-effective. It may also be that patients fail to attend for screening as they no longer perceive themselves to be at risk.Many women spontaneously clear HPV, especially younger women. It is not known over what period this occurs.

Women over 30 who show highly oncogenic HPV are less likely to clear it spontaneously. There are obviously many factors associated with immune status, but we do not fully understand these.

3 What is the role of smoking in the development of carcinoma of the cervix? Should all women with CIN lesions be encouraged to stop?

The development of cervical cancer is linked to many factors, including the age sexual activity started, the number of partners and whether barrier contraception is used. Smoking has been implicated in several studies. A recent article showed women who smoked and had a high HPV 16 load during their first examination had a 27-fold increased risk of later cancer compared with women who smoked but did not have an HPV infection1.

Women who were positive for HPV 16 (irrespective of amount of viral load) and were smokers had a 14-fold increased risk over women who were HPV 16 negative and smoked. Non-smoking women with high HPV 16 loads had just a six-fold risk compared with HPV-negative non-smokers.

The explanation for this interaction is probably localised immune suppression. It could be related to the progression of neoplastic growth, since HPV and smoking appear to alter the levels of cytokines involved in controlling abnormal cell growth. Cancer-causing chemicals from tobacco smoke have been found in the cervix. Smokers are twice as likely as non-smokers to develop CIN. If a woman is treated for CIN3, it is three times as likely to recur if she continues to smoke. So, yes, all women should be encouraged to stop smoking.

4 What should we tell women with different grades of CIN lesions about their risk of developing cervical cancer and how this is affected by treatment options?

High-grade cervical intra-epithelial neoplasia (CIN2 and CIN3) is strongly linked with cervical cancer. It would not be ethical to leave them untreated, but we believe the majority of the lesions would progress if not treated. This progression is variable – on average it probably takes five to 15 years. Some lesions may develop rapidly, especially in the very young.

Conversely, some may progress so slowly that they never develop into cancer. Some very small lesions may resolve spontaneously, especially in younger women, which is one of the reasons for delaying the start of the NHS cervical screening programme.

Treatment aims to remove all abnormal tissue on the cervix. There are many methods. The most common is loop excision of transformation zone (LETZ) under local anaesthetic in the colposcopy clinic. It takes about 15 minutes. Occasionally a cone biopsy is necessary and this usually requires a general anaesthetic. It usually means removing a deeper biopsy for a lesion extending up into the endocervical canal.

If all the abnormal tissue has been treated, the risk of recurrence is low, but the NHS cervical screening programme advises close follow-up for 10 years. This can usually be done in primary care. As long as women have cervical smears, the disease should be detected when it is only a premalignant condition and can be treated before it develops into cancer.

5 Which women with intermenstrual bleeding need investigation with endometrial sampling or measurement of endometrial thickness?

Ovarian dysfunction is the most likely cause of abnormal bleeding in women pre-menopausally, but pelvic pathology is also common. The likelihood of finding particular pathology would depend on the bleeding disturbance. In one study, out of 500 perimenopausal women attending a clinic only nine (1.8%) had intermenstrual bleeding.

Of these, two had endometrial hyperplasia and four a malignancy. Intermenstrual bleeding with or without postcoital bleeding is usually associated with surface pathology; endometrial disease (polyps, fibroids, endometritis and cancer); and cervical disease (polyps, cervicitis, ectropion and carcinoma).

Intermenstrual bleeding in younger women can be managed expectantly unless symptoms are persistent. Inherent irregularity and variation in menses in peri-menopausal women makes detection more difficult unless a high index of suspicion is maintained. Endometrial sampling and measurement of endometrial thickness is mandatory in perimenopausal women with intermenstrual bleeding but only necessary in younger women when symptoms are persistent.

6 Is it possible to quantify the increased risk of endometrial cancer in women using long-term (more than five years) cyclical HRT and topical oestrogens, and how can we reduce those risks?

There is no evidence that cyclical combined HRT increases the risk of endometrial cancer and in fact the contrary appears to be true as the addition of progestogens reduces the risk over the expected incidence of the disease.

The use of unopposed oestrogen does increase the risk of endometrial cancer from the natural incidence of 0.07% to 0.2%, a threefold increase. Studies have clearly shown that adding progestogen to oestrogen is protective. A recent paper revealed no evidence of an increase in endometrial hyperplasia or carcinoma risk2.

There is no evidence that topical oestrogen used in recommended doses and timescales increases the risk of endometrial cancer. Local oestrogen used with intermittent courses and a maintenance dose of once or twice weekly leads to very little systemic absorption and risk. Women who suffer the side-effects of the progestogen element of HRT can be treated with oestrogen and a levonorgestrel intrauterine system to protect the endometrium.

7 What percentage of women with lichen sclerosus develop vulval cancer and do any management options decrease this risk?

The risk of women with lichen sclerosus et atrophicus developing vulval cancer is between 4 and 6%, but over many years. Cancers can arise in asymptomatic cases and it is not known whether treatment can affect this incidence or modify the risk.

Awareness of changes in the vulva and change of symptoms, in particular the formation of hyperkeratotic plaques or erosions that do not respond to treatment, should arouse suspicion. Biopsy is indicated. There is no indication for surgery and simple steroid application to control symptoms does not appear to increase or decrease the risk of developing cancer.

Follow-up after diagnosis is recommended six-monthly or annually, but because of the long-term potential risk of disease this becomes impractical, so patient information leaflets and self-help are very important. Most gynaecology departments that deal with vulval pathology can provide such a leaflet to patients who then know what changes to report to their doctor.

8 Apart from lower abdominal bloating, are there other high-risk symptoms that should indicate pelvic and abdominal examination to identify ovarian lesions?

Ovarian cancer is rare under the age of 30 and most common in the sixth or seventh decade. Some 80% of ovarian cancers occur after the age of 50. Unfortunately most present with advanced disease and symptoms in that situation are due to enlarging pelvic mass and/or widespread dissemination throughout the peritoneal cavity or beyond. Ovarian malignancies are frequently asymptomatic in their early stage. The usual symptoms of pain, discomfort, abdominal swelling, abnormal uterine bleeding, gastrointestinal and urinary symptoms unfortunately appear late.

As one of the most important factors in prognosis is the stage of disease at diagnosis, any suspicious symptoms must be investigated. Vague abdominal discomfort, dyspepsia, increasing flatulence, bloating (particularly after ingesting food), mild digestive disturbances and vague pelvic symptoms may present several months before diagnosis. It is imperative to rule out ovarian cancer in a woman over 40 who presents with persistent gastrointestinal symptoms that cannot be definitely diagnosed.

9 What is the role of biochemical markers in the triage of women with pelvic masses/ovarian cysts? Should women with previous breast cancer or a strong family history of ovarian cancer be offered ultrasound or biochemical marker screening, and if so how often?

Biochemical markers are only useful taken in conjunction with the type of pelvic mass and the age of the patient. CA125 is the only readily available and accepted marker. A risk of malignancy index (RMI) can be calculated and is a combination of the menopausal state, ultrasound features and CA125 level.

It is important in women with suspected ovarian cancer that the carcinoembryonic antigen (CEA) test is done as ovarian masses can of course be secondary to bowel cancer. Hereditary ovarian cancer accounts for about 10% of ovarian carcinomas. The major risk group is those belonging to the breast/ovarian carcinoma (BRCA1 and 2) and hereditary non-polyposis colon cancer families.

A woman who has one first-degree relative with ovarian cancer has a 5% lifetime risk of developing the disease (the general population risk is 1.8%). With one first-degree and one second-degree relative, this increases to 7%, and with two first-degree relatives it can be as high as 50% – and it is in these patients that the gene mutation is most likely.

It is important to take a detailed family history of at least three generations. Ovarian cancer at a young age is more likely to be hereditary ovarian cancer. Screening should be reserved for those with high-risk family history and, as there is no accepted screening programme for ovarian cancer yet, screened women should be entered into trials such as the UK Family Ovarian Screening Study where patients have annual ultrasound and CA125 tests.

10 How dangerous is prolonged amenorrhoea in younger women with polycystic ovary syndrome (PCOS)? How should they be managed?

In PCOS amenorrhoea is secondary to acyclical ovarian activity and continuous oestrogen production. In one study 37% of women at an endocrine clinic with PCOS were amenorrhoeic. Serum prolactin is often raised and it is therefore important to exclude a pituitary cause.

Prolonged amenorrhoea in these women leads to long-term metabolic and physical consequences. There is a definite risk of endometrial hyperplasia and adenocarcinoma because of the continuous oestrogen stimulation to the endometrium. If on resumption of menses there is a history of intermenstrual bleeding or if an ultrasound shows postmenstrual endometrial thickness of greater than 10mm, an endometrial biopsy is indicated.

Mr Martin Lamb is consultant gynaecologist at Lincoln County Hospital
Dr Beth Devonald is associate specialist in colposcopy in Lincoln

Competing interests None declared

Take-home points

• Most women will clear high-risk HPV infection without ever knowing it was there: a minority will develop cervical abnormalities (CIN).
• Women who smoked and had a high HPV 16 load during their first examination had a 27-fold increased risk of later cancer.
• After CIN2/3 close follow-up is needed for the next 10 years.
• Intermenstrual bleeding in younger women only needs investigation when symptoms persist.
• In PCOS, if an ultrasound postmenstrual endometrial thickness of greater than 10mm is seen, an endometrial biopsy is indicated.
• There is no evidence that topical oestrogen in recommended doses and timescales increases the risk of endometrial cancer.
• In lichen sclerosus, simple steroid application to control symptoms does not appear to increase or decrease the already increased risk of developing cancer.
• It is imperative to rule out ovarian cancer in a woman over 40 with persistent unexplained GI symptoms.
• A woman with one first-degree relative with ovarian cancer has a 5% lifetime risk of developing the disease. Screening should be reserved for those with high-risk family history.

What I will do now

Dr Brown responds to the answers to her questions:
• This reinforces my current practice of actively encouraging women with CIN lesions to stop smoking. I will also remind younger patients of the greatly increased cervical cancer risks associated with smoking and HPV.
• Many of my patients with lichen sclerosus default from follow-up. I will source a patient information leaflet from our local vulval clinic and encourage self-monitoring.
• I will be more comfortable observing young women with intermenstrual bleeding instead of referring so many for further investigation. • Although I have a low threshold for referring women over 50 with bloating for an ultrasound scan, I had not realised that persistence of other gastroenterological symptoms might also be associated with ovarian cancer and should prompt further examination and investigation.
• I have previously recommended treatment with twice-yearly oral progestogen in women using long-term topical vaginal oestrogens to prevent endometrial hyperplasia, but it seems this is not necessary.

Dr Pam Brown is a GP in Swansea

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