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POST-COITAL BLEEDING IS DUE TO MALIGNANCY UNTIL PROVEN OTHERWISE

There are now two cancers that the human race has succeeded in producing effective vaccines against: hepatocellular carcinoma (caused by hepatitis B virus) and more recently cervical cancer (caused by HPV). Hooray! However, the parental controversy surrounding the HPV vaccine and its reduced efficacy in older, sexually active women already exposed to the virus mean that cervical cancer is something we can unfortunately still expect to encounter for many years to come.

Cervical cancer typically presents with post-coital and/or intermenstrual bleeding, so I’ve provided a differential diagnosis for both of these symptoms. I’ve also briefly discussed cervical screening and the HPV vaccine. It’s quite a lot of material but it’s all relevant stuff – I hope you find it helpful.

 


Introduction

Blausen.com staff (2014). “Medical gallery of Blausen Medical 2014”. WikiJournal of Medicine 1 (2). DOI:10.15347/wjm/2014.010. ISSN 2002-4436. (Own work) [CC BY 3.0 (http://creativecommons.org/licenses/by/3.0)], via Wikimedia Commons

ANATOMY OF THE CERVIX

  • the cervix is the lower, narrow part (or “neck”) of the uterus which separates it from the upper part of the vagina. It is about 3cm long and 2.5cm wide. Its physical presence forms a barrier between the vagina and uterus, and acts as a sphincter which supports the weight of the uterus during pregnancy.
  • it has an internal os, which opens into the uterus, and an external os which opens into the vagina.
  • between the internal and external os is the endocervix, which consists of a short narrow canal lined with columnar epithelium which produces several types of cervical mucus. This canal allows menstrual products to escape the uterus during a period, and allows sperm to enter the uterus to try and find an ovum to fertilise after sex. It also dilates during labour to allow delivery of the fetus.
  • the ectocervix is the part which projects into the vagina – this is visible on speculum examination and lined with non-keratinised stratified squamous epithelium.

PHYSIOLOGY

  • the cervix is responsive to the effects of sex hormonesoestrogen causes the cervix to open slightly and the cervical mucus to become thin and receptive to sperm, whilst progesterone causes the cervix to close and the mucus to thicken to form a plug which blocks off the opening of the uterus.
  • the area where the endocervix and ectocervix meet is known as the transformation zone (TZ) or squamocolumnar junction. This is where columnar cells of the endocervix undergo metaplasia and become squamous cells in response to exposure to the harsh acidic environment in the vagina. This is a completely normal physiological process, but it increases the risk of dysplasia or malignant change occurring in these cells. Most cases of cervical cancer originate in the transformation zone.
  • women exposed to high levels of oestrogens – such as teenagers, pregnant women and those taking the OCP – may develop a cervical ectropion. In this, the columnar epithelium of the endocervix protrudes from the external os, causing the transformation zone to move outwards and producing a red ring on the cervix. It is completely benign, but can cause excessive discharge or bleeding.
cervix transformation zone

Colposcopic view of the transformation zone (TZ) of the cervix – you can see the red columnar epithelium emerging from the external os and the junction where it undergoes squamous metaplasia (image from Family Practice Notebook http://www.fpnotebook.com)

 

TERMINOLOGY

  • cervical cancer is a malignant neoplasm arising from the tissues of the cervix
  • post-coital bleeding (PCB) is vaginal bleeding occurring immediately after sexual intercourse – this has a 6% annual incidence in the UK
  • intermenstrual bleeding (IMB) is vaginal bleeding (other than postcoital) occurring between periods – this has a 17% annual incidence in the UK

 


Epidemiology

  • cervical cancer accounts for 2% of cancers in UK women (around 3000 cases per year)
  • it is the twelfth most common cancer, and causes 1% of cancer deaths (about 1000 per year)
  • there is a lifetime risk of 0.7%, or 1 in 134, for women in the UK
  • it primarily affects those aged 30-34 (10-15 years after peak incidence of CIN) and the over 80s
  • incidence has remained stable over the past 10 years
  • the incidence is much higher in developing countries – worldwide, cervical cancer is the second most common cancer in women (around 500,000 cases per year) and the third most common cause of female mortality (around 274,000 deaths per year)

 


Aetiology and risk factors

  • the development of cervical cancer is strongly associated with persistent sexually transmitted human papillomavirus (HPV) infection, which interferes with tumour suppressor genes such as p53 and retinoblastoma to produce viral carcinogenesis
  • 95% of cases are associated with HPV infection, mainly types 16 and 18 and less commonly types 31, 33, 35 and 45
  • risk factors for exposure to HPV include early first sexual experience, multiple sexual partners (or one promiscuous male partner), history of other STIs, heterosexuality, absence of barrier contraception and low socio-economic status
  • immunosuppressed patients are at increased risk – such as those with HIV (6x risk), transplant recipients (2x risk) and malnutrition
  • hormonal factors may have a direct proliferative effect – such as early first birth, multiparity and OCP use. Exposure to diethylstilboesterol (which used to be used to prevent miscarriage) in the womb also increases risk.
  • smoking reduces cell-mediated immunity and viral clearance
  • occupational carcinogen exposure – tetrachloroethylene is used in dry cleaning/metal degreasing
  • family history in a first-degree relative confers increased risk, but this is probably due to similar lifestyle factors rather than inherited genetic predisposition.
  • non-attendance at cervical screening
  • protective factors include HPV vaccination and attendance at cervical screening

 


 Histopathological types

  • 70% squamous cell carcinoma
  • 15% adenocarcinoma
  • 15% mixed pattern
  • <1% very rare types: neuroendocrine, embryonal rhabdomyosarcoma (“sarcoma botryoides”), germ cell tumours, clear cell carcinoma, glassy cell carcinoma, lymphoma, leukaemia, melanoma and metastases from other sites

 


Symptoms

  • the patient may be completely asymptomatic and cancer may be an incidental finding on cervical smear (severe dyskaryosis or suspicion of invasion) or on samples taken during treatment for CIN
  • post-coital bleeding occurs in up to 40% of cases – likelihood of cancer is increased if bleeding is profuse or persistent over time, or if it occurs in older women
  • intermenstrual bleeding
  • less commonly menorrhagia
  • increased or altered vaginal discharge – some gynaecologists claim this has a characteristic smell
  • postmenopausal bleeding is a rare symptom in older women – <1% of cases will be due to cervical cancer
  • symptoms of advanced disease include pelvic pain, leg pain and oedema, PR bleeding, altered bowel habit, haematuria,  dysuria, urinary frequency, urinary retention, ureteric obstruction leading to hydronephrosis, fistulae (e.g. vesicovaginal), fatigue and weight loss
  • symptoms of metastatic disease may include shortness of breath and haemoptysis (lungs), jaundice and abdominal pain (liver), bone pain, hypercalcaemia and pathological fractures (bones).

 


Signs

  • general examination findings are usually normal except in advanced disease
  • abdominal examination may reveal a pelvic mass or craggy hepatomegaly in advanced cases
  • Cusco speculum examination – bleeding, discharge or obvious ulceration/mass
  • bimanual palpation – friable tissue with contact bleeding; obliteration of fornices; roughened, hard, irregular cervix which may be fixed and immobile in locally advanced disease

 


Differential diagnosis – postcoital bleeding

  • trauma
  • cervical pathology – ectropion, cervicitis, cervical or endometrial polyp, cervical cancer
  • vaginal pathology – vaginitis (e.g. severe thrush, atrophic), vaginal cancer
  • vulval pathology – vulval dermatitis, vulval cancer

 


Differential diagnosis – intermenstrual bleeding

  • physiological – 1-2% of women have “spotting” around ovulation, could be due to ectropion
  • trauma
  • ovarian pathology – oestrogen-secreting ovarian tumours
  • uterine pathology – endometritis/PID, endometrial polyp, endometrial hyperplasia, fibroids, endometrial cancer
  • cervical pathology – cervicitis (e.g. STIs), cervical polyp, cervical cancer
  • vaginal pathology – vaginitis (e.g. severe thrush, atrophic), vaginal cancer
  • vulval pathology – vulval dermatitis, vulval dystrophy, vulval cancer
  • pregnancy-related – early miscarriage, ectopic pregnancy, gestational trophoblastic disease
  • systemic problem – bleeding disorders, metastatic cancer e.g. ovarian, colorectal
  • iatrogenic – trauma, IUCD, progestogens (e.g. POP, Depo-Provera injections), oestrogens (e.g. HRT)
  • idiopathic – dysfunctional uterine bleeding (DUB)
  • exclude bleeding from somewhere else – urethra, bladder, anus, rectum, perineum

 


Investigations

IF YOU SUSPECT CANCER, DON’T DO A SMEAR – SEND THE PATIENT FOR URGENT COLPOSCOPY

Diagnostic tests for women with suspected cancer include:

  • history and clinical examination including Cusco speculum examination and bimanual palpation
  • have a low threshold for performing a pregnancy test
  • triple swabs to rule out chlamydia and other STIs
  • colposcopy with punch/loop/cone biopsies of any suspicious areas of the cervix is the key diagnostic test as it allows histological analysis (see the screening section below for details on how this works)
  • post-menopausal women may require transvaginal ultrasound scan (TVUSS) and endometrial sampling to rule out endometrial cancer as a cause of bleeding

(Tumour markers are not really used in the diagnosis of cervical cancer – CEA, tumour M2-PK and SCC antigen may be raised, but they are associated with many types of cancer so are not very specific)

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Staging investigations for women with biopsy-confirmed malignancy include:

  • blood testsFBC (for anaemia), U+E (for renal function), LFTs (for metastases)
  • imagingCXR for lung metastases, CT abdomen and pelvis for metastases +/- MRI pelvis to show local invasion and pelvic lymph nodes, PET scan may be indicated in advanced disease
  • cystoscopy to assess bladder invasion
  • intravenous urogram (IVU) to assess ureteric obstruction
  • proctoscopy, sigmoidoscopy +/- barium enema to assess rectal compression and invasion
  • surgical staging may be necessary to provide accurate assessment, as scans can often miss pelvic lymph nodes, and allow tumour debulking – this would include an examination under anaesthetic (EUA) with large loop excision of the transition zone (LLETZ), cystoscopy, hysteroscopy and fractional curettings from the endocervix and endometrium

Grading – how aggressive is it?

I’ve had a trawl through Google for useful information about the grading of cervical cancers, but haven’t been able to find much detailed or specific information, which means that it probably isn’t that important compared to staging. Lots of people have tried to develop a special grading system, but none of them have been consistently shown to have a close correlation with prognosis, so most histopathologists will use a modified version of Broder’s grading system based on the degree of keratinisation, cellular atypia and mitotic activity of the cancer cells compared to normal cells:

  • Grade I – well differentiated (good)
  • Grade II – moderately differentiated (OK)
  • Grade III – poorly differentiated (bad)
  • Grade IV – anaplastic (very bad)

Generally, high-grade cancers behave very aggressively but can be very sensitive to chemoradiotherapy. Low-grade cancers grow and spread more slowly but may be less sensitive to such treatments.

 


Staging – how far has it spread?

Staging classification uses the International Federation of Gynaecology and Obstetrics (FIGO) system:

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cervical cancer staging (FIGO)

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The TNM (tumour nodes metastasis) system can also be used, but generally, gynae-oncologists tend to prefer to use FIGO.


Management

Surgical management depends on the stage of cancer:

  • stage 0 (CIN) – can be treated colposcopically with LLETZ
  • stage Ia1LLETZ or cone biopsy (excision of large “cone” of cervical tissue under general anaesthetic) can be considered curative if excision margins are clear and preserve fertility; offer hysterectomy if family is complete
  • stage Ia2 simple hysterectomy (removal of uterus and cervix) and bilateral pelvic lymph node dissection (BPND)
  • stage Ib1 radical hysterectomy (removal of uterus, fallopian tubes, cervix, upper vagina and parametrium) and BPND
  • stage Ib2 and stage IIaradical hysterectomy and BPND can be considered if there is no evidence of lymph node involvement
  • stage IIb1 or greater – in almost all cases, these tumours are considered inoperable. Extremely radical destructive surgery (e.g. pelvic exenteration where all pelvic organs are removed) may be carried out in a small proportion of lymph node-negative cases.
  • If the patient has not yet completed her family and wishes to preserve her fertility, an alternative to hysterectomy in stage Ia2/Ib1 disease is a procedure called a radical trachelectomy. In this, most of the cervix and parametrium is removed but the vagina, internal os and uterus are preserved. The internal os is almost completely closed with stitches to allow it to support a pregnancy. This operation is only a safe option if the cancer is completely removed – during the procedure the specimens are checked using frozen section microscopy, and if the margins are involved, the patient will have to have a hysterectomy to ensure complete excision. If trachelectomy is performed, there is a risk of premature labour and the baby will have to be delivered by Caesarean section.


This little video from Pedro A Perez-Ponce on YouTube is NOT for the faint-hearted – don’t let the jazzy Spanish music fool you. It shows a cone biopsy procedure performed colposcopically using a special diathermy probe. This can be used to treat CIN and early cervical cancer. As you can see, the cone of tissue removed is quite large and extends well into the endocervical canal. Women who have this procedure are at increased risk of cervical incompetence leading to miscarriage and premature labour.

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Medical therapies may be indicated in more advanced disease:

  • radiotherapy external beam irradiation and intracavity brachytherapy are usually given after hysterectomy to reduce the risk of recurrence. Radiotherapy is an effective first-line treatment for inoperable disease, and can also be used to treat recurrences.
  • chemotherapy – when given alongside radiotherapy for inoperable disease, this has been shown to reduce the risk of recurrence and death by up to 50%. It can also be used to treat recurrences. Commonly used drugs are cisplatin +/- topotecan.
  • advanced metastatic cancer (stage IVb) requires individualised palliative treatment with chemoradiotherapy and symptom control

Follow-up and prognosis

  • the overall prognosis is good (66.6% 5-year survival), but varies with the stage of cancer (see above)
  • women who have conservative treatment of early cervical cancer need to be followed up with regular smears and annual colposcopy to check for recurrence – if this is normal after 5 years they can rejoin the normal cervical screening programme
  • women who have surgery are followed up and monitored by a specialist gynae-oncology centre

 


Prevention strategies – cervical screening

  • the NHS cervical screening programme was introduced in 1964 and uses liquid-based cytology to assess the cells of the cervix for premalignant or malignant change
  • the programme screens 3 million women per year, it prevents up to 75% of cervical cancers and is estimated to save 4,500 lives per year in the UK
  • samples are obtained using a cervical smear test – see here for the Geeky Medics OSCE guide
  • screening is available for women aged 25-65 – those aged 25-49 are screened every 3 years, then those aged 50-64 are screened every 5 years
  • 93.5% of adequate smear tests are negative
  • 3.3% show “borderline” changes requiring a repeat smear in 6 months
  • in 3.2% of smears, cytology reveals dyskaryosis (abnormalities) in the cells of the cervix, which requires investigation using colposcopy
  • colposcopy is a procedure during which the cervix is inspected and acetic acid is applied to its surface – abnormal cells have increased surface proteins, which are coagulated by the acid and turn white, producing “acetowhite” areas which can be biopsied for histological assessment
  • histology may reveal cervical intraepithelial neoplasia (CIN) – this is the term for premalignant, non-invasive neoplastic changes within the cervix, and cannot be diagnosed on a smear as it requires solid tissue samples

cervical screening results

  • CIN1 – usually managed conservatively with 6-monthly colposcopy, LLETZ may be used in some cases e.g. if HPV +ve
  • CIN2 – requires definitive treatment with LLETZ, with 6-monthly follow-up colposcopy
  • CIN3 – requires definitive treatment with LLETZ, with 6-monthly follow-up colposcopy
  • cGIN (cervical glandular intraepithelial neoplasia) is less common and harder to manage – it may indicate neoplasia  or adenocarcinoma within the glandular cells of the endocervix or uterus
  • HPV DNA testing may be offered to women with borderline smears or mild dyskaryosis to assess cancer risk – women who are positive for high-risk types of HPV are more likely to develop high-grade CIN or cancer, whereas lesions associated with a negative HPV test are very unlikely to become cancerous

 


Prevention strategies – the HPV vaccine

  • 75% of sexually active women are exposed to HPV at some point, but most of them clear the virus
  • high-risk viral subtypes for cervical cancer include 16, 18, 31, 33, 35 and 45 – these are associated with cervical, vaginal, vulval, penile, anal and oropharyngeal cancers
  • other low-risk viral subtypes, e.g. 6 and 11, may cause genital and anal warts, low-grade CIN and laryngeal papillomatosis
  • there are two main vaccines available on the current market, Cervarix and Gardasil, both of which are derived from the viral L1 capsid protein and do not contain any genetic material
  • the vaccination schedule covers all girls aged 12-13 with a course of injections at 0, 1 and 6 months – when it was implemented in 2008 there was also a catch-up programme for girls aged 14-18
  • the vaccine works best if given before the age of 12 (i.e. before any sexual exposure is likely to have occurred), but is licensed for use between the ages of 9 and 26
  • the vaccination programme is estimated to save about 400 lives per year

 

CERVARIX (bivalent)

  • initially used in the UK when vaccination started in 2008 (cheaper)
  • covers HPV subtypes 16 and 18, which cause 70% of cervical cancers
  • shows a 66-80% reduction in cases of high-grade CIN and cervical cancer
  • confers no protection against genital/anal warts or laryngeal papillomatosis

 

GARDASIL (quadrivalent)

  • UK screening programme switched to this in September 2012
  • covers HPV subtypes 16, 18, 6 and 11 and has undergone extensive clinical trials
  • 99% effective if HPV 16 and 18 naive throughout the vaccination process
  • 98% effective if HPV 16 and 18 naive at the start of the process only
  • 44% effective in all women regardless of HPV status and presence of CIN
  • confers protection against cervical cancer, other HPV-related cancers, genital and anal warts and laryngeal papillomatosis

The government have yet to make a decision about whether to vaccinate boys as well as girls – this would reduce transmission to women and also reduce the incidence of HPV-related penile, anal and oropharyngeal cancers in men. Gardasil is licensed for use in men but is not currently used in the UK (however policy changes are imminent).

There has been much public controversy since the introduction of the vaccine, fuelled by the media at large and predominantly by the frankly disgusting actions of the Daily Mail newspaper. Some parents feel that by vaccinating their children against a sexually transmitted infection they are encouraging them to become sexually active at a younger age – although I hardly see how they can justify cervical cancer as an appropriate punishment for this. The discussion of HPV vaccination with an anxious parent is ideal material for an OSCE or MOSLER communication station, so I would recommend being aware of the controversy and the details of the vaccination programme for your exams.

 


References

Images: 

1. By Haeok Lee1,2*, Mary Sue Makin3, Jasintha T Mtengezo4,5 and Address Malata6 [CC BY 4.0 (https://creativecommons.org/licenses/by/4.0)], via Wikimedia Commons

 

Further reading sources:

 


 

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