Clinical Review: Cervical cancer

Cervical cancer is the most common gynaecological cancer worldwide, with a significant socioeconomic burden.

PET scan showing the presence of a cervical carcinoma in pink (Photo: SPL)
PET scan showing the presence of a cervical carcinoma in pink (Photo: SPL)

Section 1: Epidemiology and aetiology

Cervical cancer is the fourth most common cause of cancer death in women worldwide (266,000 deaths in 2012).1 In 2010, 4m age-weighted years of life were lost to cervical cancer.2

In England over the past 20 years, the incidence of cervical cancer has decreased by a third and mortality has halved, primarily because of the efficacy of the NHS cervical screening programme.3

The call/recall system was introduced in the UK in 1988 and exceeded 80% coverage of screening for the target population. However, there has been a gradual decline, from about 82% coverage in the late 1990s to about 78% in the past five years.4

The lifetime risk of developing cervical cancer is one in 139, with more than 3,000 new cases in the UK every year.5 Of cervical cancers, 30% are detected through screening, and these mostly comprise early stage microinvasive disease.6

There is considerable variation in incidence in the UK. Parts of Scotland and the north of England have some of the highest incidences; south and east England have the lowest.

Data from 151 PCTs in England in 2012 showed the strong association between deprivation and the incidence of cervical cancer.3

Aetiology
High-risk genotypes of HPV are associated with the causation of virtually all cervical cancer cases.7 There are more than 100 genotypes of HPV, but only 13 types are oncogenic.8,9

Most cervical cancer is caused by genotypes 16 and 18.10 Four out of five women develop HPV infection in their lifetime, but 90% of infections are cleared within two years.11

Persistence of HPV infection is the most important factor in developing cervical cancer.12 The incidence of CIN and cervical cancer will reduce as the increasing cohort of women who have been vaccinated against HPV 16 and 18 progresses beyond the age of 25 years.

Women who smoke are twice as likely to develop cervical cancer than those who do not.11 Reduced immune status as a result of disease such as HIV/AIDS or immunosuppressant agents, use of the combined oral contraceptive pill, multiple sexual partners and giving birth to more than three children are some of the other risk factors and associations.

Classification
Approximately 70-80% of all cervical cancers are squamous cell carcinoma and 10-15% are adenocarcinoma.13 The incidence of adenocarcinoma and adenosquamous carcinoma is increasing as more squamous cell carcinoma cases are detected at the precancerous stage.

Malignant mesenchymal tumour comprises only a minority of cervical tumours. Of this small group, primary sarcoma is the most common subtype, with a poor prognosis.

Sarcoma botryoides occurs in a younger age group and has a much better prognosis.

The cervix can also be a site of metastasis for various cancers, including lymphoma.

Section 2: Making the diagnosis

Detection of CIN by cervical screening enables treatment of preinvasive disease and prevention of cancer.

Approximately 40,000 high-grade cervical screening abnormalities are diagnosed in England annually,4 achieving the prevention of thousands of cases of invasive cancer.

Screening also detects approximately 700 women with asymptomatic microinvasive disease,4 which is easily treated.

Early diagnosis of symptomatic cervical cancer is crucial, to optimise survival and minimise mortality.

Clinical features
Abnormal vaginal bleeding is the most common symptom of cervical cancer. Bleeding is often triggered by cervical contact, and postcoital bleeding is the classic presenting symptom. However, intermenstrual or postmenopausal bleeding may also herald cervical cancer.

Advanced disease can present as dyspareunia, pelvic pain, offensive vaginal discharge, haematuria and other non-specific symptoms, including weight loss, changes in bladder and bowel habit, and abdominal pain.

Investigations
All women with abnormal bleeding should be examined using a speculum. Urgent referral for colposcopy is indicated for the assessment of post-coital bleeding.

Locally advanced malignancy can be suspected when an irregular cervix is seen or palpated with the help of speculum or vaginal examination.14 The cervix may be felt as a fixed, hard structure, which may bleed on being touched, with the vaginal fornices obliterated.

Occasionally, the tumour may arise from within the endocervix or below the epithelium and may be impossible to visualise with speculum examination.

Cervical cytology is not reliable in symptomatic patients and should not be used to investigate postcoital or other abnormal vaginal bleeding. Its false negative rate is up to 60% in invasive cancer.15 The diagnosis is confirmed by colposcopically directed biopsy of the cervix.

Invasive carcinoma may occasionally be suspected on routine cervical screening cytology.

Staging
Staging of cervical cancer is critical in determining treatment and prognosis. For global reproducibility, the International Federation of Gynecology and Obstetrics (FIGO) staging is based on clinical findings.16

Examination under anaesthesia is often performed, with abdominal, vaginal and rectal examination, with or without colposcopy, hysteroscopy, cystoscopy and sigmoidoscopy, and biopsies as necessary.

A CT scan of the chest, abdomen and pelvis with contrast is preferred to chest X-ray to assess for metastatic disease, and PET is also being used increasingly for staging.

MRI is routinely performed to assess tumour volume and parametrial and regional lymph node metastases.

Section 3: Managing the condition

Treatment of cervical cancer is tailored to the tumour stage, subtype and grade, comorbidities and age, and to the patient's wishes regarding fertility and management options.

Treatment modalities include surgery, radiotherapy and chemotherapy, and it is mandatory to discuss the management in a specialist multidisciplinary team meeting.17

Managing long-term treatment-related morbidity, including sexual dysfunction, local and systemic side-effects of disease and treatment (for example, lymphoedema, neuropathic pain) and psychological morbidity is a major challenge.

The following treatment options are used in common subtypes of squamous cell carcinoma, adenocarcinoma and adenosquamous cancer of the cervix.

Rarer subtypes, such as neuroendocrine and lymphoma, are primarily treated with chemotherapy, with or without radiotherapy or surgery.

Early stage disease
Early microinvasive FIGO stage IA1 cervical cancer is not associated with significant risk of metastases, so local excision offers a good chance of cure. This is generally performed in a similar manner to the treatment of high-grade CIN. If the patient has completed her family, hysterectomy should be discussed.

In stage IA2 disease, local excision can be offered to preserve fertility, but there is a risk of pelvic lymph node involvement of approximately 5% and bilateral pelvic lymphadenectomy is recommended.

Larger FIGO stage IA2 cancers or those with additional risk factors may be offered radical trachelectomy, involving excision of the cervix and medial parametriae in addition to lymphadenectomy.18

Laparoscopic hysterectomy and lymphadenectomy are offered to women not wishing to retain their fertility. The presence of positive lymph nodes indicates the need for adjuvant chemoradiotherapy.

Stage IB1 tumour is generally treated with radical hysterectomy and bilateral pelvic lymphadenectomy. Radical surgery is associated with significant morbidity and complications. Morbidity may be minimised by using minimally invasive (laparoscopic or robotic) routes.

FIGO Stage IB1 cervical cancer is equally effectively treated by chemoradiotherapy, which is associated with other treatment-related morbidity, such as bowel and bladder dysfunction, vaginal stenosis and lymphoedema, and an increased risk of second pelvic primary malignancy many years after treatment.

Morbidity associated with radical surgery versus primary chemoradiotherapy should be discussed with the patient.

Teams aim to avoid the potential compounded morbidity risk, which arises when both radical surgery and chemoradiotherapy are required.

Women who wish to retain their fertility and who have a central tumour less than 2cm in size have less risk of parametrial involvement and can be offered laparoscoptic or vaginal radical trachelectomy.

Subsequent pregnancies are delivered by caesarean section.

This procedure is associated with an increased risk of obstetric complications such as miscarriage and premature labour compared with normal pregnancies, but many healthy infants have now been delivered to women who have undergone radical trachelectomy.

Concurrent chemoradiotherapy is recommended for stage IB2 and more advanced cancer.

Advanced stage disease
Advanced stage disease confined to the pelvis classically presents with disease extension to the pelvic side walls, often with hydronephrosis associated with ureteric obstruction (FIGO stage IIIB).

Provided there is no disease outside the pelvis, there is a potential for cure with radical chemoradiotherapy, but pelvic and distant recurrence rates are high and five-year survival is in the region of 10-30%.

When there is evidence of disease spread beyond the pelvis at the time of diagnosis (FIGO stage IVB), palliative treatment is generally given.

Chemotherapy and targeted radiotherapy may achieve local disease control or symptom palliation.

Changes in therapy
To avoid the side-effects of radical surgery and to retain fertility options, a trend has evolved towards less radical surgery for early cancer. The role of simple hysterectomy is currently being evaluated in the SHAPE trial.19

Section 4: Prognosis

Prognosis correlates with stage, histological diagnosis, socioeconomic status and age at presentation.

Overall, 83% of women survive one year in England and Wales.20 This drops to 67% and 63% by the fifth and tenth year, respectively. Data from Scotland also show a similar trend.21 One-year survival of patients with stage IV cancer is only 35%.

There is strong evidence that cervical cancer survival is worse in older women.

For example, one-year relative survival in patients aged 15-39 years with cervical cancer is 96%, compared with 52% in those aged 80 or older. Similarly, five-year survival in those aged 15-39 years is 86%, compared with 27% in those aged 80 or older.3

Follow-up
Currently, there is no consensus regarding the length and frequency of follow-up for patients treated for cervical cancer.

The principal aim of routine cancer follow-up is to detect salvageable early recurrence.

Colposcopy and cervical cytology are not recommended for follow-up.6 MRI may be useful in detecting local recurrence, but is not generally performed on a routine basis in the UK.

Where there is a suspicion of disease recurrence, a PET scan is more accurate in detecting nodal and metastatic disease.

PET-CT is considered in recurrent disease before planning exenterative surgery or radiotherapy.

Section 5: Case study

A 32-year-old woman was referred to the colposcopy clinic for assessment of a low-grade cytology abnormality (mild dyskaryosis). A biopsy was taken, which revealed CIN 3.

The patient underwent large loop excision to remove CIN 3 cells. The sample showed incompletely excised high-grade adenosquamous carcinoma. The patient was then referred to the regional gynaecological oncology centre.

After staging, the multidisciplinary team discussed management options. The examination and MRI suggested a primary tumour diameter of 36mm with no parametrial extension, and there was no evidence of distant metastases on PET-CT (FIGO stage IB1).

The patient considered the potential risks of radical hysterectomy and pelvic lymphadenectomy, primary chemoradiotherapy, and staging lymphadenectomy to prepare for radical hysterectomy or primary chemoradiotherapy.

She was reluctant to have two surgical procedures and keen to avoid radiotherapy, so she opted for radical hysterectomy with ovarian transposition and bilateral pelvic lymphadenectomy. The operation was performed, but lymph nodes were found to contain metastasis, so to minimise the risk of recurrence, she also had adjuvant chemoradiotherapy.

Five years later, she remains disease free, although she has experienced treatment-related morbidity.

Section 6: Evidence base

Clinical trial

  • The SHAPE trial. http://www.gcig.igcs.org/Spring2012/2012_june_shape_trial.pdf

To evaluate if simple hysterectomy in low-risk cervical cancer patients is safe and  associated with less morbidity than radical surgery, and to assess if overall survival is different compared to the radical hysterectomy group.

Textbook

  • Berek JS, Neville F (eds). Berek and Hacker’s Gynecologic Oncology. Philadelphia, Lippincott Williams & Wilkins. 2014

More online

  • Jo’s Cervical Cancer Trust. http://www.jostrust.org.uk/
  • NICE Pathways. Cervical cancer overview. http://pathways.nice.org.uk/pathways/cervical-cancer
  • NHS Choices. Cervical cancer. http://www.nhs.uk/Conditions/Cancer-of-the-cervix/Pages/gynaecological_cancer/gynaecological_cancer_hub/resources/cervical_cancer
  • NHS Cervical Screening Programme. Colposcopy and Programme Management: Guidelines for the NHS Cervical Screening Programme. http://www.cancerscreening.nhs.uk/cervical/publications/nhscsp20.html
  • National Cancer Intelligence Network cervical cancer resources. http://www.ncin.org.uk/
  • MIMS Women's Health Clinic

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Contributed by Mr Manas Chakrabarti, oncology fellow, and Mr Andy Nordin, consultant gynaecological oncologist, Queen Elizabeth the Queen Mother Hospital, Margate, Kent.

References
1. WHO GLOBOCAN Cervical Cancer Estimated Incidence, Mortality and Prevalence Worldwide in 2012. http://globocan.iarc.fr/old/FactSheets/cancers/cervix-new.asp
2. Goldstein BY, Bray FI, Parkin DM et al. Handbook of Disease Burdens and Quality of Life Measures 2010.
3. National Cancer Intelligence Network Trent Cancer Registry. Profile of Cervical Cancer in England Incidence, Mortality and Survival, 2012.
4. NHS Cervical Screening Programme Annual Review 2012. http://www.cancerscreening.nhs.uk/cervical/publications/ cervical-annual-review-2012.pdf
5. Cancer Research UK. Lifetime risk of cancer.cancerresearchuk.org/ cancer-info/cancerstats/incidence/risk/
6. SIGN. Management of cervical cancer: a national clinical guideline. SIGN Guideline 99, January 2008.
7. Meijer CJ, Snijders PJ, Castle PE. Gynecologic Oncology 2006; 103: 12-17.
8. Walboomers JMM, Jacobs MV, Manos MM et al. J Pathol 1999; 189(1): 12-19.
9. Jo's Cervical Cancer Trust. Human papillomavirus (HPV). www.jostrust.org.uk/about-cervical-cancer/hpv
10. Bosch FX, Burchell AN, Schiffman M et al. Vaccine 2008; 26: K1-16.
11. Cancer Research UK. Cervical cancer - Causes. http://www.nhs.uk/Conditions/Cancer-of-the-cervix/Pages/Causes.aspx
12. Molano M, van den Brule A, Plummer M et al. Am J Epidemiol 2003; 158: 486-94.
13. Cancer Research UK. Types of cervical cancer. http://www.cancerresearchuk.org/about-cancer/type/ cervical-cancer/about/types-of-cervical-cancer
14. NHS Cancer Screening Programmes. Clinical Practice Guidance for the Assessment of Young Women aged 20-24 with Abnormal Vaginal Bleeding. http://www.cancerscreening.nhs.uk/cervical/publications/ doh-guidelines-young-women.pdf
15. Sasieni PD, Cuzick J, Lynch-Farmery E. Br J Cancer 1996; 73: 1001-5.
16. FIGO Committee on Gynecologic Oncology. Int J Gynecol Obstet 2009; 105: 103-4.
17. DH. Guidance on commissioning cancer services: improving outcomes in gynaecological cancers - the manual. London, DH, January 1999.
18. Mahmood IS. Cervical cancer. In: Shafi M, Luesley D, Jordan JA (eds). Handbook of Gynaecological Oncology. London, Churchhill Livingstone, 2000.
19. Gynecologic Cancer Intergroup (GCIG). SHAPE trial. www.gcig.igcs.org/Spring2012/2012_june_shape_trial.pdf
20. Cancer Research UK. Cervical cancer survival statistics. http://www.cancerresearchuk.org/cancer-info/cancerstats/ types/cervix/survival/cervical-cancer-survival-statistics
21. Information Services Division, National Services Scotland. Trends in Cancer Survival in Scotland, 1983-2007. August 2010.

CPD IMPACT: EARN MORE CREDITS

These further action points may allow you to earn more credits by increasing the time spent and the impact achieved.

  • Hold a meeting with a local gynaecologist to review current treatment options for women with cervical cancer.
  • Perform a search for women who have not attended cervical screening during the past year. Determine if there are valid reasons for their non-attendance.
  • Ensure you provide up-to-date patient information about cervical screening in your surgery.

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