Summary
The majority of the cancers of the cervix arise from the lining covering (epithelium) of the neck of the womb and are squamous carcinomas (85-90% of all cases). A minority of cases of cancer of the cervix have adenocarcinomas that arise from the glands of the lining of the neck of the womb, and occasionally there are features of both types visible down the microscope (adenosquamous type).
Causes
The predisposing factors seem to suggest an infective (transmissible) agent to be linked to causation and the human papilloma virus (HPV) is the agent that has been most firmly implicated; the likelihood of infection is linked with the number of sexual partners. It is certainly not the case that infection with this agent is always carcinogenic, but it is a ‘trigger’ on the steps to carcinogenesis. The newly available HPV vaccination programme (aimed at teenage girls) is specifically aimed at reducing the HPV infection promotion of cervical cancer.
Other factors that have been related to a higher incidence of the disease are smoking and immunosuppression (e.g. renal transplant recipients have a higher risk).
Once the cancerous changes occur, there is a pre-invasive stage (CIN) which precedes the more dangerous invasive cancer stage (when the cancer cells have breached the basement epithelium of the cervix and hence gained access to blood vessels/potential routes of spread). This pre-invasive stage can last for years and it is for this reason that the screening programme is so effective because detection at this stage allows pre-emptive cure of the whole condition.
Incidence
Cervical cancer is the second most common female cancer on a worldwide basis and in some developing countries, it is the commonest cancer of all (e.g. India). In the UK, the incidence is approximately 1.25%.
There is a link between incidence and sexual behaviour, there being a higher incidence in those who start sexual activity in their early teens and have many sexual partners. Both low socioeconomic status and multiparity (many pregnancies) are also related, although these factors may not be unconnected to the others. Barrier contraceptive use seems to protect.
It is hoped that the immunisation programme of teenage girls with the HPV (human papilloma virus) vaccine will further decrease the incidence of cervical cancer in the years to come.
Symptoms & diagnosis: Cancer of the cervix
The majority of patients come to the doctor because of abnormal vaginal episodes of bleeding (after sex, in between regular periods, after the menopause etc.) or just a persistent vaginal discharge which is watery or blood tinged. Pelvic pain is a later symptom in most cases.
Diagnosis
The first test that the gynaecologist will perform is the direct inspection of the cervix of the womb (cervix = neck) which is a simple out patient procedure using a Cusco’s speculum to part the tissues to give the doctor direct vision. Sometimes the tumour is obvious and he will biopsy this but sometimes the changes are subtle and a stain will be applied topically to help distinguish the normal from abnormal areas are always biopsied or smears are taken.
Stages
The stages are complex but important to the correct therapy recommended and thence the chances of cure. The universally accepted staging system is that derived by the International Federation of Gynaecological Oncology (FIGO).
The stage of pre-cancer is called ‘cervical intraepithelial neoplasia’ (called by the initials of the first letters, CIN – and thereafter graded in the same way, i.e. grades 1-111, as outlined above for the cancer itself). This stage should always be curable, and cases of CIN 1 or even CIN 2 may regress spontaneously. Usually, cancer of the cervix has a long period of precancer/CIN before the abnormal cells break through the cervical wall’s bottom layer (the basement membrane) and thereby gets access to routes of spread via lymphatic and blood vessels, thereafter called, invasive cancer. It is this long period of pre-cancer (CIN) that allows the high cure rate in this disease and gives credence to the whole screening programme.
The first stage of invasive cancer (Stage 1) applies to cancers that are confined to the cervix, and this stage itself is divided into two parts. Microinvasive disease (Stage 1a) is that which is only recognisable by the pathologist on microscopic review of the biopsy, and represents the very earliest form of invasion below the basement membrane of the lining cervical wall.
Stage 1b refers to all other cancers that are confined to the cervix, of whatever size, but larger than the millimetre invasion that fits into stage 1a.
Stage 2 refers to cancers that have invaded the vagina or into the tissues beside the womb (called the parametria).
Stage 3 refers to cancers that have extended down to the lower vagina or as far outwards that they have reached the pelvic side wall – this fact being ascertained both by clinical examination (vaginal and rectal examinations) and by MR scanning of the pelvis.
Stage 4 cancer refers to cancer that has spread further afield (metastasised).
The staging procedures used to ascertain the correct stage include a full clinical examination, with pelvic exam, MR scanning of the pelvis together with abdominal scanning at least in the higher stage cases and a chest x-ray and blood work-up. In the more advanced stages and before surgery the kidneys and ureters may be imaged by intravenous urography.
Treatment & outcomes: Cancer of the Cervix
Under direct vision, the precancerous stage cervical intraepithelial neoplasia (CIN) may be removed by several techniques, such as laser vaporisation, radical diathermy or surgical excision – cone biopsy being a surgical excision where the whole circumferential epithelium (lining layer) is removed.
This last surgical option is currently favoured for therapy, and particularly where there is microinvasion of a millimetre or so (Stage 1a (1). Where there is deeper invasion, then a complete hysterectomy (removal of the womb) is the safer option for Stage 1a, unless the patient refuses for reasons of keeping her fertility.
For the other stages of invasive cancer, more extensive surgery or chemo-radiotherapy or both are required to effect the highest cure rates and these must be followed as appropriate, because there is a low chance of ‘second time cure’ (i.e. the doctors have one chance only at a good cure chance).
Extensive surgery is the treatment of choice for younger patients with early stage disease (Stage 1-2) although radiotherapy is an acceptable alternative for those unwilling to undergo the large operation.
In the operation, which is called a Wertheim’s hysterectomy (or an extended hysterectomy) the womb and all local pelvic lymph nodes are removed as well as a cuff of vagina. Sometimes, it may be safe to leave the ovaries in. An advantage over radiotherapy is that the vagina remains moist and pliable (albeit shorter), whereas it tends to become dry and can be contracted after radiotherapy. The complications of surgery are those of any major abdominal/pelvic operation but also include the possibility of some leg swelling due to the removal of some lymph nodes which are shared by the pelvis and legs; this is rarely severe. Sometimes the control of the bladder is affected by this operation and the patient has to self-catheterise post-operation, occasionally permanently.
Radiotherapy is an alternative to surgery and has comparable cure rates which are 80% for stage 1 and 60% for stage 2 disease. Radiotherapy usually starts with external beam therapy which comprises a long course of outpatient radiotherapy. The patient attends each week day and lies on a treatment couch, whereupon beams concentrate the ionising radiation dose on the central pelvis where the womb lies, and encompasses the regional pelvic lymph nodes. Each day the treatment is directed at the same place and slowly in a large number of small daily treatments (referred to a ‘fractions’ by the doctor) – in a fashion which is better tolerated by the normal pelvic contents (particularly the gut that is lying in the pelvis) than a small number of large treatments; the dose builds up on the cancer and proves ultimately fatal for the cancer in the majority of cases.
It has been demonstrated that the use of a chemotherapy agent (cis-platinum) during radiotherapy (usually as an intravenous injection ), has improved the results of radiotherapy and this is now routinely incorporated into this initial radiotherapy course.
At the end of this conventionally fractionated course of external beam radiotherapy, it is usual to boost the dose to the cervix by an intravaginal application of brachytherapy (the insertion of an applicator with components either side of the cervix in the vaginal vault and an intrauterine tube source; all three components carrying sealed source radioactive sources).
The rationale of this brachytherapy is that it allows the delivery of a very high dose of ionising radiation, which is concentrated on the cervix and rapidly tails off as one goes away from the cervix. . By the inverse square law (the law that says that if you are in a ship at sea and you treble your distance from a lighthouse, then the intensity of the lighthouse beam (a light beam having the same “fall off” rules as x-radiation) reduces to one ninth) the intense dose of radiation is confined to the local region around the cervix. It has been found that brachytherapy alone yields less good results than the combination with the external beam therapy because the external beam course treats disease wider of the cervix (i.e. it treats the early spread e.g. to the pelvic lymph nodes).
Conversely, brachytherapy adds to the good results of external beam therapy because it boosts the dose to the highest site of risk (i.e. the cervix itself) – See the figure posted in the outcomes section of this website. The brachytherapy sources may be sited under an anaesthetic or in the conscious patient, depending on the circumstances.
Where the patient has presented with heavy vaginal bleeding, there may be a case for using brachytherapy first, but in all other instances there is a clear rationale for shrinking the disease in towards the cervix and then boosting with brachytherapy.
The side effects of radiotherapy can be divided into the early ones like diarrhoea and bladder disturbances, together with sore pelvic skin, and late ones which include a small incidence of bowel problems, occasionally severe. Ureteric problems and occasionally rectal problems have followed high dose radiotherapy and brachytherapy plays a part in the risks. Vaginal dryness and the loss of sexuality is a problem that can be partly addressed by vaginal lubricants and HRT (hormone replacement therapy).
Since the introduction of IMRT (Intensity Modulated Radiation Therapy) more pelvic gut sparing has been possible and the incidence of gut-related side effects has consequently become much less common. However, occasionally the pelvic radiation therapy needs to be extended to cover the lymph nodes at the back of the lower abdomen (when these are obviously involved on the Radiotherapy planning scan). This can add to the chance of gut -related symptoms such as diarrhoea, nausea and tiredness.
Where the patient’s disease relapses in the pelvis after radiotherapy, there is a potential for cure by radical surgery such as the Wertheim hysterectomy. However, the complication rates following such surgery carried out after radiotherapy are greater and include fistulae (canals) between the vaginal and rectum on occasion. That is not to say that the risk is not worth the taking as it may be the only chance of cure, but simply that greater thought must go into the decision by both the doctor and the patient.
Outcome: The patient with stage 1 disease should have a greater that 80% chance of cure and greater that 60% for stage 2 disease presentation. the avoidance of relapse that threatens life is lower as the stage at presentation progresses
The patient who relapses after surgery in the pelvis could theoretically be ‘salvaged’ by pelvic radiotherapy but once again the chances of complications must be weighed up; for example, the chance of leg swelling is greater in this situation.
For the patient who relapses after radical therapy with metastatic relapse outside the pelvis, then chemotherapy is the only logical therapy that can prolong life, as it is the only therapy that goes all around the body (surgery and radiotherapy are aimed at the pelvis only).
Chemotherapy has not had a good track record in this disease but in recent years remissions have been forthcoming in a good proportion of patients with combination drug regimens usually containing cis-platinum. Furthermore, as mentioned above, the use of cis-platinum together with radiation therapy in the radical therapy of early disease is now standard practice and has improved the cure rates in early stage disease.
In the advanced disease situation, the effects of chemotherapy are temporary but may set the cancer back for many months and so many women will elect to have the course which is reasonably well tolerated if attention to anti-emetic therapy is given. Once the disease has relapsed outside the pelvis, the outlook is ultimately very gloomy – but see below.
What to do if there is relapse after therapy or patients who present to the doctor with metastatic disease – spread to distant body sites?
Where the patient relapses after first line therapy above, or when they present with metastatic disease, then chemotherapy is the most important therapy, as this therapy travels all around the body treating the cancer at all sites that are affected. the combination of a platin and taxane is the best first line chemotherapy regime. Second-line chemotherapy may temporise but durable remissions are unusual.
If the disease progresses through this then it is probably best to obtain a genomics review to see if there is (minority chance) of finding an activating oncogene mutation that is driving the cancer to continue dividing relentlessly and which is ‘druggable’ (i.e. there is a drug which inhibits the stimulatory pathway from the mutated gene to the effector protein downstream products). A fresh tissue biopsy of the cancer or else a cell-free DNA specimen form the bloodstream is required to give the up-to-date genomics (as cancers are always mutating and yesterday’s driving oncogene may not be today’s).
At the same time as this biopsy is being obtained, then the specimen should also be tested for mismatch repair deficiency (MMR deficiency) as this predicts (as does the PDL1 caner expression as a % of the cancer cells, which also should be tested) for the usefulness of immunotherapy, a new form of therapy that can be useful in refractory patients. The results om advanced cervical cancer seem less promising for immunotherapy than many other cancers – to this time point.
Credit: Dr P N Plowman MD, The Oncology Clinic, 20 Harley Street, London W1G 9PH. (Advanced genomics).
Screening
“Screening” for cervix cancer. A wooden spatula scrapes the cervix; exfoliated cells are examined at microscopy with a high “pick up” / diagnostic accuracy for cancer
In the UK at present, there is a highly organised cervical screening programme. More than 80% of pre-invasive disease will be picked up if a 5 yearly screening programme is implemented, but in the UK currently once three yearly screening is recommended to all over twenty five years and who are sexually active, in the attempt to raise this to over 90%. The screening procedure is simple and performed usually by general practitioners or trained nurses, and made annually if the smear is dysplastic in any way (e.g CIN). For those smears that are suspicious, then further investigation by gynaecological referral is required.
The American College of Obstetricians and Gynaecologists’ 2009 recommendations for screening are:
Screening should be avoided in the age group under 21 years of age. Screening should be performed every 2 years in the age group 21 to 29 years. In the age group 30 to 65 years, the recommendation is once every three years (but this only applies to those who have had three consecutive negative smears; exceptions include those with HIV, compromised immunity and those with CIN [grades 2-3] all of whom need more frequent screening). In patient over 65 years with three consecutive negative smears (no abnormal tests in the previous decade and one sexual partner), screening may be discontinued.
The effects that HPV vaccination will have on the future recommendations for screening have yet to be decided.