Medicine for Africa - Medical Information Service

ANCER   of  the   ERVIX

Definition:

The cervix is the lower part of the uterus (womb), both of which are located at the upper end of the vagina (birth canal).  The cervix (also called uterine cervix) is a canal-like structure that provides an open connection between the uterus and the vagina.  Thus, during sexual intercourse, it allows the male semen to enter the uterus and move further up the fallopian tubes to fertilize an egg and create a new human life. During a pregnancy (gestation period), it provides a certain ‘buffer zone’ between the fetus inside the uterus, in order to protect the growing fetus from the outside world. And finally, at the time of birth, it opens up wide and releases the newborn baby from the uterus into the vagina and into the world. 

Anatomically, the cervix is divided into two parts – the part closest to the uterus is called endocervix, while the part exposed to the vagina is called exocervix (or ectocervix). The area where these two parts meet is called the ‘transformation zone’, and it is here where most cervical cancers (also called cervical carcinomas) develop.

The majority of cervical cancers consist of two types – the so-called squamous cell carcinoma (80% - 90%) develops from the squamous cells that cover the exocervix, and often begins in the transformation zone; while the so-called adenocarcinoma (10% - 20%) usually develops from the mucous-producing gland cells in the endocervix.  Occasionally, cancers can be composed of both cell types, and then are termed adenosquamous carcinomas or mixed carcinomas.

The most frequently occurring and most likely cervical cancer – the squamous cell cancer (or carcinoma) of the cervix is always preceded by pre-cancerous changes, consisting of so-called dysplastic (or precancerous) changes of the cervical epithelium.  These dysplastic changes are again subdivided into atypical squamous cells (ASCs, subdivided into ASC-US [US – uncertain significance, usually HPV associated changes] and ASC-H [H – high grade atypical], or well differentiated cell changes, CIN I).  These changes can often reverse themselves within 18 months to two years, or they can progress to more severely dysplastic cell changes.

On the other extreme, the cellular changes are termed ‘squamous cell carcinoma’ (invasive cancer, CIN V), when the cancerous cells have penetrated the basement membrane of the cervical epithelium and are invading deeper tissues.  In-between those ‘extreme’ stages are ‘low grade squamous intraepithelial lesions’ (SILs, previously called moderate dysplasia or CIN II), and ‘high grade squamous intraepithelial lesions’ (HGSIL, previously called severe dysplasia and carcinoma-in-situ, or CIN III/IV). 

Thus, the development of cervical cancer is usually a slowly developing process that can be diagnosed at every step of the progression to invasive cancer, and, if diagnosed early, can, indeed, be treated most effectively, and with the least amount of inconvenience to the woman.  The most important ‘prerogative’ for this, is that every woman who has entered her child-bearing years, or engaged in her first sexual experiences, does get examined regularly (every one to two years) for the appearance of early dysplastic changes of her cervical epithelium.  This can be done very easily at any health care facility by using a cotton swap to scrape off the cervical surface epithelium and examining it under the microscope.  

Invasive cancer (CIN V) occurs when malignant cells have broken through the basement line of the normal cellular structure, and can result in spread throughout the immediate vicinity of the cervix, followed by the development of wide-spread metastases (group of cancer cells in other organs, severely impeding the chances of survival).

Research during the last few decades has unmistakably shown that infection with certain types of the Human Papilloma Virus (HPV) are the major risk factor and most frequent cause in the development of cervical cancer.  HPV is also a major candidate of sexually transmitted disease (STDs), whose prevalence (occurrence of a disease at any current point in time) is steadily increasing worldwide.

While normal healthy women can fight HPV infection more or less effectively or, at least, keep the growth of the virus under control, there are many factors that can weaken a woman’s body defense mechanisms, and allow the virus to grow in a rather uninhibited manner.  Among these factors are having first sexual intercourse at a young age, multiple sexual partners (especially associated with unprotected sex, i.e. without using a condom), stress, smoking, multi-parity (a woman who has already given birth to many children), long-term usage of birth control pills, and – most importantly – a weakened immune system, usually resulting from an infection with the human immunodeficiency virus (HIV) and the subsequent development of AIDS (acquired immunodeficiency syndrome).  In women with an active HIV infection, cervical cancer caused by HPV can develop from early dysplastic changes into a fully invasive cancer within just a few months, rather than many years as it normally occurs in otherwise healthy women (provided that no treatment has been instigated).

Cervical dysplastic changes usually occur after puberty and the first sexual encounters, and are most common between the ages of 25 and 35, the same group that is most sensitive to the infection of HPV.  Also, uncircumcised men are believed to be more likely carriers of the virus and to pass it on more easily to their sexual partners, although a strong scientific proof of this statement remains to be delivered.  Since HPV only causes visible genital warts in a small number of infected people, it is almost impossible to know whether somebody is infected with HPV, unless specific tests, that are expensive and not easily performed, can confirm the presence of HPV and any of its subtypes, and thus documenting its increased risk level of causing potentially malignant cellular changes anywhere on the cervix.    

Another potentially high risk factor consists of the presence of a Chlamydia infection. Chlamydia infections are the most common sexually transmitted disease (STD) worldwide, usually not causing any obvious clinical symptoms, yet being the cause of many pelvic diseases, where long-term Chlamydia infections can cause wide-spread pelvic inflammation, often leading to infertility.

An additional risk factor that is considered to be causative for cervical cancer is poverty or a low socioeconomic status.  This factor is mostly the result of  an inadequate access to healthcare services by this group of women, but it also includes all the women in Southern Africa who would not have sufficiently effective healthcare services available in their village, town or city, no matter whether they could pay for the services or not.

Other, less frequent causes of cervical cancer include the intake of Diethylstilbestrol (DES), a hormonal drug that was given to women between 1940 and 1971, in order to prevent the occurrence of miscarriages. About one woman in 1,000 women developed clear-cell adenocarcinoma of the cervix or vagina, following exposure to the drug.

And finally, a family history of cervical cancer, which generally is rare, but, if present, can increase the occurrence of cervical cancer by two to three times as compared to the normal overall average chance of developing this kind of cancer.

                                                                                          Normal cervix                              Squamous cell carcinoma
                                                                                     (Colposcopic view)                                   (Colposcopic view)

Cervical cancer in pregnancy – pregnant women usually do not develop cancer of the cervix. However, when it happens, and the disease is diagnosed at an early stage, she can safely complete her pregnancy.  Medical recommendations include performing a ceasarean section for the delivery of the baby, followed by a hysterectomy (removal of the uterus with the cervix, and, optionally, the fallopian tubes and ovaries.  Alternatively, a vaginal delivery could be performed, followed by a hysterectomy a few weeks later.

If the cancer is already in an advanced stage, it may be advisable to terminate the pregnancy and undergo a hysterectomy immediately, followed by radiation therapy (treatment by way of x-ray exposure to the cancerous area).  This is a difficult decision to make for any woman, and should always be made in unison with the father of the child. 

The second most frequent type of cervical cancer is the adenocarcinoma:

This cancer consists of glandular cells that usually start within the endocervix, or the lining cells of the uterus (endometrium).  Atypical glandular cells can be diagnosed at times even via a Pap test, otherwise by performing a dilation and curettage (D&C, endocervical curettage) for harvesting endocervical cells or tissue samples for cytological or histological evaluation.

Symptoms:

Cervical dysplasia, the ‘predecessor’ of cervical cancer, often does not produce any symptoms, and thus the cancer can grow silently and undetected.  Occasionally, the woman may experience some vaginal bleeding or spotting, especially following intercourse. Other signs may be an unusual vaginal discharge and odor (which can also point at a number of other sexually transmitted diseases), general pelvic pain or pain during or immediately after sexual intercourse. If a woman experiences any of these symptoms, she should contact a physician or health care facility, in order to find out what the cause of these symptoms is, and to start an appropriate treatment as soon as possible.  

Since cancer is often an insidious disease process which encroaches upon its victim in a slow unobtrusive manner, it is of utmost importance, to be very aware of any potential symptoms and to not delay a proper work-up, in order to detect the underlying cause of those symptoms.

 
Diagnosis:

While the symptoms can be few, there are a number of ways to diagnose any precancerous changes of a potentially developing cervical cancer:

First of all, there is always a proper physical exam – in this case a pelvic exam, during which the physician or examining medical person will evaluate the general condition of the vagina, cervix, the position of the uterus, as well as the fallopian tubes, ovaries and rectum. At this time, the examiner will also take a swab off the cervical surface, which is called a Papanicolaou test, or ‘Pap smear’:

A Pap smear or Pap test collects surface cells from the cervix via a swab stick (similar to a Q-tip), which will be placed onto a glass slide, then stained (according to the Papanicolaou staining method), and examined by a pathologist or cytologist for the presence of abnormal cells.  All women should undergo regular Pap tests, starting within three years after following their first sexual intercourse.  Two (2) days prior to having a Pap test done, you should NOT:

Make sure that you do not have your period at the time of taking a Pap test, since this may obscure potentially malignant cells.  Since Pap tests are easy and cheap  to perform, and can fairly accurately diagnose dysplastic cells and further advanced cell changes in almost 95% of cases, they should be repeated regularly within a few years, depending on the woman’s individual medical history and potential risk factors.

If the Pap test reveals dysplastic cells such as LGSIL or higher, a secondary examination will be performed, in order to further examine the status of the cervix. This follow-up examination will most likely be a ‘colposcopy’:

A colposcopy is performed by using a colposcope which is an instrument that the physician inserts into the vagina, in order to magnify the surface vision of the cervix in a bright light. Prior to inspecting the vagina this way, the cervix and vagina will be swabbed with a vinegar solution which will help to identify suspicious areas (called ‘Schiller test’) from which a biopsy may be taken to have any suspicious cervical cells to be examined by the pathologist.  While performing a colposcopy, an additional so-called ‘endo-cervical curettage’ – a so-called ‘dilation and curettage – D&C’, may also be performed, in order to collect additional cells from the (endo-) cervical canal.

Depending on the results of the above described tests, an additional diagnostic test may be performed – a so-called ‘cone biopsy’.  During this procedure, a cone-shaped piece of tissue consisting of the transformation zone, the area of the cervix encompassing the exocervix (or ectocervix) as well as the endocervix, will be taken.  This fairly large tissue biopsy will again be examined by the pathologist, in order to evaluate the extent of the spread of dysplastic cells.  Especially in low grade cellular dysplastic changes, this diagnostic procedure may often turn out to also be an (at least temporarily) effective therapeutic solution.

 A cone biopsy is usually performed by using a surgical scalpel or laser. This procedure is normally performed under general anesthesia – while the woman can go home the same day, she may experience cramping and bleeding for a few weeks afterward.

Other diagnostic tests, such as the LEEP (loop electrosurgical excision procedure, a variation of the cone biopsy), or a cervicography (photographic images of the surface of the cervix) require expensive equipment and specific training of the examining physician, and thus are not always available. While these procedures are less invasive and painful to the patient than some of the other tests, neither of these diagnostic test reveals more or better information than could have been achieved by any other diagnostic measurement.

Once any or all of the above listed tests have been performed and their results have been collected, and subsequently the diagnosis of ‘cervical cancer’ has been established, the cancer will be staged according to the extent of its growth.

Staging of cervical cancer describes the cancer’s:

Staging a cancer provides the treating physician with the necessary information to customize patient specific therapy plans, and to predict the prognosis of the patient’s survival rate. In general, the lower the stage of the cancer (e.g. Stage I), the better the patient’s prognosis (recovery and/or survival rate).

At this time, additional diagnostic tests may include, depending on their availability, an abdominal ultrasound examination, CT-scans (computer tomography), or a MRI (magnetic resonance imaging) exam may be performed, in order to evaluate the extent of the cancer’s spread.

Staging of cervical cancer is done by way of the so-called FIGO (International Federation of Gynecology and Obstetrics) System:

• Stage 0 – Carcinoma in situ; the tumor cells are only within the epithelium of the cervix, without having broken through the basement layer into deeper tissues;
• Stage I – invasive cancer with tumor growth strictly confined to the cervix itself;
• Stage II – invasive cancer, with growth extending beyond the cervix and/or the upper 2/3 of the vagina, but not yet extending onto the pelvic wall;
• Stage III – invasive cancer where the tumor spreads beyond the lower third of the vagina, or onto the pelvic wall; also, the tumor may block the flow of urine through (partially) blocked ureters from the kidneys to the bladder;
• Stage IV – invasive cancer – when the tumor is already spreading to other, distant parts of the body (metastases).

Stages I through IV have been further sub-classified, in order to provide an individual, most specific picture of the patient’s cancer growth. 

 
Treatment:

The treatment depends on the extent of the growth of cancer, i.e. the cancer’s stage (see above) – a non-invasive cancer can be treated much less aggressively than a cancer that has already broken the basement membrane and invaded deeper cervical tissue.

The most appropriate treatment plan depends on:

• The stage of the cancer (see Diagnosis), which includes the size of the tumor and the degree of invasiveness,
• The patient’s desire to have children in the future, and
• The patient’s age.

Treatment options during pregnancy also depend on the stage of the cancer as well as the stage of the pregnancy – treatment may be delayed until after the baby is born, especially if the cancer has only been diagnosed in the last trimester.

The three major forms of treatment include – surgery, radiation therapy, and chemo­therapy.  At times, the most effective approach may consider two or more of these methods.  If an effective cure seems not possible, treatment options would still include to remove or destroy as much cancer tissue as possible to prevent the tumor from growing and spreading to other sites for as long as possible.  Treatment that is aimed at only relieving symptoms of a cancer that is already too far advanced for effective treatment, is called ‘palliative therapy’.

Surgery – depending on the stage of the cancer, can result in a survival rate of 85% to 90%; factors that influence the choice for opting for surgery include the woman’s age, general health status and the extent of the disease.  Potential surgical procedures include:

• Cryosurgery – also called cryotherapy, in which extreme cold, produced by liquid nitrogen is used to destroy abnormal tissue.  It can be applied directly to tumor tissue with a cotton swab or spraying device; while it can effectively be applied to a number of precancerous lesions of the cervix, it is not effective for invasive tumors.

• Laser surgery – this can be an outpatient procedure, if the cancer has not spread.  Laser surgery destroys the cancerous cells on the surface by way of a focused, high-energy light beam and can even remove small tissue samples for pathological analysis; however, it cannot be used to treat invasive cervical cancer.

• Cone biopsy (conization) – used for diagnostic purposes (see above), but can also be an effective treatment in early cancerous tissue progression.   A cone biopsy can be performed by using a surgical scalpel, a laser knife or a so-called LEEP (loop electro­surgical excision procedure). Conization is rarely the sole treatment of cervical cancer – it is usually only used for women whose cancer has not invaded deep tissues yet and who want to preserve their ability to bear children.
  
• Hysterectomy – the surgical removal of the uterus, with or without the ovaries.  This option is indicated in advanced, invasive cancers, as an alternative or adjunct to radiation therapy (again depending on the cancer’s stage).  There are three types of hysterectomy:

• Simple (total) hysterectomy – indicated for invasive cancer that has not yet spread beyond the uterus itself.  This procedure includes only the cervix and leaves the ovaries, vagina and adjacent lymph nodes untouched.  A simple hysterectomy can be performed abdominally – by way of incising the lower abdomen, or vaginally – via the vagina.
• Radical hysterectomy – a much more advanced surgical procedure, is indicated when the cancer has spread beyond the boundaries of the cervix itself.  This procedure includes the removal of the uterus with cervix, both fallopian tubes and ovaries, as well as the parametrium (the tissue surrounding the uterus), the upper portion of the vagina, and some or all of the local lymph nodes.
• Pelvic exenteration – is the most extreme procedure, which fortunately is only rarely indicated.  It is used in order to treat recurrent cervical cancer or far advanced cancer that has spread well beyond the uterus to surrounding organs.  A pelvic exenteration may, at times, even include the removal of the urinary bladder, the rectum and other parts of the colon, as well as the vagina in its entirety.

Radiation therapy, or radiotherapy – uses high-energy x-rays to destroy the cancer cells.  This form of treatment is usually applied to cancers that already extend beyond the cervix itself into the pelvis, the lower vagina, and/or the urinary tract.  Radiotherapy can be used, and often is combined with surgery and/or chemotherapy; it also can relieve certain symptoms caused by advanced cancer.  It is performed by either using external beam radiation (most often used procedure) or by using radioactive implants (also called brachytherapy) that are either inserted into the cervix or inserted directly into the cancer by way of thin needles. Radiation therapy can cause numerous side effects from simple fatigue, diarrhea, vaginal dryness and itching to inflammation of the bladder and rectum, vaginal scarring with subsequent sexual difficulties, anemia and vesicovaginal fistulas (abnormal tunnel-like connections between the vagina and the bladder and/or rectum, causing repeated vaginal and urinary bladder infections). 

Chemotherapy – is the use of cytotoxic (cancer-killing) drugs, and the treatment of choice for far advanced cancer that has spread to distant organs, and thus cannot be treated anymore by surgery or radiation.  It is also used in recurrent cervical cancer, following previous surgery and/or radiotherapy.  Chemotherapy can also be indicated to relieve pain in advanced stage cancers, or to shrink a large cancer to a smaller size that can then be treated by surgical removal (‘neoadjuvent chemotherapy’).
 Chemotherapy treatments are typically given in stages, allowing the woman to recover and regain her strength between periods of treatment.  Usually, more than one drug is given, because a combination of two or three differently acting drugs may be more effective than just one drug. 

Side effects of chemotherapy can be rather extensive and, at times, somewhat debilitating, as they include:

• Nausea and vomiting,
• Hair loss (temporary – the hair will grow back after chemotherapy has been completed),
• Fatigue,
• Higher susceptibility to infections,
• Bruising and bleeding episodes,
• Anemia,
• Changes in the menstrual cycle – early menopause - infertility,
• Sores in mouth and vagina,
• Appetite changes.

Most side effects usually abate after the chemotherapy has been completed.

Another treatment option includes biological therapy, such as interferon, a protein that provides some immunity to viral infections.  Biological therapy can be used when the cancer has spread well beyond the cervix to other organs, or in combination with chemotherapy.

Treatment of adenocarcinoma of the cervix usually consists of a hysterectomy (removal of the uterus with cervix) and sampling of local lymph nodes.  If the tumor has spread beyond the cervicouterine organ, the surgery will have to become more extensive.

 
Prevention:

Cervical cancer starts with a series of pre-cancerous, dysplastic cell changes which are caused by a virus – the so-called Human Papilloma Virus, HPV. HPV is transmitted during sexual intercourse.  Thus, in order to prevent becoming infected with the virus, the same precautions for cervical cancer as for sexually transmitted diseases (STDs) apply:

• Use condoms – either a male or female condom,
• Limit the number of sexual partners, especially of promiscuous partners,
• Delay the age of first sexual intercourse,
• Do not smoke – smoking is known to double the risk for the development of cervical cancer, although the connections are not clear.

A second method of prevention consists of a newly developed vaccine against the most prevalent HPV subtypes which are associated with the development of cervical cancer.  The cancerous subtypes are HPV types 6, 11, 16 and 18 – the vaccine is, however, only effective, if given prior to an infection with those subtypes – it has no therapeutic effects, following the development of (pre-) cancerous cell changes.  Thus, it is recommended to take the vaccination prior to a girl’s first sexual encounter. 

The vaccination consists of three injections within a six month period – the first on day one, the second after two months, and the third after another four months. Side effects are usually minimal, but the costs of the vaccine series are over US-$ 350, plus doctor’s fee and other related expenses.  As the vaccine becomes more available on the market, and other competitive vaccines will be developed, it is hoped that the price will come down to more affordable levels, and thus, to a more effective public service to the general population who cannot afford the vaccine, or is not covered by a health insurance  that would pay for the vaccination.  Furthermore, booster shots after several years are still recommended, since the overall long-term effectiveness of the vaccine is not yet completely understood at this point in time.

And, of course, screening tests, consisting of a gynecological physical examination and a Pap test of the cervical surface cells, should be performed regularly – once every year until age 30, thereafter, every three years, provided the results remain negative.  Pap smears are usually read by a cytologist technician or a pathologist – recently, computerized instruments have been developed that can ‘read’ a Pap smear – however, questionable or positive results should be rechecked by a trained cytologist or pathologist.  Early detected precancerous cervical cell changes can be cured in almost 100% of all cases.

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