Cervical cancer

Cervical cancer is a malignancy of the cervix. Worldwide, it is the second most common cancer of women. It may present with vaginal bleeding but symptoms may be absent until the cancer is in advanced stages, which has made cervical cancer the focus of intense screening efforts utilizing the Pap smear. Most scientific studies have found that human papillomavirus (HPV) infection is responsible for >90% of the cases of cervical cancer. There are 7 most common types of HPV - 16, 18, 31, 33, 42, 52 and 58. Types 16 and 18 being the most common cause of the cancer. Treatment is with surgery (including local exicision) in early stages and chemotherapy and radiotherapy in advanced stages of the disease. An effective vaccine for the two most common strains of HPV has recently been licenced (see Vaccine section, below).

Signs and symptoms
The early stages of cervical cancer may be completely asymptomatic (Canavan & Doshi, 2000). Vaginal bleeding, contact bleeding or (rarely) a vaginal mass may indicate the presence of malignancy. In advanced disease, metastases may be present in the abdomen, lungs or elsewhere.

The possibility to identify premalignant changes on a cervical smear has made screening the major cause for referral of women with possible cervical neoplasia. In many countries, women are advised to have a regular Pap smear to check for premalignant changes. Recommendations for how often a Pap smear should be done vary from once a year to once every five years. If cervical cancer is detected early, it can be treated without impairing fertility. Consistently abnormal smears may be a reason for further diagnosis despite complete absence of symptoms.

Diagnosis
Diagnosis is made by doing a biopsy of the cervix, which often involves colposcopy, or a magnified visual inspection of the cervix aided by using an acetic acid (e.g. vinegar) solution to highlight abnormal cells on the surface of the cervix (the portio). A Pap smear is insufficient for the diagnosis. Many researchers recommend that since more than 99% of invasive cervical cancers worldwide contain human papillomavirus, HPV testing should be carried out together with routine cervical screening (Walboomers et al, 1999). However, given the prevalence of HPV (around 80% infection history among the sexually active population) others suggest that routine HPV testing would cause undue alarm to carriers.

Further diagnostic procedures are loop electrical excision procedure (LEEP) and conisation, in which the inner lining of the cervix is removed to be examined pathologically. These are carried out if the biopsy confirms severe dysplasia.

Histology
Types of malignant cervical tumors include the following:


 * : squamous cell carcinoma (about 80-85%)
 * : adenocarcinoma
 * : adenosquamous carcinomas
 * : small cell carcinoma
 * : neuroendocrine carcinoma
 * : melanoma
 * (varied): lymphoma

Staging
Cervical cancer is staged by the FIGO staging system, which is based on clinical examination, rather than surgical findings. It allows only the following diagnostic tests to be used in determining the stage: palpation, inspection, colposcopy, endocervical curettage, hysteroscopy, cystoscopy, proctoscopy, intravenous urography, and X-ray examination of the lungs and skeleton, and cervical conization.

The TNM staging system for cervical cancer is analogous to the FIGO stage.
 * Stage 0 - full-thickness involvement of the epithelium without invasion into the stroma (carcinoma in situ)
 * Stage I - limited to the uterus
 * IA - diagnosed only by microscopy; no visible lesions
 * IA1 - stromal invasion less than 3 mm in depth and 7 mm or less in horizontal spread
 * IA2 - stromal invasion between 3 and 5 mm with horizontal spread of 7 mm or less
 * IB - visible lesion or a microscopic lesion with more than 5 mm of depth or horizontal spread of more than 7 mm
 * IB1 - visible lesion 4 cm or less in greatest dimension
 * IB2 - visible lesion more than 4 cm
 * Stage II - invades beyond uterus
 * IIA - without parametrial invasion
 * IIB - with parametrial invasion
 * Stage III - extends to pelvic wall or lower 1/3 of the vagina
 * IIIA - involves lower 1/3 of vagina
 * IIIB - extends to pelvic wall and/or causes hydronephrosis or non-functioning kidney
 * IVA - invades mucosa of bladder or rectum and/or extends beyond true pelvis
 * IVB - distant metastasis

Note that the FIGO stage does not incorporate lymph node involvement in contrast to the TNM staging for most other cancers.

For cases treated surgically, information obtained from the pathologist can be used in assigning a separate pathologic stage but is not to replace the original clinical stage.

For premalignant dysplastic changes, the CIN (cervical intraepithelial neoplasia) grading is used.

Pathophysiology
The American Cancer Society provides the following list of risk factors for cervical cancer: human papillomavirus infection, smoking, HIV infection, chlamydia infection, dietary factors, oral contraceptives, multiple pregnancies, low socioeconomic status, use of the hormonal drug diethylstilbestrol (DES) and a family history of cervical cancer.

The presence of strains 16, 18 and 31 of human papillomavirus (HPV) is the prime risk factor for cervical cancer, and Walboomers et al. (1999) reported that the presence of HPV is a necessary condition for the development of cervical cancer. A virus cancer link with HPV has been found to trigger alterations in the cells of the cervix, leading to the development of cervical intraepithelial neoplasia and cancer.

HPV subtypes 16 and 18 introduce two genes called E6 and E7 which code for proteins that inhibit p53 and Rb, which are two important tumor suppressor genes in humans. The p53 gene product is involved in regulation of apoptosis (cell suicide), and Rb is responsible for halting the cell cycle at the G1-phase. When Rb function is impaired, the cell is allowed to progress to S-phase and complete mitosis, resulting in proliferation and hence neoplastic transformation.

Genital warts are caused by different HPV types, and are not related to cervical cancer.

The medically accepted paradigm, officially endorsed by the American Cancer Society and other organizations, is that a patient must have been infected with HPV to develop cervical cancer, and is hence viewed as a sexually transmitted disease. Not all women infected with HPV also develop cervical cancer (Snijders et al, 2006). Use of condoms will not always prevent transmission. Likewise, HPV can be transmitted by skin-to-skin-contact with infected areas. HPV is thought to grow preferentially in the epithelium of the glans penis, and scrupulous washing and cleaning of this area may be preventative. The position on circumcision is controversial: some researchers argue that routine neonatal circumcision is an acceptable way of preventing various diseases (which include cervical carcinoma); others maintain that the benefits do not outweigh the risks.

Treatment
Microinvasive cancer (stage IA) is usually treated by hysterectomy (removal of the whole uterus including part of the vagina). For stage IA2, the lymph nodes are removed as well. An alternative for patients who desire to maintain fertility is a local surgical procedure such as a LEEP or cone biopsy.

If a cone biopsy was not able to produce clear margins, there is one possible option left for those with early stage cervical cancer who would like to preserve their fertility while treating their cervical cancer: a trachelectomy. For those in stage I cervical cancer, which has not spread, this is a viable treatment option. It allows for the preservation of the ovaries and uterus while surgically removing the cervical cancer. This treatment option is not yet well known amongst doctors and is not yet considered a standard of care. Furthermore, few doctors are trained in this fertility sparing surgical option. Even the most experienced surgeon won't be able to promise that this can be performed beforehand, as the extent of the spread of cervical cancer is unknown until surgical microscopic examination is completed. As a result, there is always the possibility for the need to convert to a hysterectomy if the surgeon is not able to microscopically confirm clear margins of cervical tissue once the patient is under general anesthesia in the operating room. This can only be done during the same operation if the patient has given consent for a possible hysterectomy prior to the operation. Due to the fact of the possible risk of cancer spread to the lymph nodes in stage 1b cancers and some stage 1a cancers, the surgeon may also need to remove some lymph nodes from around the womb. Once all the checks have been done and if all is well, the cervix will be stitched closed with a cerclage. This will allow for menstruation and fertilization but not dilation for a vaginal delivery, therefore requiring any future births are delivered by cesarean section. A radical trachelectomy is a smaller operation than hysterectomy, but more importantly allows for the preservation of fertility. This operation can also be performed vaginally instead of abdominally, however there are conflicting opinions as to which approach is better. A radical abdominal trachelectomy with lymphadenecectomy usually only requires a 2 - 3 day hospital stay with most women recovering very quickly (approximately 6 weeks). Complications are generally uncommon, however women who are able to conceive after surgery are prone to preterm labor or possible late miscarriage. It is generally recommended to wait at least one year before attempting to become pregnant after surgery. Recurrence in the residual cervix is a very rare event as long as the cancer has been cleared with the trachelectomy. Even though recurrence is rare, it is generally recommended for patients to practice vigilant prevention and follow up care including pap screenings/colposcopy, with biopies of the remaining lower uterine segment as needed (every 3-4 months for at least 5 years) to monitor for any recurrance in addition to minimizing any new exposures to HPV through safe sex practices until one is actively trying to conceive. Early stages (IB1 and IIA less than 4 cm) can be treated with radical hysterectomy with removal of the lymph nodes or radiation therapy. Radiation therapy is given as external beam radiotherapy to the pelvis and brachytherapy (internal radiation). For patients treated with surgery who have high risk features found on pathologic examination, radiation therapy with or without chemotherapy is given in order to reduce the risk of relapse.

Larger early stage tumors (IB2 and IIA more than 4 cm) may be treated with radiation therapy and cisplatin-based chemotherapy, hysterectomy (which then usually requires adjuvant radiation therapy), or cisplatin chemotherapy followed by hysterectomy.

Advanced stage tumors (IIB-IVA) are treated with radiation therapy and cisplatin-based chemotherapy.

On June 15, 2006 Food and Drug Administration has approved uses combination of two chemotherapy drugs, Hycamtin and cisplatin for women with late-stage (IVB) cervical cancer treatment. Combination treatment has significant risk of neutropenia, anemia, and thrombocytopenia side effects. Hycamtin is manufactured by GlaxoSmithKline.

Epidemiology
Worldwide, cervical cancer is the second most common cancer in women (after breast cancer) and is the third leading killer (behind breast and lung cancer). It affects about 16 per 100,000 women per year and causes death in about 9 per 100,000 per year.

In the United States, however, cervical cancer is only the 8th most common cancer of women. About 12,800 women in the United States are diagnosed with cervical cancer and about 4,800 die each year (Canavan & Doshi, 2000). Among gynecological cancers it ranks behind endometrial cancer and ovarian cancer. The incidence and mortality figure for the U.S. are about half that of the rest of the world, a difference which can be attributed in part to the success of screening with the Pap smear.

In Great Britain the incidence of cervical cancer has reached alarming proportions in that the mortality in England and Wales in women younger than 35 years rose three-fold from 1967 to 1987. In a study published in 2004 (Peto J et al) scientists from the London School of Hygiene and Tropical Medicine found that had it not been for effective cervical screening, one in 65 of all British women born since 1950 would have died from cancer of the cervix.

A study published in 2002 (Castellsagué et al) reports that male circumcision can reduce the risk of penile human papillomavirus (HPV) infection in the man, and as a result that of cervical cancer in his female partner. The authors do state that "it would not make sense to promote circumcision as a way to control cervical cancer in the United States, where Pap smears usually detect it at a treatable stage". In contrast to this claim, Menczer (2004) quotes research that male circumcision probably does not contribute to a lower incidence of cervical cancer in Jewish populations.

History
Epidemiologists working in the early 20th century noted that:
 * 1) Cervical cancer was common in female sex workers.
 * 2) It was rare in nuns, except for those who had been sexually active before entering the convent.
 * 3) It was more common in the second wives of men whose first wives had died from cervical cancer.
 * 4) It was rare in Jewish women.

This led to the deduction that cervical cancer could be caused by a sexually transmitted agent. Initial research in the 1950s and 1960s put the blame on smegma (e.g. Heins et al 1958), but it wasn't until the 1970s that human papillomavirus (HPV) was identified. It has since been demonstrated that HPV is implicated in all cervical cancers. Specific viral subtypes implicated are HPV 16, 18 and 31.

Vaccine
Merck & Co. has developed a vaccine against four strains of HPV called Gardasil™. It is now on the market after receiving Food and Drug Administration approval on June 8, 2006. Gardasil™ is targeting girls and women age 9 to 26 because the vaccine works best when given to girls before they begin having sex.

A bi-valent vaccine to prevent HPV infection has been also developed by Israel and tested (Harper et al 2004). It confers immunity against the two (thus, bi-valent) HPV strains 16 & 18. This vaccine, when it is licenced and goes into production, could substantially reduce the incidence of HPV infection, the incidence of cervical cancer, and mortality (Lehtinen & Dillner 2002).

Advaxis, Inc (OTCBB: ADXS) is developing a therapeutic vaccine to treat existing cervical cancer. The therapeutic vaccine, Lovaxin C, has entered clinical trials in March 2006. The vaccine is based on a modified, genetically engineered strain of the bacteria Listeria monocytogenes.