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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 its 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 more than 90% of the cases of cervical
cancer. According to a survey of 3,076 women 18 to 75 years of age,
awareness about human papillomavirus (HPV) infection and its link to
cervical cancer is relatively low among American women. In 2006 an
estimated 10,000 women in the United States will be diagnosed with
this type of cancer and nearly 4,000 will die from it.[1] More then 60
types of HPVs are acknowledged to exist (depending on the reference,
some sources indicate more then 200 subtypes) [2].[3]. Of these,
fifteen HPV types are classified as high-risk types (16, 18, 31, 33,
35, 39, 45, 51, 52, 56, 58, 59, 68, 73, and 82), 3 are classified as
probable high-risk types (26, 53, and 66); and 12 are classified as
low-risk types (6, 11, 40, 42, 43, 44, 54, 61, 70, 72, 81, and
CP6108).[4]. .[5] Types 16 and 18 are generally acknowledged to cause
about 70% of the cancers. There are “low-risk” viruses which do not
commonly turn into cancer and “high-risk” viruses that are most likely
to develop into cervical cancer, although both can. Having several
sexual partners is a major risk factor for developing HPV. Although
most HPV infections clear up on their own, the infections could
increase to major abnormalities or cervical cancer.[6] Doctors can
test samples of cervical cells to determine types of HPV that may be
present. In some cases, HPV clears up on its own, and in some, there
were no signs until it was too late, and cervical cancer developed.
Treatment consists of surgery (including local excision) in early
stages and chemotherapy and radiotherapy in advanced stages of the
disease. An effective vaccine, the HPV 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. Also, moderate pain during sexual intercourse and vaginal
discharge are symptoms of cervical cancer. In advanced disease,
metastases may be present in the abdomen, lungs or elsewhere.
Symptoms of advanced cervical cancer may include: Loss of appetite,
Weight loss, Fatigue, Pelvic pain, Back pain, Leg pain, Single swollen
leg, Heavy bleeding from the vagina, Leaking of urine or feces from
the vagina, and Bone fractures
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.[7]
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:
[8] [9]
M8070/3: squamous cell carcinoma (about 80-85%)
M8140/3: adenocarcinoma
M8560/3: adenosquamous carcinomas
M8041/3: small cell carcinoma
M8246/3: neuroendocrine carcinoma
M8720/3: 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 ⅓ of the vagina
IIIA - involves lower ⅓ 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, 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. However, there has not been any
definitive evidence to support this claim.
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[10].
If a cone biopsy was not able to produce clear margins[11], 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[12]. 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.
[13] 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.[14] 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 [15]instead of abdominally [16], however there are
conflicting opinions as to which approach is better. [17] A radical
abdominal trachelectomy with lymphadenecectomy usually only requires a
2- to 3-day hospital stay with most women recovering very quickly
(approximately 6 weeks). Complications are generally uncommon,
although women who are able to conceive after surgery are prone to
preterm labor or possible late miscarriage.[18] It is generally
recommended to wait at least one year before attempting to become
pregnant after surgery.[19] Recurrence in the residual cervix is a
very rare event as long as the cancer has been cleared with the
trachelectomy.[20] 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 [21] 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.[22]
In Great Britain, the incidence is inline with that of the rest of
Northern Europe with an annual incidence of 8.8/100,000 (2001) and an
annual mortality of 2.8/100,000 (2003)(Cancer Research UK Cervical
cancer statistics for the UK). With a 42% reduction from 1988-1997 the
NHS implemented screening programme has been highly succesful,
screening the highest risk age group (25-40 years) every 3 years, and
those ages 41-65 every 5 years.
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.
One study suggests that prostaglandin in semen may fuel the growth of
cervical and uterine tumours and that affected women might benefit
from the use of condoms.[1][2]
History
Epidemiologists working in the early 20th century noted
that:
Cervical cancer was common in female sex workers.
It was rare in nuns, except for those who had been sexually active
before entering the convent. (Rigoni in 1841)
It was more common in the second wives of men whose first wives had
died from cervical cancer.
It was rare in Jewish women.[23]
in 1935, Syverton and Berry discovered a relationship between HPV and
skin cancer in rabbits.
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. A
description by electron microcopy was given earlier in 1949 and HPV-DNA
was identified in 1963. It has since been demonstrated that HPV is
implicated in all cervical cancers. Specific viral subtypes implicated
are HPV 16, 18, 31 and 45.
Vaccine
Main article: HPV vaccine
Merck & Co. has developed a vaccine against four strains of HPV
(6,11,16,18), called Gardasil™. It is now on the market after
receiving Food and Drug Administration approval [24] on June 8, 2006.
Gardasil is targeted at girls and women of age 9 to 26 because the
vaccine only works if given before infection occurs; therefore, public
health workers are targeting girls before they begin having sex. The
use of the vaccine in men to prevent genital warts and interrupt
transmission to women is initially considered only a secondary market.
The high cost of this vaccine has been a cause for concern. Gardasil
has received EU approval.[3]
Glaxosmithkline has developed a vaccine called Cervarix™ which has
been shown to be 100% effective in preventing HPV strains 16 and 18
and is 100% effective for more than four years[25]. The two HPV
strains (16 and 18) together cause about 70% of cervical cancer cases.
Cervarix should be approved by year's end.[4][5]
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