Prostate cancer is a form of cancer that develops in the prostate, a gland in the male

reproductive system. Most prostate cancers are slow growing; however, there are cases of
aggressive prostate cancers.[1] The cancer cells may metastasize (spread) from the prostate to
other parts of the body, particularly the bones and lymph nodes. Prostate cancer may cause pain,
difficulty in urinating, problems during sexual intercourse, or erectile dysfunction. Other
symptoms can potentially develop during later stages of the disease.

Rates of detection of prostate cancers vary widely across the world, with South and East Asia
detecting less frequently than in Europe, and especially the United States.[2] Prostate cancer tends
to develop in men over the age of fifty and although it is one of the most prevalent types of
cancer in men, many never have symptoms, undergo no therapy, and eventually die of other
causes. This is because cancer of the prostate is, in most cases, slow-growing, symptom-free, and
since men with the condition are older they often die of causes unrelated to the prostate cancer,
such as heart/circulatory disease, pneumonia, other unconnected cancers, or old age. About 2/3
of cases are slow growing "pussycats", the other third more aggressive, fast developing being
known informally as "tigers".[3]

Many factors, including genetics and diet, have been implicated in the development of prostate
cancer. The presence of prostate cancer may be indicated by symptoms, physical examination,
prostate specific antigen (PSA), or biopsy. There is controversy about the accuracy of the PSA
test and the value of screening. Suspected prostate cancer is typically confirmed by taking a
biopsy of the prostate and examining it under a microscope. Further tests, such as CT scans and
bone scans, may be performed to determine whether prostate cancer has spread.

Treatment options for prostate cancer with intent to cure are primarily surgery, radiation therapy,
and proton therapy. Other treatments, such as hormonal therapy, chemotherapy, cryosurgery, and
high intensity focused ultrasound (HIFU) also exist, depending on the clinical scenario and
desired outcome.

The age and underlying health of the man, the extent of metastasis, appearance under the
microscope, and response of the cancer to initial treatment are important in determining the
outcome of the disease. The decision whether or not to treat localized prostate cancer (a tumor
that is contained within the prostate) with curative intent is a patient trade-off between the
expected beneficial and harmful effects in terms of patient survival and quality of life.

Signs and symptoms

Early prostate cancer usually causes no symptoms. Often it is diagnosed during the workup for
an elevated PSA noticed during a routine checkup.

Sometimes, however, prostate cancer does cause symptoms, often similar to those of diseases
such as benign prostatic hyperplasia. These include frequent urination, increased urination at
night, difficulty starting and maintaining a steady stream of urine, blood in the urine, and painful
urination. Prostate cancer is associated with urinary dysfunction as the prostate gland surrounds
the prostatic urethra. Changes within the gland, therefore, directly affect urinary function.
Because the vas deferens deposits seminal fluid into the prostatic urethra, and secretions from the
prostate gland itself are included in semen content, prostate cancer may also cause problems with
sexual function and performance, such as difficulty achieving erection or painful ejaculation.[9]

Advanced prostate cancer can spread to other parts of the body, possibly causing additional
symptoms. The most common symptom is bone pain, often in the vertebrae (bones of the spine),
pelvis, or ribs. Spread of cancer into other bones such as the femur is usually to the proximal part
of the bone. Prostate cancer in the spine can also compress the spinal cord, causing leg weakness
and urinary and fecal incontinence.[10]

Pathophysiology

When normal cells are damaged beyond repair, they are eliminated by apoptosis. Cancer cells
avoid apoptosis and continue to multiply in an unregulated manner.

Prostate cancer is classified as an adenocarcinoma, or glandular cancer, that begins when normal
semen-secreting prostate gland cells mutate into cancer cells. The region of prostate gland where
the adenocarcinoma is most common is the peripheral zone. Initially, small clumps of cancer
cells remain confined to otherwise normal prostate glands, a condition known as carcinoma in
situ or prostatic intraepithelial neoplasia (PIN). Although there is no proof that PIN is a cancer
precursor, it is closely associated with cancer. Over time, these cancer cells begin to multiply and
spread to the surrounding prostate tissue (the stroma) forming a tumor. Eventually, the tumor
may grow large enough to invade nearby organs such as the seminal vesicles or the rectum, or
the tumor cells may develop the ability to travel in the bloodstream and lymphatic system.
Prostate cancer is considered a malignant tumor because it is a mass of cells that can invade
other parts of the body. This invasion of other organs is called metastasis. Prostate cancer most
commonly metastasizes to the bones, lymph nodes, rectum, and bladder.

The prostate is a zinc accumulating, citrate producing organ. The protein ZIP1 is responsible for
the active transport of zinc into prostate cells. One of zinc's important roles is to change the
metabolism of the cell in order to produce citrate, an important component of semen. The
process of zinc accumulation, alteration of metabolism, and citrate production is energy
inefficient, and prostate cells sacrifice enormous amounts of energy (ATP) in order to
accomplish this task. Prostate cancer cells are generally devoid of zinc. This allows prostate
cancer cells to save energy not making citrate, and utilize the new abundance of energy to grow
and spread. The absence of zinc is thought to occur via a silencing of the gene that produces the
transporter protein ZIP1. ZIP1 is now called a tumor suppressor gene product for the gene
SLC39A1. The cause of the epigenetic silencing is unknown. Strategies which transport zinc into
transformed prostate cells effectively eliminate these cells in animals. Zinc inhibits NF-κB
pathways, is anti-proliferative, and induces apoptosis in abnormal cells. Unfortunately, oral
ingestion of zinc is ineffective since high concentrations of zinc into prostate cells is not possible
without the active transporter, ZIP1.[11]

RUNX2 is a transcription factor that prevents cancer cells from undergoing apoptosis thereby
contributing to the development of prostate cancer.[12]

The PI3k/Akt signaling cascade works with the transforming growth factor beta/SMAD
signaling cascade to ensure prostate cancer cell survival and protection against apoptosis.[13] X-
linked inhibitor of apoptosis (XIAP) is hypothesized to promote prostate cancer cell survival and
growth and is a target of research because if this inhibitor can be shut down then the apoptosis
cascade can carry on its function in preventing cancer cell proliferation.[14] Macrophage
inhibitory cytokine-1 (MIC-1) stimulates the focal adhesion kinase (FAK) signaling pathway
which leads to prostate cancer cell growth and survival.[15]

The androgen receptor helps prostate cancer cells to survive and is a target for many anti cancer
research studies; so far, inhibiting the androgen receptor has only proven to be effective in mouse
studies.[16] Prostate specific membrane antigen (PSMA) stimulates the development of prostate
cancer by increasing folate levels for the cancer cells to use to survive and grow; PSMA
increases available folates for use by hydrolyzing glutamated folates.[17]

Screening
Main article: Prostate cancer screening

Prostate cancer screening is an attempt to find unsuspected cancers, and may lead to more
specific follow-up tests such as a biopsy, with cell samples taken for closer study. Prostate
cancer screening options include the digital rectal exam and the prostate-specific antigen (PSA)
blood test. Prostate cancer is usually slow-growing and more common among older men.
However, most cancers never grow enough to cause symptoms, and most men that have prostate
cancer will never become aware of it in their lifetimes.

In Sweden, researchers recently found that prostate cancer really is "no longer a fatal disease."
Even without treatment, researchers conclude that "only a small minority of men diagnosed with
early-stage prostate cancer die from the disease," and that there is "no need to panic." Modern
screening tests have found cancers that might never have developed into serious disease, and that
"the slight reduction of risk by surgically removing the prostate or treating it with radiation may
not outweigh the substantial side effects of these treatments," an opinion also shared by the CDC.
[18][19]

Diagnosis
The only test that can fully confirm the diagnosis of prostate cancer is a biopsy, the removal of
small pieces of the prostate for microscopic examination. However, prior to a biopsy, several
other tools may be used to gather more information about the prostate and the urinary tract.
Digital rectal examination may allow a doctor to detect prostate abnormalities. Cystoscopy
shows the urinary tract from inside the bladder, using a thin, flexible camera tube inserted down
the urethra. Transrectal ultrasonography creates a picture of the prostate using sound waves from
a probe in the rectum.
Cervical cancer is malignant neoplasm of the cervix uteri or cervical area. It may present with
vaginal bleeding but symptoms may be absent until the cancer is in its advanced stages.[1]
Treatment consists of surgery (including local excision) in early stages and chemotherapy and
radiotherapy in advanced stages of the disease.

Pap smear screening can identify potentially precancerous changes. Treatment of high grade
changes can prevent the development of cancer. In developed countries, the widespread use of
cervical screening programs has reduced the incidence of invasive cervical cancer by 50% or
more.[citation needed]

Human papillomavirus (HPV) infection is a necessary factor in the development of nearly 70%
of cases of cervical cancer.[1][2] HPV vaccine effective against the two strains of HPV that cause
the most cervical cancer has been licensed in the U.S, Canada, Australia and the EU. These two
HPV strains together are currently responsible for approximately 70%[3][4] of all cervical cancers.
Since the vaccine only covers some high-risk types, women should seek regular Pap smear
screening, even after vaccination.[5]

Signs and symptoms

The early stages of cervical cancer may be completely asymptomatic.[1][8] 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,[9] and bone fractures.

Causes
[edit] Human papillomavirus infection

In the United States each year there are more than 6.2 million new HPV infections in both men
and women, according to the CDC, of which 10 percent will go on to develop persistent
displaysia or cervical cancer. That is why HPV is known as the "common cold" of the sexually
transmitted infection world. It is very common and affects roughly 80 percent of all sexually
active people, whether they have symptoms or not. The most important risk factor in the
development of cervical cancer is infection with a high-risk strain of human papillomavirus. The
virus cancer link works by triggering alterations in the cells of the cervix, which can lead to the
development of cervical intraepithelial neoplasia, which can lead to cancer.

Women who have many sexual partners (or who have sex with men who had many other
partners) have a greater risk.[10][11]
More than 150 types of HPV are acknowledged to exist (some sources indicate more than 200
subtypes).[12][13] Of these, 15 are classified as high-risk types (16, 18, 31, 33, 35, 39, 45, 51, 52,
56, 58, 59, 68, 73, and 82), 3 as probable high-risk (26, 53, and 66), and 12 as low-risk (6, 11,
40, 42, 43, 44, 54, 61, 70, 72, 81, and CP6108),[14] but even those may cause cancer. Types 16
and 18 are generally acknowledged to cause about 70% of cervical cancer cases. Together with
type 31, they are the prime risk factors for cervical cancer.[15]

Genital warts are caused by various strains of HPV which are usually not related to cervical
cancer. However, it is possible to have multiple strains at the same time, including those that can
cause cervical cancer along with those that cause warts. 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, but most women infected with high risk HPV will not develop cervical
cancer.[16] Use of condoms reduces, but does not always prevent transmission. Likewise, HPV
can be transmitted by skin-to-skin-contact with infected areas. In males, there is no available test
to check for HPV, although HPV is thought to grow preferentially in the epithelium of the glans
penis, and cleaning of this area may be preventative.

Diagnosis
[edit] Visual inspection to detect precancer or cancer

Visual inspection of the cervix, using acetic acid or Lugol’s iodine to highlight precancerous
lesions so they can be viewed with the “naked eye”, shifts the identification of precancer from
the laboratory to the clinic. Such procedures eliminate the need for laboratories and transport of
specimens, require very little equipment and provide women with immediate test results. A range
of medical professionals—doctors, nurses, or professional midwives—can effectively perform
the procedure, provided they receive adequate training and supervision. As a screening test, VIA
performs equal to or better than cervical cytology in accurately identifying pre-cancerous lesions.
[19]
This has been demonstrated in various studies where trained physicians and mid level
providers correctly identified between 45% and 79% of women at high risk of developing
cervical cancer.[20] By comparison, the sensitivity of cytology has been shown to be between 47
and 62%.It should be noted, however, that cytology provides higher specificity than VIA. Like
cytology, one of the limitations of VIA is that results are highly dependant on the accuracy of an
individual’s interpretation. This means that initial training and on-going quality control are of
paramount importance.

VIA can offer significant advantages over Pap in low-resource settings, particularly in terms of
increased screening coverage, improved follow up care and overall program quality. Due to the
need for fewer specialized personnel and less infrastructure, training, and equipment, with VIA
public health systems can offer cervical cancer screening in more remote (and less equipped)
health care settings and can achieve higher coverage. Furthermore, providers can share the
results of VIA with patients immediately, making it possible to screen and treat women during
the same visit. This helps ensure that follow up care can be provided on the spot and reduces the
number of women who may miss out on treatment because they are not able to return to the
clinic at another time. In a “screen and treat” project in Peru, for example, only 9% of women
who screened positive failed to receive treatment in the single-visit approach, compared with
44% of women who were lost to treatment using a multi-visit model.[21]

VIA has successfully been paired with cryotherapy, a relatively simple and inexpensive method
of treating cervical lesions that can be performed by primary care physicians and mid-level
providers.[22]

[edit] Biopsy procedures

While the pap smear is an effective screening test, confirmation of the diagnosis of cervical
cancer or pre-cancer requires a biopsy of the cervix. This is often done through colposcopy, a
magnified visual inspection of the cervix aided by using a dilute acetic acid (e.g. vinegar)
solution to highlight abnormal cells on the surface of the cervix.[1]

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

This large squamous carcinoma (bottom of picture) has obliterated the cervix and invaded the lower
uterine segment. The uterus also has a round leiomyoma up higher.
Micrograph of a (cervical) adenosquamous carcinoma, a type of cervical cancer. H&E stain.

Cervical intraepithelial neoplasia, the precursor to cervical cancer, is often diagnosed on

examination of cervical biopsies by a pathologist. Histologic subtypes of invasive cervical
carcinoma include the following:[23][24] Though squamous cell carcinoma is the cervical cancer
with the most incidence, the incidence of adenocarcinoma of the cervix has been increasing in
recent decades[1].

 squamous cell carcinoma (about 80-85%[citation needed])

 adenocarcinoma (about 15% of cervical cancers in the UK [6])
 adenosquamous carcinoma
 small cell carcinoma
 neuroendocrine carcinoma

Non-carcinoma malignancies which can rarely occur in the cervix include

 melanoma
 lymphoma

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.

[edit] Staging

Cervical cancer is staged by the International Federation of Gynecology and Obstetrics (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 cervix
o 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
 o 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 cervix
o IIA - without parametrial invasion, but involve upper 2/3 of vagina
o IIB - with parametrial invasion
 Stage III - extends to pelvic wall or lower third of the vagina
o IIIA - involves lower third of vagina
o 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

Prevention
[edit] Primary Prevention

[edit] Vaccination
Main article: HPV vaccine

Gardasil, licensed and manufactured by Merck & Co. is a vaccine against HPV types 6, 11, 16 &
18. Gardasil is up to 98% effective.[25]. It is now on the market after receiving approval from the
US Food and Drug Administration on June 8, 2006.[3] Gardasil has also been approved in the EU.
[26]

GlaxoSmithKline has developed a vaccine called Cervarix which has been shown to be 92%
effective in preventing HPV strains 16 and 18 and is effective for more than four years.[27]
Cervarix has been approved some places and is in approval process elsewhere.[28]

Neither Merck & Co. nor GlaxoSmithKline invented the vaccine. The vaccine's key
developmental steps are claimed by the National Cancer Institute in the US, the University of
Rochester in New York, Georgetown University in Washington, DC, Dartmouth College in
Hanover, NH, and the University of Queensland in Brisbane, Australia. Both Merck & Co. and
GlaxoSmithKline have licensed patents from all of these parties.[29]

Together, HPV types 16 and 18 currently cause about 70% of cervical cancer cases. HPV types 6
and 11 cause about 90% of genital wart cases.

HPV vaccines are 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 or other men is initially considered only a secondary market.

The high cost of this vaccine has been a cause for concern. Several countries have or are
considering programs to fund HPV vaccination.
[edit] Condoms

Condoms offer some protection against cervical cancer.[30] Evidence on whether condoms protect
against HPV infection is mixed, but they may protect against genital warts and the precursors to
cervical cancer.[30] They also provide protection against other STDs, such as HIV and Chlamydia,
which are associated with greater risks of developing cervical cancer.

Condoms may also be useful in treating potentially precancerous changes in the cervix. Exposure
to semen appears to increase the risk of precancerous changes (CIN 3), and use of condoms helps
to cause these changes to regress and helps clear HPV.[31] One study suggests that prostaglandin
in semen may fuel the growth of cervical and uterine tumours and that affected women may
benefit from the use of condoms.[32][33]

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 remain fertile is a local surgical procedure such as a loop electrical
excision procedure (LEEP) or cone biopsy.[52]

If a cone biopsy does not produce clear margins,[53] one more possible treatment option for
patients who want to preserve their fertility is a trachelectomy.[54] This attempts to surgically
remove the cancer while preserving the ovaries and uterus, providing for a more conservative
operation than a hysterectomy. It is a viable option for those in stage I cervical cancer which has
not spread; however, it is not yet considered a standard of care,[55] as few doctors are skilled in
this procedure. Even the most experienced surgeon cannot promise that a trachelectomy can be
performed until after surgical microscopic examination, as the extent of the spread of cancer is
unknown. 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, a hysterectomy may still be
needed. This can only be done during the same operation if the patient has given prior consent.
Due to 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 uterus for
pathologic evaluation.

A radical trachelectomy can be performed abdominally[56] or vaginally[57] and there are

conflicting opinions as to which is better.[58] A radical abdominal trachelectomy with
lymphadenectomy usually only requires a two to three day hospital stay, and most women
recover very quickly (approximately six weeks). Complications are uncommon, although women
who are able to conceive after surgery are susceptible to preterm labor and possible late
miscarriage.[59] It is generally recommended to wait at least one year before attempting to become
pregnant after surgery.[60] Recurrence in the residual cervix is very rare if the cancer has been
cleared with the trachelectomy.[55] Yet, it is recommended for patients to practice vigilant
prevention and follow up care including pap screenings/colposcopy, with biopsies of the
remaining lower uterine segment as needed (every 3–4 months for at least 5 years) to monitor for
any recurrence 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). Patients treated with surgery
who have high risk features found on pathologic examination are given radiation therapy with or
without chemotherapy 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, the US Food and Drug Administration approved the use of a combination of
two chemotherapy drugs, hycamtin and cisplatin for women with late-stage (IVB) cervical
cancer treatment.[61] Combination treatment has significant risk of neutropenia, anemia, and
thrombocytopenia side effects. Hycamtin is manufactured by GlaxoSmithKline.

Cervical cancer
Cervical cancer is malignant neoplasm of the cervix uteri or cervical area. It may present with
vaginal bleeding but symptoms may be absent until the cancer is in its advanced stages.[1]
Treatment consists of surgery (including local excision) in early stages and chemotherapy and
radiotherapy in advanced stages of the disease.

Pap smear screening can identify potentially precancerous changes. Treatment of high grade
changes can prevent the development of cancer. In developed countries, the widespread use of
cervical screening programs has reduced the incidence of invasive cervical cancer by 50% or
more.[citation needed]

Human papillomavirus (HPV) infection is a necessary factor in the development of nearly 70%
of cases of cervical cancer.[1][2] HPV vaccine effective against the two strains of HPV that cause
the most cervical cancer has been licensed in the U.S, Canada, Australia and the EU. These two
HPV strains together are currently responsible for approximately 70%[3][4] of all cervical cancers.
Since the vaccine only covers some high-risk types, women should seek regular Pap smear
screening, even after vaccination.[5]

Classification
The naming and classification of cervical carcinoma percursor lesions has changed many times
over the 20th century. The World Health Organization classification[6][7] system was descriptive
of the lesions, naming them mild, moderate or severe dysplasia or carcinoma in situ (CIS). The
term, Cervical Intraepithelial Neoplasia (CIN) was developed to place emphasis on the spectrum
of abnormality in these lesions, and to help standardise treatment.[7] It classifies mild dysplasia as
CIN1, moderate dysplasia as CIN2, and severe dysplasia and CIS as CIN3. The most recent
classification is the Bethesda System, which divides all cervical epithelial presursor lesions into
2 groups: Low-grade Squamous Intraepithelial Lesion (LSIL) and High-grade Squamous
Intraepithelial Lesion (HSIL). LSIL corresponds to CIN1, and HSIL includes CIN2 and CIN3.[7]
More recently, CIN2 and CIN3 have been combined into CIN2/3.

[edit] Signs and symptoms

The early stages of cervical cancer may be completely asymptomatic.[1][8] 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,[9] and bone fractures.

[edit] Causes
[edit] Human papillomavirus infection

In the United States each year there are more than 6.2 million new HPV infections in both men
and women, according to the CDC, of which 10 percent will go on to develop persistent
displaysia or cervical cancer. That is why HPV is known as the "common cold" of the sexually
transmitted infection world. It is very common and affects roughly 80 percent of all sexually
active people, whether they have symptoms or not. The most important risk factor in the
development of cervical cancer is infection with a high-risk strain of human papillomavirus. The
virus cancer link works by triggering alterations in the cells of the cervix, which can lead to the
development of cervical intraepithelial neoplasia, which can lead to cancer.

Women who have many sexual partners (or who have sex with men who had many other
partners) have a greater risk.[10][11]

More than 150 types of HPV are acknowledged to exist (some sources indicate more than 200
subtypes).[12][13] Of these, 15 are classified as high-risk types (16, 18, 31, 33, 35, 39, 45, 51, 52,
56, 58, 59, 68, 73, and 82), 3 as probable high-risk (26, 53, and 66), and 12 as low-risk (6, 11,
40, 42, 43, 44, 54, 61, 70, 72, 81, and CP6108),[14] but even those may cause cancer. Types 16
and 18 are generally acknowledged to cause about 70% of cervical cancer cases. Together with
type 31, they are the prime risk factors for cervical cancer.[15]

Genital warts are caused by various strains of HPV which are usually not related to cervical
cancer. However, it is possible to have multiple strains at the same time, including those that can
cause cervical cancer along with those that cause warts. 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, but most women infected with high risk HPV will not develop cervical
cancer.[16] Use of condoms reduces, but does not always prevent transmission. Likewise, HPV
can be transmitted by skin-to-skin-contact with infected areas. In males, there is no available test
to check for HPV, although HPV is thought to grow preferentially in the epithelium of the glans
penis, and cleaning of this area may be preventative.

[edit] Cofactors

The American Cancer Society provides the following list of risk factors for cervical cancer:
human papillomavirus (HPV) infection, smoking, HIV infection, chlamydia infection, stress and
stress-related disorders, dietary factors, hormonal contraception, multiple pregnancies, exposure
to the hormonal drug diethylstilbestrol (DES) and a family history of cervical cancer.[10] There is
a possible genetic risk associated with HLA-B7.[citation needed]

All claims made below are ambiguous and not specifically supported by any regemented
research.

It is at this time safe to assume sexual behavior has more effect on Risks related to transmission
of HPV then any preventitive surgery.

Circumcision has not been reliably proven to reduce risk of any STD's in any consistent fashion
and all data sets based upon the evidence is incidental at best.

Claims are at best ambiguous. The research done to date would not even stand to clinic trials
testing standards set forth by the FDA.

There has not been any definitive evidence to support the claim that circumcision of the
male partner reduces the risk of cervical cancer, although some researchers say there is
compelling epidemiological evidence that men who have been circumcised are less likely to
be infected with HPV.[17] However, in men with low-risk sexual behaviour and monogamous
female partners, circumcision makes no difference to the risk of cervical cancer.[18]

[edit] Diagnosis
[edit] Visual inspection to detect precancer or cancer

Visual inspection of the cervix, using acetic acid or Lugol’s iodine to highlight precancerous
lesions so they can be viewed with the “naked eye”, shifts the identification of precancer from
the laboratory to the clinic. Such procedures eliminate the need for laboratories and transport of
specimens, require very little equipment and provide women with immediate test results. A range
of medical professionals—doctors, nurses, or professional midwives—can effectively perform
the procedure, provided they receive adequate training and supervision. As a screening test, VIA
performs equal to or better than cervical cytology in accurately identifying pre-cancerous lesions.
[19]
This has been demonstrated in various studies where trained physicians and mid level
providers correctly identified between 45% and 79% of women at high risk of developing
cervical cancer.[20] By comparison, the sensitivity of cytology has been shown to be between 47
and 62%.It should be noted, however, that cytology provides higher specificity than VIA. Like
cytology, one of the limitations of VIA is that results are highly dependant on the accuracy of an
individual’s interpretation. This means that initial training and on-going quality control are of
paramount importance.

VIA can offer significant advantages over Pap in low-resource settings, particularly in terms of
increased screening coverage, improved follow up care and overall program quality. Due to the
need for fewer specialized personnel and less infrastructure, training, and equipment, with VIA
public health systems can offer cervical cancer screening in more remote (and less equipped)
health care settings and can achieve higher coverage. Furthermore, providers can share the
results of VIA with patients immediately, making it possible to screen and treat women during
the same visit. This helps ensure that follow up care can be provided on the spot and reduces the
number of women who may miss out on treatment because they are not able to return to the
clinic at another time. In a “screen and treat” project in Peru, for example, only 9% of women
who screened positive failed to receive treatment in the single-visit approach, compared with
44% of women who were lost to treatment using a multi-visit model.[21]

VIA has successfully been paired with cryotherapy, a relatively simple and inexpensive method
of treating cervical lesions that can be performed by primary care physicians and mid-level
providers.[22]

[edit] Biopsy procedures

While the pap smear is an effective screening test, confirmation of the diagnosis of cervical
cancer or pre-cancer requires a biopsy of the cervix. This is often done through colposcopy, a
magnified visual inspection of the cervix aided by using a dilute acetic acid (e.g. vinegar)
solution to highlight abnormal cells on the surface of the cervix.[1]

Further diagnostic procedures are loop electrical excision procedure (LEEP) and conization, in
which the inner lining of the cervix is removed to be examined pathologically. These are carried
out if the biopsy confirms severe cervical intraepithelial neoplasia.
[edit] Pathologic types

This large squamous carcinoma (bottom of picture) has obliterated the cervix and invaded the lower
uterine segment. The uterus also has a round leiomyoma up higher.

Micrograph of a (cervical) adenosquamous carcinoma, a type of cervical cancer. H&E stain.

Cervical intraepithelial neoplasia, the precursor to cervical cancer, is often diagnosed on

examination of cervical biopsies by a pathologist. Histologic subtypes of invasive cervical
carcinoma include the following:[23][24] Though squamous cell carcinoma is the cervical cancer
with the most incidence, the incidence of adenocarcinoma of the cervix has been increasing in
recent decades[1].

 squamous cell carcinoma (about 80-85%[citation needed])

 adenocarcinoma (about 15% of cervical cancers in the UK [6])
 adenosquamous carcinoma
 small cell carcinoma
 neuroendocrine carcinoma
Non-carcinoma malignancies which can rarely occur in the cervix include

 melanoma
 lymphoma

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.

Prevention
[edit] Primary Prevention

[edit] Vaccination
Main article: HPV vaccine

Gardasil, licensed and manufactured by Merck & Co. is a vaccine against HPV types 6, 11, 16 &
18. Gardasil is up to 98% effective.[25]. It is now on the market after receiving approval from the
US Food and Drug Administration on June 8, 2006.[3] Gardasil has also been approved in the EU.
[26]

GlaxoSmithKline has developed a vaccine called Cervarix which has been shown to be 92%
effective in preventing HPV strains 16 and 18 and is effective for more than four years.[27]
Cervarix has been approved some places and is in approval process elsewhere.[28]

Neither Merck & Co. nor GlaxoSmithKline invented the vaccine. The vaccine's key
developmental steps are claimed by the National Cancer Institute in the US, the University of
Rochester in New York, Georgetown University in Washington, DC, Dartmouth College in
Hanover, NH, and the University of Queensland in Brisbane, Australia. Both Merck & Co. and
GlaxoSmithKline have licensed patents from all of these parties.[29]

Together, HPV types 16 and 18 currently cause about 70% of cervical cancer cases. HPV types 6
and 11 cause about 90% of genital wart cases.

HPV vaccines are 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 or other men is initially considered only a secondary market.

The high cost of this vaccine has been a cause for concern. Several countries have or are
considering programs to fund HPV vaccination.
[edit] Condoms

Condoms offer some protection against cervical cancer.[30] Evidence on whether condoms protect
against HPV infection is mixed, but they may protect against genital warts and the precursors to
cervical cancer.[30] They also provide protection against other STDs, such as HIV and Chlamydia,
which are associated with greater risks of developing cervical cancer.

Condoms may also be useful in treating potentially precancerous changes in the cervix. Exposure
to semen appears to increase the risk of precancerous changes (CIN 3), and use of condoms helps
to cause these changes to regress and helps clear HPV.[31] One study suggests that prostaglandin
in semen may fuel the growth of cervical and uterine tumours and that affected women may
benefit from the use of condoms.[32][33]

[edit] Smoking avoidance

Main article: Smoking cessation

Carcinogens from tobacco increase the risk for many cancer types, including cervical cancer, and
women who smoke have about double the chance of a non-smoker to develop cervical cancer.[34]

[edit] Nutrition
Fruits and vegetables

Higher levels of vegetable consumption were associated with a 54% decrease risk of HPV
persistence.[35] Consumption of papaya at least once a week was inversely associated with
persistent HPV infection.[36]

Vitamin A

There is weak evidence to suggest a significant deficiency of retinol can increase chances of
cervical dysplasia, independently of HPV infection. A small (n~=500) case-control study of a
narrow ethnic group (native Americans in New Mexico) assessed serum micro-nutrients as risk
factors for cervical dysplasia. Subjects in the lowest serum retinol quartile were at increased risk
of CIN I compared with women in the highest quartile.[37]

However, the study population had low overall serum retinol, suggesting deficiency. A study of
serum retinol in a well-nourished population reveals that the bottom 20% had serum retinol close
to that of the highest levels in this New Mexico sub-population.[38]

Vitamin C

Risk of type-specific, persistent HPV infection was lower among women reporting intake values
of vitamin C in the upper quartile compared with those reporting intake in the lowest quartile.[36]

Vitamin E
HPV clearance time was significantly shorter among women with the highest compared with the
lowest serum levels of tocopherols, but significant trends in these associations were limited to
infections lasting </=120 days. Clearance of persistent HPV infection (lasting >120 days) was
not significantly associated with circulating levels of tocopherols. Results from this investigation
support an association of micronutrients with the rapid clearance of incident oncogenic HPV
infection of the uterine cervix.[39]

A statistically significantly lower level of alpha-tocopherol was observed in the blood serum of
HPV-positive patients with cervical intraepithelial neoplasia. The risk of dysplasia was four
times higher for an alpha-tocopherol level < 7.95 mumol/l.[40] jojo

Folic acid

Higher folate status was inversely associated with becoming HPV test-positive. Women with
higher folate status were significantly less likely to be repeatedly HPV test-positive and more
likely to become test-negative. Studies have shown that lower levels of antioxidants coexisting
with low levels of folic acid increases the risk of CIN development. Improving folate status in
subjects at risk of getting infected or already infected with high-risk HPV may have a beneficial
impact in the prevention of cervical cancer.[41][42]

However, another study showed no relationship between folate status and cervical dysplasia.[37]

Carotenoids

Higher circulating levels of carotenoids were associated with a significant decrease in the
clearance time of type-specific HPV infection, particularly during the early stages of infection
(</=120 days). Clearance of persistent HPV infection (lasting >120 days) was not significantly
associated with circulating levels of carotenoids.[39]

The likelihood of clearing an oncogenic HPV infection is significantly higher with increasing
levels of lycopenes.[43] A 56% reduction in HPV persistence risk was observed in women with
the highest plasma [lycopene] concentrations compared with women with the lowest plasma
lycopene concentrations. These data suggests that vegetable consumption and circulating
lycopene may be protective against HPV persistence.[35][36][44]

CoQ10

Women who had either CIN or cervical cancer had markedly lower levels of CoQ10 in their
blood and in their cervical cells than the women who were healthy.[citation needed]

[edit] Secondary Prevention

[edit] Awareness

According to the US National Cancer Institute's 2005 Health Information National Trends
survey, only 40% of American women surveyed had heard of human papillomavirus (HPV)
infection and only 20% had heard of its link to cervical cancer.[45] In 2008 an estimated 3,870
women in the US will die of cervical cancer, and around 11,000 new cases are expected to be
diagnosed.[46]

[edit] Screening

The widespread introduction of the Papanicolaou test, or Pap smear for cervical cancer screening
has been credited with dramatically reducing the incidence and mortality of cervical cancer in
developed countries.[8] Abnormal Pap smear results may suggest the presence of cervical
intraepithelial neoplasia (potentially premalignant changes in the cervix) before a cancer has
developed, allowing examination and possible preventive treatment. Recommendations for how
often a Pap smear should be done vary from once a year to once every five years. The ACS
recommends that cervical cancer screening should begin approximately three years after the
onset of vaginal intercourse and/or no later than twenty-one years of age.[47] Guidelines vary on
how long to continue screening, but well screened women who have not had abnormal smears
can stop screening about age 65 (USPSTF) to 70 (ACS). If premalignant disease or cervical
cancer is detected early, it can be monitored or treated relatively noninvasively, and without
impairing fertility.

Until recently the Pap smear has remained the principal technology for preventing cervical
cancer. However, following a rapid review of the published literature, originally commissioned
by NICE [48], liquid based cytology has been incorporated within the UK national screening
programme. Although it was probably intended to improve on the accuracy of the Pap test, its
main advantage has been to reduce the number of inadequate smears from around 9% to around
1%. This reduces the need to recall women for a further smear. The UK currently uses very
different criteria for screening than that of America. In the UK a woman must be aged 25 or over
in order to have a smear test and no older than 18 to receive the HPV vaccine. This means that
the British 19-24 age group are not vaccinated currently, nor are they receiving screening.[49]

Automated technologies have been developed with the aim of improving on the interpretation of
smears, normally carried out by cytotechnologists. Unfortunately these on the whole have proven
less useful; although the more recent reviews suggest that generally they may be no worse than
human interpretation [50].

The HPV test is a newer technique for cervical cancer triage which detects the presence of
human papillomavirus infection in the cervix. It is more sensitive than the pap smear (less likely
to produce false negative results), but less specific (more likely to produce false positive results)
and its role in routine screening is still evolving. Since more than 99% of invasive cervical
cancers worldwide contain HPV, some researchers recommend that HPV testing be done
together with routine cervical screening.[15] But, 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.

HPV testing can reduce the incidence of grade 2 or 3 cervical intraepithelial neoplasia or cervical
cancer detected by subsequent screening tests among women 32–38 years old according to a
randomized controlled trial.[51] The relative risk reduction was 41.3%. For patients at similar risk
to those in this study (63.0% had CIN 2-3 or cancer), this leads to an absolute risk reduction of
26%. 3.8 patients must be treated for one to benefit (number needed to treat = 3.8). Click here to
adjust these results for patients at higher or lower risk of CIN 2-3.

[edit] 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 remain fertile is a local surgical procedure such as a loop electrical
excision procedure (LEEP) or cone biopsy.[52]

If a cone biopsy does not produce clear margins,[53] one more possible treatment option for
patients who want to preserve their fertility is a trachelectomy.[54] This attempts to surgically
remove the cancer while preserving the ovaries and uterus, providing for a more conservative
operation than a hysterectomy. It is a viable option for those in stage I cervical cancer which has
not spread; however, it is not yet considered a standard of care,[55] as few doctors are skilled in
this procedure. Even the most experienced surgeon cannot promise that a trachelectomy can be
performed until after surgical microscopic examination, as the extent of the spread of cancer is
unknown. 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, a hysterectomy may still be
needed. This can only be done during the same operation if the patient has given prior consent.
Due to 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 uterus for
pathologic evaluation.

A radical trachelectomy can be performed abdominally[56] or vaginally[57] and there are

conflicting opinions as to which is better.[58] A radical abdominal trachelectomy with
lymphadenectomy usually only requires a two to three day hospital stay, and most women
recover very quickly (approximately six weeks). Complications are uncommon, although women
who are able to conceive after surgery are susceptible to preterm labor and possible late
miscarriage.[59] It is generally recommended to wait at least one year before attempting to become
pregnant after surgery.[60] Recurrence in the residual cervix is very rare if the cancer has been
cleared with the trachelectomy.[55] Yet, it is recommended for patients to practice vigilant
prevention and follow up care including pap screenings/colposcopy, with biopsies of the
remaining lower uterine segment as needed (every 3–4 months for at least 5 years) to monitor for
any recurrence 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). Patients treated with surgery
who have high risk features found on pathologic examination are given radiation therapy with or
without chemotherapy 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, the US Food and Drug Administration approved the use of a combination of
two chemotherapy drugs, hycamtin and cisplatin for women with late-stage (IVB) cervical
cancer treatment.[61] Combination treatment has significant risk of neutropenia, anemia, and
thrombocytopenia side effects. Hycamtin is manufactured by GlaxoSmithKline.

[edit] Prognosis
Prognosis depends on the stage of the cancer. With treatment, the 5-year relative survival rate for
the earliest stage of invasive cervical cancer is 92%, and the overall (all stages combined) 5-year
survival rate is about 72%. These statistics may be improved when applied to women newly
diagnosed, bearing in mind that these outcomes may be partly based on the state of treatment
five years ago when the women studied were first diagnosed.[46]

With treatment, 80 to 90% of women with stage I cancer and 50 to 65% of those with stage II
cancer are alive 5 years after diagnosis. Only 25 to 35% of women with stage III cancer and 15%
or fewer of those with stage IV cancer are alive after 5 years.[62]

According to the International Federation of Gynecology and Obstetrics, survival improves when
radiotherapy is combined with cisplatin-based chemotherapy.[63]

As the cancer metastasizes to other parts of the body, prognosis drops dramatically because
treatment of local lesions is generally more effective than whole body treatments such as
chemotherapy.

Interval evaluation of the patient after therapy is imperative. Recurrent cervical cancer detected
at its earliest stages might be successfully treated with surgery, radiation, chemotherapy, or a
combination of the three. Thirty-five percent of patients with invasive cervical cancer have
persistent or recurrent disease after treatment.[64]

Average years of potential life lost from cervical cancer are 25.3 (SEER Cancer Statistics
Review 1975-2000, National Cancer Institute (NCI)). Approximately 4,600 women were
projected to die in 2001 in the US of cervical cancer (DSTD), and the annual incidence was
13,000 in 2002 in the US, as calculated by SEER. Thus the ratio of deaths to incidence is
approximately 35.4%.

Regular screening has meant that pre cancerous changes and early stage cervical cancers have
been detected and treated early. Figures suggest that cervical screening is saving 5,000 lives each
year in the UK by preventing cervical cancer.[65] About 1,000 women per year die of cervical
cancer in the UK.
Regular two-yearly Pap tests can reduce the incidence of cervical cancer by up to 90% in
Australia, and save 1,200 Australian women dying from the disease each year.[66]

[edit] Epidemiology

Age-standardized death from cervical cancer per 100,000 inhabitants in 2004.[67]

     no data      less than 2.4      2.4-4.8      4.8-7.2      7.2-9.6      9.6-12      12-14.4      14.4-16.8      16.8-
19.2      19.2-21.6      21.6-24      24-26.4      more than 26.4

Worldwide, cervical cancer is the fifth most deadly cancer in women.[68] It affects about 16 per
100,000 women per year and kills about 9 per 100,000 per year.[69] Approximately 80% of
cervical cancers occur in developing countries[70]

In the United States, it is only the 8th most common cancer of women. In 1998, about 12,800
women were diagnosed in the US and about 4,800 died.[8] Among gynecological cancers it ranks
behind endometrial cancer and ovarian cancer. The incidence and mortality in the US are about
half those for the rest of the world, which is due in part to the success of screening with the Pap
smear.[8] The incidence of new cases of cervical cancer in the United States was 7 per 100,000
women in 2004.[71]

In the United Kingdom, the age-standardised (European) incidence is 8.5/100,000 per year
(2006). It is the twelfth most common cancer in women, accounting for 2% of all female cancers,
and is the second most common cancer in the under 35s females, after breast cancer. The UK's
European age-standardised mortality is 2.4/100,000 per year (2007) (Cancer Research UK
Cervical cancer statistics for the UK)[72]. With a 42% reduction from 1988-1997 the NHS
implemented screening programme has been highly successful, screening the highest risk age
group (25–49 years) every 3 years, and those ages 50–64 every 5 years.

In Canada, an estimated 1,300 women will be diagnosed with cervical cancer in 2008 and 380
will die.[73]

In Australia, there were 734 cases of cervical cancer (2005).The number of women diagnosed
with cervical cancer has dropped on average by 4.5% each year since organised screening began
in 1991 (1991–2005).[74].

Worldwide it is estimated that there are 473,000 cases of cervical cancer, and 253,500 deaths per
year.[75]
[edit] History
 400 BCE - Hippocrates: cervical cancer incurable
 1925 - Hans Hinselmann: invented colposcope
 1928 - Papanicolaou: developed Pap technique
 1941 - Papanicolaou and Trout: Pap screening
 1946 - Ayer: spatula to scrape the cervix
 1976 - Zur Hausen and Gisam: found HPV DNA in cervical cancer and warts
 1988 - Bethesda System for Pap results developed

Epidemiologists working in the early 20th century noted that cervical cancer behaved like a
sexually transmitted disease. In summary:

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.
(Rigoni in 1841)
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.[76]
5. In 1935, Syverton and Berry discovered a relationship between RPV (Rabbit Papillomavirus) and
skin cancer in rabbits. (HPV is species-specific and therefore cannot be transmitted to rabbits)

This led to the suspicion that cervical cancer could be caused by a sexually transmitted agent.
Initial research in the 1940s and 1950s put the blame on smegma (e.g. Heins et al. 1958)[77].
During the 1960s and 1970s it was suspected that infection with herpes simplex virus was the
cause of the disease. In summary, HSV was seen as a likely cause[78] because it is known to
survive in the female reproductive tract, to be transmitted sexually in a way compatible with
known risk factors, such as promiscuity and low socioeconomic status. Herpes viruses were also
implicated in other malignant diseases, including Burkitt's lymphoma, Nasopharyngeal
carcinoma, Marek's disease and the Lucké renal adenocarcinoma. HSV was recovered from
cervical tumour cells.

It was not until the 1980s that human papillomavirus (HPV) was identified in cervical cancer
tissue [79]. A description by electron microscopy was given earlier in 1949 and HPV-DNA was
identified in 1963. It has since been demonstrated that HPV is implicated in virtually all cervical
cancers.[4] Specific viral subtypes implicated are HPV 16, 18, 31, 45 and others.