Cervical Cancer

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Posted by sonny 03/04/2009 @ 04:14

Tags : cervical cancer, cancers, diseases, health

News headlines
Rare anal cancer in national spotlight - Baltimore Sun
However, not all people who have HPV will develop anal cancer. •In 2008, Harald zur Hausen won the Nobel Prize in physiology or medicine for his discovery of the link between certain variants of HPV and cervical cancer, which led to the creation of HPV...
Parents hesitant about cervical cancer vaccination - Stuff.co.nz
By KIM THOMAS and REBECCA TODD - The Press Some Canterbury parents are hesitating to get their daughters vaccinated against cervical cancer because they fear it will make the teenagers sexually active. A third of Canterbury girls eligible for the free...
Condition Puts Women at Risk for Cervical Cancer - Ivanhoe
(Ivanhoe Newswire) -- Women treated for a condition called cervical intraepithelial neoplasia (CIN) have a higher risk for developing invasive cervical cancer. CIN is the abnormal growth of cells on the surface of the cervix. According to the article,...
Scott Walker's wife being treated for cervical cancer - NHL.com
Julie Walker was diagnosed with cervical cancer during the series. The good news is the condition is treatable and Julie is expected to make a complete recovery. "It was a challenge the first couple days, but we're slowly getting back to normal," the...
Davao Doc observes cervical cancer month - Mindanao Times
MAY proves to be a very important month for all the women, it is the Cervical Cancer Awareness Month and Davao Doctor's Hospital is taking part in the nationwide information drive in battling this leading deadly disease inflicting our women....
Abnormal cells in cervix raise cancer risk: study - Reuters
By Julie Steenhuysen CHICAGO (Reuters) - A woman's age and the type of treatment she gets may play a big role in the risk that abnormal cells on the cervix will return or develop into cervical cancer, US researchers said on Tuesday....
Glaxo's cervical cancer vaccine faces US battle - BusinessWeek
By LINDA A. JOHNSON New studies show GlaxoSmithKline PLC's vaccine Cervarix blocks the virus that causes cervical cancer, but if it wins approval for US sales, it will face an uphill battle against Gardasil, which has owned the market here for three...
Swindon hospital sees rise in cervical cancer queries - North Wiltshire and Kennet Gazette & Herald
The Ridgeway Hospital in Wroughton has seen a 121 per cent increase in inquiries about cervical cancer and 150 per cent increase in appointments for cervical cancer screening in the last four months. In addition, more than 20000 people have visited the...
Program helps woman avoid 'disaster' - Northwest Herald
She came across the Illinois Breast and Cervical Cancer Program, which had come to mchenry County in January 2008. The state program provides uninsured people with free preventive screenings for breast and cervical cancers. In 2008, more than 700 women...
Guarded about Gardasil? - PennLive.com
That's also when she learned that HPV, a sexually transmitted disease, can cause genital warts, cervical cancer and create cervical abnormalities that sometimes lead to cancer. Although Capp's doctor removed her precancerous cells with laser surgery,...

Cervical cancer

Ca in situ, cervix 2.jpg

Cervical cancer is malignant cancer 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. 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.

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

The naming and classification of cervical carcinoma percursor lesions has changed many times over the 20th century. The World Health Organisation classification 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. 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. More recently, CIN2 and CIN3 have been combined into CIN2/3.

The early stages of cervical cancer may be completely asymptomatic. 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 faeces from the vagina, and bone fractures.

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 or women who had many partners) have a greater risk.

More than 150 types of HPV are acknowledged to exist (some sources indicate more than 200 subtypes). 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), 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.

Genital warts are caused by various strains of HPV which are usually 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, but most women infected with high risk HPV will not develop cervical cancer. 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, HPV is thought to grow preferentially in the epithelium of the glans penis, and cleaning of this area may be preventative.

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

Despite the development of an HPV vaccine, some researchers argue that routine neonatal male circumcision is an acceptable way to lower the risk of cervical cancer in their future female sexual partners. Others maintain that the benefits do not outweigh the risks and/or consider the removal of healthy genital tissue from infants to be unethical as it cannot be reasonably assumed that a male would choose to be circumcised. There has not been any definitive evidence to support the claim that male circumcision prevents 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. However, in men with low-risk sexual behaviour and monogamous female partners, circumcision makes no difference to the risk of cervical cancer.

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.

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.

Cervical intraepithelial neoplasia, the precursor to cervical cancer, is often diagnosed on examiniation of cervical biopsies by a pathologist. Histologic subtypes of invasive cervical carcinoma include the following: 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.

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.

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.

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.

If a cone biopsy does not produce clear margins, one more possible treatment option for patients who want to preserve their fertility is a trachelectomy. 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, 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 or vaginally and there are conflicting opinions as to which is better. 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. It is generally recommended to wait at least one year before attempting to become pregnant after surgery. Recurrence in the residual cervix is very rare if the cancer has been cleared with the trachelectomy.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. Combination treatment has significant risk of neutropenia, anemia, and thrombocytopenia side effects. Hycamtin is manufactured by GlaxoSmithKline.

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. 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.

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. 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 American Cancer Society (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. 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 , 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.

Automated technologies have been developed with the aim of improving on the interpretation of smears, normally carried out by cytotechnicians. 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 .

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. 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. 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.

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 approval from the US Food and Drug Administration on June 8, 2006. Gardasil has also been approved in the EU.

GlaxoSmithKline has developed a vaccine called Cervarix which has been shown to be 100% effective in preventing HPV strains 16 and 18 and is effective for more than four years. Cervarix has been approved some places and is in approval process elsewhere.

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 Queensland University in Brisbane, Australia. Both Merck & Co. and GlaxoSmithKline have licensed patents from all of these parties.

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 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.

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. 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.

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

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.

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.

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.

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.

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.

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.

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

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.

The likelihood of clearing an oncogenic HPV infection is significantly higher with increasing levels of lycopenes. A 56% reduction in HPV persistence risk was observed in women with the highest plasma 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.

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.

In a 1999 study, Docosahexaenoic acid inhibited growth of HPV16 immortalized cells.

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 outcome may be partly based on the state of treatment five years ago when the women studied were first diagnosed.

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.

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

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.

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.

About 1,000 women per year die of cervical cancer in the UK.

Worldwide, cervical cancer is the fifth most deadly cancer in women. It affects about 16 per 100,000 women per year and kills about 9 per 100,000 per year.

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. 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. The incidence of new cases of cervical cancer in the United States was 7 per 100,000 women in 2004.

In Great Britain, the incidence is 8.8/100,000 per year (2001), similar to the rest of Northern Europe, and mortality is 2.8/100,000 per year (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 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.

Worldwide it is estimated that there are 473,000 cases of cervical cancer, and 253,500 deaths per year.

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 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. Specific viral subtypes implicated are HPV 16, 18, 31, 45 and others.

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International Cervical Cancer Foundation

The International Cervical Cancer (INCCA) Foundation (INCCA) is a non-profit organization established in 2006 to improve the health and quality of life of Peruvian women through the primary and secondary prevention of female genital tract cancers, including cervical cancer.

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Human papillomavirus

Genome organization of human papillomavirus type 16, one of the subtypes known to cause cervical cancer. (E1-E7 early genes, L1-L2 late genes: capsid)

A human papillomavirus (HPV) is a papillomavirus that infects the skin and mucous membranes of humans. Approximately 130 HPV types have been identified. Some HPV types can cause warts (verrucae) or some types of cancer, while others have no symptoms.

About 30-40 HPV types are typically transmitted through sexual contact and infect the anogenital region. Some sexually transmitted HPV types may cause genital warts. Persistent infection with "high-risk" HPV types — different from the ones that cause warts — may progress to precancerous lesions and invasive cancer. HPV infection is a cause of nearly all cases of cervical cancer. However most infections with these types do not cause disease.

A cervical Pap smear is used to detect cellular abnormalities. This allows targeted surgical removal of condylomatous and/or potentially precancerous lesions prior to the development of invasive cervical cancer. Although the widespread use of Pap testing has reduced the incidence and lethality of cervical cancer in developed countries, the disease still kills several hundred thousand women per year worldwide. HPV vaccines, Gardasil and Cervarix, which prevent infection with some of the sexually transmitted HPV types that cause the most disease may lead to further decreases in the incidence of HPV-induced cancers.

HPV is estimated to be the most common sexually transmitted infection in the United States. Most sexually active men and women will probably acquire genital HPV infection at some point in their lives. The American Social Health Association reported estimates that about 75-80% of sexually active Americans will be infected with HPV at some point in their lifetime. By the age of 50 more than 80% of American women will have contracted at least one strain of genital HPV.

It was estimated that in the year 2000, there were approximately 6.2 million new HPV infections among Americans aged 15-44; of these, an estimated 74% occurred to people between ages 15-24. Of the STDs studied, genital HPV was the most commonly acquired.

Estimates of HPV prevalence vary from 14% to more than 90%. One reason for the difference is that some studies report women who currently have a detectable infection, while other studies report women who have ever had a detectable infection. Another cause of discrepancy is the difference in strains that were tested for.

One study found that, during 2003–2004, at any given time, 26.8% of women aged 14 to 59 were infected with at least one type of HPV. This was higher than previous estimates. 15.2% were infected with one or more of the high-risk types that can cause cancer. However only 3.4% were infected with one or more of the four types prevented by the Gardasil vaccine, which was lower than previous estimates.

Note that prevalence decreases with age. This may be due to HPV infection being cleared by the immune system, or sinking to undetectable levels while still present in the body. HPV will probably remain in the infected person's cells for an indefinite time--most often in a latent state, but occasionally producing symptoms or disease. Recent studies from the Albert Einstein College of Medicine and from the University of Washington suggest that HPV may eventually be cleared in most people with well functioning immune systems. It appears that in some cases the virus does remain in the body indefinitely, producing symptoms if the immune system weakens.

Women who do not have regular cervical cancer screenings substantially increase their risk of developing cancer, because potentially precancerous lesions are not detected and they do not receive appropriate follow-up. An estimated 11% of American women do not have regular cervical cancer screenings. The American Cancer Society estimates that in 2008, about 11,070 women in the United States will be diagnosed with invasive cervical cancer, and about 3,870 US women will die from this disease.

The HPV lifecycle strictly follows the differentiation program of the host keratinocyte. It is thought that the HPV virion infects epithelial tissues through micro-abrasions, whereby the virion associates with putative receptors such as alpha integrins and laminins, leading to entry of the virions into basal epithelial cells through clathrin-mediated endocytosis and/or caveolin-mediated endocytosis depending on the type of HPV. At this point, the viral genome is transported to the nucleus by unknown mechanisms and establishes itself at a copy number between 10-200 viral genomes per cell. A sophisticated transcriptional cascade then occurs as the host keratinocyte begins to divide and become increasingly differentiated in the upper layers of the epithelium. The viral oncogenes, E6 and E7, are thought to modify the cell cycle so as to retain the differentiating host keratinocyte in a state that is amiable to the amplification of viral genome replication and consequent late gene expression. E6 in association with host E6 AP (associated protein), which has ubiquitin ligase activity act to ubiquitinate p53 leading to its proteosomal degradation. E7 (inoncogenic HPV's) acts as the primary transforming protein. E7 competes for pRb binding, freeing the transcription factor E2F to transactivate its targets, thus pushing the cell cycle forwards. All HPV can induce transient proliferation, but only 16 and 18 can immortalise cell intes (in vitro). It has also been shown that HPV 16 and 18 cannot immortalise primary rat cells alone, there needs to be activation of the ras oncogene. In the upper layers of the host epithelium, the late genes L1 and L2 are transcribed/translated and serve as structural proteins which encapsidate (Encapsidation is the process of incorporating a nucleic acid sequence (e.g., a vector, or a viral genome) into a viral particle) the amplified viral genomes. Virions can then be sloughed off in the dead squames of the host epithelium and the viral lifecycle continues.

Once an HPV viron invades a cell, an active infection occurs, and the virus can be transmitted. Several months to years may elapse before squamous intraepithelial lesions (SIL) develop and can be clinically detected. The time from active infection to clinically detectable disease makes it difficult for someone who has become infected to establish which partner was the source of infection.

Over 100 different HPV types have been identified and are referred to by number. Types 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, and 68 are "high-risk" sexually transmitted HPVs and may lead to the development of cervical intraepithelial neoplasia (CIN), vulvar intraepithelial neoplasia (VIN), penile intraepithelial neoplasia (PIN), and/or anal intraepithelial neoplasia (AIN).

About a dozen HPV types (including types 16, 18, 31 and 45) are called "high-risk" types because they can lead to cervical cancer, as well as anal cancer, vulvar cancer, and penile cancer. Several types of HPV, particularly type 16, have been found to be associated with oropharyngeal squamous-cell carcinoma, a form of head and neck cancer. HPV-induced cancers often have viral sequences integrated into the cellular DNA. Some of the HPV "early" genes, such as E6 and E7, are known to act as oncogenes that promote tumor growth and malignant transformation.

The p53 protein prevents cell growth and stimulates apoptosis in the presence of DNA damage. It causes BAX protein upregulation, which blocks the anti-apoptotic effects of the mitochondrial BCL-2 protein. In addition, p53 also upregulates the p21 protein, which blocks the formation of the Cyclin D/Cdk4 complex, thereby preventing the phosphorylation of RB and, in turn, halting cell cycle progression by preventing the activation of E2F. In short, p53 is a tumor suppressor gene that arrests the cell cycle when there is DNA damage. The E6 and E7 proteins work by inhibiting tumor suppression genes involved in that pathway: E6 inhibits p53, while E7 inhibits p53, p21, and RB.

An infection with one or more high-risk HPV types is believed to be a prerequisite for the development of cervical cancer (the vast majority of HPV infections are not high risk); according to the American Cancer Society, women with no history of the virus do not develop this type of cancer. However, most HPV infections are cleared rapidly by the immune system and do not progress to cervical cancer. Because the process of transforming normal cervical cells into cancerous ones is slow, cancer occurs in people who have been infected with HPV for a long time, usually over a decade or more.

Sexually transmitted HPVs also cause a major fraction of anal cancers and approximately 25% of cancers of the mouth and upper throat (known as the oropharynx) (see figure). The latter commonly present in the tonsil area and HPV is linked to the increase in oral cancers in non-smokers. Engaging in anal sex or oral sex with an HPV-infected partner may increase the risk of developing these types of cancers.

Studies show a link between HPV infection and penile and anal cancer, and the risk for anal cancer is 17 to 31 times higher among gay and bisexual men than among heterosexual men. It has been suggested that anal Pap smear screening for anal cancer might benefit some sub-populations of men or women who engage in anal sex. There is no consensus that such screening is beneficial, or who should get an anal Pap smear.

Genital warts are quite contagious, while common, flat, and plantar warts are much less likely to spread from person to person.

Genital or anal warts (condylomata acuminata or venereal warts) are the most easily recognized sign of genital HPV infection. Although a wide variety of HPV types can cause genital warts, types 6 and 11 account for about 90% of all cases.

Most people who acquire genital wart-associated HPV types clear the infection rapidly without ever developing warts or any other symptoms. People may transmit the virus to others even if they don't display overt symptoms of infection.

HPV types that tend to cause genital warts are not the same ones that cause cervical cancer. However, since an individual can be infected with multiple types of HPV, the presence of warts does not rule out the possibility of high risk types of the virus also being present.

HPV types 6 and 11 can cause a rare condition known as recurrent respiratory papillomatosis, in which warts form on the larynx or other areas of the respiratory tract.

These warts can recur frequently, may require repetitive surgery, may interfere with breathing, and in extremely rare cases can progress to cancer.

In very rare cases, HPV may cause epidermodysplasia verruciformis in immunocompromised individuals. The virus, unchecked by the immune system, causes the overproduction of keratin by skin cells, resulting in lesions resembling warts or cutaneous horns.

For instance, Dede Koswara, an Indonesian man developed warts that spread across his body and became root-like growths. Attempted treatment by both Indonesian and American doctors included surgical removal of the warts.

Avoiding sexual contact with an infected person is the only 100% effective prevention method; however, many people are unaware that they are infected with HPV. Condoms offer some protection, but exposed skin can transmit the virus. Two vaccines are currently available (see "HPV vaccines" below) to women between the ages of 9 and 26.

Certain types of sexually transmitted HPVs can cause cervical cancer. Persistent infection with one or more of about a dozen of these "high-risk" HPV types is an important factor in nearly all cases of cervical cancer. The development of HPV-induced cervical cancer is a slow process that generally takes many years. During this development phase, pre-cancerous cells can be detected by regular cervical cytology Papanicolaou screening, colloquially known as "Pap" smear testing. The Pap test is an effective strategy for reducing the risk of invasive cervical cancer. The Pap test involves taking cells from the cervix and putting them on a small glass slide and examining them under a microscope to look for abnormal cells. This method is 70% to 80% effective in detecting HPV-caused cellular abnormalities. A more sensitive method is a “Thin Prep,” in which the cells from the cervix are placed in a liquid solution. This test is 85% to 95% effective in detecting HPV-caused cellular abnormalities. The latter method is mainly used on women over 30. It is a combination Pap-HPV DNA test. If this test comes back negative women can usually wait 3 years before having the test done again. Detailed inspection of the cervix by colposcopy may be indicated if abnormal cells are detected by routine Pap smear. A frequently occurring example of an abnormal cell found in association with HPV is the koilocyte. (See figure.) The American College of Obstetricians and Gynecologists states that the newer liquid based cytology methods (Thinprep and Surepath) may miss 15-35% of CIN3's and cancer.

The Center for Disease Control (CDC) recommends that women get a Pap test no later than 3 years after their first sexual encounter and no later than 21 years of age. Women should have a Pap test every year until age 30. After age 30, women should discuss risk factors with their health care provider to determine whether a Pap test should be done yearly. If risk factors are low and previous Pap tests have been negative, most women only need to have tests every 2-3 years until 65 years of age (Centers for Disease Control 2005). All women are encouraged to get a yearly pap smear solely to detect cellular abnormalities caused by HPV.

Since the Pap test was developed there has been a 70% decrease in cervical cancer deaths over the last 50 years. Pap smear testing has proven to be one of the most successful screening tests in the history of medicine.

The HPV test detects many common "low" and "high-risk" HPV genotypes. This test is an important screening option, since a doctor may recommend more frequent Pap testing if the HPV test is positive for "high-risk" HPV. In March 2003, the US FDA approved a "hybrid-capture" test, marketed by Digene, as a primary screening tool for detecting HPV. This test was also approved for use as an adjunct to Pap testing, and may be performed during a routine Pap smear.

When patients are screened with both HPV testing and Pap testing the sensitivity reaches 100%. HPV testing can diagnose CIN 2-3 among women older than 30 years. The sensitivity of HPV testing alone was 94.6% and specificity was 94.1%. For patients at similar risk to those in this study (0.4% had CIN 2-3), this leads to a positive predictive value of 6.0% and negative predictive value of 100.0% (click here to adjust these results for patients at higher or lower risk of CIN 2-3).

In Australia, a self-sampling HPV DNA test - that women can do at home using an ordinary tampon - is being marketed by Tam Pap. It has been approved by the Therapeutic Goods Administration for distribution in Australia.

The recent outcomes in the identification of molecular pathways involved in cervical cancer provide helpful information about novel biomarkers that allow monitoring these essential molecular events in histological or cytological specimens. These biomarkers are likely to improve the detection of lesions that have a high risk of progression in both primary screening and triage settings. E6 and E7 mRNA detection (HPV OncoTect) or p16 cell-cycle protein levels are examples of these new molecular markers. According to published results these markers, which are highly sensitive and specific, allow to identify cells going through malignant transformation.

Although it is possible to test for HPV DNA in men, there are no FDA-approved tests for general screening in the United States or tests approved by the Canadian government, since the testing is inconclusive and considered medically unnecessary.

Genital warts are the only visible sign of low-risk HPV in men, and can be identified with a visual check of the genital area. These visible growths, however, are the result of non-carcinogenic HPV types. 5% acetic acid (vinegar) is used to identify both warts and squamous intraepithelial neoplasia (SIL) lesions with limited success by causing abnormal tissue to appear white, but most doctors have found this technique helpful only in moist areas, such as the female genital tract.

On June 8, 2006, the US Food and Drug Administration approved Gardasil, a prophylactic HPV vaccine which is marketed by Merck. The vaccine trial, conducted in adult women with a mean age of 23, showed protection against initial infection with HPV types 16 and 18, which together cause 70% of cervical cancers, and can cause other cancers, such as anal cancer. The vaccine also protects against HPV types 6 and 11, which cause 90 percent of genital warts.

GlaxoSmithKline is seeking approval for a prophylactic vaccine known as Cervarix targeting HPV types 16 and 18. It is delivered in three shots over six months. It is intended for females from 10 years of age onwards.

Gardasil vaccine is delivered in a series of three shots over six months at a cost of approximately $360 (US dollars). The CDC recommends that girls and women between the ages of 11 and 26 be vaccinated, though girls as young as 9 may benefit. Females not yet sexually active can be expected to receive the full benefit of vaccination. Women over 26 can be vaccinated at the discretion of a doctor, but the vaccination has not yet been approved by the FDA for this age range, and may not be covered by insurance. Studies have not yet conclusively shown benefits for patients over 26, possibly due to the high prevalence of infection and the fact that the vaccine has no effect upon current infections.

HPV vaccine is made up of proteins from the outer coat of the virus (HPV). There is no infectious material in this vaccine. There is also no thimerosal, a mercury based preservative, in the HPV vaccine. This vaccine has been tested in over 11,000 females (ages 9-26 years) around the world. These studies have shown no serious side effects. The most common side effect is soreness at the injection site. CDC, working with the FDA, will continue to monitor the safety of the vaccine after it is in general use.

The vaccine does not appear to protect against HPV types that females are infected with at the time of vaccination. However, females already infected with one or more vaccine HPV types before vaccination would be protected against disease caused by the other vaccine HPV types covered by the vaccine. Therefore, although overall vaccine effectiveness would be lower when administered to females who have been sexually active, and would decrease with age and likelihood of HPV exposure with increasing number of sex partners, the majority of females in this age group will derive at least partial benefit from vaccination. The vaccine will not have any therapeutic effect on existing HPV infection or cervical lesions.

Since the current vaccine will not protect women against all the HPV types that cause cervical cancer, women should continue to seek Pap smear testing, even after receiving the vaccine. Cervical cancer screening recommendations have not changed for females who receive HPV vaccine.

Both men and women are carriers of HPV. Possible benefits or efficacy of vaccinating men are being studied.

In addition to preventive vaccines, laboratory research and several human clinical trials are focused on the development of therapeutic HPV vaccines. In general, these vaccines focus on the main HPV oncogenes E6 and E7. Since expression of E6 and E7 is required for promoting the growth of cervical cancer cells (and cells within warts), it is hoped that immune responses against the two oncogenes might eradicate established tumors.

Carcinogens from tobacco and second-hand smoke are concentrated in the cervix, increasing rate of dysplasia by four to five times, and doubling the risk of cervical cancer.

Other studies have suggested that regular condom use can effectively limit the ongoing persistence and spread of HPV to additional genital sites in individuals who are already infected.

Thus, condom use may reduce the risk that infected individuals will progress to cervical cancer or develop additional genital warts. Planned Parenthood recommends condom use to reduce the risk of contracting HPV.

Ongoing research has suggested that several inexpensive chemicals might serve to block HPV transmission if applied to the genitals prior to sexual contact. These candidate agents, known as topical microbicides, are currently undergoing clinical efficacy testing. A recent study indicates that some sexual lubricant brands that use a gelling agent called carrageenan can inhibit papillomavirus infection in vitro. See Carrageenan#Sexual lubricant and microbicide for details.

Clinical trials are needed to determine whether carrageenan-based sexual lubricant gels are effective for blocking the sexual transmission of HPVs in vivo.

Therapies for conditions caused by HPV are addressed in main articles covering the various HPV-related diseases.

Infection with cutaneous HPVs is ubiquitous. Some HPV types, such as HPV-5, may establish infections that persist for the lifetime of the individual without ever manifesting any clinical symptoms. Like remora suckerfish that hitchhike harmlessly on sharks, these HPV types can be thought of as human commensals. Other cutaneous HPVs, such as HPV types 1 or 2, may cause common warts in some infected individuals. Skin warts are most common in childhood and typically appear and regress spontaneously over the course of weeks to months. About 10% of adults also suffer from recurring skin warts. All HPVs are believed to be capable of establishing long-term "latent" infections in small numbers of stem cells present in the skin. Although these latent infections may never be fully eradicated, immunological control is thought to block the appearance of symptoms such as warts. Immunological control is likely HPV type-specific, meaning that an individual may become immunologically resistant to one HPV type while remaining susceptible to other types.

A large increase in the incidence of genital HPV infection occurs at the age when individuals begin to engage in sexual activity. The great majority of genital HPV infections never cause any overt symptoms and are cleared by the immune system in a matter of months. As with cutaneous HPVs, immunity is believed to be HPV type-specific. Some infected individuals may fail to bring genital HPV infection under immunological control. Lingering infection with high-risk HPV types, such as HPVs 16, 18, 31 and 45, can lead to the development of cervical cancer or other types of cancer. In addition to persistent infection with high-risk HPV types, epidemiological and molecular data suggest that co-factors such as the cigarette smoke carcinogen benzopyrene (BaP) enhance development of certain HPV-induced cancers.

High-risk HPV types 16 and 18 are together responsible for over 65% of cervical cancer cases. Type 16 causes 41 to 54% of cervical cancers, and accounts for an even greater majority of HPV-induced vaginal/vulvar cancers, penile cancers, anal cancers and head and neck cancers.

Although genital HPV types are sometimes transmitted from mother to child during birth, the appearance of genital HPV-related diseases in newborns is rare. Perinatal transmission of HPV types 6 and 11 can result in the development of juvenile-onset recurrent respiratory papillomatosis (JORRP). JORRP is very rare, with rates of about 2 cases per 100,000 children in the United States. Although JORRP rates are substantially higher if a woman presents with genital warts at the time of giving birth, the risk of JORRP in such cases is still less than 1%.

The fact that prostitutes have much higher rates of cervical cancer than nuns was a key early observation leading researchers to speculate about a causal link between sexually transmitted HPVs and cervical cancer.

Dr. Harald zur Hausen of the German Cancer Research Centre, Heidelberg, Germany, was awarded 2008 Nobel Prize in Physiology or Medicine for his discovery of human papilloma viruses causing cervical cancer. He was interviewed as part of a radio program about the biology of HPV and the history of the discovery of its connection to cervical cancer.

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Cancer

Symptoms of cancer metastasis depend location of the tumor.

Cancer (medical term: malignant neoplasm) is a class of diseases in which a group of cells display uncontrolled growth (division beyond the normal limits), invasion (intrusion on and destruction of adjacent tissues), and sometimes metastasis (spread to other locations in the body via lymph or blood). These three malignant properties of cancers differentiate them from benign tumors, which are self-limited, do not invade or metastasize. Most cancers form a tumor but some, like leukemia, do not. The branch of medicine concerned with the study, diagnosis, treatment, and prevention of cancer is oncology.

Cancer may affect people at all ages, even fetuses, but the risk for most varieties increases with age. Cancer causes about 13% of all deaths. According to the American Cancer Society, 7.6 million people died from cancer in the world during 2007. Cancers can affect all animals.

Nearly all cancers are caused by abnormalities in the genetic material of the transformed cells. These abnormalities may be due to the effects of carcinogens, such as tobacco smoke, radiation, chemicals, or infectious agents. Other cancer-promoting genetic abnormalities may be randomly acquired through errors in DNA replication, or are inherited, and thus present in all cells from birth. The heritability of cancers are usually affected by complex interactions between carcinogens and the host's genome. New aspects of the genetics of cancer pathogenesis, such as DNA methylation, and microRNAs are increasingly recognized as important.

Genetic abnormalities found in cancer typically affect two general classes of genes. Cancer-promoting oncogenes are typically activated in cancer cells, giving those cells new properties, such as hyperactive growth and division, protection against programmed cell death, loss of respect for normal tissue boundaries, and the ability to become established in diverse tissue environments. Tumor suppressor genes are then inactivated in cancer cells, resulting in the loss of normal functions in those cells, such as accurate DNA replication, control over the cell cycle, orientation and adhesion within tissues, and interaction with protective cells of the immune system.

Diagnosis usually requires the histologic examination of a tissue biopsy specimen by a pathologist, although the initial indication of malignancy can be symptoms or radiographic imaging abnormalities. Most cancers can be treated and some cured, depending on the specific type, location, and stage. Once diagnosed, cancer is usually treated with a combination of surgery, chemotherapy and radiotherapy. As research develops, treatments are becoming more specific for different varieties of cancer. There has been significant progress in the development of targeted therapy drugs that act specifically on detectable molecular abnormalities in certain tumors, and which minimize damage to normal cells. The prognosis of cancer patients is most influenced by the type of cancer, as well as the stage, or extent of the disease. In addition, histologic grading and the presence of specific molecular markers can also be useful in establishing prognosis, as well as in determining individual treatments.

Malignant tumors (cancers) are usually named using -carcinoma, -sarcoma or -blastoma as a suffix, with the Latin or Greek word for the organ of origin as the root. For instance, a cancer of the liver is called hepatocarcinoma; a cancer of the fat cells is called liposarcoma. For common cancers, the English organ name is used. For instance, the most common type of breast cancer is called ductal carcinoma of the breast or mammary ductal carcinoma. Here, the adjective ductal refers to the appearance of the cancer under the microscope, resembling normal breast ducts.

Benign tumors (which are not cancers) are named using -oma as a suffix with the organ name as the root. For instance, a benign tumor of the smooth muscle of the uterus is called leiomyoma (the common name of this frequent tumor is fibroid). Unfortunately, some cancers also use the -oma suffix, examples being melanoma and seminoma.

Every symptom in the above list can be caused by a variety of conditions (a list of which is referred to as the differential diagnosis). Cancer may be a common or uncommon cause of each item.

Cancer is a diverse class of diseases which differ widely in their causes and biology. The common thread in all known cancers is the acquisition of abnormalities in the genetic material of the cancer cell and its progeny. Research into the pathogenesis of cancer can be divided into three broad areas of focus. The first area of research focuses on the agents and events which cause or facilitate genetic changes in cells destined to become cancer. Second, it is important to uncover the precise nature of the genetic damage, and the genes which are affected by it. The third focus is on the consequences of those genetic changes on the biology of the cell, both in generating the defining properties of a cancer cell, and in facilitating additional genetic events, leading to further progression of the cancer.

Cancer pathogenesis is traceable back to DNA mutations that impact cell growth and metastasis. Substances that cause DNA mutations are known as mutagens, and mutagens that cause cancers are known as carcinogens. Particular substances have been linked to specific types of cancer. Tobacco smoking is associated with many forms of cancer, and causes 90% of lung cancer. Prolonged exposure to asbestos fibers is associated with mesothelioma.

Many mutagens are also carcinogens, but some carcinogens are not mutagens. Alcohol is an example of a chemical carcinogen that is not a mutagen. Such chemicals may promote cancers through stimulating the rate of cell division. Faster rates of replication leaves less time for repair enzymes to repair damaged DNA during DNA replication, increasing the likelihood of a mutation.

Decades of research has demonstrated the link between tobacco use and cancer in the lung, larynx, head, neck, stomach, bladder, kidney, oesophagus and pancreas. Tobacco smoke contains over fifty known carcinogens, including nitrosamines and polycyclic aromatic hydrocarbons. Tobacco is responsible for about one in three of all cancer deaths in the developed world, and about one in five worldwide. Indeed, lung cancer death rates in the United States have mirrored smoking patterns, with increases in smoking followed by dramatic increases in lung cancer death rates and, more recently, decreases in smoking followed by decreases in lung cancer death rates in men. However, the numbers of smokers worldwide is still rising, leading to what some organizations have described as the tobacco epidemic.

Sources of ionizing radiation, such as radon gas, can cause cancer. Prolonged exposure to ultraviolet radiation from the sun can lead to melanoma and other skin malignancies.

Non-ionizing radio frequency radiation from mobile phones and other sources has also been proposed as a cause of cancer, but there is little evidence of such a link. Nevertheless, a few experts caution against prolonged exposure based on the precautionary principle.

Some cancers can be caused by infection with pathogens. Many cancers originate from a viral infection; this is especially true in animals such as birds, but also in humans, as viruses are responsible for 15% of human cancers worldwide. The main viruses associated with human cancers are human papillomavirus, hepatitis B and hepatitis C virus, Epstein-Barr virus, and human T-lymphotropic virus. Experimental and epidemiological data imply a causative role for viruses and they appear to be the second most important risk factor for cancer development in humans, exceeded only by tobacco usage. The mode of virally-induced tumors can be divided into two, acutely-transforming or slowly-transforming. In acutely transforming viruses, the virus carries an overactive oncogene called viral-oncogene (v-onc), and the infected cell is transformed as soon as v-onc is expressed. In contrast, in slowly-transforming viruses, the virus genome is inserts near a proto-oncogene in the host genome. The viral promoter or other transcription regulation elements then cause overexpression of that proto-oncogene. This induces uncontrolled cell division. Because the site of insertion is not specific to proto-oncogenes and the chance of insertion near any proto-oncogene is low, slowly-transforming viruses will cause tumors much longer after infection than the acutely-transforming viruses.

Hepatitis viruses, including hepatitis B and hepatitis C, can induce a chronic viral infection that leads to liver cancer in 0.47% of hepatitis B patients per year (especially in Asia, less so in North America), and in 1.4% of hepatitis C carriers per year. Liver cirrhosis, whether from chronic viral hepatitis infection or alcoholism, is associated with the development of liver cancer, and the combination of cirrhosis and viral hepatitis presents the highest risk of liver cancer development. Worldwide, liver cancer is one of the most common, and most deadly, cancers due to a huge burden of viral hepatitis transmission and disease.

Advances in cancer research have made a vaccine designed to prevent cancer available. In 2006, the U.S. Food and Drug Administration approved a human papilloma virus vaccine, called Gardasil. The vaccine protects against four HPV types, which together cause 70% of cervical cancers and 90% of genital warts. In March 2007, the US Centers for Disease Control and Prevention (CDC) Advisory Committee on Immunization Practices (ACIP) officially recommended that females aged 11-12 receive the vaccine, and indicated that females as young as age 9 and as old as age 26 are also candidates for immunization.

In addition to viruses, researchers have noted a connection between bacteria and certain cancers. The most prominent example is the link between chronic infection of the wall of the stomach with Helicobacter pylori and gastric cancer. Although only a minority of those infected with Helicobacter go on to develop cancer, since this pathogen is quite common it is probably responsible for the majority of these cancers.

Some hormones can act in a similar manner to non-mutagenic carcinogens in that they may stimulate excessive cell growth. A well-established example is the role of hyperestrogenic states in promoting endometrial cancer.

HIV is associated with a number of malignancies, including Kaposi's sarcoma, non-Hodgkin's lymphoma, and HPV-associated malignancies such as anal cancer and cervical cancer. AIDS-defining illnesses have long included these diagnoses. The increased incidence of malignancies in HIV patients points to the breakdown of immune surveillance as a possible etiology of cancer. Certain other immune deficiency states (e.g. common variable immunodeficiency and IgA deficiency) are also associated with increased risk of malignancy.

Excepting the rare transmissions that occur with pregnancies and only a marginal few organ donors, cancer is generally not a transmissible disease. The main reason for this is tissue graft rejection caused by MHC incompatibility. In humans and other vertebrates, the immune system uses MHC antigens to differentiate between "self" and "non-self" cells because these antigens are different from person to person. When non-self antigens are encountered, the immune system reacts against the appropriate cell. Such reactions may protect against tumour cell engraftment by eliminating implanted cells. In the United States, approximately 3,500 pregnant women have a malignancy annually, and transplacental transmission of acute leukaemia, lymphoma, melanoma and carcinoma from mother to fetus has been observed. The development of donor-derived tumors from organ transplants is exceedingly rare. The main cause of organ transplant associated tumors seems to be malignant melanoma, that was undetected at the time of organ harvest.

A few types of cancer in non-humans have been found to be caused by transmission of the tumor cells themselves. This phenomenon is seen in dogs with Sticker's sarcoma, also known as canine transmissible venereal tumor, as well as Devil facial tumour disease in Tasmanian devils.

Cancer is fundamentally a disease of regulation of tissue growth. In order for a normal cell to transform into a cancer cell, genes which regulate cell growth and differentiation must be altered. Genetic changes can occur at many levels, from gain or loss of entire chromosomes to a mutation affecting a single DNA nucleotide. There are two broad categories of genes which are affected by these changes. Oncogenes may be normal genes which are expressed at inappropriately high levels, or altered genes which have novel properties. In either case, expression of these genes promotes the malignant phenotype of cancer cells. Tumor suppressor genes are genes which inhibit cell division, survival, or other properties of cancer cells. Tumor suppressor genes are often disabled by cancer-promoting genetic changes. Typically, changes in many genes are required to transform a normal cell into a cancer cell.

There is a diverse classification scheme for the various genomic changes which may contribute to the generation of cancer cells. Most of these changes are mutations, or changes in the nucleotide sequence of genomic DNA. Aneuploidy, the presence of an abnormal number of chromosomes, is one genomic change which is not a mutation, and may involve either gain or loss of one or more chromosomes through errors in mitosis.

Large-scale mutations involve the deletion or gain of a portion of a chromosome. Genomic amplification occurs when a cell gains many copies (often 20 or more) of a small chromosomal locus, usually containing one or more oncogenes and adjacent genetic material. Translocation occurs when two separate chromosomal regions become abnormally fused, often at a characteristic location. A well-known example of this is the Philadelphia chromosome, or translocation of chromosomes 9 and 22, which occurs in chronic myelogenous leukemia, and results in production of the BCR-abl fusion protein, an oncogenic tyrosine kinase.

Small-scale mutations include point mutations, deletions, and insertions, which may occur in the promoter of a gene and affect its expression, or may occur in the gene's coding sequence and alter the function or stability of its protein product. Disruption of a single gene may also result from integration of genomic material from a DNA virus or retrovirus, and such an event may also result in the expression of viral oncogenes in the affected cell and its descendants.

Epigenetics is the study of the regulation of gene expression through chemical, non-mutational changes in DNA structure. The theory of epigenetics in cancer pathogenesis is that non-mutational changes to DNA can lead to alterations in gene expression. Normally, oncogenes are silent, for example, because of DNA methylation. Loss of that methylation can induce the aberrant expression of oncogenes, leading to cancer pathogenesis. Known mechanisms of epigenetic change include DNA methylation, and methylation or acetylation of histone proteins bound to chromosomal DNA at specific locations. Classes of medications, known as HDAC inhibitors and DNA methyltransferase inhibitors, can re-regulate the epigenetic signaling in the cancer cell.

Oncogenes promote cell growth through a variety of ways. Many can produce hormones, a "chemical messenger" between cells which encourage mitosis, the effect of which depends on the signal transduction of the receiving tissue or cells. In other words, when a hormone receptor on a recipient cell is stimulated, the signal is conducted from the surface of the cell to the cell nucleus to effect some change in gene transcription regulation at the nuclear level. Some oncogenes are part of the signal transduction system itself, or the signal receptors in cells and tissues themselves, thus controlling the sensitivity to such hormones. Oncogenes often produce mitogens, or are involved in transcription of DNA in protein synthesis, which creates the proteins and enzymes responsible for producing the products and biochemicals cells use and interact with.

Mutations in proto-oncogenes, which are the normally quiescent counterparts of oncogenes, can modify their expression and function, increasing the amount or activity of the product protein. When this happens, the proto-oncogenes become oncogenes, and this transition upsets the normal balance of cell cycle regulation in the cell, making uncontrolled growth possible. The chance of cancer cannot be reduced by removing proto-oncogenes from the genome, even if this were possible, as they are critical for growth, repair and homeostasis of the organism. It is only when they become mutated that the signals for growth become excessive.

One of the first oncogenes to be defined in cancer research is the ras oncogene. Mutations in the Ras family of proto-oncogenes (comprising H-Ras, N-Ras and K-Ras) are very common, being found in 20% to 30% of all human tumours. Ras was originally identified in the Harvey sarcoma virus genome, and researchers were surprised that not only was this gene present in the human genome but that, when ligated to a stimulating control element, could induce cancers in cell line cultures.

Tumor suppressor genes code for anti-proliferation signals and proteins that suppress mitosis and cell growth. Generally, tumor suppressors are transcription factors that are activated by cellular stress or DNA damage. Often DNA damage will cause the presence of free-floating genetic material as well as other signs, and will trigger enzymes and pathways which lead to the activation of tumor suppressor genes. The functions of such genes is to arrest the progression of the cell cycle in order to carry out DNA repair, preventing mutations from being passed on to daughter cells. The p53 protein, one of the most important studied tumor suppressor genes, is a transcription factor activated by many cellular stressors including hypoxia and ultraviolet radiation damage.

Despite nearly half of all cancers possibly involving alterations in p53, its tumor suppressor function is poorly understood. p53 clearly has two functions: one a nuclear role as a transcription factor, and the other a cytoplasmic role in regulating the cell cycle, cell division, and apoptosis.

The Warburg hypothesis is the preferential use of glycolysis for energy to sustain cancer growth. p53 has been shown to regulate the shift from the respiratory to the glycolytic pathway.

However, a mutation can damage the tumor suppressor gene itself, or the signal pathway which activates it, "switching it off". The invariable consequence of this is that DNA repair is hindered or inhibited: DNA damage accumulates without repair, inevitably leading to cancer.

Mutations of tumor suppressor genes that occur in germline cells are passed along to offspring, and increase the likelihood for cancer diagnoses in subsequent generations. Members of these families have increased incidence and decreased latency of multiple tumors. The tumor types are typical for each type of tumor suppressor gene mutation, with some mutations causing particular cancers, and other mutations causing others. The mode of inheritance of mutant tumor suppressors is that an affected member inherits a defective copy from one parent, and a normal copy from the other. For instance, individuals who inherit one mutant p53 allele (and are therefore heterozygous for mutated p53) can develop melanomas and pancreatic cancer, known as Li-Fraumeni syndrome. Other inherited tumor suppressor gene syndromes include Rb mutations, linked to retinoblastoma, and APC gene mutations, linked to adenopolyposis colon cancer. Adenopolyposis colon cancer is associated with thousands of polyps in colon while young, leading to colon cancer at a relatively early age. Finally, inherited mutations in BRCA1 and BRCA2 lead to early onset of breast cancer.

Development of cancer was proposed in 1971 to depend on at least two mutational events. In what became known as the Knudson two-hit hypothesis, an inherited, germ-line mutation in a tumor suppressor gene would only cause cancer if another mutation event occurred later in the organism's life, inactivating the other allele of that tumor suppressor gene.

Usually, oncogenes are dominant, as they contain gain-of-function mutations, while mutated tumor suppressors are recessive, as they contain loss-of-function mutations. Each cell has two copies of the same gene, one from each parent, and under most cases gain of function mutations in just one copy of a particular proto-oncogene is enough to make that gene a true oncogene. On the other hand, loss of function mutations need to happen in both copies of a tumor suppressor gene to render that gene completely non-functional. However, cases exist in which one mutated copy of a tumor suppressor gene can render the other, wild-type copy non-functional. This phenomenon is called the dominant negative effect and is observed in many p53 mutations.

Knudson’s two hit model has recently been challenged by several investigators. Inactivation of one allele of some tumor suppressor genes is sufficient to cause tumors. This phenomenon is called haploinsufficiency and has been demonstrated by a number of experimental approaches. Tumors caused by haploinsufficiency usually have a later age of onset when compared with those by a two hit process.

Often, the multiple genetic changes which result in cancer may take many years to accumulate. During this time, the biological behavior of the pre-malignant cells slowly change from the properties of normal cells to cancer-like properties. Pre-malignant tissue can have a distinctive appearance under the microscope. Among the distinguishing traits are an increased number of dividing cells, variation in nuclear size and shape, variation in cell size and shape, loss of specialized cell features, and loss of normal tissue organization. Dysplasia is an abnormal type of excessive cell proliferation characterized by loss of normal tissue arrangement and cell structure in pre-malignant cells. These early neoplastic changes must be distinguished from hyperplasia, a reversible increase in cell division caused by an external stimulus, such as a hormonal imbalance or chronic irritation.

The most severe cases of dysplasia are referred to as "carcinoma in situ." In Latin, the term "in situ" means "in place", so carcinoma in situ refers to an uncontrolled growth of cells that remains in the original location and has not shown invasion into other tissues. Nevertheless, carcinoma in situ may develop into an invasive malignancy and is usually removed surgically, if possible.

The process by which normal tissue becomes malignant is a process of somatic evolution within the body. Millions of years of biological evolution (favoring robustness over efficiency) insure that the cellular metabolic changes that enable cancer to grow occur only very rarely. Most changes in cellular metabolism that allow cells to grow in a disorderly fashion lead to cell death. Cancer cells undergo a process of natural selection, in that the few cells with new genetic changes that enhance their survival or reproduction continue to multiply, and soon come to dominate the growing tumor, as cells with less favorable genetic change are out-competed. This process is called clonal evolution. Tumors often continue to evolve in response to chemotherapy treatments, and on occasion aberrant cells may acquire resistance to particular anti-cancer pharmaceuticals.

These biological changes are classical in carcinomas; other malignant tumor may not need all to achieve them all. For example, tissue invasion and displacement to distant sites are normal properties of leukocytes; these steps are not needed in the development of leukemia. The different steps do not necessarily represent individual mutations. For example, inactivation of a single gene, coding for the p53 protein, will cause genomic instability, evasion of apoptosis and increased angiogenesis. Not all the cancer cells are dividing. Rather, a subset of the cells in a tumor, called cancer stem cells, replicate themselves and generate differentiated cells.

Cancer prevention is defined as active measures to decrease the incidence of cancer. This can be accomplished by avoiding carcinogens or altering their metabolism, pursuing a lifestyle or diet that modifies cancer-causing factors and/or medical intervention (chemoprevention, treatment of pre-malignant lesions). The epidemiological concept of "prevention" is usually defined as either primary prevention, for people who have not been diagnosed with a particular disease, or secondary prevention, aimed at reducing recurrence or complications of a previously diagnosed illness.

The vast majority of cancer risk factors are environmental or lifestyle-related in nature, leading to the claim that cancer is a largely preventable disease. Examples of modifiable cancer risk factors include alcohol consumption (associated with increased risk of oral, esophageal, breast, and other cancers), smoking (although 20% of women with lung cancer have never smoked, versus 10% of men), physical inactivity (associated with increased risk of colon, breast, and possibly other cancers), and being overweight / obese (associated with colon, breast, endometrial, and possibly other cancers). Based on epidemiologic evidence, it is now thought that avoiding excessive alcohol consumption may contribute to reductions in risk of certain cancers; however, compared with tobacco exposure, the magnitude of effect is modest or small and the strength of evidence is often weaker. Other lifestyle and environmental factors known to affect cancer risk (either beneficially or detrimentally) include certain sexually transmitted diseases (such as those conveyed by the human papillomavirus), the use of exogenous hormones, exposure to ionizing radiation and ultraviolet radiation, and certain occupational and chemical exposures.

Every year, at least 200,000 people die worldwide from cancer related to their workplace. Millions of workers run the risk of developing cancers such as lung cancer and mesothelioma from inhaling asbestos fibers and tobacco smoke, or leukemia from exposure to benzene at their workplaces. Currently, most cancer deaths caused by occupational risk factors occur in the developed world. It is estimated that approximately 20,000 cancer deaths and 40,000 new cases of cancer each year in the U.S. are attributable to occupation.

The consensus on diet and cancer is that obesity increases the risk of developing cancer. Particular dietary practices often explain differences in cancer incidence in different countries (e.g. gastric cancer is more common in Japan, while colon cancer is more common in the United States. In this example the preceding consideration of Haplogroups are excluded). Studies have shown that immigrants develop the risk of their new country, often within one generation, suggesting a substantial link between diet and cancer. Whether reducing obesity in a population also reduces cancer incidence is unknown.

Despite frequent reports of particular substances (including foods) having a beneficial or detrimental effect on cancer risk, few of these have an established link to cancer. These reports are often based on studies in cultured cell media or animals. Public health recommendations cannot be made on the basis of these studies until they have been validated in an observational (or occasionally a prospective interventional) trial in humans.

Proposed dietary interventions for primary cancer risk reduction generally gain support from epidemiological association studies. Examples of such studies include reports that reduced meat consumption is associated with decreased risk of colon cancer, and reports that consumption of coffee is associated with a reduced risk of liver cancer. Studies have linked consumption of grilled meat to an increased risk of stomach cancer, colon cancer, breast cancer, and pancreatic cancer, a phenomenon which could be due to the presence of carcinogens such as benzopyrene in foods cooked at high temperatures.

A 2005 secondary prevention study showed that consumption of a plant-based diet and lifestyle changes resulted in a reduction in cancer markers in a group of men with prostate cancer who were using no conventional treatments at the time. These results were amplified by a 2006 study in which over 2,400 women were studied, half randomly assigned to a normal diet, the other half assigned to a diet containing less than 20% calories from fat. The women on the low fat diet were found to have a markedly lower risk of breast cancer recurrence, in the interim report of December, 2006.

Recent studies have also demonstrated potential links between some forms of cancer and high consumption of refined sugars and other simple carbohydrates. Although the degree of correlation and the degree of causality is still debated, some organizations have in fact begun to recommend reducing intake of refined sugars and starches as part of their cancer prevention regimens.

In November 2007, the American Institute for Cancer Research (AICR), in conjunction with the World Cancer Research Fund (WCRF), published Food, Nutrition, Physical Activity, and the Prevention of Cancer: a Global Perspective', "the most current and comprehensive analysis of the literature on diet, physical activity and cancer". The WCRF/AICR Expert Report lists 10 recommendations that people can follow to help reduce their risk of developing cancer, including the following dietary guidelines: (1) reducing intake of foods and drinks that promote weight gain, namely energy-dense foods and sugary drinks, (2) eating mostly foods of plant origin, (3) limiting intake of red meat and avoiding processed meat, (4) limiting consumption of alcoholic beverages, and (5) reducing intake of salt and avoiding mouldy cereals (grains) or pulses (legumes).

The idea that cancer can be prevented through vitamin supplementation stems from early observations correlating human disease with vitamin deficiency, such as pernicious anemia with vitamin B12 deficiency, and scurvy with Vitamin C deficiency. This has largely not been proven to be the case with cancer, and vitamin supplementation is largely not proving effective in preventing cancer. The cancer-fighting components of food are also proving to be more numerous and varied than previously understood, so patients are increasingly being advised to consume fresh, unprocessed fruits and vegetables for maximal health benefits.

Epidemiological studies have shown that low vitamin D status is correlated to increased cancer risk. However, the results of such studies need to be treated with caution, as they cannot show whether a correlation between two factors means that one causes the other (i.e. correlation does not imply causation). The possibility that Vitamin D might protect against cancer has been contrasted with the risk of malignancy from sun exposure. Since exposure to the sun enhances natural human production of vitamin D, some cancer researchers have argued that the potential deleterious malignant effects of sun exposure are far outweighed by the cancer-preventing effects of extra vitamin D synthesis in sun-exposed skin. In 2002, Dr. William B. Grant claimed that 23,800 premature cancer deaths occur in the US annually due to insufficient UVB exposure (apparently via vitamin D deficiency). This is higher than 8,800 deaths occurred from melanoma or squamous cell carcinoma, so the overall effect of sun exposure might be beneficial. Another research group estimates that 50,000–63,000 individuals in the United States and 19,000 - 25,000 in the UK die prematurely from cancer annually due to insufficient vitamin D.

The case of beta-carotene provides an example of the importance of randomized clinical trials. Epidemiologists studying both diet and serum levels observed that high levels of beta-carotene, a precursor to vitamin A, were associated with a protective effect, reducing the risk of cancer. This effect was particularly strong in lung cancer. This hypothesis led to a series of large randomized clinical trials conducted in both Finland and the United States (CARET study) during the 1980s and 1990s. This study provided about 80,000 smokers or former smokers with daily supplements of beta-carotene or placebos. Contrary to expectation, these tests found no benefit of beta-carotene supplementation in reducing lung cancer incidence and mortality. In fact, the risk of lung cancer was slightly, but not significantly, increased by beta-carotene, leading to an early termination of the study.

Results reported in the Journal of the American Medical Association (JAMA) in 2007 indicate that folic acid supplementation is not effective in preventing colon cancer, and folate consumers may be more likely to form colon polyps.

The concept that medications could be used to prevent cancer is an attractive one, and many high-quality clinical trials support the use of such chemoprevention in defined circumstances.

Daily use of tamoxifen, a selective estrogen receptor modulator (SERM), typically for 5 years, has been demonstrated to reduce the risk of developing breast cancer in high-risk women by about 50%. A recent study reported that the selective estrogen receptor modulator raloxifene has similar benefits to tamoxifen in preventing breast cancer in high-risk women, with a more favorable side effect profile.

Raloxifene is a SERM like tamoxifen; it has been shown (in the STAR trial) to reduce the risk of breast cancer in high-risk women equally as well as tamoxifen. In this trial, which studied almost 20,000 women, raloxifene had fewer side effects than tamoxifen, though it did permit more DCIS to form.

Finasteride, a 5-alpha-reductase inhibitor, has been shown to lower the risk of prostate cancer, though it seems to mostly prevent low-grade tumors. The effect of COX-2 inhibitors such as rofecoxib and celecoxib upon the risk of colon polyps have been studied in familial adenomatous polyposis patients and in the general population. In both groups, there were significant reductions in colon polyp incidence, but this came at the price of increased cardiovascular toxicity.

Genetic testing for high-risk individuals is already available for certain cancer-related genetic mutations. Carriers of genetic mutations that increase risk for cancer incidence can undergo enhanced surveillance, chemoprevention, or risk-reducing surgery. Early identification of inherited genetic risk for cancer, along with cancer-preventing interventions such as surgery or enhanced surveillance, can be lifesaving for high-risk individuals.

Prophylactic vaccines have been developed to prevent infection by oncogenic infectious agents such as viruses, and therapeutic vaccines are in development to stimulate an immune response against cancer-specific epitopes.

As reported above, a preventive human papillomavirus vaccine exists that targets certain sexually transmitted strains of human papillomavirus that are associated with the development of cervical cancer and genital warts. The only two HPV vaccines on the market as of October 2007 are Gardasil and Cervarix. There is also a hepatitis B vaccine, which prevents infection with the hepatitis B virus, an infectious agent that can cause liver cancer. A canine melanoma vaccine has also been developed.

Cancer screening is an attempt to detect unsuspected cancers in an asymptomatic population. Screening tests suitable for large numbers of healthy people must be relatively affordable, safe, noninvasive procedures with acceptably low rates of false positive results. If signs of cancer are detected, more definitive and invasive follow up tests are performed to confirm the diagnosis.

Screening for cancer can lead to earlier diagnosis in specific cases. Early diagnosis may lead to extended life, but may also falsely prolong the lead time to death through lead time bias or length time bias.

A number of different screening tests have been developed for different malignancies. Breast cancer screening can be done by breast self-examination, though this approach was discredited by a 2005 study in over 300,000 Chinese women. Screening for breast cancer with mammograms has been shown to reduce the average stage of diagnosis of breast cancer in a population. Stage of diagnosis in a country has been shown to decrease within ten years of introduction of mammographic screening programs. Colorectal cancer can be detected through fecal occult blood testing and colonoscopy, which reduces both colon cancer incidence and mortality, presumably through the detection and removal of pre-malignant polyps. Similarly, cervical cytology testing (using the Pap smear) leads to the identification and excision of precancerous lesions. Over time, such testing has been followed by a dramatic reduction of cervical cancer incidence and mortality. Testicular self-examination is recommended for men beginning at the age of 15 years to detect testicular cancer. Prostate cancer can be screened using a digital rectal exam along with prostate specific antigen (PSA) blood testing, though some authorities (such as the US Preventive Services Task Force) recommend against routinely screening all men.

Screening for cancer is controversial in cases when it is not yet known if the test actually saves lives. The controversy arises when it is not clear if the benefits of screening outweigh the risks of follow-up diagnostic tests and cancer treatments. For example: when screening for prostate cancer, the PSA test may detect small cancers that would never become life threatening, but once detected will lead to treatment. This situation, called overdiagnosis, puts men at risk for complications from unnecessary treatment such as surgery or radiation. Follow up procedures used to diagnose prostate cancer (prostate biopsy) may cause side effects, including bleeding and infection. Prostate cancer treatment may cause incontinence (inability to control urine flow) and erectile dysfunction (erections inadequate for intercourse). Similarly, for breast cancer, there have recently been criticisms that breast screening programs in some countries cause more problems than they solve. This is because screening of women in the general population will result in a large number of women with false positive results which require extensive follow-up investigations to exclude cancer, leading to having a high number-to-treat (or number-to-screen) to prevent or catch a single case of breast cancer early.

Cervical cancer screening via the Pap smear has the best cost-benefit profile of all the forms of cancer screening from a public health perspective as, being largely caused by a virus, it has clear risk factors (sexual contact), and the natural progression of cervical cancer is that it normally spreads slowly over a number of years therefore giving more time for the screening program to catch it early. Moreover, the test itself is easy to perform and relatively cheap.

For these reasons, it is important that the benefits and risks of diagnostic procedures and treatment be taken into account when considering whether to undertake cancer screening.

Use of medical imaging to search for cancer in people without clear symptoms is similarly marred with problems. There is a significant risk of detection of what has been recently called an incidentaloma - a benign lesion that may be interpreted as a malignancy and be subjected to potentially dangerous investigations. Recent studies of CT scan-based screening for lung cancer in smokers have had equivocal results, and systematic screening is not recommended as of July 2007. Randomized clinical trials of plain-film chest X-rays to screen for lung cancer in smokers have shown no benefit for this approach.

Canine cancer detection has shown promise, but is still in the early stages of research.

Most cancers are initially recognized either because signs or symptoms appear or through screening. Neither of these lead to a definitive diagnosis, which usually requires the opinion of a pathologist, a type of physician (medical doctor) who specializes in the diagnosis of cancer and other diseases.

People with suspected cancer are investigated with medical tests. These commonly include blood tests, X-rays, CT scans and endoscopy.

A cancer may be suspected for a variety of reasons, but the definitive diagnosis of most malignancies must be confirmed by histological examination of the cancerous cells by a pathologist. Tissue can be obtained from a biopsy or surgery. Many biopsies (such as those of the skin, breast or liver) can be done in a doctor's office. Biopsies of other organs are performed under anesthesia and require surgery in an operating room.

The tissue diagnosis given by the pathologist indicates the type of cell that is proliferating, its histological grade and other features of the tumor. Together, this information is useful to evaluate the prognosis of the patient and to choose the best treatment. Cytogenetics and immunohistochemistry are other types of testing that the pathologist may perform on the tissue specimen. These tests may provide information about future behavior of the cancer (prognosis) and best treatment.

Cancer can be treated by surgery, chemotherapy, radiation therapy, immunotherapy, monoclonal antibody therapy or other methods. The choice of therapy depends upon the location and grade of the tumor and the stage of the disease, as well as the general state of the patient (performance status). A number of experimental cancer treatments are also under development.

Complete removal of the cancer without damage to the rest of the body is the goal of treatment. Sometimes this can be accomplished by surgery, but the propensity of cancers to invade adjacent tissue or to spread to distant sites by microscopic metastasis often limits its effectiveness. The effectiveness of chemotherapy is often limited by toxicity to other tissues in the body. Radiation can also cause damage to normal tissue.

Because "cancer" refers to a class of diseases, it is unlikely that there will ever be a single "cure for cancer" any more than there will be a single treatment for all infectious diseases.

In theory, non-hematological cancers can be cured if entirely removed by surgery, but this is not always possible. When the cancer has metastasized to other sites in the body prior to surgery, complete surgical excision is usually impossible. In the Halstedian model of cancer progression, tumors grow locally, then spread to the lymph nodes, then to the rest of the body. This has given rise to the popularity of local-only treatments such as surgery for small cancers. Even small localized tumors are increasingly recognized as possessing metastatic potential.

Examples of surgical procedures for cancer include mastectomy for breast cancer and prostatectomy for prostate cancer. The goal of the surgery can be either the removal of only the tumor, or the entire organ. A single cancer cell is invisible to the naked eye but can regrow into a new tumor, a process called recurrence. For this reason, the pathologist will examine the surgical specimen to determine if a margin of healthy tissue is present, thus decreasing the chance that microscopic cancer cells are left in the patient.

In addition to removal of the primary tumor, surgery is often necessary for staging, e.g. determining the extent of the disease and whether it has metastasized to regional lymph nodes. Staging is a major determinant of prognosis and of the need for adjuvant therapy.

Occasionally, surgery is necessary to control symptoms, such as spinal cord compression or bowel obstruction. This is referred to as palliative treatment.

Radiation therapy (also called radiotherapy, X-ray therapy, or irradiation) is the use of ionizing radiation to kill cancer cells and shrink tumors. Radiation therapy can be administered externally via external beam radiotherapy (EBRT) or internally via brachytherapy. The effects of radiation therapy are localised and confined to the region being treated. Radiation therapy injures or destroys cells in the area being treated (the "target tissue") by damaging their genetic material, making it impossible for these cells to continue to grow and divide. Although radiation damages both cancer cells and normal cells, most normal cells can recover from the effects of radiation and function properly. The goal of radiation therapy is to damage as many cancer cells as possible, while limiting harm to nearby healthy tissue. Hence, it is given in many fractions, allowing healthy tissue to recover between fractions.

Radiation therapy may be used to treat almost every type of solid tumor, including cancers of the brain, breast, cervix, larynx, lung, pancreas, prostate, skin, stomach, uterus, or soft tissue sarcomas. Radiation is also used to treat leukemia and lymphoma. Radiation dose to each site depends on a number of factors, including the radiosensitivity of each cancer type and whether there are tissues and organs nearby that may be damaged by radiation. Thus, as with every form of treatment, radiation therapy is not without its side effects.

Chemotherapy is the treatment of cancer with drugs ("anticancer drugs") that can destroy cancer cells. In current usage, the term "chemotherapy" usually refers to cytotoxic drugs which affect rapidly dividing cells in general, in contrast with targeted therapy (see below). Chemotherapy drugs interfere with cell division in various possible ways, e.g. with the duplication of DNA or the separation of newly formed chromosomes. Most forms of chemotherapy target all rapidly dividing cells and are not specific to cancer cells, although some degree of specificity may come from the inability of many cancer cells to repair DNA damage, while normal cells generally can. Hence, chemotherapy has the potential to harm healthy tissue, especially those tissues that have a high replacement rate (e.g. intestinal lining). These cells usually repair themselves after chemotherapy.

Because some drugs work better together than alone, two or more drugs are often given at the same time. This is called "combination chemotherapy"; most chemotherapy regimens are given in a combination.

The treatment of some leukaemias and lymphomas requires the use of high-dose chemotherapy, and total body irradiation (TBI). This treatment ablates the bone marrow, and hence the body's ability to recover and repopulate the blood. For this reason, bone marrow, or peripheral blood stem cell harvesting is carried out before the ablative part of the therapy, to enable "rescue" after the treatment has been given. This is known as autologous stem cell transplantation. Alternatively, hematopoietic stem cells may be transplanted from a matched unrelated donor (MUD).

Targeted therapy, which first became available in the late 1990s, has had a significant impact in the treatment of some types of cancer, and is currently a very active research area. This constitutes the use of agents specific for the deregulated proteins of cancer cells. Small molecule targeted therapy drugs are generally inhibitors of enzymatic domains on mutated, overexpressed, or otherwise critical proteins within the cancer cell. Prominent examples are the tyrosine kinase inhibitors imatinib (Gleevec/Glivec) and gefitinib (Iressa).

Monoclonal antibody therapy is another strategy in which the therapeutic agent is an antibody which specifically binds to a protein on the surface of the cancer cells. Examples include the anti-HER2/neu antibody trastuzumab (Herceptin) used in breast cancer, and the anti-CD20 antibody rituximab, used in a variety of B-cell malignancies.

Targeted therapy can also involve small peptides as "homing devices" which can bind to cell surface receptors or affected extracellular matrix surrounding the tumor. Radionuclides which are attached to these peptides (e.g. RGDs) eventually kill the cancer cell if the nuclide decays in the vicinity of the cell. Especially oligo- or multimers of these binding motifs are of great interest, since this can lead to enhanced tumor specificity and avidity.

Photodynamic therapy (PDT) is a ternary treatment for cancer involving a photosensitizer, tissue oxygen, and light (often using lasers). PDT can be used as treatment for basal cell carcinoma (BCC) or lung cancer; PDT can also be useful in removing traces of malignant tissue after surgical removal of large tumors.

Cancer immunotherapy refers to a diverse set of therapeutic strategies designed to induce the patient's own immune system to fight the tumor. Contemporary methods for generating an immune response against tumours include intravesical BCG immunotherapy for superficial bladder cancer, and use of interferons and other cytokines to induce an immune response in renal cell carcinoma and melanoma patients. Vaccines to generate specific immune responses are the subject of intensive research for a number of tumours, notably malignant melanoma and renal cell carcinoma. Sipuleucel-T is a vaccine-like strategy in late clinical trials for prostate cancer in which dendritic cells from the patient are loaded with prostatic acid phosphatase peptides to induce a specific immune response against prostate-derived cells.

Allogeneic hematopoietic stem cell transplantation ("bone marrow transplantation" from a genetically non-identical donor) can be considered a form of immunotherapy, since the donor's immune cells will often attack the tumor in a phenomenon known as graft-versus-tumor effect. For this reason, allogeneic HSCT leads to a higher cure rate than autologous transplantation for several cancer types, although the side effects are also more severe.

The growth of some cancers can be inhibited by providing or blocking certain hormones. Common examples of hormone-sensitive tumors include certain types of breast and prostate cancers. Removing or blocking estrogen or testosterone is often an important additional treatment. In certain cancers, administration of hormone agonists, such as progestogens may be therapeutically beneficial.

Angiogenesis inhibitors prevent the extensive growth of blood vessels (angiogenesis) that tumors require to survive. Some, such as bevacizumab, have been approved and are in clinical use. One of the main problems with anti-angiogenesis drugs is that many factors stimulate blood vessel growth in cells normal or cancerous. Anti-angiogenesis drugs only target one factor, so the other factors continue to stimulate blood vessel growth. Other problems include route of administration, maintenance of stability and activity and targeting at the tumor vasculature.

Although the control of the symptoms of cancer is not typically thought of as a treatment directed at the cancer, it is an important determinant of the quality of life of cancer patients, and plays an important role in the decision whether the patient is able to undergo other treatments. Although doctors generally have the therapeutic skills to reduce pain, nausea, vomiting, diarrhea, hemorrhage and other common problems in cancer patients, the multidisciplinary specialty of palliative care has arisen specifically in response to the symptom control needs of this group of patients.

Pain medication, such as morphine and oxycodone, and antiemetics, drugs to suppress nausea and vomiting, are very commonly used in patients with cancer-related symptoms. Improved antiemetics such as ondansetron and analogues, as well as aprepitant have made aggressive treatments much more feasible in cancer patients.

Chronic pain due to cancer is almost always associated with continuing tissue damage due to the disease process or the treatment (i.e. surgery, radiation, chemotherapy). Although there is always a role for environmental factors and affective disturbances in the genesis of pain behaviors, these are not usually the predominant etiologic factors in patients with cancer pain. Furthermore, many patients with severe pain associated with cancer are nearing the end of their lives and palliative therapies are required. Issues such as social stigma of using opioids, work and functional status, and health care consumption are not likely to be important in the overall case management. Hence, the typical strategy for cancer pain management is to get the patient as comfortable as possible using opioids and other medications, surgery, and physical measures. Doctors have been reluctant to prescribe narcotics for pain in terminal cancer patients, for fear of contributing to addiction or suppressing respiratory function. The palliative care movement, a more recent offshoot of the hospice movement, has engendered more widespread support for preemptive pain treatment for cancer patients.

Fatigue is a very common problem for cancer patients, and has only recently become important enough for oncologists to suggest treatment, even though it plays a significant role in many patients' quality of life.

Clinical trials, also called research studies, test new treatments in people with cancer. The goal of this research is to find better ways to treat cancer and help cancer patients. Clinical trials test many types of treatment such as new drugs, new approaches to surgery or radiation therapy, new combinations of treatments, or new methods such as gene therapy.

A clinical trial is one of the final stages of a long and careful cancer research process. The search for new treatments begins in the laboratory, where scientists first develop and test new ideas. If an approach seems promising, the next step may be testing a treatment in animals to see how it affects cancer in a living being and whether it has harmful effects. Of course, treatments that work well in the lab or in animals do not always work well in people. Studies are done with cancer patients to find out whether promising treatments are safe and effective.

Patients who take part may be helped personally by the treatment they receive. They get up-to-date care from cancer experts, and they receive either a new treatment being tested or the best available standard treatment for their cancer. At the same time, new treatments also may have unknown risks, but if a new treatment proves effective or more effective than standard treatment, study patients who receive it may be among the first to benefit. There is no guarantee that a new treatment being tested or a standard treatment will produce good results. In children with cancer, a survey of trials found that those enrolled in trials were on average not more likely to do better or worse than those on standard treatment; this confirms that success or failure of an experimental treatment cannot be predicted.

Complementary and alternative medicine (CAM) treatments are the diverse group of medical and health care systems, practices, and products that are not part of conventional medicine. "Complementary medicine" refers to methods and substances used along with conventional medicine, while "alternative medicine" refers to compounds used instead of conventional medicine. CAM use is common among people with cancer; a 2000 study found that 69% of cancer patients had used at least one CAM therapy as part of their cancer treatment. Most complementary and alternative medicines for cancer have not been rigorously studied or tested. Some alternative treatments which have been investigated and shown to be ineffective continue to be marketed and promoted.

Cancer has a reputation for being a deadly disease. While this certainly applies to certain particular types, the truths behind the historical connotations of cancer are increasingly being overturned by advances in medical care. Some types of cancer have a prognosis that is substantially better than nonmalignant diseases such as heart failure and stroke.

Progressive and disseminated malignant disease has a substantial impact on a cancer patient's quality of life, and many cancer treatments (such as chemotherapy) may have severe side-effects. In the advanced stages of cancer, many patients need extensive care, affecting family members and friends. Palliative care solutions may include permanent or "respite" hospice nursing.

Many local organizations offer a variety of practical and support services to people with cancer. Support can take the form of support groups, counseling, advice, financial assistance, transportation to and from treatment, films or information about cancer. Neighborhood organizations, local health care providers, or area hospitals may have resources or services available.

Counseling can provide emotional support to cancer patients and help them better understand their illness. Different types of counseling include individual, group, family, peer counseling, bereavement, patient-to-patient, and sexuality.

Many governmental and charitable organizations have been established to help patients cope with cancer. These organizations often are involved in cancer prevention, cancer treatment, and cancer research.

Cancer is responsible for about 25% of all deaths in the U.S., and is a major public health problem in many parts of the world. In the U.S., lung cancer causes about 30% of cancer deaths but only about 15% of new cancer cases; the most commonly occurring cancer in men is prostate cancer (about 25% of new cases) and in women is breast cancer (also about 25%). Cancer can also occur in young children and adolescents, but it is rare (about 150 cases per million in the U.S.), with leukemia being the most common. In the first year of life the incidence is about 230 cases per million in the U.S., with the most common being neuroblastoma.

Over a third of cancer deaths worldwide are due to potentially modifiable risk factors, which are headed by tobacco smoking, alcohol use, and diets low in fruit and vegetables. In developed countries overweight and obesity is also a leading cause of cancer, and in low-and-middle-income countries sexual transmission of human papillomavirus is a leading risk factor for cervical cancer.

Today, the Greek term carcinoma is the medical term for a malignant tumor derived from epithelial cells. It is Celsus who translated carcinos into the Latin cancer, also meaning crab. Galen used "oncos" to describe all tumours, the root for the modern word oncology.

Hippocrates described several kinds of cancers. He called benign tumours oncos, Greek for swelling, and malignant tumours carcinos, Greek for crab or crayfish. This name comes from the appearance of the cut surface of a solid malignant tumour, with the veins stretched on all sides as the animal the crab has its feet, whence it derives its name (see picture). He later added the suffix -oma, Greek for swelling, giving the name carcinoma. Since it was against Greek tradition to open the body, Hippocrates only described and made drawings of outwardly visible tumors on the skin, nose, and breasts. Treatment was based on the humor theory of four bodily fluids (black and yellow bile, blood, and phlegm). According to the patient's humor, treatment consisted of diet, blood-letting, and/or laxatives. Through the centuries it was discovered that cancer could occur anywhere in the body, but humor-theory based treatment remained popular until the 19th century with the discovery of cells.

Another very early surgical treatment for cancer was described in the 1020s by Avicenna (Ibn Sina) in The Canon of Medicine. He stated that the excision should be radical and that all diseased tissue should be removed, which included the use of amputation or the removal of veins running in the direction of the tumor. He also recommended the use of cauterization for the area being treated if necessary.

In the 16th and 17th centuries, it became more acceptable for doctors to dissect bodies to discover the cause of death. The German professor Wilhelm Fabry believed that breast cancer was caused by a milk clot in a mammary duct. The Dutch professor Francois de la Boe Sylvius, a follower of Descartes, believed that all disease was the outcome of chemical processes, and that acidic lymph fluid was the cause of cancer. His contemporary Nicolaes Tulp believed that cancer was a poison that slowly spreads, and concluded that it was contagious.

The first cause of cancer was identified by British surgeon Percivall Pott, who discovered in 1775 that cancer of the scrotum was a common disease among chimney sweeps. The work of other individual physicians led to various insights, but when physicians started working together they could make firmer conclusions.

With the widespread use of the microscope in the 18th century, it was discovered that the 'cancer poison' spread from the primary tumor through the lymph nodes to other sites ("metastasis"). This view of the disease was first formulated by the English surgeon Campbell De Morgan between 1871 and 1874. The use of surgery to treat cancer had poor results due to problems with hygiene. The renowned Scottish surgeon Alexander Monro saw only 2 breast tumor patients out of 60 surviving surgery for two years. In the 19th century, asepsis improved surgical hygiene and as the survival statistics went up, surgical removal of the tumor became the primary treatment for cancer. With the exception of William Coley who in the late 1800s felt that the rate of cure after surgery had been higher before asepsis (and who injected bacteria into tumors with mixed results), cancer treatment became dependent on the individual art of the surgeon at removing a tumor. During the same period, the idea that the body was made up of various tissues, that in turn were made up of millions of cells, laid rest the humor-theories about chemical imbalances in the body. The age of cellular pathology was born.

When Marie Curie and Pierre Curie discovered radiation at the end of the 19th century, they stumbled upon the first effective non-surgical cancer treatment. With radiation also came the first signs of multi-disciplinary approaches to cancer treatment. The surgeon was no longer operating in isolation, but worked together with hospital radiologists to help patients. The complications in communication this brought, along with the necessity of the patient's treatment in a hospital facility rather than at home, also created a parallel process of compiling patient data into hospital files, which in turn led to the first statistical patient studies.

A founding paper of cancer epidemiology was the work of Janet Lane-Claypon, who published a comparative study in 1926 of 500 breast cancer cases and 500 control patients of the same background and lifestyle for the British Ministry of Health. Her ground-breaking work on cancer epidemiology was carried on by Richard Doll and Austin Bradford Hill, who published "Lung Cancer and Other Causes of Death In Relation to Smoking. A Second Report on the Mortality of British Doctors" followed in 1956 (otherwise known as the British doctors study). Richard Doll left the London Medical Research Center (MRC), to start the Oxford unit for Cancer epidemiology in 1968. With the use of computers, the unit was the first to compile large amounts of cancer data. Modern epidemiological methods are closely linked to current concepts of disease and public health policy. Over the past 50 years, great efforts have been spent on gathering data across medical practise, hospital, provincial, state, and even country boundaries, as a way to study the interdependence of environmental and cultural factors on cancer incidence.

Cancer patient treatment and studies were restricted to individual physicians' practices until World War II, when medical research centers discovered that there were large international differences in disease incidence. This insight drove national public health bodies to make it possible to compile health data across practises and hospitals, a process that many countries do today. The Japanese medical community observed that the bone marrow of victims of the atomic bombings of Hiroshima and Nagasaki was completely destroyed. They concluded that diseased bone marrow could also be destroyed with radiation, and this led to the discovery of bone marrow transplants for leukemia. Since World War II, trends in cancer treatment are to improve on a micro-level the existing treatment methods, standardize them, and globalize them as a way to find cures through epidemiology and international partnerships.

Cancer research is the intense scientific effort to understand disease processes and discover possible therapies. The improved understanding of molecular biology and cellular biology due to cancer research has led to a number of new, effective treatments for cancer since President Nixon declared "War on Cancer" in 1971. Since 1971 the United States has invested over $200 billion on cancer research; that total includes money invested by public and private sectors and foundations. Leading cancer research organizations and projects include the American Association for Cancer Research, the American Cancer Society (ACS), the American Society of Clinical Oncology, the European Organisation for Research and Treatment of Cancer, the National Cancer Institute, the National Comprehensive Cancer Network, and The Cancer Genome Atlas project at the NCI.

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HPV vaccine

Human papillomavirus (HPV) vaccine is a vaccine that prevents infection with certain species of human papillomavirus associated with the development of cervical cancer, genital warts, and some less common cancers (e.g., anal, vulvar, vaginal, penile). Two HPV vaccines are currently on the market: Gardasil and Cervarix. Both vaccines protect against two of the HPV types that cause cervical cancer, and some other genital cancers; Gardasil also protects against two of the HPV types that cause genital warts.

Public health officials in Australia, Canada, Europe and United States recommend vaccination of young women against HPV to prevent cervical cancer and genital warts, and to reduce the number of painful and costly treatments for cervical dysplasia, which is caused by HPV. Worldwide, HPV is the most common sexually transmitted infection in adults. For example, more than 80% of American women will have contracted at least one strain of HPV by age fifty.

Although most women infected with genital HPV will not have complications from the virus, worldwide there are an estimated 470,000 new cases of cervical cancer that result in 233,000 deaths per year. About eighty percent of deaths from cervical cancer occur in poor countries. In the United States, most of the approximately 11,000 cervical cancers found annually occur in women who have never had a Pap smear, or not had one in the previous five years.

Since the vaccine only covers some high-risk types of HPV, experts still recommend regular Pap smear screening even after vaccination.

Gardasil has been shown to also be effective in males.

In work that was initiated in the mid 1980s, the vaccine was developed, in parallel, by researchers at Georgetown University Medical Center, the University of Rochester, the University of Queensland in Australia, and the U.S. National Cancer Institute In 2006, the U.S. Food and Drug Administration approved the first preventive HPV vaccine, marketed by Merck & Co. under the trade name Gardasil. According to a Merck press release, in the second quarter 2007, it had been approved in 80 countries, many under fast-track or expedited review. Early in 2007, GlaxoSmithKline filed for approval in the United States for a similar preventive HPV vaccine, known as Cervarix. In June 2007 this vaccine was licenced in Australia, and it was approved in the European Union in September 2007.

In addition to preventive vaccines, such as Gardasil and Cervarix, laboratory research and several human clinical trials are focused on the development of therapeutic HPV vaccines. In general these vaccines focus on the main HPV oncogenes, E6 and E7. Since expression of E6 and E7 is required for promoting the growth of cervical cancer cells (and cells within warts), it is hoped that immune responses against the two oncogenes might eradicate established tumors.

According to the Centers for Disease Control and Prevention, by the age of 50 more than 80% of American women will have contracted at least one strain of genital HPV. Both men and women can be carriers of HPV. HPV is the most common sexually transmitted infection in the US. A large percentage of the American population is infected with genital HPV because HPV is highly communicable. As a result, American public health experts recommend widespread HPV vaccination.

Only a small percentage of women with HPV develop cervical cancer. Each year, between 250,000 and 1 million American women are diagnosed with cervical dysplasia, which is caused by HPV and is a potential precursor to cervical cancer. About 11,000 American women are diagnosed with cervical cancer every year, and about 3,700 die per year of the disease. Most cancers occur in those who have not had Pap smears within the previous five years.

There are 19 "high-risk" HPV types that can lead to the development of cervical cancer or other genital/anal cancers; some forms of HPV, particularly type 16, have been found to be associated with a form of throat cancer. Studies have found that human papillomavirus (HPV) infection is responsible for virtually all cases of cervical cancer.

Condoms protect against HPV, but do not completely prevent transmission. College freshmen women who used condoms consistently had a 37.8% per patient-year incidence of genital HPV, compared to an incidence of 89.3% among those who did not.

No data is kept by the U.S. government on genital wart infection rates, however it is estimated that 20 million people are presently infected with genital warts, and there are six million new cases of genital warts every year in the United States.

Worldwide, cervical cancer is the fifth most deadly cancer in women. There are an estimated 470,000 new cases of cervical cancer, and 233,000 deaths per year.

Current preventive vaccines protect against the two HPV types (16 and 18) that cause about 70% of cervical cancers worldwide. Because of the distribution of HPV types associated with cervical cancer, the vaccines are likely to be most effective in Asia, Europe, and North America. Vaccines that protect against more of the types common in cancers would prevent more cancers, and be less subject to regional variation.

Only 41% of women with cervical cancer in the developing world are able to access medical treatment for their illness. Therefore, prevention of HPV by vaccination may be a more effective way of lowering the disease burden in developing countries than cervical screening.

Gardasil and Cervarix are preventative (rather than therapeutic) vaccines, recommended for women who are 9 to 25 years old and have not contracted HPV. However, since it is unlikely that a woman will have already contracted all four viruses, and because HPV is primarily sexually transmitted, the U.S. Centers for Disease Control and Prevention has recommended vaccination for women up to 26 years of age.

When Gardasil was first introduced, it was recommended as a prevention for cervical cancer for women that were 25 years old or younger. New evidence suggests that all Human Papillomavirus (HPV) vaccines are effective in preventing cervical cancer for women up to 45 years of age.

In November 2007, Merck presented new data on Gardasil. In an investigational study, their HPV vaccine reduced incidence of HPV 6, 11, 16 and 18-related persistent infection and disease in women through age 45. The study evaluated women who had not contracted at least one of the HPV types targeted by the vaccine by the end of the three-dose vaccination series. Merck planned to submit this data before the end of 2007 to the U.S. Food and Drug Administration (FDA), and to seek an indication for Gardasil for women through age 45.

In the Gardasil clinical trials, 1,115 pregnant women received the HPV vaccine. Overall, the proportions of pregnancies with an adverse outcome were comparable in subjects who receivd Gardasil and subjects who received placebo. However, the clinical trials had a relatively small sample size. Currently the vaccine is not recommended for pregnant women. The long-term effects of the vaccine on fertility are not known, but no effects are anticipated.

Gardasil can also be used in males to reduce their risk of genital warts and precancerous lesions caused by HPV. The reduction in precancerous lesions is expected to reduce the rates of penile and anal cancers in men. Since penile and anal cancers are much less common than cervical cancer, HPV vaccination of young men is likely to be much less cost-effective than for young women. From a public health point of view, vaccinating men as well as women might be useful if it decreased the virus pool within the population. Gardasil is in particular demand among gay men, who are at significantly increased risk for genital warts, penile cancer, and anal cancer.

As with females, the vaccine must be administered before infection with the HPV types covered by the vaccine occurs. Vaccination before adolescence makes it more likely that the recipient has not been exposed to HPV.

In the UK, HPV vaccines are licensed for boys aged 9–15. Merck, the maker of Gardasil, is expected to ask the FDA for permission to market the vaccine in the United States for boys and men ages 9–26. The vaccine is already available in the United States and can be used off label for the vaccination of males.

According to the FDA and CDC, the vaccine has only minor side effects, such as soreness around the injection area. The FDA and CDC consider the vaccine to be safe. It does not contain mercury, thimerosal or live or dead virus, only virus-like particles, which cannot reproduce in the human body. Merck, the manufacturer of Gardasil, will continue to test women who have received the vaccine to determine the vaccine's efficacy over a lifetime.

The latest generation of preventive HPV vaccines is based on hollow virus-like particles (VLPs) assembled from recombinant HPV coat proteins. The vaccines target the two most common high-risk HPVs, types 16 and 18. Together, these two HPV types currently cause about 70 percent of all cervical cancer. Gardasil also targets HPV types 6 and 11, which together currently cause about 90 percent of all cases of genital warts.

Gardasil and Cervarix are designed to elicit virus-neutralizing antibody responses that prevent initial infection with the HPV types represented in the vaccine. The vaccines have been shown to offer 100 percent protection against the development of cervical pre-cancers and genital warts caused by the HPV types in the vaccine, with few or no side effects. The protective effects of the vaccine are expected to last a minimum of 4.5 years after the initial vaccination.

While the study period was not long enough for cervical cancer to develop, the prevention of these cervical precancerous lesions (or dysplasias) is believed highly likely to result in the prevention of those cancers.

Although a 2006 study suggests that the vaccines may offer limited protection against a few HPV types that are closely related to HPVs 16 and 18, there are other high-risk HPV types are not affected by the vaccines. Ongoing research is focused on the development of HPV vaccines that will offer protection against a broader range of HPV types. There is also substantial research interest in the development of therapeutic vaccines, which seek to elicit immune responses against established HPV infections and HPV-induced cancers.

In developed countries, the widespread use of cervical "Pap smear" screening programs has reduced the incidence of invasive cervical cancer by 50% or more. Current preventive vaccines reduce, but do not eliminate the chance of getting cervical cancer. Therefore, experts recommend that women combine the benefits of both programs by seeking regular Pap smear screening, even after vaccination.

Commencing in 2007 The Australian federal government began funding a voluntary program to make the Gardasil vaccine available free of charge to women aged 12–26 for a period of two years, with an ongoing vaccination program for 12- and 13-year-olds as part of the pre-existing high school vaccination program.

The Australian government and the PBS (Pharmaceutical Benefits Scheme) have approved the vaccine for use and in 2007 began a nationwide vaccination program free of charge to schoolgirls in years 7 to 12. These programs are run by local councils with funding and vaccine supplies from the government. The subsidization approval process, however, appears to have been heavily influenced by political interference from politicians of all political parties, and by the Prime Minister who publicly advised that it would be approved (before approval). In addition, women between 18 and 26 years of age at the time of the first dose may receive the vaccine for free upon request from their general practitioner. After June 2009, the program will be scaled down to 12- and 13-year-old girls only. Australia also approved Gardasil for boys 9–15 years old, but Australia is not providing government funding for vaccinating boys.

Canada has approved use of Gardasil. Initiating and funding free vaccination programs has been left to individual Province/Territory Governments. In the provinces of Ontario, Prince Edward Island, Newfoundland and Nova Scotia, free vaccinations to protect women against HPV were slated to begin in September 2007 and will be offered to girls ages 11–14. Similar vaccination programs are being planned in British Columbia and Quebec.

On July 17, 2007, France issued a directive authorizing state-aided voluntary vaccination for girls aged 14–23 years who have not yet become sexually active, or have been sexually active for less than a year. The state refunds 65% of the cost, based on a program of 3 vaccinations at €135 (slightly less than $200) per shot, meaning that the patient covers €141.75 (slightly more than $200).

On March 26, 2007, early approval for Gardasil vaccinations was granted in both Germany and Italy.

On February 12, 2007, Greece made HPV vaccination mandatory for girls entering gymnasion (7th grade). All vaccines including hepatitis B are mandatory and are supplied free to everyone in Greece, with parents being allowed to opt out of vaccinating their kids. Cervarix and Gardasil are supplied free to all girls and women between the ages of 12 and 26..

In Novermber 2008, Romanian authorities launched a campaign to vaccinate 110,000 girls aged 10 and 11. The Ministry of Health acquired 330,000 vaccine doses for $23 million euros. By an order of the Ministry, the girls' parents must approve or reject the vaccination in writing, and must "fully assume the consequences for their children" if they reject the vaccination.

From September 2008, Gardasil will be available for New Zealand girls and young women born in 1990 and 1991 through primary care and from 2009, the HPV immunization program will be part of the regular immunization schedule for 12-year-old girls.

On July 27, 2007, South Korean government approved Gardasil for use in girls and women aged 9 to 26 and boys aged 9 to 15. Approval for use in boys was based on safety and immunogenicity but not efficacy.

In the UK the vaccine is licensed for girls and boys aged 9 to 15 and for women aged 16 to 26.

By the end of the catch up campaign, all girls under 18 will have been offered the HPV vaccine.

When the HPV vaccination programme begins in 2008, women over the age of 18 will not be vaccinated as it would not be cost effective in preventing cervical cancer. This is because as soon as a woman becomes sexually active, she is at risk of infection with the virus.

It will be many years before the vaccination programme has an effect upon cervical cancer incidence so women are advised to continue accepting their invitations for cervical screening.

As of late 2007, about one quarter of US females age 13–17 years had received at least one of the three HPV shots.

Almost all pieces of legislation currently pending in the states that would make the vaccine mandatory for school entrance have an "opt-out" policy.

Other states are also preparing bills to handle issuing the HPV Vaccine.

All vaccines recommended by the U.S. government for its citizens are required for green card applicants. Therefore HPV vaccine is required for young women seeking to immigrate to the United States. This requirement has also stirred controversy because of the cost of the vaccine, and because all the other vaccines so required prevent diseases which are spread by respiratory route and considered highly contagious.

There has been significant opposition from health insurance companies to covering the cost of the vaccine ($360).

Several conservative groups in the U.S. have publicly opposed the concept of making HPV vaccination mandatory for pre-adolescent girls, asserting that making the vaccine mandatory is a violation of parental rights. Both the Family Research Council and the group Focus on the Family support widespread (universal) availability of HPV vaccines but oppose mandatory HPV vaccinations for entry to public school.

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Source : Wikipedia