|Organizations and Agencies|
Many public health and governmental agencies promote awareness and prevention as well as monitor HPV transmission and infections. Additional governmental agencies regulate clinical testing for HPV as well as prevention methods such as vaccines. Clinical organizations recommend testing protocols for the detection of carcinomas that can result from HPV infections. Agencies and organizations referred to in this course are: Centers for Disease Control and Prevention (CDC) Federal Food and Drug Administration (FDA) National Cancer Institute (NCI) American Society for Colposcopy and Cervical Pathology (ASCCP)
|HPV Vaccines; Gardasil and Cervarix|
GardasilGardasil HPV vaccine contains HPV types 6, 11, 16, and 18. Those vaccinated are protected against the two viral types (6 and 11) that cause about 90% of condolymas and against the two viral types (16, 18) that cause approximately 70% of cervical cancer. Gardasil vaccination is recommended for girls 11 and 12 years old. The vaccine can be given to girls as early as 9 years of age and catch-up immunization is recommended for women ages 13-26 years.CervarixCervarix HPV vaccine contains only two HPV types, 16 and 18. Infection with either of these types is responsible for the majority of cervical carcinoma. It is approved for vaccination of women and girls ages 10-25 years.
|Low-Risk and High-Risk HPV Types|
Low-risk HPV types are types: 6, 11, 42, 43, 44, 54, 61, 70, 72, and 81. These types can cause genital lesions but are considered non-carcinogenic types as they are not associated with cancerous lesions and are very rarely associated with precancerous lesions. HPV types 6 and 11 are the most common cause of genital condylomas (genital warts).High-risk HPV types are types: 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 68, 73, and 82. Since these types are associated with cervical as well as other anogenital cancers, they are referred to as the carcinogenic or oncogenic HPV types. HPV types 16 and 18 are most commonly isolated in cervical cancer; however, infections with HPV type 16 or 18 do not always result in cancer.
|Select the statement that correctly describes the HPV genome and its endoded proteins.||View Page|
|Clinical Diseases Caused by HPV STI Types|
Most HPV infections do not cause symptoms or clinical disease. Disease-causing infections develop into lesions that form genital condylomas, precancerous changes on external genitalia, or cervical and other lower genital tract carcinomas.Condyloma acuminata - raised and cauliflower-shaped lesions Condyloma planum - flat and less common lesions High-grade intraepithelial neoplasia - precancerous lesions Cancer - HPV is the causative agent of all cervical cancer and the cause of most vaginal, penile, and anal cancer. The bar graph on the right illustrates the approximate number of HPV-associated cancer cases that occur yearly according to the CDC. This table can be accessed at:http://www.cdc.gov/cancer/hpv/statistics/cases.htm. Accessed March 16, 2011.
|HPV and Cervical Cancer|
It is recognized today that high-risk HPV(HR-HPV) types cause cervical cancer. Cervical cancer is the second most common cancer in women worldwide. According to the CDC, in the U.S., approximately 11,000 women are diagnosed each year with cervical cancer. Worldwide, there are about 450,000 new cases each year; approximately 200,000 women die from cervical cancer yearly. The HPV infection can linger for years in cervical cells and eventually convert normal cells into malignant cells. Cervical cancer occurs when a HR-HPV infection is not naturally resolved or cleared by the immune system. Approximately 10% of women with a HR-HPV infection develop these lingering infection complications.
|Additional Cervical Cancer Factors|
It is well known that some women with HPV infections will develop cancerous or precancerous conditions, while some infected women will not. Most scientists believe other patient conditions and factors along with HPV infection can increase the chances of a women developing cancer. Some of the factors associated with an increased risk of developing cervical cancer in those with a HPV infection are: Smoking Immunosuppression Chlamydia infection Diet low in fruits and vegetables Obesity Extended use of oral contraceptives Multiple pregnancies Low socioeconomic status Family history of cervical cancer
|Carcinogenesis of Cervical Cancer|
HR-HPV type viral infections, if left untreated, can convert normal cervical lining to cervical intraepithelial neoplasia (CIN). With a good immune response, the hyperplasia regresses and no carcinoma develops. This regression ocassionally occurs with CIN 2, but rarely occurs with CIN 3. If the CIN does not regress, high-grade squamous intraepithelial lesions (HSIL) develop. HSIL may progress to invasive carcinoma, typically in older individuals.
|Review: Tumor Suppressor Genes, Proto-Oncogenes and Oncogenes|
Tumor suppressor genes and proto-oncogenes regulate cell division. Tumor suppressor genes slow down or stop cell division for repair of DNA damage and promote apoptosis. A mutated tumor suppressor gene results in uncontrolled cell growth, which can be associated with the HPV-related carcinogenisis of cervical cancer. Proto-oncogenes promote cell division, initiate DNA synthesis, and inhibit apoptosis. Mutations occurring in proto-oncogenes convert them to oncogenes which can cause malignancy; this can also play a role in HPV-related malignancies.
|Carcinogenesis of Cervical Cancer Continued|
Numerous genetic events occur over a relatively long period of time that lead to the development of cervical carcinoma. The protein products of tumor suppressor genes are the regulators of cell growth as discussed previously. Two intracellular protein products of tumor suppressor genes located within human cells are p53 and Rb. As noted earlier, protein products from HPV genes E6 and E7 bind to p53 and Rb, which results in unregulated cell growth. This unregulated growth prevents normal DNA repair, allowing for mutations to accumulate in the cell. As this process continues, it is postulated that a proto-oncogene becomes mutated, which in turn activates oncogenes.The E2 gene in HPV controls the production of E6 and E7 in the normal viral life cycle. When the viral genome is integrated into host cells, the E2 gene is disturbed and uncontrolled production of E6 and E7 protein products occurs. This leads to a greater interaction and disabling of host cell tumor suppressor gene products. The genes E6 and E7 of HPV Types 16 and 18 have a greater affinity for tumor suppressor gene products than other HPV types. This explains the greater virulence associated with Types 16 and 18 and their association with 70% of cervical cancer.
|HPV infection can linger for years in cervical cells and eventually convert normal cells into malignant cells.||View Page|
Cervical cytology has been quite successful in the detection of cervical cancer. Since the carcinogenesis of cervical cancer is usually very slow, taking many years to decades to develop, cervical cytology can detect HPV-related cervical cancerous or precancerous states in most cases. The Papanicolaou-stained smear (Pap smear), is used most often to screen for pre-cancerous and cancerous processes by looking for changes to normal cervical cells. Abnormal cytology findings are investigated with colposcopy and biopsy. Colposcopy utilizes a powerful light source and lenses to locate and identify lesions that led to abnormal cells on Pap smear slides. If lesions are found, they too can be biopsied during colposcopy. For a Pap test, cervical cells are collected, fixed on a glass slide or placed in a liquid medium, fixed on slides, stained, and microscopically examined for abnormal cells. Sensitivity of a Pap smear is only 55%-80%; however its specificity is greater than 90%. Further information regarding cell types and terminology associated with the Pap test/cervical cytology testing are provided in the PDF resource that can be accessed from this page.
|Pap Smear and Cervical Cancer|
The Pap smear remains the primary screening test for cervical cancer. If regular Pap smears are performed, most cervical cancers can be detected and treated. In fact, cervical cancer is one of the most successfully treated cancers. Despite the benefits of Pap tests, many American women do not take advantage of this important form of cervical cancer screening. Slightly more than 80% of American women have Pap smear screening performed every three years. The majority of those diagnosed with invasive cervical cancer had not had a Pap smear performed in the past five years. Routine Pap smears are less utilized or available in other nations. Worldwide, cervical cancer mortality rates are higher than the rates in the United States. In many developing countries, cervical cancer has become the major cause of female cancer deaths. Pap Smear RecommendationsCurrent guidelines recommend a Pap test for women at least every three years. The first Pap test should be about three years after beginning sexual intercourse but no later than age 21.
|Pap Smear Limitations|
The Pap test is not a diagnostic test; it is only a screening test for cervical cancer or cervical changes that are precancerous. For cervical cancer diagnosis, colposcopy, biopsy and/or endocervical scraping are needed. The low sensitivity associated with the Pap smear test is another limitation and involves factors such as: inadequate collection, sample preparation errors, and the possibility of inaccurate microscopic examination (although numerous safeguards are built into the process in an attempt to prevent inaccuracies).
|Recommended Use of HPV DNA Testing in Cervical Cancer Screening|
HPV DNA testing guidelines were published by the American Society for Colposcopy and Cervical Pathology (ASCCP) in 2006 and endorsed by other pathology, cytology, and cancer organizations. HPV DNA testing must be for HR-HPV types only and performed with an FDA approved or equivalent test. HPV DNA testing is recommended: With screening Pap smear for women 30 years and older If both Pap and HPV DNA are negative, repeat both tests at three-year intervals. If Pap smear is negative and HPV DNA test is positive, repeat both tests in one year. As of March 2009, the HPV-16/18 genotyping test can follow a positive HPV DNA test. If positive for either type, colposcopy should follow. For triage management of ASC-US Pap smear report on women 21 years or older. For triage management of LSIL Pap smear in postmenopausal women. After colposcopy, for management of women of any age with AGC or ASC-H Pap smear report and after colposcopy on women 21 years and older with ASC-US or LSIL Pap smear report.
|Inappropriate Use of HPV DNA Testing|
HPV DNA testing should not be used as an STI screening test; there is no treatment for HPV as an STI for those who test positive. HPV DNA testing should not be performed to screen for infection prior to vaccination. This would unnecessarily increase the cost of vaccination. HPV DNA testing is not approved or recommended for routine cervical screening for women less than 30 years of age. For adolescents (women 20 years or younger), HPV DNA testing should not be follow-up on abnormal Pap smear test results. HPV is ubiquitous and most young women have infections after becoming sexually active. Most individuals, especially young women, resolve the infection without any intervention. The process of cervical carcinogenesis comprises many years or even decades and most HPV infections do not result in cancer. Unnecessary colposcopy procedures will be performed if young women are tested for HPV. Lesions that are found and treated with cervical excision procedures can increase the risk of premature delivery and low-birth-weight babies. As noted above, HPV DNA testing is recommended for women of any age postcolposcopy of an AGC or ASC-H Pap smear report. The DNA testing is postcolposcopy, not Pap smear follow-up. These lesions may be from non-HPV infections and HPV testing provides information on follow-up options.
|What is the recommended HPV DNA testing for Michelle, a 19-year-old female with ASC-US Pap smear report?||View Page|
|Case B Darlene|
Darlene, a 23-year-old female, has been married for five years. She has regular cervical cancer screening every three years since her Pap smear reports have been normal.Pap test this visit: ASC-US The office nurse discussed the report with her physician and HR-HPV DNA test was ordered on saved liquid cytology specimen.
|Case C Josephine|
Josephine, a 31-year-old female, receives her bill from her three-year cervical cancer screening appointment. She questions the additional HPV DNA testing in her statement since in previous screens only a Pap smear was collected.She has been married for ten years and her husband has been her only sexual partner.
|Josephine calls her physican office and questions why HPV DNA testing was done along with her Pap test?What is the best response to her question?||View Page|
|Case D Debra|
Debra is a 40-year-old female who has cervical cancer screening every three years. This visit's results: Pap smear NegativeHR-HPV DNA PositiveDebra is contacted by her physician to return in one year for repeat testing.
|Debra's cervical cancer screening report was Pap test negative but her HR-HPV DNA was positive.It was appropriate for her physician to schedule her for repeat in one year. What other step or test could have been ordered?||View Page|
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