Clinical Manifestations of HPV

Cervical Cancer

Epidemiology

In the U.S., an estimated 10,000 new cases of invasive cervical cancer are diagnosed annually; in 2005 there were approximately 3,700 deaths attributed to advanced cervical cancer. Fortunately, both incidence and mortality rates have declined appreciably over the last several decades, primarily due to the availability of Pap screening for American women. As shown in Figure 26 below, cervical cancer incidence and deaths in the U.S. have declined approximately 50 percent since the nationwide implementation of Pap screening programs in the early 1970s [National Cancer Institute Website].

Figure 26. Cervical Cancer: U.S. Trends in Incidence and Mortality

Although cervical cancer is now categorized as the 14th most common type of cancer among females in the U.S., many women in the U.S. remain at increased risk for developing this disease. Certain minority populations in the U.S., including African American women, Hispanic women, American Indian women, Vietnamese American women, and Alaska Natives exhibit higher rates of cervical cancer and mortality from advanced disease. These women often lack access to a regular source of medical care and are more likely to be uninsured. Therefore, they remain underscreened and less likely to receive adequate treatment. These women are also more likely to face a language barrier and have low income and educational levels. They are also more likely to face cultural/religious issues which may impede adequate care, particularly among the young and unmarried. Recent statistics indicate that overall rates of cervical cancer mortality among native-born women are declining, while rates among foreign-born women are increasing, particularly in the South.

As shown in Figure 27, Hispanic women have the highest incidence rate for cervical cancer in the U.S., while African American women have the highest mortality rate [Cancer Facts & Figures Website].

Figure 27. U.S. Cervical Cancer Incidence and Mortality Among Racial/ Ethnic Populations (per 100,000 population) 1997-2001

While the cervical cancer mortality rate for African American women has declined approximately 50% since 1970 to 5.6 per 100,000 women, it remains more than twice the rate among white women (2.6 per 100,000). As with all females, the highest cervical cancer incidence and mortality among African Americans occurs in those 50 years of age or older.

The median age of cervical cancer diagnosis worldwide is between 40 and 60 years (mean ~50 years); however, cervical cancer also affects many women at a relatively younger age; approximately 43% of females diagnosed with cervical cancer in the U.S. are under the age of 45 years. These younger women also account for 23.1% of all cervical cancer deaths in the U.S. each year. Among women between the ages of 20 and 39 years, cervical cancer was reported as the second most common cause of cancer-related death in the U.S. in 2002.

Link Between HPV and Cervical Cancer

The link between genital HPV infections and cervical cancer was first demonstrated by Harald zur Hausen, a German virologist, in the early 1980s. Today, the link is well-established. Using global epidemiologic data from 932 cervical samples collected from 22 countries, investigators have documented evidence of HPV in 99.7% of cervical cancers worldwide [Walboomers, 1999]. HPV is considered the primary driving force behind malignant transformation of cervical cells, with certain high-risk HPV types now identified as the first ever identified indisputable, solely infectious cause of a human cancer.

Approximately half of all cervical cancers in the U.S. and Europe are caused by HPV 16, with type 18 causing ~15%, and types 31 and 45 accounting for an additional ~10% of cervical cancer cases worldwide. In addition to differences in prevalence, these types also vary in their risk estimates (oncogenic potential) for squamous cell carcinoma of the cervix. This is represented by the differences in the odds ratios (OR) between the four types, with HPV 16 carrying the greatest risk (refer to Figure 28 below) [Muñoz, 2003].

Figure 28. Prevalence of the Four Most Common HPV Types in Cervical Cancer and Risk Estimates for Squamous Cell Carcinoma

Risk Factors

In conjunction with HPV infection, a number of other risk factors have been implicated in the pathogenesis of cervical cancer. They may influence the development of cervical cancer in the following ways:

• by influencing the exposure to and acquisition of HPV infection
• by altering the likelihood of HPV persistence versus clearance
• by increasing the risk of progression from HPV infection to high-grade lesions (or precancers) and cancer

Cofactors may be classified into 3 broad groups: behavioral, exogenous, and host-related, discussed below.

Behavioral Cofactors

These cofactors may increase the risk of exposure to and acquisition of HPV and may result in hormonal changes or involve the use of substances that facilitate the development of cervical cancer.

Female Sexual Behavior

The primary risk factor for the development of cervical cancer, HPV infection, can be linked to a woman’s sexual behavior, particularly sexual intercourse. Factors consistently related to HPV infection and cervical cancer are early age at first sexual intercourse as well as a higher number of lifetime sexual partners [Burd, 2003].

For both squamous cell carcinoma and adenocarcinoma, women who are 17 years old or younger at first sexual intercourse have been shown to have a 2- to 3-fold higher risk of cervical cancer than those whose first sexual intercourse occurred at 20 years of age or older. This may be due to the fact that squamous metaplasia (the process by which immature cervical columnar epithelial cells are transformed into mature squamous epithelium) is most active in adolescent women during puberty. The immature columnar cells, present in higher numbers in adolescents, provide a poor barrier to invasion by HPV and other pathogens. The active cellular division occurring during metaplasia is also known to enhance the replication of the virus.

For women reporting 5 or more lifetime sexual partners, the risk of cervical cancer is increased 4-fold for squamous cell carcinoma and approximately 2-fold for adenocarcinoma when compared to women with only one sexual partner.

Male Sexual Behavior

Male sexual behavior is also a key determinant of the development of cervical cancer. Studies evaluating the sexual behavior of cervical cancer patients and their husbands/partners have indicated that a woman’s risk of developing cervical cancer is predicted as much by the sexual behavior of her partner as by her own sexual behavior.

Male circumcision protects males from becoming chronic carriers of HPV infection and, as a result, protects their wives or partners from developing cervical cancer [Castellsague, NEJM, 2002].

Parity

Several studies have identified high parity (the number of full-term pregnancies) as a risk factor for cervical cancer. The effects of high parity have been shown to be related to the hormonal changes induced by pregnancy; increased levels of endogenous hormones such as estrogen and progesterone may modulate the immune response to HPV and influence the risk of persistence or progression to cervical cancer. Multiple pregnancies maintain the transformation zone on the exocervix (see Figure 29) for many years, facilitating direct exposure to HPV and possibly other cofactors (e.g., trauma, coinfection)[Castellsague, JNCI, 2003]. See section on Natural History for additional explanation of the transformation zone.

Figure 29. Exocervix

Women with HPV who have seven or more full-term pregnancies have been shown to have a four-fold increased risk of cervical cancer when compared to HPV-infected women who are nulliparous and a two-fold increase compared to women who have had 1-2 full-term pregnancies; the risk increases linearly with an increasing number of full-term pregnancies.

An International Agency for Research on Cancer (IARC) multicenter case-control study demonstrated a direct association between the number of full-term pregnancies and a woman’s risk of developing cervical cancer (Figure 30) [Muñoz, Lancet, 2002].

Figure 30. Odds Ratio for Developing Cervical Cancer Based on Pregnancy

Early age of the mother at the time of birth of her first child has also been shown to increase her risk of developing cervical cancer. Women between the ages of 15-19 years at the time of first birth have a risk up to twice that of women whose first birth was at 25 years of age or older. The immature columnar cells present during adolescence and the prolonged maintenance of the transformation zone on the exocervix during pregnancy is thought to enhance direct exposure to HPV in these young mothers.

Use of Oral Contraceptives

A woman’s use of oral contraceptives has been found to be associated with a significant increase in risk of developing cervical cancer in many studies, a risk which is strongly related to prolonged use. Studies showing evidence for the role of oral contraceptive use in HPV carcinogenesis have identified a strong dose-response correlation with increasing years of use, such that after 5 years of use, a woman’s risk has been shown to increase four-fold for invasive cervical cancer and three-fold for carcinoma in situ. Increased risk also appears to be related to time since last use of oral contraceptives, with a higher risk associated with more recent use [Castellsague, JNCI, 2003].

While the underlying mechanism by which oral contraceptives might influence cervical cancer development is not completely clear, the use of oral contraceptives (including estrogens and progestogens) has been shown to be directly linked to an increased incidence of cervical ectropion (the increased exposure of the squamocolumnar junction to potential carcinogens such as high-risk HPV infection). Estrogen and progesterone may also affect cervical cells directly through increasing proliferation of HPV-infected cells. Another possibility is that long-term use of oral contraceptives serves as a surrogate for the likelihood that a woman is more sexually active and less likely to use condoms [Moreno, 2002].

Smoking

Tobacco smoke contains more than 6000 chemicals, including at least 40 that are known human carcinogens. The effects of cigarette smoking have been well studied, and have shown a significant association with a risk of squamous cell cervical cancer. Thus, smoking is known as a universal cofactor for the development of cervical cancer among women with HPV infection [Castellsague, JNCI, 2003].

Cigarette smoke is regarded as one of the strongest inducers of oxidant stress which may lead to deregulation of typical HPV-host protein interactions. Some authors suggest that exposure to tobacco may lessen a host’s ability to mount an effective local immune response against viral infections. Several tobacco constituents, including nicotine, have been identified in the cervical mucus of patients who smoke. In vitro studies of cultured human endocervical cells have documented that cigarette smoke condensate enters and induces malignant transformation in these cells. It has also been shown that smokers maintain cervical HPV infections significantly longer than non-smokers and have a lower probability of clearing an infection with an oncogenic type of HPV than women who never smoked.

Interestingly, neither the age at which a woman first started smoking nor the intensity of smoking has been related to cervical cancer; however, the duration of smoking and current smoking have both been linked to a consistently higher risk for squamous cell carcinoma.

b. Host-related Cofactors

Genetics

An increased risk of developing severe dysplasia (CIN 3) and invasive squamous cell carcinoma of the cervix has been observed in women with a family history of cervical cancer among first-degree relatives. In studies conducted in both the U.S. and Costa Rica, the observed risk was present regardless of whether the affected relative was a mother (OR = 2.4 – 3.3), sister (OR = 2.4), or daughter (OR = 2.4). Among women with adenocarcinoma, this association was not as clear [Zelmanowicz, 2005].

Immune Status

Because cell-mediated immunity plays such an important role in controlling and/or clearing HPV infection, conditions that impair a woman’s cellular immune response (e.g., HIV, organ transplantation) increase the risk of persistence and progression to cervical cancer. In addition, medical therapies that potentially impair or suppress the cellular immune system may also be linked to the progression of cervical disease.

HPV and HIV/AIDS

While the mechanisms underlying interaction between HPV infection and HIV infection are not well-defined, it is clear that coinfected individuals are at increased risk for developing HPV-associated anogenital cancers compared with the general population. Women with HIV are more likely to be infected with multiple HPV types simultaneously as well as high-risk or oncogenic HPV types (e.g., HPV 16 and 18) [Ferenczy, 2003].

Women at risk for developing both AIDS and cervical cancer share many common high-risk social behaviors, such as high number of sexual partners, early age at first intercourse and smoking. HIV results in impaired cell-mediated immunity which leads to inability of the immunosuppressed woman to clear an HPV infection, increasing persistence of HPV and risk of progression to cancer.

Immunosuppression due to HIV has been consistently linked to the development of early dysplasias (CIN); however, immunosuppression has not been clearly associated with an increased risk of invasive cervical cancer. Severely immunosuppressed HIV-positive women (defined as CD4+ cell count below 200 x 10 6 /L) have a higher risk of CIN. Thus, one would expect HIV-positive women to have a greater risk for developing invasive cervical cancer. In 1993 after cervical cancer was shown to be the most common (1.3%) type of cancer diagnosed among women with AIDS, invasive cervical cancer was categorized as an AIDS-defining illness in HIV-positive women by the Centers for Disease Control and Prevention (CDC). However, several recent studies have failed to provide consistent evidence of a greater incidence of invasive cervical disease among HIV-positive women [Palefsky, JNCI 2003].

Women with HIV often present with advanced disease compared to HIV-negative women. Persistent or recurrent disease within 3 years after treatment of CIN has generally ranged from 38–62% among HIV-positive women, compared to 18% among HIV-negative women.

c. Exogenous/Environmental Cofactors

HSV-2

In the 1960s and 1970s, infection with Herpes simplex virus type 2 (HSV-2) was suspected as a possible etiology of cervical cancer. However, following the detection of HPV DNA in cervical cancer cells, scientists hypothesized that infection with HSV-2 instead may introduce cell mutations and increase progression to cancer in HPV-infected cervical tissue. Several studies have since examined the role of HSV-2 infection in the etiology of invasive cervical cancer and suggest that infection with genital HSV-2 may act in conjunction with HPV to moderately increase a woman’s risk of developing cancer by increasing HPV replication and/or the introduction of HPV DNA into host cells [Smith, JNCI 2002].

It has been determined that, like HPV, HSV-2 invades cervical squamous epithelial cells in the area of the squamocolumnar junction (where most cervical cancers arise). Lesions resulting from HSV-2 infection are thought to breach the integrity of the cervical mucosa and thus facilitate the introduction of HPV into the basal cell layer. Additionally, herpetic infections may induce inflammatory reactions that have the potential to suppress the body’s T-helper cell-mediated immune response and therefore prevent the host’s ability to mount an effective immune response against HPV.

Chlamydia trachomatis

Clinical data from the 1970s have demonstrated an association between genital infection with Chlamydia trachomatis and atypical cervical changes as well as invasive cervical cancer. More recent epidemiologic data indicate that concurrent infection with C. trachomatis is independently associated with persistence of high-risk HPV types (OR = 2.1). Infection with chlamydia can result in chronic cervical inflammation (cervicitis) and pelvic inflammatory disease (PID). C. trachomatis possesses an ability to persist asymptomatically when untreated, and can induce chronic inflammation and metaplasia. Chronic inflammation induced by C. trachomatis may result in an impaired ability to clear HPV infections, thus increasing the likelihood of persistence and progression to invasive cancer [Samoff, 2005]

Diet / Nutritional Status

Low serum levels of vitamin C, folate, and carotenoids (e.g., beta-carotene or vitamin A) have been postulated to play a role in increasing the risk of invasive cervical cancer. Decreased levels of serum beta-carotene and vitamin E have been shown to be inversely associated with risk for CIN and invasive cervical cancer. Despite this association, clinical trials have not demonstrated clear evidence that use of dietary supplements change or influence the progression to cancer per se [Keefe, 2001].

Natural History

Histology and Development of the Cervical Epithelium

Squamocolumnar Junction (SCJ)

The cervix is composed of squamous epithelium (which covers the exocervix or the part of the cervix next to the vagina), and columnar epithelium (which lines the endocervical canal, the part closest to the body of the uterus). The point at which they converge is known as the squamocolumnar junction (SCJ). The SCJ is an area of rapid cell turnover which often changes in response to hormonal stimulation and reproductive stages including puberty, pregnancy, and menopause [Hatch & Berek, 2002] (see Figure 6). The original SCJ is visible on the endocervix in neonates. In women of reproductive age, the SCJ moves out to the exocervix, exposing the columnar epithelial cells to the unfamiliar acidic environment of the vagina, thus, initiating the process of squamous metaplasia. Lastly, during menopause, as the cervical epithelium changes again in response to decreasing hormone levels, the SCJ begins to recede within the endocervical canal, making the SCJ difficult to visualize and adequately sample during a Pap test.

Transformation Zone

Cervical squamous metaplasia is defined as the replacement of one cell type with another mature cell type. The region of the cervix where the columnar epithelium is replaced by new metaplastic squamous epithelium is known as the “transformation zone”. It is in the transformation zone, the area between the original and current squamocolumnar junctions, that not only the process of squamous metaplasia takes place, but more importantly, where the precursor lesions to squamous cell carcinoma develop [Hatch & Berek, 2002].

During fetal development, squamous epithelium covers the entire length of the vagina as well as the exocervix. At birth, and in prepubertal females, the SCJ is located at the external os and columnar epithelial cells line the endocervical canal. The weight of the growing uterus during puberty causes the columnar epithelium to evert and thus the immature columnar cells occupy a large portion of the exocervix after menarche and throughout the reproductive years.

The transformation zone is the area of the cervix where the process of gradual replacement of the immature columnar cells with new mature metaplastic squamous epithelium occurs. This process is largely dependent on the female hormone estrogen. In premenopausal women, the transformation zone is fully located on the exocervix. After menopause, the cervix shrinks as estrogen levels decrease. As a result, the transformation zone may move partially, and later fully, into the endocervical canal (see Figure 31).

Figure 31. Transformation Zone and Squamocolumnar Junction (SCJ)

Development of Dysplasia and Cervical Cancer

Approximately 70–75% of cervical cancers arise from the flattened or “squamous” cells covering the cervix (exocervix), thus the term “squamous cell carcinoma”. Approximately 15–25% of cervical cancers are adenocarcinomas, which arise from the glandular, mucus-secreting cells of the cervical canal (endocervix) leading into the uterus. Most of the remaining 5–10% are mixed adenosquamous carcinomas (composed of both squamous epithelial and glandular elements) [Holschneider, 2003].

Development of Dysplasia

Early in the development of cancer, the balance between cell division and cell loss is disrupted, resulting in an abnormal type of excessive cell growth or “dysplasia”. The cell changes associated with dysplasia often return to normal both structurally and behaviorly, but can potentially become malignant over a period of years. Depending on its severity, dysplasia may resolve without treatment, particularly in young women. However, if untreated, the most severe cases of dysplasia progress to early cancer called “carcinoma in situ” (CIS) - uncontrolled growth of cells that remain in the original location (the epithelium above the basement membrane in the case of cervical cancer) and have not spread.

Carcinoma in situ may progress to invasive cancer. Cancer is called “microinvasive” if it has spread only 2-3 millimeters (mm) into the surrounding tissue and not into the lymph channels or blood vessels. It may take several years for dysplasia to progress to CIS or microinvasive cancer, but once this process occurs the cancer can quickly spread into nearby tissues or other organs, such as the bladder, intestines, liver, or lungs.

Cervical intraepithelial neoplasia (CIN) is a term used by pathologists to classify the severity of dysplasia when examining a cervical tissue biopsy specimen. The term CIN along with a number (1, 2, or 3) describes how much of the thickness of the epithelial lining of the cervix contains abnormal cells. CIN ranges from low-grade (mild dysplasia) or CIN 1 to high-grade (severe dysplasia) or CIN 3. CIN 3 encompasses both precancerous lesions and carcinoma in situ. Over 1 million women annually are diagnosed with CIN 1 lesions while approximately 500,000 are diagnosed with CIN 2/3 [Wright, 2003].

In most cases, CIN is believed to originate as a single focus in the transformation zone at the advancing SCJ. The anterior lip of the cervix is twice as likely to develop CIN as the posterior lip, and CIN rarely originates in the lateral angles. Once CIN occurs, it can progress horizontally to involve the entire transformation zone but usually does not replace the original squamous epithelium.

Natural History of CIN and Cervical Cancer

HPV clearance is defined by the lack of detectable HPV DNA at the site of initial infection. Approximately 90% of infections with high-risk HPVs follow a benign course and become undetectable by even sensitive DNA detection methods within 2 years. Only a small number of women infected with high-risk HPV will eventually develop CIN 3 or worse. As shown in Table 8, approximately 57% of CIN 1 lesions will spontaneously regress in the absence of intervention, whereas, CIN 2/3 lesions are much more likely to persist and may progress to invasive cervical cancer if not treated appropriately [Oster, 1993].

Table 8. Natural History of CIN

The highest rate of HPV infection (including high-risk types) typically occurs in younger women under the age of 30. In contrast, invasive cervical cancer usually manifests later, as shown in Figure 32 [Bosch, 2002].

Figure 32. Age-Specific Prevalence of HPV Infection and Incidence of Cervical Cancer (Netherlands)

HPV Persistence

The progression from HPV exposure to development of cancer typically spans at least a decade and is dependent on persistence of oncogenic types of HPV.

Figure 33. Natural History of Cervical Cancer

Persistence is defined as the detection of the same HPV type two or more times over a period of several months to one year. Differences in a host’s immune response to HPV infection are clearly important determinants for risk of persistence. Other associated factors include age ≥ 30 years and infection with multiple HPV types. It has been shown that precursor lesions of the cervix persist longer and progress more rapidly in women infected with high-risk (oncogenic) HPV types, specifically HPV type 16 [Schiffman, 2003].

Types of Cervical Cancer

Squamous Cell Carcinoma

Invasive squamous cell carcinoma (SCC) accounts for approximately 70-75% of cervical cancers. Squamous cell carcinomas in general are cancers that begin in the flat, thin squamous cells found in tissues such as the outer surface of the skin (epidermis), the lining of hollow organs, and the respiratory and digestive tracts [Rohan, 2004]. Approximately 90% of cervical squamous cell carcinomas originate within 1 centimeter (cm) of the squamocolumnar junction either on the surface exposed to the vagina or slightly higher in the endocervical canal.

Squamous cell carcinomas are identified according to the predominant cell type [Holschneider, 2003]:

• large cell nonkeratinizing (accounting for the majority of lesions)
• large cell keratinizing
• small cell carcinomas (associated with a much poorer prognosis than the other cell types).

HPV type 16 has been detected in greater than 50% of squamous cell carcinomas.

Adenocarcinoma

Adenocarcinomas of the cervix arise from glandular cells of the endocervix and account for approximately 15–25% of all invasive cancers. The age-adjusted incidence rate appears to be increasing when compared to squamous cell carcinomas of the cervix, with up to 30% of cases being diagnosed in women less than 35 years of age [Rohan, 2004]. The observed relative increase in incidence rates of cervical adenocarcinoma may be attributed to difficulty in detection despite adequate screening; improvements in the histological classification of lesions as well as an increased awareness among cytologists, may also account for increasing detection.

Adenocarcinomas are often described as large, bulky lesions that have a greater likelihood of recurring compared to squamous cell carcinomas. Because they arise from endocervical glands, they are more difficult to visualize anatomically; thus, diagnosis is often late and prognosis poorer among women due to the advanced stage of the disease. It is thought that adenocarcinomas result from the development of progressively more severe precursor changes in endocervical tissue leading to adenocarcinoma in situ (AIS), the preinvasive form of most endocervical adenocarcinomas. Histologically, AIS is localized to the squamocolumnar junction and does not typically extend below the level of normal endocervical glands. Progression from AIS to invasive adenocarcinoma spans approximately 13 years.

As with squamous cell carcinomas, numerous studies have demonstrated that HPV infection plays an important role in the development of cervical adenocarcinoma. In contrast to the predominance of HPV type 16 detected in SCC, approximately one-half of all adenocarcinomas are linked to infection with HPV type 18.

One type of adenocarcinoma which has been associated with women whose mothers took diethylstilbestrol (DES) during pregnancy is known as “clear cell” adenocarcinoma [Am Cancer Soc, at http://www.cancer.org/docroot/PED/content/PED_2_3X_Pap_Test.asp 2003]. Prior to 1972, DES was prescribed for use in pregnant women to prevent premature deliveries and miscarriages.

Adenosquamous Carcinoma

Mixed adenosquamous carcinomas make up 5–10% of cervical cancers. These tumors are composed of mixtures of malignant squamous epithelial and glandular elements and, in the majority of cases, are known to have a poorer prognosis than isolated SCC and adenocarcinomas. The term ‘collision tumor’ is used to describe the simultaneous cross-invasion of an adenocarcinoma and squamous cell tumor. One poorly differentiated type of adenosquamous carcinoma is called ‘glassy cell carcinoma’. This type of lesion is considered to have an extremely aggressive rate of progression and accounts for approximately 1–2% of all cervical cancers.

Other Malignant Cervical Tumors

Invasion of non-cervical metastatic tumors into the cervix is rare, but can include tumors originating from the endometrium (lining of the uterus), bladder and rectum.

Clinical Manifestations and Staging

Early Disease

Cervical cancer in its earliest and most treatable stages does not usually cause any symptoms. Most women do not experience clinical symptoms until the cancer is advanced and has spread. Dysplasia and early forms of cervical cancer that have not yet spread can be detected by a Pap smear. The majority of women diagnosed today with cervical cancer have either not had regular Pap smears or have not followed up after having an abnormal smear.

When manifestations of early cervical cancer are present, the most common include: abnormal vaginal bleeding (especially between menstrual periods, after intercourse or douching, and after menopause) which gradually becomes heavier and longer, and leukorrhea (a persistent vaginal discharge, which may be watery, pink, brown, or blood streaked, and is usually odorous and non-purulent).

Advanced Disease

Clinical symptoms of advanced cervical disease include weakness or fatigue (an indication of anemia), decreased appetite (with resulting weight loss), back or pelvic pain (often unilateral and radiating to the hip or thigh), incontinence of urine or feces through the vagina (a sign of fistula formation), and bone fracture (a sign of metastatic disease).

Cervical Cancer Staging

The International Federation of Gynecologists and Obstetricians (FIGO) has provided a system that classifies cervical cancer in stages 0 through IV. The FIGO Staging system is based on a physician’s clinical examination as well as other procedures (i.e., cystoscopy and proctoscopy) in some cases [Benedet, 2003].

Table 9. International Federation of Gynecologists and Obstetricians (FIGO) Staging System for Cervical Cancer

Other Malignancies

The role of oncogenic or high-risk types of human papillomavirus in the development of cervical cancer has been clearly defined. Infections with high-risk HPVs account for greater than 95% of all cases of cervical cancer. Less well-defined is the relationship between HPV and non-cervical cancers, though there is increasing evidence that HPV (specifically type 16) may play an important role in a number of genital as well as non-genital malignancies[Gonzalez Intxaurraga, 2002] (Figure 34).

Figure 34. Estimated Percentage of Cancer Cases Attributable to HPV

Anal Cancer

From a developmental standpoint the epithelial cells of the anus and those of the cervix are very closely related, having developed from the same embryologic tissue. Hence, HPVs are often found at the squamocolumnar junction (“the transformation zone”) of the anus, as well as the cervix. Unlike cervical cancer, however, anal cancer is relatively rare. Data from 2002 indicate that less than 4,000 cases of anal cancer per year are diagnosed in the U.S. The HPV types most often found in anal cancers are similar to those found in cervical cancer (i.e., HPV 16, 18, 31 and 33).

Immunosuppression, caused by either HIV or immunosuppressive drugs associated with organ transplantation, is the biggest risk factor for the development of anal cancer. Anal cancer rates are more than doubled in those patients with HIV infection. Other risk factors relate to sexual activity and include the number of sex partners, receptive anal intercourse, and infections with other sexually transmitted diseases such as Herpes simplex virus type 2 (HSV-2), Chlamydia trachomatis, gonorrhea for women and syphilis for men. A history of genital and/or anal warts is an additional risk factor for both men and women.

Anal cancer rates are increasing in the United States. Incident anal cancer rates for both men and women in the United States have doubled during the period of 1973 through 2002 [SEER].

Figure 35. U.S Anal Cancer Incidence Rates from 1973 to 2002*

Like all cancers, early detection is important. Anal pap smears are used to cytologically evaluate anal lesions. Abnormal pap smears are followed by anoscopy, a procedure similar to colposcopy which allows the viewer to see abnormalities using magnification and to more precisely direct biopsies. Early signs and symptoms of anal cancer include bleeding from the rectum, pain and pressure in and around the anus, discharge from the anus and masses found in the area of the anus. Anal cancers are difficult to treat; options include surgery, radiation and chemotherapy [Am Cancer Soc, at http://www.cancer.org/docroot/CRI/content/CRI_2_4_3X_How_Is_Anal_Cancer_Diagnosed_47.asp?sitearea.].

Vaginal Cancer

Vaginal cancer is the rarest gynecological carcinoma, and, as such, is difficult to study. The estimated occurrence rate is 1 case per 100,000 women or roughly 2,100 cases annually in the U.S. Approximately 90% of all vaginal cancers are squamous cell carcinomas, and less than 10% are adenocarcinomas. HPV DNA, most commonly type 16, has been found in almost two-thirds of all vaginal cancers. Risk factors for vaginal cancer include multiple sex partners, early age at first intercourse, infection with HSV-2, and low socioeconomic status [Spence, 2005].

Vulvar Cancer

With an estimated incidence rate of approximately 1-2 cases per 100,000 women, or approximately 3,900 cases per year, vulvar cancer is the second rarest of gynecological carcinomas in the U.S. Vulvar cancer can be divided into two distinct clinical entities: one in which it appears in women between the ages of 55 and 85, and the other in which it appears in younger women between the ages of 35 and 65. In the younger age group, cancer is usually associated with HPV types 16, 18, and 33, which are also found in vulvar intraepithelial neoplasias (VIN). Risk factors for this group’s vulvar cancer are the same as those for cervical cancer and include multiple sex partners, early age at first intercourse and abnormal pap smears. Vulvar cancer in older women is not associated with sexual risk factors or high-risk HPVs, and is a disease characterized as keratinizing vulvar carcinoma. The most common form of treatment is surgical excision, but other options such as the use of lasers and other ablative methods are also used to treat VIN [Spence, 2005].

Bowenoid papulosis is a pre-cancerous condition caused by “high-risk” HPVs, often HPV 16, that is found in the genital region of both sexes. Although most lesions remain benign, approximately 3% will transform into invasive squamous cell carcinomas of the vulva or penis.

Penile Cancer

The incidence of penile cancer is highest in some parts of Africa, Asia and South America and very low in North America and Europe. Incident rates for the U.S. are 1.5 cases per 100,000 men. In many parts of the world, incidence rates for penile cancer mirror that of cervical cancer, lending support to the sexual basis for penile cancer. However, the large discrepancy in rates suggests that, like vulvar cancer, there may be several pathways for the development of penile cancers.

The frequency with which HPV DNA is found in penile lesions varies by histologic subtype (e.g., verrucous vs. basaloid, etc.) and can range from approximately 33% to greater than 80%. As with cervical, anal, and vulvar cancer, HPV 16 is the most common type found in penile tumors followed to a lesser extent by HPV 18. Due to the rarity of this disease, the determination of risk factors has been difficult. The main risk factor appears to be lack of circumcision as a neonate, but also important are a history of genital warts, penile tears, multiple lifetime sexual partners and smoking [Gross, 2004].

Oropharyngeal Cancers

Unlike anal, vulvar and vaginal cancers, oral cancer is relatively common in the U.S. Most of these cancers are related to the use of alcohol and tobacco and are of the squamous cell variety. The role of HPV in the development of head and neck cancers is uncertain. However, since only a small fraction of smokers and drinkers develop oral cancer, it is possible that HPV may act as a cofactor. Recent data has shown that HPV DNA (types 16, 31, and 33) is more likely to be found in tumors of the tonsils and the base of the tongue than in tumors of the oral cavity, pharynx, or larynx [Gillison, 2003]. The association between HPV 16 and tonsillar cancer appears to be particularly strong.

Skin Cancer

Each year in the U.S., more than one million people are diagnosed with skin cancer. Most are non-melanoma cancers that begin in either basal cells (basal cell carcinoma or BCC) or squamous cells (squamous cell carcinomas or SCC). HPV DNA has been found in 69% of squamous cell carcinomas (SCC) and 52% of basal cell carcinomas (BCC). However, because the number of HPV genomes within each neoplasm is so small, the direct oncogenic role of HPV is questionable.

Epidermodysplasia verruciformis (EV) is a very rare disease in which individuals are unable to resolve life-long extensive wart infections. Malignant transformation of warts occurs in up to one-third of these patients [Meyer, 2001]. Often the disease has a familial pattern of inheritance which is linked to a defect in cellular immunity. Similarly, patients infected with HIV often have lesions associated with EV. The most common HPV types associated with EV are HPV 5, HPV 8, and HPV 20.

Recurrent Respiratory Papillomatosis(RRP)

Recurrent respiratory papillomatosis (RRP) is a rare disease caused by HPV infection of the respiratory tract, most often with types 6 and 11. These types are also the most common cause of anogenital warts. While the larynx is the most common site for papillomas (greater than 95% of all patients have papillomas in the larynx), they can also be found in the soft palate, epiglottis, and lungs [Derkay, 2006].

Consequences of multiple papillomas in the airway can be dire, as they can lead to blockages of the respiratory tract. The papillomas grow outward (exophytic) in an irregular manner, and can either be attached directly to normal tissue (sessile) or connected via “stalks” (pedunculated).

Figure 36. RRP Lesions of the Respiratory Tract (Courtesy of Craig S. Derkay, MD, Eastern Virgina Medical School)

Although considered a benign disease, in 3-5% of RRP patients, these papillomas can spontaneously transform into squamous cell carcinomas. Transformation is independent of risk factors, such as tobacco use or exposure to radiation therapy. When malignant transformation does occur, it is associated with high-risk HPV types 16 and 18, and the prognosis for the patient is often poor.

In children and adults over the age of 12 it is know as adult onset RRP. When RRP occurs in children less than 12 years of age it is called juvenile onset RRP.

Juvenile Onset RRP (JO-RRP)

The incidence rate for JO-RRP is 4.3 per 100,000 people in the U.S. per year with males and females being equally affected. There are roughly 2,000 new cases of JO-RRP diagnosed each year in the U.S. The prevalence rate of RRP is estimated to be 11 per 100,000. JO-RRP represents 50-66% of all RRP cases; 25% are diagnosed in the first year of life. The majority of children contract the virus in the birth canal during normal vaginal delivery. It is estimated that a baby born via vaginal delivery where the mother has genital warts has a 1 in 400 chance of developing RRP. However, a small number of patients with JO-RRP have been delivered by cesarean section, suggesting a possible intrauterine mode of transmission.

Diagnosis is often made when children present with hoarseness, stridor, or respiratory distress. Despite the rarity of RRP, it is the second most common cause of hoarseness in pediatric patients. Surgical removal of the papillomas is currently the most effective means of treating RRP; however, recurrences are very common. Along with surgery, adjuvant therapies are also commonly employed (e.g., interferon α-2A and indole-3-carbinol, an extract of cruciferous vegetables such as cabbage and broccoli). RRP is managed as a chronic condition, with repeated surgical interventions [Derkay, 2006].

Adult Onset RRP (AO-RRP)

AO-RRP is less common than JO-RRP with an estimated incidence rate of 1.8 per 100,000 and a prevalence rate of 4.5 per 100,000. AO-RRP is often seen after the age of 20 with peak incidence occurring in the third and fourth decades of life. Current literature indicates that transmission most likely occurs from oral-genital contact; however, other mechanisms may be involved such as delayed reactivation of neonatally-acquired HPV. Clinically, AO-RRP is often less severe than JO-RRP, with AO-RRP patients typically requiring less surgical intervention than JO-RRP patients.

Anogenital Warts

Introduction

The first descriptions of warts date back to the ancient Greek and Roman civilizations. However, it wasn’t until the early 1900’s that human experiments revealed the infectious nature of wart tissue. Transmission of disease occurred by inoculation of susceptible individuals with cell-free filtrates of wart extract.

The types of HPV that cause warts are designated “low-risk” due to their low oncogenic potential. Human papillomaviruses cause many different types of warts (Table 10), which are classified based on their appearance and location.

Table 10. Different Types of Warts Caused by HPV

Anogenital warts, also known as condyloma acuminata, are the most obvious sign of HPV infection, affecting an estimated 1% of the population [Gunter, 2003]. Over 90% of all anogenital warts are caused by HPV 6 and 11 (Figure 37).

Figure 37. Percentage of Anogenital Warts Caused by HPV 6 and 11

Anogenital warts are often found on the vulva, perineum, perianal area, vagina, cervix, penis and scrotum (Figure 38).

Figure 38. Common Sites of Genital Warts in Men and Women

The term Condyloma acuminata is often used to describe all anogenital warts, however, clinically there are actually four different types of warts in the genital area (Table 11).

Table 11. Different Types of Anogenital Warts

The prepuce is the most common location for warts in men, while the vulva is the most common for women (Figure 39). Warts in the perianal region do not necessarily indicate anal intercourse, but rather “auto-inoculation” from perineal HPV [Brotzman, 2005].

Figure 39. Relative Frequency of Genital Warts by Location

Warts in special circumstances

Pregnant women with genital warts often experience an exacerbation and proliferation of warts during pregnancy. Most warts regress after pregnancy. If treatment is necessary, surgical excision of genital warts is more common during pregnancy as other treatments are usually less effective [Lacey, 2005].

Buschke-Löwenstein tumors are poorly understood genital tumors, often presenting as giant condylomas on the penis of uncircumcised males prior to age 50 [Dupin, 2004]. These tumors are most commonly associated with HPV types 6 and 11. Controversy exists as to whether these tumors are benign condylomas or pre-malignant lesions.

People experience varying degrees of concern due to the presence of genital warts. In one study of Swedish women diagnosed with genital warts, 15% reported feeling disgusted and blamed themselves for their condition, while another 40% expressed anger about their diagnosis [Reitano, 1997]. The most common causes of concern were emotional and sexual, developing cervical cancer, wart recurrence, transmission of HPV and/or warts to sex partners, and pain and effectiveness of treatment (Figure 40).

Figure 40. Causes of Concern Among Men and Women with Anogenital Warts

Wart Formation

Approximately 70% of people that have sexual contact with individuals with genital warts will themselves develop warts within three months. Although the typical incubation period for the development of warts is between 3 and 4 months after inoculation, cases appearing as early as 6 weeks and as late as 2 years after infection have been documented [Bonnez, 2005]. Tears and abrasions in the skin facilitate the entry of HPV into the basal layer of the epithelium. Excessive proliferation of all epidermal layers with the exception of the basal zone occurs during the formation of warts. Hyperkeratosis is responsible for thickening of the superficial zone, and large polygonal squamous cells called koilocytes can be found in the intermediate zone (Figure 41). When surface keratinocytes die, they release newly formed virions, thereby enabling a new round of infections.

Figure 41. Epidermal Changes During Wart Formation

Epidemiology

Each year, approximately one million people in the U.S. acquire genital warts. Although overall HPV incidence rates have been estimated at 2.4 cases per 1,000, the rates for HPV 6 and 11 (the types responsible for approximately 90% of genital warts) are believed to be much higher. In 1995, cases of genital warts accounted for more than 240,000 first-time private physician office visits in the U.S. By 1999, almost 5 million physician consultations for genital warts occurred [Koshiol, 2004]. Exact incident figures are difficult to determine, but evidence seems to indicate that these numbers are on the rise. The impact of genital warts on the economics of health care costs in the U.S. over the last 25 years has been substantial. The cost of treatment for external genital warts in just the 15 to 24 age category is estimated at nearly $124 million.

Age at Acquisition: Males vs. Females

The appearance of genital warts begins in adolescent females in their late teens and peaks in their early twenties. For males, the rate of external genital warts begins to rise in their early twenties, and peaks in their late twenties [Insinga, 2003] (Figure 42).

Figure 42. New Genital Wart Cases by Age (2000)

Several reasons have been advanced to explain the earlier peak in new genital wart cases seen in women as compared to men. Some of these include:

• an earlier sexual debut in females
• the tendency for young women to have older partners
• willingness to visit physicians at an earlier age in order to have access to birth control, thereby leading to a bias of over-reporting of symptoms
• possibility that the female anatomy is more prone to tears and abrasions than the male anatomy, thus making viral entry into women easier than for men

Diagnosis

In most cases genital warts are asymptomatic, but in cases where symptoms occur, the main complaints are pruritus, burning, vaginal discharge and bleeding. Genital warts typically present as single or multiple papules. The most common feature is their cauliflower-like lesions that can be either verrucous or lobulated. Diagnosis of exophytic genital warts is made by clinical inspection, occasionally with the aid of a magnifying glass. The use of acetic acid (“acetowhitening”) can sometimes aid in the diagnosis of hard-to-see genital warts, such as flat papular warts.

Visible warts may often be confused with other conditions, such as molluscum contagiosum or other sexually transmitted diseases, especially syphilis (Figure 43).

Figure 43. Differential Diagnosis* of HPV Infection

Often warts can be differentiated based on two characteristics:

• They erode skin patterns.
• They exhibit pinpoint areas of bleeding when pared with a scalpel.

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