Preinvasive Disease of the Lower Genital Tract
Over the past 3 decades, the work of population scientists, laboratory-based researchers, and clinicians has together promoted the understanding of the pathogenesis of preinvasive disease of the lower genital tract and its associated cancers. Elucidating the progression from preinvasive disease to invasive cancer was the first step in implementing the Pap test as one of the most successful cancer screening program in developed nations and has dramatically lessened the impact of cervical cancer in the United States and other developed countries. Furthermore, with the identification of the human papillomavirus (HPV) as the principal and necessary cause of cervical cancer, the development and application of HPV vaccines will potentially further reduce the burden of cervical cancer and other HPV-induced malignancies.
EPIDEMIOLOGY
Key Points
1. The HPV is the most common sexually transmitted infection and is the necessary cause for cervical dysplasia and cancer. HPV16 and 18 are the most common high-risk types implicated in carcinogenesis.
2. Additional risk factors for genital dysplasia including tobacco smoking, immunosuppression, early age at first intercourse, and multiple sexual partners.
3. The HPV proteins E6 and E7 are critical for malignant transformation; E6 binds and inactives the tumor suppressor gene p53, whereas E7 binds and inactivates the tumor supressor gene pRb.
Incidence of Cervical Dysplasia
In the United States, 2 to 3 million women are diagnosed with cervical cytologic abnormalities annually. The most common abnormality found by liquid-based cytology is atypical squamous cells of undetermined significance (ASC-US), accounting for 2% to 5% of all Pap test results. In contrast, low-grade squamous intraepithelial lesions (LSIL) account for 2% of Pap test results, and approximately 0.5% of Pap test results are high-grade squamous intraepithelial lesions (HSIL); less than 0.5% are suggestive of invasive cancer. Atypical glandular cells of undetermined significance (AGC) account for an additional 0.2% to 0.8% of Pap test results.
Every year, between 250,000 and 1 million women in the United States are diagnosed with cervical dysplasia. Histologic diagnosis of cervical dysplasia is based on a tissue biopsy and uses the Bethesda nomenclature; this differs from the nomenclature used for cytologic abnormalities diagnosed on Pap testing. Cervical intraepithelial neoplasia (CIN) is the formal histologic diagnosis of cervical dysplasia and is graded as 1, 2, or 3 based on the proportion of atypical cells in the cervical epithelium. CIN can occur at any age; the peak incidence is in women between the ages of 25 to 35 years (Figure 4-1).
FIGURE 4-1. Incidence of CIN2 and 3 and cervical cancer. Rates shown here are per 100,000 women undergoing routine cytologic screening for CIN2 and 3, and per 100,000 women for cervical cancer. The peak incidence of invasive cervical cancer is observed approximately 25 to 30 years later than for CIN2/3. (Sources: CIN2/3 incidence among screened women [Kaiser Permanente Northwest Health Plan, Portland, Oregon, 1998-2002], Cervical cancer incidence among unscreened women [Connecticut, 1940-1944].)
Human papillomavirus (HPV) is the necessary cause of cervical dysplasia and cervical cancer. HPV is the most common sexually transmitted infection, and is estimated that 6.2 million new infections occur annually in the United States. The overall HPV prevalence in women in the United States is estimated to be 27%. Genital HPV infection has the highest prevalence in young adults under the age of 25 years, with a 25% prevalence in girls aged 14 to 19 years and 45% in women aged 20 to 24 years.1 More than 100 HPV types have been identified, and more than 40 of these infect the anal/genital area. HPV is a double-stranded DNA virus that encodes 8 open reading frames. The corresponding proteins are described as early proteins, including 6 proteins that are involved with the HPV life cycle and replication. The 2 late proteins, L1 and L2, are the structural proteins of the virus and form the major and minor capsid, respectively (Figure 4-2).
FIGURE 4-2. The 8 open reading frames of the HPV virus. The 6 early proteins (E1-E6) are involved with life cycle and replication; the 2 late proteins (L1 and L2) form the major and minor capsid.
HPV type is determined by the degree of homology within the region of the DNA that codes for the L1 protein. A new HPV type is identified when the entire genome has been sequenced and there is more than 10% difference from a known L1 sequence. HPV is not only transmitted by sexual intercourse; it is important to recognize that nonpenetrative contact may also lead to new HPV infections. In a 2-year longitudinal study of HPV-negative women, 10% of those having sexual contact, but not sexual intercourse, were positive for HPV at the end of the observation period. It appears that most of these occur within the first few years of initiating sexual activity. Prospective studies suggest a cumulative incidence of 50% within 3 years of the onset of sexual activity. For most girls/women, genital HPV infections clear within 1 to 2 years of initial detection. The median time to clearance is 8 to 12 months, with more than 90% of infections having cleared within 2 years. It is difficult to determine whether HPV infections become dormant in basal cells and later become reactivated as “latent HPV.”2
Persistent infection with 1 of the approximately 15 carcinogenic HPV types places women at increased risk for high-grade cervical dysplasia and cervical cancer. There is no consensus on the exact duration of genital HPV infection that constitutes persistent infection; although this has been described differently in many studies, in general it appears to be between 18 and 24 months of detection of the same HPV type. It is believed that persistent infection of 10 to 20 years or more is required for cervical cancer to develop. Although young women under the age of 25 years can be diagnosed with cervical cancer, this is a rare occurrence, and there is little understanding of the circumstances that lead to a more rapid progression of the steps leading to epithelial transformation to malignancy in these rare cases.
HPVs are grouped according to their carcinogenicity. Fifteen high-risk HPV types are found in cervical cancers. These high-risk types may also be found in premalignant lesions of the cervix, but they are much more common in cancer cases than in controls; this provides the epidemiologic evidence of carcinogenicity that is used to classify high-risk and low-risk HPV types. HPV16 is recognized as the most carcinogenic of the high-risk HPV types. HPV type 16 has been identified in 46% of all high-grade premalignant lesions of the cervix and approximately 55% of all cervical cancers. High-risk HPV type 18 can be detected in 16% of all cervical cancers. Other high-risk HPV include types 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 68, 73, and 82. In contrast, the low-risk HPV types 6 and 11 are the most common types detected in anogenital warts.
Incidence of Vaginal Dysplasia
Vaginal dysplasia is a relatively rare entity and comprises only 0.5% of all female genital tract lesions. The overall incidence in the United States is reported to be between 0.2 and 2 per 100,000 women. It is most commonly diagnosed in women older than 60 years of age who have current or prior diagnoses of cervical or vulvar preinvasive or invasive lesions, as they have many risk factors in common, such as HPV infection and immunosuppression. HPV DNA is present in approximately 80% of vaginal carcinoma in situ. Additional risk factors for vaginal dysplasia include prior pelvic or vaginal radiation and chronic inflammation from pessary use or prolapse. Vaginal dysplasia is usually asymptomatic with absence of a visible lesion. It is often detected by colposcopy during evaluation of an abnormal Pap test, commonly after hysterectomy for cervical dysplasia. When evident, lesions are generally white with sharp borders and are best evaluated after application of dilute acetic acid.
Vaginal intraepithelial neoplasia (VAIN) was first described in 1952 in a woman who had a total hysterectomy for cervical carcinoma in situ several years prior. VAIN was given its nomenclature in 1989 by the International Society for the Study of Vulvar Disease and includes grades 1 through 3 (mild dysplasia, moderate dysplasia, and severe dysplasia/carcinoma in situ) which are defined by the extent of microscopic cellular epithelial abnormalities.
Incidence of Vulvar Dysplasia
In the United States, the incidence of vulvar dysplasia has drastically increased by 411% between 1973 and 2000, with an incidence rate of 0.56 to 2.86 per 100,000 women, and it is becoming more common in younger women aged 20 to 35 years.3 Approximately 50% of women with vulvar dysplasia have dysplasia at other sites involving the genital tract, most commonly of the cervix.
Vulvar dysplasia was initially described by Bowen in 1912, in which a lesion of the thigh and buttocks was termed precancerous dermatosis. These lesions became known as precancerous lesions of the vulva and have adopted several different terminologies over the years, including Bowen disease, erythroplasia of Queyrat, atypical hyperplasia, lichen sclerosis et atrophicus, leukoplakia, leukokeratosis, leukoplakic vulvitis, hyperplastic vulvitis, kraurosis vulvae, neurodermatitis, atypical hyperplasia, dysplasia, atypia, carcinoma in situ, and carcinoma simplex. The original consensus for terminology was described in 1976 by the International Society for the Study of Vulvovaginal Disease, which recommended the adoption of the terms vulvar dystrophies, vulvar atypia, and squamous cell carcinoma in situ. The terminology was further revised in 1989 to include the use of the term non-neoplastic epithelial disorder when describing dysplastic conditions such as lichen sclerosis and squamous cell hyperplasia. The 1989 revisions also included the current use of the term vulvar intraepithelial neoplasia (VIN), with a grade of 1 to 3 (mild, moderate, and severe/in situ) based on the extent of microscopic cellular epithelial abnormalities, which replaced the terms atypia and carcinoma in situ. In 2004, the terminology was again revised to include the nomenclature that is currently in use to describe vulvar lesions.
Vulvar lesions are subdivided into 2 major categories: usual type VIN (including warty, basaloid, and mixed warty/basaloid types) which is associated with HPV infection and is generally seen in younger women, and differentiated type VIN, which is not associated with HPV and is generally seen in older women. A third category, unclassified type VIN, was included for rare cases that do not fit either usual or differentiated by histologic criteria.4
Risk Factors
Several risk factors for persistent HPV infection, cervical dysplasia, and cervical cancer have been identified. Because these 3 outcomes exist on a continuum, in general, the risk factors are similar for each diagnosis, with duration of exposure being the main differentiating factor. As previously described, persistent genital infection with high-risk HPV types is the most important risk factor for cervical dysplasia, and a history of high-grade cervical dysplasia is the most important risk factor for cervical cancer. When considering the specific high-risk HPV types, it appears that HPV16 infection is more likely to persist beyond 24 months and is more oncogenic than other high-risk HPV types. This is confirmed by epidemiologic data showing that HPV16 is detected in more cervical cancers than any other HPV type. In general, for all HPV infections, the longer that a type-specific infection has persisted, the more likely it is to persist. Additionally, older women with detectable HPV are more likely to have a persistent HPV infection.
Studies have found that tobacco smoking is associated with an increased risk of genital dysplasia.5 There also appears to be a close association with long-term oral contraceptive use.6 Coinfection with other sexually transmitted diseases has also been investigated as risk factors for cervical dysplasia. Chlamydia trachomatis infection is associated with cervical dysplasia. Studies investigating the role of herpes simplex virus and Trichomonas vaginalis have provided inconsistent results. There are not consistent data to support an association with nutritional intake, nutritional supplements, or alcohol use as cofactors for genital dysplasia.
Recent studies have sought to identify the role of host immunity and genetic factors such as human leukocyte antigen class I and II genes and viral factors such as HPV variants or multiple-type HPV infections, viral load, or HPV genome integration sites. More work is needed in this area, and no consistent trends have been identified.
Acquired immunosuppression, specifically human immunodeficiency virus (HIV) infection, and immunosuppressive therapy, specifically in organ transplant recipients, are closely associated with increased risk of genital dysplasia. The prevalence of all cervical cytologic abnormalities is increased in HIV-infected women, with a 3-fold increase in the prevalence of high-grade squamous intraepithelial lesions and cancer. Women receiving lifelong intense immunosuppressive therapy as a strategy to reduce the risk of organ rejection have up to a 2- to 6-fold increased risk of cervical dysplasia, 3-fold increased risk for cervical cancer, and a 50-fold increased risk for vulvar cancer.7
Other behavioral factors that are associated with and increased risk of preinvasive disease of the genital tract include early age at first intercourse, multiple sexual partners, and male partners with multiple partners.
HPV and Pathogenesis
Epidemiologic and molecular research has fully defined the relationship between persistent HPV infection and premalignant disease of the lower genital tract. High-risk HPV types 16 and 18 are the types most frequently found in cervical cancer worldwide and therefore are the most well studied. High-risk HPV infection has also been associated with the development of premalignancies and cancers of other sites, such as anal cancer, penile cancer, and malignancies of the head and neck. In contrast to cervical cancer, these cancers are preferentially associated with HPV16. Because the most is known about the molecular biology and pathogenesis at the cervix, this section focuses on specific steps that lead to premalignancy in this organ. It should be recognized, however, that there is increasing evidence that a similar pathogenesis appears to occur in other epithelial tissues where HPV has been implicated as a cause of premalignancy and cancer.
Genital HPV types preferentially infect the cervical transformation zone. Although the majority of HPV infections clear within 1 to 2 years, persistence of infection promotes the development of low-grade and high-grade cytologic and histologic abnormalities. Even after premalignant lesions are identified, some may regress, whereas others progress to an invasive malignancy after what appears to be a period of latency. In HPV-positive cancers, all malignant cells contain at least 1 copy of the viral genome that is actively transcribed. This leads to the overexpression of the viral oncoproteins E6 and E7; the long-term, continuous expression of these oncoproteins in epithelial cells leads to high-grade dysplasia and potentially malignancy.
When host epithelial cells are infected with HPV, it has been shown that the viral genome integrates into the host cell’s DNA. This occurs more frequently with high-risk HPV types, and frequency of integration increases with increasing degree of dysplasia/cancer. When integration occurs, the continuous expression of the E6 and E7 genes leads to the transformation of epithelial cells to the malignant phenotype. Both E6 and E7 have specific transforming properties. E6 induces degradation of the tumor suppressor protein p53 via the ubiquitin pathway. p53 is a cellular transcription factor that can trigger cell cycle arrest of apoptosis in response to cellular stress such as hypoxia or DNA damage. The role of p53 is to ensure the integrity of the cellular genome, preventing cell division after DNA damage or delaying it until damage has been repaired. By blocking the function of p53, E6 allows for the accumulation of chromosomal abnormalities, greatly increasing the chance of progression from normal epithelium to high-grade dysplasia and cancer. In a similar manner, E7 binds to the tumor suppressor protein retinoblastoma (pRb1) and its related pocket proteins, p107 and p130. The 3 tumor suppression proteins are critically involved in cell cycle regulation. When these proteins bind to E7, this activates the transcription of a group of genes that encode proteins essential for cell cycle progression. This allows cells to enter into S phase, when, in the absence of E7, they would otherwise undergo cell cycle arrest in G1 phase.8
Pathogenesis of Non-HPV Vulvar Dysplasia
Vulvar intraepithelial neoplasia may arise through different mechanisms. HPV-associated vulvar dysplasia is most commonly associated with the HPV16 subtype and is often multifocal and strongly associated with cigarette smoking and has a pathogenesis similar to that of cervical dysplasia. This type of VIN includes the basaloid or warty variants. In contrast, the differentiated VIN variant is not generally associated with HPV infection and is morphologically similar to invasive squamous cell carcinoma in appearance.9 Non-neoplastic epithelial disorders including lichen sclerosis, lichen simplex chronicus, and squamous cell hyperplasia are often associated with the differentiated type VIN. Although not considered premalignant lesions independently, a well-accepted hypothesis in the pathogenesis of differentiated VIN is that chronic pruritus caused by these disorders, and the resultant inflammation from scratching, plays a role in the progression from lichen sclerosis to lichen simplex chronicus and results in squamous cell hyperplasia, which then progresses to differentiated VIN, and ultimately to invasive carcinoma. Mixed dystrophy refers to lichen sclerosis which is associated with variable degrees of squamous cell hyperplasia and illustrates the progression and spectrum of changes seen in lichen sclerosis.
Lichen sclerosis is a non-neoplastic epithelial disorder of unclear etiology and is most commonly seen in postmenopausal white women. Lesions appear as pale white, flat, plaque-like areas which can resemble thinned parchment paper in advanced cases (Figure 4-3). Histologically, lichen sclerosis shows a thinned epidermis with blunting or loss of rete ridges, a middle layer of homogenous collagenized subepithelial edema, and a lower band of lymphocytic infiltration. When lichen sclerosis is associated with lichen simplex chronicus, it shows epidermal thickening instead of thinning associated with superficial dermal chronic inflammatory infiltrate with vertical collagen streaks in the papillary dermis. Lichen sclerosis with squamous cell hyperplasia has the presence of epidermal hyperplasia without inflammation, atypia, or evidence of a specific dermatosis.
FIGURE 4-3. Lichen sclerosis. White, plaque-like areas can resemble parchment paper.
Lichen planus is a dermatosis most commonly seen in women older than 40 years, although it may be present across a wide age range. When symptomatic, women present with burning and pruritus. It is often associated with similar lace-like plaques in the oral or vaginal mucosa. There is a variable appearance histologically, but it is diagnosed by the presence of a bandlike chronic lymphocytic inflammatory infiltrate and the presence of colloid bodies formed as a result of degenerated keratinocytes. Lichen planus can evolve into erosive vulvar disease, which has been associated with invasive vulvar squamous cell carcinoma.10
DIAGNOSIS
Key Points
1. The American Cancer Society recommends Pap test screening 3 years after the initiation of sexual intercourse or by 21 years of age. In contrast, the American Congress of Obstetricians/Gynecologists recommends that screening should not begin until 21 years of age.
2. Abnormal Pap tests should trigger subsequent colposcopic examination to obtain directed tissue specimens for histologic evaluation of dysplasia or cancer.
3. The most common presenting symptom of vulvar dysplasia is a pruritic lesion.
Cervical Dysplasia
As early as 1932, it was recognized that carcinoma in situ was a precursor to cervical cancer. Papanicolaou and Traut subsequently demonstrated that the exfoliated cells from the ectocervix could be used to detect carcinoma in situ and invasive cancer. In 1969, Richart hypothesized that cervical cancer develops from noninvasive stages, thereby introducing the terminology cervical intraepithelial neoplasia (CIN).
Since the 1950s, the Pap smear has been the central component of population-based cervical cancer screening in the United States. Pap-based screening has led to a more than 70% reduction in cervical cancer mortality by making it possible to identify and treat premalignant lesions of the cervix before these lesions develop into cancer. Similarly, the goal of treating vulvar and vaginal dysplasia is primarily to decrease or eliminate the risk of any individual developing cancer of these organs. The Pap smear was originally performed using a wooden or plastic spatula to scrape the ectocervix in a 360-degree circumference. The exfoliated cells were then smeared onto a glass slide, preserved with a spray fixative, processed, and examined by cytopathologists. The degree of cellular atypia and abnormal morphology lead to classifications based on the risk of a histologic abnormality.
The conventional Pap smear is arguably suboptimal due to the frequency of both false-positive and false-negative results, which likely result from the poor quality of sampling and the preparation method. The frequent presence of blood cells or inflammatory cells, poor cell fixation, and inhomogeneous distribution of cells contributes to greater difficulty in detecting epithelial cell abnormalities and impairs the reproducibility of diagnosis. In an attempt to improve test sensitivity, liquid-based cytology may demonstrate superiority to conventional Pap techniques. Exfoliated cells are collected from the ectocervix with a brush designed to match the contour of the cervix, and the cells are rinsed into a vial with a preservative solution. The solution is processed to remove inflammatory and blood cells and debris, and a single-layer slide of epithelial cells is created to facilitate detection of cellular abnormalities. Because only a portion of the preservative is used, the remaining liquid can be used for other purposes, such as HPV detection or other testing. Many prospective studies have suggested that this process improves the sensitivity and positive predictive value for the detection of moderate- or high-grade dysplasia. However, recent studies have challenged these original reports. A large cohort of almost 90,000 women has shown that liquid-based cytology has similar sensitivity and positive predictive value for preinvasive disease of the cervix as that of conventional Pap smears.11 Despite these recent reports showing similar sensitivities between the 2 methods, the additional benefit of using liquid-based cytology for HPV detection or other testing, faster reading times, and decreased processing costs through automation makes this approach superior to conventional Pap smears. Pap testing with liquid-based cytology has become the primary sampling method used in the United States.
Population-based screening programs have been successful in reducing cervical cancer mortality in developed nations. The optimal screening program has not been defined, and the approach varies throughout the world based on heath system financing and resources allocated to screening programs. For example, screening frequency varies from 5-year intervals in the Netherlands and parts of France to yearly intervals in Germany.
The American Cancer Society (ACS) and the American College of Obstetrics and Gynecology (ACOG) both publish guidelines on cervical cancer screening (Table 4-1). In general, the consensus guidelines of both organizations are supported by the United States Preventative Services Task Force. The 2003 ACS guidelines and the 2009 updated recommendations from ACOG are similar and are presented next. The main area of difference between the 2 organizations is age at which to initiate screening. The ACS recommendations are to begin screening 3 years after the initiation of sexual intercourse or by 21 years of age. In contrast, the updated 2009 ACOG guidelines recommend that screening should not begin until 21 years of age.12 The recommendation to begin screening at age 21 is based on the very low incidence rate of cervical cancer before age 21 years and the anxiety and harm that diagnosis and treatment of premalignant lesions in this age group may cause. Because the majority of abnormal cytology and premalignant lesions diagnosed in this age group will regress without the need for treatment, the risks of Pap testing may outweigh any benefits. These risks are particularly relevant with the incidence of cervical cancer in women under 21 years of age as low as 1 to 2 per 1,000,000, or only 0.1% of all cervical cancers.
Table 4-1 Comparison of ACS and ACOG Guidelines for Screening for Cervical Cancer12
Once cervical cancer screening begins, both ACS and ACOG recommend that screening occurs at a frequency of once every 2 years until age 29 years. Women ≥ 30 years of age with a history of 3 consecutive negative Pap smears may elect to have combination testing with cytology and high-risk HPV detection. With a normal Pap test and absence of high-risk HPV, further screening is deferred for 3 years, at which time the combination screen should be repeated. If HPV testing is not performed along with cytology after age 30 years of age, then testing should be performed every 2 to 3 years. ACS recommendations specify that women who choose to have high-risk HPV testing in this setting should be informed that (1) HPV infection usually is not detectable or harmful; (2) almost everyone who has had sexual intercourse has been exposed to HPV, and infection is very common; (3) a positive HPV test result does not reflect the presence of a sexually transmitted disease, but rather a sexually acquired infection; and (4) a positive HPV test result does not indicate the presence of cancer, and the large majority of women who test positive for an HPV infection will not develop advanced cancer.
Women who have an intact cervix should continue screening at the 2- to 3-year frequency until age 65 years (per ACOG guidelines) or 70 years (per ACS guidelines). Women may then choose to discontinue routine screening if they have no abnormal cytology or histologic diagnoses of the cervix for the prior 10 years and there is documentation of 3 consecutive normal Pap tests. Screening is recommended to continue, without a maximum age, for women in good health who have not previously undergone screening or if information regarding prior screening is not available. Women who are immunocom-promised by organ transplantation, chemotherapy, or chronic corticosteroid treatment or who are HIV positive should be tested twice during the first year after their immunosuppression-related diagnosis and then annually thereafter. There is no recommended age to stop screening in these women. Immunocompromised women should continue screening for as long as they are in good health and are likely to benefit from early detection and treatment of preinvasive disease.
Cytology screening is not recommended for women who have had a hysterectomy for reasons other than gynecologic cancer or cervical dysplasia. If a women has a history of CIN 2 or 3, or if it is not possible to document the absence of CIN 2 or 3 from pathologic reports, cytologic screening should take place for 10 years, and there should be documentation of 3 consecutive normal cytologic screenings at the end of this period.
It is important to recognize that Pap testing is a screening test and indicates women who are at risk for having a histologic diagnosis of cervical dysplasia. When sufficient risk exists that a patient may have cervical dysplasia or cancer, then most often the next step in diagnosis is to perform a colposcopic examination to obtain directed tissue specimens for histologic determination of the presence (or absence) of cervical dysplasia or cancer. The colposcope is a lighted binocular microscope which magnifies the surface of the tissue being examined. It is used to visualize the cervix, vagina, and vulva. Tissue can be magnified between 2 × and 25 × power. Colposcopes are equipped with various light filters to help better identify vascular patterns that may be associated with varying degrees of dysplasia or cancer. A dilute solution of acetic acid is applied to the cervix during colposcopy. The acetic acid dehydrates cells, thus exaggerating the increased nuclear-to-cytoplasmic ratio found in the cells of dysplastic tissue and cancer. Due to this increased density of DNA, dysplastic cells will reflect the light from the colposcope, and the observer sees a so-called acetowhite lesion. In addition to these acetowhite changes, other colposcopic features suggestive of dysplasia include the margin of the lesion, the presence of vascular patterns referred to punctations or mosaicisms, and size of the lesion relative to the overall size of the cervix. Furthermore, the colposcopist may apply an iodine paint (or Lugol solution) to the cervix to aid in the detection of dysplastic lesions. The iodine solution is thought to stain intra-cellular glycogen. Normal cells will absorb the iodine and appear brown when viewed through the colposcope. Dysplastic cells, however, absorb less iodine due to their increased nuclear to cytoplasmic ratio and appear yellow or variegated brown/yellow. These features of cervical dysplasia help the colposcopist determine where to biopsy and how many biopsies need to be performed.
The second objective of colposcopy is to exclude a diagnosis of invasive cancer. It is important that the colposcopist be attuned to the visual changes that are predictive of invasive cancer. Fungating lesions or areas of hyperemia and friable areas may be evidence of dysplasia or invasive cancer. In addition, large, complex acetowhite lesions obliterating the cervical os or lesions with irregular and exophytic contour are very concerning for cancer. Lesions that appear to be thick, chalky-white with raised or rolled out margins, or lesions bleeding on touch should be biopsied to evaluate for possible preclinical invasive cancer. An important feature of invasive cancer is the appearance of atypical blood vessels. Atypical vessels occur with blood vessels breaking out from mosaic formations. The atypical vessel patterns are varied and may take the form of hairpins, corkscrews, commas, or have irregular branching patterns with irregular caliber.
Vaginal Dysplasia
As with cervical dysplasia, there are minimal clinical features associated with vaginal dysplasia. The diagnosis of vaginal dysplasia follows the steps described previously for cervical dysplasia. The screening Pap test may result in a diagnosis of a cytologic abnormality; when this occurs after the cervix has been surgically removed, then colposcopy is specifically performed to detect vaginal dysplasia. A detailed examination of the complete vagina is warranted, and it may be necessary to reposition the speculum in this setting so that the lateral and anterior and posterior walls may be fully examined with acetic acid solution. It is often helpful to use Lugol solution during complete colposcopy of the vagina. Abnormal findings should be biopsied and evaluated in a manner similar to that of cervical lesions seen during colposcopic examination.
Vulvar Dysplasia
Most women with vulvar dysplasia are asymptomatic, and the diagnosis is made with a high index of suspicion, colposcopy, and biopsy. When clinically evident, the most common symptom is pruritus. Other symptoms include burning, dyspareunia, erythema, edema, and pain. Lesions have a raised surface and are pigmented in 25% of cases and can also be grey or red (Figure 4-4). Multifocality is a common feature. Lesions are frequently located at the posterior vulva or periclitoral regions and can extend to adjacent structures. Many women have concomitant or previous dysplasia in another location in the genital tract and should be evaluated with colposcopy and liberal biopsies. Half of lesions involved with VIN become acetowhite after the application of 3% to 5% acetic acid, which should be applied for at least 5 minutes before examination. Thorough examination with the colposcope should follow application of acetic acid, and punch biopsies should be taken at each site of a suspicious lesion. These small punch biopsies can be easily performed in the clinic setting after the superficial injection of lidocaine and incorporate the full thickness of the skin for diagnosis. If needed, hemostasis can be achieved with silver nitrate or a single suture across the area of the biopsy.
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