CLINICAL OBSTETRICS AND GYNECOLOGY Volume 57, Number 2, 241–255 r 2014, Lippincott Williams & Wilkins
Current Aims and Challenges Associated With Cervical Cancer Prevention NEAL M. LONKY, MD, MPH,*w KRISTINE R. PENNER, MD, MPH,z and JUSTIN T. DIEDRICH, MDy *Southern California Permanente Medical Group, Kaiser Permanente, Anaheim, California; wDepartment of Obstetrics and Gynecology, University of California, Irvine, California; zDepartment of Gynecologic Oncology, University of California Irvine School of Medicine, Irvine, California; and yWashington University in St. Louis, St Louis, Missouri Abstract: This chapter will review the current modalities available to the clinician to screen for premalignant and malignant cervical lesions, which cast a broad net. The majority who test positive are not destined to suffer from or die from cervical cancer. Many who undergo screening and are triaged are young and subsequently face a number of aggressive and destructive therapies. This calls into question whether higher-risk patients should be managed more aggressively than an average-risk patient represented in the study population used to craft the guidelines. Key words: cervical cancer, public health, prevention, vaccination, dysplasia, CIN
manage premalignant and malignant cervical lesions that cast a broad net. The majority who test positive are not destined to suffer from or die from cervical cancer. Many who undergo screening and are triaged are young and subsequently face a number of aggressive and destructive therapies. It will also address the segments of the population in which significant disparities exist, which put some women at the margin of the bell curve of the ‘‘average’’ population addressed by screening and triage guidelines. This calls into question whether higher-risk patients should be managed more aggressively than an average-risk patient represented in the study population used to craft the guidelines.
The Wide Screening Net and the Narrow Therapeutic Pathway This chapter will review the principles and practices and a subsequent chapter the modalities available to the clinician to screen and
Finding and Managing Women at Risk for Cervical Cancer
Correspondence: Neal Lonky, MD, MPH, Southern California Permanente Medical Group, Kaiser Permanente: Medical Office Building 2, 3430 E. La Palma Avenue, Anaheim, CA 92806. E-mail: nlonky@ yahoo.com
Reducing or eliminating the risk of death from cervical cancer is the goal of those who provide screening services. Because
The authors declare that they have nothing to disclose. CLINICAL OBSTETRICS AND GYNECOLOGY
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the epidemiology of cervical cancer is well defined, and the molecular underpinnings have been elucidated, our collective efforts are to mitigate the risk factors that induce cervical intraepithelial neoplasia.1 Evidence that human papillomavirus (HPV) is associated with the development of cervical neoplasia and progression to malignancy is irrefutable.2,3 Although >40 HPV types can infect the cervix, types 16 and 18 are responsible for 70% of cervical cancers. Types 31, 33, 35, 39, 45, 51, 52, 56, 58, and 59 are found in the remaining cases.4–6 Primary prevention through vaccination with concurrent secondary prevention through screening, triage, and treatment of those with precursors of malignancy as well as early treatment of malignancy (tertiary prevention) reduce morbidity and mortality and is the linchpin of our armamentarium in 2013.7 Eliminating the risk of HPV exposure through barrier methods, or medical interventions short of vaccination remains daunting, as HPV is highly infectious, and most commonly transmitted sexually rather than by vertical transmission.8,9 HPV genomic integration with host DNA is common, but the vast majority of US women with active infection during their lifetime will neither harbor persistent virus nor develop cervical cancer. The reported incidence of new HPV infections is 6.2 million per year, with an estimated 27% prevalence. The coincident rate of invasive cancer is 12,963 cases with 6605 associated deaths in the United States.10–12 The prevalence of HPV infection is highest among young women under age 25 and decreases thereafter. Datta et al13 studied 9657 women in the United States, wherein the prevalence of high-risk HPV peaked at 35% in adolescents younger than age 19 and dropped to 6% in women aged 50 to 65 years. Women aged 29 and under are the most likely to harbor CIN 1 and CIN 2, in which case the prognosis and malignant potential of precursors favors regression over persistence or progression during expectant management. Treatment may be chosen to alter the natural course of www.clinicalobgyn.com
the disease rather than to rely on the patient’s own immune recognition and elimination of the affected cells. This has been advocated for the ‘‘true’’ precursor of invasive cancer, carcinoma in situ or ‘‘CIN 3+ ,’’ in the average-risk patient.14 We cast a very wide net in screening by utilizing cytology, broad oncogenic HPV testing for all relevant subtypes (Digene Hybrid Capture 2, Qiagen, Netherlands; and AMLICOR, Roche Molecular Diagnostics, Pleasanton, CA), or specific secondary testing for subtypes 16 and 18 (AMPLICOR and Cobas HPV test, Roche Molecular Diagnostics). Type-specific HPV testing may be helpful in cases in which the malignant potential or the prognosis toward neoplastic progression is uncertain to further refine the management plan.14–16 Although the 2012 Guidelines for management of neoplastic abnormalities reduces the number of referrals to colposcopy, only a fraction of the cases in the United States referred for abnormal screening reveal carcinoma in situ or worse (CIN 3+). The histologic evidence from colposcopic workup most commonly reveals ‘‘low-grade’’ precursors without the establishment of highgrade precursor (CIN 2+) diagnosis. Screening that leads to a costly workup, wherein the resultant cases do not identify women with CIN 2+ , is problematic from a clinical follow-up standpoint, leading to observation with follow-up or their return to the screening population intervals proscribed in published guidelines.17 The management algorithms rely on the low probability of developing cervical cancer in this cohort as a whole, whereas the negative predictive value of the workup is powerful. Therefore, very few women who receive some screening, especially those with abnormalities undergoing triage during their lifetime, are placed at significant risk of developing and dying from cervical cancer. The high prevalence of HPV exposure and high probability of regression of CIN
Cervical Cancer Prevention in young, reproductive-aged female individuals influenced the screening intervals supported in new practice guidelines. There is a long latency between the time of infection to genomic expression to cancer in most cases. Circumventing the natural history with destructive therapy poses potential harm. Further complicating the situation for clinicians who provide gynecologic services is the fact that some women at high risk do not fit into the ‘‘average’’-risk population that practice guidelines describe. Screening intervals, utility of screening technologies, triage algorithms, and treatment decisions may be different among women at higher risk for cervical cancer. Virus-induced cancers rarely have a long latent phase in which clinicians can diagnose a precursor state through direct ‘‘access’’ to a ‘‘transformation zone’’ to confirm the disease process as we see with the cervix. Another virus-induced cancer may arise from infection with hepatitis B or hepatitis C. A chronic viral infection may lead to liver cancer (1 per 200 cases for hepatitis B, 1 per 45 cases for hepatitis C), which is exacerbated by coexisting cirrhosis. It should be noted, however, that the liver cancer viral model is dissimilar in that there are few effective therapies for it, no premorbid neoplastic stage to target, and uncertainty regarding regression of the malignant potential over time.20 A lack of an examination like colposcopy with a low transaction cost or risk for the diagnosis of a premalignant precursor and only a recently developed evidence-based emerging set of chemotherapeutic preventive options to alter the natural course have forced a ‘‘wait and see’’ approach, with a recommendation not to treat until a late stage in the neoplastic process.18,19
Preventive Approach Based on Epidemiologic Risk Many of the new cancer cases occur in the unscreened or underscreened population,
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which disproportionately represents disparate or special-needs populations.20–22 The ubiquitous nature of HPV and the lack of a failsafe measure to prevent sexual transmission make it a difficult task to focus on initial infection as the key epidemiologic target for intervention before infection and genomic insinuation.9 Proactive vaccination with oncogenic subtypes HPV 16 and 18 either through commercially available Gardasil (Merck and Co., NJ) or through Cervarix (Glaxo Smith Klein Pharmaceuticals, London, UK) attempts to circumvent the sequelae of disease. Rarely have we seen a pathologic entity in which the organism causing the disease is well defined and the detection very accurate, yet the therapeutic approach spans decades. The insinuation of HPV into the host genome is unlikely to result in a true cancer precursor or cancer for decades and only occurs in a fraction of those infected. Unlike many other viral and bacterial pathogens, the changes associated with HPV must persist to be mutagenic, thus are not likely to progress in the vast majority of cases.23,24 Most other nononcogenic viral pathogens lead to pathogenic expression leading to illness and damage within a very short latency period of weeks to months. The natural history and prevention model of Mycobacterium tuberculosis (TB) provides for a more fitting comparison with HPV than the hepatitis model. The latency periods from infection to expression, morbidity, and ultimate mortality are comparably long.25 Interestingly, medical history shows that before skin testing and treatment the clinical approach was similar to our approach to HPV today. Before the end of the 20th century, we recognized that most TB infections were highly contagious, exposure was frequent, and occurred in an early, premorbid state. Progression depended on a weakened or altered immune state allowing for active TB and pathogenesis. www.clinicalobgyn.com
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The Bacille Calmette-Gue´rin (BCG) vaccine, developed in the early 1930s, was not adopted in the United States because of its variable effectiveness against the most common disease manifestation, pulmonary TB. Therefore, the public health approach was to screen, triage, and treat those with advanced-stage infection and evidence of lung damage.26 Although early use of chemotherapy for TB was viewed as potentially harmful to those with inactive pulmonary infection, the advent of low-dose, longer-term administration of single-drug regimens provided the pathway to secondary prevention. This efficiently reduced the risk for active TB among those treated, with little perceived harm ascribed to therapy.27 Universal screening in education and employment settings in countries with adequate health services like the United States and directly observed therapy in the early stage of disease succeeded in drastically reducing the cases of active TB.28 Thus, moving the detection and intervention to the infective stage rather than the ‘‘true precursor’’ stage when there are active lung lesions was the tipping point in effective secondary prevention. Once proven, the efforts toward promoting early screening, mandating it for school entry and employment, and guidelines promoting and in some settings requiring chemoprophylaxis consistently changed the outcome and eventually the prevalence rate of TB in the United States.29 TB cases plummeted, and patients with active TB requiring quarantine or hospitalization became a rarity because early management of asymptomatic positive skin test cases was used. This left no one at any stage or risk in the natural history unmanaged. The fact that oncogenic viral subtypes lead to initial infection in what is labeled ‘‘early HPV infection’’ or cervical intraepithelial neoplasia grades 1 and 2 (CIN 1, CIN 2) is also irrefutable. Therefore, detecting CIN at grades 1 and 2 in the www.clinicalobgyn.com
‘‘average’’ population occurs in the majority and will regress in the majority without therapy. Women who acquire and develop these earlier lesions are predominantly young and of reproductive age. The experience of colposcopic biopsy and curettage can be painful and instill trepidation in some. In addition, most therapeutic approaches to such lesions are excisional or ablative, such invasive procedures pose a small but real risk of pregnancy complications, and all existing therapies pose innate risks to be avoided if possible.30,31 There are several epidemiologic risk factors associated with progression from HPV genomic insinuation to malignancy. Certainly those who are genetically predisposed or ‘‘impaired’’ due to immunosuppression are most at risk for carcinoma and deserve consideration outside proscribed guidelines for the average-risk population.32,33
Guidelines for the Average-risk Population The practice guidelines for cervical cancer screening and management of premalignant neoplasms, supported and developed by the committee, addresses the majority of cases in which access to care is likely and disparities in health care access or extreme risk factors are unlikely. Cofactors that could affect the probability of malignant transformation are recognized but not directly addressed in the standard management algorithms.15,17 Clinicians caring for women undergoing screening who test positive and harbor HPV or premalignant lesions face another challenge. The vast array of screening tests are sensitive early in the continuum in detecting HPV viral DNA at extremely low levels, whereas cytologic changes that loosely correlate with high-grade dysplasia or visual changes that correlate with neoplastic proliferation can also be
Cervical Cancer Prevention present.34,35 This presents a ‘‘poor specificity’’ conundrum. The paucity of therapeutic options to alter the natural course of the HPV infection toward regression and resolution along with the evidence that ablation and excisional modalities cause potential harm and reproductive sequelae creates another kind of disparity leading to not only potential harm but waste. The therapeutic options limit or negate the clinical strategic advantage of early detection before real malignant potential during which lesions may be transiently high grade and occupy a large percentage of the transformation zone. If addressed with excision or ablation at this diagnostic juncture, cervical insufficiency or stenosis poses a potentially avoidable risk so early in life.36,37
Will Vaccination Provide Efficient Prevention? The quadrivalent HPV vaccine (types 6, 11, 16, 18) ‘‘Gardasil’’ and the bivalent HPV vaccine ‘‘Cervarix’’ (types 16, 18) have been available in the United States for >5 years, and appear to provide protection to the majority of those who receive it in childhood, adolescence, or young adulthood.38,39 Primary prevention is costly, as 3 vaccine doses are needed to achieve adequate acquired immunity. Access to vaccination, especially for those in poverty, with poor health care services access, or those with poor health seeking behavior, is challenging. Access to health insurance does not guarantee that young women will receive the initial vaccine or subsequent 2 vaccinations in the series.40 The additional challenge of cultural or psychosocial fear of vaccination or the stigma associated with the vaccine being linked to sexual behavior cannot be overlooked, and remains a significant barrier to efficient vaccination of the population.41 Vaccination rates in the target population, those 9 to 26 years of age, are
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not reaching a sufficient rate to achieve prevalent herd immunity. Thus, primary prevention of the US population through vaccination is not making the impact in reducing deaths from cervical cancer that was hoped for and expected.
Screening Modalities and the Wide Net Multiple modalities have been utilized over the better part of the last century for screening, with the intention of casting a wider net to bring more ‘‘at-risk’’ women to triage, ultimately reducing deaths related to cervical cancer. Papanicolaou and Traut42 initially described the vaginal smear in 1943, which marked the first time that identification of precancerous cells could be performed. By the 1960s, the prevailing idea was such that regular Pap screenings could eradicate cervical cancer.43 This led to the paradigm of screening more women more often and treating them earlier. The concept of detecting the ‘‘precursor’’ was established,44 with less concern about the option of ‘‘wait and see,’’ the possibility of regression without therapy, or the lack of specificity (finding and managing ‘‘true’’ precursors destined for malignancy). The new detection modalities keyed into improving sensitivity. The chapters focusing on screening and therapeutic options will showcase the evolution of both improved screening and the recognition that early intervention with existing treatments might pose unintended harm in some not destined to suffer from or succumb to cervical cancer.
Destructive Therapy in the Mainstream Armamentarium The therapeutic milieu has not advanced as rapidly as our armamentarium to detect patients with lesions containing neoplastic change at an ‘‘indeterminate’’ www.clinicalobgyn.com
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TABLE 1.
Treatment Modalities of Cervical Dysplasia
Conventional Therapies
Indications
Method
Invasiveness
Cold knife conization Laser conization Loop electro-excisional procedure Cryotherapy Biopsy as therapy
CIN 2/3 CIN 2/3 CIN 2/3
Excision of transformation zone Excision of transformation zone Excision of transformation zone
Invasive Invasive Invasive
CIN 1, CIN 2, HPV+ CIN 2/3
Imiquimod
CIN 1, CIN 2
Topical application of cryoprobe Invasive Local excision of affected area Moderately invasive Topical application of imiquimod Minimally invasive
prognostic stage. Therefore, our willingness to find and treat women in a stage less than carcinoma in situ has been daunting. A subsequent chapter will review the existing destructive modalities, and then discuss the emerging nondestructive therapies on the horizon. Cervical intraepithelial neoplasia has been treated traditionally with destructive methods that destroy the transformation zone of the cervix (Table 1). These include such treatments as cold knife or laser conization, and loop electro-excisional procedures (LEEP), which provide a pathologic specimen for diagnosis and therapy. In addition, destruction of the transformational zone can be performed with cryo-ablative therapy. One of the concerns for use of treatment that removes or destroys a portion of the uterine cervix is its effect on subsequent pregnancy. In a study by Heinonen et al,31 the odds ratio for subsequent preterm birth (6600 women were randomized to HPV screening with positive women treated with cryotherapy, to screening by visual inspection and treatment with cryotherapy, or to the control group in which evaluation or treatment was delayed until 6 months. CIN 2+ was significantly less in the HPV-and-treat arm (1.5% vs. 5.6%, PCIN 2 in the last 20 years or if the patient has not had adequate negative screening in the prior 10 years. Screening intervals are shortened in all age groups for women with a history of cervical cancer, human immunodeficiency virus infection, immunocompromise of any kind, or in utero diethylstilbestrol exposure.
Adolescents (Below 21 y of Age) On examining the adolescents, population-based data show 1 to 2 cases of cervical cancer per 1,000,000 15- to 19year-old female individuals.50,51 Unfortunately, there has been no evidence of decreased incidence of cervical cancer in the under-21 age group with screening.48 HPV infection and neoplasia are common in teenage women with up to 43% HPV infection and a 5% to 7% rate of lowgrade squamous intraepithelial lesion (LSIL).52–54 Furthermore, among 477 adolescents with a diagnosis of LSIL or high-grade squamous intraepithelial lesion, persistent and progressive disease was common.53,55 Specifically, on follow-up of adolescents for 36 months after a diagnosis of LSIL, 47% had persistent disease and 18% had progression to high-grade dysplasia. Only 35% had
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resolution. Among the adolescents with high-grade dysplasia initially, 51% had persistent high-grade dysplasia, 27% had low-grade dysplasia, and only 22% had resolution to negative histology or cytology.53 Over 72 months, approximately 65% of CIN 1 regressed, but only 35% of CIN 2 or 3 regressed to CIN 1 or normal.55 Thus, although invasive cervical cancer is extremely rare in the adolescent age group, we recognize that HPV exposure, infection, and persistence often begins in the adolescent years with development of progressive dysplasia and eventually malignancy in those who do not clear the HPV infection. With a known lag time of 10 to 20 years from HPV exposure to malignancy, we see that the incidence of cervical cancer jumps to 5 per 100,000 in the 25 to 29 age group. Testing should be avoided in this population with very specific exceptions, not because treatment of dysplasia in this age group would not prevent future cervical cancer but rather because of (1) the low incidence of actual invasive malignancy within this age group; (2) the 65% regression rate of CIN 1; (3) the interventions (colposcopy, biopsy, cryotherapy, and cervical conization) and associated cost without immediate benefit; and (4) the potential negative side effects, particularly with cervical conization (LEEP or cold knife conization) with regard to increased risk for spontaneous abortion and preterm birth.31,56 Given these concerns regarding the limited available treatment options, the most important step that can be taken toward cervical cancer prevention in the adolescent population is HPV vaccination. The 3-vaccine series includes at minimum HPV types 16 and 18, which are responsible for at least 70% of cervical cancers in the United States.57 Although the CDC recommends that all girls initiate the vaccine between the ages of 11 and 12,58 the uptake of the HPV vaccine has been inadequate, with barely 50% of 13to 17-year-olds having received the first of www.clinicalobgyn.com
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the 3 doses and only 35% having received all 3 of the vaccine series.57 However, the data above also raise the question whether we are allowing excessive risk for high-grade dysplasia and possibly even cervical cancer for specific high-risk populations of adolescents. In particular, those with a sexual debut before the age of 16 have a delay of >5 years before their first cervical cancer screening. It is well established that women of color and those with 5 years between first sexual debut and cervical cancer screening is potentially medically and ethically irresponsible.
Women Aged 65 or Above Women over 65 years of age actually comprise a disproportionate share of cervical cancer cases—they make up 19.5% of new cases of cervical cancer, even though they only represent 14.1% of the population of female individuals in the United States.50 It is estimated that continued cervical cancer screening after age 65 would prevent 1.6 cancer cases and 0.5 cancer deaths for every 1000 women screened.63 There has been significant debate regarding the cost versus benefit of continued screening after the age of 65, given adequate screening before age 65. Isidean and Franco64 argue that, ‘‘continued screening would extend life expectancy by only 1 year per 1000 women, at the cost of 58 extra false-positive results, www.clinicalobgyn.com
127 extra colposcopies, and 13 extra diagnoses of CIN 2/3 that would require treatment.’’ Assuming a stable efficacy of screening, there is no way to compare screening in an older (>65) population and a younger (
Current Aims and Challenges Associated With Cervical Cancer Prevention NEAL M. LONKY, MD, MPH,*w KRISTINE R. PENNER, MD, MPH,z and JUSTIN T. DIEDRICH, MDy *Southern California Permanente Medical Group, Kaiser Permanente, Anaheim, California; wDepartment of Obstetrics and Gynecology, University of California, Irvine, California; zDepartment of Gynecologic Oncology, University of California Irvine School of Medicine, Irvine, California; and yWashington University in St. Louis, St Louis, Missouri Abstract: This chapter will review the current modalities available to the clinician to screen for premalignant and malignant cervical lesions, which cast a broad net. The majority who test positive are not destined to suffer from or die from cervical cancer. Many who undergo screening and are triaged are young and subsequently face a number of aggressive and destructive therapies. This calls into question whether higher-risk patients should be managed more aggressively than an average-risk patient represented in the study population used to craft the guidelines. Key words: cervical cancer, public health, prevention, vaccination, dysplasia, CIN
manage premalignant and malignant cervical lesions that cast a broad net. The majority who test positive are not destined to suffer from or die from cervical cancer. Many who undergo screening and are triaged are young and subsequently face a number of aggressive and destructive therapies. It will also address the segments of the population in which significant disparities exist, which put some women at the margin of the bell curve of the ‘‘average’’ population addressed by screening and triage guidelines. This calls into question whether higher-risk patients should be managed more aggressively than an average-risk patient represented in the study population used to craft the guidelines.
The Wide Screening Net and the Narrow Therapeutic Pathway This chapter will review the principles and practices and a subsequent chapter the modalities available to the clinician to screen and
Finding and Managing Women at Risk for Cervical Cancer
Correspondence: Neal Lonky, MD, MPH, Southern California Permanente Medical Group, Kaiser Permanente: Medical Office Building 2, 3430 E. La Palma Avenue, Anaheim, CA 92806. E-mail: nlonky@ yahoo.com
Reducing or eliminating the risk of death from cervical cancer is the goal of those who provide screening services. Because
The authors declare that they have nothing to disclose. CLINICAL OBSTETRICS AND GYNECOLOGY
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the epidemiology of cervical cancer is well defined, and the molecular underpinnings have been elucidated, our collective efforts are to mitigate the risk factors that induce cervical intraepithelial neoplasia.1 Evidence that human papillomavirus (HPV) is associated with the development of cervical neoplasia and progression to malignancy is irrefutable.2,3 Although >40 HPV types can infect the cervix, types 16 and 18 are responsible for 70% of cervical cancers. Types 31, 33, 35, 39, 45, 51, 52, 56, 58, and 59 are found in the remaining cases.4–6 Primary prevention through vaccination with concurrent secondary prevention through screening, triage, and treatment of those with precursors of malignancy as well as early treatment of malignancy (tertiary prevention) reduce morbidity and mortality and is the linchpin of our armamentarium in 2013.7 Eliminating the risk of HPV exposure through barrier methods, or medical interventions short of vaccination remains daunting, as HPV is highly infectious, and most commonly transmitted sexually rather than by vertical transmission.8,9 HPV genomic integration with host DNA is common, but the vast majority of US women with active infection during their lifetime will neither harbor persistent virus nor develop cervical cancer. The reported incidence of new HPV infections is 6.2 million per year, with an estimated 27% prevalence. The coincident rate of invasive cancer is 12,963 cases with 6605 associated deaths in the United States.10–12 The prevalence of HPV infection is highest among young women under age 25 and decreases thereafter. Datta et al13 studied 9657 women in the United States, wherein the prevalence of high-risk HPV peaked at 35% in adolescents younger than age 19 and dropped to 6% in women aged 50 to 65 years. Women aged 29 and under are the most likely to harbor CIN 1 and CIN 2, in which case the prognosis and malignant potential of precursors favors regression over persistence or progression during expectant management. Treatment may be chosen to alter the natural course of www.clinicalobgyn.com
the disease rather than to rely on the patient’s own immune recognition and elimination of the affected cells. This has been advocated for the ‘‘true’’ precursor of invasive cancer, carcinoma in situ or ‘‘CIN 3+ ,’’ in the average-risk patient.14 We cast a very wide net in screening by utilizing cytology, broad oncogenic HPV testing for all relevant subtypes (Digene Hybrid Capture 2, Qiagen, Netherlands; and AMLICOR, Roche Molecular Diagnostics, Pleasanton, CA), or specific secondary testing for subtypes 16 and 18 (AMPLICOR and Cobas HPV test, Roche Molecular Diagnostics). Type-specific HPV testing may be helpful in cases in which the malignant potential or the prognosis toward neoplastic progression is uncertain to further refine the management plan.14–16 Although the 2012 Guidelines for management of neoplastic abnormalities reduces the number of referrals to colposcopy, only a fraction of the cases in the United States referred for abnormal screening reveal carcinoma in situ or worse (CIN 3+). The histologic evidence from colposcopic workup most commonly reveals ‘‘low-grade’’ precursors without the establishment of highgrade precursor (CIN 2+) diagnosis. Screening that leads to a costly workup, wherein the resultant cases do not identify women with CIN 2+ , is problematic from a clinical follow-up standpoint, leading to observation with follow-up or their return to the screening population intervals proscribed in published guidelines.17 The management algorithms rely on the low probability of developing cervical cancer in this cohort as a whole, whereas the negative predictive value of the workup is powerful. Therefore, very few women who receive some screening, especially those with abnormalities undergoing triage during their lifetime, are placed at significant risk of developing and dying from cervical cancer. The high prevalence of HPV exposure and high probability of regression of CIN
Cervical Cancer Prevention in young, reproductive-aged female individuals influenced the screening intervals supported in new practice guidelines. There is a long latency between the time of infection to genomic expression to cancer in most cases. Circumventing the natural history with destructive therapy poses potential harm. Further complicating the situation for clinicians who provide gynecologic services is the fact that some women at high risk do not fit into the ‘‘average’’-risk population that practice guidelines describe. Screening intervals, utility of screening technologies, triage algorithms, and treatment decisions may be different among women at higher risk for cervical cancer. Virus-induced cancers rarely have a long latent phase in which clinicians can diagnose a precursor state through direct ‘‘access’’ to a ‘‘transformation zone’’ to confirm the disease process as we see with the cervix. Another virus-induced cancer may arise from infection with hepatitis B or hepatitis C. A chronic viral infection may lead to liver cancer (1 per 200 cases for hepatitis B, 1 per 45 cases for hepatitis C), which is exacerbated by coexisting cirrhosis. It should be noted, however, that the liver cancer viral model is dissimilar in that there are few effective therapies for it, no premorbid neoplastic stage to target, and uncertainty regarding regression of the malignant potential over time.20 A lack of an examination like colposcopy with a low transaction cost or risk for the diagnosis of a premalignant precursor and only a recently developed evidence-based emerging set of chemotherapeutic preventive options to alter the natural course have forced a ‘‘wait and see’’ approach, with a recommendation not to treat until a late stage in the neoplastic process.18,19
Preventive Approach Based on Epidemiologic Risk Many of the new cancer cases occur in the unscreened or underscreened population,
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which disproportionately represents disparate or special-needs populations.20–22 The ubiquitous nature of HPV and the lack of a failsafe measure to prevent sexual transmission make it a difficult task to focus on initial infection as the key epidemiologic target for intervention before infection and genomic insinuation.9 Proactive vaccination with oncogenic subtypes HPV 16 and 18 either through commercially available Gardasil (Merck and Co., NJ) or through Cervarix (Glaxo Smith Klein Pharmaceuticals, London, UK) attempts to circumvent the sequelae of disease. Rarely have we seen a pathologic entity in which the organism causing the disease is well defined and the detection very accurate, yet the therapeutic approach spans decades. The insinuation of HPV into the host genome is unlikely to result in a true cancer precursor or cancer for decades and only occurs in a fraction of those infected. Unlike many other viral and bacterial pathogens, the changes associated with HPV must persist to be mutagenic, thus are not likely to progress in the vast majority of cases.23,24 Most other nononcogenic viral pathogens lead to pathogenic expression leading to illness and damage within a very short latency period of weeks to months. The natural history and prevention model of Mycobacterium tuberculosis (TB) provides for a more fitting comparison with HPV than the hepatitis model. The latency periods from infection to expression, morbidity, and ultimate mortality are comparably long.25 Interestingly, medical history shows that before skin testing and treatment the clinical approach was similar to our approach to HPV today. Before the end of the 20th century, we recognized that most TB infections were highly contagious, exposure was frequent, and occurred in an early, premorbid state. Progression depended on a weakened or altered immune state allowing for active TB and pathogenesis. www.clinicalobgyn.com
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The Bacille Calmette-Gue´rin (BCG) vaccine, developed in the early 1930s, was not adopted in the United States because of its variable effectiveness against the most common disease manifestation, pulmonary TB. Therefore, the public health approach was to screen, triage, and treat those with advanced-stage infection and evidence of lung damage.26 Although early use of chemotherapy for TB was viewed as potentially harmful to those with inactive pulmonary infection, the advent of low-dose, longer-term administration of single-drug regimens provided the pathway to secondary prevention. This efficiently reduced the risk for active TB among those treated, with little perceived harm ascribed to therapy.27 Universal screening in education and employment settings in countries with adequate health services like the United States and directly observed therapy in the early stage of disease succeeded in drastically reducing the cases of active TB.28 Thus, moving the detection and intervention to the infective stage rather than the ‘‘true precursor’’ stage when there are active lung lesions was the tipping point in effective secondary prevention. Once proven, the efforts toward promoting early screening, mandating it for school entry and employment, and guidelines promoting and in some settings requiring chemoprophylaxis consistently changed the outcome and eventually the prevalence rate of TB in the United States.29 TB cases plummeted, and patients with active TB requiring quarantine or hospitalization became a rarity because early management of asymptomatic positive skin test cases was used. This left no one at any stage or risk in the natural history unmanaged. The fact that oncogenic viral subtypes lead to initial infection in what is labeled ‘‘early HPV infection’’ or cervical intraepithelial neoplasia grades 1 and 2 (CIN 1, CIN 2) is also irrefutable. Therefore, detecting CIN at grades 1 and 2 in the www.clinicalobgyn.com
‘‘average’’ population occurs in the majority and will regress in the majority without therapy. Women who acquire and develop these earlier lesions are predominantly young and of reproductive age. The experience of colposcopic biopsy and curettage can be painful and instill trepidation in some. In addition, most therapeutic approaches to such lesions are excisional or ablative, such invasive procedures pose a small but real risk of pregnancy complications, and all existing therapies pose innate risks to be avoided if possible.30,31 There are several epidemiologic risk factors associated with progression from HPV genomic insinuation to malignancy. Certainly those who are genetically predisposed or ‘‘impaired’’ due to immunosuppression are most at risk for carcinoma and deserve consideration outside proscribed guidelines for the average-risk population.32,33
Guidelines for the Average-risk Population The practice guidelines for cervical cancer screening and management of premalignant neoplasms, supported and developed by the committee, addresses the majority of cases in which access to care is likely and disparities in health care access or extreme risk factors are unlikely. Cofactors that could affect the probability of malignant transformation are recognized but not directly addressed in the standard management algorithms.15,17 Clinicians caring for women undergoing screening who test positive and harbor HPV or premalignant lesions face another challenge. The vast array of screening tests are sensitive early in the continuum in detecting HPV viral DNA at extremely low levels, whereas cytologic changes that loosely correlate with high-grade dysplasia or visual changes that correlate with neoplastic proliferation can also be
Cervical Cancer Prevention present.34,35 This presents a ‘‘poor specificity’’ conundrum. The paucity of therapeutic options to alter the natural course of the HPV infection toward regression and resolution along with the evidence that ablation and excisional modalities cause potential harm and reproductive sequelae creates another kind of disparity leading to not only potential harm but waste. The therapeutic options limit or negate the clinical strategic advantage of early detection before real malignant potential during which lesions may be transiently high grade and occupy a large percentage of the transformation zone. If addressed with excision or ablation at this diagnostic juncture, cervical insufficiency or stenosis poses a potentially avoidable risk so early in life.36,37
Will Vaccination Provide Efficient Prevention? The quadrivalent HPV vaccine (types 6, 11, 16, 18) ‘‘Gardasil’’ and the bivalent HPV vaccine ‘‘Cervarix’’ (types 16, 18) have been available in the United States for >5 years, and appear to provide protection to the majority of those who receive it in childhood, adolescence, or young adulthood.38,39 Primary prevention is costly, as 3 vaccine doses are needed to achieve adequate acquired immunity. Access to vaccination, especially for those in poverty, with poor health care services access, or those with poor health seeking behavior, is challenging. Access to health insurance does not guarantee that young women will receive the initial vaccine or subsequent 2 vaccinations in the series.40 The additional challenge of cultural or psychosocial fear of vaccination or the stigma associated with the vaccine being linked to sexual behavior cannot be overlooked, and remains a significant barrier to efficient vaccination of the population.41 Vaccination rates in the target population, those 9 to 26 years of age, are
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not reaching a sufficient rate to achieve prevalent herd immunity. Thus, primary prevention of the US population through vaccination is not making the impact in reducing deaths from cervical cancer that was hoped for and expected.
Screening Modalities and the Wide Net Multiple modalities have been utilized over the better part of the last century for screening, with the intention of casting a wider net to bring more ‘‘at-risk’’ women to triage, ultimately reducing deaths related to cervical cancer. Papanicolaou and Traut42 initially described the vaginal smear in 1943, which marked the first time that identification of precancerous cells could be performed. By the 1960s, the prevailing idea was such that regular Pap screenings could eradicate cervical cancer.43 This led to the paradigm of screening more women more often and treating them earlier. The concept of detecting the ‘‘precursor’’ was established,44 with less concern about the option of ‘‘wait and see,’’ the possibility of regression without therapy, or the lack of specificity (finding and managing ‘‘true’’ precursors destined for malignancy). The new detection modalities keyed into improving sensitivity. The chapters focusing on screening and therapeutic options will showcase the evolution of both improved screening and the recognition that early intervention with existing treatments might pose unintended harm in some not destined to suffer from or succumb to cervical cancer.
Destructive Therapy in the Mainstream Armamentarium The therapeutic milieu has not advanced as rapidly as our armamentarium to detect patients with lesions containing neoplastic change at an ‘‘indeterminate’’ www.clinicalobgyn.com
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TABLE 1.
Treatment Modalities of Cervical Dysplasia
Conventional Therapies
Indications
Method
Invasiveness
Cold knife conization Laser conization Loop electro-excisional procedure Cryotherapy Biopsy as therapy
CIN 2/3 CIN 2/3 CIN 2/3
Excision of transformation zone Excision of transformation zone Excision of transformation zone
Invasive Invasive Invasive
CIN 1, CIN 2, HPV+ CIN 2/3
Imiquimod
CIN 1, CIN 2
Topical application of cryoprobe Invasive Local excision of affected area Moderately invasive Topical application of imiquimod Minimally invasive
prognostic stage. Therefore, our willingness to find and treat women in a stage less than carcinoma in situ has been daunting. A subsequent chapter will review the existing destructive modalities, and then discuss the emerging nondestructive therapies on the horizon. Cervical intraepithelial neoplasia has been treated traditionally with destructive methods that destroy the transformation zone of the cervix (Table 1). These include such treatments as cold knife or laser conization, and loop electro-excisional procedures (LEEP), which provide a pathologic specimen for diagnosis and therapy. In addition, destruction of the transformational zone can be performed with cryo-ablative therapy. One of the concerns for use of treatment that removes or destroys a portion of the uterine cervix is its effect on subsequent pregnancy. In a study by Heinonen et al,31 the odds ratio for subsequent preterm birth (6600 women were randomized to HPV screening with positive women treated with cryotherapy, to screening by visual inspection and treatment with cryotherapy, or to the control group in which evaluation or treatment was delayed until 6 months. CIN 2+ was significantly less in the HPV-and-treat arm (1.5% vs. 5.6%, PCIN 2 in the last 20 years or if the patient has not had adequate negative screening in the prior 10 years. Screening intervals are shortened in all age groups for women with a history of cervical cancer, human immunodeficiency virus infection, immunocompromise of any kind, or in utero diethylstilbestrol exposure.
Adolescents (Below 21 y of Age) On examining the adolescents, population-based data show 1 to 2 cases of cervical cancer per 1,000,000 15- to 19year-old female individuals.50,51 Unfortunately, there has been no evidence of decreased incidence of cervical cancer in the under-21 age group with screening.48 HPV infection and neoplasia are common in teenage women with up to 43% HPV infection and a 5% to 7% rate of lowgrade squamous intraepithelial lesion (LSIL).52–54 Furthermore, among 477 adolescents with a diagnosis of LSIL or high-grade squamous intraepithelial lesion, persistent and progressive disease was common.53,55 Specifically, on follow-up of adolescents for 36 months after a diagnosis of LSIL, 47% had persistent disease and 18% had progression to high-grade dysplasia. Only 35% had
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resolution. Among the adolescents with high-grade dysplasia initially, 51% had persistent high-grade dysplasia, 27% had low-grade dysplasia, and only 22% had resolution to negative histology or cytology.53 Over 72 months, approximately 65% of CIN 1 regressed, but only 35% of CIN 2 or 3 regressed to CIN 1 or normal.55 Thus, although invasive cervical cancer is extremely rare in the adolescent age group, we recognize that HPV exposure, infection, and persistence often begins in the adolescent years with development of progressive dysplasia and eventually malignancy in those who do not clear the HPV infection. With a known lag time of 10 to 20 years from HPV exposure to malignancy, we see that the incidence of cervical cancer jumps to 5 per 100,000 in the 25 to 29 age group. Testing should be avoided in this population with very specific exceptions, not because treatment of dysplasia in this age group would not prevent future cervical cancer but rather because of (1) the low incidence of actual invasive malignancy within this age group; (2) the 65% regression rate of CIN 1; (3) the interventions (colposcopy, biopsy, cryotherapy, and cervical conization) and associated cost without immediate benefit; and (4) the potential negative side effects, particularly with cervical conization (LEEP or cold knife conization) with regard to increased risk for spontaneous abortion and preterm birth.31,56 Given these concerns regarding the limited available treatment options, the most important step that can be taken toward cervical cancer prevention in the adolescent population is HPV vaccination. The 3-vaccine series includes at minimum HPV types 16 and 18, which are responsible for at least 70% of cervical cancers in the United States.57 Although the CDC recommends that all girls initiate the vaccine between the ages of 11 and 12,58 the uptake of the HPV vaccine has been inadequate, with barely 50% of 13to 17-year-olds having received the first of www.clinicalobgyn.com
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the 3 doses and only 35% having received all 3 of the vaccine series.57 However, the data above also raise the question whether we are allowing excessive risk for high-grade dysplasia and possibly even cervical cancer for specific high-risk populations of adolescents. In particular, those with a sexual debut before the age of 16 have a delay of >5 years before their first cervical cancer screening. It is well established that women of color and those with 5 years between first sexual debut and cervical cancer screening is potentially medically and ethically irresponsible.
Women Aged 65 or Above Women over 65 years of age actually comprise a disproportionate share of cervical cancer cases—they make up 19.5% of new cases of cervical cancer, even though they only represent 14.1% of the population of female individuals in the United States.50 It is estimated that continued cervical cancer screening after age 65 would prevent 1.6 cancer cases and 0.5 cancer deaths for every 1000 women screened.63 There has been significant debate regarding the cost versus benefit of continued screening after the age of 65, given adequate screening before age 65. Isidean and Franco64 argue that, ‘‘continued screening would extend life expectancy by only 1 year per 1000 women, at the cost of 58 extra false-positive results, www.clinicalobgyn.com
127 extra colposcopies, and 13 extra diagnoses of CIN 2/3 that would require treatment.’’ Assuming a stable efficacy of screening, there is no way to compare screening in an older (>65) population and a younger (
