Berek and Hacker's Gynecologic Oncology, 5th Edition
Tumor Markers and Screening
Approximately one in three women develop cancer in their lifetime (1,2), and one in four die from the disease (3,4). Gynecological malignancies account for 12% of these cancers (2). In the last 30 years, the age-standardized incidence rates of cancers in women has increased by 32% (1975-2004). However, from 1993 to 2004, the increase was limited to 3% (2). Nevertheless, even this latter figure is two- to threefold greater than the increase in cancers in men. Most of this increase has occurred in the postmenopausal population.
Among the established strategies for combating cancer in the twenty-first century is screening the asymptomatic population for premalignant conditions and early stage disease.Such screening strategies are based on criteria laid down by the World Health Organization (WHO) (5) (Table 7.1). Mass screening for cervical cancer fulfills most of these tenets,and organized screening programs in numerous countries have led to a significant reduction in cervical cancer mortality (6,7,8,9).
Ovarian cancer is the other gynecological malignancy that may meet the criteria of a disease for which population screening is justified (10). The disease is usually diagnosed in advanced stages when chances for long-term survival are poor. Effective treatment is available for early stage disease, and there is preliminary evidence that early detection may increase long-term survival. In a randomized controlled trial of ovarian cancer screening, a strategy incorporating sequential CA125 and transvaginal ultrasound was found to significantly increase median survival in women with ovarian cancer in the screened group (72.9 months) when compared with the control group (41.8 months) (11). Annual transvaginal ultrasonic (TVS) screening has been found to decrease disease stage at detection and increase casespecific ovarian cancer survival in a recent trial involving 25,327 women. Eighty-two percent of women who had screen-detected ovarian cancer had early stage (I or II) disease versus 34% of women in the unscreened control group (p <0.0001) (12).
Mass screening for endometrial cancer is unlikely to be of benefit in the low-risk population because women present in early stages with symptomatic disease. However, screening of “high-risk” populations is recommended (13,14,15). Vaginal and vulvar cancers are too rare to justify screening, although it is important to raise the awareness of these conditions among the elderly population.
Table 7.1 World Health Organization Criteria for a Screening Program
Tumor markers are molecules or substances produced by or in response to neoplastic proliferation that enter the circulation in detectable amounts. They indicate the likely presence of cancer or provide information about its behavior. For screening protocols, the value of the marker depends heavily on its sensitivity (proportion of cancers detected by a positive test) and specificity (proportion of those without cancer identified by a negative test), which must be well established before it is adopted into routine practice. An ideal tumor marker would have a 100% sensitivity, specificity, and positive predictive value. However, in practice this is never achieved. The most limiting factor is lack of specificitybecause the majority of markers are tumor associated rather than tumor specific and are elevated in multiple cancers as well as in benign and physiological conditions. In most diseases, tumor markers are therefore not diagnostic but contribute to differential diagnosis. They may also have an important role to play in screening, determining therapeutic efficacy, detecting recurrence, and predicting prognosis.
A wide variety of macromolecular tumor antigens—including enzymes, hormones, receptors, growth factors, biological response modifiers, and glycoconjugates—have been investigated as potential tumor markers. Innovative screening strategies using new microarray and massspectrometry -based technologies exploring DNA, RNA, and protein overexpression are constantly identifying novel biomarkers that could complement those previously identified by candidate gene or antibody-based techniques. This chapter will focus on the different tumor markers relevant to gynecological malignancies and their role in screening.
Despite significant research into a large variety of markers, the number of clinically useful markers is limited. Poor study design that leads to inconsistent conclusions has been cited as an important reason. General guidelines on the application and use of tumor markers have been developed by a number of multidisciplinary groups following critical appraisal of available evidence (16,17,18,19,20). The National Cancer Institute's Early Detection Research Network has suggested five phases for biomarker development: preclinical exploration, clinical assays and validation, retrospective longitudinal repository studies, prospective screening studies, and conducting clinical randomized trials for assessing end points of cancer screening. Guidelines covering methodological issues related to measurement and internal and external quality control have also been published. However, systematic reviews such as those conducted by Cochrane Collaboration are lacking in relation to tumor markers.
The evaluation of exfoliated cells has been used for many decades. In gynecology, the cervical screening program was based on nucleocytoplasmic changes detected on microscopy of Papanicolaou stained cells obtained from cervical sampling. These changes do not entirely fulfill the criteria for true tumor markers because their presence usually denotes an underlying premalignant condition—cervical intraepithelial neoplasia—rather than frank malignancy. There are now an increasing number of sophisticated molecular techniques available for examining key events associated with the carcinogenesis, including the presence of highrisk human papilloma virus (HPV) DNA, telomerase activity, and K-ras mutation in cervical secretions.
A variety of imaging modalities are in use to identify morphological characteristics of cancer. These features, although not highly specific, may serve as very sensitive markers for screening. In gynecology, real-time ultrasound is most commonly used because it has minimal side effects and provides detailed tumor morphology, which can be quantified using a variety of scoring systems. Detailed characterization of morphology on transvaginal scanning is an important component of both ovarian and endometrial cancer screening.
Neovascularization associated with malignancy is another marker that has been exploited in screening for genital cancers. Color-flow Doppler is used to detect altered patterns of blood flow and decreased resistance in the thin-walled new vessels in ovarian and endometrial cancers. Colposcopy exploits the same phenomenon in an entirely different manner: The abnormal new vessels are directly visualized as patterns of mosaicism and punctation. An important aspect of screening is defining the risk groups. Even for cervical cancer, where mass screening is the norm, age is used to define the population undergoing screening. In the United Kingdom, current screening guidelines limit screening to women between ages 25 and 64 years (21). Risk groups for sporadic ovarian cancer are defined by age (≥50) in clinical trials and for hereditary ovarian malignancy by family history criteria and the presence of BRCA1 or BRCA2 mutations. Increased risk based on family history is also the basis of defining a target population for endometrial cancer screening.
Ovarian and Fallopian Tube Cancer
Ovarian cancer accounts for 4% of cancers occurring in women, with more than 190,000 new cases diagnosed worldwide each year. Incidence rates are highest in the United States and Northern Europe and the lowest in Africa and Asia. It is the most common gynecological cancer in England and Wales, with women having a 2.1% lifetime risk of developing the disease (22). It is also the most lethal because of the advanced stage at which most women present. Approximately 85% of cases occur after age 50, and 80% to 85% of cancers are epithelial in origin. Traditionally, serous tumors are the most common, present at an advanced stage, and have the poorest outcome (23). However, in the reproductive age group, germ-cell tumors, granulosa cell and sex-cord tumors, and mucinous and endometrioid tumors are more common.
Deficiencies in our knowledge of the molecular and biologic events in ovarian carcinogenesis have hampered our ability to screen for this disease. A screen-detectable precursor lesion for ovarian cancer has not been identified, limiting the goal of screening to detection of asymptomatic, early stage disease (10). Biochemical, morphological, vascular, and cytological tumor markers have all been explored with varying success. Even though screening can detect cancers early (24), and a survival benefit has been reported, there is as yet only preliminary evidence that ovarian cancer screening may reduce mortality (11). In addition, it is not known whether the screen-detected early stage disease will include a significant number of high-grade serous carcinomas or just the better prognosis histological cancers. Until a mortality impact has been reported, women in the general population should not be screened outside the context of research trials. The ongoing trials are expected to report around 2012 to 2014 and should help address the above issues.
CA125 is a 200-kilodalton (kd) glycoprotein recognized by the OC125 murine monoclonal antibody and first described by Bast et al. in 1981 (25). Recently on cloning, it was found to have characteristics of mucin designated as MUC16 (26). It carries two major antigenic domains, classified as A, the domain-binding monoclonal antibody OC125; and B, the domainbinding monoclonal antibody M11 (27). The first CA125 immunoassay used the OC125 antibody for both capture and detection (28,29). The second-generation heterologous CA125 II assay incorporates M11 and OC125 antibodies and is now widely used for measuring CA125. There are a number of CA125 assays available, most of which correlate well with each other and are clinically reliable (30). However, differences in reagent specificities and assay design can lead to variation in values obtained, and the results may not be interchangeable. Change in methodology may require baseline samples to be retested or parallel tested using both assays (30,31). This may be of importance for patients who are undergoing serial monitoring such as in screening trials.
CA125 is not specific to ovarian cancer and is widely distributed in adult tissues. It is found in structures derived from the coelomic epithelium (such as endocervix, endometrium, and fallopian tube) and in tissues developed from mesothelial cells (such as pleura, pericardium, and peritoneum) (32). It is expressed in the normal adult ovary (33) and has also been characterized in epithelial tissues of the colon, pancreas, lung, kidney, prostate, breast, stomach, and gall bladder (28,34).
CA125 levels in body fluids or ovarian cysts do not correlate well with serum levels. Serum concentration is a function not only of production of antigen by the tumor but also of other factors that affect its release into the circulation (35). The widely adopted cutoff value of 35 U/mL is based upon the distribution of values in healthy subjects, where 99% of 888 men and women were found to have levels below 35 U/mL (36). However, CA125 values can show wide variation and are influenced by age, race, menstrual cycle, pregnancy, hysterectomy, and a number of benign conditions. In postmenopausal women, CA125 levels tend to be lower than in the general population, and levels below 20 U/mL have been found (37,38,39,40). Levels fluctuate during the menstrual cycle and increase during menstruation (28,41). Levels in white women have been found to be higher than in African or Asian women (42). Caffeine intake, hysterectomy, and smoking in some (42) but not all reports (43,44) have been found to be associated with lower levels of CA125 (42).
A number of benign gynecological conditions such as endometriosis, fibroids, infections, and pelvic inflammatory disease may increase CA125. In pregnancy, peak CA125 values occur in the first trimester and postpartum (28,45,46,47,48,49), with wide fluctuations in levels as high as 300 U/mL, being reported at these times (28,46,47,48), and return to normal by 10 weeks postpartum (47). Levels of 112 U/mL and 65 U/mL have been found to correspond to the ninety-ninth percentile and the ninety-sixth percentile in the first trimester, respectively (50,51), but ideally different levels need to be defined for different stages of pregnancy and puerperium (52). CA125 may also be elevated by nongynecological diseases causing any inflammation of the peritoneum, pleura or pericardium, pancreatitis, hepatitis, cirrhosis, ascites, tuberculosis, and other malignancies such as pancreatic, breast, colon, and lung cancer (28,34). The benign and physiological conditions associated with an elevated CA125 can cause false positive results when CA125 is used in diagnosis or screening.
Approximately 85% of patients with epithelial ovarian cancer have CA125 levels of >35 U/mL (36,53), with elevated levels found in 50% of patients with stage I disease and more than 90% of patients with stage II to IV disease (28). CA125 levels are less frequently elevated in mucinous and borderline tumors compared to serous tumors (28,54,55).
CA125 can be elevated in the preclinical asymptomatic phase of the disease because raised levels were found in 25% of 59 stored serum samples collected 5 years before the diagnosis of ovarian cancer (38).
In a prospective ovarian cancer screening study of Swedish women, a specificity of 97% and positive predictive value (PPV) of 4.6% was achieved using CA125 (30 U/mL) in 4,290 volunteers aged 50 years and older (56). Recently published data from the Shizuoka Cohort Study on Ovarian Cancer Screening (SCSOCS) found that the interval between the first detection of a slightly elevated CA125 level and the diagnosis of disease at surgery was significantly shorter in patients with serous-type ovarian cancer, compared with those with nonserous-type disease (1.4 vs. 3.8 years, p = 0.011) (57). Although 47% nonseroustype ovarian cancers developed from slightly elevated CA125 levels between 35 and 65 U/mL, 75% serous ovarian cancers developed suddenly from a normal CA125 level (<35 U/mL) (57).
In postmenopausal women, an elevated CA125 in the absence of ovarian cancer has been found to be a risk factor for death from other malignant disease (58,59). These findings have implications when screening asymptomatic postmenopausal women.
Improving Sensitivity, Specificity, and Discriminatory Ability
Pelvic Ultrasound as a Second-Line Test
Specificity of screening with CA125 was initially improved by the addition of pelvic ultrasound as a second-line test to assess ovarian volume and morphology. Using multimodal screening incorporating sequential CA125 measurements and pelvic ultrasound, a specificity of 99.9% and PPV of 26.8% for detection of ovarian and fallopian tube cancer were achieved in 22,000 postmenopausal women (60,61). With the accumulation of data, ovarian morphology has been used to refine algorithms for the interpretation of ultrasound in postmenopausal women with elevated CA125 levels (62,63).
Risk of Ovarian Cancer Algorithm
Developing a more sophisticated approach to replace absolute cutoff levels for interpretation of CA125 titers has made further improvements to the strategy. Detailed analysis of more than 50,000 serum CA125 levels involving 22,000 volunteers followed up for a median of 8.6 years in the study by Jacobs et al. (11,61) revealed that elevated CA125 levels in women without ovarian cancer were static or decreased with time, whereas levels associated with malignancy tended to rise. This finding has been incorporated into a computerized algorithm that uses an individual's age-specific incidence of ovarian cancer and CA125 profile to estimate her risk of ovarian cancer (ROC) (64,65,66). The closer the CA125 profile to the CA125 behavior of known cases of ovarian cancer, the greater the ROC. The final result is presented as the individual's estimated risk of having ovarian cancer, so an ROC of 2% implies a risk of 1 in 50. The ROC algorithm increases the sensitivity of CA125 compared with a single cutoff value because women with normal but rising levels are identified as being at increased risk. At the same time, specificity is improved because women with static but elevated levels are now classified as low risk. For a target specificity of 98%, the ROC calculation achieved a sensitivity of 86% for preclinical detection of ovarian cancer (64).
When evaluated prospectively in a pilot randomized controlled trial of ovarian cancer screening, the specificity and PPV for primary invasive EOC were 99.8% (CI 99.7 to 99.9) and 19% (CI 4.1 to 45.6), respectively (67). It is part of the ongoing U.K. Collaborative Trial of Ovarian Cancer Screening (UKCTOCS) (available at: http://www.ukctocs.org.uk) (Figure 7.1).
The ROC algorithm is also being evaluated prospectively in pilot ovarian cancer screening trials in high-risk women under the auspices of the Cancer Genetics Network (CGN) and Gynecology Oncology Group (GOG) in the United States and in the Familial Ovarian Cancer Screening Study in the United Kingdom (UKFOCSS). The ROC algorithm is used to triage women into low-, intermediate-, and elevated-risk categories based on their CA125 result. Intermediate risk women have a repeat CA125 in 6 to 8 weeks, whereas those with elevated risk are referred for a TVS. An abnormal TVS leads to gynecological assessment with view to surgery.
Panel of Markers
Accurate discrimination between benign and malignant masses is essential to avoid unnecessary operations in women with benign lesions and to plan suitable surgery by appropriately trained gynecologic oncologists in tertiary care centers for those with cancer (68,69,70,71,72). Both prospective and retrospective data show that CA125 can be used as an adjunct in distinguishing benign and malignant masses, particularly in postmenopausal women (73,74,75,76). Using an upper limit of 35 U/mL, a sensitivity of 78%, specificity of 95%, and PPV of 82% can be achieved for ovarian cancer.
One option of improving diagnostic accuracy is using a combination or panel of markers rather than a single biomarker. However, increased sensitivity obtained is often associated with decreased specificity. TATI, CA19-9, CA72-4, and carcinoembryonic antigen (CEA) in addition to CA125 may be useful in mucinous ovarian cancer (77). Increased preoperative sensitivity for early stage disease has been reported by combining CA125 with CA72-4, CA15-3, and macrophage-colony stimulating factor (M-CSF) (78). The majority of earlier studies however reported limited ability to improve diagnostic sensitivity by the addition of other serum markers for patients with nonmucinous tumors (79,80,81,82). A panel of eight different markers—CA125, M-CSF, OVX1, lipid-associated sialic acid (LASA), CA15-3, CA72-4, CA19-9, and CA54/61—improved the sensitivity for discriminating malignant from benign pelvic masses (83). Using the same data set, a subset of four markers analyzed using an artificial neural network demonstrated improved specificity over CA125 alone (87.5% vs. 68.4%) while maintaining comparable sensitivity (79.0% vs. 82.4%) (84). In addition, greater specificity using multiple markers might be attained if serial values were employed as in the case of CA125. Preliminary data on a panel of five serum tumor markers obtained during 6 years of follow-up of 1,257 healthy women at high risk of ovarian cancer showed substantial heterogeneity of tumor marker patterns and indicated that a fixed screening cutoff level may be suboptimal to a degree that depends strongly on intraclass correlation coefficient (ICC). Longitudinal marker levels (trends) and the ICC can lead to the development of individualspecific screening rules to improve early detection of ovarian cancer(85).
Figure 7.1 The United Kingdom Collaborative Trial of Ovarian Cancer Screening (http://www.ukctocs.org.uk). After a normal risk of ovarian cancer (ROC) (<1 in 2,000), a repeat CA125 level is done in 1 year: after an intermediate ROC (>1 in 2,000 to <1 in 500), a repeat CA125 level is done in 6 weeks; and after an elevated ROC (>1 in 500), a transvaginal ultrasound and CA125 level are done in 6 to 8 weeks. The primary outcome is mortality from ovarian or fallopian tube cancer. Follow-up is by postal questionnaire and the U.K. Office of National Statistics. Women in the screened arm undergo six screens, and each woman is in the trial for 7 years.
Recently, a preliminary report using a panel of six markers (leptin, prolactin, osteopontin, macrophage inhibitory factor, IGF-2, and CA125 ) found much improved sensitivity and specificity over CA125 alone (86). Immunohistochemical data suggested that HE4 and mesothelin may be discriminatory in CA125-negative cancers (87). A recent analysis with a panel of nine markers—CA125, SMRP, HE4, CA72-4, activin, inhibin, osteopontin, epidermal growth factor, and ERBB2 (HER2)—found that the addition of HE4 to CA125 without the use of ultrasound increased sensitivity to 76.4% at a specificity of 90% and 81% at a specificity of 90%. HE4 was found to be the single most sensitive marker and also improved detection of early stage disease (88). The addition of HE4 may hold more promise in premenopausal women because it is elevated in ovarian cancer and not as frequently elevated in benign conditions commonly found in younger women. Further investigation of these markers in serum is underway.
Other Tumor Markers
Although a vast number of serum markers have been investigated, only a few have been validated for clinical use. Limited sensitivities and specificities constrain their use for screening purposes. In the past 5 years, significant progress has been made in developing novel tumor markers for early detection of ovarian cancer (Table 7.2). Most of these studies have used samples from women with clinically diagnosed ovarian cancer (i.e., in the differential diagnosis of ovarian cancer) as opposed to asymptomatic women with preclinical disease (i.e., early detection of ovarian cancer). Ovarian cancer tumor markers not associated with recent publications are not detailed in this chapter. They include CA15-3, CASA, CEA, tetranectin, tumor associated trypsin inhibitor (TATI), lysophosphatidic acid, LASA, lactate dehydrogenase, galactosyltransferase associated with tumor, OVX1, shed glycans, growth factors, CA130, HER-2/neu, p105, AKT2 gene, and sialyl SSEA-1 antigen.
Table 7.2 Tumor Markers That May Be Useful in Screening for Ovarian Carcinoma
Newer High-Throughput Approaches
Proteomics is the study of the expression, structure, and function of all proteins as a function of state, time, age, and environment (172,173,174). In the era of proteomics, there has been a great deal of interest in identifying global patterns of serum proteins and peptides that relate to cancer risk. A wide range of techniques is now available for protein identification and characterization in which high sensitivity and specificity is combined with high throughput.
Mass spectrometry (MS) techniques commonly used to volatize and ionize proteins and peptides include electrospray ionization, surface-enhanced laser desorption ionization time-offlight (SELDI-TOF) analysis, and matrix-associated laser desorption ionization time-of-flight analysis. These technologies have the potential to identify patterns or changes in thousand of proteins less than 20 kd. When combined with matrixes that selectively absorb certain serum proteins, these approaches can globally analyze almost all small proteins in complex solutions such as serum or plasma (175,176). A combination of mass spectra generated by these new technologies and artificial-intelligence-based informatic algorithms has been used to discover small sets of key protein values that discriminate normal from ovarian cancer patients (177). Two different proteomic approaches used include identification of a discriminatory pattern of peaks on mass spectroscopy and proteomic analysis to identify a limited number of critical markers that may then be assayed by more conventional methods. The latter seems more promising but requires further development.
A number of studies have reported better diagnostic sensitivities and specificities of MSgenerated profiles compared to established biomarkers (178,179,180,181). In a preliminary study, SELDI-TOF, in combination with powerful computer algorithms, identified an ovarian cancer specific serum protein signature with a sensitivity of 100%, specificity of 95%, and PPV of 94% (178). Three potential serum biomarkers for early stage ovarian cancer were identified: apolipoprotein A1 (down regulated), a truncated form of transthyretin (down regulated), and a cleavage fragment of inter-alpha-trypsin inhibitor heavy chain H4 (ITIH4, up regulated) (179). These were subsequently validated (182). SELDI-MS and artificial intelligence technology was used to identify four distinct protein peaks in plasma samples with a sensitivity of 90% to 96.3% and specificity of 100% (183). A potential biomarker to distinguish borderline from invasive cancer was reported using MALDI-MS (184), and a recent report presented a list of 80 putative biomarkers as a base for further research (185).
The initial euphoria has been significantly moderated by a number of reports pointing out potential problems and limitations related to such things as cross-platform reliability, reproducibility, and standardization of sample handling, processing, and analytical sensitivity of minute samples (186,187,188,189,190,191,192,193,194,195,196,197,198,199,200). Changes in preanalytical handling variables (e.g., transportation, room temperature, incubation time) affect profiles of serum proteins, including proposed disease biomarkers (186). Adifferent approach from healthy donors and from ovarian cancer patients has shown that CA125 remains the best single marker for nonmucinous ovarian cancer, complemented by CA15-3 or soluble mesothelin-related protein (187).
Advances in bioinformatics are leading to the development of sophisticated algorithms to analyze the large volume of preprocessed mass-spectrometric data and identify the most informative “common” peaks, but these approaches still need further refinement (188,189,190). The implications of such proteomic spectrum analysis for the identification of novel tumor markers are huge. Well-designed, large prospective, multicenter clinical trials are required to validate and standardize this technology (191,192). It is likely that future early detection of ovarian cancer (and other cancers) will include markers discovered through proteomic profiling.
Metobolomics, Epigenetics, and Epigenomics
Metabolomics refers to the rapid, high-throughput characterization and quantification of smallmolecule metabolites. Metabolites are the end products of cellular regulatory processes. Preliminary data suggest that metabolomics is a promising automated approach, in addition to functional genomics and proteomics, for analyses of molecular changes in malignant tumors. Analysis of quantitative signatures of primary metabolites in 66 invasive ovarian carcinomas and nine borderline ovarian tumors by gas chromatography and time-offlight mass spectrometry showed a separation of 88% of the borderline tumors from the carcinomas (193).
Epigenetic mechanisms have been shown to be extremely important in the initiation and progression of human cancer (194). DNA released from dead cancer cells varies in size, whereas DNA released from nondiseased cells undergoing apoptosis is uniformly truncated (195). Freely circulating hypermethylated tumor-derived DNA has been shown to be present in serum or plasma of patients with cancer (196,197). Circulating tumor DNA may serve as a surrogate marker for active, fast-growing invasive tumors (198). However, before the clinical utility of circulating epigenetic markers can be determined, a number of issues related to standardization of methodology, type of assay, reproducibility, efficacy, and comparison with other markers need to be addressed (198).
Real-time ultrasonic screening is aimed at detecting the earliest possible architectural changes in the ovary that accompany carcinogenesis. Both ovarian volume and morphology are assessed with cutoffs for volume ranging from 10 mL to 20 mL, depending on menopausal status (199). The transvaginal route is preferred because its better resolution leads to a more accurate assessment of ovarian and endometrial morphology and does not require a full bladder.
The persistence of abnormalities on repeat scanning 4 to 6 weeks after initial detection helps to reduce false positive rates (200). The lack of physiological changes in ovarian volume in postmenopausal women further decreases the number of false positives in this group compared with premenopausal women. However, even in older women, there is a high prevalence of benign ovarian lesions. In an ultrasonic and histopathological autopsy study of 52 consecutive postmenopausal women who died from causes other than gynecological or intraperitoneal cancer, 56% were found to have a benign adnexal lesion as much as 50 mm in diameter (201). Ultrasonography used in this manner can therefore lead to the detection of many benign ovarian tumors, which results in unnecessary surgery in healthy, asymptomatic women. As data accumulate with long-term follow-up of the participants of the early screening trials, it has been possible to further define the risk of ovarian cancer associated with various ultrasonic findings. Unilocular ovarian cysts <10 cm in diameter are found in 18% of asymptomatic postmenopausal women older than 50 years and are associated with an extremely low risk of malignancy.
Restricting the definition of abnormality to complex ovarian morphology to interpret pelvic ultrasound increases the specificity and PPV in multimodal screening (63). In contrast, complex ovarian cysts with wall abnormalities or solid areas are associated with a significant risk of malignancy (200,202).
To further decrease the number of false positives, some screening protocols use a weighted scoring system or morphological index based on ovarian volume, outline, presence of papillary projections, and cyst complexity (i.e., number of locules, wall structure, thickness of septae, and echogenicity of fluid). There is no standardized index as yet, with systems varying on the number and type of variables evaluated (203,204,205,206,207,208). Others use subjective assessment of the gray-scale images. Based on gross anatomic changes at the time of surgery, papillary projections have the highest and simple cysts and septal thickness the lowest correlation with a diagnosis of ovarian malignancy (209).Newer modalities, such as three-dimensional (3-D) ultrasound and 3-D power Doppler (210,211), pattern-recognition computer models, and artificial neural networks(212,213,214,215) may increase the reproducibility of results and improve ultrasonic performance.
Subjective evaluation using gray scale and Doppler (pattern recognition) by an experienced examiner has been found to be better than either CA125 alone (216) or mathematical logistic regression models (215) in discriminating between benign and malignant disease. Recently, the International Ovarian Tumor Analysis (IOTA) study reported a logistic regression model incorporating 12 variables that included ultrasound-based pattern recognition and found that it was superior to CA125 alone for discriminating benign from malignant ovarian masses. Addition of CA125 values to the model did not improve its performance (217,218). Ovarian histoscanning is another ultrasound-based technique that may hold promise for the future (219). These technologies need external validation and further comparison with other established models.
Other second-line tests have been explored to reduce the false positive rate and facilitate discrimination between benign and malignant ovarian lesions. The risk of malignancy index (RMI) combines serum CA125 values with ultrasonic-detected ovarian morphology and menopausal status and has been widely used as a discriminatory tool for the primary evaluation of patients with an adnexal mass (220). It was initially reported to have a sensitivity of 85% and a specificity of 97% (220) and has been validated both retrospectively and prospectively in gynecological oncology and general gynecological units (221,222,223,224,225,226,227,228,229), with prospective studies reporting slightly lower sensitivity, specificity, and PPV (228,229). A recent comparison found it performed as well as most logistic regression models or artificial neural networks (230). Patients with an elevated RMI score had an average 42-fold increase in the background risk of ovarian cancer (220). A higher RMI sensitivity can be achieved by increasing the RMI cutoff (223,224,225), using artificial neural networks (213), or modifying the RMI calculation (226,227). In women with an RMI cutoff between 25 and 1,000, the addition of specialist ultrasound and magnetic resonance imaging improved sensitivity (94%) and specificity (90%) (231). Ultrasonic assessment for an “ovarian crescent sign” in women with an RMI above 200 has also been shown to improve accuracy (232).
There is a move toward conservative management of adnexal cysts judged to be benign at transvaginal ultrasonic examination when they are incidentally detected in postmenopausal women (233). Follow-up data on such women in ongoing randomized screening trials will be important in determining optimal strategies for operative intervention in screening.
Neovascularization is an obligate early event in tumor growth and neoplasia (234). Fastgrowing tumors contain many new vessels that have less smooth muscle in their walls and therefore provide less resistance to blood flow when compared with vessels within benign ovarian tumors. Color-flow Doppler imaging uses these altered blood-flow patterns as markers to differentiate malignant from physiologic and benign lesions. It has been used both as a first-line screening test in combination with transvaginal ultrasound (235,236) and as a second-line test following an abnormal ultrasound (237,238) in both general and high-risk population screening.
The early promise of Doppler to differentiate between malignant and benign ovarian masses and therefore improve the specificity of ultrasound (235,236) was initially not confirmed in subsequent studies (208,239,240). Although it was demonstrated that the mean pulsatility index of vessels supplying ovarian cancers is lower than that of vessels supplying benign ovarian tumors, the overlap in vascular resistance between these two groups may prevent reliable separation of malignant from benign disease. However, morerecently, the International Ovarian Tumor Analysis (IOTA) group proposed a logistic regression model to distinguish between malignant and benign masses that incorporates both color Doppler flow indexes and tumor morphology assessed by gray-scale imaging. A sensitivity of 93% and a specificity of 76% were achieved at a probability of 0.10 (217). This model was subsequently prospectively validated in a multicenter study (218).
It has been reported that lack of blood flow in an ovarian tumor, as detected by color Doppler, may preclude cancer (240). This was not substantiated in data from the Kentucky screening trial in which 6% of ovarian tumors without blood flow were malignant (208). Even when Doppler examinations were simplified and limited to the expression of internal color flow, gray-scale sonography was a more sensitive indicator of malignancy than Doppler sonography (241).
Key issues with regard to Doppler examination as a possible second-line study for ultrasoundbased ovarian cancer screening protocols are (i) whether the examination should focus on quantitative or qualitative differences in blood flow within complex masses and (ii) the difficulties with interobserver variation and standardization. Pattern-recognition models using a combination of gray-scale and color Doppler ultrasound have been found to be better than CA125 alone at discriminating between benign and malignant adnexal masses(216). However, the effectiveness of a screening strategy that incorporates Doppler evaluation of ovarian masses in addition to gray-scale sonography has yet to be established. The UKCTOCS trial is collecting Doppler data on abnormal adnexal masses detected on ultrasonic screening, although these are not being used in the screening algorithm (http://www.ukctocs.org.uk). Recently, some studies have shown that three-dimensional power Doppler examinations may be more accurate than two-dimensional Doppler examinations (210,242), although this is also controversial (243).
Two distinct populations are at increased risk for ovarian cancer: the general population and a high-risk population.
The majority of ovarian cancers are sporadic and occur in the general population. More than 90% of sporadic cancers occur in women older than 50 years, so screening studies in the general population usually target this group. Some of the other known risk factors in the general population such as oral contraceptive use, parity, and hysterectomy can be used for determining risk. Groups are also currently investigating the role of single nucleotide polymorphisms in low-penetrance genes (244). In the future, it may be possible to identify women with increased susceptibility for sporadic ovarian cancer by virtue of their genetic profiles.
Hereditary syndromes account for approximately 5% to 10% of ovarian cancers. Female relatives of affected members from ovarian, breast, breast and ovarian, or Lynch syndrome (LS) families who have a greater than 10% lifetime risk of developing ovarian cancer are considered to be high risk. Much of this risk results from mutations arising in the BRCA1, BRCA2, and mismatch repair (MMR) genes. A recent metaanalysis indicated that the average cumulative risk by age 70 years for ovarian cancer is 40% (35% to 46%) in BRCA1 mutation carriers and 18% (13% to 23%) in BRCA2 mutation carriers (162). MMR gene-mutation carriers have a lifetime risk of ovarian cancer of approximately 10% to 12% (246).
In women with strong evidence of a hereditary predisposition, screening from the age of 35 is frequently advocated, although the efficacy of such surveillance has not yet been established (247). Screening premenopausal women can be problematic because this population has a variety of both physiological (e.g., menstrual cycle variations) and benign (e.g., endometriosis, ovarian cysts) conditions that can give rise to false positive abnormalities on ultrasound and CA125. Hence, criteria for interpretation of the screening tests need to be different from those developed for postmenopausal women in the general population.
To date, 24 studies have reported on screening for familial ovarian cancer (Table 7.3). More than 17,000 women have been screened, and 76 primary invasive epithelial ovarian and peritoneal cancers have been detected using mainly ultrasonography and CA125 levels as firstline tests. Criteria for interpreting the test results vary, and screening protocols are not always clearly reported. Most studies have used a combination of absolute CA125 levels and ultrasound. Ten of the studies have reported interval cancers, which presented between 2 and 46 months following the last screen (199,248,249,250,251,252,253,254,255,256). In addition, multifocal primary peritoneal cancer is probably a phenotypic variant of familial ovarian cancer, and neither CA125 nor ultrasound are reliable in detecting early stage disease (250,257).
Annual screening using this modality has not been found effective in detecting early stage disease (251,252,258). A modified premenopausal version of the ROC algorithm is being piloted in phase 2 of the UKFOCSS and in the CGN and GOG trials in the United States. These trials are evaluating more frequent 3- to 4-month screening and are likely to report in 2012. Women in the high-risk population who request screening should be counseled about the current lack of evidence for the efficacy of both CA125 and ultrasonic screening and the associated false positive rates. Many still opt for screening despite understanding the risks and limitations. The recommended first-line option for these women is risk-reducing salpingo-oophorectomy after completion of their families (259,260,261).
Current Ovarian Cancer Screening Trials
Two distinct screening strategies have emerged, one based on ultrasonography and the other on measurement of the serum tumor marker CA125 with ultrasonography as the secondary test (multimodal screening) (199,262,263,264,265,266,267,268,269,270). Overall, the data from large prospective studies of screening for ovarian cancer in the general population (Table 7.4) suggest that sequential multimodal screening has superior specificity and PPV compared with strategies based on transvaginal ultrasound alone. However, ultrasonography as a first-line test may offer greater sensitivity for early stage disease.
Trials in the General Population
Ongoing randomized controlled trials (RCT) in the general population aim to assess the impact of screening on ovarian cancer mortality. In the UKCTOCS trial, more than 202,638 postmenopausal women are randomized to either control or annual screening with ultrasonography or a multimodal strategy in a 2:1:1 fashion. In the multimodal group, the ROC algorithm is used to triage women into low-, intermediate-, and elevated-risk categories based on their CA125 result. Intermediate risk women have a repeat CA125 in 12 weeks, whereas those with elevated risk are referred for a TVS and repeat CA125 in 6 weeks. Apart from ovarian cancer mortality, the study also addresses the issues of target population, compliance, health economics, and physical and psychological morbidity of screening. Results are expected around 2013 (http://www.ukctocs.org.uk).
Table 7.3 Prospective Ovarian Cancer Screening Studies in Women with a Family History of Ovarian or Breast Cancer or a Personal History of Breast Cancer
Table 7.4 Prospective Ovarian Cancer Screening Studies in the General Population
The Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial has enrolled 78,000 women aged 55 to 74 at 10 screening centers in the United States with balanced randomization to intervention and control arms (Figure 7.2). For ovarian cancer, women are screened using both serum CA125 and transvaginal ultrasonography for 3 years and CA125 alone for a further 2 years. Follow-up will continue for at least 13 years from randomization to assess health status and cause of death (287). Recently published prevalence screen results in 28,816 screened women reported 29 neoplasms, of which 20 were invasive and 9 borderline. Of all screened women, 4.7% had an abnormal scan and 1.4% an abnormal CA125. The PPV for invasive cancer was 3.7%, 1%, and 23.5% for abnormal CA125, TVS, and both CA125 and TVS, respectively (288).
Figure 7.2 The National Institutes of Health Prostrate, Lung, Colorectal, and Ovarian (NIHPLCO) Cancer Screening Study (287). Ovarian screening is part of the study, and the primary outcome measure is mortality from ovarian cancer. All women will be followed up until 2013 by postal questionnaire.
The Japanese Shizuoka Cohort Study of Ovarian Cancer Screening RCT, using an annual ultrasound and absolute CA125-based strategy in 82,487 low-risk postmenopausal women, did not find a statistically significant difference in the number of screen-detected ovarian cancers (n = 27) and those in the control arm (n = 32). Eight additional interval cancers occurred in the screened arm. The proportion of stage I ovarian cancers was greater in the screened (63%) than in the control group (38%), although this did not reach statistical significance (p = 0.2285). Ovarian cancer detection rates of 0.31 per 1,000 at prevalent screen and 0.38 to 0.74 per 1,000 at subsequent screens were found (24).
Trials in a High-Risk Population
The sensitivity and effectiveness of screening in the younger high-risk population is still not established (289). Annual screening does not seem effective, hence, ongoing trials in the United Kingdom and United States are piloting a more frequent 3- to 4-month approach to screening using the ROC algorithm. The UK Familial Ovarian Cancer Screening Study is a prospective study based on annual transvaginal ultrasonography and CA125 titers every 4 months (290). This ongoing trial has recruited more than 3,700 women from 31 centers in the United Kingdom. Similar trials are under way in the United States under the auspices of the National Cancer Institute's CGN and the GOG (291), with the scope for metaanalysis in the future. In the U.S. trials, screening is based on 3-month serum CA125 levels, which are interpreted using the ROC algorithm. Preliminary results from 2,343 high-risk women in the U.S.-based CGN trial reported that 38 women underwent surgery following 6,284 screens. Five ovarian cancers were detected: two prevalent (one early, one late stage) and three incident (three early) cases, resulting in a PPV of 13%. Three further occult cancers were detected at risk-reducing salpingo-oophorectomy, and one woman developed an interval (late-stage) cancer (253).
Endometrial cancer is a disease mainly seen in postmenopausal women. Just 7% occur in the reproductive age group and are mainly linked to familial predisposition, obesity, or polycystic ovarian syndrome (PCOS). The prevalence of endometrial cancer in asymptomatic women is low, and the overall prognosis is good as women present in early stages with abnormal bleeding. Most endometrial cancers (77%) are diagnosed at an early, favorable stage. The consensus is that screening for endometrial cancer is not warranted for women who have no identifiable risk factors (292,293,294,295,296,297). The only trial to support mass screening for endometrial cancer is from Tohoku University, Japan. The study reported that early stage (88.1% vs. 65.3%), low-grade (74.7% vs. 61.0%), and 5-year survival (94% vs. 84.3%) were significantly more frequent in 126 cases of endometrial cancer detected by mass screening using endometrial smears compared with the 1,069 cases diagnosed clinically during the period 1987 to 1997 (298). However, even in women at increased risk as a result of unopposed use of estrogen, tamoxifen therapy, nulliparity, infertility or anovulation, obesity, diabetes, or hypertension, the American Cancer Society Working Group does not recommend screening for endometrial cancer. As is the case with average-risk women, individuals at increased risk who develop endometrial cancer tend to present with symptoms at an early, favorable stage.
Screening is only recommended in women with or at high risk for hereditary nonpolyposis colon cancer (HNPCC) or Lynch syndrome. LS is an autosomal dominant syndrome characterized by the development of a number of different cancers, the most common of which are colorectal and endometrial cancers. Historically, HNPCC has been diagnosed on the basis of strict family-history-based clinical criteria called the Amsterdam criteria. It is caused by a mutation in one of the DNA mismatch repair genes: MLH1, MSH2, MSH6, PMS1,and PMS2. Individuals from LS or HNPCC families have a 30% to 60% lifetime risk of endometrial cancer (246,299,300,301,302).
Various strategies have been used to screen for endometrial cancer in women with Lynch syndrome, but the efficacy of endometrial screening in these women remains unproven. The main modalities used include TVS and endometrial sampling. The latter has been used both alone and in combination with hysteroscopy. However, available data are limited, and the evidence to recommend any particular method of screening is lacking. Interval cancers occur despite screening, and the impact of screening on morbidity and mortality is unknown.
Although TVS has been used as a first-line screening tool, there is lack of consensus on an appropriate cutoff value for endometrial thickness (ET) in asymptomatic premenopausal women, and interval cancers are known to occur (303,304). Pipelle endometrial biopsy is a well-established method for endometrial sampling and is well tolerated by women as an outpatient procedure. However, it has a tissue yield and procedure failure rate of approximately 10% (305,306), and inadequate samples are more common in the postmenopausal age group. The diagnostic accuracy of pipelle is higher in postmenopausal women. A large metaanalysis of the use of pipelle reported a 99% sensitivity for the diagnosis of endometrial cancer and 81% for the diagnosis of hyperplasia in postmenopausal women. In premenopausal women, the sensitivity for endometrial cancer was 91% with a specificity of >98% (305).
Hysteroscopy-directed endometrial sampling is now routinely performed as an outpatient procedure. Hysteroscopy may permit directed biopsy from a focal lesion and can detect polyps and submucous fibroids that may be missed by both ultrasound and pipelle (307,308). The efficacy and patient acceptability of outpatient hysteroscopy is similar to the in-patient procedure. Overall, five endometrial cancers have been recently reported in two prospective series using annual hysteroscopy for endometrial surveillance in 119 high-risk women (306,309). Outpatient hysteroscopy failure rates of 8% and 11% were found in these two series, respectively.
The largest reported series of ET screening in high-risk women is from Finland. Eleven screendetected and two interval cancers were found in 175 Finnish women undergoing annual surveillance with ultrasound and endometrial biopsies (304). The interval cancers occurred in symptomatic women at 3 and 31 months after a surveillance visit. Transvaginal scans alone would have missed six of the cancers in this cohort. In addition, complex atypical hyperplasia was found in four, complex hyperplasia without atypia in eight, and simple hyperplasia in two women undergoing surveillance. Prospectively collected data in women undergoing screening suggest that cancers may present with abnormal bleeding for as long as 3 months before diagnosis (306,309). This emphasizes the importance of counseling women undergoing screening about reporting any abnormal menstrual symptoms or bleeding patterns and subsequently investigating them.
Data show that screening can lead to the detection of endometrial cancers in high-risk women. Notwithstanding the reported shortcomings, screening may have a role in women who wish to delay or avoid preventative surgery. Women in this high-risk group should be counseled about the risks and symptoms of endometrial cancer and the potential benefits, risks, and limitations of endometrial cancer screening. For women with Lynch syndrome opting for endometrial screening, most current guidelines recommend a strategy of TVS and endometrial sampling from the age of 30 to 35 years (13,14,15). Hysteroscopically directed sampling may have the added benefit of diagnosing focal premalignant lesions in asymptomatic women. Prophylactic hysterectomy and bilateral salpingo-oophorectomy is the recommended alternative for prevention of endometrial and ovarian cancer in LS women who have completed their families (310).
The most commonly used tumor marker is endometrial thickness, which is measured using transvaginal ultrasound. It is defined as the distance from the proximal to the distal interface of the hypoechoic halo that surrounds the more echogenic myometrium. It is conventional to measure double thickness (thickness of both endometrial layers) at the thickest point in the midsagittal view. Cutoffs of 12 mm in premenopausal women and 5 mm in postmenopausal women have been used in earlier trials, but there is no consensus on this, and interval cancers have been known to occur. Any abnormality such as a polyp should be investigated irrespective of endometrial thickness.
In symptomatic patients with postmenopausal bleeding who are not on hormonereplacement therapy (HRT), a cutoff for endometrial thickness of >4.0 mm has a sensitivity for detection of endometrial cancer of 98% and a negative predictive value of 99% (311). The Postmenopausal Estrogen and Progestin Interventions trial found that a ET threshold of 5 mm yielded a PPV of 9%, NPV of 99%, sensitivity of 90%, and specificity of 48% for detecting endometrial hyperplasia or cancer (312). A subsequent metaanalysis suggested an endometrial thickness of 5 mm as a cutoff for investigating postmenopausal bleeding. A negative test would reduce the likelihood of endometrial cancer to 2.5% (313). Even though these cutoffs effectively exclude endometrial atrophy, they fail to differentiate between hyperplasia and carcinoma (314). The endometrial thickness for women using sequential HRT is greater than that for those using a continuous combined preparation. The Scottish Intercollegiate Guidelines Network recommends using 3 mm as a cutoff for women in the following circumstances: (i) those on continuous combined HRT, (ii) those who have not used HRT for a year, and (iii) those who have never taken HRT. They recommend a cut off of 5 mm in women on a sequential preparation (315).
As a tumor marker in asymptomatic postmenopausal women, endometrial thickness has the same poor positive predictive value but high negative predictive value for the detection of serious endometrial disease (312). Screening studies using conventional and color Doppler ultrasonography in apparently healthy postmenopausal women have established that endometrial carcinomas can be detected at a preclinical stage (235,316,317) and that transvaginal ultrasonography is more sensitive than blind endometrial biopsy (318). However, in the absence of symptoms, repeat sampling is not warranted in patients with a thickened endometrium and negative findings at initial biopsy (319). Endometrial fluid accumulation is detected in 12% of asymptomatic elderly postmenopausal women and is rarely a sign of malignancy (317). Other techniques that are under investigation and not part of routine protocols include 3-D ultrasonography for the measurement of endometrial volume and power Doppler analysis (320,321,322) and saline infusion sonohysterography (323,324). The ability of 3-D sonography to distinguish between hyperplasia and cancer is still limited. Saline-infusion sonohysterography may be better than standard TVS at evaluating intrauterine pathology such as polyps or fibroids, but it has limited value in diagnosing hyperplasia or carcinoma (325).
Women on tamoxifen are more prone to develop endometrial polyps or hyperplasia and have a four- to fivefold higher risk of endometrial cancer. In asymptomatic women on long-term tamoxifen, abnormal ultrasonographic findings are common in the absence of underlying endometrial pathology. The apparent increase in thickness observed on ultrasound probably results from tamoxifen-induced changes in endometrial stroma and myometrium (326,327). The sensitivity and specificity of TVS as a screening tool is therefore considerably reduced, and the ideal endometrial thickness cutoff for women on tamoxifen is not known (315). Prompt investigation of abnormal vaginal bleeding rather than screening is probably the best option in this group (328,329). There may be a role for pretreatment assessment of the endometrium before tamoxifen therapy, though this needs further investigation. Limited data suggest that women at risk for severe atypical hyperplasia can be identified on the basis of hyperplastic lesions detected on endometrial biopsy before starting tamoxifen (330). No development of atypical lesions has been reported on subsequent follow-up of lesions treated before tamoxifen therapy (331).
Although the Papanicolaou stained cervical smear was designed to detect cervical cancers, it can detect the presence of malignancy in women with endometrial malignancy. The presence of normal as well as abnormal-looking endometrial cells in cervical smears in the second half of the menstrual cycle or in postmenopausal women should alert the clinician to the possibility of underlying endometrial disease. In a retrospective analysis, 13.5% of postmenopausal women with normal endometrial cells on routine smear, 23% of those with atypical cells, and 77% of those with suspicious cells had either endometrial hyperplasia or carcinoma (332). Among premenopausal women, three of 57 with normal endometrial cells in the secretory phase of the menstrual cycle had endometrial hyperplasia, whereas one of two with atypical cells had endometrial polyps, and both with cells suspicious of carcinoma had endometrial carcinoma (332). A PPV of 64% for the later diagnosis of endometrial malignancy was obtained on follow-up of 359 women who received a cytologic report of endometrial malignancy from the Victorian Cytology Service from 1982 to 1987 (333). In another series, 13.5% of women with endometrial cells of some type on Pap smears had endometrial carcinoma (334). The presence of glandular abnormalities and high-grade squamous intraepithelial lesions on smear is also associated with an increased risk of endometrial carcinoma (334,335,336,337). The sensitivity of cervical cytology performed within 2 years of the diagnosis of endometrial malignancy is 28% (333).
The low sensitivity of cytology using conventional Pap smears that indirectly sample the endometrium can be improved by directly sampling the endometrial cavity using a variety of commercially available sampling devices. Although these techniques are simple and have low risk and good yield, they are associated with technical difficulties because of cervical stenosis and varying degrees of patient discomfort. Their use in screening asymptomatic women is probably best limited to those with a positive result on first-line ultrasonic screening (338). However, they have a low positive predictive value and a lower diagnostic accuracy than pipelle biopsy (305,339).
Polymerase-chain-reaction-based technology has made possible the detection of mutations and other key events in small numbers of cancer cells scattered among large numbers of normal cells. Mutations in oncogenes and tumor suppressor genes have been used as molecular markers to detect endometrial carcinoma from cervical smears. K-ras mutations were found to be present as many as 5 months before the diagnosis of endometrial cancer. In addition to K-ras mutations, which may be present in 10% to 30% of tumors, mutations have also been found in p53 (20% cancers) and PTEN/MMACI genes (34% cancers) (340,341). However, some of these may be late events in endometrial carcinogenesis and may not be suitable for screening. Telomerase is expressed by normal cycling endometrium (342) and preferentially expressed in most malignant tissues, including endometrial carcinoma (343,344). It has been cited as a possible marker for endometrial hyperplasia and carcinoma in postmenopausal women because activity is normally absent or weak in postmenopausal atrophic endometrium (343,345,346,347,348).
Microsatellite instability (MSI) and immunohistochemistry are other molecular markers that may have potential in predicting the development of endometrial cancer in HNPCC-positive women (349,350,351). MSI may occur in as many as 75% of HNPCC- and LS-related (352,353,354,355) and 33% of sporadic endometrial tumors (353,355,356,357,358). DNA methylation has also been implicated in sporadic endometrial cancer and is the cause of MSI in these tumors (359). Endometrial hyperplasia has been shown to demonstrate MSI and to precede endometrial cancer (349,350). MSI was demonstrated in cases of endometrial cancer but not in women with normal endometrium in a pilot study (360).
DNA for molecular analysis is possible on a sample of endometrial cells obtained from pipelle (blind biopsy) (360), cervical smears (361), and even noninvasively from tampons and sanitary towels (362,363). The yield of DNA using pipelle endometrial biopsy has been found to compare well with the recovery rates of DNA from stool samples (364). The ability to obtain sufficient DNA for analysis was not found to be affected by the time of the menstrual cycle, but extraction was less effective if the sample was heavily blood stained (360).DNA screening may well serve as a useful adjunct to screening protocols in the future, but further research is needed before this can be achieved.
Other Serum Biomarkers
A host of serological markers has been investigated for a role in endometrial cancer such as CA125, CEA, SCC, CA15-3, CA125, CA19-9, CA72-4, CASA AST, ALT, SAP, gamma-GT, OVX1 antigen, CYFRA 21-1, placental protein 4, UGF, and M-CSF. However, none of them has a well-established role in screening or clinical management. Preliminary data recently suggested YKL-40 as a promising new marker for detection and prognosis (365). Proteomic studies using mass-spectrometric technologies have identified a panel of promising biomarkers including pyruvate kinase, chaperonin, and alpha-1-antitrypsin, which give a high sensitivity (0.85-0.95), specificity (0.93-0.95), and PPV (0.88-0.95) for endometrial cancer (366,367). However, these observations require further validation, and their clinical value remains to be determined.
Until the ideal tumor marker for endometrial cancer is described, screening tests will continue to be characterized by low false negative but high false positive rates. Although screening is inappropriate for the general population, a strategy of early evaluation of postmenopausal bleeding with judicious use of hysteroscopy and endometrial biopsy is important for the early detection of endometrial cancer.
Cervical cancer is the major cause of death from gynecological cancer worldwide, with most deaths occurring in the developing world. More than 90% of the cases of carcinoma in situ occur in women under 45, with the peak incidence being in the 25 to 29 age group. In contrast, the occurrence of invasive cervical cancer is fairly evenly spread across age groups older than 25, with approximately 42% to 46% occurring in the reproductive age (22,368).
Screening for cervical cancer is one of the most prevalent and successful public health measures for the prevention of cancer. Protection against cervical cancer offered by cervical screening ranges from approximately 60% to 85% (8). It is slightly lower in the age group younger than 40 than older than 40. Primary screening has traditionally involved a repetitive exfoliative cytology-based program with colposcopy as a second-line test. This has led to a significant decrease in cervical cancer incidence in the United Kingdom and the rest of the Western world. It has been suggested that an overall coverage of 80% can potentially decrease associated mortality rates by 95%. Although cytological screening may be less effective against cervical adenocarcinoma (15% of cervical cancers), it does have a substantial impact even in this subgroup. An audit of smear histories in women younger than 70 years with cervical cancer revealed that 49% occurred despite adequate cytological screening and follow-up in the 5 years before diagnosis (369). Although cervical cancer is a preventable disease and completely curable if detected at an early stage, cytological screening alone may not eradicate the disease.
Sensitivity and specificity of cervical cytology has been reported to range between 30% to 87% and 86% to 100%, respectively (370). The traditional method of obtaining cytological specimens—the Papanicolou smear—is being replaced by liquid-based cytology (LBC) in a number of centers (371). Several LBC systems such as SurePath, ThinPrep, Cytoscreen, and Labonard Easy Prep are commercially available. LBC leads to the preparation of more homogenous easier-to-read slides and a more efficient automated laboratorysample -handling process, resulting in increased productivity. However, LBC lacks formal criteria used for defining smear adequacy. Data suggest that compared to Pap smears, LBC is associated with increased sensitivity for abnormal smears and fewer inadequate or unsatisfactory smears (371). An English pilot study reported increased sensitivity of 2.8% to 12% and an 87% reduction in inadequate smears from 9% to 1.6% with LBC while maintaining specificity. It also found a reduction in the glandular neoplasms detected from 0.08% to 0.04%, though follow-up data showed no change in the number of adenocarcinomas (371). The sensitivity for low-grade smears may be higher than high-grade ones. A number of systematic reviews have advocated a preference for LBC (372,373,374), whereas others have found no difference between LBC and conventional Pap smears (375,376). A recent metaanalysis of all studies using colposcopic-directed biopsy as the gold standard found that sensitivity and specificity of LBC was not significantly different from Pap smears (377).
Human Papilloma Virus DNA
A well-established causal link has been found between HPV and all grades of cervical intraepithelial neoplasia (CIN) and invasive cervical cancer (166,378). HPV DNA has been found in 99.7% of cervical cancers, and cancer can develop 5 to 30 years after the primary infection. There is considerable worldwide variation in the distribution of high-risk viral types, but approximately 70% of cancers have been linked to HPV types 16 and 18 (379,380,381). Low-risk HPV types 6 and 11 are responsible for genital warts, low-grade cervical lesions, and respiratory papillomatosis. Multiple infections may be more common below age 30 but less common between ages 30 and 64 (381).
Recent systematic reviews and metaanalyses have shown that HPV DNA testing can accurately pick up treatment failures earlier, and its performance can exceed that of cytological follow-up (382,383,384). High-risk HPV DNA testing has been shown to have a higher sensitivity but slightly lower specificity (of the order of 8% to 12%) than cytology alone for detecting high-grade disease (382). A combination of HPV testing and cytology is associated with an even higher sensitivity (382) and may save additional years of life at reasonable costs compared with cytology testing alone (385). Modeling studies show that a screening strategy of HPV DNA testing and cytology every 2 to 3 years provides a greater reduction in cancer and is less costly than annual conventional cytology (386). Women who test negative for high-risk HPV DNA and have a normal cytology are extremely unlikely to develop CIN or cancer in the next 5 to 10 years (387,388). High-risk HPV-DNA-negative women with a smear that is borderline or shows atypical squamous cells of undetermined significance (ASC-US) have a <2% risk of high-grade CIN or cancer in the next 2 years, which is similar to women with a negative smear (389). A positive high-risk HPV DNA test in the presence of a severely dyskaryotic smear and high-grade disease at colposcopy suggests a 60% to 80% risk of CIN 3 or worse in the next 2 years (390,391).
HPV DNA testing has been recommended in triaging ASC-US (Atypical squamous cells of undetermined significance) cytology or borderline smears, predicting posttreatment recurrence risk, and the identification of women with abnormal cytology and low-grade histology needing postcolposcopic follow-up (371,392,394). It helps identify a group of women who are more likely to develop high-grade CIN or cancer. The value of HPV typing may be further increased by subtyping because some variants of HPV 16 confer a 6.5-fold increase in risk of CIN 2 or CIN 3 compared with other HPV 16 variants (395). Thus, compared to cytology alone, high-risk HPV testing can improve risk stratification and increase the efficiency of cervical cancer screening. However, it may not be as effective in adolescent women because of a low PPV resulting from a high prevalence of HPV infection and a low incidence of progressive precancerous lesions in this age group (396,397). High-risk HPV DNA testing has been incorporated into the recently published 2006 consensus guidelines adopted by the American Society for Colposcopy and Cervical Pathology and has been recommended as a co-test with cytology for routine screening in women older than 30(392,393).
Other Screening Strategies
Various other strategies such as naked eye visual inspection of the cervix after application of acetic acid (VIA), visual inspection after Lugol's iodine (VILI), visual inspection with a magnifying glass (VIAM), and HPV DNA testing are emerging as effective screening options, especially for developing countries that have limited resources and lack established efficient screening programs. A recent metaanalysis (398) of five screening strategies from 11 studies involving 58,000 women showed that VIA, VILI, and VIAM had a high sensitivity (79%) and specificity (85%) for high-grade disease. Pap smears had a lower sensitivity (57%) but higher specificity (93%). A large RCT showed that the VIA-based screening strategy is effective and can lead to decreased mortality in the screened arm (high risk of 0.65) (399). However, sensitivity reported with strategies such as VIA may be slightly inflated because of a gold standard (colposcopic-directed biopsy) misclassification error (400).
DNA Imaging Cytometry
DNA imaging cytometry is a novel, automated slide-reading method that measures the amount of DNA in the cell nuclei using an automated image cytometer, thus minimizing the need for skilled cytotechnologists. Preliminary data suggest that it can successfully detect high-grade lesions (401,402). When combined with conventional cytology and HPV DNA testing as part of a multimodal strategy, it was found to increase PPV and the identification of low-grade lesions likely to progress (403). Hyperspectral imaging, which uses novel algorithms for spectral and spatial differences to distinguish among normal, precancerous, and cancerous cells, is also being investigated (404).
Although telomerase expression is reported to be a discriminatory marker of premalignant and malignant squamous cell lesions, its clinical utility is still under evaluation. It was detected in as much as 100% of cervical cancer and 62% to 96% of high-grade CIN specimens (347,405,406): 88% to 100% of invasive smears and 40% to 59% of abnormal cytologyic specimens in women with CIN (407,408,409,410) as well as in five cases of CIN with no cytological abnormality (411). However, conflicting data showing poor (4.5% to 25%) sensitivity for high-grade CIN (405,409) and increased expression in 46% to 56% benign lesions have also been reported (347,412,413). A recent systematic review of ten studies reported the diagnostic odds ration of a positive telomerase test to be 3.2 (1.9, 5.6) for low-grade squamous intraepithelial lesion (LSIL), 5.8 (3.1, 10) for high-grade squamous intraepithelial lesion (HSIL), 8.1 (3.1, 20.3) for cervical cancer versus HSIL, and 40.9 (18.2, 91) for cervical cancer versus LSIL. The catalytic subunit of telomerase protein-human telomerase reverse transcriptase is the rate-limiting determinant of telomerase activity. It has also shown promise in determining high-grade CIN in cervical screening and predicting progressive disease (414,415).
Another approach that has been investigated for reducing the false negative rate of cytology includes immunostaining of smears using antibodies against proteins that regulate DNA replication such as CDC6 and MCM5 (416). Recently, a combination of LR67 and VEGF-C have also been found to be of value in detecting high-grade CIN, but this needs further evaluation and validation in cytological samples before they can be considered for screening purposes (417).
No serological markers have been found to be sufficiently sensitive (especially for early-stage cervical cancer) or specific for screening purposes. However, a variety of serum markers have been investigated in assessing prognosis, monitoring response to treatment, and detecting recurrence.
One of the established strategies for combating cancer in the twenty-first century is screening the asymptomatic population for premalignant conditions and early-stage disease. The effectiveness of ovarian cancer screening is being addressed by ongoing research trials both in the high and low-risk populations. These trials are expected to report by 2012-14. Screening outside the context of research trials is not recommended. Despite the vast number of serum markers studied, only a few have been validated for clinical use and limited sensitivities/specificities constrain their use for screening purposes. Serum CA125 remains clinically the most widely used marker for epithelial ovarian cancer. New imaging technologies and related algorithms may serve as useful adjuncts in distinguishing benign from malignant adnexal masses. Given the heterogeneity of cancer, a combination of modalities such as risk of ovarian cancer algorithm, transvaginal ultrasonic pattern recognition and multiple marker models may provide maximum advantage. Genomic, epigenetic, metabolomic and proteomic technologies hold tremendous promise for the future. However, they require further research and validation before this promise is realized.
Screening for endometrial cancer in the low-risk population is not recommended. The ideal method for screening asymptomatic high-risk women has not been established. While a number of molecular markers and biomarkers are under investigation for screening purposes, none has made it to clinical practice.
Well established, effective cytologic/colposcopic based screening programs for cervical cancer exist in the developed world. Significant changes have occurred over the last few years such as the introduction of liquid based cytology (LBC) and HPV DNA testing. Newer methods such as VIA/VILI/VIAM/HPV DNA testing hold potential for the developing world. No serological markers have been found to be effective in screening for cervical cancer. Despite the availability of HPV vaccination and its promise for the future, there are still a number of unresolved issues, and an effective screening program will remain the cornerstone of any preventive strategy for cervical cancer for many years to come.
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