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Advances in the Screening, Diagnosis, and Treatment of Cervical Disease Cervical Cancer • • • • Second most common cancer among women worldwide1 The American Cancer Society estimates that in 2002, ~13,000 new cases of invasive cervical cancer will be diagnosed in the United States, with about 4,100 deaths2 . In 2001, the estimates were ~ 12,900 cases and 4,500 deaths. 75% decreased incidence and 73% decreased mortality since Pap screening began in 1949 However, cervical cancer mortality has not declined in the US since the 1980s 3 1. Walboomers et al. J Pathol. 1999;189:12-19. 2. American Cancer Society, Cancer Facts & Figures 2002. 3. Chu KC et al. Cancer. 1999;86:157-169. Cervical Cancer Statistics Years Description U.S. Statistic 1998 Death rate from cervical cancer2 2000 Cervical cancer deaths2 ~ 4,600 2001 Cervical cancer deaths1 ~ 4,400 1955 - 1992 Change in the number of cervical cancer deaths1 74% 1973 - 1981 Annual change in invasive cervical cancer mortality3 4.6% 1981 - 1998 Annual change in invasive cervical cancer mortality3 1.6% 1992 - 1998 Incidence of invasive cervical cancer (overall) 3 8.7 per 100,000 women 1992 - 1998 Incidence of invasive cervical cancer by race: 3 White Black Asian/Pacific Islander American Indian/Alaskan National Hispanic 8.1 per 100,000 women 11.0 per 100,000 women 10.3 per 100,000 women 6.4 per 100,000 women 14.4 per 100,000 women 1973 - 1981 Annual change in invasive cervical cancer incidence3 4.8% 1981 - 1998 Annual change in invasive cervical cancer incidence3 1.1% 2000 New diagnoses of cervical cancer2 ~ 12,800 2001 New diagnoses of cervical cancer1 ~ 12,900 3.0 per 100,000 women U.S. Trends in Cervical Cancer Morbidity and Mortality 20,000 15,000 10,000 5,000 1970 1975 1980 1985 1990 1995 Year Source: National Cancer Institute’s Surveillance, Epidemiology and End Results (SEER) data, American Cancer Society 2001. SEER Trends in North American Incidence of Cervical Adenocarcinoma 0.30 0.25 Black, USA 0.20 White, USA 0.15 Canada 0.10 Hispanic, USA 0.05 0 1930 1940 1950 Year of Birth Source: Vizcaino AP et al. Int J Cancer.1998;75:536-545. 1960 Risk Factors Associated With Precancerous Changes and Cancer of the Cervix • Human papillomavirus (HPV) infection • Sexual activity: multiple partners; begun at an early age • Parity • Human immunodeficiency virus (HIV) • Immunosuppressed status • Smoking • History of other sexually transmitted diseases –e.g., Herpes simplex, Chlamydia, bacterial vaginosis • Oral contraceptive use • Low socioeconomic status • Poor diet–e.g., vitamin deficiency • Alcoholism Cervical Epithelium Showing Progressive Degrees of Dysplasia and Neoplasia LSIL Koilocytosis Basement membrane Normal squamous epithelium HSIL CIN1 Mild CIN2 CIN3 Moderate Severe Carcinoma in situ Dysplasia Natural History of Cervical Lesions Biopsy Result Regress Persist Progress to CIS Progress to Invasion CIN1 57% 32% 11% 1% CIN2 43% 35% 22% 5% CIN3 32% <56% Source: ÖstÖr AG. Int J Gynecol Pathol. 1993;12(2):186-192. -- >12% Natural History of Cervical Lesions Pap Diagnosis Regress to Normal (95% CI) Progress to/ Persist as HSIL in 24 months (95% CI) Progress to Invasive Cancer in 24 months (95% CI) ASCUS 68.19% (57.51, 78.86) 7.13% (0.8, 13.5) 0.25% (0, 2.25) LSIL 47.39% (35.92, 58.86) 20.81% (6.08, 35.55) 0.15% (0, 0.71) HSIL 35.03% (16.57, 53.49) 23.37% (12.82, 32.92) 1.44% (0, 3.95) Source: Melnikow J et al. Obstet Gynecol. 1998;92(4Pt2):727-735. Progression and Regression of Cervical Lesions Grade of Dysplasia Within 2 years Within 5 years Within 10 years Progression Mild to moderate or worse Mild to severe or worse Moderate to severe or worse 11.1% 2.1% 16.3% 20.4% 28.8% 5.5% 25.1% 9.9% 32.0% 74.0% 63.1% 39.1% 29.0% 87.7% 82.9% 62.2% 53.7% Regression Mild to first normal Pap 44.3% Moderate to first normal Pap 33.0% Mild to second normal Pap 8.7% Moderate to second normal Pap 6.9% Source: Holowaty P et al. J Natl Cancer Inst. 1999;91(3):252-258. Mean Age at Diagnosis of Cervical Lesions Diagnosis Mean Patient Age (Years) Predominant Patient Status Second Most Prevalent Patient Status Carcinoma 56.4 Postmenopausal (61.9%) Premenopausal (32.4%) HSIL 33.8 Premenopausal (72.2%) Postmenopausal (10.7%) LSIL 30.8 Premenopausal (74.4%) Pregnant (10.2%) Glandular Intraepithelial Lesion 48.2 Premenopausal (50.3%) Postmenopausal (38.5%) Source: Jones BA et al. Arch Pathol Lab Med. 2000;124:665-671. Cervical Cancer Screening Guidelines: American Cancer Society • All women should have yearly Pap smears starting at age 18 or when they begin having sex, whichever occurs first • The doctor may decide to do the test less often if a woman has had 3 normal tests in a row • If a hysterectomy was done for cancer, more frequent Pap tests may be recommended • Women who have had their uterus removed and those past menopause still need to have regular Pap tests Bethesda System 2001 Specimen Type: Indicate conventional Pap smear vs. liquid-based vs. other Specimen Adequacy • Satisfactory for evaluation (describe presence or absence of endocervical/transformation zone component and any other quality indicators--e.g., partially obscuring blood, inflammation, etc.) • Unsatisfactory for evaluation (specify reason) – Specimen rejected/not processed (specify reason) – Specimen processed and examined, but unsatisfactory for evaluation of epithelial abnormality because of (specify reason) Bethesda System 2001 (continued) General Categorization (optional) • Negative for intraepithelial lesion or malignancy • Epithelial cell abnormality: See interpretation/result (specify “squamous” or “glandular” as appropriate) • Other: See interpretation/result (e.g., endometrial cells in a woman 40 years of age) Automated Review: If case examined by automated device, specify device and result Ancillary Testing: Provide a brief description of the test methods and report the result so that it is easily understood by the clinician Bethesda System 2001 (continued) Interpretation/Result • Negative for Intraepithelial Lesion or Malignancy (when there is no cellular evidence of neoplasia, state this in the General Categorization above and/or in the Interpretation/Result section of the report, whether or not there are organisms or other nonneoplastic findings) Organisms – Trichomonas vaginalis – Fungal organisms morphologically consistent with Candida spp – Shift in flora suggestive of bacterial vaginosis – Bacteria morphologically consistent with Actinomyces spp. – Cellular changes consistent with Herpes simplex virus Other Non-Neoplastic Findings (optional to report; list not inclusive): – Reactive cellular changes associated with • Inflammation (includes typical repair) • Radiation • Intrauterine contraceptive device (IUD) – Glandular cells status post hysterectomy – Atrophy Bethesda System 2001 (continued) • Other (list not inclusive) – Endometrial cells (in a woman 40 years of age) (specify if ‘negative for squamous epithelial lesion’) • Epithelial Cell Abnormalities – Squamous Cell • Atypical squamous cells – Of undetermined significance (ASC-US) – Cannot exclude HSIL (ASC-H) • Low-grade squamous intraepithelial lesion (LSIL) – Encompassing: HPV/mild dysplasia/CIN1 • High-grade squamous intraepithelial lesion (HSIL) – Encompassing: moderate and severe dysplasia, CIS/CIN2 and CIN3 – With features suspicious for invasion (if invasion suspected) • Squamous cell carcinoma Bethesda System 2001 (continued) – Glandular Cell • Atypical – Endocervical cells (NOS* or specify in comments) – Endometrial cells (NOS or specify in comments) – Glandular cells (NOS or specify in comments) • Atypical – Endocervical cells, favor neoplastic – Glandular cells, favor neoplastic • Endocervical adenocarcinoma in situ • Adenocarcinoma – Endocervical – Endometrial – Extra uterine – NOS – Other Malignant Neoplasms: (specify) * NOS = Not otherwise specified Bethesda System 2001 (continued) Educational Notes and Suggestions: (optional) Suggestions should be concise and consistent with clinical follow-up guidelines published by professional organizations (references to relevant publications may be included) Bethesda 2001 Changes • • • • • • Satisfactory: Liquid-based—minimum 5,000 epithelial cells; presence of epithelial cell abnormality “SBLB” eliminated Unsatisfactory: specimen rejected/not processed; or specimen processed/examined, but unsatisfactory because of (specify reason) WNL and BCC are now Negative for Intraepithelial Lesions or Malignancy; includes BCC (e.g., organisms and reactive changes) as descriptor only The multiple subcategories of ASCUS have been reduced to ASCUS or ASC-H, with no other modifiers The subcategories of AGUS (now AGC) have been expanded to allow for a more descriptive diagnosis of glandular abnormalities; AIS is now a distinct subcategory The Bethesda System 2001 • LSIL = HPV / mild dysplasia / CIN1 • HSIL = moderate and severe dysplasia / CIS / CIN2 and CIN3 • ASCUS = ASC-US (undetermined significance) or ASC-H (cannot exclude HSIL) Annual Number of Women with Abnormal Pap Results in the US Cancers 12,800 HSIL LSIL AGC ASC Source: J. Thomas Cox, with permission. 300,000 1.25 million 180,000-300,000 2 - 3 million Sensitivity of the Pap Smear Mean Sensitivity of Conventional Pap Smear (%), 95% CI 1. Agency for Health Care Policy and Research (AHCPR). Evaluation of Cervical Cytology. 1999. 2. Fahey MT et al. Am J Epidemiol. 1995;141:680-689. Two Types of Screening Conventional Pap Smear • Cervical cell sample manually “smeared” onto slide for screening Liquid-Based • Cervical cell sample put into liquid medium for suspension before automated thin layer/monolayer slide preparation – ThinPrep® 2000 System – SurePathTM (formerly AutoCyte® PREP) Overcoming the Inherent Limitations of the Conventional Pap Smear Conventional Pap Smear Majority of cells not captured Non-representative transfer of cells Clumping and overlapping of cells Obscuring material Liquid-based Cytology* Virtually all cells of sample are collected Randomized, representative transfer of cells Even distribution of cells Minimizes obscuring material * From ThinPrep Sampling Study, Hutchinson 1994 Overview of Liquid-Based Cytology: FDA Labeling SurePath™ ThinPrep® Pap Test • Used as a replacement for the conventional Pap smear • Used as a replacement for the conventional Pap smear • Specimen quality is significantly improved over that of the conventional Pap smear in a variety of patient populations • Significantly fewer Unsatisfactory and SBLB cases as compared to the conventional Pap smear • Significantly more effective than the conventional Pap smear for the detection of low-grade and more severe lesions in a variety of patient populations • • Specimens should be collected using a broom-type • or endocervical brush/spatula combination collection device Provides similar results to the conventional Pap smear (data from a prospective split-sample comparison in a variety of patient populations and laboratory settings) • Specimens should be collected using a broom-type sampling device • Increased HSIL+ detection by 59.7% (data from a multi-site, historical control study) • Approved as a specimen medium for HPV DNA testing using Digene Hybrid Capture® 2, as well as for chlamydia and gonorrhea screening ThinPrep® Pap Test Package Insert, Cytyc Corporation AutoCyte PREPTM SYSTEM package insert (now SurePathTM), TriPath Imaging, Inc. HSIL+ Clinical Outcomes Trial • Direct-to-vial study to evaluate ThinPrep 2000 vs. conventional Pap for the detection of high-grade squamous and more severe lesions (HSIL+) • 10 metropolitan academic hospitals, two groups of subjects per site: – Routine screening population – Referred for colposcopy • ThinPrep specimens (n = 10,226) collected prospectively compared to historical control cohort (n = 20,917) • These sites demonstrated a 59.7% (p < 0.001) increase in detection of HSIL+ lesions for ThinPrep specimens HPV Testing – Essential Facts • • • • • HPV is the major etiologic agent for cervical cancer HPV detection is associated with an increased risk of high-grade CIN Essentially all women with CIN3 have detectable HPV DNA Persistent infection with high-risk HPV is necessary for development and maintenance of CIN3 HPV testing helps to clarify ambiguous cytology results and identifies persistent infection in women over 30 HPV Risk Types Hybrid Capture®2 (HC II) HPV DNA Test uses two RNA Probe cocktails to differentiate between carcinogenic and low-risk HPV types: Low-risk 6 11 42 43 44 High-risk 16 18 31 33 35 39 45 51 52 56 58 59 68 30 30 25 25 20 20 15 15 10 10 5 5 0 0 Cancer incidence per 100,000 HPV Prevalence (%) HPV Prevalence and Cervical Cancer Incidence by Age 1,2 15-19 20-24 25-29 30-34 35-39 40-44 45-49 50-54 Age (Years) 1. Sellors et al. CMAJ. 2000;163:503. 2. Ries et al. Surveillance, Epidemiology and End Results (SEER) Cancer Stats NCI, 1973-1997. 2000. Incidence of Atypical Findings Pap Smear Cytology Incidence (Manos et al) Incidence (Chhieng et al) Incidence (Stoler) HSIL 0.3% SIL+ 2.5% 0.51% LSIL 0.9% -- 1.97% ASCUS 3.5% 5.7% 2.8% AGUS 0.5% 0.5% -- 1. Manos MM, Kinney WK, Hurley LB, et al. J Am Med Assoc 1999;281(17):1605-1610. 2. Chhieng DC, Elgert PA, Cangiarella JF, et al. Acta Cytol 2000;44(4):557-566. 3. Stoler MH. Mod Pathol 2000;13(3):275-284. Comparison of HPV Testing and Repeat Pap in the Management of ASCUS Triage Strategy Referred to Sensitivity Colposcopya for HSIL+ PPV for HSIL+ Based on HPV Test b 39.5% 89.2% 15.1% Based on Repeat Pap Resultc 38.9% 76.2% 12.9% PPV = positive predictive value Notes: a. Prevalence of positive test result in women with ASCUS b. Referral to colposcopy based on positive DNA test for high-risk HPV types, from specimen on initial visit c. Referral to colposcopy based on repeat Pap test result of ASCUS or more severe Source: Manos et al, JAMA. 1999;281(17):1605-1610. ALTS Study Design • Randomized trial sponsored by NCI, 1995-2001 • Enrolled 3488 women with community-based ASCUS and 1572 with LSIL results, randomized to three management arms: – Immediate colposcopy – HPV triage – Repeat cytology • Clinical follow-up every 6 months for 2-year period • LSIL arm discontinued due to limited utility of positive test result Source: Solomon D et al. J Natl Cancer Inst. 2001;93:293-299. Sensitivity for CIN2+ by HC II & Pap by Age Clinical Center Pap Cutpoint 18-22 %(+) / Sens 23-28 %(+) / Sens 29+ %(+) / Sens HC II 71 / 98 65 / 96 31 / 94 ASCUS+ 66 / 83 63 / 88 50 / 87 Sherman M, Schiffman M, Cox JT. J Nat Cancer Inst. 2001 Risk of CIN 2/3+ for ASC referral Based on HPV status at enrollment HPV Positive HPV Negative Cox 1995 17% (14/81) 0.74% (1/136) 6.9% (15/217) Manos 1999 15% (45/300) 1.2% (6/498) 6.4% (51/801) ALTS 2001 20.1% (136/651) 1.1% (6/541) 11.9% (142/1192) Total 17.9% (195/1087) 1.1% (13/1175) Cox JT, et al. Am J Obstet Gynecol. 1995 Mar;172(3):946-54. Solomon D, et al. J Natl Cancer Inst. 2001;93:293-299. Manos et al, JAMA. 1999;281(17):1605-1610. Total risk ASCUS 9.4% (208/2210) Primary Findings: ALTS Management Modality Colposcopy Sensitivity %* Referral % PPV % NPV % 100 100 11 100 HPV 96 56 20 99 Cytology ASC-US+ 85 59 17 96 Cytology LSIL+ 59 26 26 94 Cytology HSIL+ 35 8 58 92 PPV = positive predictive value; NPV = negative predictive value *For detection of (CIN2+) Adapted from table 5, Solomon D et al. J Natl Cancer Inst. 2001;93:293-299. ASCCP Consensus Guidelines for the Management of Abnormal Cervical Cytology and Cervical Cancer Precursors • • • • Held in Sept. 2001, NCI campus, 29 national and international organizations including ACS, NCI, CDC, ACOG, all the major cytopathology organizations, etc. The guidelines were all evidence-based (to the limits of the literature) They were placed on the Consensus Guidelines Website twice during the 6 months prior to the conference for public comment and appropriate revisions were made All of the guidelines were approved by a majority and most were approved by 70-90% AGC Findings from 306 Laboratories Participating in CAP Survey 2000 AGC Rate SIL AIS CA 0.3% 40% 5.8% 5.5% Jones BA, Novis DA. Follow-up of abnormal cervical cytology: a College of American Pathologists Q Probes Study of 16,132 cases from 306 laboratories. Arch Pathol Lab Med. 2000;124:672-681. (1-C) Clinical Significance of an AGC Pap Qualifier Any High-grade Lesion High-grade Glandular Lesion Only AGUS reactive 5 – 39% 1 – 8% AGUS NOS 9 – 41% 0 – 15% 27 – 96% 10 – 93% AGUS neoplastic Source: Richart et al. Contemp Ob Gyn. 2001; 46:15-17,25-28,30-32,35-43. Management of AGC Management of LSIL: Special Circumstances • Mod: Abnormal Pap-fig 6 Management of HSIL • Mod: Abnormal Pap-fig 8 Candidates for Ablative or Excisional Therapy Patients who are suitable for ablative therapy have: • • • • The entire transformation zone visualized (satisfactory colposcopy) No suggestion of microinvasive or invasive disease No suspicion of glandular disease Corresponding cytology and histology Patients in whom excisional treatment is mandatory have: • • Unsatisfactory colposcopy Suspicion of invasion or glandular abnormality Excisional Techniques Conization • • A cone of tissue is excised for further examination and/or to remove a lesion The tissue is usually stained with iodine (Lugol’s or Schiller’s solution) to demarcate the area of resection – Cold Knife Cone • The use of a scalpel or “cold knife cone” since no electrosurgical current is used – Laser Conization • The use of a laser for excision of a cone of tissue • May be complicated by burn artifacts – LEEP (Loop Electrosurgical Excision Procedure) • The use of a thin electric wire loop, which may have cutting and cautery currents • Different sizes of loop and cautery tip available • May be complicated by burn artifacts Ablative Techniques Cryotherapy • • The use of a probe containing carbon dioxide or nitrous oxide to freeze the entire transformation zone and area of the lesion Different sizes of probe available Laser Vaporization Therapy • • • The use of a laser to vaporize the transformation zone containing the lesion Requires suction to remove smoke Different power levels are available Cervical Cancer: FIGO Nomenclature Stage 0: Carcinoma in situ, cervical intraepithelial neoplasia Grade III Stage I: The carcinoma is strictly confined to the cervix (extension to the corpus would be disregarded). Stage II: Cervical carcinoma invades beyond the uterus, but not to the pelvic wall or lower third of the vagina. Stage III: The carcinoma has extended to the pelvic wall. On rectal examination, there is no cancer-free space between the tumor and the pelvic wall. The tumor involves the lower third of the vagina. All cases with hydronephrosis or nonfunctioning kidney are included, unless they are known to be due to other causes. Stage IV: The carcinoma has extended beyond the true pelvis, or has involved (biopsy-proven) the mucosa of the bladder or rectum. A bullous oedema, as such, does not permit a case to be allotted to Stage IV. Cervical Cancer: Outcomes by FIGO Stage FIGO Stage 1. 2. 3. 5-Year 5-Year Recurrence Treatment Survival Treatment Survival (Einhorn3) (Morrow et al1) (FIGO reports – Benedet2) Stage I 82% 85% 76 – 90% Stage II 61% 66% 50 – 70% Stage III 37% 39% 30 – 35% Stage IV 12% 11% 10 – 15% Morrow CP et al. In: Morrow CP, Curtin JP (eds). Synopsis of Gynecologic Oncology, 5th ed. 1998. Benedet JL. Int J Gynecol Obstet. 2000;70(1):135-147. Einhorn N. Acta Oncol. 1996;35(2Suppl7):75-80. Cervical Screening Summary • • • • HPV is common and present in almost all cervical cancers New screening technologies, specifically ThinPrep, provide an increase in detection of LSIL, HSIL, an improved specimen, and reflex HPV testing New Bethesda nomenclature plus the results of the ALTS trial spurred new guidelines which provide an evidence-based approach to managing the problematic ASC-US Pap result Reflex HPV testing is an efficient way to manage the ASC-US Pap test result, specifying who is at risk and in need of immediate colposcopy Additional Information For a complete review of terminology and guidelines, go to: Bethesda 2001: www.bethesda2001.cancer.gov ASCCP Consensus Guidelines: www.asccp.org Solomon D, Davey D, Kurman R, et al, for the Forum Group Members and the Bethesda 2001 Workshop. The 2001 Bethesda System: terminology for reporting results of cervical cytology. JAMA. 2002;287:2114-2119.