Screening for Cervical Cancer Dr. Shanthi Manivannan, MD

Cervical cytology screening is a method that detects preinvasive as well as invasive cellular changes in the cervix.The long preinvasive state and effective treatment allows screening to potentially prevent the occurrence of cervical cancer

Screening for Cervical Cancer Objectives Introduction Introduction Risk factors Risk factors Techniques Techniques Cervical Cytology report Cervical Cytology report Management of abnormal PAP smears and HPV testing Management of abnormal PAP smears and HPV testing USPSTF and ACOG guidelines USPSTF and ACOG guidelines

Introduction Cervical cancer: 6% of all cancers in women Cervical cancer: 6% of all cancers in women In US, incidence estimated at 11,150 new cases in 2007 In US, incidence estimated at 11,150 new cases in 2007 –*American Cancer Society - Cancer Facts & Figures In US, deaths estimated at 3,670 deaths in 2007 (1.4% cancer related deaths in women) In US, deaths estimated at 3,670 deaths in 2007 (1.4% cancer related deaths in women) –*Statistics from Natl. Cancer Institute Global disparity in incidence and mortality Global disparity in incidence and mortality –*Global Cancer Statistics. CA Cancer J Clin. 1999; 49(1):33-64

Global Disparity Decrease in incidence of cervical cancer in US Decrease in incidence of cervical cancer in US Second most common cancer in developing countries Second most common cancer in developing countries *CA Cancer J Clin. 1999, 49(1): *CA Cancer J Clin. 2005, 55(2):74-108

Falling incidence of Invasive Cervical Cancer Reduction in incidence is primarily due to population based screening programs leading to early detection and treatment of pre-invasive disease Reduction in incidence is primarily due to population based screening programs leading to early detection and treatment of pre-invasive disease *Prev Med. 2007;45(2-3)

Age and Cervical Cancer Invasive cervical Cancer Invasive cervical Cancer –Under 20: 0/100,000 /yr –20-24: 1.7/100,000 –45-49: 16.5/100,000 –Mean age: 47 yrs *seer.cancer.gov/csr/ /cervix.pdf Protracted pre-invasive state Peak incidence of Cervical intraepithelial neoplasia (CIN) is yrs

Nomenclature Cervical intraepithelial neoplasia (CIN) refers to the preinvasive state of invasive cervical cancer, confined to superficial epithelial layer Cervical intraepithelial neoplasia (CIN) refers to the preinvasive state of invasive cervical cancer, confined to superficial epithelial layer Mild, moderate, severe dysplasia and carcinoma in situ although still used, have been replaced by CIN Mild, moderate, severe dysplasia and carcinoma in situ although still used, have been replaced by CIN

Nomenclature CIN I, CIN II, CIN III indicate varying thickness of the involved epithelium and are findings on HISTOLOGY CIN I, CIN II, CIN III indicate varying thickness of the involved epithelium and are findings on HISTOLOGY The cervical cytology smear refers to characteristics of the cells collected from a cervical and or vaginal smear when a cervical cytology screening procedure is performed. The cervical cytology smear refers to characteristics of the cells collected from a cervical and or vaginal smear when a cervical cytology screening procedure is performed.

Bethesda 2001 Classification Terminology Cytology Histological Correlates LGSIL CIN I Mild dysplasia HGSIL CIN II / CIN II Moderate dysplasia / Severe dysplasia / carcinoma in-situ

High Risk Group Early onset of sexual activity Early onset of sexual activity Multiple sexual partners and high risk partners Multiple sexual partners and high risk partners H/O STD (Chlamydial infn, JAMA 2001) H/O STD (Chlamydial infn, JAMA 2001) H/O Smoking (J.Natl. Can Inst, 2002) H/O Smoking (J.Natl. Can Inst, 2002) Multiparity (Lancet, 2002) Multiparity (Lancet, 2002) Immunosuppression and HIV infection Immunosuppression and HIV infection Low socioeconomic status Low socioeconomic status

Genital HPV infection Very strong association Very strong association Incidence of HPV infection in Incidence of HPV infection in –CIN I (70-78%) – CIN II/III (83-89%) –invasive squamous cell cancer (95%) –adeno/adenosquamous cancer (90%) –16% in controls *J Natl Cancer Inst 2006; 98:303 *JAMA 2000;283:81 *JAMA 1999;281:1605

HIV infection and Cervical Cancer Incidence of colposcopically confirmed CIN higher in HIV positive women (20% vs 4%) Incidence of colposcopically confirmed CIN higher in HIV positive women (20% vs 4%) Higher with progressive immune suppression Higher with progressive immune suppression Younger at presentation Younger at presentation Rapid progression Rapid progression Related to higher incidence and persistence of HPV infection Related to higher incidence and persistence of HPV infection *Obstet Gynecol 1994;84(4):591 *JAMA 2000;283(8):1413

Technique

Pelvic Examination Get all your equipment before starting the procedure: Get all your equipment before starting the procedure: –Good light source –Speculum of appropriate size (metal or plastic disposable) –Materials for PAP smear (extended tip spatula, endocervical brush, liquid medium) –Culture medium to test for infection

Pelvic Examination Equipment (continued) Equipment (continued) –Large cotton swabs –Q-tips (two) and test tubes with NaCl and KOH solution –Hemoccult cards –Gloves –Water soluble lubricants

Pelvic Examination Patient should be in Lithotomy position. Examine the external genitalia including skin, labia majora and minora, clitoris, introitus, urethral meatus Patient should be in Lithotomy position. Examine the external genitalia including skin, labia majora and minora, clitoris, introitus, urethral meatus Locate the cervix Locate the cervix Insert the closed speculum after lubrication with warm water at an angle first and then horizontally Insert the closed speculum after lubrication with warm water at an angle first and then horizontally Open the speculum and visualize the cervix Open the speculum and visualize the cervix

Methods Conventional PAP smear Conventional PAP smear Liquid based cytology Liquid based cytology

Conventional PAP Smear Cervix is visualised Cervix is visualised Using Ayre’s spatula / extended tip spatula, cervix is scraped circumferentially Using Ayre’s spatula / extended tip spatula, cervix is scraped circumferentially Endocervical cells are collected with an endocervical brush Endocervical cells are collected with an endocervical brush Cells on the spatula and brush are smeared and rolled onto a slide Cells on the spatula and brush are smeared and rolled onto a slide Cells on slide are fixed with ETOH Cells on slide are fixed with ETOH

Liquid Based Cytology Sample taken with extended tip spatula and endocervical brush or broom Sample taken with extended tip spatula and endocervical brush or broom Sample is transferred to preservative solution Sample is transferred to preservative solution Processed in a “thin prep processor” and a monolayer of cells made on a slide Processed in a “thin prep processor” and a monolayer of cells made on a slide

Thin Prep vs Conventional Prep ThinPrep allows statistically significant increase in cytological diagnosis of cervical cancer precursors ThinPrep allows statistically significant increase in cytological diagnosis of cervical cancer precursors Improved specimen adequacy Improved specimen adequacy Decrease in false negative rates Decrease in false negative rates Subsequent reports have not confirmed this Subsequent reports have not confirmed this *Obstet. Gynecol., 1997;90:

Thin Prep vs Conventional Prep With thin prep: With thin prep: –single specimen can be used for cytology, HPV, GC and Chlamydial testing –Specimen can be stored for a few weeks –Reflex HPV testing can be performed

The Cervical Cytology Report

The Cytology Report Specimen type: Conventional/Thin Prep/Vaginal smear Specimen type: Conventional/Thin Prep/Vaginal smear Specimen adequacy Specimen adequacy –> 5000 sq. cells on thin prep (or) cells on conventional smear and 10 well preserved endocervical or sq. metaplastic cells –Unsatisfactory specimen: repeat in 2-4 m –Treat cervicitis, vaginitis –Repeated unsatisfactory: refer for colposcopy *J Low Genit Tract Dis 2002;6(3):195

The Cytology Report Interpretation Negative for intraepithelial cell abnormality or malignancy Positive for epithelial cell abnormality defined by Bethesda 2001 Classification *JAMA 2002;287(16):214

Bethesda 2001 Classification An expert group of clinicians, researchers and pathologists defined the terminology for reporting various cytological findings in Subsequently, this was revised in 2001 to eliminate and clarify ambiguous terminology An expert group of clinicians, researchers and pathologists defined the terminology for reporting various cytological findings in Subsequently, this was revised in 2001 to eliminate and clarify ambiguous terminology

The Cytology Report/Interpretation Bethesda 2001 Classification Squamous Cell Abnormalities : Squamous Cell Abnormalities : *JAMA 2002;287(16):214 *JAMA 2002;287(16):214 –Atypical Squamous cells of unknown significance (ASC-US) –Atypical Squamous cells / cannot rule out High grade squamous intraepithelial lesion (ASC-H) –Low grade squamous intraepithelial lesion (LSIL) –High grade squamous intraepthelial lesion (HSIL) –Carcinoma

Bethesda 2001 Classification *JAMA 2002;287(16):214 Cytology Histological Correlates LGSIL CIN I Mild dysplasia HGSIL CIN II / CIN II Moderate dysplasia / Severe dysplasia / carcinoma in-situ

The Cytology Report/Interpretation Bethesda 2001 Classification Glandular cell abnormalities Glandular cell abnormalities –Atypical glandular cells (AGC) NOS –Atypical glandular cells, favor neoplasia –Adenocarcinoma in situ (AIS) Indicates presence of glandular cells from endocervical or endometrial origin PAP smear is not a good test with sensitivity 50-72%) *JAMA 2002;287(16):214

Remember! Screening for cervical cancer by Cervical cytology does not make a diagnosis of cancer. It only identifies patients at risk for having precancerous lesions or cancer who should undergo further definitive testing

Management of Abnormal Cervical Cytology

Management of Abnormal Cytology Natural history of precancerous lesions: Substantial number of low grade lesions will spontaneously regress Natural history of precancerous lesions: Substantial number of low grade lesions will spontaneously regress Rates of regression: Rates of regression: –ASCUS: 68% –LGSIL: 47% –HGSIL: 35% *Obstet and Gynecol; 1998, 92:727

Management of Abnormal Cytology Rates of progression to CIN II/III after two years: Rates of progression to CIN II/III after two years: –ASCUS: 7% –LGSIL: 24% –HGSIL: 1.4% to invasive cancer If surgical intervention is performed on everybody, millions of women will undergo the risk of surgery without adequate cause *Am J Obstet Gynecol 2006;195(5):1260

Management of Abnormal Cytology Three million ASCUS findings /year Three million ASCUS findings /year Classified as Classified as – ASCUS: Atypical squamous cells of uncertain significance. 5-17% incidence of precancerous CIN II/III. –ASC-H: Atypical squamous cell / cannot rule out HGSIL % icidence of CIN II/III. *Am J Obstet Gynecol 2006;195(5):1260

Management of Abnormal Cytology Atypical squamous cell of undetermined significance /LSIL triage study (ALTS) conducted by Natl. Cancer Institute from attempted to clarify management of ASCUS and confirmed the utility of HPV testing Atypical squamous cell of undetermined significance /LSIL triage study (ALTS) conducted by Natl. Cancer Institute from attempted to clarify management of ASCUS and confirmed the utility of HPV testing

HPV in Cervical Cancer Genital HPVs are ubiquitous in sexually active population Genital HPVs are ubiquitous in sexually active population Estimated prevalance: 20-40% (teenagers), 40% (in yrs of age), 5% (50 yrs), 10-12% (after 60) Estimated prevalance: 20-40% (teenagers), 40% (in yrs of age), 5% (50 yrs), 10-12% (after 60) Strong association between HPV infection and cervical cancer precursors. HPV DNA found in 70-78% pts with CINI, 83-89% in CINII/III Strong association between HPV infection and cervical cancer precursors. HPV DNA found in 70-78% pts with CINI, 83-89% in CINII/III *JAMA 2007;297(8):813 *CMAJ 2001;164(7):1017

HPV in Cervical Cancer Strong association with cervical cancer (contd): >95% in invasive sq. cell cancer, 90% in adenoCA, and only 16% in controls. *JAMA 1999; 281:1605 Strong association with cervical cancer (contd): >95% in invasive sq. cell cancer, 90% in adenoCA, and only 16% in controls. *JAMA 1999; 281:1605

Genital HPV infection Subtypes of HPV and association with cervical malignancy: Subtypes of HPV and association with cervical malignancy: –Subtype 16, 18, 31, 45: strongest association with squamous cell cancer –Subtype 18: Adenocarcinoma and undifferentiated cancer –Subtypes 6 and 11: low risk *NEJM 2003;348(6):518

HPV in Cervical Cancer Testing for HPV DNA has greater sensitivity than cytology for detecting clinically relevant lesions (100% vs 68% for conventional PAP and 88% for thinprep) Testing for HPV DNA has greater sensitivity than cytology for detecting clinically relevant lesions (100% vs 68% for conventional PAP and 88% for thinprep) *J Natl Cancer Inst 2006;98(11):765 Specificity was lower (86%) Specificity was lower (86%) High false positive rates may preclude it from use in screening High false positive rates may preclude it from use in screening

HPV in Cervical Cancer Clinical utility of HPV testing in triaging women with ASCUS was validated in 2001 by a consensus group *JAMA 2002, 287:2120 Clinical utility of HPV testing in triaging women with ASCUS was validated in 2001 by a consensus group *JAMA 2002, 287:2120 Data from ALTS trial helped clarify the management of patients with ASCUS and identify those at higher risk for precancerous lesions Data from ALTS trial helped clarify the management of patients with ASCUS and identify those at higher risk for precancerous lesions

Management of Abnormal Cytology – Options ASC-US ASC-US –Check HPV DNA: (preferred) »Positive for high risk HPV – refer for colposcopy »Negative for high risk HPV DNA - repeat PAP in 12 months –Repeat cytology in 4-6 months intervals until 2 consecutive normal results. Colposcopy if abnormal –Immediate colposcopy *Am J Obstet Gynecol 2007;197(4):346

Management of Abnormal Cytology ASC – H: refer for colposcopy. If colposcopy is negative, repeat PAP in 6-12 months ASC – H: refer for colposcopy. If colposcopy is negative, repeat PAP in 6-12 months ASC-US in special circumstances: ASC-US in special circumstances: –Postmenopause with atrophy: treat with intravaginal estrogens – repeat PAP –Immunosuppressed or HIV positive patient: refer for colposcopy *Am J Obstet Gynecol 2007;197(4):346

Management of Abnormal PAP Smears – An Algorithm LSIL: refer for colposcopy LSIL: refer for colposcopy HSIL: refer for colposcopy and endocervical screening HSIL: refer for colposcopy and endocervical screening Atypical glandular cells or Adenocarcinoma in situ: refer for colposcopy and endocervical screening Atypical glandular cells or Adenocarcinoma in situ: refer for colposcopy and endocervical screening * JAMA 2002; 287(16):2120-9

Recommendations

Cytological Screening: Who should get it? USPSTF, ACOG, ACS are in consensus on most recommendations USPSTF, ACOG, ACS are in consensus on most recommendations *Obstet Gynecol 2003;102(2):417 *CA Cancer J Clin 2002;52(6):342 * Start Screening for cervical cancer approximately 3 years after onset of vaginal sexual intercourse, but no later than 21 yrs of age Start Screening for cervical cancer approximately 3 years after onset of vaginal sexual intercourse, but no later than 21 yrs of age If sexual intercourse has NEVER occurred, provider and patient may decide to defer If sexual intercourse has NEVER occurred, provider and patient may decide to defer

Cytological Screening: Frequency Depends on type of test used, previous test results and presence of risk factors Depends on type of test used, previous test results and presence of risk factors USPSTF recommendations: USPSTF recommendations: –Annual screening PAP tests for women of all ages for the first 2-3 yrs –If above normal, extend interval to once every three years

Cytological Screening: Frequency ACOG recommendations: ACOG recommendations: –Annual screening for women younger than 30 yrs of age, regardless of technique –After 30 yrs of age, extend to every 2-3 yrs, if three annual screening tests were normal and there are no increased risk factors for CIN

Cytological Screening: Frequency ACOG Recommendations (continued) ACOG Recommendations (continued) –Women at increased risk for CIN include: »H/O CIN II/III or cervical cancer in the past »Immunocompromise »H/O of DES exposure in-utero »Screen annually

Cytological Screening: In HIV patients Recommended two times, six months apart in the the first year after diagnosis, Q1 year thereafter if both are negative Recommended two times, six months apart in the the first year after diagnosis, Q1 year thereafter if both are negative There is no clear consensus on utility of routine HPV testing There is no clear consensus on utility of routine HPV testing Some recommend using HPV testing to determine frequency of subsequent testing Some recommend using HPV testing to determine frequency of subsequent testing

Cytological Screening: Discontinuation All normal screening, discontinue at age 65 yrs (USPSTF recs); age 70 yrs (ACS recs): ACOG recommends individualization based on risk factors. All normal screening, discontinue at age 65 yrs (USPSTF recs); age 70 yrs (ACS recs): ACOG recommends individualization based on risk factors. American geriatric society recommends discontinuation at age 70 yrs, if all tests were negative in the last 10 yrs American geriatric society recommends discontinuation at age 70 yrs, if all tests were negative in the last 10 yrs

Cytological Screening: Discontinuation After Total hysterectomy: After Total hysterectomy: –For benign reasons with no H/O abnormal smears and no evidence CIN in specimen, no further screening is required –For invasive cervical cancer require frequent monitoring initially and annually thereafter

Cytological Screening: Discontinuation After Total hysterectomy (continued): After Total hysterectomy (continued): –For CIN II/III, visual inspection and cytological screening every 4-6 months until three consecutive tests are negative; annually after that until three tests are negative –Continue indefinitely for women with in- utero DES exposure

HPV Vaccines High risk HPV types 16/18/45/31 and lower risk types 6/11 account for most cervical precancerous lesions and cancers High risk HPV types 16/18/45/31 and lower risk types 6/11 account for most cervical precancerous lesions and cancers Bivalent(16/18) and quadrivalent vaccines are available Bivalent(16/18) and quadrivalent vaccines are available Efficacy in protection against HPV infection and perhaps reducing incidence of CIN demonstrated Efficacy in protection against HPV infection and perhaps reducing incidence of CIN demonstrated *Lancet 2004;364(9447):1757 *Lancet Oncol 2005;6(5):271

HPV Vaccines Advisory Committee on Immunization Practices and American College of Obstetricians and Gynecologists recommend the quadrivalent vaccine (Gardasil) to females ages 9-26yrs (0.5ml IM injn at 0,2, and 6m) Advisory Committee on Immunization Practices and American College of Obstetricians and Gynecologists recommend the quadrivalent vaccine (Gardasil) to females ages 9-26yrs (0.5ml IM injn at 0,2, and 6m) –Grade IA recommendation *MMWR Recomm Rep 2007;56(RR-2):1-24

Summary Incidence of cervical cancer is declining due to population based screening programs Incidence of cervical cancer is declining due to population based screening programs Genital HPV infn is closely associated with cervical cancer Genital HPV infn is closely associated with cervical cancer Conventional PAP smear and liquid based thin prep are acceptable methods Conventional PAP smear and liquid based thin prep are acceptable methods Patients with ASCUS should be triaged with HPV testing Patients with ASCUS should be triaged with HPV testing

Summary Immediate referral for further testing is recommended for findings of LGSIL, HGSIL, and Carcinoma Immediate referral for further testing is recommended for findings of LGSIL, HGSIL, and Carcinoma Screening should begin 3 yrs after onset of sexual activity, no later than age 21 Screening should begin 3 yrs after onset of sexual activity, no later than age 21 Screening may be discontinued at age Screening may be discontinued at age Quadrivalent HPV vaccine recommended for females ages 9-26 yrs Quadrivalent HPV vaccine recommended for females ages 9-26 yrs

References ACOG guidelines ACOG guidelines American Cancer Society - Cancer Facts & Figures American Cancer Society - Cancer Facts & Figures Am J Obstet Gynecol 2007;197(4):346 Am J Obstet Gynecol 2007;197(4):346 Am J Obstet Gynecol 2006;195(5):1260 Am J Obstet Gynecol 2006;195(5):1260 CA Cancer J Clin. 1999, 49(1): CA Cancer J Clin. 1999, 49(1): CA Cancer J Clin. 2005, 55(2): CA Cancer J Clin. 2005, 55(2): CMAJ 2001;164(7):1017 CMAJ 2001;164(7):1017 CA Cancer J Clin. 1999, Global Cancer Statistics. 49(1):33-64 CA Cancer J Clin. 1999, Global Cancer Statistics. 49(1):33-64 CA Cancer J Clin 2002;52(6):342 CA Cancer J Clin 2002;52(6):342 J Low Genit Tract Dis 2002;6(3):195 J Low Genit Tract Dis 2002;6(3):195 J.Natl. Can Inst, 2002 J.Natl. Can Inst, 2002 J Natl Cancer Inst 2006; 98 J Natl Cancer Inst 2006; 98 JAMA 1999;281:1605 JAMA 1999;281:1605 JAMA 2000;283 JAMA 2000;283 JAMA, Chlamydial infn, 2001 JAMA, Chlamydial infn, 2001 JAMA 2002, 287 JAMA 2002, 287 JAMA 2007;297(8):81 JAMA 2007;297(8):81

References Lancet, 2002 Lancet, 2002 Lancet 2004;364(9447):1757 Lancet 2004;364(9447):1757 Lancet Oncol 2005;6(5):271 Lancet Oncol 2005;6(5):271 MMWR Recomm Rep 2007;56(RR-2):1-24 MMWR Recomm Rep 2007;56(RR-2):1-24 Natl. Cancer Institute Natl. Cancer Institute NEJM 2003;348(6):518 NEJM 2003;348(6):518 Obstet Gynecol 1994;84(4):591 Obstet Gynecol 1994;84(4):591 Obstet. Gynecol., 1997;90: Obstet. Gynecol., 1997;90: Obstet and Gynecol; 1998, 92:727 Obstet and Gynecol; 1998, 92:727 Obstet Gynecol 2003;102(2):417 Obstet Gynecol 2003;102(2):417 Prev Med. 2007;45(2-3) Prev Med. 2007;45(2-3) seer.cancer.gov/csr/ /cervix.pdf seer.cancer.gov/csr/ /cervix.pdf USPSTF USPSTF