CMV PNEUMONITIS IN AN IMMUNOCOMPETENT HOST: A CASE PRESENTATION

Screening for Cervical CancerDr. Shanthi Manivannan, MD

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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

2Screening for Cervical CancerObjectivesIntroductionRisk factorsTechniquesCervical Cytology reportManagement of abnormal PAP smears and HPV testingUSPSTF and ACOG guidelines

3IntroductionCervical cancer: 6% of all cancers in womenIn US, incidence estimated at 11,150 new cases in 2007*American Cancer Society - Cancer Facts & Figures 2008. 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 Cancer Statistics. CA Cancer J Clin. 1999; 49(1):33-64

4Global DisparityDecrease in incidence of cervical cancer in USSecond most common cancer in developing countries

*CA Cancer J Clin. 1999, 49(1): 33-64*CA Cancer J Clin. 2005, 55(2):74-108

Falling incidence of Invasive Cervical CancerReduction 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)93-1006

Age and Cervical CancerInvasive cervical CancerUnder 20: 0/100,000 /yr20-24: 1.7/100,00045-49: 16.5/100,000Mean age: 47 yrs*seer.cancer.gov/csr/1973-1999/cervix.pdfProtracted pre-invasive statePeak incidence of Cervical intraepithelial neoplasia (CIN) is 25-35 yrs

7NomenclatureCervical intraepithelial neoplasia (CIN) refers to the preinvasive state of invasive cervical cancer, confined to superficial epithelial layerMild, moderate, severe dysplasia and carcinoma in situ although still used, have been replaced by CIN

NomenclatureCIN I, CIN II, CIN III indicate varying thickness of the involved epithelium and are findings on HISTOLOGYThe 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 ClassificationTerminology

CytologyHistological CorrelatesLGSILCIN IMild dysplasiaHGSILCIN II / CIN IIModerate dysplasia / Severe dysplasia / carcinoma in-situ10High Risk GroupEarly onset of sexual activityMultiple sexual partners and high risk partnersH/O STD (Chlamydial infn, JAMA 2001) H/O Smoking (J.Natl. Can Inst, 2002)Multiparity (Lancet, 2002)Immunosuppression and HIV infectionLow socioeconomic status

11Genital HPV infectionVery strong association Incidence of HPV infection inCIN 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

12HIV infection and Cervical CancerIncidence of colposcopically confirmed CIN higher in HIV positive women (20% vs 4%)Higher with progressive immune suppressionYounger at presentationRapid progressionRelated to higher incidence and persistence of HPV infection*Obstet Gynecol 1994;84(4):591*JAMA 2000;283(8):1413

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Technique

14Pelvic ExaminationGet all your equipment before starting the procedure:Good light sourceSpeculum of appropriate size (metal or plastic disposable)Materials for PAP smear (extended tip spatula, endocervical brush, liquid medium)Culture medium to test for infection

15Pelvic ExaminationEquipment (continued)Large cotton swabsQ-tips (two) and test tubes with NaCl and KOH solutionHemoccult cardsGlovesWater soluble lubricants

16Pelvic ExaminationPatient should be in Lithotomy position. Examine the external genitalia including skin, labia majora and minora, clitoris, introitus, urethral meatusLocate the cervixInsert the closed speculum after lubrication with warm water at an angle first and then horizontallyOpen the speculum and visualize the cervix

17MethodsConventional PAP smear

Liquid based cytology

Conventional PAP SmearCervix is visualisedUsing Ayres spatula / extended tip spatula, cervix is scraped circumferentiallyEndocervical cells are collected with an endocervical brushCells on the spatula and brush are smeared and rolled onto a slideCells on slide are fixed with ETOH

Liquid Based CytologySample taken with extended tip spatula and endocervical brush or broomSample is transferred to preservative solutionProcessed 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 Improved specimen adequacyDecrease in false negative ratesSubsequent reports have not confirmed this*Obstet. Gynecol., 1997;90:278-284

21Thin Prep vs Conventional PrepWith thin prep:single specimen can be used for cytology, HPV, GC and Chlamydial testingSpecimen can be stored for a few weeksReflex HPV testing can be performed

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The Cervical Cytology Report

The Cytology ReportSpecimen type: Conventional/Thin Prep/Vaginal smearSpecimen adequacy> 5000 sq. cells on thin prep (or) 8000-12000 cells on conventional smear and 10 well preserved endocervical or sq. metaplastic cells Unsatisfactory specimen: repeat in 2-4 mTreat cervicitis, vaginitisRepeated unsatisfactory: refer for colposcopy*J Low Genit Tract Dis 2002;6(3):195

24The Cytology ReportInterpretationNegative for intraepithelial cell abnormality or malignancy Positive for epithelial cell abnormality defined by Bethesda 2001 Classification

*JAMA 2002;287(16):214

25Bethesda 2001 ClassificationAn expert group of clinicians, researchers and pathologists defined the terminology for reporting various cytological findings in 1988. Subsequently, this was revised in 2001 to eliminate and clarify ambiguous terminology

26The Cytology Report/Interpretation Bethesda 2001 ClassificationSquamous Cell Abnormalities: *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

27Bethesda 2001 Classification*JAMA 2002;287(16):214

CytologyHistological CorrelatesLGSILCIN IMild dysplasiaHGSILCIN II / CIN IIModerate dysplasia / Severe dysplasia / carcinoma in-situ28The Cytology Report/Interpretation Bethesda 2001 ClassificationGlandular cell abnormalitiesAtypical glandular cells (AGC) NOSAtypical glandular cells, favor neoplasiaAdenocarcinoma in situ (AIS)Indicates presence of glandular cells from endocervical or endometrial originPAP smear is not a good test with sensitivity 50-72%) *JAMA 2002;287(16):214

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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

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Management of Abnormal Cervical Cytology

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

32Management of Abnormal CytologyRates of progression to CIN II/III after two years:ASCUS: 7%LGSIL: 24%HGSIL: 1.4% to invasive cancerIf 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

33Management of Abnormal CytologyThree million ASCUS findings /yearClassified 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. 24-94% icidence of CIN II/III.*Am J Obstet Gynecol 2006;195(5):1260

34Management of Abnormal CytologyAtypical squamous cell of undetermined significance /LSIL triage study (ALTS) conducted by Natl. Cancer Institute from 1996-1998 attempted to clarify management of ASCUS and confirmed the utility of HPV testing

HPV in Cervical CancerGenital HPVs are ubiquitous in sexually active populationEstimated prevalance: 20-40% (teenagers), 40% (in 20-27 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*JAMA 2007;297(8):813*CMAJ 2001;164(7):1017

36HPV in Cervical CancerStrong association with cervical cancer (contd): >95% in invasive sq. cell cancer, 90% in adenoCA, and only 16% in controls. *JAMA 1999; 281:1605

37Genital HPV infectionSubtypes of HPV and association with cervical malignancy:Subtype 16, 18, 31, 45: strongest association with squamous cell cancerSubtype 18: Adenocarcinoma and undifferentiated cancerSubtypes 6 and 11: low risk*NEJM 2003;348(6):518

38HPV in Cervical CancerTesting 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):765Specificity was lower (86%)High false positive rates may preclude it from use in screening

39HPV in Cervical CancerClinical utility of HPV testing in triaging women with ASCUS was validated in 2001 by a consensus group *JAMA 2002, 287:2120Data from ALTS trial helped clarify the management of patients with ASCUS and identify those at higher risk for precancerous lesions

40Management of Abnormal Cytology Options ASC-USCheck HPV DNA: (preferred)Positive for high risk HPV refer for colposcopyNegative for high risk HPV DNA - repeat PAP in 12 monthsRepeat cytology in 4-6 months intervals until 2 consecutive normal results. Colposcopy if abnormalImmediate colposcopy

*Am J Obstet Gynecol 2007;197(4):346

41Management of Abnormal Cytology ASC H: refer for colposcopy. If colposcopy is negative, repeat PAP in 6-12 monthsASC-US in special circumstances:Postmenopause with atrophy: treat with intravaginal estrogens repeat PAPImmunosuppressed or HIV positive patient: refer for colposcopy*Am J Obstet Gynecol 2007;197(4):346

42Management of Abnormal PAP Smears An AlgorithmLSIL: refer for colposcopyHSIL: refer for colposcopy and endocervical screeningAtypical glandular cells or Adenocarcinoma in situ: refer for colposcopy and endocervical screening* JAMA 2002; 287(16):2120-9

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Recommendations

44Cytological Screening:Who should get it?USPSTF, ACOG, ACS are in consensus on most recommendations*Obstet Gynecol 2003;102(2):417*CA Cancer J Clin 2002;52(6):342*www.ahrq.gov/clinic/3rduspstf/cervcan/cervcanrr.pdfStart Screening for cervical cancer approximately 3 years after onset of vaginal sexual intercourse, but no later than 21 yrs of ageIf sexual intercourse has NEVER occurred, provider and patient may decide to defer

45Cytological Screening: FrequencyDepends on type of test used, previous test results and presence of risk factorsUSPSTF recommendations:Annual screening PAP tests for women of all ages for the first 2-3 yrsIf above normal, extend interval to once every three years

46Cytological Screening: FrequencyACOG recommendations:Annual screening for women younger than 30 yrs of age, regardless of techniqueAfter 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

47Cytological Screening: FrequencyACOG Recommendations (continued)Women at increased risk for CIN include:H/O CIN II/III or cervical cancer in the pastImmunocompromiseH/O of DES exposure in-uteroScreen annually

48Cytological Screening: In HIV patientsRecommended two times, six months apart in the the first year after diagnosis, Q1 year thereafter if both are negativeThere is no clear consensus on utility of routine HPV testingSome recommend using HPV testing to determine frequency of subsequent testing

49Cytological Screening: DiscontinuationAll 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

50Cytological Screening: DiscontinuationAfter Total hysterectomy:For benign reasons with no H/O abnormal smears and no evidence CIN in specimen, no further screening is requiredFor invasive cervical cancer require frequent monitoring initially and annually thereafter

51Cytological Screening: DiscontinuationAfter 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 negativeContinue indefinitely for women with in-utero DES exposure

52HPV VaccinesHigh risk HPV types 16/18/45/31 and lower risk types 6/11 account for most cervical precancerous lesions and cancersBivalent(16/18) and quadrivalent vaccines are availableEfficacy in protection against HPV infection and perhaps reducing incidence of CIN demonstrated*Lancet 2004;364(9447):1757*Lancet Oncol 2005;6(5):271

HPV VaccinesAdvisory 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

SummaryIncidence of cervical cancer is declining due to population based screening programsGenital HPV infn is closely associated with cervical cancerConventional PAP smear and liquid based thin prep are acceptable methodsPatients with ASCUS should be triaged with HPV testing

SummaryImmediate referral for further testing is recommended for findings of LGSIL, HGSIL, and CarcinomaScreening should begin 3 yrs after onset of sexual activity, no later than age 21Screening may be discontinued at age 65-70Quadrivalent HPV vaccine recommended for females ages 9-26 yrs

References

ACOG guidelines American Cancer Society - Cancer Facts & Figures 2008.Am J Obstet Gynecol 2007;197(4):346 Am J Obstet Gynecol 2006;195(5):1260CA Cancer J Clin. 1999, 49(1): 33-64CA Cancer J Clin. 2005, 55(2):74-108CMAJ 2001;164(7):1017 CA Cancer J Clin. 1999, Global Cancer Statistics. 49(1):33-64CA Cancer J Clin 2002;52(6):342J Low Genit Tract Dis 2002;6(3):195J.Natl. Can Inst, 2002J Natl Cancer Inst 2006; 98JAMA 1999;281:1605JAMA 2000;283JAMA, Chlamydial infn, 2001JAMA 2002, 287JAMA 2007;297(8):81

ReferencesLancet, 2002Lancet 2004;364(9447):1757Lancet Oncol 2005;6(5):271MMWR Recomm Rep 2007;56(RR-2):1-24Natl. Cancer Institute NEJM 2003;348(6):518Obstet Gynecol 1994;84(4):591Obstet. Gynecol., 1997;90:278-284Obstet and Gynecol; 1998, 92:727Obstet Gynecol 2003;102(2):417Prev Med. 2007;45(2-3)93-100seer.cancer.gov/csr/1973-1999/cervix.pdfUSPSTFwww.ahrq.gov/clinic/3rduspstf/cervcan/cervcanrr.pdf