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Management of Abnormal Pap Smears and Cervical Dysplasia. Jennifer L. Ragazzo, M.D. Department of Obstetrics and Gynecology Division of Women’s Primary Healthcare April 1, 2009. Objectives. Review of cervical cancer and risk factors Outline screening guidelines

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slide1

Management of Abnormal Pap Smears and Cervical Dysplasia

Jennifer L. Ragazzo, M.D.

Department of Obstetrics and Gynecology

Division of Women’s Primary Healthcare

April 1, 2009

objectives
Objectives
  • Review of cervical cancer and risk factors
  • Outline screening guidelines
  • Overview of Pap smear results and colposcopy
  • Summarize recommendations for patients with CIN and AIS
  • Brief overview of the HPV vaccine
cervical cancer
Cervical Cancer
  • Cervical cancer is the third most common gynecological cancer in the U.S.
  • Caused by HPV – high risk types
  • Annual pap smear testing potentially reduces a woman’s chance of dying of cervical cancer by almost 90%
risk factors for cervical cancer
Risk factors for Cervical Cancer
  • Early age of first intercourse
  • Multiple sexual partners
  • Cigarette smoking
  • Immunosuppresion
    • HIV: Cervical Cancer is an AIDS-defining illness
    • Chronic steroid use
  • DES exposure
human papilloma virus
Human Papilloma Virus
  • Double-stranded DNA virus that induces epithelial cell proliferation or Papillomas
  • At least 35 of over 100 different types can infect the genital tract
  • Divided into low and high risk types
    • Low Risk – 6, 11
      • may cause genital warts
    • High Risk – 16, 18, 31, 33, 39, 45 , etc.
      • may cause cervical dysplasia and cervical cancer
human papilloma virus1
Human Papilloma Virus
  • HPV is sexually transmitted
  • But it is so common
    • NEJM 1998 – 43% of 608 college age women
    • JAMA 2001 – 46% of 467 college age women
    • Estimate lifetime risk of 80%
  • Transmission decreased with condom use
    • N Engl J Med. 2006 Jun 22;354(25):2645-54
      • 37.8 per 100 patient-years using condoms
      • 89.3 per 100 patient-years without condoms
human papilloma virus2
Human Papilloma Virus
  • In pre-cancer lesions, HPV DNA has extra-chromosomal replication
  • In cancers, the DNA is integrated in the human genome
  • Seven early genes (E1-7), two late genes (L1-2)
  • E6 and E7 genes express oncoproteins that form complexes with host regulatory proteins such as p53 and pRB
cervical cancer screening
Cervical Cancer Screening
  • Begin Pap smears at age 21
  • OR 3 years after first sexual encounter
  • Women up to age 30
    • Should undergo annual cervical cytology
women age 30 and older
Women age 30 and older
  • First option - Cervical cytology alone
      • Negative results on 3 consecutive annual Pap smears
      • May be re-screened with cervical cytology alone every 2 to 3 years
  • Second option - Combined cervical cytology and testing for high risk HPV
      • Both tests negative may repeat every 3 years
      • If only one of the tests are negative more frequent testing indicated
women age 30 and older1
Women age 30 and older
  • When to stop screening
    • After hysterectomy – for benign indications
    • ACS recommendations: After age 70, if history of 3 consecutive negative Pap smears
pap smear
Pap Smear
  • Introduced in 1939
  • Most common cancer screening test
  • Virtually unchanged in 50 years

George N. Papanicolaou

1883-1962

pap smear1
Pap Smear
  • Sample of ecto- and endo-cervix
slide14

Squamous epithelium

Columnar epithelium

pap smear results
Pap Smear Results
  • No dysplasia
  • ASC-US (atypical squamous cells of undetermined significance)
    • +/- High Risk HPV
  • ASC – H (favor high grade)
  • LSIL (low grade squamous intraepithelial lesion)
  • HSIL (high grade SIL)
  • AGC (atypical glandular cells)
    • NOS
    • Favor Neoplasia
colposcopy
Look at the cervix under a microscope

Apply Acetic Acid or Lugol’s solution to see dysplastic changes

Take colposcopic directed biopsies +/- endocervical currettage (ECC)

Colposcopy
colposcopy anatomy of the cervix
Transformation Zone: area that was initially covered by columnar epithelium, replaced by squamous epithelium through metaplasia

Squamo-columnar junction: where they two cell types are visible

Colposcopy:Anatomy of the Cervix
colposcopy1
Acetic Acid

Dehydrates cells

Abnormal areas appear white (aceto-white) because of decreased glycogen

Lugol’s Solution

Iodine is taken up by normal cells with high glycogen content

Non-staining is abnormal

Colposcopy
colposcopy grading lesions
Colposcopy - Grading Lesions
  • Less Severe >> More Severe
    • Mild acetowhite epithelium > Intensely acetowhite
    • No blood vessels > Punctation > Mosaicism
    • Diffuse vague borders > Sharp demarcation
    • Along normal cervical contours > “humped up”
    • Normal iodine reaction (dark) > Iodine-negative epithelium (yellow)
    • Leukoplakia - usually a very good (condyloma) or very bad (SCC) sign
colposcopy2
Biopsy Results

Normal

Condyloma

Cervical Intraepithelial Neoplasia (1-3)

Adenocarcinoma in situ

Cancer

Colposcopy
colposcopy biopsy results
Colposcopy – Biopsy Results

HPV Changes/

Koilocytes

CIN 2

CIN 3

Normal

natural history of cin
Natural History of CIN
  • Depends upon age and health status
  • CIN1 – about 90% regression, 10% progression
  • CIN2 – about 50% regression, 20% persistence, 30% progression
  • CIN3 – about 10% regression, 90% persistence/progression
treatment of cin
Treatment of CIN
  • Observation
  • Ablation of abnormal cells
    • Cryotherapy – freezes to a depth of up to 8mm
    • CO2 Laser Therapy – dessicates tissue
  • Diagnostic excisional procedures
    • LEEP – Loop electro-diathermy excisional procedure
    • Cold Knife Cone biopsy (CKC)
  • Hysterectomy
diagnostic excisional procedures
LEEP

Office procedure – convenient, quick, cost-effective

Margins difficult to assess

CKC

OR procedure

Larger specimen possible

Non-cauterized margins

Always for AIS

Diagnostic Excisional Procedures
treatment vs observation
Treatment vs. Observation
  • Age
  • Parity
  • Non-compliant patient
  • Unsatisfactory colposcopy
  • Discrepancy between Pap smear and biopsy results
  • CIN2 treat most of the time, CIN3 always treat
  • Adenocarcinoma in situ
  • +ECC – with CIN2 or 3
slide26

Natural History of Cervical Cancer

CIN 1,2

Avg. 6-24 mo

Avg. 10 yrs

HPV infection

CIN 2,3

Invasive CA

Avg. 6-9 mo.

HPV disappearance

Ho GY, et al. New England Journal of Medicine. 1998,338:423-428.

Bory JP, et al. Int J Cancer, 2002;102:519-525.

Nobbenhuis MAE, et al. Lancet. 1999;354:20-25.

changes to management algorithms
Changes to Management Algorithms
  • Using HPV triage
  • Age 20 years or less
  • Pregnancy
normal pap test
Normal Pap test
  • Repeat in 1 year
    • If age >30 and history of 3 normals  repeat in 3 yrs
  • HPV triage
    • -HR HPV  repeat in 1 yr for age <30 or 3 yrs for age >30
    • +HR HPV  repeat in 1 yr
management of abnormal cytology
Management of Abnormal Cytology
  • ASC-US
    • *If age 20 or less  repeat in 1 year
    • If <HSIL  repeat in 1 yr  if abnomal, colpo
    • HPV triage
      • -HR HPV  repeat in 1 year
      • +HR HPV  colposcopy
  • LSIL
    • *If age 20 or less  repeat in 1 year
    • No need for HPV triage  straight to colpo

www.asccp.org

management of abnormal cytology1
Management of Abnormal Cytology
  • ASC-H
    • No need for HPV triage  straight to colpo
    • Treat just like LSIL
      • Exception age group <20 still needs colpo
  • HSIL
    • No need for HPV triage
    • “See and treat” if age > 20 years LEEP
    • Or colposcopy with ECC

www.asccp.org

management of abnormal cytology2
Management of Abnormal Cytology

AGC - initial evaluation

  • If atypical endometrial cells  EMB, ECC  if no endometrial abnormality  colpo
  • Otherwise HPV typing if not already done, colpo, ECC, EMB

www.asccp.org

management of abnormal cytology3
Management of Abnormal Cytology

AGC - further evaluation

  • If AGC-NOS and work-up negative, use HPV
      • If HPV unknown  repeat cytology q6mos x 4
      • If -HR HPV repeat cytology/HPV at 12 mos
      • If +HR HPV  repeat cytology/HPV at 6 mos
  • If AGC-NOS and cervical or glandular neoplasia present  routine management protocols
  • If AGC-favor neoplasia and work-up negative  CKC

www.asccp.org

abnormal cytology in pregnancy
Abnormal Cytology in Pregnancy
  • LSIL
    • Colposcopy
    • OR defer colposcopy until 6 wks postpartum
  • HSIL
    • Colposcopy

www.asccp.org

management of cervical intraepithelial neoplasia
Management of Cervical Intraepithelial Neoplasia

CIN 1

  • If < age 20  repeat cytology at 12 months
      • If <HSIL, repeat cytology in 12 mos
      • If >HSIL  colposcopy
  • If preceded by ASCUS, ASC-H, LSIL  Pap q6mos x 2 or HPV testing in 1 year
      • re-colpo if abnormal cytology persists
management of cervical intraepithelial neoplasia1
Management of Cervical Intraepithelial Neoplasia

CIN 1

  • If preceded by HSIL, AGC-NOS 
    • Diagnositc excisional procedure
    • Review all pathologic specimens
    • *OR Repeat Colpo/Cytology at 6 month intervals
      • Excisional procedure if HSIL persists
management of cervical intraepithelial neoplasia2
Management of Cervical Intraepithelial Neoplasia

CIN 2,3

  • If satisfactory colpo  ablation vs excision
  • If unsatisfactory colpo  excision
  • In age 20 or less
    • If satisfactory colpo, can watch closely with cytology/colposcopy q6mos for up to 24 mos
    • If unsatisfactory or CIN3  ablation or excision is recommended
management of cervical intraepithelial neoplasia3
Management of Cervical Intraepithelial Neoplasia

CIN 2,3 - after treatment

  • Cytology and/or Colposcopy at 6 month intervals
  • If negative results x2  annual screening
  • OR HPV typing at 6 or 12 month intervals
    • Repeat colpo if abnormal Pap or +HR HPV
slide39

HPV Vaccines :

Will they Make Cervical Screening Obsolete?

slide40

HPV Vaccines

  • Prophylactic
    • target extracellular virus
    • epitopes of native proteins – viral-like particles (VLP)
    • produce antibodies
  • Humoral Immunity
  • CD4+/ MHC II
  • Therapeutic
    • target viral-infected cells
    • epitopes of MHC processed peptides
    • produce CTLs
  • Cellular Immunity
  • CD8+/ MHC I
hpv l1 vlp vaccine synthesis
HPV L1 VLP Vaccine Synthesis

L1 gene on HPV DNA

Empty viral capsids

Elicits immune response in host

Yeast cell DNA

Transcription

Capsid proteins

L1 gene inserted into genome of yeast cell

mRNA

tRNA

Translation

rRNA

Yeast Cell (or Baculovirus Expression System)

prophylactic hpv vaccines
Merck – now available

Gardasil

Recombinant L1 proteins using yeast

100% effective in preventing persistent HPV infection

Phase III Study concluded!

HPV L1 Types 6, 11, 16 and 18 vs. adjuvant

Endpoint CIN2+

GSK

Recombinant L1 proteins using baculovirus

100% effective in preventing persistent HPV infection

Phase III study ongoing

HPV L1 Types 16 and 18 vs. Hepatitis A

Endpoint CIN 2+

Prophylactic HPV Vaccines
merck phase iii study gardasil tm
Merck Phase III Study: GARDASILTM

Oct 6, 2005Infectious Disease Society of AmericaSan Francisco, California

12,167 women age 16 to 26

Vaccine: Day 1, Month 2, Month 6

Placebo: Day 1, Month 2, Month 6

www.merck.com/newsroom/press_releases_and development/2005_1006

combined phase ii iii efficacy data mean 20 month after vaccine regimen
Combined Phase II/III Efficacy Data:Mean 20 month after vaccine regimen

* Subjects are counted once per row

recommendations for gardasil
Recommendations for Gardasil
  • For girls and women ages 9 to 26
    • Exact recommended age varies
      • CDC’s ACIP - ages 11-12
      • ACOG - ages 9-26
  • Three doses
    • 1st dose, 2nd at 2 months, 3rd at 6 months
  • Not indicated for males or women over age 26