2. Steps in HPV Induced
Cervical Cancer
HPV
infection
Persistent
HPV infection
Cellular
dysregulation
High grade
CIN
Invasive
cancer
Immunologic
factors
Co-carcinogens
3. HPV genes (E6,E7) in the Cell Cycle
E6 gene product
Binds p53
E7 gene product
Binds pRb
Go G1 S G2 M Go
Growth
Signal
p53 and pRb
“ All clear signals “
Cell cycle progression
Apoptosis
Genetic
Repair
E6-E7
E6-E7
Minor DNA
damage
Major DNA
damage
4. : ~70% of cases can clear infection in 1yr and 90% in
2 yrs.
: Most of persistent infection resulting in no disease
in their life but HPV DNA are +ve or low level.
: ~30% progress to CIN 1, 10 – 20% CIN 2-3.
: Only 1% progress to cervical cancer.
6. 2° Prevention of Ca. Cx.
Persistent
HPV
or
LSIL
Normal
Epithelial
Cell
HSIL
Inv. CA
HPV
1-2 yrs 3-20 yrs6-9 Months
HR-HPV DNA +ve
Cytology -ve
VIA (M) -ve
Colposcopy -ve
HR-HPV DNA +ve
Cytology ± ve
VIA (M) ±ve
Colposcopy ±ve
HR-HPV DNA +ve
Cytology +ve
VIA (M) +ve
Colposcopy +ve
Transient
HPV
Infected
Cells
All
tests
-ve
7. Cervical cancer prevention
(Cytology based)
• Screening programme
• Sampling and processing technique
• Reporting system
• Management of abnormal Pap smear
10. Age group (yr) Frequency of screening
25 First invitation
25-49 Three yearly
50-64 Five yearly
65+ Only screen those who have not been
screened since age 50 or those who have had
recent abnormal tests
UK NHS 2011
11. Cervical cancer
50% of cases have not been screened,
60% of cases are inadequate screening,
10% have not been screened within 5
years before diagnosis.
26. Population†
USP
STF ‡
ACS/ASCCP/ASCP§
After
hysterectomy
Women of any age following a
hysterectomy with removal of the
cervix who have no history of CIN2+
should not be screened for vaginal
cancer. Evidence of adequate negative
prior screening is not required.
Screening should not be resumed for
any reason, including if a woman
reports having a new sexual partner.
28. Cervical cancer prevention
(Cytology based)
• Screening programme
• Sampling and processing technique
• Reporting system
• Management of abnormal Pap smear
44. Cervical cancer prevention
(Cytology based)
• Screening programme
• Sampling and processing technique
• Reporting system
• Management of abnormal Pap smear
45. Pap smear reporting systems
• Papanicolaou Classification ( Class 1 - 5 )
• WHO Classification ( 1973 )
• Bethesda System ( 1993 )
• Bethesda System (2001)
46. Pap WHO
Class 1 Normal
Class 2 Inflammation, Atypia
Class 3 Dysplasia (CIN)
Mild dysplasia , CIN 1
Moderate dysplasia, CIN 2
Severe dysplasia, CIN 3
Class 4 Carcinoma in situ (CIS)
Class 5 Invasive SCC
AIS
Adenocarcinoma
Malignant cells of other tumour types
Bethesda 2001
Negative for intraepithelial lesion or malignancy
Infection, inflammation, reactive changes
Squamous Intraepithelial Lesion (SIL)
ASC-US , ASC-H
Low grade (LSIL): HPV and/or CIN 1
High grade (HSIL): moderate and severe
dysplasia, CIN 2, CIN 3, CIS and
with features suspicious for invasion
Invasive Squamous cell carcinoma
Glandular cell abnormality
AGC , favour neoplastic , AIS
Adenocarcinoma
Other malignant neoplasms
47. Pap WHO
Class 1
Negative for malignancy
Class 2
Inflammation, Atypia
Bethesda 2001
Negative for intraepithelial
lesion or malignancy
Infection, inflammation,
reactive changes
48. Pap WHO
Class 3
Dysplasia (CIN)
Mild dysplasia , CIN 1
Moderate dysplasia, CIN 2
Severe dysplasia, CIN 3
Class 4 Carcinoma in situ (CIS)
Class 5 Invasive SCC
AIS
Adenocarcinoma
Malignant cells of other tumor
types
Bethesda 2001
Squamous Intraepithelial Lesion (SIL)
ASC-US , ASC-H
Low grade (LSIL): HPV and/or CIN 1
High grade (HSIL): moderate and
severe dysplasia, CIN 2, CIN 3, CIS ,
with features suspicious for invasion
Invasive Squamous cell carcinoma
Glandular cell abnormality
AGC , favour neoplastic , AIS
Adenocarcinoma
Other malignant neoplasms
49. Bethesda system 2001
Negative for Intraepithelial Lesion or Malignancy (NILM)
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
< Pap Class 1> http://bethesda2001.cancer.gov/terminology.html
53. Clue cell
Neg. for intraepithelial lesion or malignancy
Shift in flora suggestive of bacterial vaginosis
54. Actinomyces spp.
Neg. for intraepithelial lesion or malignancy
Bacteria morphologically consistent with Actinomyces spp.
55. Neg. for intraepithelial lesion or malignancy
Cellular changes consistent with Herpes simplex virus
56. Bethesda system 2001
Other Non Neoplastic findings < Pap Class 2>
- Reactive cellular changes associated with
• inflammation ( includes typical repair)
• radiation
• Intrauterine device (IUD)
- Atrophy
- Glandular cells status post hyterectomy
Other
• Endometrial cells (in woman ≥ 40 years of age)
http://bethesda2001.cancer.gov/terminology.html
57. Neg. for intraepithelial lesion or malignancy
Reactive cellular changes associated with inflammation
Inflammatory cellular change
58. Bethesda system 2001
Epithelial cell abnormality
Squamous cell
• Atypical squamous cells
– of undetermined significance (ASC-US)
– cannot exclude HSIL (ASC-H)
• Low grade squamous intraepithelail lesion (LSIL) <Pap class 3>
encompassing: HPV/mild dysplasia /CIN 1
• High grade squamous intraepithelail lesion (HSIL)
encompassing: moderate and severe dysplasia, CIS/CIN 2, 3
• With features suspicious for invasion < Pap class 4 >
• Invasive Squamous cell carcinoma < Pap class 5 >
http://bethesda2001.cancer.gov/terminology.html
59. ASC (Atypical squamous cell)
ASC-US (Atypical Sq. Cells of Undetermined Significance)
:- Cytologic changes that are suggestive of a SIL, but
lack criteria for a definitive interpretation.
ASC-H (Atypical Sq. Cells; Cannot Exclude HSIL)
:- Cytologic changes that are suggestive of HSIL, but lack
criteria for definitive interpretation.
73. It is important to note that
• Cytologic LSIL is not equivalent to CIN 1
• Cytologic HSIL is not equivalent to CIN 2,3
Am J Obstet Gynecol 2007; Oct: 340-355.
75. Cervical cancer prevention
(Cytology based)
• Screening programme
• Sampling and processing technique
• Reporting system
• Management of abnormal Pap smear
76. Abnormal Pap Smear
ASC-US, ASC-H
LSIL, HSIL
Invasive sq. cell ca.
AGC
AGC, favor neoplastic
AIS
Adenocacinoma
116. Cervical cancer prevention
(Cytology based)
• Screening programme
• Sampling and processing technique
• Reporting system
• Management of abnormal Pap smear