CERVICAL CANCER , the 2nd most common cancer in India can be easily prevented with proper adequate screening and awareness. Adequate sex education is necessary to inculcate safe sexual practices to prevent HPV infection.

1. ETIOPATHOGENESIS AND NATURAL
HISTORY OF CARCINOMA CERVIX
• HUMAN PAPILLOMA VIRUS
• HIGH RISK FACTORS

2. Dr. Niranjan Chavan
MD, FCPS, DGO, DFP, MICOG, DICOG, FICOG
Professor and Unit Chief, L.T.M.M.C & L.T.M.G.H
Chairperson, FOGSI Oncology and TT Committee (2012-2014)
Treasurer, MOGS (2017- 2018)
Chair and Convener, FOGSI Cell- Violence against Doctors (2015-2016)
Chief Editor, AFG Times (2015-2017)
Editorial Board, European Journal of Gynecologic Oncology
Editor of FOGSI FOCUS, MOGS, AFG & IAGE Newsletters
Member, Managing Committee, IAGE (2013-2017)
Member , Oncology Committee, AOFOG (2013 -2015)
Recipient of 6 National & International Awards
Author of 15 Research Papers and 19 Scientific Chapters
Course Co-Ordinator, of 11 batches, of MUHS recognized Certificate Course of
Basic Infertility Management Including Endoscopy (BIMIE) at LTMGH

3. ETIOPATHOGENESIS

4. BEFORE TAKING ABOUT THE ETIOPATHOGENESIS,
LET US FIRST UNDERSTAND
WHAT IS SQUAMOCOLUMNAR JUNCTION AND TRANSFORMATION ZONE.

5. • There are two types of
cervical epithelium
1. Columnar epithelium which
lines the endocervical canal,
and
2. Squamous epithelium, which
covers the exocervix.
• The point at which they meet
is called the
squamocolumnar junction
(SCJ)

6. • It is a dynamic point that
changes in response to puberty,
pregnancy, menopause, and
hormonal stimulation.
• Lactobacilli act on the glycogen
to lower the pH, stimulating the
subcolumnar reserve cells to
undergo metaplasia.

7. • Metaplasia advances from the
original SCJ inward, toward the
external OS and over the columnar
villi. This process establishes an area
called the transformation zone.
• The transformation zone extends
from the original SCJ to the
physiologically active SCJ, as
demarcated by the squamocolumnar
junction.
• Gland openings and nabothian cysts
mark the original SCJ and the outer
edge of the original transformation
zone.

8. NORMAL TRANSFORMATION ZONE
The original squamous epithelium of
the vagina and exocervix has four
layers (5):
• The basal layer is a single row of
immature cells with large nuclei and
a small amount of cytoplasm.
• The parabasal layer includes two to
four rows of immature cells that
have normal mitotic figures and
provide the replacement cells for
the overlying epithelium.

9. NORMAL TRANSFORMATION ZONE
• The intermediate layer includes four
to six rows of cells with larger
amounts of cytoplasm in a
polyhedral shape separated by an
intercellular space.
• The superficial layer includes five to
eight rows of flattened cells with
small uniform nuclei and a cytoplasm
filled with glycogen. The nucleus
becomes pyknotic, and the cells
detach from the surface (exfoliation).
These cells form the basis for
Papanicolaou (Pap)testing.

10. • The entire SCJ with early metaplastic cells is susceptible to oncogenic factors,
which may cause these cells to transform into CIN. Therefore, CIN is most likely
to begin either during menarche or after pregnancy, when metaplasia is most
active.
• THIS ZONE OF ACTIVE METAPLASIA IS PREDISPOSED TO DYSPLASIA, LEADING
TO CIN AND LATER CA CAERVIX
• Conversely after menopause, a woman undergoes little metaplasia and is at a
lower risk of developing CIN from de novo human papillomavirus (HPV)
infection.
• It is established that persistent high-risk oncogenic HPV infection is the
overwhelming risk factor for the development of CIN.

11. • In most cases, CIN is believed to originate as a single focus in the
transformation zone at the advancing SCJ.
• The anterior lip of the cervix is twice as likely to develop CIN as the
posterior lip, and CIN rarely originates in the lateral angles.

12. 60 % of CIN 1, 40 % OF CIN2
& 30% of CIN 3 regresses to
normal.
<1 of CIN 1 and almost 5%
and 22% of CIN 2 & CIN 3
respectively progress to ca
cervix.

13. There is long duration for progression from CIN to ca cervix. On
average is duration is 10 – 12 years.

14. HUMAN PAPILLOMA VIRUS

15. • Human papillomavirus, is a DNA virus from
the papillomavirus family, of which over 170 types are known.
• More than 40 HPV types can be easily spread through direct sexual
contact, from the skin and mucous membranes of infected people
to the skin and mucous membranes of their partners.
• They can be spread by vaginal, anal, and oral sex.

16. Sexually transmitted HPV types fall into two categories:
• Low-risk HPVs, which do not cause cancer but can cause skin warts
(technically known as condylomata acuminata) on or around the
genitals and anus. For example, HPV types 6 and 11 cause 90% of
all genital warts.
• High-risk HPVs, which can cause cancer. Two of these, HPV types
16 and 18, are responsible for most HPV-caused cancers

17. • Detection of HPV is associated with a 250-fold increase risk of high-grade CIN .
• The percentage of intraepithelial neoplasia attributed to HPV infection
approaches 90%.
• Only certain types of HPV account for about 90% of high-grade intraepithelial
lesions and cancer (HPV-16, -18, -31, -33, -35, -39, -45, -51, -52, -56, -58, -59
and -68)
• Two HPV types (16 and 18) cause 70% of cervical cancers and precancerous
cervical lesions.
• HPV-18 is more specific than HPV-16 for invasive tumors.

18. Luc Montagnier, Francoise Barre Sinoussi, Harald zur Hausen
Nobel Laureates in Medicine 2008
1985
zur Hausen group detects HPV DNA in cervical cancers
new HPVs – HPV 16 and HPV 18

19. • The peak time for acquiring infection for both women and men is shortly after
becoming sexually active.
• HPV is sexually transmitted, but penetrative sex is not required for transmission.
Skin-to-skin genital contact is a well-recognized mode of transmission.

20. • Usually, HPV infections do not persist.
• In the vast majority of cases, the infection will clear in 9 to 15 months.
• Persistent high-risk HPV infection increases the risk of high-grade disease 300-
fold and is required for the development and maintenance of Ca cervix.
• Factors that may have a role in persistence and progression include smoking,
contraceptive use, infection with other sexually transmitted diseases, or
nutrition.

21. • The cytologic changes of HPV were first recognized by Koss and Durfee
in 1956 and given the term koilocytosis .
• The HPV genome is found in all grades of cervical neoplasia.
• Infection with HPV is the primary cause of cervical cancer.
• Cervical cancer cell lines that contain active copies of HPV-16 or -18
(SiHa, HeLa, C 4–11, Ca Ski) express HPV-16 E6 and E7 oncoproteins

22. HPV INFECTION
koilocytosis
As the CIN lesions become more severe, the koilocytes disappear, the HPV
copy numbers decrease, and the capsid antigen disappears.
HPV DNA become integrated into the host cell
Expression of E6 and E7 HPV oncoproteins
Deactivates p53
Mutated cervix grows into a tumour

25. RISK FACTORS

26. • The two major histologic types of cervical cancer, adenocarcinoma and
squamous cell carcinoma, and the preinvasive disease that corresponds
with these histologies share many of the same risk factors.
• Risk factors can be roughly grouped into 2 categories:
1. Factors which leads to increased exposure to etiologic agent or aids
the HPV in pathogenesis.
2. Factors that leads to an immunocompromised state.

27. • Early onset of sexual activity
Compared with age at first intercourse of 21 years. or older, the risk is
approximately 1.5-fold for 18 to 20 years and twofold for younger than 18 years.
• Multiple sexual partners
Compared with one partner, the risk is approximately twofold with two partners
and threefold with six or more partners
• A high-risk sexual partner
A partner with multiple sexual partners or known HPV infection increases the
risk of cervical cancer.

28. • History of sexually transmitted infections
Chlamydia trachomatis, genital herpes and other STD’s increases the risk of HPV
infection. STD’s signifies unsafe sexual habits and often these patients give
history of multiple sexual factors.
• History of vulvar or vaginal squamous intraepithelial neoplasia or cancer
HPV infection is also the aetiology of most cases of these conditions, thus,
signifying increased exposure to HPV
• Early age at first birth
1st child birth at younger than 20 years old, increased risk of exposure to HPV.

29. • Increasing parity (3 or more full term births)
It is associated with an increased risk of cervical cancer; these are also likely due to
exposure to HPV through sexual intercourse.
• Oral contraceptive use has been reported to be associated with an increased risk of
cervical cancer.
 More the duration, greater is the risk.
 Adenocarcinoma appears to have a stronger association with OCP than does squamous
cell cancer.
 The mechanism for an increased cervical cancer risk in HPV-positive OC users may be
related to a metabolite of estradiol, 16 alpha-hydroxyestrone, which can act as a
cofactor with oncogenic HPV to promote cell proliferation.

30. • Immunosuppression
1. Human immunodeficiency virus infection.
2. Therapy following organ transplantation.
3. End-stage renal disease.
4. Diabetes
5. Autoimmune diseases; particularly if treated with
immunosuppressants
• Low socio economic status
low socioeconomic strata often lacks good nutrition and safe sexual habits
which leads to persistence of HPV infection.

31. CONCLUSION
• The transformation zone extends from the original SCJ to the
physiologically active SCJ, as demarcated by the squamocolumnar
junction.
• Entire transformation zone is zone of active metaplasia susceptible to
oncogenic factors, which may cause these cells to undergo dysplastic
changes leading to CIN.
• 60 % of CIN 1, 40 % OF CIN2 & 30% of CIN 3 regresses to normal.
• It is established that persistent high-risk oncogenic HPV infection is the
most important risk factor for progression of CIN to carcinoma.

32. CONCLUSION
• HPV is sexually transmitted, but penetrative sex is not required for
transmission. Skin-to-skin genital contact is a well-recognized mode of
transmission.
• HPV DNA gets integrated with host DNA and code for E6 & E7
oncoprotein which deactivates p53, thus causing oncogenic changes.
• All factors which increase the chance of HPV infection like early onset of
sexual activity, multiple sexual partner, multiparity, STDs, OCP use are a
major risk factor for ca cervix.

33. TAKE HOME MESSAGE
• CERVICAL CANCER , the 2nd most common cancer in India can be
easily prevented with proper adequate screening and awareness.
• Adequate sex education is necessary to inculcate safe sexual
practices to prevent HPV infection.