Etiopathogenesis and natural history of ca cervix

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 Columnar epithelium which lines the endocervical canal, and 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

23. RISK FACTORS

24. 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 : Factors which leads to increased exposure to etiologic agent or aids the HPV in pathogenesis. 2. Factors that leads to an immunocompromised state.

25. 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.

26. 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 1 st child birth at younger than 20 years old, increased risk of exposure to HPV.

27. 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.

28. 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.

29. 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 .

30. 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.

31. TAKE HOME MESSAGE CERVICAL CANCER , the 2 nd 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.