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Cervical cancer

Cervical cancer – Cervical cancer can be of SCC ( 70 % to 80 % ) or cervical adenocarcinoma ( about 10 % of cases ) Unusual variants include clear cell carcinoma , neuroendocrine carcinoma and adenosquamour carcinoma Main cause of cervical or pre-cancer and cancer is persistent or chronic infection with one of the high risk ( oncogenic ) types of HPV ( in the US it is estimated that high risk oncogenic HPV 16 & 18 are associated with 99.7 % of all cervical cancers ) HPV are a family of small double stranded DNA viruses that infect the epithelium ( majority of anogenital warts are caused by low risk HP types 6 or 11 ) More than 100 types and low risk HPVs are associated with genital warts ( condylomas ) Type 16 causes about 50 % of cervical cancers worldwide and types 16 & 18 together account for about 66 % of cervical cancers HPV is seen in majority of sexually active people at some stage of their life and HPV related cervical dysplasia changes have been widely studied in women only ( men are only screened as part of research protocols ) HPV is the most common STI in the USA Transmission is via intimate skin to skin contact with an infected person , most transmission happens during vaginal , penile , anal or oral sex Most infections would be cleared spontaneously but persistent infections can lead to anogenital warts , precancers and cervical , anogenital or oropharyngeal cancers HPV related cervical disease in women < 25 is largely self limiting Permanent infection with one of the oncogenic HPV types over time leads to development of cervical intraepithelial neoplasia ( CIN ) and it is known that cervical cancer happens decades after HPV infection -a process that can take 10-30 yrs.

 

Pathophysiology – Cervix -narrow inferior fibromuscular segment of uterus projecting into the vaginal cavity lined by a mucous membrane Divided into ectocervix , endocervical canal , endocervix , squamocolumnar junction and the transformation zone ( TZ )
TZ is an area of high mitotic activity and prone to HPV induced neoplastic changes HPV infects by crossing the protective squamous epithelium through epithelial abrasions to infect the cervix Most infections would be self limiting High grade precancerous lesions and cancer in a few would depend upon integration of viral DNA into the host genome and consequent blocking of regulatory enzymes.

 

If the disease is within the cervix – cytology can reveal changes in epithelium as 

○ slight dysplastic changes to cell architecture○ viral cytoplasmic changes○ intraepithelial neoplasia ( CIN )○ micro-invasive carcinoma○ frank invasive carcinoma.

 

CIN  – Non invasive disease where abnormal cells are confined to the epithelium and reflects the process of infection and integration of HPV.

 

CIN 1 overlaps with HPV infection and usually resolves spontaneously within 9-12 months studies have shown a small minority of about 25 % may progress to moderate dysplasia or worse within 5 yrs

 

CIN 2 intermediate lesion nuclear pleomorphism with mitotic activity extending to upper 2/3rd of the epithelium managed by excision and ablation during colposcopy

 

CIN 3 nuclear polymorphism which involves the full thickness of the squamous epithelium with mitotic activity at all levels high risk of progression- malignant potential.

 

Treatment and survival as for most cancers is based on stage
 of the disease . Cervical cancer staging is done based on pelvirectal examination and some tests with most widely
 used criteria of the International Federation of Gynecology and Obstetrics ( FIGO ) 2009.

 

History and presentation – Usually asymptomatic in early stages CIN and microinvasive carcinoma would usually present with no symptoms and picked up during routine screening Intermenstrual bleeding Postcoital bleeding Post-menopausal bleeding Blood stained vaginal discharge Pelvic pain / dyspareunia Ask about previous STIs Previous smears Number of lifetime partners Previous h/o HPV infection H/O vaccination against HPV Smoking Diet Long term use of oral contraceptives Long term use of intra-uterine devices Family history.

 

Assessment – HPV cannot be conventional methods Identification is by detection of HPV DNA from clinical specimens
 Any woman presenting with
○ significant alterations in menstrual cycle
○ IMB , PCB , PMB
○ vaginal discharge or pelvic pain

undertake a full pelvic examination including speculum examination of the cervix

If the cervix looks abnormal /malignancy suspected – refer for colposcopy under 2 wk USC

 

HPV vaccine Major milestone in preventing cervical cancer Monovalent HPV 16 Bivalent HPV 16, 18 Quadrivalent HPV 6, 11 , 16 and 18 9-valent vaccine- Gardasil 9 in USA Proven to be safe , immuonogenic and highly efficacious Can be administered as 2-3 dose series based on age at initiation and medical conditions In UK boys and girls aged 12 to 13 are offered HPV vaccine Two doses 1st is when they are in school year 8 and 2nd dose 6-24 months after the first dose In England individuals remain eligible for HPV vaccine up to age 25 if they did not get vaccinated previously Men who have sex with men and attend Specialist Health Services or HIV clinics can also get the vaccine It is estimated that protection from HPV vaccine lasts about 10 yrs and booster doses are not required.

 

When to refer to Gynecology for suspected cervical cancer may not be always very clear – the following points may help in deciding on the next course of action
 Symptoms can be quite non specific and easily attributed to a benign benign conditions or may not even manifest until the cancer has reached an advanced stage
 If symptomatic the most common reported symptoms include
○ abnormal vaginal bleeding
○ intermenstrual bleeding
○ post coital bleeding
○ post-menstrual bleeding

other reported symptoms may include dyspareunia and abnormal vaginal discharge

In line with above the Scottish Referral Guidelines for Suspected Cancer suggests that ” any woman with clinical features ie vaginal discharge , postmenopausal , postcoital or persistent intermenstrual bleeding and abnormality suggestive of cervical cancer on examination of the cervix ” should be referred as USC
 Women may present at any age with Ca cervix but
○ rare before age 25
○ it mainly affects sexually active women from 30-45 yrs
 Genital chlamydia trachomatis infection features can overlap with symptoms of cervical cancer – test and treat as appropriate
 It also does not help that the risk of cervical cancer is not related to the duration and extent of symptoms

References

  1. BNF- HPV Vaccine overview Human papillomavirus vaccine | Treatment summary | BNF content published by NICE
  2. Fowler JR, Jack BW. Cervical Cancer. [Updated 2021 Jan 6]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2021 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK431093/
  3. Zhang, Shaokai et al. “Cervical cancer: Epidemiology, risk factors and screening.” Chinese journal of cancer research = Chung-kuo yen cheng yen chiu vol. 32,6 (2020): 720-728. doi:10.21147/j.issn.1000-9604.2020.06.05
  4. Cohen PA, Jhingran A, Oaknin A, Denny L. Cervical cancer. Lancet. 2019 Jan 12;393(10167):169-182. doi: 10.1016/S0140-6736(18)32470-X. PMID: 30638582. ( Abstract )
  5. Denny L, Herrero R, Levin C, et al. Cervical Cancer. In: Gelband H, Jha P, Sankaranarayanan R, et al., editors. Cancer: Disease Control Priorities, Third Edition (Volume 3). Washington (DC): The International Bank for Reconstruction and Development / The World Bank; 2015 Nov 1. Chapter 4. Available from: https://www.ncbi.nlm.nih.gov/books/NBK343648/ doi: 10.1596/978-1-4648-0349-9_ch4
  6. Cervical cytology 1. Introduction and an overview of the evolution of the Pap smear to cervical cancer screening as it is today | Eurocytology
  7. Ault, Kevin A. “Epidemiology and natural history of human papillomavirus infections in the female genital tract.” Infectious diseases in obstetrics and gynecology vol. 2006 Suppl (2006): 40470. doi:10.1155/IDOG/2006/40470
  8. CDC Epidemiology and Prevention of Vaccine Preventable Diseases HPV Pinkbook | HPV | Epidemiology of Vaccine Preventable Diseases | CDC
  9. Comprehensive Cervical Cancer Control: A Guide to Essential Practice. 2nd edition. Geneva: World Health Organization; 2014. 1, Background. Available from: https://www.ncbi.nlm.nih.gov/books/NBK269623/
  10. Cervical Cancer statistics -Cancer Research UK Cervical cancer statistics | Cancer Research UK
  11. NICE Guidance NG 12 1 Recommendations organised by site of cancer | Suspected cancer: recognition and referral | Guidance | NICE
  12. British Gynaecological Cancer Society (BGCS) Cervical Cancer
    Guidelines: Recommendations for Practice *FINAL-Cx-Ca-Version-for-submission.pdf (bgcs.org.uk)
  13. Scottish Referral Guidelines for Suspected Cancer Gynaecological Cancers (scot.nhs.uk)

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