Cervical cancer

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Cervical cancer

  1. 1. Cervical Cancer KHALID SAIT FRCSC PROFESSOR COLLAGE OF MEDICINE KING ABDULAZIZ UNIVERSITY DIRECTOR OF GYNECOLOGICAL ONCOLOGY UNIT
  2. 2. Cancer of Cervix According to the Saudi registry 2007 Is the 13th most frequent cancer in saudi women and the 6th in women age 15-44 years This is in contrast to Canada where it is the second most common cancer The incidence rate in Saudi Arabia is one of the lowest in the world at 1.9 cases per 100,000 women, accounting for 2.6% of diagnosed cancer cases in women .
  3. 3. In Canada, where they have active screening, the most recent cervical cancer rate is 7 cases per 100,000 women and the most recent mortality rate is 3 deaths per 100,000 women. Prior to the introduction of screening, the rates were greater than 25 cases per 100,000 women, which is comparable to current rates in many nations in Central America
  4. 4. Current estimates in Saudi Arabia indicate that every year, 152 women are diagnosed with cervical cancer and 55 die from the disease. It is anticipated that as the population ages, there will be a dramatic increase in the incidence of cervical cancer. The estimated number of new cervical cancer cases and deaths in 2025 are 309 and 117,
  5. 5. n  Cancer cervix caused by A virus
  6. 6. On December 10 / 2008. a Nobel Prize awarded for finding HPV and proving its link to cervical cancer to Dr Harad Zur Hausen
  7. 7. Human papillomavirus n  HPV is a relatively small virus1 containing circular double-stranded DNA within a spherical shell (capsid)1 100 nm 1. Burd EM. Clin Microbiol Rev 2003; 16:1–17.
  8. 8. Global HPV Statistics 16.6%4 Concordia, Argentina 40.2%–41.6%6 Harare, Zimbabwe 13.3%2 Ontario, Canada 18%*,7 Shanxi Province, China *Among women 30–45 years of age 1. World Health Organization; 2001. Available at: http://www.who.int/vaccines/en/hpvrd/shtml. Accessed July 12, 2004. 2. Sellors JW, Mahony JB, Kaczorowski J, et al. CMAJ. 2000;163:503–508. 3. Lazcano-Ponce E, Herrero R, Muñoz N, et al. Int J Cancer. 2001;91:412–420. 4. Matos E, Loria D, Amestoy GM, et al. Sex Transm Dis. 2003;30:593–599. 5. Clavel C, Masure M, Bory JP, et al. Br J Cancer. 2001;84:1616–1623. 6. Blumenthal PD, Gaffikin L, Chirenje ZM, McGrath J, Womack S, Shah K. Int J Gynecol Obstet. 2001;72:47–53. 7. Belinson J, Qiao YL, Pretorius R, et al. Gynecol Oncol. 2001;83:439–444. n  Worldwide prevalence of HPV infection is estimated to be between 9% and 13%: ~630 million infected individuals.1 n  Estimated prevalence of HPV infection in selected geographic areas: 14.5%3 Morelos State, Mexico 15.3%5 Reims, France
  9. 9. Normal epithelium Basement membrane Basal (stem) cells Parabasal cells Squamous layer Mature squamous layer Infected epitheliu Cervical canal HPV infects basal layer of cervical epithelium HPV lifecycle in the cervix Adapted from Frazer IH. Nat Rev Immunol 2004; 4:46–54. Virus particles are assembled and virus released Virus uses host cell to replicate viral DNA and express virally encoded proteins
  10. 10. How can HPV infection lead to cervical cancer? n  There are several steps in the pathway from HPV infection to cervical cancer n  Initial infection – viral entry into target basal epithelial cells n  HPV integrates into the host genome n  HPV oncogenes (E6 & E7) are expressed n  Cytogenetic instability results n  Genetic changes allow uncontrolled cell growth (immortalization) n  Malignant transformation to cervical carcinoma occurs
  11. 11. Progression of cervical carcinogenesis Normal cervix Mild cytological abnormalities and/or CIN1 Cervical cancer Progression Infection HPV- infected cervix Precancer Persistent infection CIN = cervical intraepithelial neoplasia; CIN1 = CIN grade 1 Precancer is equivalent to CIN2/3 Adapted from Schiffman M & Kruger Kjaer S. J Natl Cancer Inst Monogr 2003; 31:14–19. CIN1: 57% CIN2: 43% CIN3: 32% Clearance : Months Years > 20 years
  12. 12. Cancer of the Cervix Clinical presentation n  Abnormal vaginal bleeding n  Postmenopausal Vaginal bleeding n  Vaginal discharge n  Pain n  Asymptomatic
  13. 13. Invasive Disease
  14. 14. Cancer of the Cervix Histological types n  Squamous cell carcinoma:cell size/keratin/grade n  Adenocarcinoma ( endocervical , endometroid, villoglandular, serious and clear cell) n  Adenosquamous n  Anaplastic small cell carcinoma (neuroendocrine type ) n  Sarcoma n  Melanoma n  Lymphoma
  15. 15. Cancer of the Cervix Mode of spread n  Direct n  Lymphatic n  Hematogenous
  16. 16. Cancer of the Cervix Investigations n  EUA n  Complete blood count n  Liver function test n  Renal function tests n  CXR/IVP or CT n  Cystoscopy n  Sigmoidoscopy
  17. 17. Cancer of the Cervix FIGO Staging ( clinical ) n  I - Tumour confined to the cervix n  II- Upper 2/3 vagina / parametrium. n  III- Lower 1/3 vagina / pelvic side wall or hydronephrosis n  IV- Adjacent organ / Distant metastasis
  18. 18. Cancer of Cervix Prognostic Factors n  Stage/extend of parametrial involvement and margin n  Bulkiness/volume of tumours n  LVS and nodal involvement n  Technique: linac. vs cobalt / point A dose/ RT delay / brachy expertise n  Performance status/age/co- morbidity/socioeconomic n  Tumour type-HPV, grade n  DNA poloidy n  Proliferation markers- apoptosis index/SF2 n  Raf kinase, p53 mutation,VEGF n  Tissue / tumour hypoxia/HG level
  19. 19. Cancer of the Cervix Treatment of patients n  Radical Hysterectomy and lymphadnectomy n  Radiation Therapy and chemotherapy
  20. 20. n  Pelvic Radiation EBR and Brachytherapy
  21. 21. EBR
  22. 22. Dose n  Unit n  GRAY (Gy) = 100 cGy n  External RT n  40 – 50 Gy over 4-5 wks( 25 fractions) n  Brachytherapy n  35 – 40 Gy(LDR) n  HDR
  23. 23. The role of chemotherapy n  To improve the results of RT n  Concurrent chemo during RT, (standard) 5 out of 7 randomized trails had shown survival benefit (10-15%) with 50% reduction in mortality. n  Cisplatin is the most active single agent
  24. 24. RECURRENT CERVICAL CANCER n  Treatment depends on: n  Site of recurrence n  Mode of primary therapy n  Pelvic recurrence after RH will be treated with external beam radiation and possible brachytherapy n  Central local recurrence: Pelvic Exenteration: n Anterior n Posterior n Total Distal Recurrence need palliative treatment with chemotherapy
  25. 25. Cancer of the Cervix stage/survival Stage 5 years survival % Ia1 100 Ia2 95 Ib1 85 Ib2 70 II 50-60 III-IV 10-40
  26. 26. Cervical Cancer Prevention n  Primary prevention n  Secondary prevention
  27. 27. Pap Smear n  Developed by Dr. George N. Papanicolaou in 1940s
  28. 28. Pap Smear n  The data for effectiveness of pap come from case control and cohort studies rather than RCT. n  Pap test become diffused so quickly that an RCT was not possible
  29. 29. Evidence of Benefit n  Cervical cancer rates have fallen more than 50% in the past 30 years in the US. The incidence of cervical cancer fell from 14.8 per 100,000 women in 1975 to 6.5 per 100,000 women in 2006. n  Iceland: 80% reduction in mortality over 20 years n  Finland: 50% reduction n  Sweden: 34% reduction
  30. 30. n  Before pap instruction:
  31. 31. Pap Smear
  32. 32. Source: ThinPrep Pap Test Package Insert ThinPrep Pap Test: FDA Labeling n  November 1996 n  Approved as a replacement for the conventional Pap
  33. 33. l Cells are collected in a vial of solution l  Fully automated l  Minimizes blood, mucus, non-diagnostic debris Dispersion Cell collection Cell transfe r Processor Liquid Based Cytology
  34. 34. Conventional Pap Smear" Liquid Based Pap Overcoming the Limitations of the Conventional Pap Smear l  Majority of cells not captured l  Non-representative transfer of cells l  Clumping and overlapping of cells l  Obscuring material l  Virtually all of sample is collected l  Randomized, representative transfer of cells l  Even distribution of cells l  Minimizes obscuring material Source: Hutchinson ML, et al. Am J Clin Pathol. 1994;101:215-219.
  35. 35. for Cervical Cytology: The 2001 Bethesda System n  Two types of atypical squamous cells (ASC)4 n  Atypical squamous cells of undetermined significance (ASC-US) n  Atypical squamous cells, cannot exclude high-grade squamous intraepithelial lesions (ASC-H) n  Squamous intraepithelial lesions (SIL)4 n  Low-grade SIL (LSIL): HPV infection, cervical intraepithelial neoplasia 1 (CIN 1) n  High-grade SIL (HSIL): Moderate and severe dysplasia, CIN 2/3, carcinoma in situ (CIS) Normal1 ASCUS2 LSIL3 HSIL3
  36. 36. ACOG revised recommendations November 20, 2009 n  From age 21 if married n  Women from ages 21 to 30 be screened every two years instead of annually, using either the standard Pap or liquid-based cytology. n  • Women age 30 and older who have had three consecutive negative cervical cytology test results may be screened once every three years with either the Pap or liquid-based cytology. n  It is reasonable to stop cervical cancer screening at age 65 or 70 among women who have three or more negative cytology results in a row and no abnormal test results in the past 10 years.
  37. 37. ACOG revised recommendations November 20, 2009 n  •. Routine cervical cytology testing should be discontinued in women (regardless of age) who have: had a total hysterectomy for noncancerous reasons, as long as they have no history of high-grade CIN n  • Women with certain risk factors may need more frequent screening, including those who have HIV, are immunosuppressed, were exposed to diethylstilbestrol (DES) in utero, and have been treated for cervical intraepithelial neoplasia (CIN) 2, CIN 3, or cervical cancer.
  38. 38. Abnormal pap does not mean that its cancer
  39. 39. Colposcopy
  40. 40. a grape-like or "sea-anemone"
  41. 41. Pap Dx Preceding Histologic High-Grade Neoplasia AGUS LSIL HSIL ASCUS Source: Kinney W, et al. Obstet Gynecol. 1998;91: 973-976. 20% 10% 31% 39%
  42. 42. Classification of Histological Findings: Cervical Intraepithelial Neoplasia 1. Bonnez W. In: Richman DD, Whitley RJ, Hayden FJ, eds. Washington, DC: American Society for Microbiology Press; 2002:569–612. 2. Ostor AG. Int J Gynecol Pathol. 1993;12:186–192. CIN1 Normal CIN 1 (condylom a) CIN 1 (mild dysplasia) CIN 2 (moderate dysplasia) CIN 3 (severe dysplasia/CIS) Invasive Cancer Histology of squamous cervical epithelium1 Basal cell Basal membrane
  43. 43. RCT
  44. 44. Basic of HPV vaccination n  Stimulate B cells to produce neutraliize antibodies. n  Neutralizing antibodies bind to HPV’s outer shell (L 1 capsid protein) and prevent infection of host cells Infection No infection HPV infects target cells in the basal layer of the cervical epithelium Neutralizing antibodies prevent HPV from infecting basal epithelial cells Basal cell layer of cervical epithelium 1. Stanley M, et al. Vaccine 2006; 24(Suppl 3):S106–S113.
  45. 45. Active protection via vaccination is mediated by neutralizing antibodies at the cervix HPV Cervical canal Neutralizing antibodies Blood vessel Epithelial tear Basement membrane Cervical epithelium 1. Stanley M. Vaccine 2006; 24:S16–S22; 2. Giannini S, et al. Vaccine 2006; 24:5937–5949; 3. Nardelli-Haefliger D, et al. J Natl Cancer Inst 2003; 95:1128–1137; 4. Poncelet S, et al. IPC 2007(poster).
  46. 46. Components of HPV Vaccine n  Virus like particals ( VLPS): mimic the native virus structure n  Adjuvant Adjuvants augment the specific immune response to vaccine antigens n  Aluminium-based compounds are the most widely used adjuvants n  AS04 was designed to enhance the immune response even more than traditional adjuvants by incorporating the immunostimulant MPL
  47. 47. + Aluminium salt (amorphous aluminium hydroxyphosphate sulphate [AAHS]) HPV 16 VLPs HPV 18 VLPs HPV 6 VLPs HPV 11 VLPs Antigens Composition of Cervarix™ and Gardasil® + HPV 16 VLPs HPV 18 VLPs Antigens AS04 adjuvant AS04-containing vaccine AAHS-containing vaccine Adjuvant + Aluminium salt (Al(OH)3) MPL Immunostimulant Cervarix™ Gardasil®
  48. 48. Product characteristics – prophylactic HPV vaccines CervarixTM1 Gardasil®2 Antigen VLPs of HPV 16 & 18 VLPs of HPV 16, 18, 6 & 11 Adjuvant AS04 (Al(OH)3 + MPL) AAHS Expression system Baculovirus expression vector Yeast Administration 0, 1 & 6 months by intramuscular injection 0, 2 & 6 months by intramuscular injection 1. CervarixTM. European Summary of Product Characteristics, 2007; 2. Gardasil®. European Summary of Product Characteristics, 2008.
  49. 49. HPV VACCINE n  Sustained high efficacy for up to 7.5 years against HPV 16 and 18 incident and persistent infections, and CIN1+ and CIN2+ lesions n  Modelling studies predict that high antibody titres could be sustained for decades n  The actual duration of protection will only be established by long-term efficacy studies
  50. 50. Even with the vaccine pap smear should continue to be done…..
  51. 51. Jeddah Cervical Screening program JCSP
  52. 52. Suggested Screening Strategy n  Use the high sensitivity of HPV test initially n  Digene Hybrid capture 2 test is suitable n  Positive HPV test has reflex pap testing n  If both positive colposcopy is performed n  If HPV neg repeat screen in 5 years n  If HPV +ve and pap neg, repeat HPV and pap in 1 year
  53. 53. Jeddah Cervical Screening program n Who's legible for the program v  Women at or above 30 year and not more the 65 year old v  Married for 3 years.
  54. 54. Jeddah Cervical Screening program n  What are the unique about this program v  Free test . v  For Saudi and Non Saudi. v  Screening , diagnosis ( colposcopy) and treatment in one center v  Continuous follow up and recall and reminder v  Maintaining confidentiality v  Academic staff and comfortable environment v  Raise awareness and education on prevention methods v  Allow self registration online v  Kauh file is not required
  55. 55. Jeddah Cervical Screening program n  Objectives of the program v  Decrease the incidence of cervical cancer. v  Early detection of preinvasive cervical disease. v  Provide treatment and optimal management for patients with cervical cancer. v  Provide recall and reminder systems to ensure adequate follow-up of women with screen-detected abnormalities. v  Ensuring optimal quality of Pap smear reading through a quality assurance program for laboratories
  56. 56. Cervical Cancer KHALID SAIT FRCSC PROFESSOR COLLAGE OF MEDICINE KING ABDULAZIZ UNIVERSITY DIRECTOR OF GYNECOLOGICAL ONCOLOGY UNIT

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