Natural history and pathogenesis of hpv

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Natural history and pathogenesis of hpv

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Natural history and pathogenesis of hpv

  1. 1. NATURAL  HISTORY  AND   PATHOGENESIS  OF  HPV. HASSAN  M  LATIFAH  MD  FRCSC   GYNECOLOGIC  ONCOLOGY   KFSH&RC  -­‐  JEDDAH  
  2. 2. §  Incidence  and  worldwide  burden  of  cervical   cancer.   §  Phylogenetic  tree  of  HPV.   §  Pathogenesis  and  natural  history.   §  Genomic  background.   §  HPV  infection  at  cellular  level.   §  Conditions  required  for  transition  into   cervical  cancer  .   §  Cofactor  interaction  with  HPV.   §  Summary.    
  3. 3. Ferlay J, et al. GLOBOCAN 2002 Cancer Incidence, Mortality and Prevalence Worldwide. IARC CancerBase; Lyon; 2004. The most frequent cancers in women: incidence and mortality Global data Incidence Mortality Age-standardized rate per 100,000 Breast Cervix Colon/ Rectum Lung Stomach Ovary Corpus 0 5 10 15 20 25 30 35 40 37.4 16.2 14.6 12.1 10.3 6.6 6.5 Breast Lung Cervix Stomach Colon/ Rectum Liver Ovary 0 2 4 6 8 10 12 14 13.2 10.3 9.0 7.9 7.6 5.7 4.0 Age-standardized rate per 100,000
  4. 4. Worldwide Cancer Burden* 471 379 154 193 142 101 75 132 117 55 65 39 0 100 200 300 400 500 600 579 91 292 125 175 91 114 34 16 66 47 61 100200300400500600 Breast Cervix uteri Colon/Rectum Stomach Lung Ovary Corpus uteri Liver Oesophagus Non-Hodgkin lymphoma Leukaemia Pancreas More developed Less developed 2,176,000 2,562,000 Thousands Total Women
  5. 5. PAPILLOMAVIRUS  INFECTIONS  OF   THE  HUMAN  GENITAL  TRACT   §  Over  100  HPV  types  have  been  identified  to   date,  of  which  over  40  infect  the  genital  tract.   §  HPVs  primarily  target  infections  of  the  basal   cells  in  the  stratified  squamous  epithelium   and  metaplastic  cells  within  squamocolumnar   junctions.  
  6. 6. Muňoz N, et al. Int J Cancer 2004; 111:278–285. HPV  types  in  cervical  cancer   worldwide  HPVgenotype 35 58 52 33 31 45 18 16 53.5 70.7 77.4 80.3 82.9 85.2 87.4 88.8 0 10 20 30 40 50 60 70 80 90 100 Cervical cancer cases attributed to the most frequent HPV genotypes, % 53.5 17.2 6.7 2.9 2.6 2.3 2.2 1.4 Cumulative percentage
  7. 7. Papillomavirus  phylogenetics   important  to  understand  cross   protection    HPV18-­‐  Related     45,  39,  59,  51,  56   HPV16-­‐  Related     31,  33,  35,  52,  58  
  8. 8. Normal     epithelium   Basement  membrane   Basal  (stem)     cells   Parabasal     cells   Squamous     layer     Mature     squamous   layer   Infected     epithelium   Cervical  canal             HPV  Lifecycle  in  the  Cervix    Frazer  IH.  Nat  Rev  Immunol  2004;4:46–54   Infection  of   basal  cells                       Viral  assembly                                                                                                   Shedding  of  virus-­‐ laden  epithelial  cells   Episomal  viral  DNA  in   cell  nucleus                                                                                                   Viral  DNA  replication                                                                                                   Uptake  &  internalisation  of   HPV  occurs  within  2  hours  
  9. 9. Co-factors: OC use, parity, other STDs Co-factors: smoking, host (HLA, p53 polymorphism) Persistent HPV infection with oncogenic types Transient HPV infection Sexual activity: woman and her male partners Invasive cervical cancer Low grade lesions High grade lesions Normal cervical epithelium Viral factors: variants and viral load Co-factors: nutrition A Multifactorial Model of Cervical Cancer Etiology Spence, et al. AJC 2005.
  10. 10. Natural  Course  of  Genital  HPV   Infection   First Lesion Immune Response Incubation Active Growth       Sustained clinical remission Persistent or recurrent disease Infection Seroconversion Average time 9mo Low risk HPVs clear more rapidly than high risk HPVs HPV 16 infection lasts on average 12-18 months
  11. 11. Genomic  background   §  All  PV(s)  share  a  similar   genomic  organization   consisting  of  an  early  (E)   gene  region  ,  a  late(L)   gene  region  and  a   regulatory  region.     §  The  5  early  proteins   (E1,E2,E5,E6and  E7)          are  required  for  viral   replication  and  /or   cellular  transformation.    
  12. 12. Role  of  E6  and  E7.   §  Expression  of  the  E6  oncoprotein  allows  the  infected  cell   to  be  insensitive  to  antigrowth  signals  and  to  evade   apoptosis.   §  Expression  of  the  E7  oncoprotein  leads  to  insensitivity  to   antigrowth  signals  and  the  immortalization  of   keratinocytes.    
  13. 13. §  HPV    mediated  oncogenesis  requires   accumulation  of  additional  genetic  mutations   over  time  .     §  This  suggests  a  long  precancerous  state  in   most  cases  of  invasive  cancer  that  allows  the   accumulation  of  secondary  genetic  mutations   along  with  other  cofactors  such  as  smoking  ,   carcinogens  and    hormonal.              
  14. 14. Human  PV(s)  and  cervical   neoplasia.   §  4  steps  in  the  development  of  cervical   cancer  :            1-­‐Infection  of  the  metaplastic  epithelium  of   the    TZ  with  one  or  more  carcinogenic  HPV.          2-­‐Viral  persistence  .          3-­‐Progression  to  CIN3.          4-­‐Invasion.  
  15. 15. Anatomy  of  the  TZ   §  The  TZ  is  defined  as  that   area  lying  between  the   original  SCJ  and  the   colposcopic  new  SCJ   §  Cervical  Cancer   originates  within   the  TZ.  
  16. 16. Squamous  metaplasia  :  a  pivotal  process   in  cervical  carcinogenesis   §  The  increase  in    E2   level  during  puberty   leads  to  eversion  of   the  endovervical   columnar  epithelium.   §  The  process  of  repair   results  in  replacement   with  squamous   metaplastic   epithelium.        
  17. 17. §  Potential  carcinogens  at  times  of  active   metaplasia  can  deviate  it  to  a  neoplastic   pathway.     §  The  lifetime  risk  for  development  of  cervical   cancer  is  increased  26  folds  if  age  at  first   intercourse  is  within  1  yr  of  menarche  .  
  18. 18. Steps  in  the  development  of   cervical  cancer.  
  19. 19. HPV  Immunology   §  Unlike  Hepatitis,  HPV  is   stealthy  &  evades   the  immune  system       §  Natural  infection  with  HPV  does  not  reliably   protect  against  future  infection  or   reactivation     §  Antibodies  are  considered  an  important   mediator  of  vaccine-­‐induced  protection  by   preventing  entry  of  the  virus  into  the  basal   cell    
  20. 20. Turn off the alarm systems Keep a low profile Don’t cause trouble – no violence       HPV – a Lesson in How to Evade the Forces of Law and Order
  21. 21. §  Most  HPV  infections  are  transient  and  usually   cleared  within  several  months  to  2  yrs.   §  90%  of  women  clear  a  specific  HPV  type  after   2  yrs  of  observation.   §  Only  persistent  high  risk  infection  of  the   cervical  epithelium  appears  to  trigger   neoplastic  progression.   §  HPV  type  is  the  strongest  factor  affecting  the   risk  of  viral  persistence  .      
  22. 22. §  Only  1  in  10  to  1  in  30  HPV  infections  are   associated  with  abnormal  cervical  cytology.   §  HPV  16  is  highly  carcinogenic  with  an  absolute   risk  of  CIN  3  approaching  40%          at    3-­‐5  yrs.     §  Up  to  1/3  of  women  have  more  than  1  HPV  type  .   §  The  average  time  from  HPV  infection  to  CIN  3            is  7-­‐15  yrs  ,  peaking  at  25-­‐30  yrs.      
  23. 23. Transition  into  invasive   cancer     §  The  seed  :  High  risk  HPV.     §  The  soil  :  Immature  metaplastic  epithelium  of   the  TZ.   §  The  median  age  of  women  with  cervical   cancer  is  2-­‐3  decades  later  than  for  CIN  3.   §  This  suggests  generally  a  long  average  transit   time  for  CIN  3  to  invasive  cancer.    
  24. 24. Time to acquisition of HPV infection among women free of HPV infection at enrollment 630 college-age women followed from 1996-01 Richardson, et al. CEBP 2003; 42:485-490. McGill-Concordia University  Student Cohort: 0 10 20 30 40 Time since enrollment (months) 0 0.1 0.3 0.2 0.5 0.4 0.6 0.7 Probabilityof incidentHPVinfection 0 10 20 30 40 Time since enrollment (months) 0 0.1 0.3 0.2 0.4 0.5 Probabilityoflow-riskHPV 0 10 20 30 40 Time since enrollment (months) 0 0.1 0.3 0.2 0.4 0.5 Probabilityof incidenthigh-riskHPV Any types Non-oncogenic types Oncogenic types
  25. 25. Clearance of a New HPV Infection: Ludwig-McGill and McGill-Concordia Cohorts 1.00 0.75 0.50 0.25 0.00 0 4 12 16 20 24 28 32 368 1.0 0.8 0.6 0.4 0.2 0.0 Time Since Diagnosis of Infection ProportionRemainingPositive ForAnyHPVType 0 12 24 36 40 Franco, et al. JID 1999; 180:1415-1423. Richardson, et al. CEBP 2003; 42:485-490.
  26. 26. Cofactor  Interaction  with  HPV.     §  Cigarette  smoking  has  been  demonstrated  to  be  a   risk  factor  for  cervical  and  vulvar  carcinoma.       §  Nicotine,  cotinine,  hydrocarbons,  and  tars  are  found   in    cervical  secretions  of  smokers.   §  The  mutagenic  activity  of  these  products  in  cervical   cells,  similar  to  that  observed  in  lung  cells,  point  to   an  important  role  for  these  compounds  in  cervical   carcinogenesis.                              International  Collaboration  of  Epidemiological  Studies  of  Cervical  Cancer.                          Carcinoma  of  the  cervix  and  tobacco  smoking  :collaborative  reanalysis  of  individual  data  on  13  541  women  with  carcinoma  of  the  cervix   and  23  017  women  without  carcinoma  of  the  cervix  from  23  epidemiological  studies.  Int  J  Cancer  2006    
  27. 27. Infection  by  Other  Microbial   Agents.   §  Disruption  of  epithelial  integrity  and  reparative   metaplasia  associated  with  acute  cervicitis  caused  by   Chlamydia  trachomatis,  NG,    HSV,  or  Trichomonas   vaginalis  may  increase  susceptibility  to  genital  HPV   infection.     §   Chlamydial  infection  in  HPV-­‐positive  women  is  also   associated  with  development  of  high-­‐grade  CIN  and   invasive  cancer  suggesting  a  possible  cofactor  role  .                      Samoff  E,  et  al.  Association  of  Chlamydia  trachomatis  with  persistence  of  high-­‐risk   human  papillomavirus  in  a  cohort  of  femal  eadolescents.  Am  J  Epidemiol2005:668–675  
  28. 28. Sex  hormonal  influences   §  Condylomata  acuminata  increase  rapidly  in  size  and  number  in   pregnancy.   §  Epidemiologic    studies  have  shown  an  increased  risk  of  CIN  in   long-­‐term  oral  contraceptive  pill  (OCP)  users.   §  Prospective  follow-­‐up  of  high-­‐risk  HPV-­‐positive  women  does  not   demonstrate  an  increased  risk  of  CIN  3  among  OCP  users  .       §  There  has  been  no  demonstrable  clinical  value  to  ceasing  oral   contraceptives  in  the  management  of  HPV-­‐associated  disease.                          Castle  PE  et  al    Hormonal  contraceptive  use,  pregnancy  and  parity,  and  the  risk  of  cervical   intraepithelial  neoplasia  3  among  oncogenic  HPVDNA-­‐positive  women  with  equivocal  or  mildly   abnormal  cytology.                            Int  J  of  Cancer  2005;117:1007–1012.        
  29. 29. Exogenous  and  endogenous   immunosuppression.   §  Renal  transplant  patients  have  16  times  higher   chance  of  developing  CIN  compared  to  general   population.     §  The  risk  of  CIN  and  Cx  Cancer  is  increased  in  HIV   positive  women  .   §  Hodgkin s  disease  ,  leukemia  and  collagen  vascular   diseases  are  associated  with  an  increased  incidence   and  recalcitrancy  of  HPV  associated  disease.    
  30. 30. Dietary  factors     §  Deficiencies  of  vitamin  A  or  beta  carotene   may  increase  the  risk  of  CIN  and  cervical   cancer  .   §  >  50  %  reduction  in  persistence  of  high  risk   HPV  DNA  has  been  shown  in  patients  with   higher  levels  of  Vit  A  byproducts  within  their   system  .  
  31. 31. Summary   §  There  are  over  40  common  genital  HPV  types   that  are  primarily  sexually  transmitted.       §  The  vast  number  of  women  will  be  infected  with   one  or  more  HPV  types  in  their  sexual  lifetime.     §  Persistent  infection  with  HPV  types  can  cause   abnormal  cytology  (Pap  tests)  including   diagnoses  of  ASC,  AGC,  LSIL,  and  HSIL,  as  well   as  abnormal  histology  identified  following  biopsy   diagnosis  as  CIN  1  to  3,  AIS,  and  cancer.  
  32. 32. §  Only  a  small  subset  of  women  infected  with  high-­‐risk   carcinogenic  HPV  will  develop  invasive  cervical  cancer.     §  Although  carcinogenic  HPV  is  a  necessary  cause  of  invasive   cervical  cancer,  a  number  of  cofactors  have  been  associated   with  HPV  persistence  and  HPV-­‐related  disease  progression   including:              (1)  viral  factors  such  as  genotype  (eg,  HPV  16)              (2)  tobacco  and  long-­‐term  oral  contraceptive  use            (3)  genetic  and  immunologic  host  factors  including  innate   immunity.    
  33. 33. Thank  you  

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