Human Papillomavirus  and Oral Cancer   in Taiwan  Speaker: Ken-Liao Liu Instructors: Prof. Huei Lee, Ya-Wen Cheng Dec. 19...
 
Oral cancer in Taiwan (Epidemiologic data) <ul><li>4 th  incidence & mortality rate in  men . </li></ul><ul><li>1 st  in 2...
In the past 20 years…  (Worldwide data) <ul><li>Treatment Strategies: </li></ul><ul><li>Operable :  Surgery +/- Radiochemo...
<ul><li>Particularly urgent question in  oral  and  oropharyneal  cancers:  </li></ul><ul><li>The acute & prolonged toxici...
In the past 20 years: <ul><li>HPV causes Cervical cancers. </li></ul><ul><li>HPV associated with some S.C.C. & their precu...
<ul><li>38.3%  (92/240) HPV16-positive HNSCC.  </li></ul><ul><li>HPV-16-positive  : independently associated with sexual b...
<ul><li>72/100 HPV16 DNA in paraffin-embedded tumor specimens </li></ul><ul><li>64% of cancers seropositive for HPV16 onco...
<ul><li>Maura Gillison, JHKCC (2008): </li></ul><ul><li>“ The risk factors are completely  distinct  and  do not overlap ....
<ul><li>“ Someday, HPV +/- tumors might be staged as  two separate diseases , in the way that small-cell & non-small-cell ...
<ul><li>IARC  in Dec. 2007 concluded: </li></ul><ul><li>“ Sufficient evidence in humans for the  carcinogenicity  of HPV 1...
<ul><li>Clinical question : </li></ul><ul><li>“Are there useful tumor biomarkers ?” </li></ul><ul><li>“Should the HPV-posi...
<ul><li>Epidemiologic & Laboratory studies. </li></ul><ul><li>Clinical Treatment trial : still in planning stage ! </li></ul>
Clinical impact <ul><li>Jatin Shah, M.D., Memorial Sloan-Kettering Cancer Center, chairs AJCC  H.&N. (2008): </li></ul><ul...
Clinical impact: HPV effect on tumor staging & treatment ? <ul><li>“ The time may come when HPV status will be a factor, …...
HPV effect on tumor staging & treatment ? <ul><li>Arlene Forastiere, professor of JHKCC, chairs NCCN H.&N. committee (2008...
Prevention & Screening? <ul><li>Aimee Kreimer, Ph.D., division of cancer prevention at NCI in Bethesda (2008): </li></ul><...
Prevalence of HPV in Oral Cancer
 
HPV16: 68.2% 86.7% 69.2%
 
 
<ul><li>Tumor site-specific HPV prevalence was higher among studies from North America compared with Europe & Asia. </li><...
HPV appears to play an etiologic role in many cancers of the oropharynx and possibly a small subgroup of cancers of the or...
<ul><li>From  Australia </li></ul><ul><li>American Journal of Pathology.  2003;163:2185-2189  </li></ul><ul><li>0 /16 HPV ...
In Taiwan… <ul><li>HPV ? </li></ul><ul><li>Areca ? </li></ul><ul><li>Mechanism? </li></ul><ul><li>Subgroup of  HNSCCs ? </...
Clinical Question: <ul><li>Different propensity to metastasis (lymph nodes, lung, bone, liver) in different patients ? </l...
In Taiwan… <ul><li>HPV association with Oral Cancer ? </li></ul>
Am J Clin Pathol 2003; 120: 909-916
<ul><li>High-risk HPV types and all HPV types had odds ratios of 3.97 (P = .0097) and 3.92 (P = .006), respectively.  </li...
The positive rates : 75%  (69/92) by  nested PCR-based genechips , 53%  (49/92) by  overexpression of p16INK4A  (ISH),   4...
aDepartment of Otolaryngology, Chang Gung Memorial Hospital-Kaohsiung Medical Center,  Chang Gung University College of Me...
<ul><li>12.6%  (14/111, 1992~2005)  T SCC HPV-positive </li></ul><ul><li>The favorable 5-year survival rate correlated sig...
In Taiwan…. <ul><li>HPV vs Areca ? </li></ul>
<ul><li>30% oral dysplasia, 38% oral SCC (n=106) with p53+ staining by IHC studies of BQ-related lesions, but a consistent...
29 OSCC cases 29 controls In situ  PCR ISH
<ul><li>Univariate analysis:  </li></ul><ul><li>HPV16, 18 </li></ul><ul><li>betel quid chewing  significant risk factors <...
Our Data:
 
Comparison of HPV16/18 prevalence in tumor sites of cases & controls. 4 (9.1%) 35 (46.1%) Oral Cavity 12 (26.1%) 14 (22.6%...
 
 
HPV vs Areca-chewing in cases & controls
HPV vs Areca-chewing in cancer cases  Higher HPV16 + in Non-areca-chewing pharyngeal cancer
HPV v.s. P53 in oral cancers: Molecular Classification
p53  mutations in  25 /138
 
 
 
Joint assessment of  p53 /HPV status :  4 biomarker subgroups
Summary: HPV <ul><li>HPV 16 + : </li></ul><ul><li>Cancer  > control  </li></ul><ul><li>( 25.4% vs 5.6%, p<0.001) </li></ul...
Summary: HPV/Areca <ul><li>Most cancer cases are advanced stages, but HPV16/18+ prevalence is significantly higher in  T1 ...
Summary: p53 <ul><li>Higher  p53  mutation in pharynx than in oral cavity (33.9% vs 11.8%) in cancer cases. </li></ul><ul>...
Summary <ul><li>Joint assessment of p53/HPV status shows difference between oral cavity & pharynx. </li></ul><ul><li>HPV i...
Ongoing/Future Work <ul><li>Survival Analysis & Tx/Prognostic significance ? </li></ul><ul><li>Mechanisms of HPV Infection...
<ul><li>Developing strategies for : </li></ul><ul><li>the screening, diagnosis, prevention and treatment of HPV-associated...
<ul><li>Thanks for Your Attention  ! </li></ul>
 
 
 
 
 
 
 
 
 
 
Brief Summary <ul><li>Oral & pharyngeal Ca. dominant in Male. </li></ul><ul><li>(96.4% v.s. 3.6%) </li></ul><ul><li>HPV 16...
In cancer cases <ul><li>Higher  HPV 16/18 + in  oral cavity  than in pharynx  </li></ul><ul><li>(49.2 % v.s. 14.3%,  P<0.0...
<ul><li>HPV 16/18 + more in  Stage I  cancer cases </li></ul><ul><li>(table 2.) </li></ul><ul><li>HPV 16, Gender, Areca-ch...
<ul><li>In Taiwan,  Buccal Ca  dominant in oral cavity. </li></ul><ul><li>Very different from Non-areca-chewing countries ...
Clinical Implications of HPV vs HNSCC (OSCC) poorly differentiated Basaloid, advanced stage Histopathology ♂ ♂ =♀ Gender L...
Molecular Classification
 
 
 
 
<ul><li>J Oral Maxillofac Surg 2008, 66(9): 1875-80. </li></ul><ul><li>The overall frequency of HPV16 in oral tongue cance...
<ul><li>From  Italy </li></ul><ul><li>Modern Pathology. 2008 Oct 31   </li></ul><ul><li>2% of 314 SCC limited to oral cavi...
<ul><li>Oral Oncol 2008, 44(3): 242-50 </li></ul><ul><li>19%  cases HPV DNA + (14/72)  </li></ul><ul><li>5%  of controls (...
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HPV & Oral Cancer in Taiwan by Dr. Ken Liao Liu 劉耿僚

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HPV & Oral Cancer in Taiwan by Dr. Ken Liao Liu 劉耿僚

  1. 1. Human Papillomavirus and Oral Cancer in Taiwan Speaker: Ken-Liao Liu Instructors: Prof. Huei Lee, Ya-Wen Cheng Dec. 19, 2008.
  2. 3. Oral cancer in Taiwan (Epidemiologic data) <ul><li>4 th incidence & mortality rate in men . </li></ul><ul><li>1 st in 25~44 y/o men since 2005 . </li></ul><ul><li>Cost in National Health Insurance: </li></ul><ul><li>4 billion in 2007. </li></ul><ul><li>Smoking, Alcohol (Western); </li></ul><ul><li>+ Areca in Taiwan ! </li></ul><ul><li>(NPC excluded) </li></ul>
  3. 4. In the past 20 years… (Worldwide data) <ul><li>Treatment Strategies: </li></ul><ul><li>Operable : Surgery +/- Radiochemotherapy </li></ul><ul><li>Inoperable : CCRT </li></ul><ul><li>5-yr Survival: ~ 40% , not improved much in the past 2 decades. </li></ul>
  4. 5. <ul><li>Particularly urgent question in oral and oropharyneal cancers: </li></ul><ul><li>The acute & prolonged toxicity of current treatment can result in life-long problems with swallowing & speech. </li></ul><ul><li>Pts are more likely to be young, that can mean many decades of severely impaired quality of life. </li></ul>
  5. 6. In the past 20 years: <ul><li>HPV causes Cervical cancers. </li></ul><ul><li>HPV associated with some S.C.C. & their precursors -- skin, vulva, vagina, penis, esophagus, conjunctiva, paranasal sinuses, & bronchus. </li></ul><ul><li>HPV DNA detection in HNSCC: 0~100% worldwide. </li></ul>
  6. 7. <ul><li>38.3% (92/240) HPV16-positive HNSCC. </li></ul><ul><li>HPV-16-positive : independently associated with sexual behavior and exposure to marijuana , </li></ul><ul><li>But not with tobacco smoking, alcohol drinking, or poor oral hygiene. </li></ul><ul><li>CONCLUSIONS: HPV-16-positive and HPV-16-negative HNSCCs have different risk factor profiles , indicating that they should be considered to be distinct cancers . </li></ul>Johns Hopkins Kimmel Comprehensive Cancer Center JNCI 2008 100(6):407-420
  7. 8. <ul><li>72/100 HPV16 DNA in paraffin-embedded tumor specimens </li></ul><ul><li>64% of cancers seropositive for HPV16 oncoprotein E6 or E7 </li></ul>Johns Hopkins Bloomberg School NEJM 2007;356;1944-56
  8. 9. <ul><li>Maura Gillison, JHKCC (2008): </li></ul><ul><li>“ The risk factors are completely distinct and do not overlap .” </li></ul><ul><li>“ These are actually completely different cancers that happen to occur in the same place.” </li></ul>
  9. 10. <ul><li>“ Someday, HPV +/- tumors might be staged as two separate diseases , in the way that small-cell & non-small-cell lung cancer are.” </li></ul>
  10. 11. <ul><li>IARC in Dec. 2007 concluded: </li></ul><ul><li>“ Sufficient evidence in humans for the carcinogenicity of HPV 16 in the oral cavity & oropharynx .” </li></ul>
  11. 12. <ul><li>Clinical question : </li></ul><ul><li>“Are there useful tumor biomarkers ?” </li></ul><ul><li>“Should the HPV-positive tumors be treated the same or differently ?” </li></ul>
  12. 13. <ul><li>Epidemiologic & Laboratory studies. </li></ul><ul><li>Clinical Treatment trial : still in planning stage ! </li></ul>
  13. 14. Clinical impact <ul><li>Jatin Shah, M.D., Memorial Sloan-Kettering Cancer Center, chairs AJCC H.&N. (2008): </li></ul><ul><li>“… This is very groundbreaking work, …but it remains to be proven that these are distinct pathological entities.” </li></ul>
  14. 15. Clinical impact: HPV effect on tumor staging & treatment ? <ul><li>“ The time may come when HPV status will be a factor, … but there needs to be a lot more science before that.” </li></ul>
  15. 16. HPV effect on tumor staging & treatment ? <ul><li>Arlene Forastiere, professor of JHKCC, chairs NCCN H.&N. committee (2008): </li></ul><ul><li>“ It wound be premature to make (clinical) practice changes … quite dangerous, really.” </li></ul>
  16. 17. Prevention & Screening? <ul><li>Aimee Kreimer, Ph.D., division of cancer prevention at NCI in Bethesda (2008): </li></ul><ul><li>“ It’s so new. We don’t know the natural history of oral HPV infection.” </li></ul>
  17. 18. Prevalence of HPV in Oral Cancer
  18. 20. HPV16: 68.2% 86.7% 69.2%
  19. 23. <ul><li>Tumor site-specific HPV prevalence was higher among studies from North America compared with Europe & Asia. </li></ul><ul><li>Small sample size & publication bias complicate the assessment of the prevalence in H.& N. beyond the oropharynx. </li></ul>
  20. 24. HPV appears to play an etiologic role in many cancers of the oropharynx and possibly a small subgroup of cancers of the oral cavity. The most common HPV type in genital cancers (HPV16) was also the most common in these tumors. The mechanism of transmission of HPV to the oral cavity warrants further investigation.
  21. 25. <ul><li>From Australia </li></ul><ul><li>American Journal of Pathology. 2003;163:2185-2189 </li></ul><ul><li>0 /16 HPV DNA+ in tonsil cancer specimens from Chinese patients </li></ul><ul><li>46% (31/67) from Australian patients </li></ul><ul><li>(PCR & Sequencing) </li></ul>
  22. 26. In Taiwan… <ul><li>HPV ? </li></ul><ul><li>Areca ? </li></ul><ul><li>Mechanism? </li></ul><ul><li>Subgroup of HNSCCs ? </li></ul><ul><li>Prognostic Significance ? </li></ul>
  23. 27. Clinical Question: <ul><li>Different propensity to metastasis (lymph nodes, lung, bone, liver) in different patients ? </li></ul><ul><li>Different response to (post-operative) radiochemotherapy ? </li></ul><ul><li> No Useful Clinical Markers to Differentiate ! </li></ul>
  24. 28. In Taiwan… <ul><li>HPV association with Oral Cancer ? </li></ul>
  25. 29. Am J Clin Pathol 2003; 120: 909-916
  26. 30. <ul><li>High-risk HPV types and all HPV types had odds ratios of 3.97 (P = .0097) and 3.92 (P = .006), respectively. </li></ul><ul><li>The results suggest that HPVs, particularly high-risk HPVs, might be associated with the development of OSCCs, especially the non-OH-associated OSCCs. </li></ul>
  27. 31. The positive rates : 75% (69/92) by nested PCR-based genechips , 53% (49/92) by overexpression of p16INK4A (ISH), 44% (40/92) by high-risk HPV (ISH) Both overexpression of P16INK4A and high-risk HPV (ISH) positivity were associated with favorable prognoses and also independent prognostic factors .
  28. 32. aDepartment of Otolaryngology, Chang Gung Memorial Hospital-Kaohsiung Medical Center, Chang Gung University College of Medicine, Kaohsiung 83301, Taiwan Oral Oncology,2008, 44(2), 174-179
  29. 33. <ul><li>12.6% (14/111, 1992~2005) T SCC HPV-positive </li></ul><ul><li>The favorable 5-year survival rate correlated significantly with : </li></ul><ul><li>HPV positivity ( p  = 0.007) </li></ul><ul><li>female ( p  = 0.046) </li></ul><ul><li>early tumor (T) ( p  < 0.001) </li></ul><ul><li>Cox’s regression analysis : status of HPV ( p  = 0.04) and T stage ( p  = 0.004) were independent prognostic factors for survival. </li></ul><ul><li>Conclusion: </li></ul><ul><li>Prevalence of HPV-related Tonsil SCC is much lower in Taiwan comparing with the Western population , </li></ul><ul><li>Better prognosis of HPV+ than HPV- in TSCC. </li></ul>
  30. 34. In Taiwan…. <ul><li>HPV vs Areca ? </li></ul>
  31. 35. <ul><li>30% oral dysplasia, 38% oral SCC (n=106) with p53+ staining by IHC studies of BQ-related lesions, but a consistent absence in VH and VC. </li></ul><ul><li>p53-positive SCCs had a higher recurrence rate than p53-negative ones. </li></ul><ul><li>HPV-6/11 was detectable in 10% of dysplasia and 13% of SCC, but in neither VH nor VC. </li></ul><ul><li>HPV-16/18, however, was consistently negative for all types of lesions. </li></ul><ul><li>HPV plays an insignificant role in the tumorigenesis of BQ-related oral cancers, although a cooperative role may exist between the benign -type HPV and BQ chewing. </li></ul>
  32. 36. 29 OSCC cases 29 controls In situ PCR ISH
  33. 37. <ul><li>Univariate analysis: </li></ul><ul><li>HPV16, 18 </li></ul><ul><li>betel quid chewing significant risk factors </li></ul><ul><li>cigarette smoking </li></ul><ul><li>. (HPV6 and 11 were not.) </li></ul><ul><li>Multivariate analysis: </li></ul><ul><li>HPV16 infection (adjusted OR = 11.21) </li></ul><ul><li>betel quid chewing (adjusted OR = 17.06) remained to be independent factors for OSCC. </li></ul><ul><li>CONCLUSIONS: HPV16 and betel quid chewing were two major risk factors for OSCC in Taiwan </li></ul><ul><li>( different mechanisms ?) </li></ul>
  34. 38. Our Data:
  35. 40. Comparison of HPV16/18 prevalence in tumor sites of cases & controls. 4 (9.1%) 35 (46.1%) Oral Cavity 12 (26.1%) 14 (22.6%) Pharynx Control 16/90 Case 49/138 HPV16 or 18+
  36. 43. HPV vs Areca-chewing in cases & controls
  37. 44. HPV vs Areca-chewing in cancer cases Higher HPV16 + in Non-areca-chewing pharyngeal cancer
  38. 45. HPV v.s. P53 in oral cancers: Molecular Classification
  39. 46. p53 mutations in 25 /138
  40. 50. Joint assessment of p53 /HPV status : 4 biomarker subgroups
  41. 51. Summary: HPV <ul><li>HPV 16 + : </li></ul><ul><li>Cancer > control </li></ul><ul><li>( 25.4% vs 5.6%, p<0.001) </li></ul><ul><li>Esp. in oral cavity ( 34.2% vs 0%) </li></ul><ul><li>In control group, </li></ul><ul><li>HPV 16/18 prevalence: </li></ul><ul><li>pharynx > oral cavity </li></ul><ul><li>(26.1% vs 9.1%, p<0.05) </li></ul><ul><li>But contrarily in cancer group, </li></ul><ul><li>pharynx < oral cavity </li></ul><ul><li>(22.6% vs 46.1%, p<0.05) </li></ul>
  42. 52. Summary: HPV/Areca <ul><li>Most cancer cases are advanced stages, but HPV16/18+ prevalence is significantly higher in T1 & Stage I . </li></ul><ul><li>Areca-chewing/HPV are significantly correlated only in pharyngeal cancer : Higher HPV+ in non-areca-chewing . </li></ul>
  43. 53. Summary: p53 <ul><li>Higher p53 mutation in pharynx than in oral cavity (33.9% vs 11.8%) in cancer cases. </li></ul><ul><li>Prevalence of p53 “mutations” is indeed lower (18.1% by sequencing) in our cases than expected. </li></ul><ul><li>? Because p53 protein degradation by E6 may supercede p53 mutations in HPV+ cancers. </li></ul><ul><li>p53 mutation increases N+ significantly, esp. in pharyngeal cancer. </li></ul>
  44. 54. Summary <ul><li>Joint assessment of p53/HPV status shows difference between oral cavity & pharynx. </li></ul><ul><li>HPV infection plays a role in oral cavity cancers without p53 mutation. </li></ul>
  45. 55. Ongoing/Future Work <ul><li>Survival Analysis & Tx/Prognostic significance ? </li></ul><ul><li>Mechanisms of HPV Infection & Carcinogenesis in Oral Cancers ? </li></ul><ul><li>? p16 overexpression in HPV+ cases </li></ul>
  46. 56. <ul><li>Developing strategies for : </li></ul><ul><li>the screening, diagnosis, prevention and treatment of HPV-associated diseases </li></ul>
  47. 57. <ul><li>Thanks for Your Attention ! </li></ul>
  48. 68. Brief Summary <ul><li>Oral & pharyngeal Ca. dominant in Male. </li></ul><ul><li>(96.4% v.s. 3.6%) </li></ul><ul><li>HPV 16 + significantly increased in ca. cases </li></ul><ul><li>(25.4% v.s. 5.0%) </li></ul><ul><li>(table 1.) </li></ul>
  49. 69. In cancer cases <ul><li>Higher HPV 16/18 + in oral cavity than in pharynx </li></ul><ul><li>(49.2 % v.s. 14.3%, P<0.001, table 2.) </li></ul><ul><li>Lower p53 mutation rate in oral cavity than in pharynx </li></ul><ul><li>(11.5% v.s. 26.5%, P=0.042, table 4.) </li></ul>
  50. 70. <ul><li>HPV 16/18 + more in Stage I cancer cases </li></ul><ul><li>(table 2.) </li></ul><ul><li>HPV 16, Gender, Areca-chewing : statistically significant related </li></ul><ul><li>(table 3.) </li></ul>
  51. 71. <ul><li>In Taiwan, Buccal Ca dominant in oral cavity. </li></ul><ul><li>Very different from Non-areca-chewing countries (50% v.s. 10%). </li></ul>
  52. 72. Clinical Implications of HPV vs HNSCC (OSCC) poorly differentiated Basaloid, advanced stage Histopathology ♂ ♂ =♀ Gender Less sensitive, poor prognosis Sensitive, better prognosis ( Less “field cancerization”) Treatment (R/T , C/T) older - 5 years younger Age ┼ ─ /┼ Tobacco/alcohol ─ ↑ p16 expression ─ ↓ Protein p53 & pRb Mutated Wild type TP53 & Rb1 genes Non-HPV related HPV related
  53. 73. Molecular Classification
  54. 78. <ul><li>J Oral Maxillofac Surg 2008, 66(9): 1875-80. </li></ul><ul><li>The overall frequency of HPV16 in oral tongue cancer in this study was 1.96% (1/51). </li></ul><ul><li>[PCR with HPV L1 consensus primers (GP 5+/GP 6+) and HPV-16-specific E6 primer pairs] </li></ul>
  55. 79. <ul><li>From Italy </li></ul><ul><li>Modern Pathology. 2008 Oct 31 </li></ul><ul><li>2% of 314 SCC limited to oral cavity proper. </li></ul>
  56. 80. <ul><li>Oral Oncol 2008, 44(3): 242-50 </li></ul><ul><li>19% cases HPV DNA + (14/72) </li></ul><ul><li>5% of controls (6/129) </li></ul><ul><li>43% of cases (9/21) among tonsi l-related cancers (palatine tonsil and base of tongue) </li></ul><ul><li>19.32 (95%CI: 2.3-159.5) OR for tonsil-related cancers for high-risk HPV types </li></ul><ul><li>31.51 (95%CI: 4.5-219.7) equivalent OR for HPV 16 seropositivity </li></ul><ul><li>2.14 (95%CI: 0.4-13.0) OR of non-tonsillar oral cancers for high risk HPV DNA in oral cells </li></ul><ul><li>3.16 (95%CI: 0.8-13.0) OR for oral cancer seropositivity. </li></ul><ul><li>Results: Evidence supporting a strong causal association between HPV infection and tonsil-related cancers. The evidence for an etiologic link is less clear for non-tonsillar oral cancers. </li></ul>

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