HPV Infections, Cervical Dysplasia and the HPV Vaccine; What will the future bring?
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This document discusses HPV infections, cervical dysplasia, and the HPV vaccine. It provides information on HPV epidemiology, risk factors for cervical cancer, pathogenesis and progression of HPV infection to cervical dysplasia and cancer. Screening recommendations and management of abnormal Pap smears and cervical dysplasia are summarized. The history and development of HPV vaccines including Gardasil and Cervarix are briefly outlined.
HPV Infections, Cervical Dysplasia and the HPV Vaccine; What will the future bring?
- 1. Darlene G. Gibbon, MD Medical Director of Gynecologic Oncology Summit Medical Group HPV Infections, Cervical Dysplasia and the HPV Vaccine What Will the Future Bring?
- 2. The Partnership Summit Medical Group MD Anderson Cancer Center offers cancer patients in Northern New Jersey access to cancer treatments that are among the most advanced in the nation. Our experts adhere to the multi-disciplinary care, treatment innovations and standards of care of MD Anderson Cancer Center’s clinical leadership and provide a full range of multi-disciplinary care options, including medical oncology, surgery and radiation. We offer leading oncology services covering all aspects of patient care, from routine screenings, diagnostics, treatment and surgery to survivorship in Berkeley Heights, Morristown and Florham Park. New Radiation Oncology Department in Berkeley Heights Artist rendering of Florham Park facility opening this year.
- 3. Summit Medical Group MD Anderson Cancer Center Cancer services include: • Breast Care Center • Hematology and Oncology • Infusion Center • Gynecologic Oncology • Radiation Oncology • Surgical Oncology
- 4. Cervical Carcinoma • 2016 ACS estimates 12,990 women diagnosed 4,120 will die • Most common cancer in developing countries Higher incidence and mortality rates • 80% of all cases and deaths occur • Decline incidence and mortality developed countries Establishment Pap smear screening programs • 50% women diagnosed with cervical cancer never had Pap Smear 10% not screened within prior 5 years prior diagnosis.
- 5. Epidemiologic Risk Factors for Cervical Carcinoma • Young age at first coitus 26 fold increase if within 1 year menarche • Multiple sexual partners • Sexual partner with multiple sexual partners • Sexual partner with sexual partner with cervical cancer • Smoking • Lower socioeconomic status • Young age at first pregnancy or marriage
- 6. HPV and Cervical Carcinoma • Mid-1970’s causal relationship HPV and cervical neoplasia Epidemiologic research suggested sexually transmitted etiology • HPV DNA detected > 90% cervical cancers Up to 94% of women pre-invasive lesions 46% women with cytologically normal findings Environmental, viral and host-related factors involved for cancer to occur • Smoking • Most infections are transient Cleared in an average of 8-24 months
- 7. Shah, KV. Sexually Transmitted Diseases, 1990 The HPV Virus • Non-enveloped double stranded DNA virus More than 70 types sequenced • High Risk Types 16,18,45,56 • Intermediate Risk Types 31,33,35,39,51,52,55,58,59,66,68 • Low Risk Types 6,11,26,42,44,54,70,73
- 8. US HPV Statistics • More than 50% sexually active men and women infected with HPV sometime in their life.1 • 6.2 million people infected each year1 • Estimated 74% new HPV infections occur 15-24 year olds.2 Women <25 prevalence rates 28%-46%. 3,4 • $8 Billion estimate of expenditures prevention and treatment of HPV related disease (https://www.ncbi.nlm.nih.gov/pubmed/22867718) 1. CDC. Rockville, Md: CDC National Prevention Information Network; 2004. 2. Weinstock H, Berman S, Cates W Jr. Perspect Sex Reprod Health. 2004;36:6–10. 3. Burk RD, Ho GYF, Beardsley L, Lempa M, Peters M, Bierman R. J Infect Dis. 1996;174:679–689. 4. Bauer HM, Ting Y, Greer CE, et al. JAMA. 1991;265:472–477.
- 9. HPV Associated Cancers US Site Female Male HPV Positive (% Total) Cervix 10,846 100 Vulva 2,266 40 Vagina 601 40 Anal/rectal 1,935 1,083 90 Airway 1,702 5,658 26 Penis 628 80 Total 17,350 7,568 Watson M et al. Cancer 2008;113:2841
- 10. De San Jose et al. Lancet Infect Dis. 2007; 7: 453-9. meta-analysis of 78 studies including 157,879 women with normal cytology Estimated Worldwide HPV Prevalence
- 11. Cohen. Science. 2005; 308:620-21. HPV Infection and Cervical Cancer
- 12. HPV Infections and Adolescents • 50% adolescent and young women acquire HPV within 3 years after initiating sexual intercourse • 40% women aged 14-19 years were infected with HPV • Younger women higher rates cervical infections than older women • HPV is a transient infection Duration infections generally 7-10 months 70-93% infection undetectable within 3 years • Cervical dysplasia is a result of HPV viral replication • 90% LSIL young women regress within 2-3 years Average time to clearance of LSIL is 8 months Regression of dysplasia parallels the clearance of the HPV virus
- 13. HPV Life Cycle in Squamous Epithelium Kahn. NEJM 2009;361:271-8.
- 14. HPV Persistence • Majority infections transient 80% clear 12 to 18 months • Resolution HPV type results in immunity to that type 50-60% women develop serum antibodies after natural infection • Women who do not clear the infection or have persistent disease remain at risk for cancer • Possible risk factors for persistence HPV type (16, 18) Immune suppression and genetic/HLA markers Variants of specific HPV type Infection with multiple HPV types High viral load Age
- 15. HPV Infection and Progression Cervical Dysplasia Wheeler. Obstet Gynecol Clin N Am 2008;35:519–536
- 16. Median Time Detection Dysplastic Abnormalities Abnormality From first detection of HPV to developing CIN2 or CIN3 First detection HPV to developing abnormal Pap Smear No cases of CIN grade 2-3 among HPV negative women 1048 person-years of observation Winer et al. J Infect Dis. 2005;191:731-8. Median Time 14.1 months 4 months
- 17. Lau and Franco. CMAJ. 2005;173:771-4. Prevalence of HPV LGSIL, HGSIL by Age
- 18. Rationale HPV Testing and Cervical Cancer Screening • More sensitive than Pap test • Upstream carcinogenic process Longer safety margin for screening interval • Automated, centralized and quality-checked for large specimen throughput • More cost-effective than cytology if deployed for high- volume testing • More logical choice screening if vaccinated against HPV
- 19. Changes Last 21 Years • FDA Approvals 1996 ThinPrep® approved for Pap Smear Screening 1999 Surepath approved 2002 HPV Test (Digene ®) approved 2002 Chlamydia and Gonorrhea testing approved from ThinPrep ® Pap Test Vial 2005 ThinPrep ® approved detection endocervical and endometrial glandular lesions 2006 Approval of Gardasil ® for HPV related diseases 2008 Approval of Gardasil ® for HPV related Vulvar and Vaginal diseases 2009 Approval of Gardasil ® for prevention Genital Warts in men 2009 Approval of Cervarix ® for prevention HPV related diseases in women 2014 Approval of Gardasil 9 ® 2015 Approval Gardasil 9 ® extended to include boys/men 16 – 26 2016 Approval Gardasil 9 ® to include 2 dose regimen individuals 9 - 14
- 21. Liquid Based Cytology • First approved FDA in 1996 • Cells suspended liquid transport medium Minimizes artifact interferes with interpretation • Can perform reflex HPV DNA testing • Bethesda Pap Smear Classification System Standardize reporting Pap smear results Communicate cytologic findings unambiguous terms that were clinically relevant Facilitate peer review and quality assurance
- 22. Bethesda Pap Smear Classification System • Requirements Statement of Adequacy • Blood, inflammation • Cell sampling Diagnostic Categorization Description of Cytologic Abnormality • Inflammation • Infection with organism specified • Reactive or reparative change • Epithelial cell abnormalities • Hormonal evaluation
- 23. Diagnostic Categorization Bethesda System (2001) • Atypical Squamous Cells Undetermined Significance (ASCUS) • Atypical Squamous Cells Undetermined Significance – cannot exclude High Grade Squamous Epithelial Lesion (ASC-H) • Atypical Glandular Cells (AGC) Specify endocervical or endometrial glandular cells Atypical glandular cells favor neoplastic • Low-grade squamous intraepithelial lesion (LSIL) • High-grade squamous intraepithelial lesion (HSIL) • Endocervical adenocarcinoma in situ (AIS) • Squamous Cell Carcinoma or Adenocarcinoma
- 24. Screening Recommendations ACOG Practice Bulletin 2016
- 25. Management Abnormal Pap Smear • Based on American Society of Colposcopy and Cervical Pathology guidelines Historically treatment decisions based on Cytology results alone • Variables to consider Age of patient Severity of cytologic abnormality HPV status
- 26. HPV Positive Normal Cytology
- 27. ASCUS Pap Smear
- 28. ASCUS – H Pap Smear 21-24 Year-Olds
- 29. ASCUS-H Pap Smear 30 and Older
- 30. Low Grade Squamous Intraepithelial Lesion
- 31. ASCUS or Low Grade SIL 21 – 24 Year-Olds
- 32. Colposcopy and Directed Biopsy • Lighted binocular microscope • Indications Abnormal pap smear or HPV testing Abnormal or suspicious cervix Unexplained bleeding after intercourse History utero diethylstilbesterol (DES) exposure • Application acetic acid Clean off mucous Dehydration cells areas increased nuclear density leads to acetowhite epithelium • Transformation Zone Area metaplastic squamous epithelium Located between original squamocolumnar junction and new squamocolumnar junction • Directed biopsy treatment planning based pathology
- 33. Colposcopic Images • Assessment abnormalities cervix Acetowhite epithelium Mosaicism Punctation Abnormal Vasculature
- 34. Management Cervical Dysplasia and Carcinoma • Based upon severity of dysplasia and treatment algorithms • Observation • LEEP (Loop Electrocautery Excisional Procedure) • Cold Knife Cone Biopsy • Simple Hysterectomy Used to treat either dysplasia or microinvasive carcinomas Women no longer interested in childbearing • Radical Hysterectomy Used to treat cervical cancer Women not interested in childbearing or lesion too large • Radical Trachelectomy Used to treat cervical cancer For women diagnosed with cancer still interested in childbearing
- 36. Management of Abnormal Pap Smear
- 38. Management CIN 2,3 in Young Women
- 39. Management Cervical Dysplasia • Loop Electrocautery Excision Procedure (LEEP) • Laser ablation or laser cone • Cold knife cone biopsy • Hysterectomy
- 40. Cold Knife Cone Procedure (www.medicalimages.allrefer.com)
- 42. Da Vinci Robotic Platform
- 43. Risk Factors for Cervical Carcinoma • Young age at first coitus 26 fold increase if within 1 year menarche • Multiple sexual partners Sexual partner with multiple sexual partners • Sexual partner with sexual partner with cervical cancer • Smoking • Lower socioeconomic status • Young age at first pregnancy or marriage • Immunosuppression
- 44. Diagnosis Cervical Carcinoma • Symptoms include Abnormal vaginal bleeding • Intermenstrual bleeding • Abnormal menstrual bleeding • Bleeding after intercourse (Postcoital) • Postmenopausal bleeding Vaginal discharge Pelvic pain Pain in hip, groin or leg (sciatic) • Diagnosis made by history and physical examination Tissue biopsy Staging based upon clinical extent of disease
- 45. Radiographic Imaging in Cervical Cancer Staging • Positron Emission Tomography (PET) scans Useful in detecting metastatic disease Uptake of dye is based on metabolism of cells • CT scans of the Abdomen and Pelvis Treatment planning and evaluation lymph node • Nodes greater than 1cm considered abnormal • Not utilized in staging • MRI Determine tumor diameter and parametrial infiltration (tissue next to the cervix) • Useful adjunct to clinical evaluation in treatment planning
- 46. Surgical Management of Cervical Carcinoma • Cold Knife Cone Biopsies Microinvasive squamous cell or adenocarcinomas Adenocarcinoma in-situ • Simple hysterectomy Microinvasive squamous cell or adenocarcinomas • Radical hysterectomy with pelvic and periaortic lymph node dissection • Radical trachelectomy (Fertility preservation)
- 47. Radiation Therapy with Chemotherapy • Early stage disease Age, obesity, size of cervical lesion Metastatic disease to lymph nodes • Advanced stage disease • External beam and intracavitary radiation • External beam radiation Decrease the size of the cervical tumor Directed upper vagina, cervix, paracervical tissues and pelvic nodes Daily Monday to Friday for 5 ½ weeks • Intracavitary radiation or Brachytherapy Delivers higher dose radiation to cervix and surrounding tissue • Chemotherapy is given with the first part of radiation the External Beam treatment Weekly and usually Cisplatin is used as a radiation sensitizer
- 48. Brachytherapy
- 49. So what can we do to prevent the development of Cervical Dysplasia or Cervical Carcinoma?
- 50. VACCINATE!
- 51. HPV Vaccine • HPV L1 protein antigen in both vaccines Proteins assemble themselves into virus-like particles Identical to HPV virus without viral DNA core • Induce a virus neutralizing antibody response No infectious or oncogenic risk • Gardasil ® 6,11,16,18 • Cervarix ® 16, 18 • Gardasil 9® 6, 11, 16, 18, 31, 33, 45, 52, and 58
- 52. Efficacy: Gardasil 99.5% Efficacious Against HPV -16 and -18 Related CIN 2/3 or ACIS Population Protocol 005* Protocol 007 FUTURE I FUTURE II Combined protocols n 755 231 2,200 5,301 8,487 Gardasil Cases 0 0 0 1 1 n 750 230 2,222 5,258 8,460 Placebo Cases 12 1 19 42 53 Efficacy 100% 100% 100% 98% 99.5 95% CI 65.1- 100 -3734.9-100 78.5- 100 86- 100 92.9- 100 * Evaluated only the HPV-16 L1 VLP component of Gardasil
- 53. Vaccination Recommendations Advisory Committee on Immunization Practices • Routine vaccination children ages 11-12 Can start as early as age 9 • Vaccination recommended women ages 13-26 • Vaccination recommended men ages 13-21 Men between 22 – 26 can be vaccinated Men who have sex with men or are immunocompromised should be vaccinated through age 26 • Should be Gardasil ® or Gardasil9® • HPV vaccine schedule interrupted the vaccine series does not have to be restarted • Cannot be administered if anaphylactic latex allergy • Not recommended for use pregnant women Pregnancy test prior to vaccination not required www.cdc.gov
- 54. Monitoring Vaccine Safety • Vaccine Adverse Event Reporting System (VAERS) Early warning public health system used by CDC and FDA No proven causal association between vaccine and adverse event • Only association is time cannot establish causal relationship Non-serious adverse events are those other than hospitalization, death, permanent disability or life threatening illness. • Vaccine Safety Datalink (VSD) Project CDC and 8 health organizations Study patterns in reports detected by VAERS Determine if vaccine is causing side effect • Clinical Immunization Safety Assessment (CISA) Network Project between 6 academic centers US conduct research adverse events caused by vaccines
- 55. Adverse Events Following HPV Vaccine (www.cdc.org) • Most common adverse reactions Local reactions at the site of injection. Pain, redness, or swelling, were reported by 20% to 90% of recipients. • Temperature of 100°F during the 15 days after vaccination was reported in 10% to 13% of HPV vaccine recipients. A similar proportion of placebo recipients reported an elevated temperature. • Variety of systemic adverse reactions have been reported by vaccine recipients, including nausea, dizziness, myalgia and malaise. However, these symptoms occurred with equal frequency among both HPV vaccine and placebo recipients. • No serious adverse events associated with HPV vaccine. Syncope (fainting) can occur after any medical procedure, including vaccination. Adolescents should be seated or lying down during vaccination and remain in that position for 15 minutes after vaccination.
- 56. Conclusions • Cervical dysplasia and cervical cancer can be prevented by preventing infection by the HPV virus • Vaccination of children and young adults is critical to stopping HPV related disease • Following established guidelines can prevent the progression of cervical dysplasia to the development of a cervical cancer. • In the future screening for cervical cancer will likely be based on HPV testing alone.