Presented by Darlene G. Gibbon, MD, Medical Director of Gynecologic Oncology at Summit Medical Group

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

20. Liquid Based Cytology

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

35. Management Low
Grade Dysplasia

36. Management of
Abnormal Pap Smear

37. Management Low
Grade Dysplasia

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)

41. Types of Hysterectomies

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.