Pediatric Grand Rounds

Outline • Overview of Human Papillomaviruses

Genital Human Papillomavirus Infections Impact, Control, and Prevention

• What Are We Trying to Prevent? Epidemiology of Genital HPV Infections and Diseases

William Bonnez, M.D. Associate Professor of Medicine University of Rochester School of Medicine and Dentistry Rochester, New York

• How to Prevent? – Condoms – Cytologic Screening – HPV vaccination

The Women and Children's Hospital of Buffalo 219 Bryant St, Buffalo, NY Friday, June 27, 2008

Human Papillomaviruses (HPV) • Nonenveloped viruses enclosing a double stranded, circular DNA genome • Species specific • Tissue specific: Infect the stratified squamous epithelia and the cervical glandular epithelium • 107 fully characterized types (L1 gene DNA sequence); many more types exist • Cause latent, subclinical, and clinical infections

OVERVIEW OF HUMAN PAPILLOMAVIRUSES (HPV)

– Benign (warts, papillomas, condylomas) – Potentially malignant (precancers/incipient cancers = intraepithelial neoplasias = dysplasias) – Malignant (cancer) 3

HPV Types and Disease Association Frequent Association (HPV Type)

Less-Frequent Association (HPV Type)

Cutaneous warts

1, 2, 4

3, 7, 10, 26, 27, 28, 29, 38, 41, 49, 57, 63, 65, 75, 76, 77

Epidermodysplasia verruciformis

5, 8, 9, 12, 14, 15, 17

19, 20, 21, 22, 23, 24, 25, 36, 37, 38, 47, 49, 50, 93

Condylomata acuminata (Laryngeal papillomas)

6, 11

30, 42, 43, 44, 45, 51, 54, 70

Intraepithelial neoplasia

6, 11, 16, 18

30, 31, 33, 34, 35, 39, 40, 42, 43, 44, 45, 51, 52, 53, 56, 57, 58, 59, 61, 62, 64, 66, 67, 68, 69, 71, 72, 74, 82

Cervical carcinoma

Frazer IH. Nat Rev Immunol. 2004;4:46-54.

Anatomic Distribution of HPVs

Cutaneous HPVs Epidermodysplasia verruciformis HPV

16, 18

Mucosal/Genital HPVs (low risk) Mucosal/Genital HPVs (high risk)

31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 66, 67, 68, 70, 73, 82

Frazer IH. Nat Rev Immunol. 2004;4:46-54. Munoz N et al. N Engl J Med. 2003;348:518-527.

1

S. corneum S. granulosum S. spinosum S. basale Basal lamina 3rd Plexus

Acanthosis

Dead keratinocyte releasing viral particles Dead keratinocyte S. corneum Keratin S. granulosum

Infection

Epidermis

Hyperkeratosis Parakeratosis Koilocyte

Papillomatosis

HPV Induces Epidermal Proliferation

Koilocytosis Is a Characteristic Hallmark of HPV Infection

Keratohyaline granule Koilocyte Vacuole Nucleus Inclusion body

Dermis

S. spinosum Tonofibrils

2nd Plexus Artery

S. basale

Vein 1st Plexus

A

HPV virion HPV DNA

Lymphatic vessel

Basal lamina

B

Source: Bonnez W, Reichman RC. Papillomaviruses. In: Mandell GL et al eds. Principles and Practice of Infectious Diseases. 6th ed. Philadelphia, Pa: Elsevier/Churchill Livingstone; 2005:1841-1856.

The Transformation Zone Is Most Vulnerable to HPV-related Disease

Courtesy of Mark Stoler, MD.

The Transformation Zone Birth to M enarche

The squamo-columnar junction marks the transition from a stratified squamous to a glandular epithelium

NSCJ

NSCJ

OSCJ

M enarche - 40's

T-zone

Peri- Postmenopausal

NSCJ

OSCJ

T-zone

OSCJ

T-zone

Cutaneous HPVs Epidermodysplasia verruciformis HPVs Mucosal/Genital HPVs (low-risk)

TZ

TZ

Mucosal/Genital HPVs (high-risk) Squamous epithelium Columnar epithelium

From Condyloma to Cancer Bethesda Classification Cervical Intraepithelial Neoplasia

Normal

Low-grade squamous intra-epithelial lesion Flat CIN 1 condyloma

High-grade squamous intra-epithelial lesion CIN 2

CIN 3

O SCJ = O riginal squamo-columnar junction NSCJ = New squamo-columnar junction T-zone = Region between original and new squamo-columnar junction

HPV16 GENOMIC ORGANIZATION Invasive cancer

Histology of the Squamous Cervical Epithelium basal layer basal membrane

Associated HPV Types (Relative Frequency)

negative or other HPV types HPV 6, 11, 42, 43, 44 HPV 31, 33, 35, 52, 58

90% 80% 70% 60% 50% 40%

HPV 16

30%

HPV 18, 45, 56

10%

20%

The prevalence of high-risk oncogenic HPVs increases with the severity of the lesion Modified from Bonnez W. Papillomavirus. In: Richman RD et al eds. Clinical Virology. 2nd ed. Washington, DC: American Society for Microbiology; 2002:557-596.

2

HPV E6 & E7 Oncogenic Proteins Interact With Some of the Main Cancer Gene Pathways Controlling Cell Birth and Cell Death

From Condyloma to Cancer Bethesda Classification

E6

E7

Normal

Cervical Intraepithelial Neoplasia

High-grade squamous intra-epithelial lesion

Low-grade squamous intra-epithelial lesion Flat CIN 1 condyloma

CIN 2

CIN 3

Invasive cancer

Histology of the Squamous Cervical Epithelium basal layer basal membrane

Associated HPV Types (Relative Frequency)

negative or other HPV types

90% 80%

HPV 6, 11, 42, 43, 44 HPV 31, 33, 35, 52, 58

70% 60% 50% 40%

HPV 16

30%

HPV 18, 45, 56

10%

20%

The prevalence of high-risk oncogenic HPVs increases with the severity of the lesion Modified from Bonnez W. Papillomavirus. In: Richman RD et al eds. Clinical Virology. 2nd ed. Washington, DC: American Society for Microbiology; 2002:557-596.

Vogelstein B & Kinzler KW. Nature Medicine. 2004; 10: 789

Clinical Spectrum of Genital Infections

Clinical Spectrum of Genital Infections

Cervical Condyloma Genital Warts

CIN 2,3

Invasive Cancer

Laryngeal Papilloma Courtesy of JT Cox, MD.

Prevalence and Incidence of HPV Infection in the US * • Approximately 20 million people are currently infected with HPV in the United States1

The Economic Burden of Genital HPV Infections in the United States, 20001 General Population

Persons 15–24 Years of Age

– 50% are aged 15 to 24 years

• Annual incidence of sexually transmitted HPV infection is ~6.2 million1 – 74% of new infections occur in 15 to 24 year

olds2

• Overall, an estimated 80% of sexually active men and women are exposed to HPV at some point in their lives3

$ 3.6 billion

$ 2.7 billion $ 146.4 million $ 167.4 million

$ 108.3 million $ 123.9 million

Follow-up of Abnormal Paps and Treatment of CIN US Census (2004) (15-44 years old) = 124 million. HPV=human papillomavirus. 1. Weinstock H et al. Perspect Sex Reprod Health. 2004;36:6-10. 2. Chesson HW et al. Perspect Sex Reprod Health. 2004;36:11-19. 3. Koutsky LA et al. Epidemiol Rev.1988;10:122-163.

Treatment of Invasive Cervical Cancer Treatment of External Anogenital Warts 1. Chesson HW, Blandford JM, Gift TL, Tao G, Irwin KL. Perspect Sex Reprod Health. 2004;36:11–19.

3

HPV Cervical Infections Descriptive Epidemiology

EPIDEMIOLOGY

19

HPV Infections in the United States 1% 4% 10%

25%

Genital warts Detected by colposcopy or cytology HPV DNA positive: Colposcopy negative

~75% of population exposed to HPV

Presence of antibodies (negative HPV test) Not currently infected

60%

Factors Associated With Higher Risk of HPV Infection Women • Age1,2 • Sexual behavior1,2 – Increased risk associated with a greater number of male sexual partners1-3 – Risk increases with earlier age of first sexual intercourse4 • Sexual behaviors of previous male sexual partners1,2 • Immunological status2 – HPV more likely in immunosuppressed women

Age-Specific Prevalence of HPV Infection • In the US, there is a constant decline with advancing age • In other countries (eg, Costa Rica), there is an unexplained recrudescence past age 50 40 35

Portland, OR

30

Guanacaste, Costa Rica

25

Men • Lifetime number of sexual partners5 • Number of recent sexual partners5 • Uncircumcised5 • Same sex encounters6

4. Moscicki AB et al. JAMA. 2001;285:2995-3002. 5. Schiffman M et al. J Natl Cancer Inst Monogr. 2003;31:14-19. 6. Chin-Hong PV. J Infect Dis. 2004;190:2070-2076.

1. Ho GY et al. N Engl J Med. 1998;338:423-428. 2. Koutsky L et al. Am J Med. 1997;102:3-8. 3. Karlsson R et al. Sex Transm Dis. 1995;22:119127

Koutsky L et al. Am J Med. 1997;102:3-8.

HPV + (%)

20

Prevalence of HPV Infection Among Women in the US1, 2 Add Health1

NHANES2

Sample Source

Urine

Vaginal

Relative Sensitivity of Assay

~75%

100%

Overall

26.9%

26.8%

Ages 18-26

26.9%

Prevalence

20

Ages 14-19

15

Ages 20-24

10

1 lifetime sexual partner

5

High-risk types Types included in the vaccine

0 16-20 21-25 26-30 31-35 36-40 41-45 46-50 51-55 56-60 61-65 66-70 71-75 76+ Age Schiffman M, Kjaer SK. J Natl Cancer Inst. 2003;3:14-19.

1.3,262 sexually active women age 18-25 from the Wave III of the National Longitudinal Study of Adolescent Health (Add Health) Manhart LE et al. Sex Transm Dis. 2006; 33: 502-508

44.8% 27.4% 14.3%

11.5%

20%

15.2%

10%

3.4%

2.1,921 females age 14-59 participating to the National Health and Nutrition Examination Survey (NHANES) Dunne EF et al. JAMA. 2007: 297: 813-819

4

All High-Risk HPV Are not Equally Carcinogenic

All High-Risk HPV Are not Equally Carcinogenic

Clifford G, Franceschi S, Diaz M, et al. Vaccine 2006;24 Suppl 3:S26-34

Clifford G, Franceschi S, Diaz M, et al. Vaccine 2006;24 Suppl 3:S26-34

Prevalence of HPV Cervical Diseases HPV Cervical Diseases Descriptive Epidemiology

• Low-grade squamous intraepithelial lesion (LSIL)

1.97%

• High-grade squamous intraepithelial lesion (HSIL)

0.51%

• Squamous cell carcinoma

0.026%

• Adenocarcinomas

2.5%

0.0046%

• Atypical squamous cells (ASC)

2.8%

– Of unknown significance (ASC-US) – Cannot exclude HSIL (ASC-H)

27

Prevalence of HPV Cervical Diseases

Stoler MH. Mod Pathol. 2000;13:275-284.

Epidemiology of Cervical Cancer Cervical Cancer is the second most common cancer in women worldwide

• Low-grade squamous intraepithelial lesion (LSIL)

1.97%

• High-grade squamous intraepithelial lesion (HSIL)

0.51%

• Squamous cell carcinoma • Adenocarcinomas

0.026% 0.0046%

Lung

2.5%

Breast

499 558

Stomach Liver

543

Cervix uteri Oesophagus

– Of unknown significance (ASC-US) – Cannot exclude HSIL (ASC-H)

2.8%

337 293

902 810

Colon/Rectum

Prostate

• Atypical squamous cells (ASC)

370 446

255

Bladder Non-Hodgkin lymphoma Leukaemia

405 398 384 204

233 133 111 76 33 121 68 113 86 97 47 101 101 71 34 192 114

99 167 93 144 109 170 81 116 112 119 57

Oral cavity Pancreas Ovary

1000 800 600 400 200

Parkin DM. Lancet Oncol. 2001;2:533-543.

1050

234 318 241 166 165

279 227 260

Kidney

Stoler MH. Mod Pathol. 2000;13:275-284.

Women 4.7 million cases 2.7 million deaths

Men 5.3 million cases 4.7 million deaths

0

471

200 400 600 800 1000

(Thousands)

5

Epidemiology of Cervical Cancer

Epidemiology of Cervical Cancer, United States 16

Cervical cancer is more common in the developing world More developed 2,176,000

Breast 579 Cervix uteri Colon/rectum

471 91

379

292

154 125

Stomach

193

175

Lung

142 91

Ovary Corpus uteri

101 75

114

Liver

132

34

Esophagus Non-Hodgkin lymphoma Leukemia Pancreas

16

117

66 47 61

Incidence Mortality

14

Less developed 2,562,000

55 65 39

0 100 200 300 400 500 600 400 300 200 100 (Thousands) Parkin DM. Lancet Oncol. 2001;2:533-543. 600 500

Epidemiology of Cervical Cancer, United States • Estimated incidence is 9.1/100,0001 – ~11,150 new cases and ~3,670 deaths annually1

• Cervical cancer is the 14th cause of cancer in incidence and 16th in mortality1

Rate per 100,000 Population

Total

Women

12 10 8 6 4 2 0 1975

1980

1985

1990

1995

2000

• Although US cervical cancer incidence and mortality rates have declined, there were still an estimated 3670 deaths in 20072

1. Ries LAG, Eisner MP, Kosary CL, et al, eds. SEER Cancer Statistics Review, 1975–2002, National Cancer Institute. Bethesda, Md; 2005. 2. Jemal A et al. CA Cancer J Clin. 2007; 57: 43-66

Epidemiology of Cervical Cancer, United States • 50% of cervical cancer cases occur in women never screened, and an additional 10% in women not screened within the past 5 years1 • 11% of women are not screened regularly2

• >50 million Pap smears are performed each year2 1. 2.

Jemal A et al. CA Cancer J Clin. 2007; 57: 43-66 Sirovich BE et al. J Gen Intern Med. 2004;19:243-250

1. NIH Consensus Statement Online 1996 April 1-3. Available at: ttp://consensus.nih.gov/1996/ 1996CervicalCancer102html.htm. Accessed September 21, 2005.. 2. Sirovich BE et al. J Gen Intern Med. 2004;19:243-250.

Epidemiology of Cervical Cancer, United States • Characteristics associated with lower rates of screening based on women 18 years of age and older with no history of hysterectomy (N=13,745)1: – No contact with primary care physician in the past year

HPV AND CANCER

– Lack of usual source of care – Low family income – Less than high school education – Unmarried – No health insurance (