Transcript handout ( format)

HPV Infection
ACHA May 2014
Why Talk About HPV Today?
 HPV is one of the “Now” diseases
 Recent new information
 HPV is the disease of the future
 We are seeing new HPV science every day
 In 10 years this will be a completely new and
different lecture
A Time of Transition
 To screening for anal cancer in certain
populations
 To recognition of HPV role in
 Anal cancer
 Oropharyngeal cancer
 Esophageal cancer
 To expanded use and versions of vaccine for
HPV infection
Human Papillomaviruses
 dsDNA, circular (8 kb)
 non-enveloped
 Encode proteins that promote cell growth
 100 types of HPV- divided generally by
tissue tropism
 Cutaneous versus mucosal
 HPV causes the most commonly diagnosed
STI’s
High risk genotypes include 16 and 18 (cervical
cancer), and many others
Clinical Syndromes
◦ Warts
◦ Asymptomatic
◦ Soft, flesh-colored warts
that develop weeksmonths after sexual
contact
◦ Cytologic changes
detected by Pap staining
◦ Dysplasia to cancer is 1-4
years if HPV 16, -18 or -31
Downloaded from: StudentConsult (on 20 February 2008 04:00 PM)
© 2005 Elsevier
Papillomavirus Epidemiology
 Non-enveloped** -- resists inactivation
 Transmitted by fomites
 Acquired by direct contact through small breaks
in the skin or mucosa (sex, childbirth)
 Skin warts are common, mostly in children and
young adults
 Worldwide, no seasonal incidence
Papillomavirus pathogenesis
 HPV hides from immune responses
 Low levels of antigen for presentation
 Keratinocytes are immune privileged site
 HPV oncogenic potential
 HPV-16 and -18 cause cervical dysplasia
 85% of cervical carcinomas contain integrated HPV DNA
 E6 and E7 genes are oncogenes -- when expressed, cells are
more susceptible to mutations, chromosomal
aberrations….cancer
HPV-Cervical Involvement
 Estimated that prevalence of anogenital
infection in US is 20 million
 Annual incidence of new cases is estimated to
be 5.5 million
 Estimated that 75-80% of sexually active adults
will have at least one HPV infection by age 50
 Infections are most often transient
– 58% clear infection within 18 months, persistence is a risk
for development of cancer
Human Papillomavirus—Prevalence of High-risk and Low-risk Types
Among Females Aged 14–59 Years, National Health and Nutrition
Examination Survey, 2003–2004
Prevalence, %
45
Low-risk HPV*
40
High-risk HPV
35
30
25
20
15
10
5
0
14–19
20–24
25–29
30–39
40–49
Age
* HPV = human papillomavirus.
NOTE: Error bars indicate 95% confidence intervals. Both high-risk and low-risk HPV types were detected in some females.
SOURCE: Dunne EF, Unger ER, Sternberg M, McQuillan G, Swan DC, Patel SS, et al. Prevalence of HPV infection
among females in the United States. JAMA. 2007;297(8):813-9.
Copyright ©2007 American Medical Association. All rights reserved.
50–59
Lab Diagnosis
 Warts -- confirm by
microscopy (hyperplasia
and prickle cells)
 Pap smears
 PCR from cervical
swabs to diagnose and
type HPV
 No ELISAs or culturing
Pap smear
Normal Pap smear shows
normal cervical cells
Abnormal Pap smear
Shows malformed cells,
enlarged nuclei (due to
transformation of cells)
Where HPVs are Found:
FIngernails4
Oral
Cavity5
Anogenital
area2,3
Fluid/secretions
HPV can be
spread via
sexual contact
and non-sexual
routes such as
vertical &
horizontal
transmission and
autoinnoculation.1,2
Hands4
Cervix
Vagina
Vulva
Anus
Penis
scrotum
Coronal
sulcus/Glans
1. Castellsague X et al. BMC ID 2009; 9:74. 2. Hernandez B et al. EID 2008;14(6):888-894. 3. Moscicki AB et al. AIDS 2003;17:311-20. 4. Sonnex C et al.
STI 1999;75:317-319. 5. Sanchez-Vargas LO et al. Infect Agent Cancer 2010;5:25.
HPV Involvement Elsewhere
 Skin: warts
 Anus: risk of cancer
 Similar to cervical pathway
 Head and neck: risk of cancers
Prevalence of HPV across Anogenital Sites in a
Cohort of 222 Heterosexual Men in the US1
100
90
80
70
60
50
40
30
20
10
0
71.2
63.1
24.8
21.3
16.6
5.4 9
Anal canal
Any HPV
41.9
31.5
10.8
4.1
Perianal
46.9
36
13.1
5.9
Either or
Both Anal
Sites
Glans, Shaft,
or Scrotum
Any Oncogenic
Any Sitea
Any Non-oncogenic
• The prevalence of anal HPV infection was 25%
• The prevalence of HPV infection at any of the 7 sites was 71%
aPenile
shaft, coronal sulcus/glans penis, urethra, scrotum, perianal region, anal canal & semen.
1. Nyitray A et al. JID 2008;197:1676-84.
Acquisition of Any Anal HPV Infection in a
Cohort of Women During a 12 Month Period1
Hawaii HPV Cohort Studya
• 50% of sexually active females developed
incident anal infections within 1 year.
9%
41%
50%
(N= 431)
aA
• 9% had an anal HPV infection at baseline
but no incident infections.
Acquired new anal HPV
Remained Anal HPV Baseline Anal HPV +
longitudinal study of a cohort of sexually active women (N=431) recruited from 5 medical clinics in Hawaii who were
able to read, understand, and sign an informed consent form and medical release form. Potentially eligible patients
included those with appointments for new or annual gynecological examinations or for family-planning services who
were not pregnant or postpartum within the past 6 months. At baseline and at 4-month intervals, interviews were
conducted and cervical and optional anal cell specimens were obtained for detection of HPV DNA. 1
1.Shvetsov YB et al. Clin Infect Dis. 2009;48:536-46.
Anal HPV in Women:
Hawaii HPV Cohort Study1,2
Site of
Infection
Prevalence
of HPV at
Study Entry
One Year
Clearance
Median
Duration of
HR HPV
Anal1,a,b
42%
87%
5 months
Cervical2,a, c
26%
70-80%
~8 months
a These
two groups are from the same cohort of sexually active women in Oahu, Hawaii.
431 women who consented for anal testing. 1
c N= 972 women from entire cohort for cervical testing. 2
b N=
1. Shvetsov YB et al. Clin Infect Diseases 2009;48:536–546. 2. Goodman MT et al. Cancer Res. 2008;68:8813–8824.
Distribution of Certain HPV Types in AIN
and Anal Cancer1a
80
70
60
50
AIN 1
AIN 2/3
Anal cancer
40
30
20
10
0
aMeta-analysis
studies
HPV 16 HPV 18 HPV 6 HPV 11
of 29
1.De Vuyst H et al. Int J Cancer 2009;124:1626-1636.
Anal Intraepithelial Neoplasia (AIN):
A Precursor to Anal Cancer
 HPV infection is associated with development of anal
SIL.1
 Anal cancer is analogous to cervical cancer.
 Both cancers arise in their respective transformation
zones.1
 Histology and molecular characteristics are similar to
cervical cancer, for example, anal HSIL resembles
cervical HSIL.1
 AIN 2/3 is believed to be a precursor to invasive anal
malignancy.1
1. Chang GJ et al. Clin Colon Rectal Surg. 2004;17:221–230.
Anal Cancer
A Disease Affecting Both Men and Women
 Women account for 60% of the cases of anal
cancer.1
 Risk of anal cancer is elevated among women with
cervical and vulvar cancers.2
 Oncogenic HPV infections may spread to the anal
canal from the cervix and vulva.3
 Although anal cancer occurs in both
heterosexuals and men who have sex with men,
MSM are at particularly high risk for anal HPVassociated disease.3,4
1.Cancer Facts and Figures 2010. American Cancer Society Web site. http://www.cancer.org. Accessed March 12, 2011. 2. Saleem AM et al. Obstetrics
and Gynecology 2011;117:643-649. 3.Hoots BE et at. Int J Cancer 2009;124: 2375-2383. 4. Daling JR et al. Cancer 2004;101(2): 270-280.
U.S. Anal Cancer Epidemiology:
Increasing Incidence of Anal Cancer
 Incidence is increasing
at ~2% per year.1
 Anal cancer represents
~4% of all lower GI
tract cancers in U.S.2
 Age-adjusted rates
from 1975 to 2007
doubled from 0.8 to
1.6 per 100,000.1
Rates are per 100,000 and are age-adjusted to the 2000 US
STD population3
1. SEER Fast Stats http://seer.cancer.gov/faststats/Horner MJ et al. SEER Cancer Statistics Review 1975-2006. SEER Web site.
http://seer.cancer.gov/sr/1975_2006/. Accessed December 1, 2010. 2. Clark MA Lancet Oncology ;Vol 5 2004 pp149-157. 3. Altekruse /SEER Cancer
Statistics Review, 1975-2007, National Cancer Institute. Bethesda, MD, http://seer.cancer.gov/faststats/selections.php?series=cancer.
U.S. Anal Cancer Epidemiology
 Estimated 5260 new
cases of anal cancer in
4000
3260
3000
2000
the United States in
2010.1
 ~3260 females (60%)
 ~2000 males (40%)
Women
Men
2000
1000
0
Estimated Cases in 2010
 Lifetime Risk2:
 Based on rates from 2005-2007, 0.16% of men and
women born today (1 in 610 men and women) will be
diagnosed with cancer of the anus, anal canal, and
anorectum at some time during their lifetime.
1.Cancer Facts and Figures 2010. American Cancer Society Web site http://www.cancer org/Research/CancerFactsFigures/cancer-facts-and-figures-2010.
Accessed February 7,2011. 2. SEER Stat Fact Sheets: Anal Cancer. http://seer.cancer.gov/statfacts/html/anus.html. Accessed March 11, 2011.
Risk Factors for Anal Cancer
Strong Evidence1
Moderately strong evidence1

Cigarette smoking

History of receptive anal intercourse

Long-term use of corticosteroids

HPV Infection (anogenital warts)

HIV infection

History of cervical, vulvar, or vaginal cancer

More than 10 sexual partners

History of STD

Immunosuppression after solid-organ
transplantation
 Populations in which risk factors are more prevalent have higher
incidences of anal cancer.2
 Anal intercourse is a risk factor but is not required for anal HPV
infection or cancer development in men or women.3
1. Ryan DP NEJM 2000; 342(11):792-800. 2. Daling JR et al. Cancer 2004;101(2):270-280. 3. Goodman MT JID 2010;201:(9)1331-1339.
Anal Cancer
Symptoms and stage at presentation1,2
 Signs and symptoms:1a
 Rectal bleeding (~45%)
 Pain or sensation of a rectal mass
(~30%)
 Stage at presentation:
 While most anal cancers are
detected at an early stage, many
people are diagnosed when the
disease is more advanced.2
 There are currently no standard
anal cancer screening
recommendations for the general
population.2
a Approximately
100
90
80
70
60
50
40
30
20
10
0
58
Stage at
Presentation
22.2
6.7
In Situ
twenty percent of individuals may have no rectal symptoms.1
1. Ryan DP et al. NEJM 2000;342:792-800. 2. Joseph DA Cancer 2008;113:2892-2900.
Regional
Distant
Anal Cancer is a Similar Disease in
Men and Women
Anal Cancer in a Male
Photographs Courtesy of M. Stoler, M.D.
Anal Cancer in a Female
Male and Female Genital Anatomy
 The close proximity of genital organs to one another
supports the concept that HPV infection may affect the
entire anogenital field, possibly resulting in
multifocal/multicentric disease.1,2
Medical Illustration Copyright© 2011 Nucleus Medical Media, All
rights reserved. www.nucleusinc.com.
1. Saleem AB et al. Obstet Gynecol 2011;117(3):643-649. 2. Moscicki AB et al. AIDS 2003;17:311-320.
Penis
Anal Intercourse is Not Required for the
Development of Anal Cancer
Percentages of men and women with anal cancer who reported no history of anal
intercourse from selected studiesa.
Study
Females
Males
(sexual
orientation n/a)
Daling1b
66%
2004
[83/127]
Daling2c
83%
74%
1987
[74/89]
[43/58]
aStudies
N/A
Heterosexual
males
NonHeterosexual
Males
100%
12.5%
[54/54]
[6/48]
N/A
N/A
included anal and rectal cancer cases.
bBetween
1986 and 1998 in the Seattle area, men (n 119 patients) and women (n 187 patients) diagnosed with anal cancer were identified through the local
Surveillance, Epidemiology, and End Results registry. Random-digit telephone dialing was used to ascertain control participants (n 1700) and identified
participants were interviewed in person and provided blood samples. Archival tumor tissue was tested for human papillomavirus (HPV) DNA, and serum
samples were tested for HPV type 16 (HPV-16).1
cPersons under 70 years of age were identified from records of population based cancer registries of 3 counties in whom anal cancer was diagnosed from
Jan. 1978-Dec.1985. All histologic types of tumors were included. To elucidate risk factors for anal cancer, individuals were interviewed and blood specimens
were obtained from 148 persons with anal cancer and from 166 controls with colon cancer. Interviewers were not blinded to the subjects' diagnoses or to
hypotheses in general.
1. Daling JR et al. Cancer 2004;101:270-280. 2. Daling JR et al. NEJM 1987;317(16):973-977.
Current Anal Screening Methods
 Ascertaining risk factors.1
 Components of screening evaluations include:1
 Pap tests using conventional methods or the liquid
medium technique (Anal Paps)
– HPV testing has an uncertain role in screening
 Digital Rectal Examinations
 High Resolution Anoscopy (HRA)
 Dysplasia screening presents an opportunity to screen
for other anal STIs (sexually transmitted infections).1
1. Mathews Top HIV Meds 2003;11( 2):45-49.
Treatment Options for Anal Disease
AIN/Condyloma1 Intra-Anal Lesions1
Chemical therapy
Cryotherapy
Infrared Coagulation
Laser therapy
Electrocautery
Anal Cancer2
Surgery
Radiation
Combined Radiation
and Chemotherapy
AIN=anal intraepithelial neoplasia
1.Palefsky JM et al. Obstet Gynecol Clin N Am. 2009;36:187–200. 2.Anal Cancer Treatment (PDQ®) - National Cancer Institute accessed February 8, 2011.
Adverse Effects of Anal Cancer Treatment
 Late adverse effects of radiation therapy, such as anal ulcers, stenosis,
and necrosis, may necessitate the need for a colostomy in 6 to 12% of
patients.1
 Patients treated with radiation or radiotherapy report acceptable overall
long-term quality of life scores, but poor sexual function scores. A
significant percentage report having difficulty with diarrhea, bowel
control, and different aspects of sexual function.2
Radiation proctitis
Radiation-related skin
inflammation
Photographs Courtesy of S. Goldstone, M.D
1.Ryan DP et al. NEJM 2000;342(11):792–800. 2.Das P et al. Cancer 2010;822-829.
Post-radiation
anal stenosis
Oropharyngeal Cancer
 The majority of cases are linked to HPV
Esophageal Cancer
 Data is variable, but the newer studies
demonstrate HPV genome in about 50% of
tumors
Screening for Cervical Cancer
 A model of success for finding HPV related
cancer of the cervix
 Broad acceptance
 Refined guidelines
 Proven effectiveness
 The likely path for other HPV cancers
 Like anal cancer
Bethesda 2001 Workshop Cosponsors


American Cancer Society*
American College Health Association*
American College of Obstetricians and Gynecologists*
American Social Health Association*
American Society of Cytopathology*
American Society for Colposcopy and Cervical Pathology*
American Society of Clinical Pathologists*
American Society for Cytotechnology*
Asociación Mexicana de Patologos
Association of Reproductive Health Professionals
Association of Women's Health, Obstetric and Neonatal Nurses
Australian Society of Cytology
British Society for Clinical Cytology
Canadian Society of Cytology – Société Canadienne de Cytologie*
Centers for Disease Control and Prevention
Chinese Society of Cytopathology
College of American Pathologists*
Deutsche Gesellschaft für Zytologie
Food and Drug Administration
Gynecologic Oncology Group, ACOG*
Health Care Financing Administration
International Academy of Cytology
International Society of Gynecological Pathologists
Irish Association for Clinical Cytology*
Japanese Society of Clinical Cytology
Korean Society for Cytopathology
Magyar Onkológusok Társasága-Cytodiagnosztikai Sectio
National Committee for Clinical Laboratory Standards
Nurse Practitioners in Women's Health
Öesterreichische Gesellschaft fuer Zytologie*
Papanicolaou Society of Cytopathology*
Planned Parenthood Federation
Romanian Society of Cytology
Sociedad Argentina de Citologia
Sociedad Chilena de Citologia
Sociedad Española de Citologia*
Sociedad Peruana de Citologia
Sociedade Boliviana de Citologia
Sociedade Brasileira de Citopatologia
Società Italiana di Anatomia Patologica e Citopatologia Diagnostica
Société Belge de Cytologie Clinique—Belgische Vereniging voor Klinische Cytologie*
Société Française de Cytologie Clinique*
Society of Gynecologic Oncologists*
Suid Afrikaanse Vereniging vir Kliniese Sitologie—South African Society of Clinical Cytology*
*Indicates that the society has endorsed the 2001 Bethesda System.
SPECIMEN ADEQUACY
 Satisfactory for evaluation (note
presence/absence of endocervical/ transformation
zone component)
 Unsatisfactory for evaluation . . . (specify reason)
Specimen rejected/not processed (specify
reason)
Specimen processed and examined, but
unsatisfactory for evaluation of epithelial
abnormality because of (specify reason)
GENERAL CATEGORIZATION
 Negative for intraepithelial lesion or malignancy
 Epithelial cell abnormality
 Other
Epithelial Cell Abnormalities

Squamous cell
* Atypical squamous cells (ASC)
- of undetermined significance (ASC-US)
- cannot exclude HSIL (ASC-H)
* Low-grade squamous intraepithelial lesion (LSIL)
encompassing: human papillomavirus/mild
dysplasia/cervical intraepithelial neoplasia
(CIN) 1
* High-grade squamous intraepithelial lesion (HSIL)
encompassing: moderate and severe dysplasia,
carcinoma in situ; CIN 2 and CIN 3
* Squamous cell carcinoma
ASCUS
LGSIL
HGSIL
Glandular cell

Atypical glandular cells (AGC) (specify
endocervical, endometrial, or not otherwise
specified)

Atypical glandular cells, favor neoplastic
(specify endocervical or not otherwise specified)

Endocervical adenocarcinoma in situ (AIS)

Adenocarcinoma
Other (List not comprehensive)

Endometrial cells in a woman ≥40 years of
age
Anal Pap
 A proposed screening system to obtain cells
from the anal transitional zone for cytologic
examination
 Standardization still not fully established
 Collection technique
 Expected quality performance measures
 Clinical utilization –target groups
 Preparation of patient
Anal Anatomy
 Most of the anal canal is
lined by squamous
mucosa.1
 The dentate line
represents a border
between more distal
squamous mucosa and a
transitional area of
squamous and
nonsquamous mucosa.1
 Anal cancers arise from
the transformation zone.2
 Immature squamous
metaplastic cells of the
transformation zone are
most susceptible to
oncogenic HPV.2
Adapted from [Shia, J., An Update on Tumors of the Anal Canal. Arch
Pathol Lab Med. 2010;134:1601–1611] with permission from Archives of
Pathology & Laboratory Medicine. Copyright 2010. College of American
Pathologists.
1. Ryan DP et al. NEJM. 2000;342(11):792-800. 2. Chang GJ et al. Clin Colon Rectal Surg. 2004;17:221–230.
YouTube
CAP
 Recognizes emerging role of anal cytology
 Requires use of 2001 Bethesda guidelines
 Recommends that ASCUS or higher receive
high resolution anoscopy
 States role of HPV testing still not established
but accepts that negative results can have high
negative predictive value
Anal Pap at McKinley
 Clinician collection
 Moisten Dacron swab with tap water
 Walk specimen through process
 Call reference lab to discuss
 No enema or douche in previous 24 hours
 No trauma/receptive anal sex in previous 24
hours
 Report will follow Bethesda terminology
 HPV reflex testing not automatic, make
arrangements
HRA
 High Resolution Anoscopy
 Very Similar to colposcopy
 Uses 3% acetic acid (not 5%)
 Suspicious areas biopsied
 Uses Bethesda classification
 Not generally covered by insurance for
screening
Colposcopy
CDC
 There is no HPV test recommended for men
 Screening for anal cancer is not routinely
recommended for men
 Some experts do perform the test (anal pap) for gay,
bisexual and HIV positive men
 There is no test for “HPV status” in men
 There are no routine screening tests
recommended for HPV related cancers in
women other than for cervical cancer
IDSA
 HIV infected men and women with human
papillomavirus (HPV) infection are at increased risk
for anal dysplasia and cancer. MSM, women with a
history of receptive anal intercourse or abnormal
cervical Pap test results, and all HIV-infected persons
with genital warts should have anal Pap tests (weak
recommendation, moderate quality evidence).
Guidelines NY State DOH AIDS
Institute
 For HIV positive patients
 Anal cytology for HIV positive men who have sex
with men
 Also for HIV positive men or women with a history of
anogenital condylomas
 Also for HIV positive women with abnormal
cervical/vulvar histology
Most Insurance
 Anthem (Blue Cross) and AETNA will not pay for
anal pap or HRA
Potential Expansion of Anal Pap
Screening
 All HIV positive people
 All MSM with history of anogenital warts
 All MSM
 All women with history of anogenital warts
 All women with history of abnormal paps
 All sexually active people
Horizon
 Oropharyngeal and esophageal cancers may
follow the path of cervical cancer and anal
cancer towards greater recognition
 The real question will be how to perform
appropriate screening to these sites
A recent patient request
 “I want an HPV test on my pharynx because I
performed fellatio last week and now I am
worried!”
 Her internet exploration:
 A dentist in Chicago promotes HPV testing in his
office for all such patients
 Cost for initial visit: $1,000.
Prevention-HPV vaccines
 Gardasil
 Quadrivalent recombinant protein vaccine
 L1 coat proteins from HPV 6, 11, 16, 18
 Administered to females or males
 $360 for a 3-part vaccination
 Cervarix – bivalent (HPV 16 and 18 L1 coat
proteins)
HPV Vaccine Update
 CDC says HPV vaccine should now be routine
for all boys age 11-12, and all boys age 13-21
should catch up
 US pediatricians recommend routine HPV
vaccine age 11-12, and all boys age 13-21
should catch up
In Conclusion
 New recommendations about HPV vaccine use
 New frontiers in anal cancer screening
 New understanding of oropharyngeal and
esophageal cancers
 Role of HPV