Anal Dysplasia and Cancer in At-Risk Groups: What Providers Need to Know

Lori Panther, MD, MPH Assistant Professor, Harvard Medical School BIDMC Division of Infectious Diseases Associate Director of Clinical Research The Fenway Institute Boston, MA

Continuing Medical Education Disclosure

Program Faculty: Lori Panther, MD, MPH Current Position: Clinical Director of the Infectious Diseases Dysplasia Clinic, Beth Israel Deaconess Medical Center; Medical Provider at Fenway Health, and Associate Medical Director for Clinical Research, The Fenway Institute, Fenway Health Disclosure: No relevant financial relationships. Content of presentation contains no use of unlabeled and/or investigational uses of products.

It is the policy of The National LGBT Health Education Center, Fenway Health that all CME planning committee/faculty/authors/editors/staff disclose relationships with commercial entities upon nomination/invitation of participation. Disclosure documents are reviewed for potential conflicts of interest and, if identified, they are resolved prior to confirmation of participation. Only participants who have no conflict of interest or who agree to an identified resolution process prior to their participation were involved in this CME activity.

Learning Objectives

 Summarize the current epidemiology of anal HPV infection and among MSM and women  Describe the clinical manifestations of anal HPV infection  Identify currently available screening methods for anal cancer  Review methods of preventing HPV infection Learning Objectives

 Summarize the current epidemiology of anal HPV infection and anal cancer among MSM and women Human Papillomavirus (HPV) Noncoding regulatory region Transformation (inhibits p53)

Genome copy Modulation Major capsid (inhibits pRb) protein

Minor capsid DNA protein replication

Membrane signaling protein incytepathology.wordpress.com Gene expression/ incytepathology.wordpress.com Assembly and release Life Cycle of HPV

 HPV infects basal cells  Parabasal cells and HPV replicate together . E1, E2, E6, E7 expressed . E6 inhibits p53: cell immortalization . E7 inhibits RBP: accelerates cell cycle progression  Suprabasal cells terminally differentiate; HPV replicates . L1, L2 expressed  Surface cells die and lyse . millions of infectious HPV/cell released HPV Evades the Immune System  Little tissue destruction associated with HPV . Target of infection not an antigen-presenting cell . Infected keratinocytes less susceptible to cytotoxic lymphocyte-mediated lysis  No blood-borne phase of infection  Limited and delayed expression of late viral capsid proteins (L1, L2)

Tindle RW. Nat Rev Cancer. 2002;2:1–7; Scott M, Nakagawa M, Moscicki A-B. Clin Diagn Lab Immunol. 2001;8:209–220; Frazer IH. Nature Rev. 2004;4:46–54

Tindle RW. Nat Rev Cancer. 2002;2:1–7; Scott M, Nakagawa M, Moscicki A-B. Clin Diagn Lab Immunol. 2001;8:209–220; Frazer IH. Nature Rev. 2004;4:46–54 HPV Transmission

 HPV is released from infected desquamating cells  Transmission mainly via direct contact with infected cells  Transmission of genital HPV typically occurs through sexual contact

► Practically everyone gets infected at some point during their lives. HPV Clearance and Persistence

 ~80% of HPV infections are transient . 70% of new HPV infections clear within 1 year and 91% within 2 years . Median duration of infection = 8 months  Persistence of high-risk HPV is crucial for development of disease  Other associated factors: . Age at acquisition (≥30 years) . Immunosuppression . Infection with oncogenic HPV types (more likely to persist)

1. Meijer CJLM, Helmerhorst TJM, Rozendaal L, van der Linden JC, Voorhorst FJ, Walboomers JMM. Histopathology. 1998;33:83–86. 2. Schiffman M, Kjaer SK. J Natl Cancer Inst Monogr. 2003;31:14–19. 3. Ho GYF, Bierman R, Beardsley L, Chang CJ, Burk RD. N Engl J Med. 1998;338:423–428. Anal HPV Infection

 Cross sectional studies of any HPV detected in anal canal: . HIV neg MSM 40-60% . HIV pos MSM 60-90+% . HIV neg women 40% . HIV pos women 75%  Factors: . Age . CD4 count

Goldstone et al J Infect Dis. 2011 Jan 1;203(1):66-74. Palefsky et al J Infect Dis. 2001 Feb 1;183(3):383-91 Chin-Hong J Infect Dis. 2004 Dec 15;190(12):2070-6

Anal vs. Cervical HPV Infection in Women

90 80 70 60 50 % 40 Anal 30 Cervical 20 10 0 HIV- HIV+ CD4 HIV+ CD4 HIV+ CD4 >500 200-500 <200

Palefsky et al. HPV Causes Two Diseases

1. CANCER 2. . due to high risk . due to low risk (oncogenic) HPV (non-oncogenic) types: 16, 18, 31, HPV types: 6, 11, 33, 35, 39, 45, 51, 40, 42, 43, 44, 54 52, 58

1. Howley PM. In: Fields BN, Knipe DM, Howley PM, eds. Fields Virology. 4th ed. Philadelphia, Pa: Lippincott-Raven; 2001:2197– 2229. Reprinted with the permission of Lippincott-Raven. 2. Schiffman M, Castle PE. Arch Pathol Lab Med. 2003;127:930–934. 3. Wiley DJ, Douglas J, Beutner K, et al. Clin Infect Dis. 2002;35(suppl 2):S210–S224. 4. Muñoz N, Bosch FX, de Sanjosé S, et al. N Engl J Med. 2003;348:518–527. 5. Clifford GM, Smith JS, Aguado T, Franceschi S. Br J Cancer. 2003:89;101–105. Natural History of HPV Infection

Transient Cleared HPV Infection Infection

Initial HPV Warts Infection

Low-Grade High-Grade Persistent Dysplasia Dysplasia Infection (X)IN 1 (X)IN 2/3

Invasive Cancer T I M E (YEARS) 0-2 2–5 4–12 9–20 HIV INFECTION COMPRESSES THE NATURAL HISTORY OF HPV INFECTION

Adapted from: 1. Pagliusi SR, Aguado MT. . 2004;23:569–578. 2. Pinto AP, Crum CP. Clin Obstet Gynecol. 2000;43:352–362. HPV: Terminology

“low risk” “high risk” HPV type HPV type

“low grade” “high grade” term term General General pathologic pathologic

Normal ASCUS/LSIL HSIL CIS ICC Cytology Cytology

(X)IN 1 (X)IN 2 (X)IN 3 Normal (moderate Invasive (condyloma/mild (severe dysplasia/CIS) Cancer dysplasia) dysplasia)

Histology

(X ) can be cervical (C), anal (A), penile (P), vulvar (V), vaginal (VA)

HPV Infection Statistics: United States

 At least 80% of us will have an HPV infection by the time we reach 50 . 3/4 of first-time HPV infections occur at <25 y. o.  About 20 million new infections annually . Half of these are 15-24 years of age . 5-30% of these infected with multiple HPV types

1. Centers for Disease Control and Prevention. Genital HPV infection fact sheet. CDC National Prevention Information Network; 2004. 2. Weinstock H et al. Perspect Sex Reprod Health. 2004;36:6–10. 3. Burk RD et al. J Infect Dis. 1996;174:679–689. 4. Bauer HM et al. JAMA. 1991;265:472–477. Who Gets Anal Cancer? In 2013: Estimated Cancer Cases, 2013  About 7,000 cases . 65% in women . 35% in men  About 900 deaths

of Number Cases

CA CANCER J CLIN 2013;63:11–30 Incidence Rates of AIDS-defining and Non-AIDS-defining Cancer, 1996-2000 CANCER TYPE SIR (95%CI) AIDS-Defining KS 5600 (4400-7200) AIDS-defining cancer NHL 23.1 (17.8-30.0) Cervical 16.6 (9.3-27.4)

Non-AIDS-defining cancer Non-AIDS-defining Head and neck 5.1 (2.8-8.6) Anus 39 (18.7-71.7) Liver 16.5 (8.8-28.2) Lung 29 (5.5-3.7-8.0) Hodgkin’s 9.8 (4.2-19.2)

AIDS 2008, 22:489-496 Risk of HPV-Associated Cancers in HIV+ Patients

Relative Risk Cancer Type [95% CI] Cervix 5.4 [3.9-7.2] Vulva/Vagina 5.8 [3.0-10.2] Penis 3.7 [2.0-6.2] Anus (female) 6.8 [2.7-14.0] Anus (male) 37.9 [33.0-43.4] Tonsillar cancer (men) 2.6 [1.8-3.8] Oropharynx 6.0 [3.5-9.7]

Frisch et. al. Learning Objectives

Describe the clinical manifestations of anal HPV infection Warts

 HPV 6 and 11 responsible for >90% of anogenital warts  Peak prevalence . Women 20–24 years . Men 25–29 years

vulvar internal anal meatal penile cervical lingual oral external anal Genital Warts: Statistics

 New cases per year in the United States: . 1 million  Sexually active adults with visible genital warts: . 1 in 100 (1 in 20 HIV+ patients)  People who will develop genital warts in their lifetime: . 1 in 10

Fleischer AB et al. Sex Transm Dis. 2001;28:643–647. 2. Koutsky L. Am J Med. 1997;102:3–8. 3. Franco EL et al. In: Franco EL, Monsonego J, eds. New Developments in Cervical Screening and Prevention. Blackwell Science; 1997:14–22.

1. Fleischer AB et al. Sex Transm Dis. 2001;28:643–647. 2. Koutsky L. Am J Med. 1997;102:3–8. 3. Franco EL et al. In: Franco EL, Monsonego J, eds. New Developments in Cervical Screening and Prevention. Blackwell Science; 1997:14–22. Invasive Anal Incidence rate:

 60-80 cases/100,000 HIV+ MSM . Twice that of HIV- MSM rates

Typical HIV+ patient:  MSM 42 years old  CD4 count 200/mm3 or less  Low nadir CD4 count

Mortality rate at 5 years:  50-80% Perianal Squamous Carcinoma-in- situ (Bowen’s Disease)

 Symptoms: pruritis, mass, bleeding, pain  Increased incidence in HIV+ patients, and not predictably associated with internal lesions  Perianal Bowen’s has higher incidence of invasion (10- 14%) compared to SCCIS of other sites (3-4%)  High rate of recurrence: 1/3 of cases recurred in 5 years

Sarmiento et al., Dis Colon Rectum 40(8); 1997 Chin-Hong et al., Clin Inf Dis 35(9); 2002

HPV and

Fakhry, JNCI 2008 Fakhry, JNCI 2008 # Lifetime Oral Odds OR, HPV16+ Sex Partners Ratio (OR) tumors 0 1 1 1-5 1.9 3.8

NEJM, May 2007 >6 3.4 8.6 NEJM, May 2007 Learning Objectives

Identify currently available screening methods for anal cancer A Brief History of the Pap Smear

 1915: initially noted cyclic changes in vaginal cytology of the guinea pig  1923: abnormal vaginal cytology in women with uterine cancer  1943: published “Diagnosis of Uterine Cancer by the Vaginal Smear”  1960s: noted decrease in from 1st George Nicholaus Papanicolaou, 1883-1962 to 3rd most common cancer in women Transformation Zones of ♀ and ♂ Have Identical Embryologic Origins How to Collect Anal Cytology 1. Wet dacron or rayon (NOT cotton) swab ~1½˝ into canal . No prior douching, enemas or K-Y 2. Gentle outward pressure swabbing circumference 3. Process using dry slide or liquid media

-OR- -IN--IN - -OR- Anal Cytology Screening: Current Approach

 All MSM, regardless of HIV status . HIV+: annually . HIV-: every 2-3 years  Women with high-grade cervical or vulvar disease  HIV-positive men and women, regardless of route of transmission  Transplant recipients (immunocompromised)

Mitra S, Crane L. Curr Infect Dis Rep. 2012 Feb;14(1):61-6 Cervical and Anal Cytology Screening in HIV Abnormal Cervical Abnormal Anal Pap Pap, Prevalence in MSM, Relative Risk RR

>500 200-499 <200<200 >500 200-499 <200

CD4 count, cells/ml Detailed histological grades for paired cytological specimens

76% with HSIL on anal cytology had ≥ AIN2 on histopathology 36% with LSIL on anal cytology had ≥ AIN2 on histopathology 95% with negative anal cytology had ≤AIN1 on histopathology

For HSIL anal cytology: . sensitivity = 47% (95% CI, 35%–59%) . specificity=90% (95% CI, 81%–96%) . PPV=81% (95% CI, 66%–92%) . NPV=65% (95% CI, 55%–74%) Panther L A et al. Clin Infect Dis. 2004;38:1490-1492

© 2004 by the Infectious Diseases Society of America Genital Warts May Harbor High Grade Dysplasia

Schlecht et al., CID July 2010 Abnormal Anal Cytology: What Next?

. External examination: biopsy if lesion seen, and if AIN2-3 refer for surgical management . Internal examination: high resolution anoscopy (HRA) with biopsy and ablation of AIN2-3 High Resolution Anoscopy High Resolution Examination of Transformation Zones 3% Acetic Acid Lugol’s

Anus

Cervix NORMAL

HIGH-GRADE DYSPLASIA

INVASIVE INTERNAL SCC

INVASIVE EXTERNAL SCC

Algorithm for the Management of Anal Pap Smear Results

ANAL PAP SMEAR

NORMAL ASCUS or LSIL HSIL

continue screening schedule yearly for HRA HIV+ MSM, every 2 years for HIV- MSM

LESION NOT FOUND LESION FOUND

REPEAT PAP in 6 months BIOPSY

AIN1 AIN2 or AIN3

REPEAT PAP and REPEAT PAP and HRA in 6 months, ABLATE if stable x 2 exams, PAP and HRA in 4-6 months HRA every 12 months ASCUS, atypical squamous cells of uncertain significance; LSIL, low -grade squamous intraepithelial lesion; HSIL, high-grade squamous intraepithelial lesion; AIN, anal intraepithelial neoplasia; HRA, high resolution anoscopy. Learning Objectives

Review methods of preventing HPV infection Condom Effectiveness

100

80 Pregnancy HIV

60 Gonorrhea Chlamydia 40 Syphilis HSV 20 HPV Estimated % protection 0 NIAID Workshop Summary, June 2000; Herpes. 2002 Apr;9(1):10-4; Am J Epidemiol. 2004 Feb 1;159(3):242-51; Am J Epidemiol 2003;157:218–226

NIAID Workshop Summary, June 2000; Herpes. 2002 Apr;9(1):10- 4; Am J Epidemiol. 2004 Feb 1;159(3):242-51; Am J Epidemiol 2003;157:218–226 HPV Vaccine

 Quadrivalent 6/11/16/18 ()  Bivalent 16/18 ()  Both are virus-like particle (VLP)

Nanomedicine: Nanotechnology, Biology and Medicine Volume 8, Issue 2 2012 131 - 135 HPV Vaccine HPV 16/18–related High Grade Dysplasia in Females 16-26 years old

HPV 16 and/or 18 Positive at Day 1 Cases in subjects – 6 receiving PLACEBO: Placebo, 95% CI 201. Of these, 81 (40%) Vaccine, 95% CI 5 were new infections.

4 39% ↓ 3 95% CI: 23–52 High rates of 2 prevalent disease early Cases in subjects receiving VACCINE:

Related Related 2/3CIN or AIS,% 1 122. Of these, 1 (1%) was a new infection.

Cumulative Incidence of HPV 16/18 0 0 6 12 18 24 30 36 42 48 Time Since Month 1 (in Months))

CIN = cervical intraepithelial neoplasia. AIS = adenocarcinoma in situ. Data available on request from Merck & Co., Inc. Please specify information package 20651480(1)-GRD. N Engl J Med 2007; 356:1928-1943. HPV Vaccine: Genital Warts in Females 16-26 years old

HPV 6, 11, 16 and/or 18 Positive at Day 1

7 Cases in subjects Placebo, 95% CI receiving PLACEBO: 6 Vaccine, 95% CI 184. Of these , 136

5 (74%) were new infections. 4 3 69% ↓ Prevalent 95% CI: 58–77 Related Genital Warts, % Related 2 disease early 1 Cases in subjects receiving VACCINE: Cumulative Incidence of HPV 0 58. Of these, 9 (16%) – 6/11/16/18 0 6 12 18 24 30 were new infections. Time Since Month 1 (in Months))

Data available on package insert. Prevention: HPV Vaccine

 ACIP approved for females and males 9-26 y.o.  FDA approved for prevention of: . cervical dysplasia . cervical, vulvar, vaginal cancers . genital warts in females and males . anal dysplasia and cancer in females and males  Guidelines for vaccination same for HIV-positive as for HIV-negative patients  Vaccine schedule: IM, 0.5 ml, at 0, 2 and 6 months

Why vaccinate if exposure to or disease from HPV has already happened?

Baseline HPV Status of Women Enrolled in Clinical Trials for Gardasil

. 93% were naïve Baseline HPV Status to ≥3 vaccine HPV Naïve to all 4 types types (6, 11, 16, or 18) at Positive to 1 type 73% 20% enrollment

Positive to 2 types 6% . 27% of subjects Positive to 3 types had evidence of prior exposure to Positive to 4 types 1.2% or ongoing 0.1% infection with at least 1 of the types Data available on package insert. Summary  HPV causes two diseases  Persistent HPV infection underlies most genital epithelial cancers  HIV+ persons are at higher risk for the development and recurrence of HPV-associated disease  Cytology screening is effective in some HPV- related diseases  Implementation of HPV vaccine may substantially change HPV-associated cancer epidemiology in coming decades  Remember to examine the genital tract!

Resources

 The National LGBT Cancer Project: Out with Cancer: http://lgbtcancer.com/  National LGBT Cancer Network: http://www.cancer-network.org/  HPV Vaccine Information: http://www.cdc.gov/hpv/vaccine.html