Anal Intraepithelial lesions in women with HPV-related disease

Prof. Silvio Tatti MD, MSc, Phd, FACOG Past President IFCPC Hospital de Clínicas “José de San Martín” University of Buenos Aires

HPV in AIN and Anal Carcinoma • Approximately 85% of cases associated with HPV infection worldwide. • 87% of anal cancers are caused by HPV 16 and 9% by HPV 18. • HPV DNA is also detected in the majority AIN and the prevalence of HPV increases with the severity of the lesion, 75% in AIN1, 86% in AIN2, and 94% in AIN3. Vaccine 2006, Vol. 24, Supl 3; Vaccine 2008, Vol. 26, Supl 10; IARC Monographs 2007, Vol. 90

AIN in HIV-positive and HIV-negative women in the Women’s Interagency HIV Study 50%

AIN CIN

40% 30% 20%

16% 16%

10%

4%

5%

0%

HIV-positive

Hessol NA et al. AIDS. 2009;23:59-70.

HIV-negative

WHO/ICO HPV Information Centre

• Anal carcinoma and their precursor lesions have increased in the last decades, especially among MSM, renal transplant (5%), other causes of immunosuppression (52%) • Women HIV+ : RR x 6.8 compared to the general population. • 1996: introduction of HAART. It didn´t reduce its incidence. Lancet Infect Dis 2006; 6:21-31 Palefsky,J.M. Journal of Infectious Diseases. 2001; 183:383-01. Palefsky JM. http://www.medscape.com/ Conference Report. HPV Infection and Genital Neoplasia. HIV Management 2006: The New York Course; May 5-6, 2006; New York, NY

Anal Carcinoma • Anal cancer represents 1-2 % of gastrointestinal carcinomas • Incidence= 1.7 / 100.000 men and women per year • Rate of death= 0.2 / 100.000 men and women

2005-2009 (USA) http://seer.cancer.gov/statfacts/html/anus.html Palefsky J.M, Holly E.A, et al. AIDS 1998; 12: 495-503

AIN and Anal carcinoma Anal carcinoma • Men = 60 yrs. • Women = 63 yrs. AIN • HIV(+) men = 42 yrs (24-64) • VIH(-) men = 45 yrs (26-73) • Women = 48 yrs Median age of mortality = 64 yrs 2005-2009 (USA) http://seer.cancer.gov/statfacts/html/anus.html Palefsky J.M, Holly E.A et al. AIDS 1998; 12: 495-503

Common characteristics Anal cancer HPV-16 (73%) HPV-18 (7%) HPV-31

• Embryological • Epidemiological

Cervical cancer HPV-16 (50%) HPV-18 (14%) HPV-31 (5%) HPV-45 (8%) Others (23%)

Pap smear Colposcopy incidence

• Anatomical • Histological

Precursors - High grade intraepithelial lesions Vaccines open question in the long term

Frisch M et al. Cancer Res 1999;59:753–757 Daling JR et al .Cancer 2004; 101:270 –280.

Ryan NEJM 2000;342(11):792-800

Squamous columnar Junction Pectineus line

Pre-specified Endpoint in MSM Substudy Represents a Shift to the Left on This Spectrum AIN 1+ CIN 2+ Histology

AIN 1

AIN 2

… …

AIN 3

Adapted from Lowy DR, Schiller JT. J Clin Invest. 2006 May;116(5):1167-73.

12

Low Grade AIN

High Grade AIN

Anal Cancer

Risk factors for progression of anal intraepithelial neoplasia:

– Persistent infection of anal HPV – Multiple HPV types – HIV+: low CD4

Palefsky J, Holly E, Hogeboom C et al. J Acquir Immune Defic Syndr Hum Retrovirol 1998;17:314-319.

RISK FACTORS • HIV+ • Low CD4 • Renal transplant or other causes of immunosuppression • Anal sexual intercourse • Abnormal cervical Pap smear • Persistent infection of HPV • Multiple types of HPV infection • External genital warts • Smoking

Nadal S et al. Rev Bras Coloproct, 2005;25(3): 217-222.

Natural history of anal HPV infection in young women • 75 women (mean age, 24 years) who tested positive for anal HPV were followed for a mean of 84.5 ± 44.9 months • Significant factors in multivariable model for persistent anal HPV 16 infection: • concurrent cervical HPV 16 (P < .001) • weekly alcohol use (P = .015) • anal touching during sex (P = .045), • recent anal sex (P = .04) • no condom use during anal sex (P = .04) Moscicki AB et al CID 2014; 58(6):804-11

IFCPC Terminology of the vulva Including the anus

J Low Genit Tract Dis. 2012 Jul;16(3):290-5.

(cont.)

J Low Genit Tract Dis. 2012 Jul;16(3):290-5.

Diagnosis

• Citology • High Resolution Anoscopy The aims are to visualize the transformation zone to identify acetowhite changes, mosaic, punctuation, irregular vessels; and to make a biopsy to confirm the diagnosis.

• Gold Standard in Diagnostic: Histopatology of Anal Biopsy

High-resolution anoscopy uses the same basis and procedures cervical colposcopy does § Instruments l

  

Anoscope Colposcope Acetic Acid 3% - Lugol Solution Tischler or similar

Intraanal Evaluation: § More difficult than cervical evaluation § Normal anal tissue frequently turns acetowhite with acetic acid § Hipertophic Papilas sometimes seem to be condyloma acuminata

High Resolution Anoscopy: •

Evaluation of the lower genital tract with cytology, colposcopy and biopsy of suspicious lesions

• Anal cytology (citobrush). • Digital rectal examination. • High Resolution Anoscopy: Examination of the anal canal with magnification. Acetic acid + colposcopy • Biopsy of suspicious images

Anal citology Similar to cervical citology (50-70%) HIV (+): Sensitivity: 81% Specificity: 63%. HIV (-): Sensitivity : 50% Specificity: 92% Abbasakoor F, Boulos PB. Br J Surg 2005;92:277-290

“Program of Prevention, Diagnosis, Therapeutics and Vaccination in Lower Genital Tract Diseases” Hospital de Clínicas “José de San Martín” University of Buenos Aires - Argentina

Sensitivity and specificity of High Resolution Anoscopy for the diagnosis of High grade AIN: Sensitivity: 84.61% Specificity: 96.22% PPV: 62.85% - NPV: 98.8%

AIN is part of a HPV MULTICENTRIC DISEASE in the lower genital tract

HPV infection can affect the cervix, vagina, vulva, perineal, perianal region as well as anal canal, urethra and oral cavity.

Treatment of HSIL  Prevention of anal cancer  Relief of symptoms

Choice of treatment  Location internal or external  Size of the lesion or volume of disease  Type of lesion: LSIL or HSIL  Patient preference and tolerance

Treatment of HSIL •

Which is the progression from AIN 2/3 to Anal Cancer?

•

Will the screening and treatment of anal lesions decrease the incidence of anal cancer?

•

Is AIN treatment cost-effectiveness?

Treatment of HSIL •

•

There are not clinical guides to treat intraepitelial anal lesions. Treatment of Low Grade AIN is not always recommended because it has alow possiblitity to advance to invaive lesions and can cause pain associated to treatment.

Treatment of HSIL • Infrared coagulation: – Approved by FDA for the treatment of hemorroids and anal condylomatta. – Involves the direct application of pulsed irradiation at 1.5 seconds in the infrared range of the anal epithelium. – Tissue destruction achieved is at a depth of 1.5 mm. – Possible complications include postoperative bleeding and infections – Recurrence rate: 30%

Treatment of HSIL • Surgery: • Ideal for treating lesions > 1cm, preferably no circumferential • It is difficult to treat postoperative pain • In extensive lesions is recommended perform several and small surgeries to prevent stenosis

A new proposal for topographic and therapeutic classification of AIN Tatti S , Suzuki V , Maldonado V , Fleider L , Tinnirello MA , Caruso R Hospital de Clínicas “José de San Martín”. University of Buenos Aires. Objetive: To propose a classification for anal lesions related to HPV infection

UNIFOCAL AIN

Material and Methods: 481 women with HPV related lesions in the lower genital tract were studied with high resolution anoscopies Results: After performing 481 high resolution anoscopies we propose to classify HIGH GRADE ANAL INTRAEPITHELIAL NEOPLASIA into: 1. Localized 2. Multifocal 3. Circunferential Conclusions: Due to the multiple ways of presentation of AIN and the possible complications because of the use of different therapeutic methods in the anal transformation zone we consider it is necessary to establish unified terminologies for topographic and therapeutic approaches.

MULTIFOCAL AIN

CIRCUNFERENTIAL AIN

481 patients were studied 134 of 481 women (27.86%) had anal intraepithelial neoplasia (AIN): •28 (5.82%) had high-grade AIN •106 (22%) had low-grade AIN

Women with high-grade cervical intraepithelial neoplasia (CIN 2, 3) had 2 times the odds of developing AIN compared with women with low-grade CIN (CIN 1) (odds ratio = 1.91, J Low Genit Tract Dis. 2012 Oct;16(4):454-9. Tatti S, Suzuki V, Fleider L, Maldonado V, Caruso R, Tinnirello MA 95% CI = 1.1-3.6).

Anal Intraepithelial Lesions in Women with HPV-related Disease • Patients with diagnosis of High-grade intraepithelial lesions received surgical treatment (Colorectal Surgery Department) • Anal condylomas were treated with electrofulguration. • Patients were followed-up with anal cytology and high resolution anoscopy every 6 months.

J Low Genit Tract Dis. 2012 Oct;16(4):454-9. Tatti S, Suzuki V, Fleider L, Maldonado V, Caruso R, Tinnirello MA

Who should be screened?  Women with high-grade cervical or vulvar lesions or cancer  All HIV+ women  Women with perianal condyloma  Solid organ transplant recipients • Over 25 years if immunosuppressed, inc. HIV • Over 40 years if immunocompetent

The ANCHOR Study _

AIDS Malignancy Consortium Protocol A01 Joel Palefsky, MD (Principal Investigator) Funded by the National Cancer Institute

The Anchor Study

Screen >17,385

Enroll 5,085 Active Monitoring

Follow for 5 or more years

Treatment

Conclusions • AIN is increasing all over the word and is HPV related in the majority of the cases • The diagnosis is more difficult in anal region than in cervix • The natural history and the possibility to progress to invasive lesions is not well known • Vaccines available for primary prevention of ASIL work in about 80% of the etiology

Conclusions • Treatment: – Small lesions are easier to treat. – All low-grade lesions