ANAL DYSPLASIA :

RITCHE HAO, MD NOVEMBER 10, 2020 ANAL : BURDEN OF DISEASE

• 2019: 8,300 new cases of in the general population • 2,770 in men • 5,530 in women

(American Cancer Society, 2019)

• 2011 to 2015 anal cancer rates: • 2.2 per 100,000 person-years among women • 1.3 per 100,000 person-years among men (Center for Disease Control and Prevention, 2018) ANAL CANCER: BURDEN OF DISEASE

• Diagnoses of anal cancer are on the rise in the United States: • among women in the general population • among men who have sex with men (MSM), regardless of HIV status • among men and women with HIV

(Hessol, et al. 2013; Islami, et al. 2017; Palefsky 2017) ANAL CANCER: BURDEN OF DISEASE

• Incidence of of the anus (SCCA) is also rising in the United States, in both men and women; • Deshmukh, et al. (2019): from 2001-2015 • distant-stage SCCA incidence tripled and • regional stage SCCA incidence nearly doubled

• Current incidence rates of SCCA among MSM with HIV are higher than the rates of that prompted adoption of universal screening of women for cervical dysplasia (Gustafsson, et al. 1997; Machalek, et al. 2012; Silverberg, et al. 2012) HIV AND ANAL CANCER RISK

• HIV is an independent for anal high-grade squamous intraepithelial lesions (HSIL)  confers additional risk for development of anal cancer • Higher rates of HSIL have been documented among men and women with HIV than among the general population • Other risk factors associated with include: • in MSM with HIV • lower CD4 count • cigarette • Some data suggest that immune reconstitution with the use of antiretroviral therapy (ART) reduces but does not eliminate the risk of anal cancer

https://www.hivguidelines.org/hiv-care/anal-dysplasia-cancer/#tab_1 HIV AND ANAL CANCER RISK: MEN

• Men living with HIV  particularly men who have sex with men (MSM): • have higher rates of anal human papillomavirus (HPV) disease than other populations • anal cancer incidence in MSM with HIV was 131 per 100,000 person-years between 1996 and 2007 (Palefsky, 2017) • HPV-associated occur more often among individuals with HIV than in the general population (Jemal, et al. 2013; Thompson, et al. 2018)

https://www.hivguidelines.org/hiv-care/anal-dysplasia- cancer/#tab_1 HIV AND ANAL CANCER RISK: MEN

• Machalek, et al 2012 • incidence of anal cancer to be 45.9 per 100,000 among MSM with HIV • and 5.1 per 100,000 among MSM who did not have HIV

• In MSM with HIV, receptive anal intercourse is the most common risk factor for anal cancer, likely reflecting concurrent HPV infection.

• HIV is also associated with a higher risk of anal cancer among men who have sex with women (MSW)  risk lower than for MSM

https://www.hivguidelines.org/hiv-care/anal-dysplasia-cancer/#tab_1 HIV AND ANAL CANCER RISK: WOMEN

• Women with HIV have a higher incidence of anal cancer than women without HIV. • Silverberg, et al, 2012: anal cancer incidence of 30 per 100,000 person-years among women with HIV and no cases among those without • Women with HIV are significantly more likely to have abnormal anal cytology or results than women without HIV • Stier, et al., 2019: 27% prevalence of anal HSIL among women with HIV

https://www.hivguidelines.org/hiv-care/anal-dysplasia- cancer/#tab_1 HIV AND ANAL CANCER RISK: WOMEN

• Abnormal cervical cytology results are a risk factor for abnormal anal cytology results, however, women may have anal dysplasia without concomitant cervical disease. • prevalence of HPV-related anal disease in some studies, was higher than HPV-related cervical disease in women • Data are inconsistent regarding the role of anal intercourse as a risk factor for anal dysplasia in women with HIV

https://www.hivguidelines.org/hiv- care/anal-dysplasia-cancer/#tab_1 HPV TYPE AND ANAL DYSPLASIA

• HPV infection is responsible for approximately 91% of anal cancers, including anal and rectal SCC • HPV type 16 is the most common high-risk type among individuals with or without HIV

(CDC 2018; Lin, et al 2018) ANAL DYSPLASIA AND PROGRESSION TO ANAL CANCER

• Generally accepted: • anal dysplasia is the precursor to invasive anal carcinoma • Progression from anal dysplasia to anal cancer is slower than the progression from cervical dysplasia to cervical cancer • Berry, et. al, 2014: average time for progression from diagnosis of HSIL to anal cancer was 5 years

https://www.hivguidelines.org/hiv-care/anal-dysplasia- cancer/#tab_1 ANAL DYSPLASIA AND PROGRESSION TO ANAL CANCER

• Limited data to support the notion of a stepwise progression from low grade squamous intraepithelial lesion (LSIL) to HSIL to invasive carcinoma • Spontaneous regression of anal dysplasia, including HSIL – has been described • Tong, et al (2013) 20% of HSIL spontaneously regressed in 20% of participants with HIV

https://www.hivguidelines.org/hiv-care/anal-dysplasia- cancer/#tab_1 ANORECTAL ANATOMY Anorectal Anatomy

The anus is approximately 2 to 3 inches long and composed of skin type cells also known as squamous cells.

https://analcancerinfo.ucsf.edu/obtaining-specimen-anal-cytology Anorectal Anatomy

The upper portion of the anus, or that part that connects to the rectum, is known as the squamocolumnar junction.

https://analcancerinfo.ucsf.edu/obtaining-specimen-anal-cytology Anorectal Anatomy

The squamocolumnar junction is where the columnar or glandular epithelial cells of the rectum transition to the squamous cells of the anus

https://analcancerinfo.ucsf.edu/obtaining-specimen-anal-cytology Anorectal Anatomy

The squamo-columnar junction is the area most commonly affected by HPV and where many of the lesions are likely to arise

https://analcancerinfo.ucsf.edu/obtaining-specimen-anal-cytology ANAL PAP SMEAR: INTRUCTION FOR PATIENTS

• Within the last 24 hours, do NOT to: • douche or • have an enema • or insert anything into the anus

https://analcancerinfo.ucsf.edu/obtaining-specimen-anal-cytology ANAL PAP SMEAR

• Do not use lubricants prior to obtaining a cytology sample • lubricant may interfere with the processing and interpretation of the sample. • Typical position for obtaining sample  patient lying on their left side

https://analcancerinfo.ucsf.edu/obtaining-specimen-anal-cytology HOW TO DO THE ANAL PAP SMEAR

• The buttocks are retracted to visualize the anal opening • Use a Dacron or polyester tipped swab moistened in tap water

https://analcancerinfo.ucsf.edu/obtaining-specimen-anal-cytology HOW TO DO THE ANAL PAP SMEAR

The swab is rotated 360 degrees with firm lateral pressure applied to the end of the swab,  swab is bowed slightly  then it is slowly withdrawn over a period of 15 to 30 seconds from the anus  continuing to rotate the swab in a circular fashion.

https://analcancerinfo.ucsf.edu/obtaining-specimen-anal-cytology HOW TO DO THE ANAL PAP SMEAR

• For liquid based cytology  swab is placed in a preservative vial and vigorously agitated to disperse the cells

https://analcancerinfo.ucsf.edu/obtaining-specimen-anal-cytology PREVENTING ANAL CANCER WHAT DO THE GUIDELINES SAY? PRIMARY CARE GUIDELINES FOR THE MANAGEMENT OF PERSONS WITH HIV: 2013 UPDATE BY THE HIV MEDICINE ASSOCIATION OF THE INFECTIOUS DISEASES SOCIETY OF AMERICA

Screening for Anal Human Papillomavirus Recommendation • Anal for: • MSM • Women with a history of receptive anal intercourse or abnormal cervical Pap test results • All patients with HIV with genital

(weak recommendation, moderate quality evidence) PRIMARY CARE GUIDANCE FOR PERSONS WITH HIV: 2020 UPDATE BY THE HIV MEDICINE ASSOCIATION OF THE INFECTIOUS DISEASES SOCIETY OF AMERICA

• Anal cancer screening recommended for persons with a history of: • Receptive anal intercourse • Abnormal cervical PAP test results • All persons with genital warts

IF ACCESS TO APPROPRIATE REFERRAL FOR FOLLOW UP including high resolution anoscopy is available

*no national screening guidelines for the use of anal Pap tests *guidance does not specify frequency of anal pap test PRIMARY CARE GUIDANCE FOR PERSONS WITH HIV: 2020 UPDATE BY THE HIV MEDICINE ASSOCIATION OF THE INFECTIOUS DISEASES SOCIETY OF AMERICA

• IF anal Pap test indicates – abnormal or atypical cells  high resolution anoscopy should be performed with of abnormal areas and appropriate therapy based on results 2015 SEXUALLY TRANSMITTED DISEASES TREATMENT GUIDELINES (CDC)

• Data insufficient to recommend routine anal cancer screening with anal cytology in persons with HIV infection, MSM without HIV infection, and the general population • Annual digital anorectal examination (DARE) may be useful to detect masses on palpation that could be anal cancer in persons with HIV and possibly HIV negative MSM with a history of anal receptive intercourse 2015 SEXUALLY TRANSMITTED DISEASES TREATMENT GUIDELINES (CDC)

• More data needed re: • natural history of anal intraepithelial neoplasia • not known whether treating the high-grade disease prevents anal cancer • best screening methods • target populations • safety and response to treatments • other programmatic considerations 2015 SEXUALLY TRANSMITTED DISEASES TREATMENT GUIDELINES (CDC)

• Acknowledges – clinical centers perform anal cytology to screen for anal cancer for high risk populations (persons with HIV, MSM, history of receptive anal intercourse)  HRA for abnormal results (ASC-US or worse)

• Oncogenic HPV tests not clinically useful for anal cancer screening among MSM because of high prevalence of anal HPV infection GUIDELINES FOR THE PREVENTION AND TREATMENT OF OPPORTUNISTIC IN ADULTS AND ADOLESCENTS WITH HIV (2018 UPDATE)

Preventing Anal Cancer • screening for lesions using anal cytology and treating anal precancerous lesions to reduce risk of anal cancer may be cost effective may provide clinical benefits comparable to measures to prevent other opportunistic infections GUIDELINES FOR THE PREVENTION AND TREATMENT OF OPPORTUNISTIC INFECTIONS IN ADULTS AND ADOLESCENTS WITH HIV (2018 UPDATE)

• No national recommendations exist for routine screening for anal cancer • Optional recommendation based on expert opinion: anal cytologic screening or high resolution anoscopy for men and women who are HIV seropositive NEW YORK STATE GUIDELINES (MARCH 2020)

• For all patients with HIV ≥35 years old, regardless of HPV status, clinicians should: • Inquire annually about anal symptoms, such as itching, bleeding, palpable masses or nodules, pain, tenesmus, or a feeling of rectal fullness • Perform a visual inspection of the perianal region • Perform DARE if anal symptoms are present

https://www.hivguidelines.org/hiv-care/anal- dysplasia-cancer/#tab_3 NEW YORK STATE GUIDELINES (MARCH 2020)

• For all patients with HIV ≥35 years old, regardless of HPV vaccine status, clinicians should: • Provide information about anal cancer screening and engage the patient in shared decision- making regarding screening, including anal cytology prior to digital anorectal examination (DARE) • Anal cytology recommended for MSM, cisgender women, transgender women, and transgender men • not currently recommended for men who have sex with women (MSW); • clinicians may perform anal cytology testing for any patient with HIV who requests it NEW YORK STATE GUIDELINES (MARCH 2020)

• Clinicians should promote smoking cessation for all patients with HIV, especially those at increased risk for anal cancer • For all patients with HIV ≥35 years old, clinicians should recommend and perform annual DARE to screen for anal pathology • Clinicians should evaluate any patient with HIV who is <35 years old and presents with signs or symptoms that suggest anal dysplasia • Upper limit for anal screening – not established: • Consider stopping screening for patients > 75 years and with 3 consecutive negative screening test and no longer sexually active NEW YORK STATE GUIDELINES (MARCH 2020)

• Clinicians should conduct or refer for high resolution anoscopy (HRA) and histology (via biopsy) any patient with abnormal anal cytology • Clinicians should refer patients with suspected anal cancer determined by DARE or histology to an experienced specialist for evaluation and management NEW YORK STATE GUIDELINES (MARCH 2020)

• Use of HPV typing for HPV related anal disease – still understudy • High prevalence of HPV among MSM with HIV – limits use of test in this population • Current data are inconclusive regarding the role of HPV typing to screen for anal cancer or guide its treatment NEW YORK STATE GUIDELINES (MARCH 2020)

• Sambursky, et al 2018 • Anal HPV screening for high-risk types, as an adjunct to anal cytology  improved identification of HSIL • patients with benign anal cytology results who tested positive for high-risk HPV had a 31-fold greater risk for HSIL than those who tested negative • Screening for high risk HPV may be useful in stratifying risk among patients with benign results on anal cytology HISTOPATHOLOGIC CLASSIFICATION OF ANAL CYTOLOGY

• Bethesda Classification System for cervical cytology has also been used for anorectal cytology results • Squamous intraepithelial lesion (SIL) • Low grade (LSIL) • High grade (HSIL). - considered prescursor to invasive carcinoma • atypical squamous cells (ASCs) of undetermined significance (ASC-US)  lesion cannot be distinguished as low grade or high grade

https://www.hivguidelines.org/hiv-care/anal-dysplasia-cancer/#tab_3 ANAL CYTOLOGY

• 70% sensitivity for detection of SIL or the presence of any abnormality • 34% specificity for HSIL prediction in subsequent biopsy • Cytologic HSIL result is predictive of HSIL on biopsy • 60-91% risk of anal HSIL at biopsy for anal cytology that is ASC-US and LSIL

https://www.hivguidelines.org/hiv-care/anal-dysplasia-cancer/#tab_3 New York State Guidelines (March 2020) TREATMENT OF ANAL HSIL

• Topical treatments • Tricholoroacetic acid • Imiquimod • (5-FU) • Local destruction with infrared coagulation • Electro cautery ablation • Surgical excision • Expectant management https://www.hivguidelines.org/hiv-care/anal-dysplasia- cancer/#tab_5 THANK YOU!