Disclosures Teresa M Darragh, MD

Transcription

1 Below the Belt: Screening for HPV-associated Cancers Teresa M. Darragh, MD UCSF Departments of Pathology and Obstetrics, Gynecology & Reproductive Sciences Disclosures Teresa M Darragh, MD Hologic: Research supplies for anal cytology BD: Advisory Board Roche: Advisory Board & Honorarium for lectures TheVax: Consultant Antiva: Consultant Objectives Cervical Cancer Screening & Management Very brief update Dear Pap Smear It s over Anal Cancer Screening? Populations at high-risk for HPV-associated anal disease Approaches to anal cancer screening in target populations Challenges in anal cancer screening and management Adele Richards Manager Cytology Douglass Hanly Moir Pathology

2 Cervical Cancer Screening Countries Implementing 1 HPV Screening 21 st century Hybrid model Pap + HPV U.S. 21 st century Molecular model Primary HPV screening Objective interpretation 20 th Century Morphology Model - Cytology Subjective interpretation Netherlands: 1st country, started 2016 Australia: Implemented December 2017 New Zealand: Starting in 2018 United Kingdom: Large national pilot study France and Italy: Option Countries with successful HPV vaccination Countries with little/no screening Countries with poorly developed cervical cytology programs USPHS Draft Recommendations September 2017 Does your laboratory offer 1 HPV testing? A.Yes B. No 75% Age Cervical cytology every 3 years Ages 30-65: HPV testing alone every 5 years No cotes ng 25% Yes No

3 FDA-approved high-risk HPV tests Assay HC2 Cervista cobas Aptima Detection of HPV DNA HPV DNA HPV DNA HPV E6/E7 mrna # of HPV types Assay type Internal control for specimen adequacy HPV 16/18 genotyping available RNA-DNA hybrids Invader technology PCR RNA amplification/ hybridization Approved for primary screening No Yes Yes No No Yes Yes Included Yes + type 45 Extended genotyping BD Onclarity PCR based assay β-globin internal control FDA Approved February 2018 Extended genotyping 6 discrete HR HPV genotypes (16, 18, 31, 45, 51, 52) 8 additional high-risk genotypes reported in three small groups: (33, 58), (35, 39, 68) and (56, 59, 66). Indications include 1 HPV Screening Primary HPV Screening: >25 yrs Triage with 16/18 Genotyping and Reflex Cytology HPV Testing HPV 12 other hrhpv+ HPV16/18+ q 3 years Routine screening reflex Cytology COLPOSCOPY NILM ASC-US FDA-approved algorithm Follow up in 12 months COLPOSCOPY Wright et al. (2015) Gynecol Oncol Primary HPV Screening Triage to colpo if positive for HPV 16/18 Reflex cytology for triage if non-16/18 Other future methods of triage include: Molecular triage HPV testing with extended genotyping Methylation Morphologic triage: Dual staining

4 HPV Testing: Clinical Uses Screening: Reflex testing for ASC-US Cotesting in women 30 years Primary screening Triage: Partial and extended genotyping +/- Morphologic triage Post-colposcopy Management Post-treatment Management Screening test: Risk stratification Treatment Colposcopy Increased surveillance Repeat screen Courtesy of N. Wentzensen Management options (Exit screening) Repeat screen at regular intervals Increased surveillance Shorter screening interval Colposcopy Treatment Cervical Cancer Screening Options Rapid Evolution Advantage of screening and management recommendations based on risk thresholds New assays can be integrated into current recommendations more easily based on risk equivalence studies

5 NCI-ASCCP Risk-based Management Consensus Conferences Develop risk-based approach to management of abnormal cervical screening results Develop Clinical Action Thresholds Risk matrix: Input variety of clinical and laboratory data Clinical tool 2 nd generation app Clinical and Pathology/Laboratory Societies Include patient advocacy groups Deliberative Method 1 st planning face-to-face meeting: February 2018 Cutting out the complexity Negative Routine Screening Screening test(s) 12 other hrhpv + Black box Cytology Increased Surveillance Type 16 Positive Colposcopy Schiffman M, Wentzensen N. A Suggested Approach To Simplify and Improve Cervical Screening in the United States. Journal of lower genital tract disease. 2016;20(1):1-7. Equal Management for Equal Risk Anal Cancer Screening Why? Whom? How? Part 2 Image: Alan Waxman, M.D.

6 Objectives Why? Anal cancer statistics Parallels between cervical and anal cancer Whom? Risk groups for HPV-associated anal disease How? Anal cancer screening: Anal cytology High resolution anoscopy (HRA) and anal biopsy? HPV testing Anal Cancer Statistics, U.S. Incidence rates: Women: 1.8 / 100K Men: 1.4 /100K Median age at diagnosis: 61 years 10+ years later than cervical cancer American Cancer Society: SEER: Anal Cancer Rates by Birth Cohort Anal Cancer and Cervical Cancer New cases in 2018: Deaths in 2018: Coming of age: Sexual revolution HIV epidemic Cervical cancer in US: Prior to Pap screening Currently Anal cancer: Women, general pop. HIV+ women HIV- MSM* HIV+ MSM* Rates per 100, / 100K 7.5 / 100K 1.8 / 100K 30 / 100K 35 / 100K 131 / 100K Simpson J A D, Scholefield J H BMJ 2011;343:bmj.d6818 *MSM = men who have sex with men Silverberg M et al. CID 2012; 54: SEER:

7 Anal Cancer: Who is at risk? Targeted screening Men who have sex with men (MSM) Patients with HIV disease Start >25 years in immunosuppressed Women with HSIL / cancer Multifocal HPV-related disease Vulvar / perianal > cervix Other causes of immunosuppression Solid organ transplantation? Other causes of immunosuppression, e.g. Autoimmune disease Inflammatory bowel disease Start >35 years in immunocompetent Journal of Lower Genital Tract Disease Journal of Lower Genital Tract Disease Anal Cancer and Cervical Cancer Common risk factors Sexual intercourse Vaginal Anal HPV infection High-risk HPV HPV 16 and 18 HPV16 Anatomic commonality: Transformation zones Regions of active squamous metaplasia Vulnerable to high-risk HPV Morphologic similarity Precursor lesions HSIL and LSIL Cytology and histology Cancer: Squamous cell carcinoma International Journal of Cancer Volume 124, Issue 10, pages , 15 DEC 2008 DOI: /ijc

8 Cervix and Anus: Lesions morphologically similar Low grade High grade Netter Presenter Image Copyright 2003, Icon Learning Systems. All rights reserved. Cervix Anus Anal Cancer: U.S. Screening Guidelines HPV-related Lesions of the Cervix and Anal Canal SIMILARITIES >> DIFFERENCES Screening and Diagnostic approaches similar Link screening to treatment!!!! CDC: Acknowledges that some experts recommend anal cytologic screening for HIV+ men and women ACS: Anal cytology, sometimes called the anal Pap test, may be useful in early diagnosis of anal cancer and precancer (called anal intraepithelial neoplasia (AIN)... New York State Department of Public Health AIDS Institute: Clinicians should obtain anal cytology at baseline and annually in the HIV-infected populations American Society of Colorectal Surgeons: Include anal cytology in its Practice Parameters HIV Medicine Association of the Infectious Diseases Society of America Include anal cytology recommendations

9 Anal Cancer: Screening and Diagnosis The Bethesda System: Anal Cytology HPV-related lesions of the anogenital tract Anal Cytology Digital anal-rectal examination (DARE) High resolution anoscopy (HRA) HRA-directed anal biopsy 2001: Relatively new tool Screen for HPV-related lesions of anal canal Screen high-risk individuals, e.g.: MSM HIV disease Use Bethesda System terminology Diagnostic criteria similar to GYN cytology HPV-related changes parallel those for GYN cytology: LSIL, HSIL, ASC-US, ASC-H Guidelines for specimen adequacy Does your laboratory evaluate anal cytology? A. No B. Occasionally (<10/week) C. Frequently (10-25/week) D. Often (>25/week) No 58% Occasionally (<10/week) 34% Frequently (10-25/week) 7% 2% Often (>25/week) Anal Cytology at UCSF Approximately 3300 anal samples in 2017 HSIL+ ~15% ASC-H ~3-5% LSIL ~30% ASC-US ~25-30% Negative ~25-30% Unsat ~1-3% Liquid-based cytology High-risk population High abnormal rate Low unsatisfactory rate High prevalence of disease If even 1 abnormal cell, sample is not unsat HSIL on cytology almost always confirmed on biopsy But not unusual for even those with benign cytology to have HSIL on biopsy

10 Anal Cytology: Technique Use moistened Dacron swab Insert into canal until resistance is met Above anal verge to distal rectum Do not use pre-scored swab! Rotate / apply firm pressure to walls of canal while removing sampling device Liquid-based cytology or direct smear the swab Anal Cytology: Goal Sample entire anal canal the type of collection device is probably less important than the skill and experience of the clinician in collecting a representative sample Leiman G. Anal screening cytology. Cytojournal 2005; 2: 5. Netter Presenter Image Copyright 2003, Icon Learning Systems. All rights reserved. Anal transition zone Analogous to cervical TZ Squamous metaplasia Non-keratinized squamous mucosa Keratinized squamous mucosa

11 Anal Cytology: Specimen Adequacy... Liquid vs. conventional pap Better cell preservation Cellular harvest Bacteria / fecal contamina on Mechanical / air-dry artifacts Minimum cellularity: nucleated squamous cells ThinPrep (20 mm): 1 to 2 nucleated cells / hpf SurePath (13 mm): 3 to 6 nucleated cells / hpf > 6/hpf (Arain et al) Anal Cytology: Normal components Transformation Zone components: Rectal columnar cells Squamous metaplasia Nucleated squamous cells Anucleate squames Darragh TM and Palefsky JM: Anal Cytology. Chapter 8. The Bethesda System for Reporting Cervical Cytology. R. Nayar. D.C. Wilbur (Eds). Springer, 3rd ed Anal Cytology: Bugs Anal Cytology: Bugs Unique to anal cytology Local organisms vs passing through Commensul vs. Infection Ameba, pinworm, strongyloides Similar to Pap tests Herpes Candida

12 The Bethesda System: Epithelial Cell Abnormalities Squamous cell abnormalities Atypical squamous cells of undetermined significance (ASC-US) Cannot exclude HSIL (ASC-H) Low grade SIL (LSIL) High grade SIL (HSIL) Squamous cell carcinoma Glandular cell abnormalities Anal Cytology: Squamous Atypia Atypical squamous cells that quantitatively or qualitatively are not sufficiently atypical to warrant an interpretation of LSIL or HSIL ASC-US Suggestive of LSIL ASC-H Cannot exclude HSIL ASC-US ASC-H Anal LSIL Anal HSIL

13 Anal Squamous Cell Carcinoma Anal HPV Testing? No FDA-approved HPV test for anus Laboratories need to validate for this site Screening and triage? Mixed reports of usefulness but good NPV! High prevalence of HPV in highest-risk populations High negative predictive value May be useful in post-hra and post-treatment management HPV 16 genotyping? A combination of anal cytology and HPV genotyping provided the highest accuracy for detecting anal precancer. Wentzensen et al. Journal of Clinical Microbiology. 2014;52(8): Screening for Anal SIL Anal Cytology Screening Digital Anorectal Exam (DARE) Negative ASC-US LSIL HSIL Palpate for areas of: Induration Repeat q year (HIV+) Repeat q 2-3 yr (HIV-) No lesions seen High-resolution Anoscopy with biopsy Low grade AIN High grade AIN Nodularity, etc Pain This is the cancer screening test! Chin-Hong and Palefsky. HIV/AIDS 2002;35: Follow q 6 months or Tx if symptomatic Treat

14 High-resolution Anoscopy: A, B,C s +V Anal Colposcopy Acetowhite lesions Borders Contour changes Vascular changes Low Grade SIL High Grade SIL Anal Squamous Cell Carcinoma

15 Current Unknowns What is the progression rate of anal HSIL to cancer? Will anal screening and treatment of anal HSIL lower the incidence of anal cancer? Is effective treatment of anal HSIL possible? Anal Cancer Screening? Era of evidence-based medicine Need randomized controlled trial Never done for the Pap test Does treatment of anal HSIL reduce the rate of anal cancer? 15+ sites in US Anal Cancer Screening Screen~17K HIV+ men & women, ages 35 and older ~5000 with HSIL on anal biopsy Follow for 5+ years Two arms: Treatment Active monitoring Does treatment of anal HSIL effect natural history? should we screen for anal cancer + its precursors? Anal Cancer/HSIL Outcomes Research Study The Bad News The incidence of anal HSIL and cancer is high in at-risk populations HAART has limited positive effect on HPV-related neoplasia Evidence is mounting that the incidence of anal cancer will continue to rise among HIVpositive MSM

16 The Good News At-risk men and women should be screened for anal cancer with a digital anorectal exam Early detection of anal cancer has real benefits At-risk men and women should be considered for screening and treatment of anal HSIL Treatment is improving! HPV vaccines have the potential to prevent anal HPV infection and ultimately, anal cancer Thank you