1. Anal Intra-Epithelial Neoplasia(AIN)
Dr Catherine Cheng
Tuen Mun Hospital

2. Case Male, 77 years old Chairbound, lives with family Medical History
NPC completed RT in 2001 with bilateral vocal cord palsy and recurrent aspirations, on PEG feeding and has a tracheostomy
Laparoscopic Cholecystectomy for cholecystitis 2012

3. Case Bleeding anal polyp with excision done June 2017
Pathology AIN 3 with areas of SCC, AIN extends to resected margin, invasive foci negative at margin
What would you do now?

4. Options 1) Discuss for re-excision of lesion
2) Consult oncology for radiotherapy
3) Observe, watchful waiting
4) Upfront local treatment with 5-FU or Electrocautery

5. Case
Multidisciplinary Meeting - Managed conservatively in view of poor premorbid
Admitted to medical end of November 2017 with pneumonia
Found to have persistent PR bleeding and anal mass. Hb 9.5

7. Wide Local Excision with Advancement Skin Flap performed on 23rd January 2018

8. Pathology Moderately differentiated SCC
Invasive foci not present in margin
12 o’clock margin showed AIN 3

9. Joseph R Roberts. World J Gastrointest Oncol. 2017; 9(2): 50–61
Definition
Pre-malignant lesion of the anal mucosa
Anal canal 2 – 4cm in length
A precursor to Anal Cancer
Can progress to Anal Cancer (SCC) from AIN I/II/III
Anal canal length 2-4cm
Joseph R Roberts. World J Gastrointest Oncol. 2017; 9(2): 50–61

10. Presentations Anal/Pelvic Pain Per Rectal Bleeding Rectal Mass
Tissue Prolapse
Local soiling
Incontinence to flatus or stool
Constipation
Common
Less common

11. Siegel RL. et al. CA cancer J Clin. 2018; 68 (1): 7
Incidence
~8600 cases of anal cancer per year in USA
Incidence on rising trend
Anal Cancer USA:
Rectal cancer, Anal cancer: CA cancer J Clin. 2018; 68 (1): 7
Rectal + Anal CA ~ new cases per year in Hong Kong
(~40,000 cases of rectal cancer in USA)
Incidence rate ~15 per 100,000 (0.0015%)
2.7% of all GI cancers in USA
97,000 colon cancer
Siegel RL. et al. CA cancer J Clin. 2018; 68 (1): 7

12. Risk factors HIV Men having sex with men (MSM) HPV infection
History of Cervical CA/Gynaecological CA
Smoking
Post-transplant/Inflammatory Bowel Disease/Immunosuppressed individuals
More common in older patients i.e. 60 yrs old or older

13. Darragh TM. et. al. Arch Patho Lab Med. 2012; 136(10):1266-97
LAST Criteria
Low Anogenital Squamous Terminology
LSIL – AIN 1, Condyloma, ASCUS
HSIL – AIN 2, AIN 3, Bowen’s disease, SCC in-situ
(CIN, VaIN, VIN, PeIN)
SISCCA (Superficial invasive squamous cell carcinoma) – Anus/Vulva/Vagina/Cervix/Penis
Darragh TM. et. al. Arch Patho Lab Med. 2012; 136(10):

14. <=LSIL <=LSIL: low grade squamous intraepithelial lesion
HSIL to SCC up to 19.6%
<=LSIL
<=LSIL: low grade squamous intraepithelial lesion
Berry J M. et al. Int J Cancer. 2014; 1;134(5):
William C. Mathews et. al. Plosone

15. Screening methods PR examination Anal cytology +/- DNA detection
Swab stick, Papanicolaou stain (Pap Smear), +/- PCR
High resolution anoscopy (HRA) +/- biopsy
Acetic acid, ‘acetowhite lesions’ (acetowhite epithelium - AWE), Lugol’s Iodine
Wolf forceps
4 quadrant biopsy
Lugol’s iodine: normal cells are stained = brown, dysplastic cells not stained = pink
Acetic acid: normal cells remain pink, dysplastic cells become white (acetowhite)
Cytology sensitivity: 69% - 93%
Cytology specificity: 32% - 59% or %

16. Siekas LL et. al, AIDS Read. 2009;19:178–186

17. Recommendation - Palefsky and Rubin (2009)
Palefsky JM et al. Obstet Gynecol Clin North Am. 2009;36:187–200

18. How risky are high risk patients?
High risk AIN patients  Anal Cancer VS General population  Colon CA = x1.2 higher
Joseph R Roberts. World J Gastrointest Oncol. 2017; 9(2): 50–61

19. 2011
Double-blind study
602 healthy MSM 16-26y old received quadrivalent HPV vaccine or placebo
Both Intention to treat and per-protocol analysis were used
Primary end point: any detection of AIN or Anal CA on cytology during any follow at 7m, 12m, 18m, 24m, 30m, 36m

20. SPANC Trial Study of the Prevention of Anal Cancer
Epidemiology of anal HPV in homosexual men aged 35 and older
Prospective longitudinal cohort study
Community based study
Sydney, Australia
Started in September 2010 and will concluded in mid-2015
Follow-up continuing to 2018
5 study visits over 3 years
By July 2013, approximately 404 men had been assessed for inclusion and over 350 men have been recruited into the study

21. Treatment Options Trichloroacetic acid (TCA) 5-flurouracil
Imiquimod Cream
RFA
Electrocautery (diathermy)
Infra red coagulation
Surgical treatment
Topical therapy
TCA – retrospective studies
Imiquimod Cream – RCT double blind study
Electrocautery most recommended
Surgical treatment – not recommended (highest rate of recurrence)
Ablative therapy
Operative treatment

22. Considerations Size Number Location Grade of lesions
Duration of treatment
Side effect profile
Patient compliance rate

23. Stephen E Weis. Onco Targetes Ther 2013. 6: 651–665.
Advantages
Disadvantages
5-flurouracil
Easy to use
Multifocal lesions
Effective if compliant
Significant side effect profile
Poor compliance
Imiquimod Cream
Unknown systemic absorption toxicity profile
Significant side effect profile & Poor compliance
Flu-like symptoms
Trichloroacetic acid (TCA)
1st line treatment of condyloma acuminatum – 2 <= lesions (US Centre of DCP)
Cheap
Safe for pregnancy
Minimal side effects
Significant SE profile (Inflammatory reaction  pain, itchy, burning)
Prolonged and frequent regimen --> poor compliance
Stephen E Weis. Onco Targetes Ther : 651–665.

24. Stephen E Weis. Onco Targetes Ther 2013. 6: 651–665.
Advantages
Disadvantages
Electrocautery (diathermy)
Lower rates of recurrence
Creates smoke vapour
Infrared coagulation
Minimal sphincter disturbance (limited depth of destruction)
Suitable in OPD setting
No smoke vapour
No standardized regimen/protocol
Surgery
Final pathology
Use in extensive disease
Risk of sphincter disturbance
GA/SA required
Expensive
RFA: studies in progress especially for HIV –ve patient treatments - so far: minimal SE profile, minimal pain
CO2 laser – adjunct with imiquimoid or surgery
- Advantage: suitable in OPD setting , can treat extensive disease (also infrared coagulation)
- Disadvantage: Also creates smoke vapour
Stephen E Weis. Onco Targetes Ther : 651–665.

25. Stephen E Weis. Onco Targetes Ther 2013. 6: 651–665.
Anal Function Compromised
Developed Anal Cancer
Surgery
0-15%
0-11%
Electrocautery (diathermy)
nil
0.4%
Infra-red Coagulation 0%
5-FU
0 - 13%
Imiquimod Cream
0-3%
Trichloracetic Acid (TCA)
Surgery FU times 32 – 60 months
IRC FU times – months
Electrocautery FU times – 21 months
5-FU FU times – nil (0%), nil (0%), 39 months (13%)
Imiquimod cream FU times – nil (0%), 9.5 (0%), 36 (3%)
TCA FU Times – nil (0%)
Stephen E Weis. Onco Targetes Ther : 651–665.

26. Filip Troicki et. al. J Med Case Reports. 2010; 4: 67.
Role of Radiotherapy
No evidence to support to use of radiotherapy in AIN
?Role in recurrent AIN
Filip Troicki et. al. J Med Case Reports. 2010; 4: 67.

27. Palefsky JM et al. Obstet Gynecol Clin North Am. 2009;36:187–200
Recommendation
LSIL: observation
Treatment only to reduce symptoms (not risk of CA)
HSIL: recommended for treatment
Periodic HRA for early detection of Anal SCC (earlier SCC staging  better prognosis) for those choosing not to have treatment
Exception – poor pre-morbid with short survival predicted (little benefit from treatment)
LSIL: FU every 6months
HSIL refuse treatment: FU every 3-4 months
Palefsky JM et al. Obstet Gynecol Clin North Am. 2009;36:187–200

28. Amsterdam, MSM 18 years or older, 246 patients
16 weeks imiquimod (3 times per week) – CR = 13, recurrence 71% by 72 weeks
16 weeks topical fluorouracil (2 times per week) – CR = 8, recurrence 58% by 72 weeks
4 months electrocautery (monthly) – CR = 18, recurrence 68% by 72 weeks
Recurrence at 24 weeks, 48 weeks, 72 weeks

29. ANCHOR TRIAL Anal Cancer HSIL Outcomes Research 12 United States sites
Aims to determine whether screening and treatment of HSIL is effective in reducing subsequent anal cancer in high risk groups (i.e. HIV positive)

30. Summary Clinical case Definition, risk factors, treatment options
Management recommendations
Upcoming trials

31. References
AIN: a review of diagnosis and management -
Progression rates of AIN to anal cancer, HRA examples - World J Gastrointest Oncol Feb 15; 9(2): 50–61.
Diagnosis / Treatment / Surveillance Algorithm - Palefsky JM, Rubin M. The epidemiology of anal human papillomavirus and related neoplasia. Obstet Gynecol Clin North Am. 2009;36:187–200
HPV Vaccine against Anal HPV Infection and Anal Intraepithelial Neoplasia – NEJM Med 2011; 365:
Comparison of imiquimod, topical fluorouracil, and electrocautery for the treatment of anal intraepithelial neoplasia in HIV-positive men who have sex with men: an open-label randomised controlled trial – The Lancet Oncology. April 2013, Volume 14, Issue 4: 346 – 353
Evaluation and Management of Anal Intraepithelial Neoplasia in HIV-Negative and HIV-Positive Men Who Have Sex with Men – Current Infectious Disease Reports March 2010, Volume 12, Issue 2, p
LAST Criteria – Archives of Pathology Lab Med. 2012;136:1266–1297
Onco Targets Ther. 2013; 6: 651–665.
Filip Troicki et. al. Radiation therapy of recurrent anal squamous cell carcinoma in-situ: a case report. J Med Case Reports. 2010; 4: 67.

32. Questions