Post Colposcopy Management of ASC-US and LSIL Pap Tests (PALS Trial): Pilot Study

1. BACKGROUND In 2010 the estimated age standardized incidence and mortality rates for cancer of the uterine cervix in Canada were 7 and 2 per 100,000 women respectively. Squamous cell carcinoma is the most frequent type and arises from a premalignant squamous dysplasia called cervical intraepithelial neoplasia (CIN). There are 3 grades of CIN from I to III in order of increasing severity. A systematic review of 73 studies on the natural history of CIN, determined nearly 89% of CIN I regressed to normal or a benign lesion or persisted unchanged, and progression to CIN III occurred in 11% and to cancer in 1%. In contrast, CIN III and II had a greater malignant potential as 12% and 5% respectively progressed to cancer. The low incidence and mortality rates of cervical cancer are largely attributed to the availability of screening for CIN with the Pap test (Papanicolaou stained cervical smear) and the colposcopic management of cytologic abnormalities. While rates have plateaued in recent years, decreases are expected with additional improvements in Pap test performance and pre-colposcopy management of cytologic abnormalities. Changes to the post-colposcopy management of cytologic abnormalities could also improve the rates, but rigorous investigation of potential changes is lacking.

1.1 Management and outcome of cytological abnormalities The Bethesda System (TBS) is the recommended Pap test reporting terminology in Canada. TBS 2001 classifies results as negative for intraepithelial lesion or malignancy (NILM), or an epithelial cell abnormality. The latter includes 1) atypical squamous cells of undetermined significance (ASC-US), 2) atypical glandular cells (AGC), 3) low grade squamous intraepithelial lesion (LSIL), 4) atypical squamous cells, cannot exclude HSIL (ASC-H), 5) high-grade SIL (HSIL), 6) adenocarcinoma in situ (AIS), and 7) malignant.

Management of cytological abnormalities may involve colposcopic examination. The colposcope magnifies the cervix and allows directed biopsy of any visualized mucosal abnormality (impression). A repeat Pap test and tissue sampling of the endocervical canal (endocervical curettage; ECC) can also be carried out. CIN II, III and cancer diagnosed at the first colposcopy exam are considered to be incident disease undersampled by the referral Pap test (incident >/=CIN II) 3. CIN II or higher detected within the subsequent 24 months is categorized as progressive disease. Some investigators however, also consider it incident disease that escaped earlier colposcopic detection and refer to incidentally detected and progressive CIN II or higher as cumulative CIN II (CIN 2+).

Approximately 1% of cytological results in the United States is an HSIL, 4.4 % is an ASCUS (atypical squamous cells of undetermined significance to include ASC-US and ASC-H) and 1.6% an LSIL. Canadian data is somewhat similar (Calgary Laboratory Services unpublished quality assurance data), Since upwards of 60-80% of HSIL is a CIN II/III colposcopic examination and treatment is appropriate so as to prevent cervical cancer. Uncertainty and controversy in regard to the outcome of ASC-US and LSIL existed until the completion of the ALTS (ASCUS and Low Grade Triage Study) randomized clinical trial. The trial determined 13% of the combined ASCUS and LSIL cohorts had an incident >/=CIN II and an additional 8% progressed to CIN II/III. These results underscored the importance of managing low grade cytological abnormalities to prevent cervical cancer.

1.2 Pre-colposcopy management of ASC-US and LSIL Current management of ASC-US and LSIL in Canada is guided by the Clinical Practice Guidelines of the Society of Obstetricians and Gynecologists of Canada (SOGC) and the 2001 and 2006 guidelines of the American Society for Colposcopy and Cervical Pathology (ASCCP). Management options include referral to colposcopy after a single or double test result of ASC-US or LSIL or a single ASC-US result testing positive for HPV (Human Papilloma Virus) DNA (deoxyribonucleic acid). Management in Canada is mostly based on repeat Pap testing since HPV testing is not routinely available in every jurisdiction. For example, in Alberta, 2 years of repeat Pap testing carried out at 6-month intervals is the standard for an ASC-US or LSIL detected during routine screening and referral to colposcopy occurs when follow up Pap tests show persistence or progression.