LSIL / HSIL Forum Draft

LSIL/HSIL Forum

LSIL / HSIL Forum Draft

1991 Bethesda System

Squamous Intraepithelial Lesion (SIL)

Low-grade squamous intraepithelial lesion (LSIL)

High-grade squamous intraepithelial lesion (HSIL)

2001 Recommendations

Issue 1: Terminology used for squamous intraepithelial lesions.

Background: Since its adoption in 1988, the two-tiered terminology used by TBS to designate the spectrum of noninvasive cervical epithelial abnormalities has received widespread criticism. These criticisms have focused on three issues. First, it has been argued that the two-tiered TBS terminology provides less information to clinicians taking Papanicolaou smears than does the three-tiered CIN terminology (i.e., CIN 1, CIN 2, CIN 3). In other words, some clinicians would manage patients with a cytological diagnosis of CIN 2 (moderate dysplasia) differently than they would manage patients with CIN 3 (severe dysplasia/carcinoma in situ). The second criticism has been that the dividing line between LSIL and HSIL was set incorrectly. Instead of being set between CIN 1 and CIN 2, it has been argued that the dividing line should have be set between CIN 2 and CIN 3.10 One argument for moving the dividing line is that the natural history of CIN 2 is closer to that of CIN 1 than it is of CIN 3. A review of the published literature indicates that when left untreated, 43% of CIN 2 lesions will spontaneously regress and 35% will persist.8 For comparison, 57% of untreated CIN 1 lesions and 32% of untreated CIN 3 lesions spontaneously regress, and 32% and 56% of untreated CIN 1 and CIN 3 lesions persist, respectively. Another argument for moving the dividing line is that in some European countries CIN 1 and CIN 2 are grouped together for treatment purposes. The third criticism has been that since cervical cytology has an inherent error rate, a given cytological diagnosis should be considered as simply indicating that there is a given probability that a specific grade of histological lesion is present on the cervix. For example, there is an overall 10-15% discrepancy rate between LSIL and HSIL interpretations on Pap slides.12 This means that about 12% of the time, biopsy-proven cytology slides referenced as LSIL are interpreted as HSIL by cytologists/cytopathologists. In addition, approximately 15-18% of women with LSIL on cervical cytology will be found to have a high-grade squamous intraepithelial (CIN 2,3) of the cervix when colposcopy/cervical biopsy is performed.6 In some series, up to 20% of women diagnosed as HSIL on cervical cytology actually have a histologically confirmed low-grade squamous intraepithelial lesion (CIN 1) of the cervix.

Whether or not to revert to a three-tiered (CIN 1, 2, 3) cytological terminology was debated on the Bethesda 2001 Bulletin Board as well as at the Bethesda 2001 Meeting. Consideration was also given to moving the dividing line between LSIL and HSIL so that CIN 2 is included in the LSIL category. In general, there appeared to be general support for retaining the current two-tiered LSIL / HSIL terminology. This support is based on the fact that that there continues to be strong biological justification for a two-tiered LSIL / HSIL terminology in which the dividing line is placed between CIN 1 (mild dysplasia) and CIN 2 (moderate dysplasia).3, 5, 9, 13 In addition, it was recognized that both national and international management guidelines that are based on LSIL and HSIL cytological results have now been adopted and that clinical practice has successfully adapted to the current LSIL / HSIL terminology. However, among the members of the Forum Group and commenters on the Bulletin Board there continued to be a minority opinion favoring a CIN 1, CIN 2, CIN 3 terminology in order to make the Bethesda 2001 terminology more flexible and more attractive to clinicians in other countries. Although this might better reflect the natural history of CIN 2 and would make the terminology more attractive in European countries where CIN 1 and CIN 2 are managed in a similar fashion, it was generally felt that moving the dividing line between LSIL and HSIL so that CIN 2 is included in the LSIL category would lead to widespread confusion among clinicians. Moreover a reproducibility analysis was presented from the ALTS trial that assessed the agreement of diagnoses between a masked comparison of cytological diagnoses made by the academic cytopathologists at the clinical sites and a panel of "expert" cytopathologists. This analysis demonstrated that the cytologists could distinguish between CIN 1 and CIN 2 with a fair to good degree of reproducibility, but that the distinction between CIN 2 and CIN 3 was unreliable with a Kappa value of only 0.28. This argues for retaining a two-tiered LSIL / HSIL terminology with the dividing line between CIN 1 (mild dysplasia) and CIN 2 (moderate dysplasia).11

In order to allow TBS terminology to better reflect the uncertainty as to the specific grade of lesion present on the cervix in cases of LSIL, consideration was given by the forum group and at the Bethesda 2001 Meeting to recommending that a diagnosis of LSIL should be accompanied by a modifying statement indicating that a significant percentage of women with LSIL on cervical cytology will be found to have a high-grade squamous intraepithelial (CIN 2,3) of the cervix at colposcopy. However, it was the general opinion that this sort of modifying statement reflecting the uncertainty inherent in cervical cytology was neither necessary nor desirable.

Recommendation: LSIL and HSIL should continue to be included as two separate categories under Epithelial Cell Abnormalities - Squamous Cell. Moreover, the dividing line between LSIL and HSIL should be between CIN 1 (mild dysplasia) and CIN 2 (moderate dysplasia).

Issue 2: Retention of cellular changes associated with HPV cytopathic effect (so-called koilocytotic atypia) in the LSIL category.

Background: Some cytologists have proposed that cellular changes associated with HPV cytopathic effect (so called koilocytotic atypia) be separated from the LSIL category. Several studies have demonstrated lower rates of biopsy-confirmed HSIL in women referred to colposcopy on the basis a Papanicolaou smear demonstrating HPV changes only compared to LSIL.7 However, other studies have found that the criteria used to differentiate between HPV cytopathic effect and LSIL are not reproducible and multiple studies have recently demonstrated that in the majority of women with a cytological diagnosis of LSIL are infected with high-risk types of HPV.1, 2, 4

Recommendation: No modification should be made to TBS in this regard and cervical cytology specimens with the cellular features associated with HPV cytopathic effect (e.g., koilocytosis) should continue to be included under Epithelial Cell Abnormalities - Squamous Cell – Low-grade squamous intraepithelial lesion (LSIL).

Issue 3: Classification of gynecological cytology samples showing HSIL in which invasion cannot be ruled-out.

Background: Some laboratories currently add a qualifying statement to gynecological cytology reports from cases showing HSIL in which there is a suggestion that invasion may be present in order to alert the provider to the possibility of an invasive process. The use of a qualifying statement allows the cytology laboratory to alert the provider without making a definitive diagnosis of invasion in questionable cases.

Recommendation: Gynecological cytology cases showing diagnostic HSIL in which there is non-diagnostic cytological evidence of invasion should be diagnosed as HSIL and accompanied by the comment “with features suspicious for invasion”.

Proposed 2001 Bethesda System

Squamous Intraepithelial Lesion (SIL)

Low-grade squamous intraepithelial lesion (LSIL)

High-grade squamous intraepithelial lesion (HSIL)

Definition: Squamous intraepithelial lesion encompasses a spectrum of noninvasive cervical epithelial abnormalities traditionally classified as flat condyloma, dysplasia/carcinoma in-situ, and CIN. In TBS, the spectrum is divided into low-grade and high-grade lesions. Low-grade lesions encompass the cellular changes associated with HPV cytopathic effect (so-called koilocytotic atypia) and mild dysplasia/CIN 1. High-grade lesions encompass moderate dysplasia, severe dysplasia, and carcinoma in situ/CIN 2,3). Gynecological cytology cases showing diagnostic HSIL in which there is non-diagnostic cytological evidence of invasion should be diagnosed as HSIL and accompanied by the comment “with features suspicious for invasion”.

Members of LSIL / HSIL Forum

Richard DeMay MD, Rose Marie Gatscha CT (ASCP), Lydia Howell MD, Ron Luff MD MPH, Volker Schneider MD, Leo Twiggs MD, Tom Wright MD.

References

1 (2000) Human papillomavirus testing for triage of women with cytologic evidence of low-grade squamous intraepithelial lesions: baseline data from a randomized trial. The Atypical Squamous Cells of Undetermined Significance/Low-Grade Squamous Intraepithelial Lesions Triage Study (ALTS) Group [see comments]. J. Natl. Cancer Instit. 92: 397-402

2 Bergeron C, Jeannel D, Poveda J, et al (2000) Human papillomavirus testing in women with mild cytologic atypia. Obstet Gynecol 95: 821-827

3 Chung TK, Cheung TH, Lo WK, et al (2000) Loss of heterozygosity at the short arm of chromosome 3 in microdissected cervical intraepithelial neoplasia. Cancer Lett 154: 189-194.

4 Clavel C, Masure M, Bory JP, et al (1999) Hybrid Capture II-based human papillomavirus detection, a sensitive test to detect in routine high-grade cervical lesions: a preliminary study on 1518 women. Br J Cancer 80: 1306-1311

5 Hering B, Horn LC, Nenning H, et al (2000) Predictive value of DNA cytometry in CIN 1 and 2. Image analysis of 193 cases. Anal Quant Cytol Histol 22: 333-337.

6 Jones BA and Novis DA (2000) Follow-up of abnormal gynecologic cytology: a college of American pathologists Q-probes study of 16132 cases from 306 laboratories. Arch Pathol Lab Med 124: 665-671.

7 Melnikow J, Nuovo J, Paliescheskey M, et al (1997) Detection of high-grade cervical dysplasia: impact of age and Bethesda system terminology. Diagn Cytopathol 17: 321-325.

8 Mitchell MF, Tortolero-Luna G, Wright T, et al (1996) Cervical human papillomavirus infection and intraepithelial neoplasia: a review. J Natl Cancer Inst Monogr 21: 17-25

9 Park TJ, Richart RM, Sun X-W, et al (1996) Association between HPV type and clonal status of cervical squamous intraepithelial lesions (SIL). J. Natl. Cancer Instit. 88: 355-358

10 Robertson AJ, Anderson JM, Beck JS, et al (1989) Observer variability in histopathological reporting of cervical biopsy specimens. J Clin Pathol 42: 231-238.

11 Schiffman M (2001) (personnal communication of data from ALTS trial).

12 Woodhouse SL, Stastny JF, Styer PE, et al (1999) Interobserver variability in subclassification of squamous intraepithelial lesions: Results of the College of American Pathologists Interlaboratory Comparison Program in Cervicovaginal Cytology. Arch Pathol Lab Med 123: 1079-1084.

13 Wright TC and Kurman RJ (1996) A critical review of the morphologic classification systems of preinvasive lesions of the cervix: the scientific basis for shifting the paradigm. In: Lacey C (eds) papillomavirus reviews: current research on papillomaviruses. Leeds, Leeds Medical Information pp 215-225

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