Case 1 -

CIN ll Exists - Pro Christopher Crum Brigham and Women’s Hospital Boston, MA

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Clinical History Three cases (8 images) of cervical specimens are supplied for your review. Review each set of images in each case and grade the lesion in each of the images. Then, give your diagnosis for the case. Each image and case will be discussed at the session, which will focus on the existence (or non-existence) of CIN2. Case 1a - Figure 1 Case 1a - Figure 2 Case 1a - Figure 3 Case 1b - Figure 1 Case 1b - Figure 2 Case 1c - Figure 1 Case 1c - Figure 2 Case 1c - Figure 3 Let's begin with the cases Case 1 consisted of three images. Shown to the right as A, B, and C. They depict a range of atypia from mild to severe. I would classify A as CIN1 (LSIL), B as CIN2 (HSIL) and C as CIN3 (HSIL). D is an adjacent invasive squamous carcinoma. Case 2 consisted of two images Shown as A and B. I would classify A as CIN2, and B as CIN1. C is an adjacent squamous cell carcinoma. Case 3 consisted of three images, shown as A, B and C. I would classify A as CIN1, B as CIN2 and C as CIN1. The purpose of this exercise is to illustrate the range of epithelial atypia that can be seen in association with squamous intraepithelial lesions, including those associated with malignancy. In our experience of polling groups of individuals, it has become clear that the practitioner tailors their response to the number of options. The more options that are provided, the more the diversity of opinion albeit within a defined range. What if you were given the following options for given diagnosis? 1 Negative Follow 2. Probably LSIL Follow 3. Definitely LSIL (CIN1) Follow 4. Possibly CIN2 Follow 5. Definitely CIN2 LEEP 6. CIN2 or CIN3 LEEP 7. CIN3 LEEP If you were to poll multiple observers using this spectrum of choices for a given case there would frequently be a distribution of responses that predominated at one end (such as 1-3, or 5-7) or in the middle (3-5). The most important distribution is the latter, in as much as interpretation of lesions in the CIN1 or CIN2 range will determine whether they will receive a LEEP. Excepting the rare instances of subtle malignancy, the most pressing responsibility of the practicing pathologist is to identify which individuals with epithelial abnormalities require a LEEP. Reproducibility in cervical precursor pathology has been an issue of concern for years. The two most problematic cut-points in terms of interobserver concordance are between negative and CIN1 (or flat condyloma) and between CIN1 and CIN2. Interestingly, the advent of the LEEP solved the first problem and exacerbated the second. Office cryotherapy could be used for either CIN1 or CIN2, resulting in both the over-treatment of CIN1 but the management of CIN2 was less involved. LEEP on the other hand, was sufficiently traumatic and expensive to require excluding patients with CIN1, sparing them a procedure in most cases. Unfortunately, LEEP put an untold number of cervices at the mercy of the pathologist's ability to distinguish CIN1 from CIN2. Considering the problems encountered in separating these two entities, it could be argued that CIN2 does not exist, being a shadowy area of diagnostic uncertainty between CIN1 and CIN3. As interpreted in practice, CIN2 is fundamentally no different from ASCUS. It is an entity that is diagnosed with variable precision and thus signifies multiple biologic processes. As we have learned with ASCUS, ignorance of its biologic meaning in any given case and lack of diagnostic precision are not impediments to including the term in the lexicon of precursor terminology. However, the lack of precision compels us to accept the diagnosis as one that becomes more meaningful if there is some additional supporting evidence. In the case of ASCUS, we had a choice of qualifying the diagnosis (as in ASCUS favor LSIL etc), subjecting it to review by more than one cytopathologist, or using HPV testing as an adjunct. HPV testing is the clear winner, because it provides objective confirmation that HPV is present and in essence tells us that about half of our ASCUS diagnoses signify something with a 10-20% risk of HSIL biopsy outcome, versus a 1% risk if the test is negative. What are our options for CIN2? In our experience and that of others, if two or more pathologists agree on the diagnosis of CIN2, the frequency of HPV16 approaches 50%. If the concurrent cytology is HSIL, the frequency of HPV16 is over 60%. The rate of spontaneous disappearance in young women with a majority diagnosis of CIN2 biopsy alone is approximately 40%. The risk of a follow-up diagnosis of invasive carcinoma, at least in the short term, is less than one in 200. Are there markers that will predict "progression" from CIN1 to CIN2 or higher or will predict persistence of CIN2? Central to this issue is whether progression to CIN2 takes place. I believe it is uncommon. Moreover, we have found that when it is reported, there is the real risk that the initial or (more likely) follow-up biopsy was overcalled, revisiting the conundrum of diagnostic accuracy. Thus, when both biopsies are critically reviewed, we find the risk of CIN2 outcome after a biopsy diagnosis of CIN1 (LSIL) to be 5% or less. Assuming that progression does occur in some, will biomarkers be of value? The question has yet to be answered. Approximately 70% of LSILs will stain strongly for p16. The absence of linear uninterrupted p16 staining makes a strong case for a low risk HPV (or no HPV). However, most LSILs contain high-risk HPVs and will stain more diffusely with p16, yet they frequently will not "progress". So what is to be done? I believe every suspected CIN2 should be confirmed by a second observer. This exercise does not guarantee that the lesion has a high risk of persistence or progression to malignancy, but it does elevate the threshold for a histologic diagnosis of HSIL and will spare some patients a needless LEEP. p16 is a sensitive biomarker for CIN2 or higher and may be no worse a strategy than consensus review; however, I would not depend on it as an ultimate arbiter for a decision to perform a LEEP. We use it principally to distinguish neoplastic from non-neoplastic atypias. Ultimately, the fundamental question is not whether CIN2 exists, but whether there should be a specific management algorithm for lesions falling between CIN1 and CIN3. Should there be a LEEP-sparing strategy for CIN2 that takes into several parameters, such as age (less than 25 years), biomarker staining, HPV genotyping, and a defined follow-up period to allow for regression prior to opting for a LEEP? In 1-2 decades this conundrum might all but disappear in the United States as the number of young women who have been vaccinated increases and the relative proportion of SILs classified as high-grade diminishes. Then, this debate could become moot, as CIN2 becomes less tightly linked to HPV 16 and more likely to signify a lesion at lower risk of progressing to cervical cancer. References Chen EY, Tran A, Raho CJ, Birch CM, Crum CP, Hirsch MS. Histological 'progression' from low (LSIL) to high (HSIL) squamous intraepithelial lesion is an uncommon event and an indication for quality assurance review. Mod Pathol. 2010;23:1045-51 Crum CP, Mitao M, Levine RU, Silverstein S. Cervical papillomaviruses segregate within morphologically distinct precancerous lesions. J Virol. 1985;54:675-81. Crum CP. Laboratory management of CIN 2: the consensus is consensus. Am J Clin Pathol. 2008;130:162-4 Galgano MT, Castle PE, Atkins KA, Brix WK, Nassau SR, Stoler MH. Using biomarkers as objective standards in the diagnosis of cervical biopsies. Am J Surg Pathol. 2010;34:1077-87. Galgano MT, Castle PE, Stoler MH, Solomon D, Schiffman M. Can HPV-16 genotyping provide a benchmark for cervical biopsy specimen interpretation? Am J Clin Pathol. 2008;130:65-70 Khan MJ, Castle PE, Lorincz AT, Wacholder S, Sherman M, Scott DR, Rush BB, Glass AG, Schiffman M. The elevated 10-year risk of cervical precancer and cancer in women with human papillomavirus (HPV) type 16 or 18 and the possible utility of type-specific HPV testing in clinical practice. J Natl Cancer Inst. 2005;97:1072-9 Wheeler CM, Hunt WC, Schiffman M, Castle PE; Atypical Squamous Cells of Undetermined Significance/Low-Grade Squamous Intraepithelial Lesions Triage Study Group. Human papillomavirus genotypes and the cumulative 2-year risk of cervical precancer. J Infect Dis. 2006;194:1291-9.