Case 1 -
CIN ll Exists - Pro
Brigham and Women’s Hospital
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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.
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.
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high (HSIL) squamous intraepithelial lesion is an uncommon event and an indication for quality assurance
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- 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.
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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
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or 18 and the possible utility of type-specific HPV testing in clinical practice. J Natl Cancer Inst.
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