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What exactly is
ASCUS, LSIL or CIN1?
What does that mean for me?

A ASCUS, LSIL or CIN1 is a mild abnormality or in other, more scientific or medical words, a pre-cancerous lesion, with great emphasis on "pre-”cancerous. It is not cancer and the likelihood of it becoming cancer is very low! That's why many people use the following comparison: It is a type of common cold, but not pneumonia that requires hospital treatment.

ASCUS stands for: Atypical Squamous Cells of Undetermined Significance

LSIL stands for Low grade Squamous Intraepithelial Lesion Both terms are used when a cervical smear was the basis of the diagnosis.

CIN1 stands for Cervical Intraepithelial Neoplasia grade 1 and is used if a biopsy was taken.
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Cancer or no cancer?
A preliminary stage means that altered cells have been found on the cervix. A LSIL/CIN1 means that mild cell changes have been detected. For ASCUS the cell changes are even milder, between healthy and mild. However, no cancer cells are present! The altered cells could have been caused by an infection with a virus or triggered by a specific virus, the human papilloma virus, or HPV for short.
LSIL/CIN1 is the switch point at which it either goes in one direction or the other – i.e. LSIL/CIN1 regresses and the woman becomes healthy again all by herself or whether it progresses and ends in disease.
Frequently asked questions
Everything you need to know (about ASCUS/LSIL/CIN1)!
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Development

In most women, this pre-cancerous stage heals on its own within 1 – 2 years without anything having to be done. In most cases the immune system is fighting successfully against disease. Only in very few women (approx. 5 percent) does the precancerous stage progress slowly and eventually become cancer, typically about 10 years later.

What to do?

By detecting the capsid protein L1, every woman can find out whether her ASCUS/LSIL/CIN1 will disappear on its own or not: simply, quickly and reliably! Scientifically confirmed by many studies.

L1 - what is that?

The L1 capsid protein is a so-called prognostic protein, i.e. it predicts the further course of the cell changes with a high degree of probability.

How do I prove L1?

L1 is detected on a smear test or a biopsy. The gynecologist can request the L1 test from the laboratory by referral and the health insurance company will cover the costs, in most countries worldwide.

I have the L1 - what now?

Great! Now you can wait and drink tea. Your immune system is defending itself against the altered cells. Promote your immune system by living healthy; reduce smoking or drinking alcohol if relevant in your life style. However, as a kind of watchful waiting, you should still visit your gynecologist every 3-6 months for a smear test.

I don't have an L1 - what now?

Too bad. Your immune system has not recognized the threat and is not doing anything about it. Talk to your gynecologist about what measures should be taken now. A retesting should be considered to see if 3-6 month later the L1 situation has changed.

When does it become cancer?

On average, it takes between 5 and 10 years for a ASCUS/LSIL/CIN1 to develop into cancer. So plenty of time to take the right steps – and no acute danger that should tempt you to make hasty decisions that you may regret one day.

When to have a cone?

Conization should be considered, as the immune system is not activated by the missing L1. The earlier, the better, as this prevents the altered cells from spreading further.

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Info on HPV
No cervical cancer without HPV! HPV stands for “human papillomavirus”. There are hundreds of types of this virus. Low-risk types cause genital warts, for example. High-risk types of HPV are responsible for changes in the cervix, including cancer. The most common high-risk types are 16, 18, 31 and 33.
The most common transmission route for HPV is sexual intercourse. The virus can also be transmitted during oral sex. The virus is transmitted through mucosal contact, but – according to current knowledge – not through saliva, or blood!

If a smear is abnormal, an HPV test is carried out to determine whether it was caused by human papillomavirus. The types are also determined; often the high-risk types 16 and 18, but there are others. Unfortunately, determining the HPV type does not indicate whether the altered cells will regress on their own or not.

An HPV infection, even with so-called high-risk types, only very rarely leads to cancer, even with a ASCUS/LSIL/CIN1! Whether a pre-cancerous stage actually develops into cancer essentially depends on whether the immune system successfully fights against the virus.
HPV negative? An infection with HPV is a prerequisite for the development of cancer of the cervix. If the virus cannot be detected in the ASCUS/LSIL/CIN1, the development of cancer is practically ruled out. Nevertheless, check-ups with a gynecologist should not be neglected to rule out a false negative HPV test!

Various vaccines against HPV are available, but they only work optimally if they are administered before the first sexual intercourse. You can find more information here: https://www.who.int/news-room/fact-sheets/detail/cervical-cancer

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01. The Smear
When the cell smear is taken during the gynecologist's check-up, it is sent to a laboratory for assessment. There, the smear is assessed under a microscope and classified into different categories, as normal (NIL = no intraepithelial lesion) or abnormal as ASCUS, LSIL, HSIL or ASC-H
(https://en.wikipedia.org/wiki/Bethesda_system)
02. What does CIN mean?

If not only a cell smear is taken with a brush, but also a tissue sample (biopsy), which reveals abnormal findings, this is classified as CIN (for Cervical Intraepithelial Neoplasia). These are also precursors of cervical cancer.

A distinction is made between three stages:
CIN I describes a mild cell change in the cervix, similar to LSIL.

CIN II describes a moderate cell change, similar to HSIL.

CIN III describes a severe cell change. In this case, there is a high probability of a transition to cervical cancer. For this reason, conization is often recommended for CIN III.

Who pays the costs for the L1 analysis?

The gynecologist can request the L1 test from the laboratory by referral, the health insurance company covers the costs for the L1 test in most countries worldwide.

Cytoactiv – HPV L1 detection
Scientific publications (commented)

E. Y. Ki et al., 2019
Utility of human papillomavirus L1 capsid protein and HPV test as prognostic markers for cervical intraepithelial neoplasia 2+ in women with persistent ASCUS / LSIL cervical cytology.
International Journal of Medical Sciences, Vol. 16, p. 1096

Absence of HPV L1 capsid expression and presence of HPV type 16 or 18 infection are reliable predictors of progression to CIN2+. Only 4.1% of Cytoactiv-positive LSIL and 13.8% of Cytoactiv-positive ASCUS progressed. 89% of progressive cases were HPV16/18 positive. Only 1.5% of non-HPV16/18, L1-positive cases progressed.

F. Carozzi et al., 2018
Molecular Cytology Applications on Gynecological Cytology. In: Schmitt F. (eds) Molecular Applications in Cytology.
Springer

Chapter 8.3.1 “Biomarkers of the Productive Phase of the HPV-Induced Carcinogenesis” provides an overview of Cytoactiv HPV L1 detection.

Y.-J. Choi et al., 2018
E2/E6 ratio and L1 immunoreactivity as biomarkers to determine HPV16-positive high-grade squamous intraepithelial lesions (CIN2 and 3) and cervical squamous cell carcinoma.
Journal of Gynecologic Oncology

Validation of HPV L1 capsid protein expression combined with decreased HPV E2/E6 ratio as predictive markers of ≥CIN2 lesions. Using 226 ThinPrep slides, Cytoactiv was shown to be effective in combination with HPV integration markers. Combined AUC was 0.87.

G. Mehlhorn et al., 2014
HPV16-L1-specific Antibody Response Is Associated with Clinical Remission of High-risk HPV-positive Early Dysplastic Lesions.
Anticancer Research 34: 5127–5132

Detection of HPV16-L1-specific antibodies strongly correlates with clinical remission. The risk of progression to CIN3 in L1 antigen and HPV16-L1 antibody double-positive women is extremely low (approx. 6%).

S.-J. Lee et al., 2014
Clinicopathological Implications of HPV L1 Capsid Protein Immunoreactivity in HPV16-Positive Cervical Cytology.
International Journal of Medical Sciences, 11(1):80–86

HPV L1 expression is low in advanced dysplasia. Absence of L1 in HPV16-positive ASCUS and LSIL is strongly associated with high-grade histopathology (≥CIN3).

G. Mehlhorn et al., 2013
HPV L1 detection discriminates cervical precancer from transient HPV infection: a prospective international multicenter study.
Modern Pathology, 26: 967–974

Prospective multicenter study (n=908) confirmed that only ~20% of L1-positive cases progressed to CIN3, whereas 84% of L1-negative cases progressed. Cytoactiv reliably distinguishes transient from progressive HPV infections.

S. W. Byun et al., 2013
Immunostaining of p16INK4a/Ki-67 and L1 Capsid Protein on Liquid-based Cytology Specimens from ASC-H and LSIL-H Cases.
International Journal of Medical Sciences

Combined analysis of p16INK4a, Ki-67 and L1 capsid protein improves prediction of high-risk precursor or invasive cervical lesions.

R. Hilfrich, 2013
HPV L1 Detection as a Prognostic Marker for Management of HPV High Risk Positive Abnormal Pap Smears.
InTech – Human Papillomavirus

Comprehensive summary of scientific data supporting Cytoactiv as a prognostic marker in abnormal Pap smear management.

I. Norman et al., 2013
High-risk HPV L1 capsid protein as a marker of cervical intraepithelial neoplasia in HR-HPV-positive women with minor abnormalities.
Oncology Reports 30

Loss of L1 expression predicts CIN2+. L1-positive ASCUS/LSIL lesions have low malignant potential and support a “wait and see” strategy.

Ch. A. Brown et al., 2012
Role of Protein Biomarkers in the Detection of High-Grade Disease in Cervical Cancer Screening Programs.
Journal of Oncology, Volume 2012

Review of protein biomarkers including Ki-67, p16INK4a, BD ProEx C and Cytoactiv HPV L1.

L. Benerini-Gatta et al., 2011
Diagnostic Implications of L1, p16, and Ki-67 Proteins in Low-grade Cervical Intraepithelial Neoplasia.
International Journal of Gynecological Pathology

Malignant transformation correlated with L1– / p16+ cases (100% of CIN2/3 and SCC). Approximately 23% of CIN1 cases showed malignant transformation.

G. Böhmer, Th. Weyerstahl, 2011
Management of abnormal results of the cervix uteri during cervical cancer screening.
Thieme Gynaecology up2date

Review of current management recommendations; Cytoactiv clearly distinguished as a prognostic marker.

S. J. Lee et al., 2011
Correlation between HPV L1 immunocytochemistry and behavior of low-grade cervical cytology.
Journal of Obstetrics and Gynaecology Research

Positive predictive value of HPV L1-positive cases for non-progression was 91.7%.

M. T. Galgano et al., 2010
Using Biomarkers as Objective Standards in the Diagnosis of Cervical Biopsies.
American Journal of Surgical Pathology

Cytoactiv showed superior specificity (96.7%) and highest reproducibility compared to p16 and Ki-67.

Y. S. Choi et al., 2010
HPV L1 Capsid Protein and HPV16 as Prognostic Markers in CIN1.
International Journal of Gynecological Cancer

HPV L1 protein expression is closely related to spontaneous regression in CIN1.

H. Griesser et al., 2009
HPV vaccine protein L1 predicts disease outcome of HR-HPV+ early dysplastic lesions.
American Journal of Clinical Pathology

Progression occurred in only 20% of L1-positive cases versus 97% of L1-negative cases.

Th. Scheidemantel et al., 2008
Expression pattern of HPV L1 capsid protein in PAP tests.
Abstract, American Society of Cytopathology

None of the Cytoactiv-positive patients progressed to cervical cancer.

G. Negri et al., 2008
p16 and HPV immunohistochemistry in low-grade dysplastic lesions.
American Journal of Surgical Pathology

Confirms prognostic value of Cytoactiv and benefit of combination with p16 and HPV testing.

R. Hilfrich, J. Hariri, 2008
Prognostic relevance of HPV L1 detection combined with p16.
Analytical and Quantitative Cytology and Histology

Progression in 83.9% of L1-negative cases versus 27.5% of L1-positive cases; Cytoactiv specificity 100%.

D. Rauber et al., 2008
Prognostic significance of HPV L1 detection in mild to moderate dysplasia.
European Journal of Obstetrics & Gynecology and Reproductive Biology

Progression rate of L1-positive cases was only 12.3%.

H. Griesser et al., 2004
Correlation of HPV L1 detection with regression of HR-HPV positive dysplasia.
Analytical and Quantitative Cytology and Histology

First Cytoactiv publication demonstrating strong prognostic value of HPV L1 detection.

Do you have questions on the topic or would you like to request information material?
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