**1. Introduction**

### **1.1. Cervical cancer and HPV**

Cervical cancer is still the 2nd most common cancer in women worldwide, and especially women in developing countries are suffering from the disease [1].

If detected at an early stage Cervical Cancer is preventable. In almost all places around the world the traditional Pap smear is used as primary screening tool and even from being far away to be a perfect test, the benefits of Papanicolaou based cervical cancer screening programs in reducing morbidity and mortality are well accepted.

About 50 years after Papanicolaou has started his initial work, Meisels & Fortin published in 1976 a report in which they showed that the "halo cell" in pap smears, was a koilocyte - the pathognomic cell of an HPV infection [2] and that low grade or mild dysplasia of the cervix had the histological features of a papillomavirus infection [3].

Shortly thereafter Lutz Gissmann in the zur Hausen laboratory in Erlangen cloned from genital warts 'condyloma acuminata', a novel HPV DNA classified as HPV6 [4].

The idea that Cervical Cancer and cancers at other sides could be caused by a viral infection developed afterwards step by step.

In the meantime both concepts are merged and it is accepted that a persisting infection caused by the sexual transmitted human papillomavirus (HPV), is almost always the trigger for the occurrence of cervical cancer and the main agent for cervical epithelial dysplasias.

Of the more than 120 HPV subtypes known today, the anogenital ones are further divided into low risk (LR-HPV) and currently at least 15 high risk types (HR-HPV; HPV 16, 18, 45, 31, 33, 52, 58 are most frequent). While the former are only in rare cases cancerogenic, HR-HPV are detected virtually regularly in high-grade intraepithelial neoplasias and invasive cervical cancers, of which more than 70% are HPV 16 and HPV 18 [5].

Based on Ostors meta-analysis it's common sense that treatment isn't warranted for early dysplastic lesions as for atypical squamous cells of undetermined significance (ASCUS) and mild dysplasia (LSIL) since only 10% of the mild dysplastic lesions will progress to

HPV L1 Detection as a Prognostic Marker for Management of HPV High Risk Positive Abnormal Pap Smears

http://dx.doi.org/10.5772/55902

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A cytological follow up with colposcopic evaluation is recommended for these women and if necessary directed biopsies of abnormal-looking cervical tissue for diagnosis are taken.

The cervical histopathologic diagnoses of these samples are graded according to the cervical intraepithelial neoplasia (CIN) system as normal, CIN1, CIN2, CIN3, and cervical cancer [11].

So far diagnosis of CIN2 or worse is the clinical threshold leading to ablative or excisional

In the meantime a discussion started if moderate dysplasias, the cytological CIN2 equivalent, should be called low grade or high grade lesion. Ostor reported that only 20% of the moderate dysplasitic lesions progressed to CIN3+, typically a threshhold that should not warrant

As a consequence of the current situation conisations are being performed frequently, with potentially negative impact on reproductive outcomes for fertile women, including preterm

Despite the conservative recommendation in the Munich Nomenclature II, not to treat CIN2, conisation was one of the most common surgical procedures performed in women of fertile

The dilemma is that neither cytological follow up, colposcopy nor HPV DNA testing could indicate whether a remission or progression of the precursor lesion to invasive cancer will occur. Therefore more specific tools like prognostic markers would be of great value, allowing

delivery and low-birth-weight infants [12] with possible life long fatal disabilities.

an individualized management of cervical lesions depending on their risk profil.

**3. HPV L1 detection as prognostic marker for early dysplastic lesions**

Over the last couples of years cytological samples as well as colposcopically guided punch biospsies, have been used to determine if Cytoactiv HPV L1 detection is able to predict the

Moderate dysplastic lesions, being part of HSIL, have been investigated as well since the Munich nomenclature II, in contrast to TBS, groups moderate dysplastic lesions, together with mild dysplasias, in the category IIID, with recommendation for cytological follow up and

This different risk assesement offered the unique possibility to follow up these women with

age in Germany during 2010, accounting for more than 50.000 cases [13].

clinical outcome of HPV high risk positive early dysplastic lesions.

CIN3+ [10].

invasive procedures.

colposcopy.

moderate dysplasias as well.

therapy in the United States and Europe.

The negative predictive value of the highly sensitive DNA determination of HR-HPV in the cervical smear cell material is with more than 99% very high, i.e. women not infected with these HPV subtypes very probably have no high-grade intraepithelial lesion and no cervical cancer.

On the other hand the use as primary screening tool for cervical cancer is limited because the positive predictive value of a HPV DNA test is low.

The majority of HR-HPV infections remain morphologically undetected and even in mild dysplasias with persisting infections the probability for the development of high grade intraepithelial lesions is only about 20% focusing on young women.

Therefore even if thinking about the possibility to replace cytology as primary screening tool, the Pap-test will remain to verify a positive HPV DNA test, to confirm the presence of abnormal cells and most important to determine the severity or grade of disease, a unique feature of the morphological methods.
