**2. Cervical cancer screening**

Since the early days of cervical cytology it is known that the morphologically identified lesions of different grades are mixtures of distinct biological stages resulting in different clinical outcomes, remission or progression [6].

Today with the knowledge that HPV is a necessary but not sufficient cause for the development of most cervical cancers, transient HPV infection and precancer are often used synonymous for these biologically different conditions.

Traditionally cervical cancer prevention programs rely on the repeated application of a 3-step strategy:


For Pap smear diagnosis different reporting systems are in use worldwide. Besides the original WHO classification [7], The Bethesda System (TBS) [8] is internationally accepted, while the Munich Nomenclature II is being recommended in Germany [9].

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 CIN3+ [10].

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

94 Human Papillomavirus and Related Diseases – From Bench to Bedside A Diagnostic and Preventive Perspective

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

On the other hand the use as primary screening tool for cervical cancer is limited because the

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

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

Since the early days of cervical cytology it is known that the morphologically identified lesions of different grades are mixtures of distinct biological stages resulting in different clinical

Today with the knowledge that HPV is a necessary but not sufficient cause for the development of most cervical cancers, transient HPV infection and precancer are often used synonymous

Traditionally cervical cancer prevention programs rely on the repeated application of a 3-step

**2.** Follow up of the cytology positive women with HPV DNA testing colposcopic evaluation and directed biopsy of abnormal-looking cervical tissue for diagnosis; and if necessary

**3.** Excisional or ablative treatment of the cervical tissue in women diagnosed with CIN2+ or

For Pap smear diagnosis different reporting systems are in use worldwide. Besides the original WHO classification [7], The Bethesda System (TBS) [8] is internationally accepted, while the

cancers, of which more than 70% are HPV 16 and HPV 18 [5].

intraepithelial lesions is only about 20% focusing on young women.

positive predictive value of a HPV DNA test is low.

cancer.

strategy:

precancer.

morphological methods.

**2. Cervical cancer screening**

outcomes, remission or progression [6].

for these biologically different conditions.

**1.** Screening by cervical cytology with the Pap - Test;

Munich Nomenclature II is being recommended in Germany [9].

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 therapy in the United States and Europe.

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 invasive procedures.

As a consequence of the current situation conisations are being performed frequently, with potentially negative impact on reproductive outcomes for fertile women, including preterm delivery and low-birth-weight infants [12] with possible life long fatal disabilities.

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

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