Background 1.1. HPV and dysplasias of the cervix uteri Human papillomaviruses (HPV)
are the most common sexually transmitted pathogens worldwide. The prevalence in both
male and female populations is high. Epidemiological estimates suggest that 85-91%
of sexually active adults acquire at least one genital HPV infection by the age of
50, with approximately 95% of HPV infections being spontaneously eliminated within 2
years in terms of HPV immunological clearance. HPV preferentially infects the
epithelial cells of the anogenital area and, through incorporation of HPV DNA into
the host genome of the basal cells of the squamous epithelium of the cervix and
subsequent expression of viral components, causes dysplastic changes in the cervical
epithelium that, if left untreated, can develop into invasive carcinoma of the
cervix (cervical carcinoma). Cervical carcinoma is the fourth most common cancer as
well as the fourth leading cause of cancer-related death in women worldwide,
responsible for 6.6% (570,000) of all new cancer cases and 7.5% (311,000) of
cancer-related deaths in women in 2018. The precursor of squamous cell carcinoma of
the uterine cervix (approximately 80% of all cervical cancers) is cervical
intraepithelial neoplasia (CIN), which has three grades of expression (CIN1, CIN 2,
and CIN 3). Compared with invasive cervical carcinoma, the incidence of precancerous
lesions of the cervix uteri is much higher. It is estimated that approximately
100,000 women in Germany develop high-grade dysplasia (CIN2/CIN3) annually.
1.2. Surgical treatment If precancerous lesions with the potential to develop into
an invasive cervical tumor are detected, conization (= surgical removal of a cone of
tissue from the cervix) is the method of choice for removing the diseased tissue.
Worldwide standard as surgical procedure for conization is LLETZ-conization (Large
Loop Excision of the Transformation Zone). In addition to the risk of local
persistence of the precancerous lesion if the cervical dysplasia is incompletely
removed, LLETZ also increases the risk of preterm birth in a subsequent pregnancy.
This risk increases with increasing volume of removed tissue. To reduce or avoid the
aforementioned complications, conization should be performed under colposcopic
vision and as little healthy cervical tissue as possible should be removed. One
method of LLETZ that is as tissue-conserving as possible is the intraoperative use
of the so-called 'iodine test'.
1.3. The iodine test For the identification of healthy squamous epithelium of the
cervix uteri, the so-called Schiller's iodine test can be used, which has been part
of the clinical routine in the context of colposcopy of cervical dysplasias for
decades. In the iodine test, a 5% iodine solution (so-called Lugol's solution) is
dabbed onto the cervix uteri, resulting in an intense and characteristic brown
staining of the healthy cervical epithelium. Sites without staining are termed
iodine negative and may contain dysplastic cells. The strength of iodine testing
lies in its high specificity, i.e., the reliable ability to exclude false-positive
results. Not all iodine-negative areas contain CIN, but iodine-positive areas are
almost certainly healthy. In some centers, because of these characteristics of the
iodine sample, it is used during LLETZ to define the resection line of LLETZ. The
aim of this approach is to select the resection line with a high degree of certainty
in healthy (i.e., iodine-positive) tissue in order to reduce the rate of cervical
dysplasia that is not completely removed (so-called 'non-in-sano resection' or 'R1
resection'). Systematic survey data from the dysplasia units certified in Germany on
the question of the use of intraoperative iodine testing in Germany are lacking. The
current S3 guideline of the German Society of Gynecology and Obstetrics on the
diagnosis and therapy of cervical dysplasia (as of March 2020) also refers to
intraoperative iodine testing as a possible option for performing LLETZ. However,
exact figures from controlled studies on the usefulness of iodine test-guided LLETZ
are lacking in the literature (PubMed search on 10/15/2021; search terms: cervical
dysplasia, colposcopy, Lugol's test, iodine test, Lugol's staining; LLETZ; LEEP;
conization). At our certified dysplasia center, it is the decision of the respective
surgeon whether an additional intraoperative iodine test is performed or not.