Persistent infections with high-risk human papillomaviruses (HPVs) induce dysplastic lesions of the lower genital tract. Some of these lesions eventually progress to invasive cancers, particularly of the uterine cervix. In many advanced preneoplastic cervical lesions and most derived carcinomas, HPV genomes are found to be integrated into the host cell chromosomes. Although HPV integration seems to play an important role in the progression of cervical dysplasia, the underlying mechanisms are still unclear. To investigate the pathogenic role of genomic integration of HPV genomes in greater detail, we analysed integration sites of HPV16 and 18 genomes in 21 anogenital precancerous and cancerous lesions using a ligation-mediated chain reaction (DIPS) and the recently described amplification of papilloma virus oncogene transcripts (APOT) assay. On the genomic level, only singular integration events were observed in individual neoplastic cell clones. At many integration sites, a short overlap between HPV and genomic sequences was observed, suggesting that the integration of HPV genomes is mediated by nonhomologous sequence-specific recombination. APOT analysis revealed that the majority of integrated HPV genomes was actively transcribed. These data suggest that in the progression of cervical preneoplasia to invasive carcinomas, integration of viral genomes occurs only at single or few chromosomal loci in a given cell clone. Disruption of cellular genes might support malignant transformation in rare cases; however, it is not a pathogenic prerequisite. The main function of HPV integration seems to be the stabilization of oncogene transcription.
These data indicate that high-grade dysplastic lesions in the female lower genital tract may emerge primarily as monoclonal lesions from a transformed cell population derived from the uterine cervix.
In most cases, the endometrioid adenocarcinoma of the endometrium is preceded by hyperplasia with different risk of progression into carcinoma. The original histologic slides from 560 consecutive cases with complex and atypical hyperplasia were re-examined to assess the interobserver-correlation. The hyperplasias were analyzed separately for their likelihood of progression to carcinoma in patients with and without progestogen hormonal therapy. In all cases, a fractional re-curreting was performed to establish the state of the disease. The leading symptom was vaginal bleeding in 65.5% of the cases in the postmenopausal period. Eighty-six percent of the patients presented with obesity (BMI > 30 kg/m(2)), 23% had had an exogeneous use of estrogens. Twenty-two cases were reclassified as simple hyperplasia and excluded from further analysis. The interobserver-correlation was 91% for complex, 92% for atypical hyperplasia, and 89% for endometrioid carcinoma, representing an overall correlation of 90%. Two percent of the cases with complex hyperplasia (8/390) progressed into carcinoma and 10.5% into atypical hyperplasia. Fifty-two percent of the atypical hyperplasias (58/112) progressed into carcinomas. In the case of progestogen treatment (n = 208; P < 0.0001) 61.5% showed remission confirmed by re-curetting, compared with 20.3% of the cases without hormonal treatment (n = 182; P < 0.0001). Endometrial hyperplasia without atypia is likely to respond to hormonal treatment. Especially in postmenopausal situation, atypical hyperplasia should be treated with total hysterectomy.
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