Aim of this study was to investigate the histologic outcome of cervical intraepithelial neoplasia (CIN) during observational management. Consecutive women with histologically verified CIN and observational management were included. Histologic findings of initial and follow-up visits were collected and persistence, progression and regression rates at end of observational period were assessed. Uni- and multivariate analyses were performed. A systematic review of the literature and meta-analysis was performed. In 783 women CIN I, II, and III was diagnosed by colposcopically guided biopsy in 42.5%, 26.6% and 30.9%, respectively. Younger patients had higher rates of regression (p < 0.001) and complete remission (< 0.001) and lower rates of progression (p = 0.003). Among women aged < 25, 25 < 30, 30 < 35, 35 < 40 years, and > 40 years, regression rates were 44.7%, 33.7%, 30.9%, 27.3%, and 24.9%, respectively. Pooled analysis of published data showed similar results. Multivariable analysis showed that with each five years of age, the odds for regression reduced by 21% (p < 0.001) independently of CIN grade (p < 0.001), and presence of HPV high-risk infection (p < 0.001). Patient’s age has a considerable influence on the natural history of CIN – independent of CIN grade and HPV high-risk infection. Observational management should be considered for selected young patients with CIN.

Recently, a role of the receptor for advanced glycation endproducts (RAGE) in myasthenia gravis was described. RAGE and its ligand high mobility group box 1 (HMGB1) play key roles in autoimmunity and cancer. To test whether these molecules are involved in patients with thymic abnormalities we applied immunohistochemical analysis in 33 cases of thymic epithelial tumors, comprising 27 thymomas and 6 thymic carcinomas, and 21 nonneoplastic thymuses. Both molecules were detected in neoplastic epithelial cells: RAGE staining was most intense in WHO type B2 thymomas and thymic carcinomas (p<0.001). HMGB1 nuclear staining was strongest in A and AB, and gradually less in B1 = B2>B3>thymic carcinoma (p<0.001). Conversely, HMGB1 cytoplasmic staining intensities were as follows: A and AB (none), B1 (strong), B2 (moderate), B3 and thymic carcinoma (weak); (p<0.001). Fetal thymic tissue showed a distinct expression of RAGE and HMGB1 in subcapsular cortical epithelial cells which was found in 50% of myasthenic patients. Furthermore RAGE and HMGB1 were expressed in thymocytes, macrophages, Hassall's corpuscles, thymic medulla, and germinal center cells in myasthenic patients. Immunohistochemistry results were complemented by systemic measurements (immunosorbent assay): serum levels of soluble RAGE were significantly reduced in patients with epithelial tumors (p = 0.008); and in invasive tumors (p = 0.008). Whereas RAGE was equally reduced in thymic hyperplasia and epithelial tumors (p = 0.003), HMGB1 was only elevated in malignancies (p = 0.036). Results were most pronounced in thymic carcinomas. Thus, RAGE and HMGB1 are involved in the (patho-)physiology of thymus, as evidenced by differentiated thymic and systemic expression patterns that may act as diagnostic or therapeutic targets in autoimmune disease and cancer.

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