Objective To revise FIGO staging of carcinoma of the cervix uteri, allowing incorporation of imaging and/or pathological findings, and clinical assessment of tumor size and disease extent. Methods Review of literature and consensus view of the FIGO Gynecologic Oncology Committee and related societies and organizations. Results In stage I, revision of the definition of microinvasion and lesion size as follows. Stage IA: lateral extension measurement is removed; stage IB has three subgroups—stage IB1: invasive carcinomas ≥5 mm and <2 cm in greatest diameter; stage IB2: tumors 2–4 cm; stage IB3: tumors ≥4 cm. Imaging or pathology findings may be used to assess retroperitoneal lymph nodes; if metastatic, the case is assigned stage IIIC; if only pelvic lymph nodes, the case is assigned stage IIIC1; if para‐aortic nodes are involved, the case is assigned stage IIIC2. Notations ‘r’ and ‘p’ will indicate the method used to derive the stage—i.e., imaging or pathology, respectively—and should be recorded. Routine investigations and other methods (e.g., examination under anesthesia, cystoscopy, proctoscopy, etc.) are not mandatory and are to be recommended based on clinical findings and standard of care. Conclusion The revised cervical cancer staging is applicable to all resource levels. Data collection and publication will inform future revisions.
Cervical tumors are marked by the presence of an immunoregulatory environment, and harbor equal proportions of 'inactive' n Tregs; activated n Tregs; and Tregs operating via TGFbeta. nTregs in cervicitis and CIN may be a potential marker of persistence.
Oestrogen controls Foxp3 expression in regulatory T cells (Treg cells) via a mechanism thought to involve oestrogen receptor alpha (ERα), but the molecular basis and functional impact of ERα signalling in Treg cells remain unclear. We report that ERα ligand oestradiol (E2) is significantly increased in human cervical cancer (CxCa) tissues and tumour-infiltrating Treg cells (CD4+CD25hiCD127low), whereas blocking ERα with the antagonist ICI 182,780 abolishes FOXP3 expression and impairs the function of CxCa infiltrating Treg cells. Using a novel approach of co-immunoprecipitation with antibodies to E2 for capture, we identified binding of E2:ERα complexes to FOXP3 protein in CxCa-derived Treg cells. Chromatin immunoprecipitation analyses of male blood Treg cells revealed ERα occupancy at the FOXP3 promoter and conserved non-coding DNA elements 2 and 3. Accordingly, computational analyses of the enriched regions uncovered eight putative oestrogen response elements predicted to form a loop that can activate the FOXP3 promoter. Together, these data suggest that E2-mediated ERα signalling is critical for the sustenance of FOXP3 expression and Treg cell function in human CxCa via direct interaction of ERα with FOXP3 promoter. Overall, our work gives a molecular insight into ERα signalling and highlights a fundamental role of E2 in controlling human Treg cell physiology.
Cervical screening is not available for the majority of women in resource-poor countries. An important factor is a lack of skilled operators necessary for high-throughput assessment of the Papanicolaou (Pap) test currently in use. We compared the efficacy of immunocytochemistry for minichromosome maintenance (MCM) proteins vs standard Pap testing at detecting disease in 455 cervical smears processed in a typical Indian screening laboratory. Conventional (non-monolayer) smears were stained manually and then examined by a cytotechnologist and a cytopathologist. The MCM test was called positive when immunolabelled cells were identified as dyskaryotic by the Pap counterstain. The MCM test was read more quickly than the Pap test (approximately 2 vs 10 min) and there was 100% inter-observer agreement compared with 85% for Pap (Po0.0001). The MCM test detected 10 biopsy-proven cancers or pre-cancers that were not detected by Pap (P ¼ 0.002; P ¼ 0.016 excluding three cases where the Pap was deemed unsatisfactory on review). The cases in question included one recurrent squamous carcinoma and one adenocarcinoma in a screening patient who would have returned to 5 year recall. There were no false positive MCM test results. We propose that MCM immunocytochemistry has considerable advantages for cervical screening in developing countries like India.
Cancer-Associated Fibroblasts (CAFs) are crucial in genesis and progression of tumors; however, cervical CAFs (C-CAFs) are not well characterized. Estradiol (E2) has been implicated as a cofactor in human papillomavirus (HPV)-mediated cervical cancer (CxCa), both in animal models and in women using oral contraceptives; however, the exact role of the hormone is unclear. Human C-CAFs have recently been shown to express estrogen receptor alpha (ER-α). We investigated gene expression patterns in ex vivo cultured early and late stage C-CAFs in the context of E2. CAFs were isolated from four patients with early and two patients with late stage CxCa. ER-α expression in CxCa tissues was localized to stromal fibroblast-like cells and confirmed in ex vivo cultured C-CAFs. Two ER antagonists (ICI 182,780 and Methyl Piperidino Pyrazole) were used to unravel ER signaling in CAFs. Microarray technology was used for expression profiling and validated by quantitative reverse transcription PCR. The transcriptomes of C-CAFs across stages indicated their activated state. C-CAFs had gene expression patterns associated with both pro-tumorigenic and pro-inflammatory signaling. Late-stage C-CAFs compared to those of early stage appeared to be more actively metabolizing and cycling but expressed fewer genes related to immune function. We report differential expression profiles between C-CAFs: early vs. late stage and in the presence of ER antagonists. Both ER antagonists seemed to modulate C-CAF function by down regulating genes associated with cell cycle and metabolism, affecting angiogenesis and cancer progression. This study characterized C-CAFs from early and late stage disease, and experiments with ER inhibitors emphasized the probable importance of canonical ER-α signaling. Interfering with paracrine signaling through fibroblast ER-α is worth exploiting as a targeted therapy in CxCa management.
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