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To investigate prognostic factors in patients with recurrent cervical cancer after treatment of early-stage disease in order to identify high-risk patients who might benefit from alternative treatment strategies.The authors retrospectively analyzed clinical and pathology data from 130 recurrent cervical cancer patients after surgical treatment for early-stage disease. Patients were compared with a recurrence-free control group matched for age, FIGO Stage, and adjuvant treatment. Univariate and multivariate Cox regression analyses were performed to determine prognostic factors for recurrence and survival.Of 889 patients, 130 (14.6%) developed recurrent disease after primary treatment for early-stage cervical cancer. Local or loco-regional metastasis was observed in 45%, distant metastasis in 31%, and combined pelvic and distant metastasis in 24%. Median survival after recurrence was 12 months (range 1-107 months). Median five-year survival was 96% in the control group and 29% in the recurrence group. Tumor size ≥ 40 mm and lymph node metastasis were independent unfavorable prognostic factors for overall survival (OS) and disease-free survival (DFS). The number of positive lymph nodes (≥ one) and bilateral occurrence of pelvic lymph node metastasis were associated with adverse clinical outcome.Tumor size ≥ 40 mm and lymph node metastasis were independent unfavorable prognostic factors in surgically treated, early-stage cervical cancer patients. The combination of these factors was particularly associated with recurrence. Future trials should focus on the role of alternative adjuvant treatment strategies in patients at high risk of recurrent disease (e.g., by chemotherapy, immunotherapy or combinations thereof).

Immunotherapy of usual vulvar intraepithelial neoplasia (uVIN) is promising; however, many patients still fail to show clinical responses, which could be explained by an immune escape through alterations in human leukocyte antigen (HLA) expression. Therefore, we analyzed a cohort of patients with a primary (n = 43) and subsequent recurrent uVIN lesion (n = 20), vaccine-treated uVIN patients (n = 12), patients with human papillomavirus (HPV)-induced vulvar carcinoma (n = 21) and healthy controls (n = 26) for the expression of classical HLA-class I/II and nonclassical HLA-E/-G and MHC class I chain-related molecule A (MICA). HLA-class I was downregulated in 70% of uVIN patients, including patients with a clinical response to immunotherapy. Downregulation of HLA-class I is probably reversible, as only 15% of the uVIN cases displayed loss of heterozygosity (LOH) and HLA-class I could be upregulated in uVIN keratinocyte cultures by interferon γ. HLA-class I downregulation is more frequently associated with LOH in vulvar carcinomas (25-55.5%). HLA-class II was found to be focally expressed in 65% of uVIN patients. Of the nonclassical molecules, MICA was downregulated in 80% of uVIN whereas HLA-E and -G were expressed in a minority of cases. Their expression was more prominent in vulvar carcinoma. No differences were found between the alterations observed in paired primary and recurrent uVIN. Importantly, downregulation of HLA-B/C in primary uVIN lesions was associated with the development of recurrences and progression to cancer. We conclude that downregulation of HLA is frequently observed in premalignant HPV-induced lesions, including clinical responders to immunotherapy, and is associated with worse clinical outcome. However, in the majority of cases downregulation may still be reversible.

One of the hallmarks of cancer is the influx of myeloid cells. In our study, we investigated the constitution of tumor-infiltrating myeloid cells and their relationship to other tumor-infiltrating immune cells, tumor characteristics and the disease-specific survival of patients with cervical cancer (CxCa). Triple-color immunofluorescence confocal microscopy was used to locate, identify and quantify macrophages (CD14), their maturation status (CD33) and their polarization (CD163) in a cohort of 86 patients with cervical carcinoma. Quantification of the numbers of myeloid cells revealed that a strong intraepithelial infiltration of CD14+ cells, and more specifically the population of CD14+CD33-CD163- matured M1 macrophages, is associated with a large influx of intraepithelial T lymphocytes (p = 0.008), improved disease-specific survival (p = 0.007) and forms an independent prognostic factor for survival (p = 0.033). The intraepithelial CD8+ T-cell and regulatory T-cell (Treg) ratio also forms an independent prognostic factor (p = 0.010) and combination of these two factors reveals a further increased benefit in survival for patients whose tumor displays a dense infiltration with intraepithelial matured M1 macrophages and a high CD8 T-cell/Treg ratio, indicating that both populations of immune cells simultaneously improve survival. Subsequently, we made a heatmap including all known immune parameters for these patients, whereby we were able to identify different immune signatures in CxCa. These results indicate that reinforcement and activation of the intratumoral M1 macrophages may form an attractive immunotherapeutic option in CxCa.