Human Leukocyte Antigen-DR Expression is Significantly Related to an Increased Disease-Free and Disease-Specific Survival in Patients With Cervical Adenocarcinoma.

OBJECTIVES: Human leukocyte antigen (HLA) class II antigens are expressed on antigen-presenting cells, that is, macrophages, dendritic cells, and B lymphocytes. Under the influence of IFN-γ, HLA class II molecules can also be expressed on T lymphocytes, epithelial and endothelial cells. In addition, HLA class II antigens can be expressed in a variety of malignancies; however, the link with prognosis and ultimately patient survival is controversial. METHODS: The pattern of HLA-DRA expression in cervical carcinoma was studied using immunohistochemistry. In total, 124 cervical carcinomas were examined, of which 60 (48.4%) were squamous cell carcinomas and 64 (51.6%) were adenocarcinomas. RESULTS: In squamous cell carcinoma, HLA-DRA was expressed in 41 (68.3%) of 60 tumors, whereas in adenocarcinoma, HLA-DRA was expressed in 60 (93.8%) of 64 tumors (P < 0.001). In adenocarcinoma, HLA-DRA expression was associated with an increased disease-free survival (211.0 ± 13.0 vs 53.3 ± 30.5 months; P = 0.004) and disease-specific survival (226.45 ± 11.5 vs 75.8 ± 27.6 months; P = 0.002). CONCLUSIONS: Upregulation of HLA-DRA is significantly related to an increased disease-free and disease-specific survival in cervical adenocarcinoma. These data warrant further analysis of the functional role of HLA-DRA in these tumors.

Vaccination against Oncoproteins of HPV16 for Noninvasive Vulvar/Vaginal Lesions: Lesion Clearance Is Related to the Strength of the T-Cell Response.

PURPOSE: Therapeutic vaccination with human papillomavirus type 16 (HPV16) E6 and E7 synthetic long peptides (SLP) is effective against HPV16-induced high-grade vulvar and vaginal intraepithelial neoplasia (VIN/VaIN). However, clinical nonresponders displayed weak CD8(+) T-cell reactivity. Here, we studied if imiquimod applied at the vaccine site could improve CD8(+) T-cell reactivity, clinical efficacy, and safety of HPV16-SLP (ISA101). EXPERIMENTAL DESIGN: A multicenter open-label, randomized controlled trial was conducted in patients with HPV16(+) high-grade VIN/VaIN. Patients received ISA101 vaccination with or without application of 5% imiquimod at the vaccine site. The primary objective was the induction of a directly ex vivo detectable HPV16-specific CD8(+) T-cell response. The secondary objectives were clinical responses (lesion size, histology, and virology) and their relation with the strength of vaccination-induced immune responses. RESULTS: Forty-three patients were assigned to either ISA101 with imiquimod (n = 21) or ISA101 only (n = 22). Imiquimod did not improve the outcomes of vaccination. However, vaccine-induced clinical responses were observed in 18 of 34 (53%; 95% CI, 35.1-70.2) patients at 3 months and in 15 of 29 (52%; 95% CI, 32.5-70.6) patients, 8 of whom displayed a complete histologic response, at 12 months after the last vaccination. All patients displayed vaccine-induced T-cell responses, which were significantly stronger in patients with complete responses. Importantly, viral clearance occurred in all but one of the patients with complete histologic clearance. CONCLUSIONS: This new study confirms that clinical efficacy of ISA101 vaccination is related to the strength of vaccine-induced HPV16-specific T-cell immunity and is an effective therapy for HPV16-induced high-grade VIN/VaIN. Clin Cancer Res; 22(10); 2342-50. ©2016 AACRSee related commentary by Karaki et al., p. 2317.

Loss of heterozygosity and copy number alterations in flow-sorted bulky cervical cancer.

Treatment choices for cervical cancer are primarily based on clinical FIGO stage and the post-operative evaluation of prognostic parameters including tumor diameter, parametrial and lymph node involvement, vaso-invasion, infiltration depth, and histological type. The aim of this study was to evaluate genomic changes in bulky cervical tumors and their relation to clinical parameters, using single nucleotide polymorphism (SNP)-analysis. Flow-sorted tumor cells and patient-matched normal cells were extracted from 81 bulky cervical tumors. DNA-index (DI) measurement and whole genome SNP-analysis were performed. Data were analyzed to detect copy number alterations (CNA) and allelic balance state: balanced, imbalanced or pure LOH, and their relation to clinical parameters. The DI varied from 0.92-2.56. Pure LOH was found in ≥40% of samples on chromosome-arms 3p, 4p, 6p, 6q, and 11q, CN gains in >20% on 1q, 3q, 5p, 8q, and 20q, and losses on 2q, 3p, 4p, 11q, and 13q. Over 40% showed gain on 3q. The only significant differences were found between histological types (squamous, adeno and adenosquamous) in the lesser allele intensity ratio (LAIR) (p = 0.035) and in the CNA analysis (p = 0.011). More losses were found on chromosome-arm 2q (FDR = 0.004) in squamous tumors and more gains on 7p, 7q, and 9p in adenosquamous tumors (FDR = 0.006, FDR = 0.004, and FDR = 0.029). Whole genome analysis of bulky cervical cancer shows widespread changes in allelic balance and CN. The overall genetic changes and CNA on specific chromosome-arms differed between histological types. No relation was found with the clinical parameters that currently dictate treatment choice.

Patterns of parametrial involvement in radical hysterectomy specimens of cervical cancer patients.

A tumor in the parametria, either continuous with or separate from the primary malignancy, is an unfavorable prognostic factor in cervical cancer. The incidence of a parametrial tumor localized in blood or lymph vessels, or in tissue, and the relationship of these involvement patterns with pathologic characteristics and prognosis were investigated. Seventy-nine of 763 surgically treated cervical cancer patients (10%) had a tumor in the parametria in hysterectomy specimens. The available patient material was reviewed to discriminate between continuous and discontinuous parametrial tumor growth. The involvement pattern for discontinuous growth was specified on the basis of immunohistochemical staining with different specific markers. Fifty percent of the parametrial tumor involvement found postoperatively was caused by continuous extension of the primary process into the parametria. In the other 50%, the parametrial tumor was separate from the primary process. In this discontinuous group, we found a frequent presence of tumor in the lymph nodes and/or lymph vessels (together 79%) and even a rare appearance of tumor in the blood vessels (14%). A tumor was further found in unspecified vessels in 2 patients (5%), and as isolated foci in 6 patients (14%). Fourteen patients (33%) had more than 1 involvement pattern. Positive pelvic lymph nodes were more frequent in the discontinuous group. The involvement pattern was no independent predictor of overall survival. Parametrial blood vessel involvement was related to the development of distant metastases. The majority (79%) of parametrial involvement in the discontinuous group is caused by lymphatic metastases. Parametrial blood vessel involvement might be an independent predictor for the development of distant metastasis.

Abdominal scar recurrences of cervical cancer: incidence and characteristics: a case-control study.

BACKGROUND: Tumor recurrence in the surgical scar after radical hysterectomy for cervical cancer has been reported, but the incidence is unknown. Facts about patient and tumor characteristics and follow-up are lacking. The objective of this study was to analyze the incidence and characteristics of cervical cancer scar recurrences. METHODS: All patients who were surgically treated for cervical cancer in our center between 1984 and 2007 were reviewed for scar recurrences. For each case, 5 random controls were selected. Clinical characteristics were compared between the cases and controls. RESULTS: Eleven (1.3%) of 842 patients developed a scar recurrence. Mean time between surgery and scar recurrence was 16 months (range, 2-45 months). For 8 patients (73%), the scar recurrence was the first disease recurrence. Five patients (45%) died, and 2 (18%) were lost to follow-up. Mean time between scar recurrence and death was 9 months. Ninety-one percent of the cases had recurrent disease besides the scar recurrence during follow-up. The case group had a higher percentage of advanced FIGO (International Federation of Gynecology and Obstetrics) stage and postoperatively found involvement of parametria or resection margins and tumor diameter greater than 4 cm, whereas lymph nodes were more often involved in the control group. CONCLUSIONS: The incidence of scar recurrences after primary surgery for cervical cancer was 1.3%. Time to development was variable, and prognosis was poor. Besides higher FIGO stage and concurrent unfavorable pathological characteristics, we found no outstanding characteristics of patients with scar recurrence. Scar recurrences go hand in hand with recurrent disease at other locations and seem a manifestation of tumors with extensive metastatic potential.

Nerve-sparing radical hysterectomy: local recurrence rate, feasibility, and safety in cervical cancer patients stage IA to IIA.

UNLABELLED: To clarify the debate about the possible threat of sparing the pelvic autonomic nerves in radical hysterectomy for cervical cancer to radicality, comparative studies of nerve-sparing and conventional surgery are necessary. The aim of his study was to analyze and compare local recurrence rate, feasibility, and safety of nerve-sparing and non-nerve-sparing radical hysterectomy. METHODS: In a cohort study with 2 years of follow-up, 246 patients with cervical cancer of stages IA to IIA were analyzed: 124 in the non-nerve-sparing group (1994-1999) and 122 in the group where nerve-sparing was the intention-to-treat (2001-2005). Local recurrence rate, local recurrence-free survival, feasibility, and safety were analyzed and compared. RESULTS: The clinical characteristics of the treatment groups were comparable. Sparing the nerves unilaterally or bilaterally was possible in 80% of cases of the nerve-sparing group. Local recurrence rates in the non-nerve-sparing (4.9%) and nerve-sparing (8.3%) group were not significantly different. Mean local recurrence-free survival within 2 years were 22.7 and 22.0 months, respectively. Univariate and multivariate regression analyses showed that nerve-sparing treatment was not a significant prognostic factor for local recurrence. With respect to perioperative and postoperative parameters, operating time and blood loss were less in the nerve-sparing group and mortality was equal (1 patient); the postoperative course of the nerve-sparing group was similar to the state-of-the-art of conventional radical hysterectomy. CONCLUSIONS: On the basis of the results of our study, we consider the nerve-sparing technique for cervical cancer stages IA to IIA feasible and safe.