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Objective: To evaluate whether C-reactive protein (CRP) serum levels can be used as a prognostic parameter in patients with cervical cancer., Methods: In the present study, CRP serum levels were measured in 215 patients with cervical cancer. CRP serum levels were measured prior to therapy for cervical cancer and were correlated to clinical data., Results: The median CRP serum level in patients with cervical cancer was 0.5 mg/dl (interquartile range 0.5-0.9 mg/dl). CRP serum levels were significantly associated with advanced tumor stage (p<0.001), lymph node involvement (p=0.01) and patients' age (p=0.01), but not with histological grade (p=0.1) and histological type (p=0.9). In a univariate and multivariate analysis CRP serum levels, tumor stage, and lymph node involvement, but not histological grade, histological type and patients' age were associated with overall and disease-free survival., Conclusion: CRP serum levels can be used as additional prognostic parameter in patients with cervical cancer.

Objective: The enzyme matrix metalloproteinase (MMP)-1 is involved in ovarian carcinogenesis. A common guanine insertion-deletion promoter polymorphism within the gene encoding MMP-1 (MMP1) has been suggested to be a candidate gene for ovarian cancer. We investigated whether this common polymorphism can also serve as independent prognostic parameter in a large series of affected women., Methods: The MMP1 promoter polymorphism was examined in 151 Caucasian patients with epithelial ovarian cancer using polymerase chain reaction. Results were correlated with clinical data., Results: No associations were ascertained between the MMP1 polymorphism and tumor stage (P = 1.0, odds ratio [OR] 1.08), lymph node involvement (P = 1.0, OR 0.8), tumor grading (P = 0.2, OR 0.5), and patient's age at diagnosis (P = 1.0, OR 1.04). Besides the clinically established prognosticators, tumor stage and histological grade, presence of the MMP1 polymorphism was associated with a shortened disease-free and overall survival in a univariate Kaplan-Meier analysis (P = 0.01) and a multivariate Cox regression model (P = 0.04)., Conclusion: Presence of the MMP1 gene promoter polymorphisms was found to be a negative prognostic parameter in patients with ovarian cancer.

Objectives: Thrombospondin-1 (TSP-1) is a multifunctional matricellular glycoprotein involved in several mechanisms critical to the formation and progression of solid tumors including cell adhesion, proliferation, migration, invasion, and angiogenesis. The present study was designed to investigate the expression of TSP-1 in invasive vulvar squamous cell carcinoma., Methods: A total of 75 invasive vulvar squamous cell carcinomas were evaluated for TSP-1 expression by immunohistochemistry. Results were correlated with the clinicopathologic parameters including tumor stage, groin lymph node status, tumor grade, patient's age, patients' disease-free, and overall survival., Results: TSP-1 expression was detected in 35/75 (46.7%) specimens of invasive vulvar squamous cell carcinomas. The expression of TSP-1 was generally localized to the cytoplasm and occasionally seen in the nucleus. An increased TSP-1 expression was detected in patients with an advanced tumor stage (P = 0.01) and a positive groin lymph nodes status (P = 0.01). Tumor stage and groin lymph node status were associated with patients' disease-free and overall survival. All other parameters failed to be of prognostic significance., Conclusions: We are the first to report on the immunohistochemical expression of TSP-1 in invasive vulvar squamous cell carcinoma. Increased TSP-1 expression was associated with an advanced tumor stage and a positive groin lymph node status, suggesting its pro-angiogenic potential in vulvar carcinogenesis.

Objective: To determine whether SCC-Ag serum levels can be used as a prognostic parameter in surgically treated early stage vulvar cancer., Methods: SCC-Ag serum levels were measured preoperatively in 61 surgically staged patients with squamous cell vulvar cancer (UICC pT1 and pT2). Results were correlated to clinical data., Results: Mean (standard deviation) SCC-Ag serum levels in patients with vulvar cancer were 1.5 (1.99) ng/mL. SCC-Ag serum levels were significantly higher in patients with pT2 vulvar cancer (2.2 [2.6] ng/mL) compared with patients with pT1 vulvar cancer (1.0 [1.2] ng/mL, P = 0.034). SCC-Ag serum levels were not associated with lymph node involvement (P = 0.1), tumor grade (P = 0.6), and patients' age (P = 0.5). Multivariate Cox regression models considering tumor stage, lymph node involvement, patients' age, and SCC-Ag serum levels as covariates showed that lymph node involvement (P = 0.04 and P = 0.01) and tumor stage (P = 0.006 and P = 0.009), but not SCC-Ag serum levels (P = 0.8 and P = 0.6), and patients' age (P = 0.08 and P = 0.22) are prognostic factors for disease-free and overall survival, respectively., Conclusion: SCC-Ag serum levels cannot be used as an additional prognostic parameter in patients with surgically treated early stage vulvar cancer.

Objective: The aim of the study was to determine the diagnostic accuracy and feasibility of sentinel lymph node (SLN) detection using a gamma probe in patients suffering from vulvar cancer., Methods: From May 1998 to November 2000, 26 patients with early vulvar cancer, planned for local wide excision or vulvectomy including groin dissection, were eligible for the study. Two to 3 h before the planned procedure we injected technetium(99) m-labeled microcolloid intradermally at four locations around the tumor. Dynamic and static images were recorded using a gamma camera. SLN locations were marked on the overlying skin. In the operating theater SLNs were identified at the beginning of the procedure using a handheld gamma-detection probe. After resection of suspected SLNs a standard unilateral or bilateral groin dissection was performed, subsequently followed by local wide excision or, if indicated, radical vulvectomy. Sentinel node detection using technetium(99) m-labeled microcolloid was compared with final histopathological and immunohistochemical results., Results: Scintigraphy showed focal uptake in all 26 patients. Intraoperatively we detected all sentinel nodes by handheld gamma probe. In 20 patients, one sentinel node was identified unilaterally, while in 6 patients two or more nodes were identified bilaterally. Histologically positive SLNs were found in 9 patients. In our preliminary series we did not find any false-negative SLN., Conclusion: Identification of sentinel nodes in vulvar cancer is feasible with preoperatively administered technetium(99)m-labeled microcolloid. We confirm the results of previous studies and improve the evidence that the SLN procedure could be implemented in future therapy concepts.

Background: Cytokines are intercellular hormones, believed to play a functional role in the natural history of various malignant diseases. In vitro and in vivo studies have indicated that interleukin 6 (IL-6) may provide autocrine and paracrine growth stimulation in ovarian cancer cells., Methods: In the present study we measured IL-6 in the serum of 73 patients with FIGO stage I to IV ovarian cancer. Enzyme-linked immunosorbent assay (ELISA) was used to determine IL-6 serum levels. Results were correlated to clinical data. Serum levels of IL-6 were additionally evaluated in a panel of 50 normal controls., Results: Median serum levels of IL-6 in patients with ovarian cancer and normal controls were 55.6 (minimum 0, maximum 2869.0) pg/ml and 0.5 (minimum 0, maximum 2.14) pg/ml, respectively (Mann-Whitney U test, P = 0.0001). When serum levels of IL-6, taken prior to therapy, were grouped by FIGO stage, lymph node involvement, and grading of tumor cells, we found a statistically significant correlation with FIGO stage (Mann-Whitney U test, P = 0.04). Lymph node involvement and grading of tumor cells were not correlated with IL-6 levels. Elevated IL-6 serum levels prior to therapy were significantly correlated with poorer disease-free (log-rank test, P = 0.003) and overall survival (log-rank test, P = 0.01)., Conclusion: Elevated IL-6 serum levels prior to therapy are correlated with a poor relapse-free and overall survival in ovarian cancer patients.

Clinical and experimental evidence is consistent with a key role of point mutations of the p53 tumor suppressor gene in the etiology of squamous cell carcinoma. To determine the relation of tumor behavior and patient survival in vulvar cancer in regard to p53 status, we retrospectively analyzed 38 paraffin-embedded specimens of primary vulvar cancer for genetic alterations of exons 5-8 of the p53 gene. For detection of p53 point mutations we used in vitro amplification by polymerase chain reaction (PCR) and temperature gradient gel electrophoresis (TGGE) and, as a detection method, direct sequencing for mutation verification. p53 point mutations were detected in 12/38 tumor specimens. Patients bearing p53 point mutations showed a significantly shorter relapse-free (log-rank test, P = 0.002) and overall survival time (log-rank test, P = 0.0006). We conclude that PCR-TGGE is an appropriate method for detection of p53 point mutations in paraffin-embedded material. We show that loss of wild-type p53 is an adverse prognostic factor in patients suffering from vulvar cancer.

Microvessel density (MVD) and expression of vascular permeability factor/vascular endothelial growth factor (VPF/VEGF), acting as a highly specific inducer of angiogenesis, were evaluated in tissue specimens of 25 patients with squamous cell cancer of the vulva. MVD was quantified by immunostaining for factor VIII-related antigen at one field of 0.25 mm2. VPF/VEGF expression was evaluated immunohistochemically using a monoclonal anti-VEGF antibody. FIGO stages I, II, and III were diagnosed in 12, 7, and 6 patients, respectively. MVD >20/field was found in 10 of 25 tumors and moderate or strong expression of VPF/VEGF in 10 of 25 tumors. High MVD was significantly more frequent in tumors with moderate or strong VPF/VEGF expression compared to tumors with no or weak VPF/VEGF expression (P = 0.01). Overall survival rates of patients with tumors of high MVD (P = 0.01) and strong VPF/VEGF expression (P < 0.01) were significantly poorer compared to those patients with low MVD or poor VPF/VEGF expression. Strong VPF/VEGF expression and high MVD are considered important parameters of tumor angiogenesis and therefore are related to poor survival probability in vulvar cancer patients.

Aberrant expression of the cell adhesion molecule CD44 has been detected in human tumors and the expression of specific CD44 isoforms (splice variants) has been shown to be associated with metastasis and poor prognosis in human malignancies. We used three different variant exon sequence-specific murine monoclonal antibodies to epitopes encoded by exon v5, exon v6, or exon v7-v8 of human variant CD44 to study the expression of CD44 splice variants by immunohistochemistry in human cervical cancer. One-hundred five patients with surgically treated squamous cell carcinomas of the cervix stages IB to IIB were included in the study. CD44 splice variants CD44v5, CD44v6, and CD44v7-8 were detected in 70, 67, and 26%, respectively. Tumors expressing exon v6 had significantly more often metastasized to the pelvic nodes (58 vs 79%, P = 0.04). Expression of exon v6 was significantly correlated with a greater probability of vascular space invasion (73 vs 50%, P = 0.04) and a significantly lower rate of inflammatory stromal reaction (48 vs 78%, P = 0.004). Patients suffering from tumors expressing splice variant CD44v6 showed poorer overall survival (P = 0.03). In cases with negative pelvic lymph nodes we found a poorer prognosis when tumors expressed CD44v6 (P = 0.01) or CD44v7-8 (P = 0.02). Among the investigated CD44 splice variants expression of exon v6 is the most promising prognostic marker in surgically treated cervical cancer.

The present study evaluates the prognostic value of mutant p53 protein overexpression in 109 surgically treated cervical cancer stages IB to IIB. Squamous cell carcinoma stages IB, IIA, and IIB were present in 52, 13, and 44 cases, respectively. We performed immunohistochemistry using a monoclonal antibody against the p53 suppressor gene product (clone BP53-12). Data were analyzed for the end points of disease-free survival and overall survival. In 109 tissue specimens we detected 22 cases of p53 expression. Six of 22 patients with p53 expression and 21 of 87 patients without p53 expression showed tumor recurrences. p53 expression showed no significant correlation to age, tumor stage or lymph node involvement. In the univariate analysis p53 expression showed no prognostic value for disease-free (P = 0.5) and overall survival (P = 0.6). Multivariate analysis showed a significant prognostic value for established prognostic parameters while p53 expression had no prognostic value for recurrence-free (P = 0.6) and overall survival (P = 0.5). In contrast to other malignancies mutant p53 overexpression showed no relation to prognosis in surgically treated cervical cancer stage IB to IIB.

The purpose of this study was to evaluate the serum tumor markers CYFRA 21-1 and squamous-cell carcinoma antigen (SCC) in the follow-up of squamous-cell cervical cancer patients. One hundred-ninety-three serum samples, which were collected pretherapeutically and during follow-up of 30 patients suffering from squamous-cell cervical cancer FIGO stage III, were analyzed for SCC and CYFRA 21-1. Cutoff values for SCC and CYFRA 21-1 were 3 and 3.3 micrograms/liter, respectively. Fifteen cases were keratinizing and 15 nonkeratinizing squamous-cell carcinomas. Serum tumor marker results were correlated to the results of the clinical and radiologic examinations. We calculated sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of serum SCC and serum CYFRA 21-1 for the whole study group and separately for the keratinizing and nonkeratinizing squamous-cell carcinoma group. Sensitivity, specificity, PPV, and NPV of serum SCC were 66, 91, 93, and 60%, respectively. Serum CYFRA 21-1 showed a sensitivity of 63%, specificity of 96%, PPV of 96%, and NPV of 59%. The combination of SCC and CYFRA 21-1 increased the sensitivity to 78%, with a specificity, PPV, and NPV of 87, 91, and 69%, respectively. In keratinizing squamous-cell carcinoma serum SCC, CYFRA 21-1 and the combination of both had a sensitivity of 76, 64, and 85%, respectively. In nonkeratinizing squamous-cell carcinoma sensitivity was 58, 61, and 72%, respectively. The detection of cervical cancer recurrences with SCC is improved by the combination with CYFRA 21-1. Especially in nonkeratinizing squamous-cell carcinoma CYFRA 21-1 showed promising results.