The prognostic significance of leukocytosis in cervical cancer

Cervical cancer is a frequent tumor with established prognostic factors such as FIGO stage and hemoglobin levels among others. Despite the fact that paraneoplastic leukocytosis is relatively common in many solid tumors, only isolated cases of cervical cancer patients presenting this abnormality have been published; hence, the clinical significance of leukocytosis is unknown in this tumor type. Retrospective review on the medical records of 294 consecutive newly diagnosed and untreated locally advanced cervical cancer patients who received radiotherapy and concurrent cisplatin was conducted. Leukocytosis was defined as a persistent white blood cell count exceeding 10,800/microL, determined at least twice before commencing chemoradiation providing that patients were free of any active acute or chronic infection or any other condition known to elevate the leukocyte count. The frequency of leukocytosis and their correlation with clinicopathologic features were investigated, as well as their impact on tumor response and survival. Leukocytosis with a median value of 13,300/microL (11,100-28,800) was observed in 35 (11.9%) patients at diagnosis. Leukocytosis was statistically associated only with advanced stages. Clinical complete response was observed in 57% versus 86% of the patients with and without leukocytosis, respectively. In the univariate analysis, leukocytosis, stage, and hemoglobin levels were significant predictors of survival; however, only leukocytosis and the hemoglobin level remained significant predictors of survival in the multivariate analysis. Leukocytosis is common in cervical cancer patients and has a negative prognostic significance.     

CD44v6 expression is an independent prognostic factor in node-negative FIGO stage IB cervical carcinoma

Adhesion molecules such as CD44 play an important role in the metastatic cascade by mediating tumor cell interaction with the endothelium and the subendothelial matrix. As a so-called "lymphocyte homing receptor," CD44 is physiologically involved in migration of circulating lymphocytes to lymphatic tissue. In the present study, we investigated the expression of CD44v3 and v6 in 237 patients with stage IB, N0 cervical carcinoma by means of immunohistochemistry. These results were correlated with the GOG score and other prognostic variables. Median follow-up was 82.6 months (39–110 months). Thirty-nine patients recurred and 35 died from disease within the observation period. In univariate analysis, the GOG score, histologic subtype, and CD44v6 expression were statistically significant predictors for poor overall survival (OS). In multivariate (Cox regression) analysis, the GOG score (< 40 vs. 40–120, RR: 1.37 (95% CI: 1.10–1.71); 40–120 vs. > 120, RR: 2.23 (95% CI: 1.28–3.88); P = 0.004), histologic subtype (adenosquamous carcinomas) (RR: 4.56 (95% CI: 1.49–13.92), P = 0.007) and CD44v6 expression (RR: 2.42 (95% CI: 1.14–5.10), P = 0.021) were independent predictors for poor OS. The expression of CD44v3 did not correlate with prognosis. Furthermore we found a strong correlation between CD44v6 expression and lymphovascular space invasion (LVSI) (χ² = 17.01, P = 0.0001). Tumor expansion into the loco-regional lymphatic system is the preferred way of tumor spread in cervical carcinoma. The strong correlation of CD44v6 with LVSI produces a significant degree of suspicion that cervical carcinoma cells expressing CD44v6 could, by mimicking lymphocytes, exploit their pathways.     

Prognostic implications of thrombocytosis in patients with stage III and IV cervical cancer

Gücer F, Tamussino K, Panzitt T, Taucher A, Haas J, Petru E, Winter R. Prognostic implications of thrombocytosis in patients with stage III and IV cervical cancer. Int J Gynecol Cancer 1998; 8 : 369–373.
The purpose of this study was to evaluate the prognostic significance of thrombocytosis in patients with advanced (stage III and IV) cervical cancer. A total of 128 patients without conditions associated with thrombocytosis who received a diagnosis of stage III or IV cervical carcinoma at our department between 1985 and 1993 were included in the study. Thrombocytosis was defined as a platelet count above 400,000/μl. Ninety-two of 128 patients (72 %) had stage III and 36 (28%) had stage IV disease. Squamous cell carcinomas accounted for 109 (85%) of the carcinomas. Median follow-up was 11 months (range 1–106 months). Thrombocytosis was present in 33 of 128 (26%) patients. The mean pretreatment platelet count ± standard deviation ( SD ) was 345,000 ± 135,000. The estimated overall five-year survival rate was 16%. The five-year survival rate of the 33 patients with thrombocytosis was significantly worse than that of the 95 patients with a platelet count <400,000/μl (3.5 % vs 22%, P = 0.035). In patients with stage III disease and thrombocytosis, the five-year survival rate was significantly lower than in those without thrombocytosis (5% vs 26%, P = 0.036). In stage IV patients, there was no significant difference (0% vs 6%, P > 0.05). In multivariate analysis, age, hemoglobin, and treatment (vs palliation) were significantly associated with prognosis, whereas thrombocytosis was not. Thrombocytosis is not an independent prognostic factor in advanced stage cervical cancer.     

Correlation of angiogenesis and recurrence-free survival of early stage cervical cancer patients undergoing radical hysterectomy with pelvic lymph node dissection

AIM: To assess the correlation between the intensity of tumor angiogenesis, expressed as microvessel density, and recurrence-free survival in patients with early stage cervical cancer. METHODS: In a historical cohort study of patients with early stage cervical cancer undergoing radical hysterectomy with pelvic lymph node dissection at Songklanagarind Hospital during January 1998-December 2004, histological slides were immunostained for factor VIII-related antigen. Microvessel density was scanned at low magnification to identify the area with the highest number of vessels. Stained microvessels were counted at high magnification (x200) in an examination area of 0.25 mm2. Microvessel density and other potential prognostic factors were considered as covariates in multivariate Cox-proportional hazards regression models to evaluate their association with recurrence-free survival. RESULTS: One hundred and sixty-four patients were included in the study, and 16 patients developed recurrent disease during follow-up. The overall 5-year recurrence-free survival was 86.9% (95% confidence interval [CI] 78.9-92.0). In the multivariate analysis, microvessel density (hazard ratio [HR], for > or =9 vs <6 vessels per high power field: 5.8, 95% CI 1.5-22.7; P = 0.013), tumor size (HR for maximum diameter > or =2 vs <2: 3.6, 95% CI 1.2-10.7; P = 0.017) and parity (HR for > or =3 vs <3: 3.6, 95% CI 1.2-10.7; P = 0.018) were identified as significant independent prognostic factors for recurrence-free survival. CONCLUSION: Microvessel density is an independent prognostic parameter for recurrence-free survival in patients with early stage cervical cancer. Microvessel density at or above the cut-off point of nine vessels per high power field had significantly poorer recurrence-free survival.     

Hypermethylation of the COX-2 gene is a potential prognostic marker for cervical cancer

AIM: The aim of the present study was to evaluate the DNA hypermethylation profiles of 14 genes known to be associated with tumor behavior and their clinical significance in cervical cancer. METHOD: The clinical features of 82 patients with stage IB cervical cancer were analyzed in terms of DNA hypermethylation of 14 genes (hMLH1, p16, COX-2, CDH1, APC, DAPK, MGMT, p14, RASSF1A, RUNX3, TIMP3, FHIT, THBS1, and HLTF). RESULTS: Of 14 genes investigated, only hypermethylation of COX-2 showed significant association with poor disease-free survival (P = 0.001). To further investigate an alteration in COX-2 expression by DNA hypermethylation, immunohistochemistry for COX-2 protein was performed in the cervical cancer tissues. We found no significant association between hypermethylation and expression patterns of the COX-2 gene. CONCLUSIONS: The present results suggest that DNA hypermethylation of the COX-2 gene may be a potential prognostic marker in early stage cervical cancer, the underlying mechanism of which is independent of gene silencing.     

Quantification of human papillomavirus DNA in the plasma of patients with cervical cancer

Plasma human papillomavirus (HPV)-DNA level was measured to evaluate the clinical usefulness of circulating DNA for cervical cancer management. DNA extracted from pretreatment plasma of 50 cervical cancer patients and from serial longitudinal plasma of 21 patients was quantified for HPV16/HPV18 by means of quantitative polymerase chain reaction. Another 15 patients with low-grade lesion (LG), 18 patients with high-grade lesion (HG), and 96 normal individuals were studied as controls. Plasma HPV16-DNA was detectable in 50% of cancer patients. The incidence and median level were statistically higher than those in LG patients and normal, but similar to HG patients. Plasma HPV18-DNA was only detected in 6% of cancer patients and 1% of normal. Same type of HPV present in plasma was also detected in its primary tumor; and the level of plasma HPV16-DNA was dependent on the viral load in primary tumor. Plasma HPV-DNA was not detected in 16 of 21 patients after treatment, and those patients had complete response to therapy. HPV-DNA persisted or reappeared in five patients after treatment (one had persistent disease and another had recurrence). Plasma HPV-DNA might be a valuable marker for monitoring therapeutic response and disease progression in cervical cancer.     

C-reactive protein is a prognostic parameter in patients with cervical cancer

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.     

Adjuvant radiotherapy in carcinomas of the uterine cervix: the prognostic value of hemoglobin levels

Anemia has been associated with a poorer treatment response and reduced survival in women undergoing primary radiotherapy (RT) or radiochemotherapy for advanced cervical carcinoma. This study aimed to determine the influence of anemia on outcome in patients with cervical carcinoma undergoing adjuvant RT. Medical records were reviewed for 183 cervical cancer patients who had received adjuvant RT because of risk factors after radical surgery (n= 109) or inadequate primary surgery (simple hysterectomy; n= 74). Kaplan-Meier and Cox regression analyses were used to study hemoglobin levels before and during adjuvant RT in relation to recurrence-free and overall survival. Hemoglobin values > or =11 g/dL were considered normal, while those <11 g/dL indicated anemia. Hemoglobin levels before RT influenced significantly overall survival and recurrence-free survival across the whole group (overall survival--log rank(all patients)= 7.5; df = 1; P= 0.006). However, subgroup analysis showed that the observed difference was mainly due to the group of women who had undergone inadequate primary surgery (overall survival--log rank(inadequate surgery)= 10.8; df = 1; P= 0.001). Multifactorial regression analyses comparing hemoglobin before RT with grading and tumor stage confirmed the prognostic value of hemoglobin values. Maintaining normal hemoglobin values before and during adjuvant RT seems to be important, especially in patients who have had inappropriate simple hysterectomy, which may resemble a therapeutic situation.     

HE4 is an independent prognostic marker in endometrial cancer patients

Objective

To evaluate the prognostic value of pretherapeutic serum HE4 in endometrial cancer in comparison to CA125.

Methods

HE4 and CA125 serum levels were analyzed by means of chemiluminescent microparticle immunoassays in 183 patients with endometrial cancer treated at the Department of Obstetrics and Gynecology, Innsbruck Medical University, between 1999 and 2009. The Kaplan-Meier method and Cox's proportional hazards analysis were performed to determine the prognostic significance of HE4, CA125 and the combination of both markers.

Results

In univariate analysis both markers, HE4 and CA125, were of prognostic value for overall survival (p < 0.001 and p = 0.028) and disease-free survival (p = 0.015 and p = 0.045). In multivariate analysis HE4 was seen to have independent prognostic value in overall survival (HR 2.407, p = 0.017) in contrast to CA125. The combination of both markers showed a higher hazard ratio (HR 4.04, p = 0.023) for overall survival in comparison to HE4 alone. In the subgroup endometrioid histological type (n = 132) only HE4 was of prognostic value for overall survival in univariate (p = 0.001) and multivariate analysis (p = 0.023).

Conclusions

Pretherapeutic serum HE4 levels alone and in combination with CA125 are an independent prognostic marker in endometrial cancer patients.     

The prognostic factors for patients with early cervical cancer treated by radical hysterectomy and postoperative radiotherapy

PURPOSE: This study was undertaken to evaluate the efficacy of postoperative radiotherapy (post-OP RT) and to investigate the prognostic factors for early-stage cervical cancer patients who were treated by radical surgery, and the pathological findings suggested a relatively high risk of relapse with surgery alone. MATERIALS AND METHODS: From January 1990 to December 1995, 222 patients with stage IB-IIA cervical cancer, treated by radical surgery and a full course of post-OP RT, were included in this study. The indications for post-OP RT were based on pathological findings, including lymph node metastasis, positive surgical margins, parametrial extension, lymphovascular permeation, and invasion of more than two-thirds of the cervical wall thickness. The radiation dose of external beam was 44-45 Gy to the whole pelvis and 50-54 Gy to the true pelvis. One hundred seventy-two patients also received intravaginal brachytherapy as a local boost. The minimal follow-up period was 2 years. RESULTS: The actuarial 5-year overall and disease-specific survival rates for all patients were 76 and 82%, respectively. The tumor control rate within the pelvis reached 94%, and distant metastasis was the major cause of treatment failure. Univariate analysis of clinical and pathological parameters revealed that clinical stage, bulky tumor size, positive lymph nodes, parametrial extension, and histologic type were significant prognostic factors. After multivariate analysis, only positive lymph nodes (P = 0.01), bulky tumor size (P = 0.02), and parametrial extension (P = 0.05) independently influenced the disease-specific survival (DSS). For patients with lymph node metastasis, the number and location of the nodal involvement significantly affected the prognosis. The 5-year DSS for patients with no, one, and more than one lymph node metastasis were 87, 84, and 61% (P = 0.0001), respectively. Patients with upper pelvic lymph node metastasis had a higher incidence of distant metastasis (50% vs 16% in lower pelvic node group, P = 0.03). In the subgroup of single lower pelvic nodal metastasis, the prognosis was similar to that of patients without lymph node involvement (5-year DSS 85% vs 87%, P = 0.71). CONCLUSION: Our results indicate that post-OP RT can achieve very good local control in stage IB-IIA cervical cancer patients whose pathological findings show risk features for relapse after radical surgery. The prognostic factors for treatment failure identified in this study can be used as selection criteria for clinical trials to test the effects of other adjuvant treatments, such as chemotherapy. Patients with a single lower pelvic lymph node metastasis have a relatively good prognosis and may not need adjuvant treatment beyond radiation therapy.     

Squamous cell carcinoma antigen serum levels as prognostic parameter in patients with early stage vulvar cancer

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.     

Indications for primary and secondary exenterations in patients with cervical cancer

OBJECTIVE: Fifty years after the introduction of exenterative surgery in gynecologic oncology, the indication for primary and secondary exenteration is controversially discussed in cervical cancer patients. In addition, the term "palliative exenteration" is not precisely defined. We evaluate the role of primary exenteration in patients with stage IVA cervical cancer and the role of secondary palliative exenteration. METHODS: The study retrospectively analyzed surgical and oncologic data of 55 patients who underwent exenterative surgery in the Department of Gynecology at the University of Jena between February 1998 and January 2004. Primary surgery was performed in 20 patients with laparoscopically confirmed stage IVA cervical cancer, while 35 patients with recurrent cervical cancer underwent secondary exenteration. Fifty-one had total, 3 posterior and 1 anterior exenteration. Survival was analyzed in relation to the patient's age, indication (primary versus secondary, curative versus palliative), previous therapy (operation, radiation, chemotherapy, radiochemotherapy), histology, resection margins, pelvic nodal involvement, time interval from primary therapy to recurrence, type of exenteration and adjuvant therapy. Early and late postoperative complications as well as perioperative mortality were reviewed. RESULTS: The overall cumulative survival of all patients after exenteration was 36.8% at 5 years with 52.5% in the primary group and 26.7% in the recurrent one (p=0.0472). Complications were noted in 56.9% of patients, most commonly fistulas or gastrointestinal complications. Operative mortality was 5.5%. Survival correlated significantly with the time interval between primary treatment and recurrence (within 1-2 years 16.8% five-year survival, 2-5 years 28%, >5 years 83.2%, p=0.0105) as well as with curative or palliative intention (2-year survival rate of 60% in patients with curative intent, 10.5% in those with palliative intent, p=0.0001) and with tumor-free resection margins (2-year survival of 10.2% for positive margins, 5-year survival of 55.2% for negatives ones, p=0.0057). The age, the type of exenteration, the histologic type and the metastatic spread to pelvic lymph nodes had no significant influence on long-term survival. CONCLUSION: In patients with histopathologically confirmed stage IVA cervical cancer primary, exenteration is a valid alternative to primary chemoradiation. In patients with persistent or recurrent tumor limited to the pelvis, secondary exenteration should be offered in the absence of other therapeutic options. Palliative and curative attempts can best be differentiated by the resection margin status.     

Phenotypic features with p53 alterations related to human papillomavirus and prognostic evaluation in cervical cancer

Cervical cancer is one of the most common tumor affecting women worldwide. Human papillomavirus (HPV) was found to have a causal relationship with cervical cancer and its precursors. The interaction between HPV E6 protein and p53 was identified in in vitro studies. The aim of the study was to evaluate the prevalence of p53 alterations related to HPV infection and the prognostic significance of p53 alterations in cervical cancer. Studies were identified by a MEDLINE search, and all relevant articles were retrieved from 1991 to March 2004. The prevalence of p53 mutations is a rare event in cervical cancer. The correlation between p53 mutations and HPV or prognosis is controversial. Loss of heterozygosity (LOH) of p53 is more commonly found in cervical cancer and is related with the prognosis of this disease. There is no significant correlation between p53 polymorphism and development of cervical cancer. The p53 mutations were not commonly found in cervical cancer. LOH of p53 may contribute to the progression of this malignancy. p53 polymorphism failed to be an independent prognostic factor in predicting the outcome of patients with cervical cancer. Further, epidemiologic surveys should be undertaken in larger populations and in different geographical regions.     

Survivin, a novel anti-apoptosis inhibitor, expression in uterine cervical cancer and relationship with prognostic factors

A novel inhibitor of apoptosis, Survivin, seems to be involved in the critical steps of cancer onset and progression and may be associated with unfavorable clinical outcome. We investigated the expression of Survivin in patients with cervical intraepithelial neoplasia grade 3 (CIN3) and uterine cervical cancer, to determine whether Survivin expression is related to poor prognosis. Fourteen cases of CIN3, 53 cases of invasive uterine cervical squamous cell carcinoma (SCC), and 11 cases of normal control group were analyzed retrospectively. Immunohistochemical staining and Western blot was performed with antihuman Survivin antibody and analyzed with respect to patient outcome. Survivin was significantly expressed in cervical cancer groups compared to the normal control group (P < 0.05). Significant Survivin expression was also noted in cancer patients with lesion size > or =4 cm, lymphovascular invasion, elevated SCC antigen levels, and no response to initial therapy. In more advanced stages, Survivin expression tended to increase but without statistical significance (P = 0.081). No association was noted between Survivin expression and survival rate (P = 0.1011). We conclude that Survivin expression provides some prognostic information regarding uterine cervical cancer, even though it was not correlated with survival. It could represent a possible new prognostic marker of uterine cervical SCC patients.     

同步放化疗治疗Ib2和IIa2期宫颈癌疗效及预后相关因素分析

目的:探讨同步放化疗治疗Ib2期和IIa2期宫颈癌的疗效和不良反应,并分析预后影响因素。方法:回顾分析2000年1月至2010年12月首都医科大学附属北京妇产医院妇瘤科收治的73例接受同步放化疗的Ib2和IIa2期宫颈癌患者的临床病理资料。统计有效率和疾病控制率评价近期疗效,统计3年、5年无瘤生存率(DFS)及总生存率(OS)评价远期疗效,记录患者的不良反应,并分析可能影响患者预后的相关因素。结果:同步放化疗治疗Ib2期和IIa2期宫颈癌的有效率(CR+PR)为91.78%,疾病控制率(CR+PR+SD)为97.26%;3年DFS为84.93%,0S为86.30%;5年DFS为79.45%,0S为82.19%。所有不良反应患者均可耐受,对症治疗后均可缓解。单因素分析显示,患者的生存率与肿瘤的病理类型、分化程度、大小、有无淋巴结转移以及治疗前后血鳞状细胞癌抗原(SCC-Ag)值有关(P0.05)。多因素分析表明,肿瘤病理类型、大小、有无淋巴结转移及治疗后1个月血SCC-Ag值为远期疗效的独立影响因素。结论:同步放化疗治疗Ib2期和IIa2期宫颈癌的近、远期疗效肯定,不良反应可耐受,是一种可供选择的方法。病理类型为腺癌、肿瘤直径﹥5cm、有淋巴结转移、治疗后1个月血SCC-Ag值≥1.5ng/ml者预后较差,需进一步加强研究。     

505例宫颈癌临床病例分析

目的 本研究探讨宫颈癌患者预后相关危险因素,以指导其处理及随访.方法 收集北京大学深圳医院近10年间宫颈癌患者505例,研究其临床病理特点与预后的相关因素,采用SPSS 19.0软件分析,P＜0.05为差异有统计学意义.结果 ①本研究患者发病年龄高峰为35～45岁,呈单峰,3年、5年总体生存率分别为94％、93％;②多因素分析,临床分期、组织分化程度、以铂类为基础的同步化放疗是影响宫颈癌预后的独立危险因素(P＜0.05).结论 本研究患者发病年龄高峰为35～45岁,呈单峰.3年、5年总体生存率高于文献报道.临床分期、组织分化程度、以铂类为基础的同步化放疗是影响宫颈癌预后的独立危险因素.     

不同治疗方法对Ⅰb2～Ⅳ期子宫颈癌患者预后的影响

目的 探讨不同治疗方法对子宫颈癌预后的影响。方法 对1996年1月～2004年1月间我院收治的51例Ⅰb2期以上的子宫颈癌患者的临床资料及预后进行回顾性分析，比较各种治疗方案与患者的预后及生存情况的关系。结果 术前介入组和术前放疗组相比，复发及死亡率无明显差异（P〉0．05），但介入组的手术时间明显短于放疗组（P〈0．05），术中出血量略少于放疗组（P〉0．05）。结论 子宫颈癌患者的综合治疗很重要。新辅助化疗与术前放疗相比，对患者的预后影响差异无显著性，但可降低手术难度，减少术中出血量。