Prevalence and prognostic significance of COX-2 expression in stage IB cervical cancer

OBJECTIVES: To evaluate the prevalence of cyclooxygenase-2 (COX-2), correlation with various clinicopathologic factors and prognostic significance of COX-2 in stage IB cervical cancer patients. METHODS: 89 paraffin-embedded specimens of patients with stage IB cervical cancer underwent radical hysterectomy and pelvic lymphadenectomy at King Chulalongkorn Memorial Hospital during 1 January 1997-31 December 2002 and were stained with polyclonal goat antiserum against COX-2 using immunohistochemical method. Medical records were reviewed; clinicopathological variables were retrieved and used for analysis. RESULTS: The prevalence of positive COX-2 expression in stage IB cervical cancer in this study was 49.4%. Positive COX-2 expression in cervical adenocarcinoma was higher than squamous cell carcinoma (86.7% versus 40.6%, P < 0.05) and significantly expressed when lymph node metastasis was presented (100% versus 46.4%, P < 0.05). However, COX-2 expression was possibly associated with parametrial involvement (80% versus 47.6%, P > 0.05). There was no correlation between COX-2 expression and patient's age, tumor size, depth of stromal invasion and lymphovascular space invasion. Five-year disease free survival and 5-year overall survival in patients with positive COX-2 expression were 81% and 98% which were not differed from patients with negative COX-2 expression (92% and 95%, P > 0.05). CONCLUSIONS: Strong correlation was found in cervical adenocarcinoma and lymph node metastasis. However, COX-2 expression failed to demonstrate as a significant prognostic factor in stage IB cervical cancer.     

COX-2和VEGF在宫颈癌组织中的表达及其生物学意义

目的　探讨环氧化酶 2 (COX - 2 )和血管内皮生长因子 (VEGF)在宫颈癌中的表达及其与宫颈癌临床病理特征的关系。方法　采用免疫组化SP法检测COX - 2、VEGF在 6 8例宫颈癌、 14例正常宫颈组织中的表达。结果　COX - 2和VEGF蛋白在宫颈癌和正常宫颈组织中的表达差异有显著性 (P <0 0 1)。COX - 2蛋白表达与宫颈癌分化程度、组织学类型、淋巴结转移等显著相关 (P <0 0 5 ) ;VEGF蛋白表达与宫颈癌临床分期、淋巴结转移有显著相关 (P <0 0 5 )。宫颈癌中VEGF与COX - 2的表达密切相关。结论　COX - 2和VEGF 2种蛋白与宫颈癌的发生发展相关 ,并在宫颈癌的侵袭转移中起一定作用。     

High cyclooxygenase-2 expression in stage IB cervical cancer with lymph node metastasis or parametrial invasion

OBJECTIVE: The enzymes cyclooxygenase (COX)-1 and -2 are necessary for the synthesis of prostaglandins. COX-2 is usually absent in normal cells and is upregulated and expressed as a product of the "immediate early" gene during inflammatory processes. In previous studies, the expression of COX-2 has been shown to be induced by proinflammatory cytokines, and suggestions have been made that overexpression of COX-2 suppresses apoptosis and is directly related to tumor growth. We have attempted to determine a relationship between tumor invasion and metastasis of uterine cervical cancer and COX and apoptosis by comparing the protein expression of apoptosis, COX-1, and COX-2 in tumor tissues. METHODS: The subjects were 36 patients who were FIGO stage IB uterine cervical cancer patients who underwent surgery at Ajou University Hospital. There were 12 cases with lymph node or parametrial involvement. All tissues were subjected to immunohistochemical staining for COX-1, -2, and TUNEL method for apoptosis detection, and the following results were obtained. RESULTS: Tumor tissues confirmed by cytokeratin were separated into tumor surface, tumor stroma, and invasion site portions, in which decreased apoptosis was observed in the invasion sites. COX-2 expression was observed in all tumor tissues and was especially strong in the tumor invasion site. Therefore, it is suggested that COX-2 expression may suppress cell apoptosis at the tumor invasion site. When COX-2 expression was investigated according to the groups with regard to the presence of lymph node or parametrial involvement, there was a statistically significant (Mann-Whitney U test) COX-2 expression difference in the tumor invasion site (P value = 0.040) and the tumor stroma (P value = 0. 028). CONCLUSIONS: In surgically treated stage IB cervical cancer patients, COX-2 was significantly expressed when lymph node or parametrial involvement was present. These results suggest that the expression of COX-2 in stage IB cervical cancer may downregulate apoptotic processes and thus enhance tumor invasion and metastasis.     

Lymph node pathway in the spread of endometrial carcinoma

OBJECTIVE: To elucidate the sentinel nodes of endometrial carcinoma, the spread pathway was clarified. The correlation between lymph node spread and other clinicopathological variables was also analyzed. METHODS: Dissected lymph node samples in 342 patients who underwent pelvic and selective paraaortic lymphadenectomy were reviewed. Pelvic and paraaortic node (PLN and PAN) status was compared with clinicopathological parameters. RESULTS: Lymph node metastasis was demonstrated in 52 patients, including 46 cases with PLN metastasis and six patients with independent PAN metastasis. The metastatic sites were most frequent in the obturator and internal iliac nodes. Eleven of 49 patients who underwent PAN dissection were positive for metastasis. Sixteen of 23 cases with parametrial metastasis also metastasized in the retroperitoneal lymph node. CONCLUSION: The lymph node spread pathway in endometrial carcinoma consists of a major route via the obturator node or internal iliac node with or without parametrial involvement, and rarely a direct PAN pathway.     

Association between RCAS1 expression and microenvironmental immune cell death in uterine cervical cancer

OBJECTIVE.: The presence of regional lymph node metastasis is one of the prognostic factors for uterine cervical cancer. The development of metastasis requires that cancer cells avoid lymphocyte attack. Impaired lymphocyte function is mediated by apoptotic factors including receptor-binding cancer antigen expressed on SiSo cells (RCAS1), Fas ligand (FasL), and tumor necrosis factor-alpha (TNF-alpha). Our aim was to evaluate the association between expression of these factors and microenvironmental lymphocyte apoptosis in this disease. METHODS.: Immunohistochemical methods were used to determine the relationship between the expression of RCAS1, FasL, and TNF-alpha, and the number of apoptotic lymphocytes in primary lesions and metastatic lymph nodes in patients with cervical cancer. RESULTS.: Expression of these apoptosis-inducing molecules was quite different in primary tumors and metastatic lymph nodes: RCAS1 expression in lymph nodes was significantly higher than that in primary lesions (P < 0.0001), whereas FasL and TNF-alpha expressions at these two locations were not significantly different. The number of cells with positive expression of RCAS1, but not of FasL or TNF-alpha, was significantly correlated with the number of apoptotic lymphocytes in uterine cervix and metastatic lymph nodes (P < 0.0001 for both). CONCLUSION.: RCAS1 expression may be related to tumor cell evasion of immune surveillance via induction of lymphocyte apoptosis in primary lesions and metastatic lymph nodes in uterine cervical cancer.     

Presence of Oncogenic HPV DNAs in Cervical Carcinoma Tissues and Pelvic Lymph Nodes Associating with Proliferating Cell Nuclear Antigen Expression

The presence of oncogenic HPV DNAs (HPV-16/18) in cervical carcinomas and their normal and metastatic pelvic lymph nodes and the expression patterns of proliferating cell nuclear antigen (PCNA) in cervical carcinomas were retrospectively studied to elucidate the possible roles of them in malignant transformation and progression of the disease. HPV-16/18 DNAs were detected by polymerase chain reaction using HPV E6 type-specific primers in 79 patients with cervical cancer: 31 patients who had pelvic lymph node metastasis (group I) and 48 patients without pelvic lymph node metastasis (group II) who were proven by pathologic examination of surgical specimens. HPV-16 or -18 DNAs were detectable in cervical carcinoma tissues in 60 patients from 79 cervical cancer patients (75.9%; HPV-16 was 67.1% and HPV-18 was 8.9%). HPV DNAs were amplified from metastatic pelvic lymph nodes in 13 patients of group I (42%) and from nonmetastatic lymph nodes in 7 group I patients (22.5%). Recurrence was identified in 9 group I patients (29.0%) in 3 years of follow-up. HPV DNAs were amplified from nonmetastatic lymph nodes in 11 group II patients (22.9%). Two group II patients, who had HPV-16 DNA by PCR in nonmetastatic nodes, were recurrent. PCNA was overexpressed in 66.7% of HPV-16- or -18-positive cervical cancers and 16.7% of HPV-16- or -18-negative cervical cancers. However, the expression levels of PCNA in cervical cancers were not influenced by the presence of oncogenic HPV DNA or pathologic metastasis in the pelvic lymph nodes. In conclusion, HPV DNA could be amplified from some metastatic and nonmetastatic pelvic lymph nodes and the detectability of oncogenic HPV DNA in pelvic lymph nodes may represent the poor outcome in the treatment of disease. The expression of PCNA protein which was associated with presence of oncogenic HPV DNAs in cervical cancers, suggesting activation of S phase of cell cycle, may contribute to the malignant progression by HPV-16 or -18.     

The expression of epidermal growth factor receptor, vascular endothelial growth factor, matrix metalloproteinase-2, and cyclooxygenase-2 in relation to human papilloma viral load and persistence of human papillomavirus after conization with negative margins

The aim of this study was to investigate the correlations between human papillomavirus (HPV) load and vascular endothelial growth factor (VEGF), epidermal growth factor receptor (EGFR), matrix metalloproteinase-2 (MMP-2), and cyclooxygenase-2 (COX-2), and to identify biomarkers that may predict high-risk HPV clearance or persistence after conization with negative margins. The following samples were analyzed: 77 paraffin-embedded specimens from patients with cervical intraepithelial neoplasia (CIN), including 27 CIN 2 conization specimens and 50 CIN 3 conization specimens. Immunohistochemical analysis was performed with antibodies to VEGF, EGFR, MMP-2, and COX-2. Hybrid capture II testing was used to detect HPV DNA. VEGF expression was significantly associated with HPV load (rho = 0.27186, P = 0.0191), while COX-2 expression was significantly and inversely associated with HPV load (rho = -0.34309, P = 0.0028). In univariate analysis, HPV load (P = 0.0112) and VEGF expression (P = 0.0274) were significantly associated with high-risk HPV clearance or persistence after conization with negative margins. In multiple regression analysis, high viral load (relative light unit/positive control > 500) and positive VEGF expression were significantly associated with high-risk HPV persistence after conization with negative margins (odds ratio [OR]: 9.915, CI: 1.891-51.994; OR: 6.661, CI: 1.208-36.722, respectively). In conclusion, VEGF expression is related to HPV load, while COX-2 expression is inversely related to HPV load, and immunohistochemical analysis of VEGF expression and HPV viral load are a significant and an independent prognostic indicator of high-risk HPV persistence after conization with negative margins.     

早期子宫颈癌脉管间隙及宫旁浸润危险因素1245例分析

目的:探讨子宫颈癌淋巴脉管间隙浸润(lymph-vascular space invasion,LVSI)及宫旁浸润与其他临床病理因素的关系。方法:回顾性分析2009年1月至2019年1月期间于西安交通大学第一附属医院妇科接受手术治疗1245例早期子宫颈癌患者的临床资料,分别根据是否LVSI及宫旁浸润分为LVSI组、无LVSI组和宫旁浸润组、无宫旁浸润组,采用单因素和多因素Logistic回归分析脉管及宫旁浸润危险因素。结果:1245例LVSI率14.1%(175/1245),宫旁浸润率1.85%(23/1245)。单因素分析显示LVSI的发生与病灶类型、病理类型、肿瘤细胞分化程度、子宫颈浸润深度、淋巴转移、切缘阳性、宫旁浸润比较,差异有统计学意义(P<0.05)。根据淋巴转移情况分层分析发现,在淋巴未转移组LVSI的发生率与年龄、病灶类型、病理类型、子宫颈浸润深度比较,差异有统计学意义(P均<0.05)。Logistic回归分析显示病灶类型为内生型、病理为鳞癌、子宫颈深肌层浸润和淋巴转移相较于非内生型、非鳞癌、子宫颈浸润浅肌层、无淋巴转移早期子宫颈癌患者是发生LVSI的独立危险因素(OR>1,P<0.05)。单因素分析显示宫旁浸润与病灶类型、子宫颈浸润深度、累及阴道、累及宫体下段、切缘阳性、淋巴转移、LVSI有关(P<0.05)。Logistic回归分析示病灶类型为内生型、累及宫体下段、淋巴转移相较于非内生型、未累及宫体下段、无淋巴转移的早期子宫颈癌患者是发生宫旁浸润的独立危险因素(OR>1,P<0.05)。结论:子宫颈深肌层浸润、淋巴结转移、内生型的子宫颈鳞癌患者更可能发生LVSI;病灶类型为内生型、累及宫体下段、淋巴转移的患者更可能发生宫旁浸润。     

Predictive value of HPV DNA in lymph nodes in surgically treated cervical carcinoma patients--a prospective study

OBJECTIVE: High-risk types of HPV are etiological factors in cervical cancer. Lymph node involvement in cervical cancer patients reduces 5-year survival rates by 25-60%. However, the influence on survival of HPV DNA positivity in histopathologically negative lymph nodes remains unresolved. METHODS: The study included 116 of 148 patients who underwent Piver type III radical hysterectomy and pelvic lymphadenectomy and who showed HPV DNA positivity in the primary lesion. Lymph node tissues were tested for the presence of HPV DNA, using a PCR technique. RESULTS: We found the presence of HPV DNA sequences in lymph nodes dissected intraoperatively in 81 (69.83%) cases. In analysis, we compared patients from 3 groups: HPV- and metastatic-negative (LN HPV-M-); HPV-positive metastatic-negative (LN HPV+M-); and metastatic-positive (LN M+). We discovered that survival in groups LN M+ and LN HPV+M- did not differ statistically (p=0.37). However, the survival periods in these two groups differed when compared with LN HPV-M- patients (p<0.001). Using Cox's proportional hazards model, we found that the presence of lymph node HPV DNA, and FIGO stage, and primary lesion volume were independent parameters correlating with survival and mortality risk. CONCLUSION: We conclude that the presence of HPV DNA in lymph nodes is an early sign of metastasis and should be treated as such in prognostic outlook and planning the therapeutic strategy.     

Expression of ras oncogene product and EGF receptor in cervical squamous cell carcinomas and its relationship to lymph node involvement.

The expression of ras oncogene product p21 and epidermal growth factor (EGF) receptor was studied immunohistochemically in tissues obtained from 52 patients with squamous cell carcinoma of the uterine cervix. We examined the relationship between p21 and EGF receptor expression and lymph node metastasis in cervical cancer. The data demonstrate that the patients with positive staining for ras p21 in cervical carcinomas have a higher incidence of lymph node metastasis than the patients with negative staining for p21 (P = 0.027). Although the levels of p21 expression in the metastatic sites were reduced compared to those in the primary sites, tumor cells in metastatic lymph nodes also expressed p21. No relationship was found between EGF receptor expression and lymph node metastasis. These results suggest that expression of ras oncogene product may be associated with the biological aggressiveness of cervical carcinomas.     

Postoperative pelvic radiotherapy for cervical cancer patients with positive parametrial invasion

OBJECTIVE: To evaluate patterns of failure in cervical cancer patients with histopathologic parametrial invasion treated with postoperative pelvic radiation therapy. METHODS: Records of 117 stages IB-IIB cervical cancer patients with parametrial invasion treated with postoperative radiation therapy from 1985 to 2002 were retrospectively reviewed. Patients were divided into two groups based on status of pelvic lymph nodes. Patterns of recurrence and prognosis by status of pelvic lymph nodes were statistically analyzed. RESULTS: Status of pelvic lymph nodes had significant impact on both recurrence and survival. Extrapelvic recurrence was observed in 23 of 66 node-positive patients compared with 6 of 51 node-negative patients (P = 0.005). Of 66 patients with a positive pelvic lymph node, 18 developed visceral metastases, whereas only three visceral metastases were noted in the 51 node-negative patients (P = 0.003). Five-year overall survival in node-positive and -negative patients was 52% and 89%, respectively (P = 0.0005). Corresponding rates for recurrence-free survival were 44% and 83%, respectively (P = 0.0002). The correlation between nodal metastasis and prognosis was enhanced when node-positive patients were stratified into two groups based on number of positive nodes (n = 1 and n > or = 2). Five-year recurrence-free survival rates for patients with negative, one positive, and two or more positive nodes were 83%, 61%, and 31%, respectively (P = 0.0001). CONCLUSIONS: Extrapelvic recurrence was uncommon in node-negative patients with parametrial invasion. These findings do not support use of systemic therapy for cervical cancer patients with parametrial invasion if pelvic lymph node metastasis is negative.     

Multivariate analysis of histopathologic prognostic factors for invasive cervical cancer treated with radical hysterectomy and systematic retroperitoneal lymphadenectomy

BACKGROUND: The aim of this study was to identify the independent histopathologic prognostic factors for patients with cervical carcinoma treated with radical hysterectomy including paraaortic lymphadenectomy. METHODS: A total of 187 patients with stage IB to IIB cervical carcinomas treated with radical hysterectomy and systematic retroperitoneal lymphadenectomy were retrospectively analyzed. The median follow-up period was 83 months. Cox regression analysis was used to select independent prognostic factors. RESULTS: Using multivariate Cox regression analysis, lymph node (LN) status (negative vs. metastasis to pelvic nodes except for common iliac nodes vs. common iliac/paraaortic node metastasis), histopathologic parametrial invasion, lymph-vascular space invasion (LVSI), and histology of pure adenocarcinoma were found to be independently related to patients' poor survival. For patients who had a tumor histologically confined to the uterus and have neither parametrial invasion nor lymph node metastasis, LVSI was the most important prognostic factor, and histologic type, depth of cervical stromal invasion, and tumor size were not related to survival. The survival of patients with a tumor extending to parametrium or pelvic lymph node(s) was adversely affected by histology of pure adenocarcinoma. When the tumor extended to common iliac or paraaortic nodes, patients' survival became quite poor irrespective of LVSI or histologic type of pure adenocarcinoma. Patients' prognosis could be stratified into low risk (patients with a tumor confined to the uterus not associated with LVSI: n = 80), intermediate risk (patients with a tumor confined to the uterus associated with positive LVSI, and patients with squamous/adenosquamous carcinoma associated with pelvic lymph node metastasis or parametrial invasion: n = 86), and high risk (patients with pure adenocarcinoma associated with pelvic lymph node metastasis or parametrial invasion, and patients with common iliac/paraaortic node metastasis: n = 21) with an estimated 5-year survival rate of 100 +/- 0 (mean +/- SE)%, 85.5 +/- 3.9%, and 25.1 +/- 9.7%, respectively. CONCLUSIONS: LN status, parametrial invasion, LVSI, and histology of pure adenocarcinoma are important histopathologic prognostic factors of cervical carcinoma treated with radical hysterectomy and systematic retroperitoneal lymphadenectomy. Prognosis for patients with cervical carcinoma may be stratified by combined analysis of these histopathologic prognostic factors. Postoperative therapy needs to be individualized according to these prognostic factors and validated for its efficacy using randomized clinical trials.     

IGF-IR在宫颈癌和淋巴结转移组织中表达的临床意义

目的:研究宫颈癌和淋巴结转移组织中胰岛素样生长因子Ⅰ受体(insulin- like growth factor-Ⅰreceptor,IGF-IR)的表达及其与淋巴结转移、预后的关系。方法:用免疫组化S-P法检测IGF-IR在46例宫颈癌、12例正常宫颈组织和22例转移淋巴结组织中的表达。结果:宫颈癌组织中IGF-IR蛋白表达率为45．7%(21/46),转移淋巴结组织中阳性率为45．5%(10/22),分别高于良性组织;淋巴结转移组原发灶中IGF-IR蛋白表达率明显高于无转移组原发灶中的表达(x~2=5．497,P=0．019)。结论:宫颈癌广泛存在IGF- IR蛋白过表达,检测IGF-IR蛋白表达可能有助于判断宫颈癌的预后,并可能为判断宫颈癌生物学行为提供有意义的指标。     

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.     

Human papillomavirus (HPV) DNA in primary cervical cancer and in cancer free pelvic lymph nodes--correlation with clinico-pathological parameters and prognostic significance

OBJECTIVE: To assess whether the presence of human papilloma virus (HPV) DNA and/or several genotypes of HPV DNA in primary cervical cancer and cancer free pelvic lymph nodes are correlated with several clinicopathological parameters of well-defined prognostic significance and whether virological parameters are predictors of long-term survival in cancer patients. PATIENTS AND METHODS: 223 cases of cervical cancer patients included in this retrospective study underwent follow-up evaluation. Survival and cause of death were examined for 204 (91.4%) patients, with a mean follow-up time of 4.4 years. HPV DNA was detected using the high sensitive polymerase chain reaction (PCR) method followed by HPV DNA sequencing for HPV genotyping. These results were correlated with well-defined clinicopathological parameters and survival data. RESULTS: HPV DNA was detected by PCR in 150 of 203 (73.4%) tissue specimens of cervical cancer patients. DNA sequence analysis revealed the presence of HPV 16 (n = 68, 45.3%), HPV 18 (n = 49, 32.6%) and rare HPV types (n = 33, 22.1%). HPV genotypes correlated significantly with histological tumor types, node status, blood vessel invasion and lymph space involvement. The presence of HPV DNA in cervical cancer as well as the genotype of HPV 16 could also be confirmed as significant prognostic factors in the univariate Cox Regression Analysis (RR 2.856, p < 0.003 resp. RR 3.444, p < 0.0001). The presence of HPV DNA in cancer free pelvic lymph nodes was significantly correlated to the concomitant manifestation of pelvic lymph node metastases (RR 3.1, p < 0.0001). In the multivariate analysis, however, HPV DNA in primary tumor and in negative pelvic lymph nodes failed to be of prognostic relevance. Exclusively, HPV 16 appears to impact independently on the overall survival in cervical cancer patients (RR 3.653, p < 0.002). CONCLUSION: The detection of HPV 16 genotype may play an important adjunct role in assessing prognosis of cervical cancer patients. The clinical impact of the presence of HPV DNA in primary tumors and cancer free pelvic lymph nodes remains to be investigated in further studies. The exact mechanisms by which HPV influence the prognosis of cervical cancer patients have to be defined.     

Fas ligand expression in cervical adenocarcinoma: relevance to lymph node metastasis and tumor progression

OBJECTIVE: Adenocarcinoma of the cervix carries a worse prognosis than its squamous counterpart. In particular, tumors with lymph node metastasis have a miserably poor prognosis. Fas ligand (FasL) could allow the tumor cells to evade host immune surveillance and would thus promote tumor survival and possibly metastasis formation. We decided to compare FasL expression in cervical adenocarcinoma with lymph node status to determine whether FasL plays a role in lymph node metastases. METHODS: Using immunohistochemistry, we investigated FasL expression in sections of formalin-fixed, paraffin-embedded tissue from 24 cervical adenocarcinomas. We also studied sections of seven cases with lymph node metastases. The percentage of FasL-positive cells in each tumor was recorded. FasL expression in cervical adenocarcinoma was compared with lymph node status. Statistical analysis was performed by using the Fisher exact test and the Kaplan-Meier method. RESULTS: FasL expression was detected in 62.5% (15 of 24) of primary lesions. Significantly higher incidence of positive FasL reactivity was demonstrated in 10 of 11 tumors with lymph-vascular space (P = 0.0188), in 10 of 10 with deep stromal invasion (P = 0.0015), and in 8 of 9 cancers with lymph node metastasis (P = 0.0481). All 9 metastatic cervical adenocarcinoma in the lymph nodes showed FasL immunoreactivity in 60.7 +/- 17.7% of the metastatic cancer cells, and 7 (78%) of these had FasL immunoreactivity in greater than 50% of the cells. The survival times of patients with FasL-expressing cervical adenocarcinomas were significantly reduced compared to patients with low FasL-expressing tumors (P = 0.0018). CONCLUSIONS: These findings indicate that FasL plays an important role in immune evasion, and progression and metastasis of cervical adenocarcinoma.     

Surgical pathologic factors in patients with early-stage cervical carcinoma treated with radical hysterectomy and pelvic lymph node dissection: association with administration of adjuvant radiotherapy and effect on survival

PURPOSE OF INVESTIGATION: To identify surgical pathologic factors that best correlate with administration of adjuvant radiotherapy and best predict survival in early-stage cervical carcinoma treated with radical hysterectomy and pelvic lymph node dissection (RHND). METHODS: Data from the files of 126 patients with cervical carcinoma treated by RHND at the Soroka Medical Center from 1962 through 2005 were analyzed. RESULTS: Fifty-four percent of the patients received postoperative adjuvant radiotherapy. In a univariate analysis, each of the following factors: positive pelvic lymph nodes, lower uterine segment involvement, lymph vascular space involvement, penetration > or = 50% of the cervical wall, grade 2+3, parametrial and/or paracervical involvement, vaginal margin involvement, non-squamous histologic type, tumor size > or = 3 cm and Stage IB2 + IIA was significantly associated with administration of radiotherapy. In a multivariate analysis, positiviy of pelvic lymph nodes was persistently the most significant factor associated with administration of radiotherapy. The 5-year survival rate was 82.6% overall. In a univariate analysis, a significant worsening in survival was demonstrated with positivity of pelvic lymph nodes and positivity of lymph vascular space involvement. In a "better fit" model of multivariate analysis, pelvic lymph node status was the strongest and the only significant predictor of survival. CONCLUSIONS: In patients with early-stage cervical carcinoma treated with radical hysterectomy and pelvic lymph node dissection, pelvic lymph node status is the strongest factor affecting administration of adjuvant radiotherapy and the most significant predictor of survival.     

HPV status in sentinel nodes might be a prognostic factor in cervical cancer

OBJECTIVE: Although there have been studies that focused on the correlation between the HPV presence of pelvic lymph nodes and pathological metastasis in patients with cervical cancer, the biologic role of HPV DNA in lymph nodes still remains uncertain. We performed this study to investigate the correlation between the sentinel-node HPV status and pelvic lymph node metastasis in patients with cervical cancer. The patients were followed up for 3 years to evaluate the clinical role of HPV in sentinel nodes as a prognostic factor. METHODS: From August 2001 to July 2003, 57 patients affected by stages IB-IIA cervical cancer had sentinel-node biopsies performed during radical hysterectomy and pelvic and paraaortic lymphadenectomy. Each detected sentinel node was divided into two parts. One part of them was submitted for frozen section examination and the other was submitted for HPV typing by oligonucleotide microarray. After follow-up, we analyzed the outcome of the patients with respect to the influence of sentinel-node HPV. RESULTS: Sentinel nodes were identified in all patients. A total of 79 nodes from 57 patients were detected as sentinel nodes. Metastasis in the sentinel nodes were found in 10 patients (17.6%) by frozen section and 11 patients by pathologic examination. The results of sentinel lymph node frozen biopsy were statistically significant for predicting the metastasis of the pelvic lymph nodes (P<0.05), but showed one false-negative case. HPV DNA was detected in the cervical cancer lesions of 55 patients (96.5%) and 80.0% (44/55) of them were found to have HPV DNA in the sentinel nodes as well. HPV DNA was detected in sentinel nodes of 10 patients among 11 patients with lymph node metastasis. Disease recurred in five patients and one of them did not show pelvic lymph node metastasis at surgery. But, all of these patients had HPV in sentinel nodes. The combination of sentinel-node frozen biopsy and HPV typing showed a negative predictive value of 100% in predicting non-metastasis of lymph node and no recurrence of disease. CONCLUSION: Our results suggested the possibility that sentinel-node HPV typing could play a supportive role to reduce the false-negative rate of the sentinel-node biopsy. All of five patients with recurrence had HPV infection in the sentinel nodes. Absence of HPV in sentinel nodes showed reliable negative predictive value for lymph node metastasis and recurrence. Additional study will be needed to confirm the clinical application of the sentinel-node procedure and to determine whether there is a correlation of HPV status of sentinel nodes to lymph node metastasis and recurrence in cervical cancer patients.     

EGFR、VEGF及LRP mRNA在卵巢上皮性癌组织中的表达及其意义

目的:探讨表皮生长因子受体(epidermal growth factor receptor,EGFR)、血管内皮细胞生长因子(vascular endothelial growth factor,VEGF)和肺耐药蛋白(lung resistanceprotein,LRP)mRNA在卵巢癌的表达及意义。方法:用逆转录聚合酶链反应(RT-PCR)技术检测15例正常卵巢、13例卵巢良性肿瘤及51例卵巢上皮癌组织中EGFR mRNA、VEGF mRNA和LRP mRNA的表达,并分析它们的相关性。结果:卵巢上皮癌组织中EG-FR、VEGF和LRP阳性表达率显著高于正常卵巢及卵巢良性肿瘤组织(P<0.05);EGFRmRNA表达与卵巢上皮癌手术病理分期有关,Ⅲ~Ⅳ期的阳性表达率及表达强度高于Ⅰ~Ⅱ期(P<0.05);VEGF mRNA表达与卵巢上皮癌手术病理分期及淋巴结转移有关,Ⅲ~Ⅳ期和有淋巴结转移组的表达强度分别高于Ⅰ~Ⅱ期和无淋巴结转移组(P<0.05);LRP mRNA表达与卵巢上皮癌患者年龄、临床分期、分化程度、病理类型及淋巴结转移等临床病理参数无关(P>0.05);EGFR和VEGF基因之间(r=0.460,P<0.05)、EGFR和LRP基因之间表达显著相关(r=0.749,P<0.01)。结论:EGFR与卵巢癌血管生成和化疗耐药产生有关,可能参与了卵巢癌的发生发展,检测卵巢癌EGFR、VEGF和LRP可能对靶向化疗有指导作用。     

Expression of cyclooxygenase-2 in association with clinicopathological prognostic factors and molecular markers in epithelial ovarian cancer

OBJECTIVES: This study examines whether expression of COX-2 is associated with clinicopathological features and other molecular markers of ovarian cancer. METHODS: Sixty-four paraffin-embedded tissue specimens were obtained from patients with ovarian cancer who received cytoreductive surgery and combination chemotherapy. Tissue specimens were subjected to immunohistochemical analysis using antibodies to COX-2, p53, and VEGF. RESULTS: Increased COX-2 expression significantly correlated with histologic type (mucinous 5.6% vs. non-mucinous 65.2%, P<0.001). COX-2 expression was also significantly associated with stage, tumor grade, residual disease status, and presence of ascites. COX-2 expression correlated positively with expression of p53 (P=0.006) and VEGF (P=0.025). Although survival was lower in patients with high COX-2 expression than in those without high COX-2 expression (P<0.001), only tumor grade and stage were independent prognostic indicators. In patients with non-mucinous cancer, COX-2 expression correlated with stage (P<0.001) and presence of ascites (P=0.033). CONCLUSIONS: Our results suggest that expression of COX-2 in ovarian cancers is specific to histologic type of tumor and is associated with poor clinicopathologic prognostic factors. Expression of COX-2 also correlates well with expression of p53 and VEGF.