Expression of matrix metalloproteinases in patients with uterine smooth muscle tumors: an immunohistochemical analysis of MMP-1 and MMP-2 protein expression in leiomyoma, uterine smooth muscle tumor of uncertain malignant potential, and leiomyosarcoma

OBJECTIVE: Matrix metalloproteinases (MMPs) have been suggested to play an important role in tumor invasion and metastasis. We compared the expression of MMP-1 and MMP-2 protein in patients with leiomyoma, uterine smooth muscle tumor of uncertain malignant potential (STUMP), and leiomyosarcoma (LMS). METHODS: MMP-1 and MMP-2 expression was investigated by immunohistochemistry from paraffin-embedded tissue in 26 patients with leiomyoma, in 24 patients with STUMP, and in 21 patients with LMS. RESULTS: MMP-1 was expressed in 92% of leiomyomas, in 83% of STUMP, and in 86% of LMS, whereas MMP-2 was expressed in 12% of leiomyomas, in 17% of STUMP, and in 48% of LMS. A statistically significant difference regarding the frequency of MMP-2 expression was observed between LMS and STUMP (P =.025) as well as between LMS and leiomyoma (P =.006), but not between STUMP and leiomyoma (P >.05). Likewise, the staining intensity did significantly differ between LMS and leiomyoma (P =.025), but no statistical significant difference was observed between LMS and STUMP (P >.05) and between STUMP and leiomyoma (P >.05). CONCLUSION: The stronger MMP-2 expression in patients with LMS compared with STUMP and leiomyoma indicates that this protein might be a marker for tumor invasion or metastasis in patients with uterine LMS. Furthermore, MMP-2 seems to be a useful immunohistochemical parameter to distinguish cases of smooth muscle tumors in which histologic features are ambiguous or borderline. Further studies including larger numbers of patients are necessary to establish MMP-2 as a routine marker for tumor invasion and progression.     

Ki-67 and vascular endothelial growth factor expression in uterine leiomyosarcoma

OBJECTIVE: Uterine leiomyosarcomas (LMS) are rare female neoplasms of high malignant potential. The importance of different prognostic parameters in these malignancies remains controversial. The aim of the present study was to evaluate the prognostic value of Ki-67 and vascular endothelial growth factor (VEGF) in uterine LMS. METHODS: Ki-67 and VEGF expression was assessed using immunohistochemistry from paraffin-embedded tissue in 20 patients with uterine LMS. RESULTS: Ki-67 was expressed in 10 of 20 cases (50%) of uterine LMS. A statistically significant positive correlation was observed between vascular space involvement and Ki-67 expression (P = 0.05). There was no statistically significant relationship between Ki-67 expression and clinical stage (P = 0.38), recurrent disease (P = 0.86), and age (P = 1.0). An expression of VEGF could be observed in 1 of 20 (5%) cases. The median disease-free survival was 13 months (range: 3-23 months). Eleven (55%) patients died of the disease with a median overall survival of 47.4 months (range: 1-227 months), resulting in a 5-year-overall survival rate of 45%. In a univariate analysis a statistically significant shortened disease-free survival in patients with Ki-67 positive tumors could be observed (P = 0.01). CONCLUSIONS: Our results suggest that the significant expression of Ki-67 in uterine LMS, correlating with vascular space involvement and being associated with a shortened disease-free survival, may be an indicator of the biological aggressiveness of these rare tumors.     

Evaluating prognostic parameters in women with uterine leiomyosarcoma. A clinicopathologic study

OBJECTIVE: To evaluate the prognostic impact of different clinicopathologic parameters in patients with uterine leiomyosarcoma. STUDY DESIGN: Twenty-one patients with histologically proven uterine leiomyosarcoma were included in the analysis. Leiomyosarcomas were defined as uterine smooth muscle tumors with > or = 5 mitoses per 10 high-power fields and nuclear atypia and/or necrosis. RESULTS: The median follow-up time was 47 months; 5-year overall survival was 41%. A univariate Cox model revealed that early tumor stage (P = .00001), age at diagnosis < 50 years (P = .02), absence of vascular space involvement (P = .04), low myometrial invasion (P = .006) and low histologic grade (P = .04) were associated with lengthened overall survival. Adjuvant radiotherapy and/or chemotherapy (P = .1) did not influence overall survival. CONCLUSION: Early tumor stage, age at diagnosis < 50 years, absence of vascular space invasion, low myometrial invasion and low histologic grade were parameters of a good prognosis in women with uterine leiomyosarcoma. Adjuvant chemotherapy and/or radiotherapy showed no benefit in these patients.     

Expression of thrombospondin 1 (TSP 1) in patients with uterine smooth muscle tumors: an immunohistochemical study

OBJECTIVE: Angiogenesis is an essential component for tumor development regulated by both proangiogenic and antiangiogenic factors. Thrombospondin 1 (TSP 1) suppresses angiogenesis by inhibiting endothelial cell proliferation and inducing endothelial cell apoptosis. The aim of this study was to compare the expression of TSP 1 in cases with leiomyoma, uterine smooth muscle tumor of uncertain malignant potential (STUMP) and leiomyosarcoma (LMS). Furthermore, we evaluated the prognostic relevance of TSP 1 in uterine LMS. METHODS: TSP 1 expression was investigated by immunohistochemistry from paraffin-embedded tissue in 26 patients with leiomyoma, in 24 patients with STUMP and in 21 patients with LMS. Standard immunohistochemical techniques were used to study the expression of TSP 1 in 5-mum-thick tumor sections. TSP 1 expression was correlated with survival using the Kaplan-Meier method and log-rank test for univariate analysis. RESULTS: TSP 1 was expressed in 77% of leiomyomas, in 13% of STUMP and in 24% of LMS. A statistically significant difference regarding the frequency of TSP 1 expression was observed between leiomyoma and LMS (P < 0.05) as well as between leiomyoma and STUMP (P < 0.05), but not between LMS and STUMP (P > 0.05). Furthermore, a statistically significant correlation between vascular space involvement and TSP 1 expression was observed in patients with uterine LMS, with patients without vascular space involvement having more frequently TSP 1 positive tumors (P = 0.04). No statistically significant correlation between TSP 1 and clinical stage, age and recurrence disease could be detected (P > 0.05). CONCLUSIONS: We found that TSP 1 was more frequently expressed in leiomyoma compared to STUMP and LMS. Additionally, the statistically significant negative correlation between vascular space involvement and TSP 1 expression in patients with uterine LMS shows that TSP 1 might work as a predictive factor in patients with LMS. Further clinical studies are necessary to prove our results and to clarify the role of TSP 1 in uterine smooth muscle tumors.     

Bcl-2 receptor expression in patients with uterine smooth muscle tumors: an immunohistochemical analysis comparing leiomyoma, uterine smooth muscle tumor of uncertain malignant potential, and leiomyosarcoma

OBJECTIVE: Bcl-2 protein is an apoptosis-inhibiting gene product that prevents the normal course of apoptotic cell death in a variety of cells. Additionally, bcl-2 can promote cell replication by reducing the requirement for growth factors. This protein seems, therefore, to play an important role in the growth of tumors. Our aim was to investigate the different expression of bcl-2 in uterine leiomyomas, smooth muscle tumors of uncertain malignant potential (STUMP), and leiomyosarcomas (LMS). Furthermore, the correlation between bcl-2 expression and various clinicopathologic parameters in leiomyosarcomas was assessed to evaluate its prognostic value. METHODS: This study included 26 cases of leiomyoma, 22 cases of STUMP, and 21 cases of LMS of the uterus. Bcl-2 expression was investigated by immunohistochemistry from paraffin-embedded tissue. The immunohistochemical findings were compared and correlated with different clinicopathologic parameters. Clinical information, including follow-up data, was obtained from the database of the Department of Gynecology and Obstetrics. RESULTS: Bcl-2 was present in 12 of 21 LMS, eight of 22 STUMP, and 20 of 25 leiomyomas. Significant differences regarding the frequency of bcl-2 expression and the staining intensity were observed between LMS and leiomyoma as well as between STUMP and leiomyoma (P <.05) but not between LMS and STUMP (P >.05). Regarding the outcome of uterine LMS, patients with bcl-2 positive tumors showed less vascular space involvement and longer overall survival (P <.05). CONCLUSION: Bcl-2 was expressed more frequently and more strongly in leiomyomas compared with LMS and STUMP. Regarding the outcome of uterine LMS, patients with bcl-2-positive tumors showed less vascular space involvement and longer overall survival. The stronger bcl-2 expression in benign leiomyomas and the better clinical outcome of bcl-2-positive LMS indicate that this protein seems to act as a good prognostic factor. Further studies including larger numbers of patients are necessary to establish bcl-2 as a routine marker for improved prognosis in malignant uterine smooth muscle tumors.     

Expression of vascular endothelial growth factors (VEGF-A/VEGF-1 and VEGF-C/VEGF-2) in postmenopausal uterine endometrial carcinoma

OBJECTIVE: We investigated the expression of two angiogenic vascular endothelial growth factors, VEGF-A/VEGF-1 and VEGF-C/VEGF-2, in 228 cases of uterine endometrial carcinomas from postmenopausal patients to evaluate the correlation with histopathologic features and clinical outcome. METHODS: Immunohistochemistry was used to assess VEGF-A/VEGF-1 and VEGF-C/VEGF-2 expression in 228 primary surgically treated cases of postmenopausal endometrial carcinomas and the results were statistically analyzed in relation to vascular invasion, depth of invasion (myometrial vs serosal-parametrial invasion), lymphatic vessel invasion, lymph node metastasis, disease-free 5-year survival rate (DF5YR), and disease-free 10 year-survival rate (DF10YR). RESULTS: The results of univariate analysis showed that VEGF-A/VEGF-1 and VEGF-C/VEGF-2 expression correlated with vascular invasion (P < 0.0001, P = 0.0006), depth of invasion (P = 0.0004, P = 0.043), lymphatic vessel invasion (P = 0.021, P < 0.0001), lymph node metastasis (P = 0.0017, P = 0.0008), DF5YR (P = 0.0081, P = 0.0002), and DF10YR (P = 0.0077, P = 0.0001). Multivariate analysis showed that lymph node metastasis (P = 0.0017, P = 0.0008), parametrial-serosal invasion (P < 0.0001, P < 0.0001), and VEGF-C/VEGF-2-positive status (P = 0.03, P = 0.01) were significant factors in DF5YR and DF10YR. CONCLUSIONS: We conclude that VEGF-A/VEGF-1 and VEGF-C/VEGF-2 expression was predictive of these histopathologic features of endometrial carcinoma and clinical outcome.     

Endometrial tumor invasiveness is related to metalloproteinase 2 and tissue inhibitor of metalloproteinase 2 expressions

Matrix metalloproteinase (MMPs) expression has been linked to gynecological tumor aggressiveness. The objective of this study was to determine MMP-2, MMP-7, and MMP-9 and tissue inhibitors of metalloproteinases (TIMP)-1 and TIMP-2 expression in endometrial malignancies and their relation to clinical and histologic parameters. Formalin-fixed, paraffin-embedded tumor samples from 50 patients with endometrial carcinoma treated between 1999 and 2004 were stained with specific monoclonal antibodies. The tumors were grouped according to the FIGO classification. The staining results were compared to histologic and clinical data. Semiquantitative analysis of MMP and TIMP expression showed a significant difference in TIMP-2 expression according to the histologic subtype (P = 0.03) and also a trend towards a difference in MMP-9 expression (P = 0.05). MMP-2 expression increased and TIMP-2 expression fell as the histologic grade increased (P = 0.0007, P < 0.0001, respectively). MMP-2 expression correlated with lymph node metastasis (P = 0.04), while TIMP-2 expression correlated with the depth of myometrial invasion (P = 0.01), vasculolymphatic space involvement (P = 0.02), and lymph node metastasis (P = 0.0003). These results support the involvement of MMPs and TIMPs in endometrial tumor growth and progression. High MMP-2 and low TIMP-2 expression were the most potent markers of endometrial tumors with a high risk of local and distant spread.     

Prognostic significance of stromal metalloproteinase-2 in ovarian adenocarcinoma and its relation to carcinoma progression

OBJECTIVES: MMP-2 expression in ovarian cancer cells has been correlated with poor prognosis. This study attempts to assess the prognostic importance of stromal MMP-2 in patients with ovarian endometrioid and serous adenocarcinoma. METHODS: MMP-2, MMP-2 activator, MT1-MMP, and its inhibitor (TIMP-2) were immunostained in 84 primary epithelial ovarian carcinomas (EOCs) (35 endometrioid adenocarcinomas [ECs] and 49 serous adenocarcinomas [SCs]). Results were correlated to pathological subtypes, tumor stage, grade, size, and to recurrence-free and cancer-specific survival. RESULTS: MMP-2 and stromal MMP-2 were detected in all carcinoma cells of 22.2% of EC and 77.8% of SC tumors. MT1-MMP co-localized with MMP-2. TIMP-2 staining was weak and cytoplasmically distributed in all tumors. Univariant analysis showed expression of stromal MMP-2 significantly associated with advanced stage (P = 0.018), higher grade (P = 0.005), serous subtype (P = 0.02), smaller tumor size at operation (P = 0.001), and higher incidence of recurrence (P = 0.042), but not with the rate of death due to cancer. By multiple Cox proportional hazard regression analysis, patient survival and disease-free survival were significantly related to the presence of stromal MMP-2 in EC but not SC patients (P < 0.05). However, after multivariant analysis, the associations with patient age, tumor stage, grade, and size no longer existed. In stepwise selection, tumor stage remained the most important predictor of patient survival and disease-free survival in ovarian EC and SC, but stromal MMP-2 remained the most important predictor of recurrence-free survival in patients with EC. CONCLUSIONS: Stromal MMP-2 occurs early and may play a role early in EOC invasion. Tumor stage and stromal MMP-2 are important predictors of disease-free survival.     

Leiomyosarcoma of the uterus: a clinicopathologic study of 21 cases

BACKGROUND: The purpose of the present study was to identify the prognostic factors of and to determine the most appropriate mode of treatment for uterine leiomyosarcoma. METHODS: We reviewed the hospital records, including surgical notes and pathologic reports, of 21 patients with uterine leiomyosarcoma treated at Chang Gung Memorial Hospital, Kaohsiung, Taiwan, between 1987 and 1997. Univariate analysis was performed using the log-rank test. Cox regression was used to identify independent prognostic factors. RESULTS: The mean follow-up time was 30 months, and the 5-year disease-free survival rate was 55%. Evaluating the correlation between clinicopathologic parameters and survival, early stage (p = 0.0002), tumor cells without necrosis (p = 0.0026), low-grade tumor (p = 0.015), absence of vascular space involvement (p = 0.006), and tumor without atypia (p = 0.016) were associated with good prognosis. However, in a multivariate analysis using the Cox model, only advanced stage (p = 0.032) and tumor necrosis (p = 0.032) were found to be independent poor prognostic factors. The 5-year disease-free survival was only 21% in patients with the presence of any one or both of these two factors. Five of 11 patients in this group had received aggressive adjuvant therapy after surgery, and none of them survived more than 19 months. CONCLUSIONS: We found that patients with advanced stage or presence of tumor necrosis had an extremely poor prognosis. Adjuvant therapy seemed to play a limited role, and provided no survival benefit. Treatment for these patients should be palliative until effective therapeutic modalities prove otherwise.     

Expression of p16 protein in patients with uterine smooth muscle tumors: an immunohistochemical analysis

OBJECTIVE: The loss of cell cycle control is a critical step in the development of neoplasia. The p16 protein has been identified as a tumor suppressor protein, which binds specifically to the cyclin-dependent kinase CDK-4, inhibiting the catalytic activity of the CDK4-cyclin D complex, and thereby acts as a negative cell cycle regulator. In the present study, we compared the expression of p16 protein in cases with leiomyoma, uterine smooth muscle tumor of uncertain malignant potential (STUMP), and leiomyosarcoma (LMS). METHODS: P16 expression was investigated by immunohistochemistry from paraffin-embedded tissue in 26 patients with leiomyoma, in 24 patients with STUMP, and in 21 patients with LMS. RESULTS: P16 was expressed in 12% of leiomyomas, in 21% of STUMP, and in 57% of LMS. A statistically significant difference regarding the frequency of p16 protein expression was observed between LMS and STUMP (P < 0.05) as well as between LMS and leiomyoma (P < 0.05), but not between STUMP and leiomyoma (P > 0.05). Likewise, the staining intensity did significantly differ between LMS and leiomyoma and between LMS and STUMP (P < 0.05), but no statistical significant difference was observed between STUMP and leiomyoma (P > 0.05). No statistically significant correlation between p16 expression and clinical stage, age, vascular space involvement, and recurrence disease could be found in patients with LMS (P > 0.05). Additionally, the overall survival did not significantly differ between p16-positive and p16-negative cases (P > 0.05). CONCLUSIONS: We found that p16 was more frequently and more strongly expressed in LMS compared to STUMP and leiomyoma. We therefore concluded that p16 might play an important role in sarcomagenesis. Furthermore, p16 might be a useful immunohistochemical marker, which could help to distinguish cases of smooth muscle tumors in which histologic features are ambiguous or borderline, but the use of p16 in a diagnostic setting should await further clinical studies and clarification of the mechanisms.     

Surgical resection of pulmonary and extrapulmonary recurrences of uterine leiomyosarcoma

OBJECTIVE: The objective was to determine long-term survival and predictors of outcome in a retrospective cohort of patients who underwent surgical resection of recurrent uterine leiomyosarcoma (LMS). METHODS: Between January 1991 and March 2001, 41 patients who underwent surgical resection for recurrent uterine leiomyosarcoma were identified. The records of these patients were reviewed and abstracted data included patient age, date of initial diagnosis, tumor histology and grade, residual tumor after all operations, the use of adjuvant therapy, dates and sites of all recurrences, and disease status at last follow-up. Survival was determined from the time of first recurrence to last follow-up. Survival curves were estimated using the Kaplan-Meier method and P values were generated using the likelihood ratio test from the Cox proportional hazards model and chi(2) analysis. RESULTS: Forty-one patients with recurrent uterine LMS (17 local pelvic, 18 distant, 6 both) underwent surgical resection at time of first recurrence. A thoracic procedure alone was performed in 13 cases. Information on residual disease was available for 37 patients. The disease-specific 2-year survival for all 41 patients was 71.2% (95% CI: 58.1, 87.3). In univariate analysis, time to first recurrence and optimal resection were significantly associated with longer overall survival. CONCLUSION: Optimal surgical resection for recurrent uterine leiomyosarcoma may provide an opportunity for long-term survival in a select patient population. Time to first recurrence and optimal surgical resection were predictors of improved outcome in this study.     

Improved survival with an intact DNA mismatch repair system in endometrial cancer

OBJECTIVE: To correlate survival and surgical-pathologic factors with DNA mismatch repair status in patients with endometrial cancer. METHODS: Specimens from 336 patients with endometrial cancer were used to create a tissue microarray. Immunohistochemistry with antibodies against the mismatch repair genes MLH1, MSH2, MSH6, and PMS2 were used to stain the tissue microarray. Clinical, pathologic, and survival data were collected and correlated with the immunohistochemistry results. RESULTS: Mismatch repair deficiency was seen in 29% (84 of 294) of cases. Correlation was noted between lack of expression of MLH1 and an increased risk for lymphvascular space involvement (32% versus 21%, P=.05) and cervical involvement (26% versus 14%, P=.02). Lack of expression of either MLH1 or MSH2 was associated with thinner patients (85% had a body mass index less than 40 versus 73% of patients with normal expression, P=.02), as well as with the absence of a history of previous primary malignancy (0 verus 13 cases [4%], P=.023). The estimated disease-free survival is 88%; despite a small number of recurrences, there was a nonsignificant improvement in disease-free survival in tumors with an intact mismatch repair system (P=.1). Significantly improved disease-free survival was seen in patients with normal MLH1 and MSH2 expression compared with those with abnormal expression (92% versus 81%, P=.035). CONCLUSION: Defects in DNA mismatch repair in endometrial cancer is correlated with negative prognostic factors and worse progression-free survival (without a difference in overall survival) compared with tumors with an intact mismatch repair system. LEVEL OF EVIDENCE: II-3.     

MMP-2 and TIMP-2 expression correlates with poor prognosis in cervical carcinoma--a clinicopathologic study using immunohistochemistry and mRNA in situ hybridization.

OBJECTIVE: The spread of malignant neoplasms is closely associated with matrix and basement membrane degradation, mediated by various classes of proteolytic enzymes. Matrix metalloproteinases (MMP) appear to have a key role in the sequence of events that lead to local invasion and metastasis. The present study evaluated the role of matrix metalloproteinase-2 (MMP-2), tissue inhibitor of metalloproteinases-2 (TIMP-2), and membrane-type metalloproteinase (MT1-MMP) in cervical neoplasia. METHODS: We have analyzed 49 uterine cervical squamous cell carcinomas, 10 cases of high-grade cervical intraepithelial neoplasia (CIN II-III), and 10 control cervices for the presence of MMP-2, TIMP-2, and MT1-MMP using in situ hybridization. MMP-2 protein expression was evaluated using immunohistochemistry. Results were analyzed for possible correlation with disease outcome. RESULTS: MMP-2, TIMP-2, and MT1-MMP mRNA were localized to both stromal and tumor cells. However, an intense signal for MMP-2 was detected almost exclusively in tumor cells and was uniformly absent from CIN lesions and control cervices. Conversely, intense signals for TIMP-2 and MT1-MMP were detected in both stromal and tumor cells of invasive carcinomas, more often for the former. As with MMP-2, they were absent from CIN lesions. MMP-2 protein expression was enhanced in tumor cells compared to CIN cases and controls, significantly compared to the latter (P = 0.01). The presence of both MMP-2 and TIMP-2 mRNA in tumor cells correlated with advanced stage (P = 0.003 for MMP-2, P = 0.002 for TIMP-2) and with poor survival (P = 0.003 for MMP-2, P = 0.002 for TIMP-2) in univariate analysis. In addition, their presence in tumor cells intercorrelated (P = 0.002). In multivariate survival analysis, MMP-2 presence retained its association with survival (P = 0.004), in addition to patient age (P = 0.027) and advanced stage (P = 0. 0002). CONCLUSIONS: Both MMP-2 and TIMP-2 have a key role in extracellular matrix invasion in cervical carcinoma, largely through their elaboration by tumor cells. The presence of mRNA for both proteins is interrelated and is associated with poor survival.     

Expression of latent matrix metalloproteinase 9 (MMP-9) predicts survival in advanced ovarian cancer

OBJECTIVE: Matrix metalloproteinases (MMPs) are frequently expressed in malignant tumors and play an important role in tumor invasion and metastasis. MMP-2 and MMP-9 expression has been correlated with poor survival in some tumors, but data for ovarian cancer are lacking, despite clinical trials with MMP inhibitors. The aim of this study was to assess activity of MMP-2 and MMP-9 and correlate it to prognosis in ovarian cancer. METHODS: MMP-2 and MMP-9 gelatinolytic activity was analyzed in 84 patients with advanced ovarian cancer FIGO stage III and 19 benign ovarian tumors by gelatin zymography. MMP-9 immunoreactivity was detected by immunohistochemistry and gelatinolytic activity was localized in ovarian cancer tissue by in situ zymography. RESULTS: were correlated with patient survival, with a median follow-up period of 55 months. Results. Median pro-MMP-9 activity was at 0.00 U/microg protein in benign ovarian tissues and 4.82 U/microg protein in ovarian cancer (P = 0.001); activated MMP-9 was not detected. Pro-MMP-2 expression in benign ovarian tissue did not differ from that of malignant ovarian tissue, whereas active MMP-2 was present in 52% of ovarian cancers, but absent in benign ovarian tissues. Analyzing all patients high pro-MMP-9 activity was associated with short overall survival (P = 0.019) while pro-MMP-2 and activated MMP-2 did not predict overall survival. When analyzing the subgroups of patients with and without residual tumor mass at the time of surgery, pro-MMP-9 was of prognostic value only in the subgroup of patients with no residual tumor mass. In univariate analysis pro-MMP-9 activity, residual tumor mass, age, ascites volume, and grading were of prognostic significance for overall survival. However, in multivariate analyses, including all biological and clinicopathologic variables, only pro-MMP-9 and residual disease remained statistically independent prognostic factors. In situ zymography localized gelatinolytic activity predominantly to the tumor cell nests displaying MMP-9 immunoreactivity. CONCLUSIONS: Pro-MMP-9 gelatinolytic activity, but not active MMP-2 or MMP-9, serves as a useful statistically independent prognostic factor in ovarian cancer FIGO stage III, thus helping to identify ovarian cancer patients with an aggressive form of the disease.     

A comparison of prognoses of FIGO stage IB adenocarcinoma and squamous cell carcinoma

OBJECTIVES: The objective of this study was to compare clinical and pathologic variables and prognosis of FIGO stage IB adenocarcinoma and squamous cell carcinoma of uterine cervix. METHODS: A retrospective review was performed of 521 patients with stage IB squamous cell carcinoma and adenocarcinoma of cervix who treated primarily by type 3 hysterectomy and pelvic and/or para-aortic lymphadenectomy at Hacettepe University Hospitals between 1980 and 1997. RESULTS: Age, tumor size, grade, depth of invasion, lymph node metastasis, parametrial, vaginal, and lymphvascular space involvement (LVSI) were not different between two cell types except number of the lymph nodes involved. Metastasis to three or more lymph nodes was significantly higher in adenocarcinoma. Overall and disease-free survival were 87.7%, 84.0% versus 86.4%, 83.1% for squamous cell carcinoma and adenocarcinoma, respectively (P > 0.05). The rate and site of recurrence were not different between two cell types. Multivariate analysis of disease-free and overall survival revealed independent prognostic factors as tumor size, LVSI, number of involved lymph node, and vaginal involvement. CONCLUSION: Prognosis of FIGO stage IB cervical cancer patients who were treated by primarily radical surgery was found to be same for those with adenocarcinoma and squamous cell carcinoma.     

早期子宫颈鳞癌盆腔淋巴结转移的影响因素

目的 探讨早期(Ⅰ b～Ⅱa期)宫颈鳞癌盆腔淋巴结转移的影响因素.方法 回顾性分析2004年2月-2007年1月在浙江大学医学院附属妇产科医院接受治疗、资料完整的135例早期宫颈鳞癌患者的临床病理资料.选择10个非重复的特征性因素,包括患者年龄、临床期别、肿瘤直径、病理分化程度、深肌层浸润、脉管浸润、治疗前血清鳞状细胞癌抗原水平,以及治疗前血小板数量、血浆纤维蛋白原和血红蛋白水平,通过单因素和多因素分析研究这些特征性因素与盆腔淋巴结转移之间的关系.结果 135例宫颈鳞癌患者中,术后病理检查证实共切除盆腔淋巴结3996枚,平均每例29.6枚(20～47枚).其中,病理检查证实盆腔淋巴结转移的患者有17例,盆腔淋巴结转移率为12.6%(17/135).单因素分析结果 显示,肿瘤直径(P=0.003)、深肌层浸润(P=0.004)、脉管浸润(P<0.01)、血小板数量(P=0.006)、血浆纤维蛋白原水平(P<0.01)是与盆腔淋巴结转移明显相关的因素.多因素分析结果 显示,脉管浸润(OR=3.674,95%CI:1.825～7.393,P<0.01)和血浆纤维蛋白原水平(OR=4.568,95%CI:1.779～11.725,P=0.002)是与盆腔淋巴结转移明显相关的因素.结论 脉管浸润和高血浆纤维蛋白原水平是影响早期宫颈鳞癌患者盆腔淋巴结转移的高危因素.     

Expression of gelatinase (MMP-2 and MMP-9) and cyclooxygenase-2 (COX-2) in endometrial carcinoma

OBJECTIVE: Matrix metalloproteinases (MMPs) are key players in the degradation of extracellular matrix and basement membranes, and are thus important in tumor invasion. Gelatinases (MMP-2 and MMP-9) in particular are prognostic factors in many solid tumors. In this study the immunohistochemical expression of both COX-2 and matrix metalloproteinases has been shown for the first time in endometrium carcinoma. METHODS: Forty-two endometrial carcinoma tissues were immunostained for MMP2 antibody (1:100, Rabbit polyclonal), MMP9 antibody (1:100, Rabbit polyclonal) and CoX2 antibody (1:100, Epitope specific rabbit antibody). RESULTS: 90.5% of the cases were positive for MMP-2 and MMP-9, and 83.3% of the cases were positive for COX-2. A statistically significant association was found between COX-2 overexpression and FIGO stage (p = 0.001). A positive correlation was also found with histological grade (p = 0.006), myometrial invasion (p = 0.033), vascular invasion (p = 0.017), and lymphatic invasion (p = 0.007). A positive correlation was found between MMP-2 overexpression and vascular and lymphatic invasion (p = 0.030 and p = 0.003, respectively). MMP-9 overexpression was also found to be correlated with vascular and lymphatic invasion (p = 0.001 and p = 0.012, respectively). Furthermore, there was a statistically significant correlation between MMP-2 and MMP-9 overexpression (p = 0.0001). CONCLUSION: The results showed that COX-2, MMP-2 and MMP-9 were expressed in a high percentage of primary endometrial carcinomas and their expressions may be associated closely with parameters of tumor aggressiveness.     

MMP-1 and MMP-2 in the cervix uteri in different steps of malignant transformation--an immunohistochemical study.

OBJECTIVES: Enzymatic degradation of the extracellular matrix (ECM) represents a key element in the multistage process of tumor invasion and metastasis. This process requires extensive degradation of ECM components such as basement membrane collagen (type IV) and interstitial collagen (type I, II, III). Matrix metalloproteinase-2 (MMP-2) specifically cleaves collagen type IV, the major collagen of the basement membrane. MMP-1 digests interstitial collagen type I and III, the main collagen types of the stromal extracellular matrix. We investigated protein levels of MMP-1 and MMP-2 in different stages of malignant transformation. METHODS: Using the APAAP method we analyzed 10 normal cervical tissues, 11 cervical intraepithelial neoplasia 1 (CIN 1), 8 CIN 2 and 10 CIN 3 lesions, and 15 invasive squamous cell carcinomas. These data were compared with the HPV DNA status tested by hybrid capture II. RESULTS: Only a few isolated epithelial cells stained positively for MMP-1 and MMP-2 in normal cervical tissue and CIN 1 lesions. The CIN 2 and CIN 3 group displayed a heterogeneous distribution of MMP expression. 3 CIN 2 and 8 CIN 3 lesions showed strong MMP-2 and weak MMP-1 expression in the dysplastic epithelial cells. 5 CIN 2 and 2 CIN 3 lesions stained negatively. Invasive carcinomas showed a coexpression for MMP-1 and MMP-2 in malignant epithelial cells and peritumoral stroma cells. All MMP-2-positive cases tested positive for the HPV high-risk group. CONCLUSIONS: The expression of MMP-2 protein in preinvasive lesions of the cervix uteri and a consecutive coexpression of MMP-1 and MMP-2 in invasive cancer suggest a gradually increasing invasive potential. MMP-2 expression, when focally observed in high-grade squamous intraepithelial lesions of the cervix, may indicate tumor areas with an increased risk for invasive growth.     

Prognostic factors and impact of adjuvant chemotherapy for uterine leiomyosarcoma

OBJECTIVE: The aim of this study was to investigate prognostic factors and impact of adjuvant therapy for uterine leiomyosarcoma (LMS). METHODS: All cases with uterine LMS were retrieved from medical registry (1984 through 2003) of Chang Gung Memorial Hospital. After excluding cases with initial surgery at outside the hospital, missing chart, and wrong pathologic diagnosis, 51 patients (41 for stage I, 7 for stage III, and 3 for stage IV) met the study criteria. Approximate stratified analysis and Cox proportional hazards model were used to adjust confounding factors. RESULTS: The median follow-up for survivors was 47 months. Five-year overall survival and recurrence-free survival (RFS) rates were 67.4% and 59.2% for the whole series. Multivariate Cox regression analyses selected age (>50 versus < or =50 years: relative risk [RR], 11.07 [95% CI 1.53-80.34]), tumor size (>11 versus < or =11 cm: RR, 11.63 [95% CI 2.14-63.12]), stage (III and IV versus I: RR, 21.24 [95% CI 2.20-204.98]), and adjuvant chemotherapy (yes versus no: RR, 0.08 [95% CI 0.01-0.81]) as significant predictors of death. Besides, surgical stage (P = 0.021), tumor size (P = 0.005), and adjuvant chemotherapy (P = 0.011) were significantly correlated with RFS. After approximate stratification, the use of adjuvant chemotherapy also significantly decreased RR of death. CONCLUSIONS: This is the first report to demonstrate benefit of adjuvant chemotherapy for LMS despite the limitation of sample size and its retrospective nature. Prospective multicenter trials are necessary to clarify the role of chemotherapy, selecting criteria, and optimal chemotherapy regimen for uterine LMS.     

Nm23 expression in node-positive and node-negative endometrial cancer.

OBJECTIVE: To examine the relationships between the expression of protein Nm23 and surgical stage, histologic grade, histopathologic findings, and survival in women with endometrial carcinoma. METHODS: 19 patients with lymph node involvement were matched with 24 patients without lymph node involvement and the best paraffin-embedded blocks were selected for Nm23 immunohistochemical staining. The slides were evaluated semiquantitatively according to their degree of cytoplasmic staining. Statistical analysis was performed to determine whether there was a relationship between Nm23 expression and surgical stage, histologic grade, depth of myometrial invasion, lymph node metastasis, and/or lymphovascular space involvement. Survival analysis was also performed. RESULTS: Slides from 15 patients (79%) with lymph node involvement and 22 patients (88%) without lymph node involvement were found to be positive for Nm23 (P=0.01). No significant relations were observed between Nm23 expression and surgical stage, histologic grade, depth of myometrial invasion, or lymphovascular space involvement. Nm23 expression was found to be significantly related to lower rates of lymph node metastasis and longer survival (P=0.02). CONCLUSION: Elevated Nm23 expression is related to lower rates of lymph node metastasis and longer survival.