Intratumoral Blood Flow Analysis in Endometrial Cancer: Does It Differ among Individual Tumor Characteristics?

To evaluate whether intratumoral blood flow analysis in endometrial cancer provides individual tumor characteristics, 36 patients with endometrial cancer (5 in stage IA, 14 in stage IB, 5 in stage IC, 4 in stage II, and 8 in stage III) underwent transvaginal color and pulsed Doppler ultrasound before surgery. Histologically, there were 18 patients with well-differentiated adenocarcinoma, 8 with moderate differentiated adenocarcinoma, 4 with poorly differentiated adenocarcinoma, 4 with adenoacanthoma, and 2 with carcinosarcoma. Intratumoral blood flow was recorded, and peak systolic velocity (PSV) and resistance index (RI) were calculated. Endometrial thickness (ET) was also measured. There were no significant differences among PSV and RI values for each stage. There were also no significant differences among PSV and RI values for each histological diagnosis. ET in stages IA, IB, and II was significantly thinner than that in stage III (P< 0.05). Moreover, ET in stage IA was significantly thinner than that in stage IC (P< 0.05). There were significant differences in ET for some histological diagnoses. These results suggest that intratumoral blood flow analysis in endometrial cancer could not predict the tumor staging and histological diagnosis. However, in view of the small number of patients, these observations must be considered preliminary.     

Intratumoral color Doppler analysis in endometrial carcinoma: is it clinically useful?

OBJECTIVE: The aim was to study the effectiveness of subjective color Doppler evaluation and spectral Doppler parameters in preoperative characterization of endometrial carcinomas. METHODS: Seventy-six patients with endometrial carcinoma were preoperatively analyzed by color Doppler ultrasound in order to subjectively evaluate the amount of intratumoral blood flow (color score) and to analyze the lowest resistance index (RI), the highest peak systolic velocity (PV), and the highest time averaged maximum velocity (TAMVX). These parameters were analyzed according to clinico-pathological characteristics. RESULTS: In 13 patients no intratumoral arterial vessels were detected by color Doppler examination. No lymph node metastases were found in this group of patients. Positive nodes were found in 24% of patients with detectable arterial vessels, although the difference did not reach the statistical significance. No differences were found in spectral Doppler parameters (RI, PV, TAMVX) according to tumor characteristics or nodal involvement. A higher percentage of cases with a color score of 3 was found in stage >I than in stage I patients (69 vs 42%, P < 0.05), and in patients with myometrial invasion greater than 50% than in those with less than 50% invasion (72 vs 38%; P = 0.05). CONCLUSIONS: Nodal metastases were found in 24% of patients with detectable vessels at color Doppler examination. Subjective analysis of vessel density correlated >50%, myometrial invasion, but spectral Doppler analysis was not predictive of surgical stage, tumor grade, myometrial invasion, or lymph node metastases. These results do not support the use of preoperative intratumoral blood flow analysis as a clinical test in evaluating tumor characteristics or in predicting lymph node metastases.     

The relationship between mutant p53 gene, DNA contents and conventional clinicopathological prognostic variables in cases with endometrial carcinoma

PURPOSE OF INVESTIGATION: To determine whether p53 expression and DNA ploidy are related to traditional prognostic indicators in patients with endometrial cancer. METHODS: Tumor material (n=136) was analyzed regarding flow cytometric DNA ploidy and immunohistochemical p53 expression. Pearson's correlation, Fisher's exact test, Cox's regression analysis and the Kaplan-Meier survival test were used, as appropriate. RESULTS: P53 overexpression and DNA ploidy were higher in patients with nonendometrioid histology, FIGO advanced stage, poor grade, positive peritoneal cytology, lymphovascular space invasion (LVSI) and lymph node involvement (LNI). Histologic subtype, stage, grade, LVSI, LNI, tumor recurrence and overall survival rate correlated with p53 and DNA ploidy. No association of depth of myometrial invasion and age with p53 and DNA ploidy was observed. P53 was related to DNA ploidy. Of the factors analyzed, histologic subtype and myometrial invasion were found to be most important independent determinants of recurrence. Utilizing survival as the endpoint for multivariate analysis, when considering p53 and DNA ploidy together, histologic subtype, stage, peritoneal cytology, LNI and DNA ploidy were independent prognostic indicators. CONCLUSION: p53 expression and DNA ploidy were related to histologic subtype, FIGO stage, grade, LVSI, LNI, peritoneal cytology, tumor recurrence and overall 5-year survival. As compared to p53, DNA ploidy was the stronger independent predictor factor for survival. Neither p53 nor DNA ploidy were significant independent factors for tumor recurrence when submitted to multivariate analysis in this study. However, since p53 or DNA ploidy were found to be significant factors in univariate analysis and were correlated with tumor recurrence, they could be useful factors in making prognoses.     

Lymphvascular space involvement: an independent prognostic factor in endometrial cancer

PURPOSE OF INVESTIGATION: To evaluate whether lymphvascular space involvement (LVSI) is a risk factor for relapse of disease and lymph node metastasis in endometrial cancer. METHODS: From 1978 till 2003, 609 patients with epithelial endometrial cancer were treated at the Groningen University Medical Center. The association of LVSI and relapse of disease was evaluated in the total group of 609 patients and in a 'low' and 'high' risk stage I endometrial cancer group. In 239 surgically staged patients, the relation of LVSI and lymph node metastasis was investigated. RESULTS: The median age at diagnosis was 63 years (range 27-92 years) with a median follow-up of 58 months (range 0-236 months). More than half of the patients (56%) received adjuvant radiotherapy. LVSI was present in 123 patients (25,6%), and a prognostic factor for relapse of disease (multivariate analysis, P < 0.0001). In the 'low' and 'high' risk stage I endometrial cancer patients an increase of 2.6 times in relapse of disease was observed in the presence of LVSI. LVSI positive tumors were more likely to have metastasized to the pelvic lymph nodes (multivariate analysis, P = 0.001). In patients with proven negative nodes, LVSI was a prognostic factor for relapse of disease (univariate analysis, P = 0.02). CONCLUSION: LVSI is a predictor of nodal disease and an independent prognostic factor for relapse of disease in all stages of endometrial cancer. Patients with stage I endometrial cancer with positive LVSI are at risk for relapse of disease and might therefore benefit from adjuvant therapy. CONTENT: The presence of lymphvascular space involvement (LVSI) in endometrial cancer is significantly and independently associated with an increased risk of pelvic lymph node metastases and/or relapse of disease.     

The impact of age on long-term outcome in patients with endometrial cancer treated with postoperative radiation

PURPOSE: Endometrial cancer is the most commonly diagnosed gynecologic malignancy in the United States. Age has been associated with worse outcome in univariate analysis. However, the patterns of failure and associated risk factors in older patients remain unclear. We reviewed our institution's experience to assess the effect of age in a population of endometrial cancer patients treated with surgery and adjuvant radiation therapy. METHODS: From 1992-2002, 243 endometrial cancer patients underwent a total abdominal hysterectomy and adjuvant radiation. Forty-nine patients with stage I-II (occult) endometrial adenocarcinoma (no clear cell or serous papillary) were treated postoperatively with vaginal intracavitary high-dose rate (HDR) brachytherapy alone using Iridium-192 (median dose 30 Gy) to a median length of 4 cm. Forty-eight patients with stage I-III endometrial adenocarcinoma (no clear cell or papillary serous) were treated with postoperative pelvic RT (median dose 45 Gy) and intracavitary HDR brachytherapy (median dose 20 Gy). One hundred forty-six patients underwent postoperative whole abdomino-pelvic irradiation (WAPI) secondary to unfavorable histology (clear cell or serous papillary) or two of the following: deep myometrial invasion, grade 3, or FIGO stage III. Age was analyzed as a continuous and a categorical variable. The age of 63 year split the age group using various statistical analyses. RESULTS: Median follow-up of all patients was 4.2 years. Patients grouped by age of < or =63 years or older had similar FIGO stage (P = 0.5), grade (P = 0.09), treatment modality (P = 0.7), and lymphovascular space invasion (LVSI) (P = 0.6). Twenty-five percent (60/243) of patients developed recurrence. Of these failures, 15% (15/102) were age < or =63 years and 32% (45/141) were age >63 years at diagnosis (P = 0.02). For all patients, the 5-year event-free survival (EFS), cause specific survival (CSS), and overall survival (OS) were 64%, 82%, and 72%, respectively. Five-year EFS for patients age < or =63 years and >63 years was 76% vs. 55% (P < 0.001). Five-year OS for age < or =63 years and >63 years was 85% vs. 63% (P < 0.001). Five-year CSS for age < or =63 years and >63 years was 91% vs. 75% (P = 0.003). Various factors were analyzed to determine an association with age. Older patients with stage III-IVA had significantly more failures than patients less than age 63 (P = 0.002). Older patients (>63 years) were found to have serous papillary histology (28%) more often than younger patients (15%) (P = 0.02). Greater depth of invasion was associated with older age (P = 0.01). On univariate analysis, older age (P = 0.003), LVSI (P = 0.002), FIGO stage (P < 0.001), grade (P < 0.001), and depth of invasion (P = 0.03) predicted for failure. On Cox multivariate analysis, older age (P = 0.006, HR 2.83), higher FIGO stage (P = 0.001, HR 1.96), and higher grade (P = 0.002, HR 2.66) were significant prognostic factors for recurrence. No difference was seen between the two age groups from date of surgery and start of radiation. The duration of therapy was not different between the two groups. CONCLUSIONS: Older endometrial cancer (age >63 years) patients have a significantly decreased overall survival, cause-specific survival, and greater risk of recurrence following postoperative RT independent of other prognostic factors and/or treatment technique. The impact of treatment-related variables did not alter the age-related outcome.     

Angiogenesis of endometrial carcinomas assessed by measurement of intratumoral blood flow, microvessel density, and vascular endothelial growth factor levels

OBJECTIVE: To evaluate the relationship between blood flow in the tumor assessed by color Doppler ultrasound, microvessel density, and vascular endothelial growth factor levels in endometrial carcinoma. METHODS: Forty-nine patients undergoing surgery for endometrial carcinoma were enrolled. Transvaginal color Doppler ultrasound was performed preoperatively and the lowest resistance index (RI) in the tumor was recorded for analysis. Vascular endothelial growth factor in the tumor was quantified by enzyme immunoassay. The microvessel density of the excised tumor was assessed immunohistochemically. The relationships between the corresponding RI, microvessel density, and vascular endothelial growth factor level of the tumor tissues and clinical and pathologic parameters were analyzed. RESULTS: Significantly lower RIs were noted in tumors of stage II or greater (0.37 compared with 0.50, P <.001), of high histologic grade (grade 3) (0.34 compared with 0.49, P =.004), with deep myometrial invasion (one-half depth or greater) (0.39 compared with 0.49, P =.002), with lymphovascular emboli (0.38 compared with 0.49, P <.001), or with lymph node metastasis (0.30 compared with 0.49, P <.001) compared with stage I tumors and tumors of histologic grade 1 or 2, with superficial myometrial invasion, without lymphovascular emboli, or with no lymph node metastasis. Increased vascular endothelial growth factor levels and microvessel density (x200 field) also were detected in tumors of stage II or greater (975 compared with 129 pg/mg, P =.014; and 88 compared with 61, P =.018, respectively), with lymphovascular emboli (1138 compared with 120 pg/mg, P =.002; and 86 compared with 63, P =.023), or with lymph node metastasis (1011 compared with 95 pg/mg, P <.001; and 98 compared with 61, P =. 019). Resistance index, microvessel density, and vascular endothelial growth factor levels in the tumor showed linear correlations (RI compared with microvessel density: r = -.32, P =. 03; RI compared with vascular endothelial growth factor levels: r = -.40, P =.004; microvessel density compared with vascular endothelial growth factor levels: r =.36, P =.011). CONCLUSION: Blood flow assessed by color Doppler ultrasound has histologic and biologic correlations with angiogenesis and vascular endothelial growth factor levels and might play an important role in predicting tumor progression and metastasis in endometrial carcinoma.     

Intratumoral blood flow characteristics and prognostic factors in patients with endometrial carcinoma

Purposes of the study were to evaluate the correlation between intratumoral blood flow and stage, histologic grade, depth of myometrial invasion and lymph node metastasis in endometrial carcinoma and to assess if vascular/lymphatic spaces invasion is predictable by Doppler ultrasound. Fifty-three patients with endometrial carcinoma were enrolled before surgical treatment. Transvaginal Color Doppler Ultrasound was performed to detect the areas of increased vascularity (≥3) and to record the lowest resistance index (RI) from the blood flow signals within the tumour. Formalin fixed, paraffin embedded pathology slides were reviewed by a senior pathologist to evaluate histologic grading, depth of myometrial invasion, presence of lymph node metastasis and vascular/lymphatic spaces invasion. The number of patients with positive lymph node metastasis was too small to perform any statistical evaluation. Significantly lower RI was noted in tumours of advanced stage (>FIGO Stage I), tumours with higher histologic grade (Grade 3) and with presence of vascular invasion. No correlation was found for myometrial invasion (>50%). A high number of vascular areas was positively correlated with all the prognostic signs. Assessment of tumour changes in vascularity using colour Doppler ultrasound provides useful information for the preoperative prediction regarding stage and histologic grade. The good correlation between Doppler ultrasound results and histological finding of vascular/lymphatic spaces invasion is another point in favour of routine colour Doppler studies in patients with endometrial carcinoma. We believe this technique is useful both for preoperative staging and that recording of tumour recurrence pattern may lead to early selection of those patients that need additional therapy. Received: 5 February 2001 / Accepted: 14 July 2001 Correspondence to P. Greco     

Surgical-pathological predictors of disease-free survival and risk groupings for IB2 cervical cancer: do the traditional models still apply?

OBJECTIVE: To evaluate how the independent predictors of recurrence for stage IB2 cervical cancers treated with up-front radical hysterectomy apply to established risk models. METHODS: Patients with IB2 cervical cancers diagnosed from 1990 to 2000 were identified from tumor registries of two institutions. Patients were classified into risk groups: high-risk (HR) (positive nodes, parametria, or margins), intermediate-risk (IR) (positive lymph vascular space involvement (LVSI) with any cervical stromal invasion (CSI), or (-) LVSI and > middle- CSI), or low-risk (LR) (absence of HR or IR characteristics). Disease-free survival (DFS) was estimated by Kaplan-Meier method and comparisons between subgroups were studied by log rank. A Cox proportional hazards model was used to determine independent predictors of recurrence. RESULTS: We identified 86 patients with stage IB2 tumors treated by RH. We found 34% of patients to be HR, 60% IR, and 6% LR. Of the 52 IR patients, 28 had (+) LVSI with superficial, middle, and outer 1/3 CSI, and 24 had (-) LVSI with middle or outer 1/3 invasion. Overall, postoperative adjuvant radiation (PRT) was used in 52% of the 86 patients, including 0/5 LR, 16/52 IR, and 29/29 HR patients. Univariate predictors of recurrence were pelvic nodal disease, (+) LVSI, (+) parametria, outer 1/3 CSI, and tumor size > 6 cm. Age, grade, histology, and the use of postoperative radiation were not associated with recurrence. Multivariate analysis identified LVSI as the only independent predictor of recurrence (RR 5.2, P = 0.03). Two-year DFS for LR, IR, and HR patients was 100%, 83%, and 60%, respectively. Only 4/24 (17%) IR patients with (-) LVSI got PRT compared with 12/28 (43%) of IR patients with (+) LVSI. The 2-year DFS for IR patients with (-) LVSI was 96%. IR (+) patients recurred more frequently with a 2-year DFS of 71%. CONCLUSIONS: Overall, 66% of patients with IB2 disease were classified as having low or intermediate-risk disease. IR patients with (-) LVSI and all LR patients did well with surgery alone. This study defines the independent importance of LVSI and questions the utility of published IR models when applied to stage IB2 cervical cancer.     

Association between Bcl-2 expression and tumor recurrence in cervical cancer: a matched case-control study

OBJECTIVES: To evaluate the association between bcl-2 expression, some pathological factors (lymph-vascular space invasion (LVSI), tumor grade, depth of stromal invasion), and tumor recurrence in cervical cancer. METHODS: A matched case-control study was performed in cervical cancer patients who underwent radical hysterectomy and were found to have negative lymph node between January 1992 and June 1998 in Bangkok Metropolitan Administration Medical College and Vajira Hospital and Maharaj Nakorn Chiangmai Hospital, Thailand. Cases were 32 patients who had tumor recurrence within 5 years after surgery. Controls were 63 patients who were disease free for at least 5 years after surgery. Cases and controls were matched for age, stage, histology, and tumor size. All except one case, who had only one matching control, had two controls. Paraffin-embedded cervical cancer tissues of cases and controls were immunohistochemical stained for bcl-2. RESULTS: Bcl-2 positive was demonstrated in 43.7% of tumor from recurrent cases, which was not different from 50.8% from non-recurrent controls (P = 0.378). Tumor grade and LVSI had significant association with tumor recurrence. From multivariable analysis, the patients with grade 2-3 tumors had the odds ratio of 6.9 for recurrence compared to patients with grade 1 tumors. The patients whose tumors had LVSI had the recurrent odds ratio of 5.4 compared to those without LVSI. CONCLUSIONS: There was no association between bcl-2 expression and tumor recurrence in cervical cancer, while tumor grade and LVSI had significant association with tumor recurrence.     

Lymphovascular space involvement in early stage well-differentiated endometrial cancer is associated with increased mortality

Objective  To study the relationship between lymphovascular space involvement (LVSI) in stage 1a or 1b well-differentiated endometrial cancer and survival.
Design  Retrospective study consisting of a search of an oncology database to identify women with endometrial cancer between January 1990 and December 2004.
Setting  Tertiary referral centre, Dublin, Ireland.
Sample  Women who had well-differentiated stage 1a or 1b endometrial cancer.
Methods  During the period 1990–2004, 226 patients with endometrial cancer were treated in the National Maternity Hospital, Dublin. We looked at all patients who had well-differentiated endometrioid adenocarcinoma of the endometrium with invasion of <50% thickness of the myometrium. Forty-one patients fulfilled these inclusion criteria. The presence or absence of LSVI was determined by review of haematoxylin and eosin sections. Patients were followed for 5 years or till death if earlier. Mortality was calculated. Statistical analysis was performed using Fisher's exact test. An odds ratio and 95% confidence interval was calculated using fixed effect Mantel–Haenszel model.
Main outcome measures  Death from recurrence of endometrial cancer.
Results  Of the 41 patients, five (12%) were found to have (LVSI). Of the five patients with LVSI, three (60%) patients died of recurrence. All patients with recurrence died of disease and none of the patients without LVSI died (0 of 36). Overall, the survival rate was 92.7%. The presence of LVSI was a highly significant predictor of recurrence ( P  < 0.001).
Conclusion  In patients with early stage well-differentiated adenocarcinoma of the endometrium, the presence of LVSI is associated with a high risk of death.     

A comparison of stages IB1 and IB2 cervical cancers treated with radical hysterectomy. Is size the real difference?

OBJECTIVE: To compare stages IB1 and IB2 cervical cancers treated with radical hysterectomy (RH) and to define predictors of nodal status and recurrence. METHODS: Patients with stage IB cervical cancers undergoing RH between 1990 and 2000 were evaluated and clinicopathological variables were abstracted. The perioperative complication rate, estimated blood loss (EBL), and OR time were also tabulated. Variables were analyzed using X(2) and t tests. Disease-free survival (DFS) was calculated by Kaplan-Meier method. Multivariate analysis was performed via stepwise logistic regression. Cox-proportional hazards were used to identify independent predictors of recurrence. RESULTS: RH was performed on 109 stage IB1 and 86 stage IB2 patients. Mean age, EBL, and perioperative complication rates were similar. Overall, 38 patients (14 IB1 vs. 24 IB2) had positive nodes (P = 0.01) including 9 patients with positive para-aortic nodes (2 IB1 and 7 IB2). Parametrial involvement (PI) and outer 2/3 depth of invasion (DOI) were significantly more common in the IB2 tumors as well. Patients with IB2 disease received adjuvant radiation more frequently than IB1 patients (52% vs. 37%, P = 0.04). Univariate predictors of nodal status included lymphovascular space involvement (LVSI) (P = 0.001), DOI (P = 0.011), PI (P = 0.001), and stage (P = 0.011). Multivariate analysis identified only LVSI (OR 6.4, CI 2.4-17, P = 0. 0002) and PI (OR 8, CI 3.1-20, P = 0. 0001) as independent predictors of positive nodes. With a median follow-up of 35 months, estimates of DFS revealed tumor size (P = 0.008), nodal status (P = 0.0004), LVSI (P = 0.002), PI (P = 0.004), and DOI (P = 0.0004) as significant univariate predictors. Neoadjuvant chemotherapy, age, grade, histology, and adjuvant radiation were not associated with recurrence. The significant independent predictors of DFS were LVSI (ROR 5.7, CI 2-16, P = 0.0064) and outer 2/3 DOI (OR 5.8, CI 2-20, P = 0.0029). Neither tumor size nor nodal status was a significant predictor of DFS. CONCLUSIONS: The prognosis in stage IB cervical cancer seems to be most influenced by presence of LVSI and DOI and not by tumor size as the staging criteria would suggest. These factors are best determined pathologically after radical hysterectomy. This report contains the largest comparison of IB1 and IB2 patients managed by RH. Tumor size failed to predict recurrence or nodal status when stratified by LVSI, DOI, and PI. Treatment decisions based on tumor size alone should be reconsidered.     

Should the presence of lymphvascular space involvement be used to assign patients to adjuvant therapy following hysterectomy for unstaged endometrial cancer?

Objective. Thegoal of this study was to determine the influence of LVSI (lymphvascular space involvement) on the risk of lymph node metastases from endometrial cancer.Methods. All patients with surgically staged endometrial cancer from 1998 to 2000 were identified from divisional databases. The influence of LVSI on the risk for nodal metastases was determined after controlling for tumor grade and depth of invasion, and comparisons were made with the chi(2) or Fisher's exact tests. Multivariable analysis was performed using a logistic regression model.Results. We identified 366 patients who fit the study criteria. Pathologically, 92/366 (25%) tumors had LVSI, and 46 patients (13%) had evidence of pelvic lymph node metastases. Cancers with LVSI were significantly more likely to have nodal disease (35/92 versus 11/274, P < 0.001). When controlled for tumor grade, the presence of LVSI led to an increased incidence of pelvic node metastases (P < 0.001 for all grades). When stratified by depth of invasion in thirds, the presence of LVSI led to a significantly increased chance of pelvic lymph node metastases (P < 0.05 for each strata). When tumor grade and depth of invasion were evaluated together, LVSI led to a significantly increased risk of pelvic node metastases in patients with deeply invasive tumors. In a multivariable analysis, LVSI led to a significantly increased risk for pelvic lymph node metastases (P < 0.05).Conclusion. LVSI leads to an independent and significantly increased risk for pelvic lymph node metastases. As such, the presence of LVSI may indicate the need for lymphadenectomy or adjuvant therapy for potential regional lymph node metastases in patients with unstaged endometrial cancer.     

Color Doppler assessment of blood flow in endometrial cancer

OBJECTIVE: To determine the location and intensity of angiogenesis as well as selected flow parameters by transvaginal color Doppler (TVCD) and to evaluate the relation of myometrial invasion, histological grading, lymph nodes, and omental and adnexal metastasis on blood flow characteristics in endometrial cancer. METHODS: Transvaginal colour Doppler and pulsed Doppler ultrasound were performed on 90 women with endometrial cancer. The degree of invasion as well as adnexal, omental, and pelvic lymph node metastasis was evaluated. Location of the blood vessels (peripheral, central, mixed) and vascular density as well as selected Doppler blood flow indices: PSV, RI of neoplastic infiltration was assessed. RESULTS: The median age of the 90 women was 63.3 +/- 12.3 years (range 32 to 86 years); of these 92.2% were postmenopausal. Cancer concerned only the endometrium (E), with superficial (S) and deep infiltration (D) established in 14.4%, 45.6% and 40%, respectively. The histological maturity was as follows: G1 - 17.6%, G2 - 66.7%, G3 - 16.6% of cases. Adnexal, omental and lymph node metastasis was found in 12.2%, 3.3% and 16.6%, respectively. Abnormal low impedance and high velocity flow (mean RI 0.38 +/- 0.09, PSV 20.45 +/- 9.6 cm/sec) were found in 88.9% of cases. In types E, S, D in 61.5%, 92.7% and 94.4%, respectively (p = 0.003). Differences in RI and PSV between groups with high and low vascular density were statistically significant (p = 0.005 and 0.001, respectively). In all cases peripheral and mixed vascularity were found more frequently (p < 0.05). A positive significant correlation between vascular density increase and surgicopathological stage of cancer was found more frequently (p < 0.005). There were significant differences in vascular density, Doppler blood flow indices and vascular location in each type of histological malignancy (p < 0.05). No significant differences in each flow parameter in hematogenous-adnexal/omental metastatic and non metastatic cases were found, whereas pelvic lymph node involvement and vascular density were shown to be statistically significant (p < 0.02). There were significant differences in vascular density in lymph-node positive cases whereas the remaining flow parameters did not differ. CONCLUSIONS: These results suggest that TVCD evaluation of endometrial cancer is a reliable method for assessing endometrial angiogenesis. Our results indicate that blood flow rates correspond with increased angiogenesis in endometrial cancers, and might potentially be used as a good prediction factor for tumor progression and metastasis in affected women. Preoperative ultrasound examination should be seen as an important tool in the establishment of individualized treatment programs for women with endometrial cancer.     

Parametrial spread is a prognostic factor in endometrial carcinoma

OBJECTIVE: Parametrial spread of endometrial carcinoma, including the histopathological pattern of the spread and its significance as a prognostic factor, as well as its correlation with other prognostic factors are not well understood. METHODS: We reviewed histopathologically the resected parametria from 269 patients with endometrial carcinoma who underwent radical or modified radical hysterectomy with pelvic lymphadenectomy. The relationship between parametrial spread and other histopathological features, including histological type, tumor grade, depth of myometrial invasion, lymph vascular space invasion (LVSI) of the myometrium, cervical invasion, adnexal metastasis, lymph node metastasis and peritoneal cytology was studied. Clinical outcomes of the patients with parametrial spread were also evaluated. RESULTS: Parametrial spread was demonstrated in 16 patients (5.9%). Direct invasion of cancer cells to connective tissue, LVSI and lymph-node metastasis in the parametrium were seen in 13, seven and three cases, respectively. Three patients had all three spread patterns. According to the FIGO surgical stage, parametrial spread was found in none of the 164 patients in Stage I, two (6.3%) of 32 in Stage II, 12 (16.9%) of 71 in Stage III, and two (100%) of two in Stage IV. The presence of parametrial involvement was significantly correlated with depth of myometrial invasion, cervical involvement, lymph-node metastasis, adnexal metastasis. LVSI in the myometrium and peritoneal cytology (each, p < 0.01). With a median follow-up of 68.3 months, six (37.5%) of 16 patients with parametrial involvement developed recurrence and died. CONCLUSION: Direct parametrial extension or lymphatic involvement within the parametrium can occur in endometrial carcinoma. Patients with parametrial spread have a poor prognosis.     

Preoperative lymph-vascular space invasion is associated with nodal metastases in women with early-stage cervical cancer

OBJECTIVE: To determine the association between findings on review of preoperative biopsy specimens and the risk of lymph node involvement (LNI) at radical hysterectomy in patients with early-stage cervical cancer. METHODS: Eighty-one patients were included in this retrospective review. Preoperative biopsy features evaluated were stage, grade, histologic subtype, lymph-vascular space invasion (LVSI), and depth (>4 mm) of invasion. RESULTS: Twelve patients (14.8%) had LNI at radical hysterectomy. Stage, grade, and histologic subtype were not associated with LNI. LVSI and depth of invasion >4 mm were both significantly associated with LNI (25.6% vs. 4.8%, P=0.01, and 25.0% vs. 4.5%, P=0.01, respectively). LVSI with >4 mm invasion was 6.6 times more likely to have LNI at the time of radical hysterectomy (RR=6.6; 95% confidence interval, 2.1-21.9). CONCLUSION: Patients with preoperative LVSI are at higher risk for LNI at radical hysterectomy and should be counseled regarding potential implications for management.     

Lymph-vascular space invasion and number of positive para-aortic node groups predict survival in node-positive patients with endometrial cancer

OBJECTIVE: The aim of this study was to determine pathologic variables associated with disease-specific survival of node-positive patients with endometrial carcinoma treated with combination of surgery including pelvic and para-aortic lymphadenectomy and adjuvant chemotherapy. METHODS: Survival of 55 node-positive endometrial carcinoma patients prospectively treated with surgery and adjuvant chemotherapy between 1982 and 2002 at Hokkaido University Hospital was compared to various histopathologic variables. All patients underwent primary surgical treatment including pelvic and para-aortic lymphadenectomy followed by adjuvant chemotherapy consisting of intravenous cisplatin, doxorubicin, and cyclophosphamide. Survival analyses were performed by the Kaplan-Meier curves and the log-rank test. Independent prognostic factors were determined by multivariate Cox regression analysis using a forward stepwise selection. RESULTS: Among 303 consecutive endometrial cancer patients treated during the period of this study, 55 patients (18.2%), including 44 without peritoneal metastasis (FIGO stage IIIc) and 11 with peritoneal metastasis (FIGO stage IV), were found to have retroperitoneal lymph node metastasis. Multivariate Cox regression analysis revealed that peritoneal metastasis and lymph-vascular space invasion (LVSI) were independently related to poor survival in node-positive endometrial carcinoma. The estimated 5-year survival rate of stage IIIc patients with or without moderate/prominent LVSI was 50.9% and 93.3%, respectively with statistically significant difference (P=0.0024). The estimated 5-year survival rate of stage IV patients was 20.0%. Prognosis of stage IIIc patients could be stratified into three groups by the number of positive para-aortic node (PAN) with an estimated 5-year survival rate of 86.4% for no positive PAN (n = 23), 60.4% for one positive PAN (n = 13), and 20.0% for > or = 2 positive PAN (n = 8). The difference of survival rate between no or one positive PAN and > or = 2 positive PAN was statistically significant (P = 0.0007 for no positive PAN vs > or = 2 positive PAN, P = 0.0319 for one positive PAN vs > or = 2 positive PAN). Multivariate analysis including number of positive PAN groups showed that LVSI, number of positive PAN groups were independent prognostic factors for survival. Survival of patients with stage IIIc disease could be stratified into three groups by combination of LVSI and number of positive PAN groups with an estimated 5-year survival rate of 93.3% for no or one positive PAN group with nil or minimal LVSI, 62.6% for no or one positive PAN group with intermediate or prominent LVSI, and 20.0% for > or = 2 positive PAN groups irrespective of LVSI (P = 0.0002 for no or one positive PAN group with nil or minimal LVSI vs > or = 2 positive PAN groups, P = 0.0223 for no or one positive PAN group with nil or minimal LVSI vs no or one positive PAN group with intermediate or prominent LVSI, P = 0.0388 for no or one positive PAN group with intermediate or prominent LVSI vs > or = 2 positive PAN groups). CONCLUSIONS: LVSI and number of positive PAN groups were independent prognostic factors for stage IIIc endometrial cancer patients. Postoperative therapy and follow-up modality need to be individualized according to LVSI and the number of positive PAN for stage IIIc patients. New molecular markers to predict the prognosis of endometrial cancer patients preoperatively should be found for individualization of treatment. New chemotherapy regimen including taxane needs to be considered as an adjuvant therapy for patients with node-positive endometrial cancer.     

Association between CD31 expression and histopathologic features in stage IB squamous cell carcinoma of the cervix

This study was undertaken to evaluate the association between the expression of CD31 in the tumor and the histopathologic findings in patients with carcinoma of the cervix. This study included prospectively 30 women, aged 46.6 +/- 10.7 years, with stage IB squamous cell carcinoma of the cervix submitted to radical hysterectomy from November 2001 to September 2002. Samples from the tumor were taken and immunohistochemically evaluated by a monoclonal antibody for CD31. Clinicopathologic characteristics such as stage, tumor size, grade of differentiation, lymphatic vascular space invasion (LVSI), parametrial involvement, and status of pelvic lymph nodes were also recorded. The clinical stage (FIGO) was IB1 in 22 patients (73.3%) and IB2 in 8 patients (26.7%). The expression of CD31 was significantly associated with tumor size and the presence of LVSI, but not with grade of differentiation and vaginal or parametrial involvement (P= 0.03, P= 0.032, P= 0.352, P= 0.208, and P= 0.242, respectively). On univariate analysis, the presence of pelvic lymph node metastasis was influenced by LVSI (P= 0.003) and CD31 expression (P= 0.032). However, on multivariate analysis, the presence of LVSI (P= 0.007) was the only independent predictor of pelvic lymph node metastasis. The CD31 expression in tumor is significantly associated with LVSI and tumor size in patients with early-stage squamous cell carcinoma of the cervix.     

Missing association between telomerase activity and clinicopathological features in patients with early stage carcinoma of the cervix

OBJECTIVES: This study was undertaken to evaluate the association between the telomerase activity in the tumor and clinicopathological findings in patients with stage IB-IIA (FIGO) carcinoma of the cervix. METHODS: Thirty-eight patients with carcinoma of the cervix submitted to radical hysterectomy were prospectively from January 1998 to November 2001. Samples from the tumor were taken and analyzed by the telomerase PCR-TRAP-ELISA kit. Clinicopathological characteristics such as age, stage, tumor size, grade of differentiation, lymphatic vascular space invasion (LVSI), parametrial involvement and status of pelvic lymph nodes were also recorded. RESULTS: Patient's mean age was 49.3+/-1.99 years (29-76 years). The clinical stage (FIGO) was IB in 35 patients (92.1%) and IIA in 3 patients (7.9%). The histological classification identified squamous cell carcinoma in 33 patients (86.8%) and adenocarcinoma in 5 patients (13.2%). There was no association between age, clinical stage, histological classification, tumor size, grade of differentiation and presence of LVSI with tumoral telomerase activity. The telomerase activity was not associated with the presence of vaginal involvement (P=0.349), parametrium involvement (P=0.916), pelvic lymph node metastasis (P=0.988) or tumoral recurrence (P=0.328) in patients with carcinoma of the cervix. CONCLUSIONS: Telomerase activity in the tumor is not associated with clinicopathological findings or tumor recurrence in patients with early stage cervical carcinoma.     

Factors predicting recurrence in patients with stage IA endometrioid endometrial cancer: what is the importance of LVSI?

The aim of this study is to define the clinical and pathological prognostic factors for recurrence and to evaluate the recurrence patterns and adjuvant therapies used in this group of patients with stage IA endometrioid type endometrial cancer (FIGO 2009—International Federation of Gynecology and Obstetrics). Among the patients with epithelial endometrial cancer operated between January 1993 and May 2013 in a single institution, 720 patients with stage IA endometrioid endometrial cancer were included. Patients with a tumor type of serous, clear cell, mucinous, undifferentiated, and mixed type and with a tumor containing sarcomatous component and the patients with a secondary primer cancer were excluded from the study. Lympho-vascular space invasion (LVSI) was present in 60 (8.3%) patients. Pelvic and para-aortic lymphadenectomy was performed in 266 (36.9%) patients. Median follow-up time was 48 months (range 3–240). Recurrence occurred in 23 (3.4%) patients and 6 (0.9%) died of disease. The median time-to recurrence (TTR) was 24 months (range 4–52 months) in the patients with recurrence. LVSI was associated with recurrence in the univariate analysis. Five-year disease-free survival (DFS) decreased from 96.8 to 80.1% in the presence of LVSI (p < 0.001). This association could not be shown in patients who had had lymphadenectomy (p = 0.136). Extra-pelvic recurrence occurred in 6.7% and 1% of the patients with and without LVSI, respectively, (p = 0.001). Any independent prognostic factor could not be detected in the multivariate analysis. Only LVSI and tumor grade were associated with DFS and disease-specific survival (DSS), respectively, in the 686 patients with stage IA endometrial cancer in the univariate analysis, since these associations could not be shown in multivariate analysis.