1447 The Prognostic Significance of Vascular Invasion by Endometrial Carcinoma Yoshiki lnoue, M.D. Koshiro Obata, M.D. Kunio Abe, M.D. Gen Ohmura, M.D. Kunihiko Doh, M.D. Tadaaki Yoshioka, M.D. Hiroshi Hoshiai, M.D. Kiichiro Noda, M.D. Department of Obstetrics and Gynecology, Kinki University School of Medicine, Osaka-Sayama, Osaka, Japan. BACKGROUND. Recently, invasion of vascular spaces by endometrial carcinoma has received particular attention as a prognostic factor. The goal of the current investigation was to re-examine the effect of vascular invasion on tumor recurrence and survival in patients with endometrial carcinoma. METHODS. Surgical specimens from 238 patients with endometrial carcinoma were examined for the presence of vascular invasion by tumor cells. Vascular invasion was compared with clinicopathologic features and postoperative survival. SuMval curves by vascular invasion were evaluated by the Kaplan-Meier method. RESULTS. In a histopathologic review of 238 cases of endometrial carcinoma, 82 neoplasms demonstrated vascular invasion. Vascular invasion significantly correlated with the extension of primary tumor, depth of myometrial invasion, and histologic grade. Patients with lymph node metastasis had a significantly higher incidence of vascular invasion. Survival at 5 years for patients with vascular invasion was 73.4%. This was significantly lower than the survival rate of 91.5% for women without this finding ( P i 0,001). Among patients with lymph node metastasis, 80.2% of the patients with vascular invasion survived for 5 years compared with 95.3% of the patients without vascular invasion ( P < 0.05). Ten of 47 patients with no lymph node metastasis but with vascular invasion developed recurrent carcinoma. Nine of these ten patients apparently had extrapelvic recurrences. CONCLUSIONS. The presence of vascular invasion is a reliable prognostic indicator. Recording of tumor recurrence pattern may lead to a better selection of patients for adjuvant systemic therapy after surgery. Cancer 1996; 781447-51. 0 1996 American Cancer Society, KEYWORDS endometrial carcinoma, vascular invasion, tumor recurrence, prognosis. T Address for reprints: Yoshiki Inoue, M.D., Department of Obstetrics and Gynecology, Kinki University School of Medicine, 377-2, OhnoHigashi, Osaka-Sayama, Osaka 589, Japan. Received February 29, 1996; revision received May 28, 1996; accepted May 28, 1996. 0 1996 American Cancer Society he prognostic factors in endometrial carcinoma that have been most extensively investigated are histologic grade,’ cell myometrial i n ~ a s i o n ,and ~ , ~lymph node m e t a ~ t a s i s .Recently, ~,~ invasion of vascular spaces by an endometrial carcinoma has received particular attention as a prognostic fa~tor.9-l~ Tumor cells first develop the capacity for local tissue invasion and then spread through gaps between endothelial cells into vascular spaces of the stroma. Once vascular space penetration has occurred, tumor cells have the potential for metastasizing to other sites. In general terms, invasion of vascular spaces by a tumor is indicative of an aggressive neoplasm that has a marked tendency to metastasize to the lymph node and to recur locally or distantly. The current investigation attempts to reinforce the effect of vascular invasion on tumor recurrence and survival in patients with endometrial carcinoma. SUBJECTS AND METHODS Subjects for this investigation were 238 patients with endometrial carcinoma who were treated at the Department of Obstetrics and 1448 CANCER October 1,1996 / Volume 78 I Number 7 TABLE 1 Vascular Invasion in Relation to Histopathologic Variables of Endometrial Carcinoma Extent of the primary tumor Confined to corpus Extension to cervix Extrauterine spread Histologic grade I 2 3 Myornetrial invasion Endometrium only Inner half Outer half Tumor cell type Endometrioid Adenocarcinoma Adenosquamous Adenoacanthoma Serous Clear cell Squamous a TABLE 2 Relation between Histologic Grade and Myometrial Invasion and Vascular Invasion No. of patients Vascular invasion 157 43 38 39 (25%) 21 (48.8%) 22 (58%) < 0.01 149 70 19 35 (23.5%) 34 (48.6%) 13 (68.4%) < 0.01 24 143 71 0 (0%) 33 (23.1%) 49 (69%) < 0.01 216 9 9 1 2 1 69 (31.9%) 6 (66.7%) 4 (44.4%) 1 (100%) 1150%) 1(100%) P value Histologic “grade” Myornetrial invasion Vascular invasion positiveltotal (%) 1 Endometrium only Inner half Outer half Endometrium only Inner half Outer half Endometrium only Inner half Outer half 0/21 (0%) 191102 (18.6%) 16/26 (61.5%) 0/3 (0%) 12/37 (32.4%) 22/30 (73.3%) 010 2/4 (50%) 11/15 (73.3%) 2 3 < 0.05a Adenocarcinorna versus adenosquamous, Gynecology,Kinki University School of Medicine, from 1976 to 1993. All patients were initially treated with a total abdominal hysterectomy and bilateral salpingooophorectomy without prior radiation therapy. Pelvic lymph node dissection was performed at the time of hysterectomy on 210 patients. Selective aortic lymph node dissection was performed on 42 patients. External radiation to the whole pelvis was used when disease extended outside the uterus and in patients who had pelvic lymph node metastasis. For patients with histologically positive aortic lymph nodes, extendedfield radiation therapy with an aortic portal was planned. Hematoxylin and eosin-stained sections from hysterectomy specimens were examined for the presence of vascular invasion by tumor cells. Vascular invasion was considered to be present when tumor cells were noted within or attached to the wall of a blood vessel or lymphatic space lined by flattened endothelial cells. Lymphatic vessel invasion was considered positive only when tumor cells and the lymphocyte were noted together in a lymphatic space. Blood vessel invasion was considered positive only when tumor cells and red blood cells were noted together in a blood vessel space. The relationship between vascular space invasion and various histopathologic variables was evaluated. Histologic classification was performed according to the World Health Organization cla~sification.’~ Once P value < 0.01 < 0.01 > 0.05 TABLE 3 Vascular Invasion in Relation to Pelvic and Aortic Lymph Nodes in Endometrial Carcinoma Pelvic lymph node Positive Negative Aortic lymph node Positive Negative No. of patients Vascular invasion 29 181 22 (75.9%) 48 (27%) < 0.01 10 32 9 (90%) 10 (31.3%) < 0.01 P value an endometrioid carcinoma with squamous differentiation was identified, the squamous cells were classified as histologically malignant (adenosquamous carcinoma) as opposed to histologically benign (adenoacanthoma). Statistical analysis of the data was performed using the chi-square test on tables to determine the significance of the various correlations with P < 0.05 considered significant.Survivalwas calculated from the date of surgery according to the method of Kaplan and Meier. RESULTS In a histopathologic review of 238 cases of endometrial carcinoma, 82 neoplasms demonstrated vascular invasion. The relationship between vascular invasion and various histopathologic variables of endometrial carcinoma is shown in Tables 1, 2, and 3. The incidence of vascular invasion increased with the extension of the primary tumor; 25% in tumors confined to the corpus, 48.8% in tumors that invaded to the cervix, and 58% in tumors that extended beyond the uterus ( P < 0.01). The incidence of vascular invasion was 23.5%, 46.8%, and 68.4% in Grade 1, 2, and 3 carcinomas, respectively. The frequency of vascular invasion increased with progressing tumor grade ( P < 0.01). Vascular in- Vascular Invasion in Endometrial Carcinoma/lnoue et al. 1449 T,4BLE 4 Relationship of Vascular Invasion to Tumor Recurrence and the Site of Tumor Recurrence No. of patients Tumor recurrence Lymphatic vessel invasion 54 12 (22.2%] Blood vessel invasion Lymphatic and blood vessel invasion 13 15 4 (30.8%) 4 (26.7%) vasion was not found among tumors confined to the endometrium. The frequency of vascular invasion was found in 23.1% of patients with tumor invasion to less than one-half of the myometrium, and 69% of patients with tumor invasion to more than one-half. The incidence of vascular invasion increased with depth of myometrial invasion ( P < 0.01). The relationship between histologic grade and myometrial invasion and vascular invasion is shown in Table 2. As the tumor becomes less differentiated, the possibility of deep myometrial invasion increases. In Grade 1 and 2 carcinoma, the incidence of vascular invasion increased with depth of myometrial invasion ( P < 0.01). Compared with pure adenocarcinoma, adenosquamous carcinoma had a significantlyhigher incidence of vascular invasion ( P < 0.05). The relationship between lymph node metastasis and vascular invasion is shown in Table 3. Of 29 patients with positive pelvic lymph node metastasis, 11 (37.9%)had Grade 2 carcinomas, 5 (17.2%) had Grade 3 carcinomas, 19 (65.5%) had tumor invasion to more than one-half of the myometrium, 2 (7%)had adenoacanthoma, 1 (3%)had adenosquamous carcinoma, and 1 (3%)had clear cell carcinoma. Of 10 patients with aortic lymph node metastasis, 5 (50%) had Grade 2 carcinomas, 2 (20%) had Grade 3 carcinomas, 7 (70%) had tumor invasion to more than one-half of the myometrium, and all patients had pure adenocarcinoma. Of 9 patients with both pelvic and aortic lymph node metastasis, 4 (44.4%)had Grade 2 carcinomas, 2 (22.2%)had Grade 3 carcinomas, and 7 (77.8%) had tumor invasion to more than one-half of the myometrium. The incidence of vascular invasion was found in 75.9% of patients with pelvic lymph node metastasis and in 27% of patients without pelvic lymph node metastasis ( P < 0.01). Vascular invasion was found in 90% of patients with aortic lymph node metastasis and in 31.3% of patients without aortic lymph node metastasis ( P < 0.01). Twenty-six of the 238 patients in this investigation developed recurrent endometrial carcinoma. Recurrent cancer was documented in 20 (24.4%) of 82 patients with vascular invasion as opposed to 6 (3.8%) of 156 patients without this finding ( P < 0.01). Tumor Site of recurrence Lung: 4; abdominal cavity: 2; lunglabdominal cavity: 1;vaginal cuff 1; vestibule: 1; aortic lymph node: 1; hone: 1; Virchow's lymph node: 1 Lunn: 2; abdominal cavitv: 1; vaginal cuff: 1 Lung: 2; abdominal cavity: 1; ab;iorninaJ cavitylaortic lymph node: 1 TABLE 5 Tumor Recurrence in 180 Patients without Lymph Node Metastasis in Relation to Vascular Invasion Vascular invasion Present Absent No. of patients Tumor recurrence 47 133 10 (21.3%) 3 (2%1 P value < 0.01 characteristics of 20 patients with vascular invasion who had recurrent cancer are shown in Table 4. Lymphatic vessel invasion was found in 54 patients, blood vessel invasion in 13, and lymphatic and blood vessel invasion in 15. Recurrence was detected in 12 of 54 patients with lymphatic vessel invasion, in 4 of 13 patients with blood vessel invasion, and in 4 of 15 patients with lymphatic and blood vessel invasion. The difference in the recurrence rates was not significant. The most frequent sites of recurrence in the three groups were the lung and the abdominal cavity. Tumor recurrence in 180 patients without lymph node metastasis in relation to vascular invasion is presented in Table 5. Of 133 patients without vascular invasion, only 3 developed tumor recurrence. In contrast, 10 of 47 patients with vascular invasion developed recurrent cancer. Of these ten patients, six had Grade 2 carcinomas, one had Grade 3 carcinoma, and six had tumor invasion to more than one-half of the myometrium. In these ten patients, recurrence occurred in the lung (four), abdominal cavity (one), abdominal cavity/aortic lymph node (one), Virchow's lymph node (one), vestibule (one), bone (one), and vaginal cuff (one). Eight of these patients apparently had extrapelvic recurrences. Survival at 5 years for patients with vascular invasion was 73.4%. This was significantly lower than the survival rate of 91.5% for women without vascular invasion (P< 0.001). Survival from vascular invasion for patients without lymph node metastasis is shown in Figure 1. Among patients without lymph node metastasis, the 5-year survival rate was 80.2% for the vascu- CANCER October 1,1996 I Volume 78 I Number 7 1450 increased with the progressing extent of the primary tumor, tumor grade, and depth of myometrial invasion. Patients with lymph node metastasis had a significantly higher incidence of vascular invasion. Patients with vascular invasion had a significantly higher recurrence rate and a significantly poorer survival rate Vascular invasion than those without vascular invasion. In this series, p o s i t i v e n=49 only 1 case (0.4%) was serous. This is a low number by North American standards. The reason is unknown. However, in a population-based study from Norway, p(0. 05 it was only l.l%24 and in Australia 2.8%.'5 This may be typical of the distribution of cell types in Japan. 2o Vascular invasion comprises lymphatic vessel invasion and blood vessel invasion. Several reports26-28 h 5 on rectal carcinoma indicated that the presence of venous invasion had an independent effect on survival FIGURE 1. Survival from vascular invasion for patients without lymph after radical resection. In contrast, Jass et aLZ9found node metastasis. venous invasion to be a weak variable in their new prognostic system. In addition, Minsky et al.30reported that blood vessel invasion was not found in their study to be an independent prognostic variable. In contrast, lar invasion group compared with 95.3% for patients without vascular invasion ( P < 0.05). lymphatic vessel invasion was an independent prognostic variable from a proportional hazards analy~is.~' DISCUSSION Only tumor cells with unquestionable endothelialVascular invasion by tumor cells has been shown to be lined spaces were regarded as evidence of vessel invaof clinical significance in several malignan~ies.+'~~'~-'~ sion. However, it was occasionally difficult to differenTalbot et al." reported that the follow-up studies on tiate lymphatics from blood vessels. In our study of patients with rectal carcinoma showed the corrected 82 patients with vascular invasion, 54 had lymphatic vessel invasion, 13 had blood vessel invasion, and 15 5-year survival rate was significantly worse when vehad lymphatic and blood vessel invasion. In this series, nous invasion was present. Patients with Stage IB carcinoma of the uterine cervix with vascular invasion blood vessels were differentiated from lymphatics by treated by radical hysterectomy had a 59.4% 5-year the discovery of red blood cells within the lumen, and survival rate that increased dramatically to 90% when more smooth muscle than found in lymphatics. Lymthere was no invasion." phatic vessel invasion was observed most frequently in patients with vascular invasion. The difference beThere have been several studies of the significance tween lymphatic vessel invasion and blood vessel inof vascular invasion by endometrial carcinoma. Hanvasion with regard to tumor recurrence and the recurson et aLI3 reported that 16 of 111 Stage I endometrial rence site was not significant. carcinomas (14%) had tumors demonstrating vascular Previous reports indicated that the risk of pelvic invasion. The frequency of vascular invasion increased lymph node metastasis is significant in endometrial with progressing tumor grade and depth of myome~ a r c i n o m a . ~ In ' - ~this ~ series, tumor recurrence and trial invasion. Vascular invasion was noted most comsurvival for patients without lymph node metastasis monly in adenosquamous carcinomas, but was conwas evaluated. Patients with vascular invasion have spicuously absent in adenoacanthomas. Tumor recura significantly poorer prognosis than those without rence developed in 44% of patients whose tumors vascular invasion. It must be emphasized that poor demonstrated vascular invasion as opposed to only prognosis with vascular invasion was also a feature of 2% of patients without this finding. They concluded patients without lymph node metastasis. Ten of 47 that vascular invasion by tumor cells is an important prognostic variable in Stage I endometrial carcipatients with no lymph node metastasis with vascular invasion developed recurrent cancer. Nine of these ten noma.13 patients had apparently extrapelvic recurrences. The Sivridis et aI.l4 reported that a multivariative remainstay of treatment for endometrial carcinoma is gression analysis showed that vascular invasion was a separate indicator of poor prognosis that was indepensurgery. However, this alone is obviously an incomplete therapy for patients with endometrial carcinoma dent of stage, histologic grade, or depth of myometrial invasion. whose tumor has invaded vascular spaces. We conclude that examining for the presence of vascular invaIn this study, the frequency of vascular invasion Vascular invasion n e g a t i v e n=132 t Vascular Invasion in Endometrial Carcinoma/lnoue et al. sion gives reliable prediction of recurrences after resection of endometrial carcinoma. 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