Lymph node mapping and involvement in endometrial cancer

Transcription

1 American Journal of Clinical Cancer Research Burcu Kasap et al. American Journal of Clinical Cancer Research 2013, 1:1-10 American Journals of Clinical Cancer Research Vol. 1, Article ID , Page 1 10 of 10 pages Research Article Lymph node mapping and involvement in endometrial cancer Burcu Kasap 1, Aykut Özcan 1, Hakan Yetimalar 1, Aşkın Yıldız 1*, İncim Bezircioğlu 1, Dilek Uysal 1, Derya Kılıç Sakarya 1 1 Department of Obstetrics and Gynecology Clinic, Izmir Katip Celebi University, Ataturk Training and Research Hospital, Turkey Abstract Objectives: The aim of this study was to evaluate the outcome of pelvic and/or para-aortic lymph node dissection in patients with endometrial cancer with regard to lymph node positivity. Materials and Methods: Retrospective chart review of 125 women with pathologically proven endometrial carcinoma who underwent a systematic surgical staging including lymphadenectomy between January 2006 and January 2011 was performed. Patients characteristics, histological findings, lymph node localization and involvement were analyzed. Detailed description of the extirpated and affected lymph nodes divided by area in the 125 patients with endometrial cancer were done. Results: The medical records for 125 patients were eligible for analysis. The mean number of all lymph nodes removed in operation was 38.9± (range 9 to 81 nodes). The mean number of pelvic lymph nodes (PLN) removed was 32± (range 9 to 75 nodes) and the mean number of para-aortic lymph nodes (PALN) removed was 7±5.123 (range 0 to 20 nodes). In the 24 patients with nodal metastasis, the mean number of all lymph nodes removed was 37.88± (range 9 to 81 nodes). The mean number of PLNs removed was 30.71±14.79 (range 9 to 66 nodes) and the mean number of PALNs removed was 7.17±4.198 (range 0 to 16 nodes). Nodal metastasis was shown in 24 (19.2%) patients. Isolated pelvic lymph node metastasis was shown in nine (37%) patients; isolated para-aortic lymph node metastasis was shown in one (4%) patient; both pelvic and para-aortic lymph node metastasis was shown in 14 (59%) patients. The most affected lymph node area was left external iliac artery with a ratio of 14%. Conclusions: In the field of gynecologic cancer surgery, for the determination of adequate number of lymph nodes to be retrieved, lymph node mapping plays a crucial role, and this issue should be investigated in studies performed with larger number of cases in order to standardize procedure of lymphadenectomy. Keywords: endometrial carcinoma; lymph node metastasis; lymphadenectomy Peer Reviewers: Reuven Reich, PhD, Institute for Drug Research, Hebrew University of Jerusalem School of Medicine, Israel; Athanasios Papatsoris, MD, PhD, University of Athens School of Medicine, Greece Received: December 22, 2012; Accepted: March 6, 2013; Published: March 8, 2013 Competing Interests: The authors have declared that no competing interests exist. Copyright: 2013 Aşkın Yıldız et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. * Correspondence to: Aşkın Yıldız, Department of Obstetrics and Gynecology, Izmir Ataturk Training and Research Hospital, Izmir, Turkey. ayild68@yahoo.com

2 Page 2 of 10 Introduction Endometrial cancer (EC) is the most common female gynecologic malignancy, with an estimated annual incidence of per women. The lifetime risk of developing EC is approximately 2.5%, while the lifetime probability of dying from this cancer is estimated at 0.52% [1]. Endometrial carcinoma is surgically staged according to the joint 2010 International Federation of Gynecology and Obstetrics (FIGO)/TNM classification system [2]. Total extrafascial hysterectomy with bilateral salpingo-oophorectomy with pelvic and paraaortic lymph node dissection is the standard staging procedure for endometrial carcinoma [3]. However, no specifications regarding the type and extent of pelvic lymph node dissection have been established. As lymph node metastases can be found in approximately 10% of women who clinically have cancer, removal of all pelvic and para-aortic lymph nodes (lymphadenectomy) is widely advocated. However, the extent (sampling or dissection) and performance of additional para-aortic sampling varies from surgeon to surgeon [4]. Particularly, in patients with a low risk for lymph node metastases (due to superficial depth of invasion, small size of tumour and low tumour grade), a routine lymph node dissection is often not performed. Moreover, substantial co-morbidities such as obesity or old age are considered contraindications to a full pelvic and/or para-aortic lymphadenectomy. Therefore, pelvic and/or para-aortic lymph node dissection has been a subject of continuous debate [5, 6]. Some recent studies have investigated the impact of the extent of lymph node removal in surgical treatment of EC. The results demonstrated an impact on survival for patients with a higher number of dislodged lymph nodes, especially in cases showing high-risk clear-cell or serous-papillary histology [7, 8]. In 2007, a retrospective analysis by the Surveillance Epidemiology and End Results program in the U.S.A. reviewed a large population database and concluded that lymphadenectomy results in improved survival of patients with EC [9, 10]. However, in a recent prospective study, there was no evidence of benefit from pelvic lymphadenectomy in terms of overall or recurrence-free survival in women with early EC [11]. Objectives The aim of this study was to evaluate the outcome of pelvic and/or para-aortic lymph node dissection in patients with EC with regard to lymph node positivity. Materials and Methods Study Design: We retrospectively reviewed the medical records of women with pathologically proven EC who were treated between January 2006 and January Institutional review board approval was obtained in advance for this retrospective study. Patients characteristics, histological findings, lymph node localization and involvement were analyzed. Demographic data including age at diagnosis, body mass index (BMI), parity, presenting symptoms, personal background, and family history were obtained from the archive records. All operations were performed by gynecologic oncologists. All patients underwent surgical staging including washing cytology, total abdominal hysterectomy, bilateral salpingo-oophorectomy, and PLN and/or PALN dissection. The depth of tumour invasion, cervical extension and the tumour diameter were intraoperatively assessed via fresh frozen section of the removed uterus. Bilateral pelvic lymphadenectomy included complete skeletonization of the common, external and internal iliac vessels and the harvesting of all lymphatic tissue in the upper and lower parts of obturator fossa after visualization of the obturator nerve and lumbosacral trunk. The superior surgical margin of dissection for the pelvic nodes was where the ureters cross the common iliac arteries. The anterior distal surgical margin of the pelvic lymphadenectomy was the circumflex iliac vein. The para-aortic lymphadenectomy was performed by mobilizing the paracolic peritoneum along the lateral border of the ascending and descending colon, permitting identification of the proximal ureters and high division of the ovarian vessels. This allowed

3 Page 3 of 10 visualization of the whole retroperitoneum up to the superior borders of the renal veins. All lymphatic tissue was then harvested from the lateral, anterior, and medial aspects of the vena cava and aorta up to the renal veins. Postoperative pathologic specimens were evaluated for tumour stage, histologic type, histologic grade (three grades according to the International Federation of Gynecology and Obstetrics (FIGO) surgical staging system adopted in 2010), and lymph node metastasis (present or absent). Statistical Analysis: Data were analyzed using the Statistical Package for Social Sciences 11.0 for Windows (SPSS Inc., Chicago, IL). The following statistical tests were performed: Chi-square test, t test for independent samples, and the analysis of variance (ANOVA) test. The results for all items were expressed as mean±sd, assessed within a 95% reliance and at a level of p<0.05 significance. (3.2%) of the family members of the study group. Clinical and demographic variables were shown in Table 1. Results The medical records for 125 (mean age 61.49±11.02; range 36 to 85 years) patients were eligible for analysis. All patients underwent surgical staging including washing cytology, total hysterectomy, bilateral salpingo-oophorectomy, and PLN and/or PALN dissection. 21.4% of the cases were in reproductive stage and 88.6% were in postmenopausal stage. Obesity was observed in 10 (8.1%) cases. Mean body mass index was 30.5 kg/m². Multiparity was observed in 106 (84.8%) patients, primiparity was observed in 15 (12%) patients, and nulliparity was observed in 4 (3.2%) patients in the study group. Postmenopausal bleeding was the most common presenting symptom with 64.8% of the patients followed by menometrorrhagia in 16%, inguinal pain in 12%, vaginal discharge in 3.2%, and abdominal distension in 4% of the patients. Personal background of the study group revealed hypertension in 26 (21%) patients, diabetes mellitus in 17 (13.7%) patients and both diabetes mellitus and hypertension in 17 (13.7%) cases. Family history was negative in 120 (96%) patients. Carcinoma was present in 5 (4%) and specifically endometrium carcinoma was present in 4

4 Page 4 of 10 Table 1: Demographic and clinical variables of the patients Variable n (%) Body Mass Index Underweight (<18.5 kg/m²) 4 (3.2%) Normal ( kg/m²) 29 (23.4%) Overweight ( kg/m²) 82 (66.1%) Obese (>30 kg/m²) 10 (8.1%) Parity Nulliparity 4 (3.2%) Primiparity 15 (12%) Multiparity 106 (84.8%) Presenting symptoms Postmenopausal bleeding 81 (64.8%) Menometrorrhagia 20 (16%) Inguinal pain 15 (12%) Vaginal discharge 4 (3.2%) Abdominal distension 5 (4%) Personal background Hypertension 26 (21%) Diabetes mellitus 17 (13.7%) Diabetes mellitus + Hypertension 17 (13.7%) Coronary artery disease 3 (2.4%) Chronic obstructive pulmonary disease 3 (2.4%) Family history Carcinoma 5 (4%) Endometrium carcinoma 4 (3.2%) Breast carcinoma 1 (0.8%) Negative 120 (96%) Detailed description of the extirpated and affected lymph nodes divided by area in the 125 patients with EC was shown in Table 2. The mean number of all lymph nodes removed in operation was 38.9± (range 9 to 81 nodes). The mean number of PLNs removed was 32± (range 9 to 75 nodes) and the mean number of PALNs removed was 7±5.123 (range 0 to 20 nodes).

5 Page 5 of 10 Table 2: Detailed descriptions of the extirpated and affected lymph nodes divided by area in the 125 patients with endometrial cancer Lymph node number Lymph-node areas N-status mean±sd % All region LN N0 38.9± % N+ 1.34±4.084 Total PLN N ± % N+ 1.03±3.365 PALN N0 6.93± % N+ 0.31±1.066 Right external iliac LN N0 5.12± % N+ 0.14±0.605 Left external iliac LN N0 5.01± % N+ 0.18±0.53 Right internal iliac LN N0 2.91± % N+ 0.08±0.413 Left internal iliac LN N0 1.90± % N+ 0.07±0.363 Right common iliac LN N0 4.15± % N+ 0.09±0.492 Left common iliac LN N0 4.42± % N+ 0.14±0.564 Right obturator LN N0 4.49± % N+ 0.19±0.859 Left obturator LN N0 3.96± % N+ 0.13±0.718 LN= Lymph node Nodal metastasis was shown in 24 patients (19.2%) in the study group. Detailed description of the extirpated and affected lymph nodes divided by area in the 24 patients with nodal metastasis was shown in Table 3. The mean number of all lymph nodes removed in operation was 37.88± (range 9 to 81 nodes). The mean number of PLNs removed was 30.71±14.79 (range 9 to 66 nodes) and the mean number of PALNs removed was 7.17±4.198 (range 0 to 16 nodes) (Figure 1). Isolated PLN metastasis was shown in nine (37%) patients; isolated PALN metastasis was shown in one (4%) patient; both PLN and PALN metastasis was shown in 14 (59%) patients. The most affected lymph node area was left external iliac artery with a ratio of 14 percent.

6 Page 6 of 10 Table 3: Detailed descriptions of the extirpated and affected lymph nodes divided by area in the 24 patients with nodal metastasis Lymph node number Lymph-node areas N-status mean±sd % All region LN N ± % N+ 7.00±6.972 Total PLN N ± % N+ 5.38±6.056 PALN N0 7.17± % N+ 1.63±1.974 Right external iliac LN N0 5.04± % N+ 0.75±1.225 Left external iliac LN N0 5.29± % N+ 0.96±0.859 Right internal iliac LN N0 2.38± % N+ 0.42±0.881 Left internal iliac LN N0 1.79± % N+ 0.38±0.77 Right common iliac LN N0 3.46± % N+ 0.46±1.062 Left common iliac LN N0 4.25± % N+ 0.75±1.113 Right obturator LN N0 4.54± % N+ 1.00±1.769 Left obturator LN N0 3.96± % N+ 0.67±1.551 Figure 1: Patients with positive PLNs and PALNs classified according to their localization

7 Page 7 of 10 Postoperative clinical and histopathological findings in the study group were shown in Table 4. Of the 125 patients, 93 (74.4%) were found to be FIGO stage 1 patients while 32 (25.6%) were in advanced stage (FIGO stage 2,3, and 4). Grade of differentiation was Grade 1 in 34 (19.5%) patients, Grade 2 in 123 (70.7%) patients, and Grade 3 in 17 (9.8%) patients. Histological type was adenocarcinoma in 113 (90%) patients, papillary serous carcinoma in 7 (5.6%) patients and clear cell adenocarcinoma in 3 (2.4%) patients. Table 4: Postoperative findings in the study group n (%) Clinical stage (FIGO) Ia 72 (57.6%) Ib 21 (16.8%) II 6 (4.8%) IIIa 2 (1.6%) IIIc1 9 (7.2%) IIIc2 11 (8.8%) IV a 4 (3.3%) Postoperative grade Grade 1 34 (19.5%) Grade (70.7%) Grade 3 17 (9.8%) Histological type Adenocarcinoma 113 (90%) Papillary serous carcinoma 7 (5.6%) Clear cell adenocarcinoma 3 (2.4%) Others 2 (1.6%) Removed total LN Removed PLN and PALN 39 (100%) Removed PLN 32 (82.2%) Removed PALN 7 (17.8%) Removed metastatic LN Removed metastatic PLN and PALN 38 (100%) Removed metastatic PLN 31 (81.1%) Removed metastatic PALN 7 (18.9%) Discussion Despite the unquestionable role of lymph node metastasis in EC, there is a controversy and debate about the therapeutic relevance of systematic lymphadenectomy. The rate of lymph node metastasis in endometrial cancer is usually below 15% [12]. Preoperative assessment of the lymph node involvement represents critical steps for determining the extent of surgery in patients with endometrial carcinoma. If the presence of lymph node metastasis could be predicted accurately before surgery, management plans for patients could be individualized. Earlier protocols defined that a lymph node sampling in the para-aortic region should be performed at least up to the insertion of the inferior mesenteric artery (IMA). However, recent sporadic reports revealed high rates of lymphatic metastasis above the IMA, indicating the need for systematic lymphadenectomy up to the renal vessels, equivalent to the dissection performed for epithelial ovarian cancer [13, 14]. Bakkum-Gamez et al. commented that there is no evidence that inadequate lymphadenectomy is superior to complete exclusion of lymphadenectomy [15]. ASTEC-study group showed no advantage in terms of

8 Page 8 of 10 overall survival for pelvic lymphadenectomy alone in women with early EC [16]. A comparison of the Gynecologic Oncology Group (GOG)-99 (lymphadenectomy performed) and the Post Operative Radiation Therapy in Endometrial Carcinoma (PORTEC)-trials (no lymphadenectomy performed) would also seem to suggest that lymphadenectomy does not affect survival in patients with intermediate-risk tumors confined to the uterus [17-19]. In an assessment of over 400 EC patients, Mariani et al. found that 77% of the patients with para-aortic lymphatic spread had positive lymph nodes in the area above the IMA [13]. Para-aortic lymph node involvement occurs in approximately 7-8 % of EC patients overall and in about 50 % of patients with positive pelvic nodes [20]. In the present analysis we found a considerable high rate of affected PALNs; more than 50% of them presented positive PALNs located above the IMA up to the level of the renal veins. In a study performed by Cragun et al., an association between extensive lymph node dissection (>11 lymph nodes) with a prolonged survival was found in patients they defined as a higher risk group without any macroscopic evidence of metastatic endometrial carcinoma [21]. Kilgore et al. performed selective lymphadenectomies from multiple areas in 649 patients with Stage I disease (average number of lymph nodes, 11). Better survival rates were detected in this group of patients when compared with the patients who hadn t undergone lymphadenectomies [22]. Several expert opinions have explained very improved survival rates achieved in the patients who had undergone extensive lymphadenectomies by the beneficial effect of extensive lymphadenectomy in the planning of adjuvant treatment [23, 24]. Since FIGO introduced surgical staging of EC in 1988, an essential question have remained unanswered: What is the extent of an optimal lymphadenectomy?. In various studies, different number of lymph nodes has been reportedly removed from each site. Benedetti-Panici et al. recommended removal of PLNs, and PALNs during systematic lymphadenectomies [25]. Kitchener et al. reported average number of PLNs, and PALNs removed as 20 (range 14-28), and 123 (range 8-24) respectively [11]. In their study, Köhler et al. estimated average number of PLNs, and PALNs retrieved during systematic lymphadenectomies as 22 (range 16-34), and 14 (range 12-24), respectively [26]. Vergote et al. advised removal of 20 PLNs, and 10 PALNs during systematic lymphadenectomy [27]. In our series consisting of 125 patients, on an average, totally 39 lymph nodes were dissected which comprised of 32 PLNs, and 7 PALNs. In the metastatic lymph node group (n=24 patients) mean number of PLNs and PALNs were found to be 31, and 7 pieces, respectively. In 60% of the cases with affected PLNs, PALN involvement was also detected [27]. In our series of 125 cases (incl. 24 cases with metastatic lymph nodes) who underwent systematic lymphadenectomies, nearly 80% the lymph nodes were distributed in the PLN, and 20% of them in the PALN regions. Lymph nodes were similarly distributed on the right, and the left side of the pelvis. Majority of lymph nodes were detected in the external iliac lymph node region in accordance with the lymphatic distribution, while the least number of lymph nodes were localized in the internal iliac lymph node region, bilaterally. In the endometrial cancer surgery, for the determination of adequate number of lymph nodes, lymph node mapping might guide the surgical approach. The following limitations of the current study must be acknowledged. First, this was a small scale retrospective study, and since the number of our patients was limited, only restricted conclusions can be derived from our data regarding the prognostic impact of lymph node metastases. Conclusions In the field of gynecologic cancer surgery, for the determination of adequate number of lymph nodes to be retrieved, lymph node mapping plays a crucial role, and this issue should be investigated in studies performed with larger number of cases in order to standardize procedure of lymphadenectomy.

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