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ORIGINAL ARTICLES |
From the Departments of Gynecologic and Breast Tumors (EB, SU, ED), Pathology (AC, PC), and Nuclear Medicine (DG), Hôpital Tenon, Assistance Publique des Hôpitaux de Paris, Paris, France.
Correspondence: Address correspondence and reprint requests to: Emmanuel Barranger, MD, Service de Gynécologie-Obstétrique, Hôpital Tenon, 4 rue de la Chine, 75020 Paris, France; Fax: 33-1-56-01-60-62; E-mail: emmanuel.barranger{at}tnn.ap-hop-paris.fr
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Methods: Between July 2001 and June 2003, 26 patients (mean age, 50.3 years) with cervical cancer underwent a laparoscopic SN procedure based on dual labeling with patent blue and radiocolloid. After the SN procedure, all the patients underwent complete laparoscopic pelvic lymphadenectomy and laparoscopic radical hysterectomy (n = 19), the Schauta-Amreich operation (n = 5), or trachelectomy (n = 2). The results of the SN procedure were compared between 11 patients who received neoadjuvant chemoradiotherapy and 15 patients who did not receive neoadjuvant treatment.
Results: The SN identification rates were 100% in the 11 patients who underwent neoadjuvant chemoradiotherapy and 93.3% in the 15 patients who did not receive adjuvant therapy. A total of 59 SNs were removed. Eight SNs (13.6%) from five patients (19.2%) were found to be metastatic at the final histological assessment. Three SN involvements were detected by hematoxylin and eosin staining of the SN. Immunohistochemical studies identified five metastatic SNs in three patients. There were no false-negative SN results.
Conclusions: This study suggests that SN detection with a combination of radiocolloid and patent blue is feasible and accurate in patients with cervical cancer undergoing neoadjuvant chemoradiotherapy or primary surgery. The combination of laparoscopy and the SN procedure permits minimally invasive management of cervical cancer.
Key Words: Sentinel node biopsy • Laparoscopy • Cervical cancer • Neoadjuvant chemoradiotherapy • Trachelectomy
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Lymph node status is a major prognostic factor and a decision criterion for adjuvant therapy in this setting. Pelvic lymph node metastases are detected in 0% to 4.8% and 0% to 17% of patients with stage Ia and Ib cervical cancer, respectively,8–11 compared with 12% to 27% and 25% to 39% of patients with stage IIa and IIb disease, respectively.8–11 Thus, most patients with locally advanced disease derive no benefit from systematic pelvic or para-aortic lymphadenectomy; on the contrary, this procedure may increase the morbidity of combined surgery and radiotherapy.2
The sentinel node (SN) concept has been accepted in many malignancies, such as melanoma12 and, more recently, breast cancer.13 The use of SN identification procedures is well established in vulvar cancer.14–16 The feasibility and accuracy of laparoscopic and laparotomic SN procedures has been demonstrated in women undergoing primary surgery for early cervical cancer.17–24 SN procedures are not markedly affected by neoadjuvant chemotherapy of breast cancer, but no equivalent data are available on locally advanced cervical cancer treated with neoadjuvant chemoradiotherapy. In our previous study, only 2 of 13 patients underwent neoadjuvant chemoradiotherapy before a laparoscopic SN procedure, so we cannot evaluate its accuracy in this specific setting.24 The aim of this prospective study was to evaluate the feasibility and accuracy of a laparoscopic SN procedure based on dual labeling with patent blue and radiocolloid in patients with locally advanced cervical cancer after neoadjuvant chemoradiotherapy compared with patients with early cervical cancer treated by a primary surgical approach.
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PATIENTS AND METHODS |
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TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Patients with stage Ia2 or Ib1 disease, who did not qualify for neoadjuvant chemoradiotherapy, underwent a laparoscopic SN procedure, together with systematic pelvic lymphadenectomy and laparoscopic radical hysterectomy (Piver type III), the Schauta-Amreich operation, or trachelectomy, depending on the tumor size and the patient’s desire to preserve her childbearing potential.
Patients with stage Ib2, IIa, or IIb disease qualified for neoadjuvant chemoradiotherapy and underwent combined external irradiation and brachytherapy with concomitant chemotherapy. Chemotherapy was administered during the first and fourth week of radiotherapy and consisted of a cisplatin bolus (15 mg/m2) 1 hour before radiotherapy and continuous 5-fluorouracil infusion at a dose of 1000 mg/m2 for four consecutive days. The pelvic radiation dose was 40 Gy in 18 fractions over 29 days (upper limit, L4-5). A vaginal booster dose of 20 Gy was given 5 to 6 weeks after surgery by means of brachytherapy. Brachytherapy was administered with vaginal molds and cesium-137 sources. Point A was determined by measuring 2 cm along the intrauterine tandem from the superior extent of the lateral vaginal fornix and 3 cm lateral to the plane of the intracavitary system. Point P was 6 cm lateral to the midline from a point 2 cm vertically above the lateral vaginal fornix. The neoadjuvant therapies were followed by the same laparoscopic SN procedure plus systematic pelvic lymphadenectomy and radical hysterectomy (Piver type II). In accordance with our institutional guidelines, para-aortic lymphadenectomy was performed in both groups when a metastatic pelvic lymph node (detected by intraoperative pathologic examination) or a para-aortic SN was detected.
The protocol was approved by our institutional review board. All patients gave their written consent after receiving all relevant information, including the potential adverse effects of patent blue, radiocolloid, general anesthesia, and the laparoscopic procedure and the possible need to convert to open surgery.
SN Procedure
Four injections of .2 mL (20 MBq each) of unfiltered 99mTc-labeled sulfur colloid (Nanocis; CIS Bio International, Saclay, France) were made with a 25-gauge spinal needle in each quadrant of the cervix on the day before surgery. Scintigraphic images were obtained 2 hours after the injections and then every 30 minutes until the SN was visualized, by using a triple-head gamma camera (Irix; Marconi Corp., Cleveland, OH). A 5-minute static, anterior projection was acquired with a low-energy/high-resolution collimator and a matrix size of 512 x 512 pixels. When the SN was not visualized on the day of the injections, imaging was repeated the next day, 2 hours before surgery.
Under general anesthesia, the patients were placed in a low lithotomy position. A speculum was placed in the vagina, and patent blue (Bleu Patenté V; Guerbet Laboratory, Issy les Moulineaux, France) was injected pericervically with a 25-gauge spinal needle at 3 and 9 o’clock (1 mL per injection). Antimicrobial chemoprophylaxis (cefazolin 2 g intravenously) was administered at the beginning of the operation. Prophylactic subcutaneous heparin was administered the day before surgery and was continued for 10 days. For the laparoscopic procedure, after pneumoperitoneal insufflation with a Veress needle, a 10-mm laparoscope was inserted through an umbilical incision and connected to a video monitor. Three stab incisions were made in the suprapubic area: one of 12 mm in the midline (Versaport; Auto Suture Co., Elancourt, France) and one of 5.5 mm in each iliac fossa. Five instruments were used: unipolar and bipolar electrocautery forceps, scissors, grasping forceps, and a lavage system.
After patent blue injection, the pelvic and lower para-aortic regions were carefully inspected for lymph ducts and specific dye uptake by lymph nodes. "Hot" pelvic and para-aortic nodes were located by using an endoscopic gamma probe (Eurorad, Strasbourg, France) inserted through the 12-mm suprapubic trocar. Hot nodes were sought before opening the peritoneum. The gamma probe was angled laterally to avoid detection of residual radioactivity emitted from the injection site.
After the SN was located, the peritoneum was opened above the external iliac vessels to the round ligament. Each blue and/or hot node was removed separately in an endoscopic bag (Auto Suture Co.). The count rate and the position of each SN relative to the major pelvic vessels were recorded.
Laparoscopic bilateral pelvic lymphadenectomy was performed systematically after the SN procedure. All nodal tissue along the obturator fossa and the external vessels up to the iliac bifurcation was removed and extracted in an endoscopic bag. The absence of residual pelvic or para-aortic radioactivity was verified before laparoscopic radical hysterectomy. Patients with early-stage cervical cancer underwent laparoscopic radical hysterectomy (Piver type III), the Schauta-Amreich operation, or trachelectomy, as previously described.26–28 All patients with locally advanced cervical cancer underwent laparoscopic radical hysterectomy (Piver type II). All patients were operated on by the same surgeons (E.D. and E.B.).
The duration of the laparoscopic procedure was calculated from the insertion of the Veress needle to the last skin suture. The duration of the SN procedure was calculated from insertion of the laparoscope until extraction of the last SN from the abdomen.
Histopathology
SNs and other nodes were inspected by a pathologist. Grossly metastatic nodes were sectioned. Normal-appearing SNs were cut perpendicular to the long axis. All SNs were submitted to intraoperative imprint cytology. Air-dried cytological smears were prepared by scraping the cut surfaces and staining with a rapid May-Grünwald-Giemsa method. Each half-SN was sectioned at 3-mm intervals. Each 3-mm section was analyzed by four additional levels of 150 µm and four parallel sections; one was used for hematoxylin and eosin (H&E) staining. H&E-negative sections were examined by immunohistochemistry (IHC) with an anti-cytokeratin antibody cocktail (cytokeratin AE1–AE3; Dako Corp., Glostrup, Denmark). Other nodes were totally submitted and blocked individually at 3-mm distances and with H&E staining.
The size of nodal metastases was estimated with an eyepiece micrometer. Micrometastasis was defined as a single focus of metastatic disease per node, measuring no more than 2 mm. The presence of single noncohesive tumor cells was also recorded. SN were considered positive if they contained macrometastases, micrometastases, or isolated tumor cells.
Analysis of SNs
SNs were recorded as blue stained and/or hot (in vivo count exceeding three times the background). The false-negative rate was calculated as the number of procedures with a negative SN and one or more positive non-SNs divided by the number of procedures with any positive pelvic lymph node.
Statistical Analysis
Parametric and nonparametric continuous variables were compared by using Student’s t-test, and categorical variables were compared by using the 
2 test, Fisher’s exact test, or the Mann-Whitney U-test, as appropriate. P values <.05 were considered statistically significant.
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RESULTS |
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TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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In the group with neoadjuvant chemoradiotherapy, three patients had stage Ib2 disease, six had stage IIa disease, and two had stage IIb disease. All of these patients underwent laparoscopic radical hysterectomy. The mean tumor size differed significantly between groups (P < .0001; Table 1).
Both patent blue and radiocolloid were used in all SN procedures. None of the patients had evidence of lymph node involvement on magnetic resonance imaging.
Lymphoscintigraphy
Lymphoscintigraphy was always performed the day before surgery and showed 1 focus or several uptake foci corresponding to SNs in 25 of the 26 patients. The remaining patient, who had not received neoadjuvant chemoradiotherapy, had stage Ib1 disease (tumor size, 15 mm), without preoperative conization. Eight patients in the group without neoadjuvant chemoradiotherapy and four patients in the group with neoadjuvant chemoradiotherapy had bilateral hot SNs. Lymphoscintigraphy failed to visualize SN on the day of radiocolloid injection in 2 of the 11 patients with neoadjuvant chemoradiotherapy; repeat imaging the next day identified SNs in both of these patients. All the patients found the radiocolloid injection painful, but all refused analgesic drugs.
Laparoscopic SN Procedure
The mean interval between patent blue injection and the beginning of the laparoscopic SN procedure was 6 minutes (range, 5–10 minutes; no difference between groups). The mean durations of the laparoscopic SN procedure in the groups with and without neoadjuvant therapy were 15.3 minutes (range, 10–30 minutes) and 18.8 minutes (range, 10–35 minutes), respectively.
The overall rate of SN detection was 96.2% (25 of 26 patients). The patient (International Federation of Gynecology and Obstetrics stage Ib1) in whom no SN was identified by lymphoscintigraphy had no blue or hot SN detected during laparoscopy.
A total of 59 SNs were removed. Of these, 42 (71.2%) were both blue and hot; 14 (23.7%) were only hot; and 3 (5.1%) were only blue. The mean number of SNs per patient in the groups with and without neoadjuvant therapy was 2.2 (range, 1–4) and 2.5 (range, 1–5), respectively. No difference in the number of removed SNs, the SN identification rate, or the frequency of bilateral SN identification was found between groups (Table 2). The mean SN size in the groups with and without neoadjuvant chemoradiotherapy was 9.2 mm (range, 4–20 mm) and 10.7 mm (range, 3–17 mm), respectively.
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The mean total operating time in the groups with and without neoadjuvant therapy (including the laparoscopic SN procedure, complete nodal tissue removal, and radical hysterectomy) was 248 minutes (range, 180–330 minutes) and 223 minutes (range, 180–300 minutes), respectively (no difference between groups). There were no anaphylactic reactions to patent blue, no complications due to the laparoscopic SN procedure, and no conversions to laparotomy.
Histological Findings
None of the 59 SNs showed signs of malignancy on intraoperative imprint cytology. Therefore, none of the patients underwent para-aortic lymphadenectomy during the initial operation.
Eight SNs (13.6%) from 5 patients (19.2%) were found to be metastatic at the final histological assessment. Three of these five patients had not received neoadjuvant therapy. Of these eight positive SNs, three were diagnosed by H&E staining and five by IHC.
H&E staining revealed a macrometastasis and a micrometastasis (1 mm) in two SNs from one patient (stage Ib1). These two positive SNs (solely hot) were situated bilaterally, in the medial external iliac region. The SNs were the only histopathologically positive lymph nodes in this patient. In this patient, who underwent a trachelectomy, a second laparoscopic operation that included a hysterectomy, a bilateral ovarian transposition, and a para-aortic lymphadenectomy, none of 20 removed para-aortic lymph nodes was metastatic, and no residual tumor was found on the uterus. The third positive SN by H&E (macrometastasis), found in the second patient (stage Ib2), was located in the interiliac area. The SN was the only histopathologically positive lymph node in this patient.
IHC analysis revealed micrometastases in two SNs and isolated tumor cells in three SNs from three patients. The two micrometastatic SNs (one hot and blue; one solely hot), found in the same patient, were located bilaterally, in the obturator fossae. The second patient had single malignant cells in two SNs (hot and blue) located bilaterally, in the medial external iliac region. The third patient had a single malignant cell in an SN (solely blue) located in the medial external iliac region. The SNs were the only histopathologically positive lymph nodes in these four patients.
There were no false-negative SN results. No further external radiotherapy was prescribed to patients with SN micrometastases or isolated malignant cells.
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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The overall SN identification rate was 96.2%, which compares well with the results of previous studies (Table 4), in which the SN identification rate ranged from 15% to 100% according to the technique used. Wide variations in SN detection rates have been reported by authors using blue dye alone.17,18,29 Only two studies have given high identification rates (89% and 93%) with radiocolloid alone.21,30 However, in the study by Kamprath et al.,30 using radiocolloid alone, SN detection was performed extracorporeally after laparoscopic total lymphadenectomy. Previous studies based on dual labeling have given SN identification rates of 80% to 100%.19,20,22–24,30 Malur et al.31 reported that dual labeling gave a higher identification rate (90%) than labeling with patent blue alone (55%) or with radiocolloid alone (76%).
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To our knowledge, this is the first assessment of a laparoscopic SN procedure after neoadjuvant chemoradiotherapy for cervical cancer. We found no increase in perioperative complications after neoadjuvant chemoradiotherapy and found a detection rate similar to that obtained in patients treated with primary surgery. It was initially suggested that neoadjuvant chemotherapy contraindicated SN procedures in women with breast cancer because of potential changes in the lymphatic anatomy and in physiologic drainage of lymphotropic agents such as radiocolloid and patent blue.32–35 We found that lymphoscintigraphy was always conclusive when performed 2 hours after pericervical injection of radiocolloid in patients without neoadjuvant therapy. In contrast, in 2 of the 11 patients who had undergone neoadjuvant chemoradiotherapy, the SNs were detected only by lymphoscintigraphy the day after radiocolloid injection, 2 hours before surgery. This suggests that neoadjuvant chemoradiotherapy might delay SN uptake of radiocolloid. Nevertheless, our results, although preliminary, demonstrate the feasibility of a dual-labeling laparoscopic SN procedure after neoadjuvant therapy for cervical cancer.
Although we performed pericervical injections, a unilateral pelvic SN was detected in 13 (50%) of 26 patients. These data are in keeping with previous studies showing that whatever the injection site (peritumoral or cervical), the frequency of unilateral SNs varied from 50% to 61.5%.17,19,21 This relatively high rate of unilateral SNs could be explained by the following facts: the lymphatic drainage from the cervix, which is not well established, is probably not symmetrical, and the injections performed around the cervix are not strictly symmetrical. Furthermore, the pathologic pattern of pelvic lymph node metastases in cervical cancer is not systematically bilateral. Indeed, Michel et al.9 showed that unilateral pelvic nodal involvement was found in only 55.7% of patients with cervical cancer.
All but one of the SN identified in this study were located in the external iliac area, in keeping with previous reports.17–21,24 Previously reported SN detection rates in the common iliac region ranged from 0% to 17%.17–21,24 We detected no parametrial SN, possibly owing in part to the high level of background radiation related to the proximity of the cervical injection sites. Likewise, we found no para-aortic SN. Levenback et al.19 found para-aortic SNs in 9% of patients, but the presence of para-aortic SNs with or without external or common iliac SNs was not specified. Our patient with a common iliac SN also had two ipsilateral external-iliac SNs. This is in keeping with reports that skip lymph node drainage is rare in patients with cervical cancer.17–21,24 Our findings also support the concept that the main lymph drainage route in cervical cancer runs along the caudal, medial, or cephalic surface of the external iliac vein.36
Five (19.2%) of our 26 patients had nodal metastases. IHC SN examination identified occult metastasis in three patients. As in breast cancer, the prognostic significance of micrometastasis in cervical cancer is controversial. In our institution, their presence does not influence the treatment regimen. However, despite the absence of lymph node involvement and clear surgical margins around primary cervical tumors, pelvic recurrences occur in up to 10% of cases, suggesting that occult metastasis may impair the prognosis.37 Furthermore, Yabushita et al.38 showed that positive cytokeratin staining of lymph nodes containing metastases that were not identified by H&E staining was a risk factor for recurrence in patients with endometrial cancer.
Two main end points are used to assess the success rate of SN procedures: the SN identification rate and the false-negative rate. The latter is particularly important, because it may influence the risk of recurrence and patient survival. In our series, no metastatic lymph nodes were found when the SN was negative, even after neoadjuvant chemoradiotherapy. Levenback et al.16 reported a false-negative result in a patient with a positive medial parametrial node that was resected with the primary tumor (Table 4).19 [[38–41]]Malur et al.31 observed 1 false-negative case in a series of 50 patients but did not state the location of the positive node.
The SN procedure is promising in cervical cancer, although experience is too limited to recommend replacing systematic pelvic lymphadenectomy with SN biopsy. The main advantage of SN procedures is that they may improve intraoperative histological analysis because they are limited to a few nodes that may benefit from multiple sectioning. From the clinical point of view, the feasibility of the SN procedure could modify therapeutic strategies to select patients who could benefit from a trachelectomy, to decide on a para-aortic lymphadenectomy, or to renounce surgical treatment in case of lymph node involvement. Moreover, the use of a laparoscopic SN procedure, combined with laparoscopic radical hysterectomy or the Schauta-Amreich operation, may contribute to minimal-access surgery.
In conclusion, this study suggests that a dual-labeling laparoscopic SN procedure is feasible and accurate in patients with cervical cancer, whether or not they have undergone neoadjuvant chemoradiotherapy.
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FOOTNOTES |
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Received for publication September 5, 2003. Accepted for publication December 22, 2003.
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REFERENCES |
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TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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This article has been cited by other articles:
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  E. Barranger, C. Coutant, A. Cortez, S. Uzan, and E. Darai Sentinel node biopsy is reliable in early-stage cervical cancer but not in locally advanced disease Ann. Onc., August 1, 2005; 16(8): 1237 - 1242. [Abstract] [Full Text] [PDF]
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