Update on sentinel node mapping in uterine cancer: 10-year experience at Memorial Sloan Kettering Cancer Center

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1 bs_bs_banner doi: /jog J. Obstet. Gynaecol. Res. Vol. 40, No. 2: , February 2014 Update on sentinel node mapping in uterine cancer: 10-year experience at Memorial Sloan Kettering Cancer Center Nadeem R. Abu-Rustum Gynecology Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, USA Abstract Endometrial cancer is the most common gynecologic malignancy. In the majority of patients, the disease will present at an early stage, without metastasis, and with an excellent prognosis. Although the rate of metastasis in patients with early stage endometrial cancer is low, the standard of treatment still includes a complete or selective pelvic and para-aortic lymphadenectomy for staging. Many patients will undergo a comprehensive lymphadenectomy despite having disease confined to the uterus, resulting in detrimental side-effects, including lower extremity lymphedema. Recent studies, such as A Study in the Treatment of Endometrial Cancer, have shown that there is no therapeutic benefit to a complete lymphadenectomy in early stage endometrial cancer, although further study is needed to confirm these findings. The use of sentinel lymph node (SLN) mapping in endometrial cancer may provide an appropriate middle ground between the two schools of thought of complete lymphadenectomy versus no nodal evaluation. SLN mapping, which is gaining everincreasing acceptance in many cancer types, is based on the concept that lymph node metastasis is the result of an orderly process, that is, the lymph drains in a specific pattern away from the tumor, and therefore if the SLN, or first node, is negative for metastasis, then the nodes after the SLN should also be negative. We present here the Memorial Sloan Kettering Cancer Center experience with SLN mapping in uterine cancer, a technique we first began using in 2003 and have improved over the years. Key words: endometrial cancer, lymphadenectomy, sentinel lymph node, sentinel lymph node mapping, uterine cancer. Introduction The term sentinel node was coined by Gould in 1960 with his observations of carcinoma of the parotid gland. 1 Gould suggested that examining the sentinel lymph node (SLN) for metastatic disease could help determine whether or not a patient needed a radical neck dissection. This approach, which is gaining everincreasing acceptance in other cancers, is rooted in the idea that lymph node metastasis occurs sequentially as the lymph drains in an orderly pattern away from the tumor; therefore, if the SLN, or first node, is negative for metastasis, then the ensuing nodes should also be negative. In 1977, Cabanas 2 described the SLN in patients with penile carcinoma, this time with the use of lymphography an imaging procedure rather than simply identifying an anatomic location as Gould did. This type of image-guided procedure is known as SLN mapping, and its use has now been well established in the treatment of melanoma 3 and breast cancer. 4 SLN mapping in endometrial cancer was introduced by Burke et al. in 1996, 5 but has only gained in popularity over the last 5 years. At Memorial Sloan Kettering Cancer Center (MSKCC), we began using SLN Received: May Accepted: June Reprint request to: Dr Nadeem R. Abu-Rustum, Gynecology Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, USA. abu-rusn@mskcc.org 2013 The Author 327

2 N. R. Abu-Rustum mapping for uterine cervical cancer in 2003, and have found that when using a cervical injection in apparent early stage endometrial cancer cases, SLN are three times more likely to harbor disease than non-sln. 6 Rationale for SLN Mapping in Endometrial Cancer Endometrial cancer is the most common gynecologic malignancy; an estimated women will be diagnosed with the disease in the USA in Most endometrial cancers present at an early stage, and the majority of patients with stage I disease (90%) will not have metastasis, 8 limiting the amount of deaths to approximately 8190 per year. 7 As most of these tumors will be confined to the uterus (International Federation of Gynecology and Obstetrics [FIGO] stage I), the 5-year overall survival rate is 80 90%. 9,10 Although the rate of metastasis in this patient population is low, the standard of treatment still involves a complete or selective pelvic and para-aortic lymphadenectomy for staging disease. As with all cancers and associated treatment, a surgeon is constantly confronted with the dilemma of over- versus undertreating a patient. As some of these patients will actually have metastasis, and nearly 15% of patients deemed to have grade 1 tumors preoperatively will actually have higher grade tumors on post-hysterectomy pathology, 11 it is imperative to stage and treat these patients thoroughly, and avoid missing undetected metastatic disease that may upstage the patient and change adjuvant therapy. On the other hand, many patients will undergo a comprehensive lymphadenectomy despite having uterine confined disease. The use of SLN mapping in endometrial cancer may be the solution, providing an appropriate middle ground between the two schools of complete lymphadenectomy and no nodal evaluation. Gaining Acceptance of SLN Mapping in Endometrial Cancer Incorporating a lymphadenectomy into a surgical procedure contributes to increased operative time and blood loss, and the side-effects include lower extremity lymphedema and postoperative symptomatic lymphocyst formation. 8 Although the revised 2009 FIGO staging system still incorporates lymph node status for diagnosis and prognosis, recently reported trials have questioned the survival benefit of a comprehensive lymphadenectomy in this disease. For example, a randomized, multicenter study A Study in the Treatment of Endometrial Cancer (ASTEC) suggested there was no therapeutic benefit to lymphadenectomy in early stage endometrial cancer; 12 in the study, however, almost half of the patients randomized to the lymph node dissection arm had nine or fewer nodes removed. In a previous study we had shown that the incidence of isolated paraortic lymph node metastasis with negative bilateral pelvic nodes is less that 3% 13, and in another study, we found that the removal of 10 or more regional nodes was needed to assign select patients to the appropriate surgical stage; 14 there is, in fact, an overall lack of consensus regarding the number of nodes that should be removed in specific cases. The ASTEC trial was further criticized because many patients were treated with postoperative radiation regardless of lymph node status. As for the sideeffects of lymphadenectomy, in an early study of 1289 MSKCC patients with uterine corpus malignancies, leg lymphedema was limited to the 16 (3.4%) of 469 patients who had 10 or more lymph nodes removed at their primary surgery. 15 As the evidence mounts against the use of a comprehensive lymphadenectomy in endometrial cancer staging, more surgeons are embracing SLN mapping as a possible means of detecting microscopic disease and reducing morbidity. In a 2009 study of 42 patients with grade 1 endometrioid endometrial cancer from March 2006 to August 2008, we found that the most common anatomic sites where SLN were identified were the internal iliac (n = 52 [36%]), external iliac (n = 43 [30%]), obturator (n = 34 [23%]), and common iliac (n = 11 [8%]) regions (Fig. 1). These are areas where nodes are removed in a pelvic nodal dissection. Alternatively, para-aortic SLN involvement was identified in only five cases (3%) (Fig. 2). 11 A para-aortic lymph node dissection involves the removal of nodal tissue over the distal vena cava from the level of the inferior mesenteric artery to the mid right common iliac artery and removal of the nodal tissue between the aorta and left ureter from the inferior mesenteric artery to the left mid common iliac artery. High infrarenal para-aortic lymph node dissections have also been described, but growing evidence is beginning to identify the para-aortic nodal dissection as a possible area of overstaging, which would be limited with successful negative bilateral pelvic SLN mapping; this area of research requires further study. In another 2009 MSKCC study, 847 (44%) of 1942 patients had both pelvic and para-aortic nodes removed during initial surgery. Only 12 (1.6%) of 734 patients who had The Author

3 SLN mapping in uterine cancer Figure 1 Blue lymphatic channels leading into a right external iliac sentinel lymph node. such cases had isolated para-aortic nodal metastasis when pelvic nodes were negative. 13 We strongly believe that with a bilateral negative pelvic SLN mapping (including ultrastaging) the chance of an isolated positive para-aortic node will be less than or equal to 3%. Even the pelvic lymph nodes, which are more likely to harbor metastatic disease, may be overstaged in some cases. The most distal external iliac lymph nodes, or the circumflex iliac lymph nodes, are often removed in a routine bilateral pelvic lymphadenectomy; these nodes are usually benign, especially when other nodal areas are also negative for malignancy. 16 Removing these nodes, based on our observations, seems to cause lymphatic obstruction to the lower extremity, likely increasing the risk of leg lymphedema. 17 These observations have been recently confirmed by elegant studies from colleagues in Japan. The use of a comprehensive lymphadenectomy to stage apparent uterine-confined, early stage endometrial cancer has been consistently criticized of late, and SLN mapping is rapidly gaining acceptance, and with more research and technical development, could possibly surpass lymphadenectomy as the preferred approach. SLN Mapping Techniques Figure 2 Schematic representation of the location and approximate frequency of sentinel lymph nodes in grade 1 endometrial cancer. The proximal obturator nodes and the internal iliac nodes are anatomically difficult to distinguish and frequently overlap. negative pelvic nodes were found to have isolated positive para-aortic nodes. Using our previously published cut-off of eight or more negative pelvic nodes for an adequate pelvic node dissection, only seven (1%) of 640 SLN mapping entails the injection of a radioactive tracer and colored dye (often blue or green) to locate hot nodes or visualize colored nodes. SLN are considered positive if they contain macrometastasis (tumor clusters larger than 2 mm), micrometastasis (tumor clusters mm in size), or isolated tumor cells (single tumor cells or tumor clusters smaller or equal to 0.2 mm in size). Our group considers SLN containing only isolated cytokeratin-positive cells negative for metastasis. 15 The available SLN mapping techniques are categorized based on three different types of injections: (i) uterine subserosal; (ii) cervical; and (iii) endometrial via hysteroscopy. 18,19 At MSKCC, we have found that a cervical injection is adequate for effective SLN mapping, although others have argued that a peritumoral injection, either hysteroscopic or fundal, is more appropriate. Our rationale for using a cervical injection includes the following: (i) the main lymphatic drainage to the uterus is from the parametria, therefore, a combined superficial (1 3 mm) and deep (1 2 cm) cervical injection is adequate; (ii) the cervix is easily accessible; (iii) the cervix in women with endometrial cancer is rarely distorted by anatomic 2013 The Author 329

4 N. R. Abu-Rustum Figure 4 Sentinel lymph node mapping after cervical indocyanine green injection in endometrial cancer. The right lymphatic trunks and external iliac sentinel lymph node are shown. Figure 3 The most common drainage routes. variations, such as myomas, which sometimes make uterine serosal mapping impossible; (iv) the cervix in women with endometrial cancer is rarely scarred from prior procedures, such as conization or bulky tumor infiltration; and (v) a uterine fundal serosa mapping does not reflect the parametrial lymphatic drainage of the uterus (the main route of drainage) (Fig. 3), and the majority of early stage endometrial cancers do not have disease infiltrating and ulcerating the uterine fundal serosa. 20 Lymphoscintigraphy A radiolabeled colloid, usually technetium-99 ( 99m Tc), is injected into the cervix the day of or the day before surgery. The 99m Tc is then carried via lymph through the lymphatic capillaries to the SLN. In the short protocol (day of surgery), mci of the 99m Tc is injected. In the long protocol (20 24 h before surgery), an additional mci of colloid is used. A preoperative planar lymphoscintigram is taken min after injection for a short protocol, and immediate dynamic images and subsequent static images are taken to locate the nodes. Gamma probes, such as the C-Trak laparoscopic SLN probe or a handheld openprocedure SLN probe, are used to detect the hot nodes. Single photon emission computed tomography (SPECT), which uses 3-D localization of hot nodes also detected through a gamma probe, can be used. 21 Colored dye injection The colored dye, such as isosulfan blue 1% (Lymphazurin), Methylene Blue 1%, Patente Blue 2.5% sodium (Bleu Patente V sodique), or Indocyanine green (ICG) (Fig. 4), is injected while the patient is under anesthesia in the operating room. The dye is injected in a similar fashion to that of the radiotracer. A spinal needle or Potocky-type needle is used to inject 4 ml of dye into the cervical submucosa and stroma. The 4 ml can be divided into four separate injections, one into each quadrant of the cervix (1 ml each). The injections also can be given at the 3 and 9 o clock positions, which correspond to the parametria and will keep the bladder flap from being stained, which is seen with the 12 o clock injection (Fig. 5). 22 The dye should be injected slowly, at a rate of 5 10 s per quadrant. 19 Complications with blue dye are rare, consisting mainly of allergic reactions. A 2002 study by Montgomery et al. reported a 1.6% incidence of allergic reactions, but also a 0.5% incidence of hypotensive reactions, in 2392 breast cancer patients undergoing SLN mapping. 23 Most of the allergic reactions with blue dye include swelling and pruritis of the hands, feet, abdomen, and neck. Severe reactions include edema of the face and glottis, respiratory distress, and shock. Blue dye will also turn the urine blue-green for up to 24 h. Pathology Our institutional protocol for SLN evaluation is as follows: the initial examination is performed using hematoxylin eosin (HE) staining. If the HE assessment is negative, two adjacent 5-μm sections are cut from each paraffin block at each of two levels 50 μm apart. At each level, one side is stained with HE and the other with immunohistochemistry (IHC) using the The Author

5 SLN mapping in uterine cancer (a) (b) (c) Figure 5 Three different options for direct cervical injection: (a,b) the 4-quadrant options and (c) a 2-sided option. Courtesy Abu-Rustum et al. 22 Table 1 Incidence of HE macrometastases in sentinel lymph nodes by final histologic grade and depth of myometrial invasion DMI Grade 1 Grade 2 Grade 3 Total No invasion HE 0 HE 1 HE 1 2/242 = 0.8% n = 165 n = 39 n = 38 <50% invasion HE 6 HE 4 HE 6 16/198 = 8.0% n = 80 n = 62 n = 56 50% invasion HE 6 HE 3 HE 8 17/68 = 25.0% n = 16 n = 15 n = 37 Total 12/261 = 4.6% 8/116 = 6.9% 15/131 = 11.5% 35/508 = 6.9% With permission from Kim et al. 24 DMI, depth of myometrial invasion; HE, hematoxylin eosin. Table 2 Incidence of ultrastage-detected, low-volume metastases in sentinel lymph nodes by final histologic grade and depth of myometrial invasion DMI Grade 1 Grade 2 Grade 3 Total No Invasion MM 1 MM 0 MM 0 2/242 = 0.8% ITC 1 ITC 0 ITC 0 n = 165 n = 39 n = 38 <50% invasion MM 2 MM 0 MM 0 16/198 = 8.0% ITC 4 ITC 4 ITC 6 n = 80 n = 62 n = 56 50% invasion MM 0 MM 0 MM 1 5/68 = 7.4% ITC 2 ITC 0 ITC 2 n = 16 n = 15 n = 37 Total 10/261 = 3.8% 4/116 = 3.4% 9/131 = 6.9% 23/508 = 4.5% With permission from Kim et al. 24 DMI, depth of myometrial invasion; ITC, isolated tumor cells; MM, micrometastasis. anti-cytokeratin AE1:AE3 (Ventana Medical Systems) for a total of four slides per block. 21 With this IHC ultrastaging, we are able to detect an additional 3 4% of micrometastases to SLN, which may have been otherwise missed by routine HE staining (Tables 1,2). 6,24 26 Sentinel Lymph Node Mapping Algorithm In a study of 498 endometrial cancer patients who received blue dye cervical injections at our institution 2013 The Author 331

6 N. R. Abu-Rustum from September 2005 to April 2011, Barlin et al. showed that incorporating an SLN mapping algorithm significantly reduced the false-negative rate of the procedure (Fig. 6). 27 An SLN was identified in 401 (81%) of the 498 patients. The SLN correctly diagnosed nodal metastases in 40 of 47 patients who had at least one SLN mapped, for a 14.9% false-negative rate. After applying the algorithm, the false-negative rate dropped to 1.9%, because the algorithm takes into account any grossly enlarged suspicious nodes as well as a side-specific lymphadenectomy for the non-mapping hemi-pelvis. Only one patient with an isolated positive right para-aortic lymph node was not picked up by the algorithm. Furthermore, sensitivity increased from 85.1% to 98.1% and negative predictive value increased from 98.1% to 99.8% (Table 3). The SLN surgical algorithm entails the following: (i) peritoneal and serosal evaluation and washings; (ii) retroperitoneal evaluation, including the removal of all SLN and suspicious nodes; and (iii) if there is no Peritoneal & serosal evaluation & washings Retroperitoneal evaluation Excision of all mapped SLN w/ ultrastaging If there is no mapping on a hemi-pelvis, a side-specific LND is performed Paraaortic LND at attending discretion Any suspicious nodes must be removed regardless of mapping Figure 6 Sentinel lymph node mapping algorithm. LND, lymph node dissection; SLN, sentinel lymph node. mapping on a hemi-pelvis, a side-specific pelvic, common iliac and interiliac lymph node dissection should be performed. Performing a para-aortic lymphadenectomy is left to the attending s discretion. 27 During the earlier part of this study, a small portion of our patients received a blue dye injection into the fundus, but after approximately 75 cases, we moved more to using only cervical injections of blue dye, minimizing injections at other sites and lymphoscintigraphy, which adds to cost and patient discomfort, and in our experience, does not improve detection rates. A recent meta-analysis showed that cervical injection was significantly associated with an increased detection rate, and hysteroscopic and subserosal injection was associated with a decreased detection rate and sensitivity, respectively, 28 but prospective, randomized trials are needed to confirm these findings. Since incorporating the SLN mapping algorithm in 2008, the percentage of patients undergoing a full lymphadenectomy decreased from 65% to 23% at our institution, leading to a decrease in median operating room time of approximately 1 h and median operative time of approximately 40 min. The median number of nodes removed also significantly decreased from a median of 20 to 7. This decrease in comprehensive lymphadenectomy and number of nodes removed has not compromised the rate of detection of metastatic nodal involvement, even in stage IIIC disease, 29 which further validates the use of the algorithm. Continued Improvements in Sentinel Lymph Node Mapping The major apprehensions with SLN mapping involve the associated detection rate and false-negative rate. A false negative is a situation in which an SNL is found to Table 3 Performance of SLN alone compared to the algorithm for all patients LN positive LN negative SLN alone Calculation Result SLN positive Sensitivity 40/ SLN negative Negative predictive value 354/ False-negative rate 7/ LN positive LN negative Algorithm Calculation Result Algorithm positive Sensitivity 53/ Algorithm negative Negative predictive value 420/ False-negative rate 1/ With permission from Barlin et al. 26 LN, lymph node; SLN, sentinel lymph node The Author

7 SLN mapping in uterine cancer be negative for metastatic disease even though lymph node metastasis is in fact found during the lymphadenectomy. An acceptable false-negative rate (typically <5%) is imperative for SLN mapping to be considered a viable alternative to the current standard. A failed mapping should not be confused with a false-negative event. Failed mappings are situations in which an SLN is not identified, which is the opposite of the detection rate, 17 and in our algorithm, a failed mapping requires a side-specific lymphadenectomy to exclude disease. In our 2009 study of 42 patients with a diagnosis of grade 1 endometrial carcinoma, all node-positive cases were picked up by the SLN, and there were no false negatives. The sensitivity of the SLN procedure in the 36 patients (86%) who had an SLN identified was 100%. Surgeons should strive for an SLN detection rate of 90% or greater. 20 Khoury-Collado et al. reported on 115 patients with endometrial cancer treated at our institution from September 2005 to March 2009; their objective was to determine the SLN detection rate for these patients, but also to determine how many SLN mapping cases a surgeon needed to perform in order to reach that 90% benchmark. Most of the patients (71%) received only a cervical injection of blue dye, but 29% had a combined cervical/fundal injection or cervical injection of 99m Tc. The overall SLN detection rate was 85%. The results were then analyzed according to two study periods an early phase from September 2005 to December 2007 and a late phase from January 2008 to March During the early phase, an SLN was identified in 50 (78%) of 64 cases, with two false negatives. During the late phase, an SLN was identified in 48 (94%) of 51 cases, with no false negatives. Upon closer look, it became obvious that detection rates increased with surgeon experience with SLN mapping; the rate of successful mapping significantly increased from 77% to 94% (P = 0.033) after 30 cases. 20 Although there were no false negatives in the latter phase, there were four failed mappings: 1 One patient was morbidly obese (body mass index [BMI] of 52). 2 A second patient was also morbidly obese (BMI of 40) and had multiple prior laparotomies, including a ventral hernia repair with mesh; her surgery required the removal of her uterus before the lymphadenectomy because of limited exposure. 3 The third patient was a 72-year-old woman with a history of rectal cancer for which she had undergone a low anterior resection followed by pelvic radiation; she had dense adhesions in the pelvis, including in the retroperitoneal spaces. 4 In the fourth patient, a blue channel ending in the right external chain was identified; tissue labeled as an external iliac node was removed, but the final pathologic examination did not identify nodal tissue. As surgeons gain experience in SLN mapping for endometrial cancer and achieve detection rates of 90% or greater, with a combined decrease in false-negative rates, SLN mapping moves closer to becoming the standard procedure of surgical staging in this patient population. For now, the standard staging and treatment approach continues to include a comprehensive lymphadenectomy in many practices, but as negative reports on its therapeutic benefit (ASTEC and the study by Benedetti Panici et al. 30 ) and associated sideeffects (lymphedema) continue to be published, its status may change. Prospective studies are needed to validate the use of SLN mapping in patients with early stage endometrial cancer. Disclosure There are no conflicts of interest to disclose. References 1. Gould EA, Winship T, Philbin PH, Kerr HH. Observations on a sentinel node in cancer of the parotid. Cancer 1960; 13: Cabanas RM. An approach for the treatment of penile carcinoma. Cancer 1977; 39: Morton DL, Wen DR, Wong JH et al. Technical details of intraoperative lymphatic mapping for early stage melanoma. Arch Surg 1992; 127: Cody HS, Hill AD, Tran KN, Borgen PI. Credentialing for breast lymphatic mapping: How many cases are enough? Ann Surg 1999; 229: Burke TW, Levenback C, Tornos C et al. Intraabdominal lymphatic mapping to direct selective pelvic and paraaortic lymphadenectomy in women with high-risk endometrial cancer: Results of a pilot study. Gynecol Oncol 1996; 62: Khoury-Collado F, Murray MP, Hensley ML et al. Sentinel lymph node mapping for endometrial cancer improves the detection of metastatic disease to regional lymph nodes. Gynecol Oncol 2011; 122: Siegel R, Naishadham D, Jemal A. Cancer statistics, CA Cancer J Clin 2013; 63: Orr JW, Holloway RW, Orr PF, Holimon JL. Surgical staging of uterine cancer: An analysis of perioperative morbidity. Gynecol Oncol 1991; 42: Creasman WT, Odicino F, Maisonneuve P et al. Carcinoma of the corpus uteri. J Epidemiol Biostat 2001; 6: The Author 333

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