REVIEW URRENT C OPINION
Sentinel lymph node biopsy in the management of gynecologic cancer David Cibula a, Maaike H.M. Oonk b, and Nadeem R. Abu-Rustum c
Purpose of review To summarize current knowledge and recent advances in sentinel lymph node (SLN) concept in the three most frequent gynecological cancers. Recent findings In cervical cancer, SLN biopsy and ultrastaging has high sensitivity in lymph node staging in patients with bilaterally detected SLN. The presence of micrometastasis is associated with shortened survival. In endometrial cancer, SLN biopsy incorporating an institutional mapping algorithm and ultrastaging has been shown to significantly reduce false-negative rates and increase sensitivity and negative predictive value. Summary SLN biopsy and ultrastaging is useful in current management of patients with early-stage cervical cancer for multiple reasons, such as the reliable detection of key lymph nodes, identification of micrometastasis and intraoperative triage of patients. Although a complete or selective pelvic and paraaortic lymphadenectomy for adequate staging remains the standard treatment approach in patients with early-stage endometrial cancer, SLN biopsy has been shown to be safe and effective in detecting lymph node metastases. The application of the SLN procedure is safe in patients with early-stage unifocal squamous cell cancer of the vulva (2 cm largest diameter) (P ¼ 0.042) and in the presence of LVSI (P ¼ 0.004). 68
www.co-obgyn.com
&&
&&
&&
ENDOMETRIAL CANCER Of the estimated 52 630 women who will be diagnosed with endometrial cancer in 2014 [16], approximately 90% will present with early-stage disease [17]. Despite the low rate of metastases in this patient population, the standard of therapy still includes a complete or selective pelvic and paraaortic lymphadenectomy for adequate staging, which is the most important prognostic factor [17]. However, the number of lymph nodes removed during staging has a correlative association with potential side-effects, particularly lower leg lymphedema. Furthermore, Volume 27 Number 1 February 2015
Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
Sentinel lymph node in gynecologic oncology Cibula et al.
two large randomized, prospective studies have shown no survival benefit with the use of a comprehensive lymphadenectomy in early-stage endometrial cancer [18,19], thus, opening the door for the increasing use of sentinel lymph node (SLN) mapping in these patients. SLN mapping in the treatment of endometrial cancer has evolved considerably since Burke et al. [20] first introduced the method in 1996. Burke et al. used injections of isosulfan blue dye into the subserosal myometrium during laparotomy to identify ‘targets for selective nodal biopsy’. Currently, Memorial Sloan Kettering Cancer Center uses a combined superficial (1–3 mm) and deep (1–2 cm) cervical injection for SLN mapping in patients with endometrial cancer, although others have argued for uterine subserosal injections or endometrial injections via hysteroscopy. The evolution of SLN mapping in endometrial cancer continues, however, as we, as gynecologic oncologists, pursue advances in SLN mapping/biopsy, such as the incorporation of algorithms [21 ], ‘ultrastaging’ to minimize falsenegative rates and improve the detection of micrometastases [21 ,22,23], and the use of the latest technologies and imaging compounds [8 ]. A recent study by Barlin et al. [21 ] showed that incorporating an institutional SLN mapping algorithm significantly reduced the false-negative rate (14.9 to 1.9%) and increased sensitivity (85.1 to 98.1%) and the negative predictive value (98.1 to 99.8%) of SLN mapping in 498 endometrial cancer patients who received blue dye cervical injections. The algorithm, which takes into account grossly enlarged suspicious nodes as well as a side-specific lymphadenectomy for the nonmapping hemipelvis, is depicted in Fig. 1. Memorial Sloan Kettering Cancer Center began incorporating the SLN mapping algorithm in 2008. Since then, the rate of complete lymphadenectomy has decreased from 65 to 23% at the institution. This &
&
&
&
Peritoneal and serosal evaluation and washings
decrease has been associated with parallel decreases in median operation room time (1 h) and median operative time (40 min). The median number of lymph nodes removed has also decreased (20 to seven lymph nodes). Of note, this change in surgical practice has not compromised the rate of detection of nodal metastases [21 ]. Furthermore, the algorithm takes ‘ultrastaging’ into account. In the process of ultrastaging, if hematoxylin & eosin (H&E) assessment is negative upon staining, two adjacent 5-mm sections are cut from each paraffin block at each of two levels 50 mm apart. At each level, one side is stained with H&E and the other with immunohistochemistry using the anticytokeratin AE1:AE3, totaling four slides per block [24]. In recent studies, immunohistochemistry ultrastaging was able to detect up to an additional 4.5% of low-volume metastases to SLNs (four of 508 patients with micrometastases, and 19 of 508 patients with isolated tumor cells), which could possibly have been missed by routine H&E staining [22,23]. These studies also supported the use of pathologic ultrastaging of SLNs in endometrial cancer in the presence of myoinvasion [23]. Twenty (87%) of the 23 patients with ultrastage-detected low-volume metastases also had some degree of myoinvasion as opposed to only 0.8% in those with no myoinvasion, which if further validated, may indicate that ultrastaging in patients with no myoinvasion is superfluous and unnecessary [22,23]. Yet another advancement in SLN mapping for the treatment of patients with endometrial cancer has been the incorporation of NIR fluorescence imaging with the fluorophobe indocyanine green (ICG). A recent study of 227 patients with uterine or cervical cancer showed an improved bilateral detection rate, which is a better clinical indicator of a successful SLN mapping than unilateral detection, in patients mapped with ICG. Bilateral mapping was achieved in 156 (79%) of 197 ICG-only cases and 23 (77%) of 30 ICG and blue dye cases, which are comparable rates, thus rendering blue dye unnecessary [8 ]. Furthermore, the bilateral SLN mapping rate using blue dye alone is 61%; it is 75% when using blue dye and technetium (99mTC), likely rendering 99mTC unnecessary as well [8 ]. &
&
Retroperitoneal evaluation Excision of all mapped SLN w/ultrastaging*
Any suspicious nodes must be removed regardless of mapping
&
VULVAR CANCER If there is no mapping on a hemi-pelvis, a side-specific LND is performed Paraaortic LND – at attending discretion
FIGURE 1. Sentinel lymph node mapping algorithm. LND, lymph node dissection; SLN, sentinel lymph node. Ultrastaging described below.
Surgical treatment of vulvar cancer patients has changed dramatically over the last 5 years. Since in 2008 the results of the Groningen International Study on Sentinel nodes in Vulvar cancer (GROINSS-V) were published, the SLN procedure has been incorporated in the standard of care for patients with early-stage vulvar cancer in many countries. GROINSS-V was a
1040-872X Copyright ß 2015 Wolters Kluwer Health, Inc. All rights reserved.
www.co-obgyn.com
Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
69
Gynecologic cancer
multicenter observational study in which patients with a negative SLN no longer underwent inguinofemoral lymphadenectomy. The eligibility criteria of this study were unifocal squamous cell cancers, less than 4 cm, without suspicious nodes at clinical examination. In 2.3% of these patients (6/259), groin recurrences were diagnosed during follow-up. This number of groin recurrences in sentinel-node negative patients seems to be at least comparable to that reported for patients with early-stage vulvar cancer treated with formal lymphadenectomy of any type. Therefore, it was concluded that it is safe to omit inguinofemoral lymphadenectomy in patients with a negative SLN [25 ]. The accuracy of the SLN procedure was confirmed by Levenback et al. [26 ] in the same category of patients. In this study of the Gynecological Oncology Group, the SLN biopsy was routinely followed by inguinofemoral lymphadenectomy. In patients with tumors less than 4 cm and a negative SLN, 2% was false negative [26 ]. Recently Robison et al. [27] published their results of the SLN procedure in 69 patients who underwent the SLN procedure, without lymphadenectomy in case of a negative SLN. They observed groin recurrences in three of the 57 patients with a negative SLN (5.3%). However, the authors mention that two of these patients had vulva recurrence preceding the groin recurrence [27]. In these cases, metastases from the recurrent local tumor are probably more likely than an ‘isolated’ groin recurrence. The SLN procedure is preferably performed by the combined technique; the combination of a radioactive tracer and blue dye. The SLN detection rate with a radioactive tracer is much higher compared with blue dye alone. Combining the tracer with blue dye is thought to make the procedure easier and the learning curve shorter. SLN biopsy using 99mTc and blue dye with ultrastaging may be considered the most cost-effective strategy based on the outcome of survival free of morbidity for 2 years [28]. The performance of a lymphoscintigram preoperatively is thought to be useful, as it identifies the site (unilateral or bilateral) and number of SLNs that should be removed. Coleman et al. [29 ] showed that in lateral ambiguous lesions (lesions within 2 cm of the midline, but not involving the midline), unilateral SLN identification is safe when the lymphoscintigram shows only unilateral lymphodrainage. &&
&&
&&
&
Pitfalls of the procedure Patients with multifocal disease are not thought to be suitable for SLN detection [25 ], and also patients who underwent radio(chemo)therapy on the vulva and/or groin should probably be excluded because damage to the lymph vessels might influence the &&
70
www.co-obgyn.com
procedure [30]. A SLN totally replaced by tumor can cause stasis of lymph flow and might cause bypassing of the SLN [31,32]. Preoperative imaging is therefore advised in patients eligible for SLN detection, to rule out gross nodal involvement. Earlier reviews indicated ultrasound combined with fine-needle aspiration cytology had the highest sensitivity. The high sensitivity and specificity were recently confirmed in a German study [33]. However, surgical assessment is still mandatory to accurately determine lymph node status, especially because missing metastases is often fatal. The clinical significance of micrometastases in the SLN is currently unclear. Groin recurrences have been described in vulvar cancer patients with only micrometastases in the SLN [25 ]. Review of SLN pathology of GROINSS-V data also showed that in patients with SLN micrometastases (
Sentinel lymph node biopsy in the management of gynecologic cancer David Cibula a, Maaike H.M. Oonk b, and Nadeem R. Abu-Rustum c
Purpose of review To summarize current knowledge and recent advances in sentinel lymph node (SLN) concept in the three most frequent gynecological cancers. Recent findings In cervical cancer, SLN biopsy and ultrastaging has high sensitivity in lymph node staging in patients with bilaterally detected SLN. The presence of micrometastasis is associated with shortened survival. In endometrial cancer, SLN biopsy incorporating an institutional mapping algorithm and ultrastaging has been shown to significantly reduce false-negative rates and increase sensitivity and negative predictive value. Summary SLN biopsy and ultrastaging is useful in current management of patients with early-stage cervical cancer for multiple reasons, such as the reliable detection of key lymph nodes, identification of micrometastasis and intraoperative triage of patients. Although a complete or selective pelvic and paraaortic lymphadenectomy for adequate staging remains the standard treatment approach in patients with early-stage endometrial cancer, SLN biopsy has been shown to be safe and effective in detecting lymph node metastases. The application of the SLN procedure is safe in patients with early-stage unifocal squamous cell cancer of the vulva (2 cm largest diameter) (P ¼ 0.042) and in the presence of LVSI (P ¼ 0.004). 68
www.co-obgyn.com
&&
&&
&&
ENDOMETRIAL CANCER Of the estimated 52 630 women who will be diagnosed with endometrial cancer in 2014 [16], approximately 90% will present with early-stage disease [17]. Despite the low rate of metastases in this patient population, the standard of therapy still includes a complete or selective pelvic and paraaortic lymphadenectomy for adequate staging, which is the most important prognostic factor [17]. However, the number of lymph nodes removed during staging has a correlative association with potential side-effects, particularly lower leg lymphedema. Furthermore, Volume 27 Number 1 February 2015
Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
Sentinel lymph node in gynecologic oncology Cibula et al.
two large randomized, prospective studies have shown no survival benefit with the use of a comprehensive lymphadenectomy in early-stage endometrial cancer [18,19], thus, opening the door for the increasing use of sentinel lymph node (SLN) mapping in these patients. SLN mapping in the treatment of endometrial cancer has evolved considerably since Burke et al. [20] first introduced the method in 1996. Burke et al. used injections of isosulfan blue dye into the subserosal myometrium during laparotomy to identify ‘targets for selective nodal biopsy’. Currently, Memorial Sloan Kettering Cancer Center uses a combined superficial (1–3 mm) and deep (1–2 cm) cervical injection for SLN mapping in patients with endometrial cancer, although others have argued for uterine subserosal injections or endometrial injections via hysteroscopy. The evolution of SLN mapping in endometrial cancer continues, however, as we, as gynecologic oncologists, pursue advances in SLN mapping/biopsy, such as the incorporation of algorithms [21 ], ‘ultrastaging’ to minimize falsenegative rates and improve the detection of micrometastases [21 ,22,23], and the use of the latest technologies and imaging compounds [8 ]. A recent study by Barlin et al. [21 ] showed that incorporating an institutional SLN mapping algorithm significantly reduced the false-negative rate (14.9 to 1.9%) and increased sensitivity (85.1 to 98.1%) and the negative predictive value (98.1 to 99.8%) of SLN mapping in 498 endometrial cancer patients who received blue dye cervical injections. The algorithm, which takes into account grossly enlarged suspicious nodes as well as a side-specific lymphadenectomy for the nonmapping hemipelvis, is depicted in Fig. 1. Memorial Sloan Kettering Cancer Center began incorporating the SLN mapping algorithm in 2008. Since then, the rate of complete lymphadenectomy has decreased from 65 to 23% at the institution. This &
&
&
&
Peritoneal and serosal evaluation and washings
decrease has been associated with parallel decreases in median operation room time (1 h) and median operative time (40 min). The median number of lymph nodes removed has also decreased (20 to seven lymph nodes). Of note, this change in surgical practice has not compromised the rate of detection of nodal metastases [21 ]. Furthermore, the algorithm takes ‘ultrastaging’ into account. In the process of ultrastaging, if hematoxylin & eosin (H&E) assessment is negative upon staining, two adjacent 5-mm sections are cut from each paraffin block at each of two levels 50 mm apart. At each level, one side is stained with H&E and the other with immunohistochemistry using the anticytokeratin AE1:AE3, totaling four slides per block [24]. In recent studies, immunohistochemistry ultrastaging was able to detect up to an additional 4.5% of low-volume metastases to SLNs (four of 508 patients with micrometastases, and 19 of 508 patients with isolated tumor cells), which could possibly have been missed by routine H&E staining [22,23]. These studies also supported the use of pathologic ultrastaging of SLNs in endometrial cancer in the presence of myoinvasion [23]. Twenty (87%) of the 23 patients with ultrastage-detected low-volume metastases also had some degree of myoinvasion as opposed to only 0.8% in those with no myoinvasion, which if further validated, may indicate that ultrastaging in patients with no myoinvasion is superfluous and unnecessary [22,23]. Yet another advancement in SLN mapping for the treatment of patients with endometrial cancer has been the incorporation of NIR fluorescence imaging with the fluorophobe indocyanine green (ICG). A recent study of 227 patients with uterine or cervical cancer showed an improved bilateral detection rate, which is a better clinical indicator of a successful SLN mapping than unilateral detection, in patients mapped with ICG. Bilateral mapping was achieved in 156 (79%) of 197 ICG-only cases and 23 (77%) of 30 ICG and blue dye cases, which are comparable rates, thus rendering blue dye unnecessary [8 ]. Furthermore, the bilateral SLN mapping rate using blue dye alone is 61%; it is 75% when using blue dye and technetium (99mTC), likely rendering 99mTC unnecessary as well [8 ]. &
&
Retroperitoneal evaluation Excision of all mapped SLN w/ultrastaging*
Any suspicious nodes must be removed regardless of mapping
&
VULVAR CANCER If there is no mapping on a hemi-pelvis, a side-specific LND is performed Paraaortic LND – at attending discretion
FIGURE 1. Sentinel lymph node mapping algorithm. LND, lymph node dissection; SLN, sentinel lymph node. Ultrastaging described below.
Surgical treatment of vulvar cancer patients has changed dramatically over the last 5 years. Since in 2008 the results of the Groningen International Study on Sentinel nodes in Vulvar cancer (GROINSS-V) were published, the SLN procedure has been incorporated in the standard of care for patients with early-stage vulvar cancer in many countries. GROINSS-V was a
1040-872X Copyright ß 2015 Wolters Kluwer Health, Inc. All rights reserved.
www.co-obgyn.com
Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
69
Gynecologic cancer
multicenter observational study in which patients with a negative SLN no longer underwent inguinofemoral lymphadenectomy. The eligibility criteria of this study were unifocal squamous cell cancers, less than 4 cm, without suspicious nodes at clinical examination. In 2.3% of these patients (6/259), groin recurrences were diagnosed during follow-up. This number of groin recurrences in sentinel-node negative patients seems to be at least comparable to that reported for patients with early-stage vulvar cancer treated with formal lymphadenectomy of any type. Therefore, it was concluded that it is safe to omit inguinofemoral lymphadenectomy in patients with a negative SLN [25 ]. The accuracy of the SLN procedure was confirmed by Levenback et al. [26 ] in the same category of patients. In this study of the Gynecological Oncology Group, the SLN biopsy was routinely followed by inguinofemoral lymphadenectomy. In patients with tumors less than 4 cm and a negative SLN, 2% was false negative [26 ]. Recently Robison et al. [27] published their results of the SLN procedure in 69 patients who underwent the SLN procedure, without lymphadenectomy in case of a negative SLN. They observed groin recurrences in three of the 57 patients with a negative SLN (5.3%). However, the authors mention that two of these patients had vulva recurrence preceding the groin recurrence [27]. In these cases, metastases from the recurrent local tumor are probably more likely than an ‘isolated’ groin recurrence. The SLN procedure is preferably performed by the combined technique; the combination of a radioactive tracer and blue dye. The SLN detection rate with a radioactive tracer is much higher compared with blue dye alone. Combining the tracer with blue dye is thought to make the procedure easier and the learning curve shorter. SLN biopsy using 99mTc and blue dye with ultrastaging may be considered the most cost-effective strategy based on the outcome of survival free of morbidity for 2 years [28]. The performance of a lymphoscintigram preoperatively is thought to be useful, as it identifies the site (unilateral or bilateral) and number of SLNs that should be removed. Coleman et al. [29 ] showed that in lateral ambiguous lesions (lesions within 2 cm of the midline, but not involving the midline), unilateral SLN identification is safe when the lymphoscintigram shows only unilateral lymphodrainage. &&
&&
&&
&
Pitfalls of the procedure Patients with multifocal disease are not thought to be suitable for SLN detection [25 ], and also patients who underwent radio(chemo)therapy on the vulva and/or groin should probably be excluded because damage to the lymph vessels might influence the &&
70
www.co-obgyn.com
procedure [30]. A SLN totally replaced by tumor can cause stasis of lymph flow and might cause bypassing of the SLN [31,32]. Preoperative imaging is therefore advised in patients eligible for SLN detection, to rule out gross nodal involvement. Earlier reviews indicated ultrasound combined with fine-needle aspiration cytology had the highest sensitivity. The high sensitivity and specificity were recently confirmed in a German study [33]. However, surgical assessment is still mandatory to accurately determine lymph node status, especially because missing metastases is often fatal. The clinical significance of micrometastases in the SLN is currently unclear. Groin recurrences have been described in vulvar cancer patients with only micrometastases in the SLN [25 ]. Review of SLN pathology of GROINSS-V data also showed that in patients with SLN micrometastases (
