Can a Sentinel Node Mapping Algorithm Detect All

Ann Surg Oncol DOI 10.1245/s10434-014-4245-x

ORIGINAL ARTICLE – GYNECOLOGIC ONCOLOGY

Can a Sentinel Node Mapping Algorithm Detect All Positive Lymph Nodes in Cervical Cancer? Rosyane Rena de Freitas, MD, MSc1,2, Glauco Baiocchi, MD, PhD3, Se´rgio Bruno Bonatto Hatschbach, MD4, Jose´ Clemente Linhares, MD4, Joa˜o Antoˆnio Guerreiro, MD4, Claudiane Ligia Minari, MD4, Reitan Ribeiro, MD4, Juliana Jung, MD5, Taiza Zukovski, MD6, and Ademar Lopes, MD, PhD7 Department of Gynecologic Oncology, Hospital Sa˜o Francisco de Assis, Jacareı´, Brazil; 2Department of Abdominal Surgery, Hospital Municipal Dr. Jose´ de Carvalho Florence, Sao Paulo, Brazil; 3Department of Gynecologic Oncology, AC Camargo Cancer Center, Sao Paulo, Brazil; 4Department of Gynecologic Oncology, Hospital Erasto Gaertner, Curitiba, Brazil; 5Department of Pathology, Hospital Erasto Gaertner, Curitiba, Brazil; 6Instituto de Medicina Nuclear do Parana´, Curitiba, Brazil; 7Department of Pelvic Surgery, AC Camargo Cancer Center, Sao Paulo, Brazil 1

ABSTRACT Objectives. The aims of this study were to determine the sensitivity and negative predictive value (NPV) of sentinel lymph node (SLN) detection in cervical cancer using a combination technique, and to test the SLN algorithm that was proposed by the Memorial Sloan Kettering Cancer Center (MSKCC). Methods. The study included 57 FIGO stage IA2–IIA patients who were treated at the Erasto Gaertner Hospital, Curitiba, from 2008 to 2010. The patients underwent SLN mapping by technetium lymphoscintigraphy and patent blue dye injection. Following SLN detection, standard radical hysterectomy, including parametrectomy and systematic bilateral pelvic lymphadenectomy, was performed. The SLNs were examined by immunohistochemistry (IHC) when the hematoxylin and eosin results were negative. Results. The median age of patients was 42 years (range 24–71), the median SLN count was 2 (range 1–4), and the median total lymph node (LN) count was 19 (range 11–28). At least one SLN was detected in 48 (84.2 %) patients, while bilateral pelvic detection of SLNs was noted in 28 (58.3 %) cases—one case had bilateral pelvic SLNs and a para-aortic SLN, 19 (39.6 %) had unilateral pelvic LNs, and one (2.1 %) had an SLN in the para-aortic area. Metastatic LNs were found in 9 of 57 (15.8 %) patients. Eight

Ó Society of Surgical Oncology 2014 First Received: 10 August 2014 R. R. de Freitas, MD, MSc e-mail: [email protected]

of nine patients with LN metastasis had a positive SLN, yielding an overall sensitivity of 88.9 % and NPV of 97.5 %. Of the 75 sides that were mapped, the SLN detection method predicted LN involvement in 74 (98.6 %) hemi-pelvises. A total of ten hemi-pelvises had LN metastasis, nine of which involved the SLN, resulting in a sensitivity of 90 %, NPV of 98.5 %, and a false negative (FN) of 10 %. In two cases (4.2 %), the SLN was positive only after IHC. Conclusions. Our SLN procedure is a safe and accurate technique that increases metastatic nodal detection rates by 4.2 % after IHC. The SLN method performed better when analyzing each side; however, one FN occurred, even after applying the MSKCC algorithm. Cervical cancer is the third most common cancer among women worldwide, with approximately 500,000 new cases per year and over 250,000 deaths.1 Although lymph node (LN) status is not included in the current International Federation of Gynecology and Obstetrics (FIGO) staging system,2 it is considered the most important prognostic factor of early disease after surgical treatment.3–5 Moreover, adjuvant treatment is tailored after the diagnosis of LN metastasis because these patients should receive adjuvant chemoradiation.6 The standard procedure for metastatic LN diagnosis in cervical cancer remains systematic LN dissection (LND). However, because the entire lymphatic basin is resected, LND is associated with high morbidity, such as vascular injury and increased blood loss, longer surgery, nerve injury, lymphocysts, deep venous thromboembolism, and lower-limb lymphedema.7,8 Conversely, the prevalence of

R. R. de Freitas et al. TABLE 1 Clinical and pathological characteristics of the 57 patients with cervical cancer who underwent a sentinel node procedure

Study Design and Patients

Variable Age [years; median (range)]

42 (24–71)

Body mass index [kg/m2 (range)]

24.1 (17.3–32.8)

Median SLN dissected (range)

2 (1–4)

Median pelvic LN dissected (range)

19 (11–28)

Follow-up median time [months (range)]

25 (4–36) No. of patients (%)

Histologic type Adenocarcinoma

7 (12.3)

Squamous cell carcinoma

50 (87.7)

Previous conization No

30 (52.6)

Yes

27 (47.4)

FIGO stage IA2

METHODS

11 (19.3)

We performed a single-center, prospective, longitudinal study that included 61 patients who underwent radical hysterectomy and systematic bilateral pelvic lymphadenectomy at the Erasto Gaertner Hospital from March 2008 to November 2010. The Institutional Review Board approved this study and all patients provided written informed consent prior to entry into the study. FIGO stage IA2–IIA patients were included, and four patients who did not complete the SLN protocol were excluded. Thus, 57 consecutive patients were ultimately enrolled. Median follow-up time was 25 months (range 4–36), and all subjects with macrometastases received adjuvant chemoradiation. Three surgeons performed the sentinel node procedures, all of whom were surgical oncologists with experience in the sentinel node technique for melanoma and breast cancer.

IB1

29 (50.9)

IB2

14 (24.5)

IIA

3 (5.3)

Preoperative Lymphoscintigraphy

No

49 (86)

Yes

8 (14)

Up to 17 h before the procedure, a radioactive tracer that was labeled with technetium (99mTc) was injected into the four cardinal points of the uterine cervix (two mCi74 MBq). The lymphoscintigram images were obtained after 20 min. If no SLNs were found after 60 min, a late image was taken at 120 min. The sites of the SLNs were painted on the patient’s skin to guide the intraoperative search.

Presence of LVSI

Adjuvant treatment No

41 (71.9)

Radiotherapy

7 (12.3)

Chemoradiation

9 (15.8)

SLN sentinel lymph node, LN lymph node, LVSI lymphovascular space invasion, FIGO International Federation of Gynecology and Obstetrics

LN metastasis in surgically treated stage IB1 cervical cancer is low—estimated at 15 % or less.9,10 Sentinel LN (SLN) procedures have been developed to increase the accuracy of the status of the lymphatic basin, decrease the morbidity of full LND, detect micrometastatic disease, and define the site of LN metastasis in anatomic templates. SLN mapping in cervical cancer has been studied by leading gynecological oncology groups worldwide, but despite the encouraging data it has not been adopted as a standard of care.11,12 Our aims were to assess the sensitivity and NPV of our SLN procedure using a combination technique (patent blue dye and lymphoscintigraphy), and to test the SLN algorithm that was developed by the Memorial Sloan Kettering Cancer Center (MSKCC).13

Patent Blue Injection and Surgical Procedure The surgical procedures were performed in a single center, and all patients received open radical hysterectomies. After anesthesia, 1 ml 2.5 % patent blue was injected into each of the four cardinal points of the uterine cervix— 0.5 ml superficially and 0.5 ml 1-cm deep. The pelvic and para-aortic LNs were examined before the peritoneum was opened. SLNs were defined as blue and/or radioactive if the gamma probe was used. SLNs were selectively extracted, and their radioactivity was noted before and after extraction. The absence of residual radioactivity was confirmed in the LNs that remained in situ. Following the SLN procedure, standard radical hysterectomy, including parametrectomy and systematic bilateral pelvic lymphadenectomy, was performed for all patients. No SLN was submitted for frozen section analysis.

Can a Sentinel Node Mapping Algorithm Detect All Positive Lymph Nodes in Cervical Cancer? TABLE 2 Site of sentinel lymph node mapping according to detection method Laterality and site

PB (n) Tc (n) PB and Tc (n) Total [n (%)]

Unilateral pelvic mapping 1

4

14

19 (33.3)

Bilateral pelvic mappinga 0

3

25

28 (49.1)

Para-aortic SLN not mapped

1

0

1 (1.8) 9 (15.8)

0

Tc Tecnetium (99mTc), SLN sentinel lymph node, PB patent blue dye a

One patient had bilateral SLN and a para-aortic SLN was detected

Histopathology All LNs were examined histologically. SLNs were sectioned every 200 lm perpendicular to its long axis and stained with hematoxylin and eosin (H&E). If the H&E staining was negative, a section from the same level was analyzed by immunohistochemistry (IHC) using mouse monoclonal anti-cytokeratin AE1/AE3 (Dako, Carpinteria, CA, USA). Non-SLNs were processed by routine H&E staining on a single level. Isolated tumor cells (ITCs) were defined as tumor cells that measured B0.2 mm; micrometastases were defined as tumor cells [0.2 mm but B2 mm; and macrometastases were defined as tumor cells that were greater than 2 mm.14 Statistics A positive SLN was defined as an LN that contained a macrometastasis, a micrometastasis, or ITCs. A true positive (TP) was defined as having at least one positive SLN; a true negative (TN) was defined as all LNs (SLNs and nonSLNs) being negative; and a false negative (FN) was defined as all SLNs being negative and at least one nonSLN being positive. Because a positive SLN indicated node metastasis, false-positive results could not arise. A ‘side-specific’ analysis was also performed, considering each hemi-pelvis as a distinct unit. Descriptive statistics were generated for the entire cohort. Sensitivities, negative predictive values (NPVs), and FN rates were calculated. The database was constructed using SPSS, version 16.0 for Mac (SPSS, Inc., Chicago, IL, USA). The association between variables was analyzed using the v2 or Fischer’s exact test. For all tests, an alpha error up to 5 % (p \ 0.05) was considered significant. SLN statistics solely included patients with SLN detected. RESULTS Overall, 57 patients were included in the study, with a median age of 42 years (range 24–71). Their

clinicopathological characteristics are shown in Table 1. There were seven (12.3 %) cases of adenocarcinoma, and 50 (87.7 %) cases of squamous cell carcinoma. Twentyseven (47.4 %) cases underwent previous conization. The median body mass index (BMI) was 24.1 (range 17.3–32.8), the median SLN count was 2 (range 1–4), and the median total LN count was 19 (range 11–28). During follow-up, one patient experienced a locoregional relapse, received chemoradiation, and had a followup time of 9 months after recurrence. This patient had a tumor size of 2 cm, absence of lymphovascular space invasion, and no LN metastases. Fifty-five patients (96.5 %) remained alive, with no evidence of disease, and one patient died from other causes. The patients with LN metastasis that was detected by IHC did not receive adjuvant treatment and were alive with no evidence of disease after 20 and 27 months of follow-up. Sentinel Node Detection Rate and Laterality Forty-eight (84.2 %) patients had at least one SLN detected and were subjected to further statistical analysis. Bilateral pelvic SLNs were observed in 28 (58.3 %) cases—one case had bilateral pelvic SLNs and a paraaortic SLN, 19 (39.6 %) had unilateral pelvic SLNs, and one (2.1 %) had only an SLN in the para-aortic area. Of the patients who had unilateral pelvic LNs, 14 (73.7 %) were labeled by 99mTc and patent blue, four (21 %) were labeled by Tc only, and one (5.3 %) was stained with patent blue only. In patients with bilateral pelvic LNs, 24 (88.9 %) were labeled by 99mTc and patent blue, and three (21 %) were detected by 99mTc only. 99mTc alone detected the only case with an isolated para-aortic SLN, while the case with concomitant bilateral and paraaortic SLNs was labeled by 99mTc and patent blue (Table 2). A total of 88 SLNs were dissected from the 48 patients. In 55 cases (62.5 %), 99mTc and patent blue marked the SLN. The detection rates with 99mTc alone and patent blue alone were 28.4 % (25 cases) and 9.1 % (8 cases), respectively. Notably, six of eight patients with SLNs that were stained solely by patent blue had SLNs that were detected by preoperative lymphoscintigraphy. Of the 114 possible hemi-pelvises, 75 (65.8 %) sides were mapped, and 39 (34.2 %) sides failed to be mapped with either blue dye or 99mTc (Table 3). We were more likely to find SLNs after conization, which failed to be detected in 1 of 27 patients (3.7 %) with previous conization, compared with 8 of 30 (26.7 %) who did not have previous conization (p = 0.73). Moreover, BMI was not related to SLN detection failure (p = 0.79). All nine patients with unmapped SLNs had negative pelvic LNs.

R. R. de Freitas et al. TABLE 3 Sentinel lymph node mapping defined as patient-specific vs. side-specific, and performance of different criteria Variable

Patient-specific [n (%)]

Side-specific [n (%)]

At least one SLN mapped

48 (84.2)

75 (65.8)

Failed mapping

9 (15.8)

39 (34.2)

Bilateral pelvic mapping Sensitivity

28 (49.1) 88.9a

NA 90b

NPV

97.5a

98.5b

False negative rate

11.1

a

10b

method predicted LN involvement in 74 (98.6 %) hemipelvises. A total of ten hemi-pelvises had LN metastasis, nine of which involved the SLN, resulting in a sensitivity of 90 %, NPV of 98.5 %, and FN rate of 10 % (1/10) (Table 3). The sole side-specific FN had a negative SLN and a non-sentinel pelvic metastatic LN. Notably, it was a patient that had both 99mTc and patent blue SLN found bilaterally. One side harbored a positive SLN, and the contralateral side contained a positive non-SLN with a negative SLN. There were no enlarged or clinically suspicious LNs.

SLN sentinel lymph node, NPV negative predictive value a

Patient-specific

b

Side-specific

Considering the unmapped cases, there was a similar failure rate between the three surgeons, who had SLNs unmapped in 15.8 % (3/19), 16.6 % (4/24), and 14.2 % (2/14) of cases. With regard to SLN site, 48 SLNs (54.5 %) were found in the obturator region, 38 SLNs (43.2 %) lay in the external iliac area, and two were in the para-aortic region (2.3 %). We did not detect any parametrial SLNs but recorded 2 parametrial nonsentinel nodes in 1 patient without metastasis. Histopathology Of the 48 patients who had SLNs that were detected, eight (16.7 %) developed SLN metastasis. In two cases (4.2 %), the SLN was positive only after IHC, representing 25 % of all positive SLNs. The two micrometastases were 0.5 mm and 0.65 mm in size. For these two patients, the only positive LN was the SLN—all non-SLNs were negative. Patient-Specific Analysis We noted metastatic LNs in 9 of 48 patients (18.7 %), eight of whom had a positive SLN, yielding a sensitivity of 88.9 % and NPV of 97.5 %. The only patient with a falsenegative SLN had FIGO stage IA2 disease. The SLN was detected by 99mTc on only one side, and a contralateral positive node was found after LND. There were no enlarged or clinically suspicious LNs. This finding resulted in an FN rate of 11.1 % (1/9) (Table 3). Side-Specific Analysis Of the 75 sides that were mapped, including the patient with bilateral pelvic SLNs and a para-aortic SLN, the SLN

DISCUSSION Our study confirms the feasibility of this sentinel node detection procedure using a combination of labels (patent blue and 99mTc), and our findings are consistent with previous studies. The overall detection rate was 84.2 %, but bilateral detection was seen in only 49.1 % (28/57) of cases. Moreover, of the 48 cases with SLN detected, bilateral detection was found in 58.3 % (28/48) of cases. Overall sensitivity was 88.9 %, and the NPV was 97.5 %. In 2008, Altgassen et al.15 performed a multicenter validation trial, reporting a lower overall sensitivity (77 %), in which 42 % of patients mapped bilaterally. They applied a uniform mapping method and their results (low sensitivity) might reflect a learning curve effect. In the subsequent SENTICOL study,16 SLN procedures were implemented using a combination method (blue dye and Tc), generating a sensitivity and NPV of 92 and 98.2 %, respectively, as well as greater bilateral mapping (76 % of patients). The overall FN rate was 8 % (2/25 patients), but no FN was detected among patients with SLNs in both hemi-pelvises. These positive results might be attributed in part to the inclusion of small tumors, the use of two tracers, and surgeons who were experienced in the SLN technique. We also used two tracers, but 25 % of our patients had larger or more advanced tumors (stage IB2 or IIA), and our low rate of bilateral finding might reflect our initial unfamiliarity with the method. The theoretical advantage of using two tracers was not corroborated by Cormier et al.,13 who failed to note any significant differences in the diagnostic performance of the SLN technique with blue dye and Tc compared with blue dye alone. This group also claimed that both tracers are important only when learning to apply the SLN technique in cervical cancer. However, as other studies have suggested, the detection rate rises when Tc is added to blue dye,15,17 with detection rates ranging from 80 % to 100 %;15–19 thus we opted to use both tracers in our study. The rate of bilateral sentinel detection varies between 19 % and 90 %.15, 17,18,20–22 Most groups support the value

Can a Sentinel Node Mapping Algorithm Detect All Positive Lymph Nodes in Cervical Cancer?

of bilateral detection and argue that lymphatic drainage involves both pelvic sides, because the cervix is a midline organ. This hypothesis claims that SLN status on one side of the pelvis does not predict the presence or absence of metastasis on the contralateral side.12 Although unilateral LN metastases have been reported in 73 % of patients,23 some studies have suggested that unilateral SLN detection is inadequate and that SLNs should be evaluated per side, not per patient.17,24,25 In our series, 41.7 % of patients with unilateral SLNs should still undergo full unilateral LND if this model is valid. Cormier et al.13 performed a side-specific (each hemipelvis is a distinct unit) and patient-specific (in which each individual patient represents a diagnostic entity) analysis, the former of which had better diagnostic performance (sensitivity 92.6 vs. 87.5 %, NPV 98.9 vs. 96.8 %, and FN rate 7.4 vs. 12.5 %). Notably, 83 % (5/6) of the metastatic LNs were grossly abnormal on the sides that were not successfully mapped. Our study is consistent with the study by Cormier et al. Nevertheless, it is generally accepted that if an SLN is found in a hemi-pelvis, it nearly always predicts the status of that side.26 The most common exception is parametrial nodes that are difficult to identify due to cervical proximity, and are ultimately diagnosed after definitive specimen analysis.10,13,17 In our series, no metastatic parametrial nodes were detected. The only FN in the side-specific analysis had a negative SLN and a non-sentinel pelvic metastatic LN, which developed in a patient who had SLNs bilaterally that were labeled by Tc and patent blue. On one side there was a positive SLN, and the contralateral side contained a positive non-sentinel node with a negative SLN. There were no enlarged or clinically suspicious pelvic LNs. Cormier et al. (MSKCC) 13 proposed an algorithm to map SLNs in which side-specific evaluation is combined with the removal of clinically suspicious LNs and parametrectomy. They suggested that after applying the algorithm, nearly 75 % of patients could be spared from complete bilateral LND. However, in our study, the MSKCC algorithm could not determine the only FN to be side-specific because there was no suspicious LN and no parametrial LN involvement. Because this patient had a contralateral positive node, she would have been correctly staged and received the proper adjuvant treatment. However, if the MSKCC algorithm was applied to the only case with an FN in the patient-specific analysis, the FN rate would have been 0 % because the contralateral side metastases (where no SLN was found) would not have been missed after LND. One advantage of the SLN procedure is its ability to examine potentially unusual locations.13,27 Cormier et al.13 found parametrial and para-aortic SLNs in 3 % of cases

each, while other studies have described SLNs in the presacral area in nearly 5 % of cases.28–30 We failed to detect SLNs in the parametrium or presacral area, but two patients had para-aortic SLNs (both negative); these nodes might have gone unnoticed if they had not been mapped, potentially causing an FN. Another advantage of the SLN technique is its higher metastatic detection rate due to the serial sectioning and IHC.31 Ultrastaging allows one to identify micrometastases, which is associated with a worse prognosis.32–35 Recently, Cibula et al.36 analyzed the prognostic value of micrometastases in a large series of 645 patients from eight centers and found that the presence of micrometastases in SLNs correlated with a significant decline in overall survival, equaling that of patients with macrometastases. These data support the value of SLN biopsy and ultrastaging analysis in the management of cervical cancer. In our study, 25 % of metastatic patients were detected only after IHC; these cases would have been misdiagnosed if only routine LN analysis had been performed. CONCLUSIONS Overall, our series was comparable in size to most of the notable studies on this topic and contributes valuable data to the literature. The SLN procedure is a safe and accurate technique that increases metastatic nodal detection rates by 4.2 % after IHC. The SLN method performed better after side-specific analysis, but one FN occurred, even after the MSKCC algorithm was applied, possibly reflecting a learning curve, which is to be expected after widespread use of the SLN procedure in the management of cervical cancer. Notably, new dyes such as indocyanine green and near-infrared fluorescence imaging may improve the detection rates.37 However, the robotic platform is not available in most developing countries where cervical cancer is a public health problem. We also believe that the SLN method should go beyond the identification of either blue or hot nodes, and the MSKCC algorithm is a good approach for patients with early cervical cancer, but should be validated by other studies. REFERENCES 1. Jemal A, Bray F, Center MM, et al. Global cancer statistics. CA Cancer J Clin. 2011;61(2):69–90. 2. Pecorelli S, Zigliani L, Odicino F. Revised FIGO staging for carcinoma of the cervix. Int J Gynaecol Obstet. 2009;105:107–8. 3. Delgado G, Bundy B, Zaino R, Sevin BU, Creasman WT, Major F. Prospective surgical–pathological study of disease-free interval in patients with stage IB squamous cell carcinoma of the cervix: a Gynecologic Oncology Group study. Gynecol Oncol. 1990;38:352–7.

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