Prospective clinical study of sentinel node detection in bladder cancer using a hybrid tracer - Towards replacement of pelvic lymph node dissection in cases with sentinel node visualization on SPECT/CT?

Abstract

Purpose: Nodal staging in patients with muscle invasive bladder cancer (MIBC) or very high risk non-muscle invasive bladder cancer (vhNMIBC) aids to predict survival. The sentinel node (SN) procedure holds the promise to identify the diagnostically relevant first tumor-draining nodes while limiting the complication rate associate with a pelvic lymph node dissection (PLND), still considered the gold standard of nodal staging. Following an initial technical feasibility study, we prospectively evaluated the clinical impact of using peri-tumoral injections with the hybrid tracer indocyanine green (ICG)-^99mTc-nanocolloid for SN procedures in bladder cancer.

Methods: A total of 30 patients with vhNMIBC or MIBC, cN0M0 (with or without neo-adjuvant systemic therapy) scheduled for radical cystectomy with pelvic lymph node dissection (PLND) were enrolled in a prospective study. Patients received four to six transurethral peritumoral injections of ICG-^99mTc-nanocolloid into the bladder for SN tracing. Preoperative lymphoscintigraphy and Single Photon Emission Computed Tomography (SPECT)/CT was performed the day before surgery. The intraoperative detection of SNs was supported by both fluorescence (utilizing a hand-held camera or fluorescence laparoscope) and radio-guidance (using hand-held, laparoscopic or DROP-IN probe tracing). Resected specimens, comprising both SNs and PLND tissue, were analyzed by the pathologist. Complications related to the tracer injection were documented and cancer-specific survival (CSS) and overall survival (OS) were studied using Kaplan-Meier survival curves.

Results: SPECT/CT imaging revealed 31 SNs in 19 patients with non-visualization of SN in 11 patients (36.7%). During surgery, 4 additional SNs were identified based on fluorescent signals in 3 patients. In 1 patient who underwent open cystectomy, ex vivo evaluation of the PLND-specimen revealed an additional radioactive SN. The PLND yielded 592 lymph nodes (LNs; median 17 LNs/patient). In 5 out of 35 SNs (14.2%; no additional tumor positive LN in complementary PLND) and 3 out of 592 LNs (0.5%; 2 patients with non-visualization of SN) were identified as tumor-positive upon pathological evaluation. At mean follow up of 82 months (SD ± 7.1 months) 17% of patients died of disease. The 2 patients with non-visualization of SN and nodal metastases (0%) did worse than SN positive patients (75%). Of the 24 patients classified as pN0 8% died.

Conclusions: Preoperative SN-visualization on SPECT/CT was achieved in the majority of patients. Patients with SN non-visualization had an increased risk of nodal metastases and poorer outcome. In patients with metastases in the SN no additional nodal metastases were found in the complementary PLND.

Keywords: Bladder cancer; Fluorescence; Radio-guided surgery; Robotic surgery; Sentinel lymph node.

Fig. 1

Graphic workflow of pre- and intra-operative imaging, surgical approach and histopathology. A Needle puncturing the bladder wall during flexible cystoscopy for injection of the hybrid tracer ICG-^99mTc-nanocolloid. B SPECT/CT showing bilateral SNs (C) Patients underwent either open or robotic surgery, aided by intra-operative radioactivity and (D) intra-operative fluorescence. E Histopathology evaluation of SN specimen. In brown Keratine AE 13/1 staining, containing metastasis. Abbreviations: ICG = indocyanin green, SPECT/CT = Single photon emission computed tomography – computed tomography, SN = sentinel node, PLND = pelvic lymph node dissection

Fig. 2

SN locations by anatomy. Graphical distribution of SNs locations: A At Pre-operative SPECT/CT imaging (13/31 SNs in Obturator area, 3/31 SNs in common iliac, 13/31 SNs in external iliac, 1/31 SNs in internal iliac, 1/31 SNs in paravesical area). B At intra-operative detection (14/35 SNs in Obturator area, 3/35 SNs in common iliac, 14/35 SNs in external iliac, 1/35 SN in internal iliac region, 2/35 SNs in paravesical area, 1/35 SNs in Marcille fossa, 1/35 unknown (detected ex vivo from PLND template)). C Of positive SNs at histopathology (4/35 SNs in external iliac, 1/35 SNs in obturator region found to harbor metastases). Abbreviations: SN = Sentinel node; SPECT/CT = Single photon emission computed tomography – computed tomography; PLND = pelvic lymph node disscetion

Fig. 3

Preoperative SPECT/CT SN imaging. A: fusion of low-dose CT and SPECT image with localization of SN (green arrow). B SPECT imaging (C) Low dose CT with localization of SN (green arrow). D A 3D volume rendering of SPECT/CT image. In this patient, an intense SN was seen on the left obturator region marked with by the green arrow, on the right a faint SN was seen on SPECT/CT in the right obturator region, as better shown in the 3D volume rendering.. Abbreviations: CT = computed tomography; SPECT = Single photon emission computed tomography; SN = Sentinel node

Fig. 4

Example of robotic sentinel node identification using a fluorescence camera in combination with a drop-in gamma probe. A and B Intraoperative fluorescence detection with Firefly fluorescence laparoscope. C and D intraoperative of image of localizing a sentinel node with C with gamma Drop-in probe and in D same node confirmed with fluorescence imaging

Fig. 5

Kaplan Meier survival curves. Kaplan–Meier curves of (A) Overall survival (log-rank test, p value = 0.015), B Cancer specific survival (log-rank test, p value < 0.001). Abbreviations: Left overall survival, right cancer specific survival. Red curve = pN + patients with no visualization of SN, Blue curve = pN + with tumor positive SN, Green curve is pN0 patients