Sentinel node detection in muscle-invasive urothelial bladder cancer is feasible after neoadjuvant chemotherapy in all pT stages, a prospective multicenter report

The results of this prospective investigation show that SNd is feasible in NAC patients as well as in chemo-naïve patients, w/wo downstaging to pT0. The concept of the SN was first described by Gould et al. in the parotid gland [14] and clinically implemented by Cabanas in penile cancer [15]. One definition of the SN describes it as the initial lymph node to which the tumor drains [16]. The SN is considered being specific for a given tumor and the SN content reflecting the status of regional lymphatics. SN biopsy became well established in malignant melanoma and breast cancer. Utilized markers for detection were blue dye and radioactive tracers, yet a standardized method was lacking. How to deposit the tracers differed between investigators. The choice of radioactive tracer can also differ as, for example 99-m Tc-labeled Albures (Amersham Health, Buckinghamshire, England) with 250–500 nm particles displaying slow kinetics compared to Nanocoll with a much smaller carrier and subsequently much faster kinetics [7]. Other factors can affect the levels of accumulated tracers in a given SN; firstly, the position in the drainage order and the number of lymphatic vessels exit the individual node. Secondly, the lymph flow rate being influenced by physical exercise, medication and hydration status. In case of metastatic spread, the metastatic deposit may obstruct the entrance of lymph flow, leading to redirection of the lymphatics resulting in FN detection. This was seen in the current material where the majority of the metastasized lymph nodes were found in non-SNs. Hypothetically, chemotherapy might affect tumor lymph drainage by increasing the level of cell debris, thus obstructing lymph pathways in pN+ patients. The subgroup of lymph node metastasized patients is also too small for drawing any conclusions. The SN concept was introduced and shown feasible in MIBC in 2001 [7, 8]. Injections of tracer in MIBC-SNd are performed at four peritumoral positions of the tumor or tumor scar, preferably in non-tumorous detrusor muscle. The method was reproduced at an independent center [11], and both research groups found that >1 SN/tumor was often detected and that utilizing the handheld Geiger meter resulted in the highest SN yield. Liedberg et al detected SNs in 87 % with mean of 2.4 SN/patient. This in line with the results of the current study shows detection rates of 84.6 % (SNdef1) and 92.4 % (SNdef2) with means of 3.42 and 3.49 SNs, respectively. To define all radioactive nodes as SNs appears problematic. In melanoma, Kroon et al [13] found that defining the SN as 50 % of the hottest node yielded a FN rate of 7 %. A stepwise increase in FNR was seen for every added 10 %. In contrast to previous endeavors on SNd in MIBC, we focused on Geiger meter detected SNs and applied two different SN definitions. The 10 % rule yields a slightly larger number of SNs and a higher mean of SN/patient while decreasing the mean of FN nodes. The difference is greatest in the subgroup of chemo-naïve patients (Table 4). Regardless of SN definition, neither pT stage subgroup nor NAC affects the number of true positive SNs. SNd in postresection scars has also been feasible in penile cancer after previous removal of primary tumor [17]. The effect of NAC on SN biopsies was studied thoroughly in breast cancer showing increase in FNR [18]. However, the parallel to MIBC is not fully compatible; the use of NAC in breast cancer has increased the use of SNd on larger high-risk tumors. In contrast, our use of SNd in MIBC is not aimed at minimizing the extent of lymph node dissection or detecting nodal metastases. Due to the diversity of lymphatic drainage for MIBC in the minor pelvis, our results contravene SNd as a method for nodal staging. This is probably also due to the diversity of lymphatic drainage for MIBC in the pelvic cavity. Another challenge would be to correlate the detected SNs with a molecular signature combined with clinical factors. Our prospective series, including the present material, also forms the matrix for ongoing immunological investigations with focus on T cells, B cells, cytokines and T regulatory cells. Induction of immune responses to tumor antigens has been detected in SNs, therefore being considered a good source for harvesting tumor-specific T lymphocytes [10, 19]. These findings enabled adoptive immunotherapy utilizing autologous SN-derived T cells, both in colon cancer and in MIBC [20‐22]. For performing SN-based autologous cell therapy, the technical ability to perform SNd is a primary condition, also in patients undergoing NAC, regardless of individual pathoanatomical responses. All patients in the present series underwent open cystectomy with standard SNd. We anticipate from other groups, investigations of similar character with minimal invasive surgery (MIS) as, for example, with robotically assisted radical cystectomy. SNd with MIS has shown promising results by utilizing for instance indocyanine green fluorescence imaging [23]. Limitations of the current study include the uneven distribution of NAC patients versus chemo-naïve, only 8/65 patients having nodal dissemination and a heterogeneous group of both urologic surgeons and pathologists from totally six centers.