Good and complete responding locally advanced rectal tumors after chemoradiotherapy: where are the residual positive nodes located on restaging MRI?

All consecutive locally advanced rectal cancer patients treated with neoadjuvant chemoradiotherapy between January 2006 and November 2013 were considered for inclusion in this retrospective study. The study was conducted as part of ongoing clinical studies on nodal imaging, which were approved by the local institutional review board and for which all patients provided written informed consent. Inclusion criteria consisted of (a) biopsy proven rectal cancer with an inferior tumor margin less than 15 cm from the anal verge, (b) age >18 years, (c) long course neoadjuvant treatment, (d) evidence of a good or complete (yT0-2) response of the primary rectal tumor after CRT (either histopathologically proven after TME/TEM or—in case of “wait-and-see” treatment—confirmed by at least 2 years FU and biopsy results without evidence of residual/recurrent tumor or metastatic nodes), and (e) availability of a lesion-by-lesion comparison of lymph nodes between MRI and histology in the patients undergoing resection. Exclusion criteria were (a) pregnancy, (b) non-resectable disease, and (c) contraindications for MRI. In total, 228 consecutive patients underwent long course preoperative chemoradiotherapy. The routine neoadjuvant treatment schedule consisted of 50.4 Gy radiation combined with 2 × 825 mg/m²/day capecitabine. Of these patients, 144/228 (63.2%) showed a good or complete response of their primary tumor (yT0-2). Forty-nine were excluded for the following reasons: 42 were treated with organ preservation but did not reach a follow-up period of at least 2 years at the time of writing, 5 were inoperable due to synchronous metastatic disease, and in 2 patients a lesion-by-lesion MR-histological comparison could not be performed. This left a total study population of 95 patients (62 male, 33 female; median age 69 years, range 35–88) with a complete or good tumor response (yT0-2) after CRT.

All patients underwent a primary staging MRI and a second, restaging MRI routinely performed 6–8 weeks after completion of the preoperative CRT. Patients did not receive bowel preparation. To reduce bowel motility, 20 mg of scopolamine butylbromide (Buscopan, Boehringer Ingelheim, Germany) was administered intravenously just before the MRI, either in case of anticipated bowel movement artifacts on the sagittal planning scan (during the first half of the study period) or routinely (during the second half of the study period). Imaging was performed at a 1.5T MR unit (Intera or Intera Achieva; Philips Medical Systems, Best, The Netherlands) using a phased array body coil. The standard clinical MR protocol consisted of 2D T2-weighted fast spin echo sequences in 3 planes (sagittal, axial, and coronal). Additionally, a 3DT1-weighted gradient echo sequence (TR/TE 9.8/4.6 ms, 15° flip angle, 1 NSA, 1.15 × 1.15 × 1.00 mm voxel size, and 6.30 min acquisition time) was acquired to optimally depict the lymph nodes. The latter sequence was used for nodal evaluation in the current study.

An experienced pelvic MR reader (LAH) evaluated each MRI and performed a careful search for all visible lymph nodes within the mesorectal compartment on the 3D-T1weighted GRE sequence. Extramesorectal (lateral) lymph nodes were not taken into account. Multiplanar reformatting of the images was performed to accurately determine the position of each visible lymph node with regard to the primary rectal tumor in three-dimensional plane.

Similar to the methodology described in previous reports, all nodes visualized on the 3DT1-weighted MRI were drawn on an anatomical map [11, 12]. In the patients undergoing resection, this map was used as a template to ensure accurate node-by-node matching with histopathology. The TME resection specimens were sectioned transversely each 5 mm, perpendicular to the tumor axis. A dedicated pathologist carefully searched for lymph nodes in each section. Each node was placed in a marked individual tray and multiple histological sections were analyzed for each node (for small 1–2 mm nodes only one section was assessed). At microscopic examination, the pathologist reported each node as benign or malignant. For each malignant node, the volume of metastatic disease within the node (%) was estimated. In the patients undergoing a local excision or a ‘wait-and-see’ policy with a recurrence-free follow-up period of 2 years, all nodes visualized on MRI were considered benign lymph nodes.

For each individual lymph node depicted on the 3D-T1W GRE sequence (including MPR reformatting), the following parameters were recorded: [1] N⁺ or N⁻ node (based on histopathology and/or long-term FU), [2] size (short axis diameter in mm), [3] position relative to the primary tumor as determined on sagittal or coronal reconstructed plane (i.e., at the level of the tumor, or ×mm distal or proximal to the primary tumor), [4] distance from the primary tumor in axial plane (mm), [5] location (…o’clock) of the lymph node in axial plane/supine position (with 12 o’clock being anterior and 3 o’clock being left lateral location). The nodes localization procedure is illustrated in Fig. 1.

Patient characteristics are provided in detail in Table 1. Of the 95 study patients, 61 underwent TME and 34 underwent organ-preserving treatment (4 TEM and 30 a wait-and-see policy) with >2 year follow-up. Fifty-four patients had a yT0, 10 a yT1, and 31 a yT2 status. The overall incidence of yT0-2N⁺ disease was 7/95 (7.4%): 3/54 (5.6%) in patients with a complete tumor response (yT0) and 4/41 (9.8%) in patients with a good tumor response (yT1-2). In the 61 patients who underwent a total mesorectal excision, a total number of 671 nodes was harvested from the mesorectal fat at histopathology (median 12 nodes per patient, range 1–25, 660 benign, 11 malignant). In addition, 209 nodes were observed on restaging MRI in the patients undergoing TEM or wait-and see with >2 year FU, and these nodes were all considered benign. Hence, the total number of metastatic nodes after CRT was 11/880 (1.3%).

The 11 metastatic nodes were observed in 7 patients. Median size (as measured on MRI) of the non-metastatic nodes was 3 mm (range 1–19 mm), compared to 6 mm (range 3–12 mm) for the metastatic nodes. In the metastatic nodes, the total tumor volume (viable tumor cells ± necrosis) within the node was <25% in 5 nodes (46%), 25%–50% in 1 node (9%), 50%–75% in 3 nodes (27%), and >75% in 2 nodes (18%). Figures 2 and 3 both show an example of a micrometastatic and macrometastatic lymph node, respectively.

The location of the metastatic lymph nodes in relation to the primary rectal tumor is schematically illustrated in Fig. 4. Further details on the characteristics and location of the individual metastatic lymph nodes are provided in Table 2. No metastatic nodes were found distal to the tumor. Fifty-five per cent of the metastatic nodes were located at the level of the (former) rectal tumor; the other 45% were located proximal to the tumor site at a median distance of 14 mm (10–29 mm) from the most proximal tumor margin. In axial plane, 82% of the metastatic nodes were located at the ipsilateral circumference of the tumor bed and 18% contralateral. The median distance of the metastatic nodes to the tumor bed in axial plane was 9 mm (0–22 mm). Of the non-metastatic nodes 5.4% was located distal to the tumor site, 18.5% was located at the level of the tumor, and 76.1% was located proximal to the tumor.