Does Lateral Pelvic Lymph node matters in rectal cancer

The lymph nodes draining the rectum below the peritoneal reflection is found to follow two major pathways (a) Along the superior rectal artery and the inferior mesenteric artery into the para-aortic nodes (b) Along the middle and inferior rectal artery into the obturator, internal iliac and external iliac nodes. The majority of the first group of nodes are resected as a part of Total Mesorectal Excision (TME) [1,2]. The second group of nodes, the lateral pelvic nodes, albeit being recognised long before, have triggered a significant interest in the field of rectal cancer surgery on the approach, recurrence and survival.


Significance of lateral lymph node metastasis
Synchronous lateral lymph node (LLN) disease among locally advanced rectal tumours is reported in 10-25% [5]. According to the Japanese Society for Cancer of the Colon and Rectum data, the incidence of LLN involvement in tumours below the peritoneal reflection, with positive mesorectal nodes, is 27% [4]. Though, it appears that the reported incidence of LLN involvement varies between the East and  (Table 1).
LLNs are also reported to be the major cause for local recurrence following curative resection. About 50% of the local recurrences occur in the LLN basin without evidence of distant metastasis [15]. In another single-institution study conducted in Korea, 35.5% of the patients who had TME following positive response to nCRT developed local recurrence. 19.4% of them developed pelvic wall recurrence and interestingly, 16.1% developed in situ LLN metastasis, in the same site, which was suspected preoperatively [16].

Managing the LLNs -differences between the east and the west
The AJCC classifies LLN involvement as metastatic disease except for the internal iliac nodes. As the LLNs apart from the internal iliac group are considered as metastatic disease, they were dealt with less aggressively. However, radiation oncologists in the US nowadays are preferring to deal with the non-regional nodes with treatment intensification, either Radiotherapy (RT) boost or Surgical LLND [3].
The Japanese classification, on the other hand, considers all LLN involvement as regional disease, irrespective of the site. As a result, LLN dissection is routinely performed in this part of the world. The difference in approach between the East and West is shown in table 2.

Advantages of LLND dissection
According to the Japanese Society for Cancer of Colon and Rectum (JSCCR), Lateral Lymph Node Dissection (LLND) is expected to decrease the intra-pelvic recurrence by 50% and improve the 5-year survival by 8-9% [4]. The result of a multicentre trial from Japan, JCOG2012, failed to conclude the non-inferiority of TME alone versus TME+LLND in terms of local recurrence rates. The secondary end points from the same study including the incidence of urinary and male sexual dysfunction was not found to be higher in the LLND group [17][18][19].
A prospective, multicentre, randomized single-blinded, phase III trial for TME versus TME +LLND for suspicious LLN involvement is currently recruiting patients at China and is expected to end by 2022. Notably, the size of the node in MRI is used as criteria to define LLN involvement. These patients with suspicious LLN involvement are randomized and receive nCRT before proceeding to either TME or TME+LLND [5].

Approaches to decrease complications in LLND
Though the results of JCOG2012 claim that the incidence of urinary and sexual incontinence is not increased by combining LLND, they still remain as a significant morbidity following the procedure [17][18][19]. Laparoscopic approach is considered safer and less morbid compared to open approach [20]. Laparoscopic LLND based on vesicohypogastric fascia and uretero-hypogastric nerve fascia is found to have improved surgical outcome and decreased complication rate (Japan) [21]. Robotic LLND is feasible with better short-term outcomes and lymph node harvest. It is reported to be advantageous in male narrow pelvis [22,23].

Selective Lymph node dissection
Many studies advocate selective lymph node dissection based on various nodal characteristics on imaging pre and post-chemo radiation. Node size is commonly used as a marker and the size criteria have varied between 6mm, 8mm and 10mm amongst the authors [8,10,11]. Rather than the size, heterogeneous MR signal and irregular border of the lymph node capsule are more reliable in predicting malignancy of the nodes on MRI [9,24]. Also, CRT significantly alters the nodal parameters in imaging that the size criteria can fail [25]. In a study, among the group that had positive response to CRT and TME subsequently, none of the nodes in follow up were more than 5mm [16].
The response to CRT is also a good prognostic indicator. The subgroup of patients that had suspicious nodes but positive response to chemotherapy had better recurrence rates than the non-responders. Also, there is no significant difference in the recurrence free survival and overall survival between the non-suspicious LLN group and LLN responding to CRT. This raises the question if LLND can be reserved for the subgroup of patients with LLN disease unresponsive to CRT [26].

Role of prophylactic LLND
Tamura et al. [27] have concluded that there is no role in prophylactic LLND in stage 4 rectal cancers when there is no clinical LLN metastasis. Again, clinical LLN metastasis was defined as node > 10mm in CT. There is no adequate literature so far regarding the role of prophylactic LLND. Since the JCOG2012 is only a non-inferiority trial, a future randomized clinical trial, such as a superiority study of LLND + TME versus chemo-radiotherapy + TME or LLND + chemo-radiotherapy + TME versus chemo-radiotherapy + TME, may be needed to verify the true benefit of LLND for occult lateral nodal metastases [28].

Conclusion
Although the role of prophylactic LLND is unclear, it may have a role in clinically positive lateral nodes and those that are resistant to CRT. The major question that remains still unanswered is whether routine TME + LLND post CRT in stage II and stage III rectal cancer needs to be advocated globally based on the oriental experience. The results from ongoing RCTs might provide an answer [5].