Lymph Node Revealing Solutions in Colorectal Cancer
Lymph Node Revealing Solutions in Colorectal Cancer
The most commonly described benefit of using lymph node revealing solutions is the pure increase in the numbers of lymph nodes harvested, many of which are of a smaller size than might be identified by manual dissection. Studies have shown a variable increase in harvested lymph nodes. In one study, a mean harvest of 76.4 and 73.7 lymph nodes was seen after application of alcohol in colonic and rectal resections, respectively. In the same study, a secondary manual dissection identified a mean of 18.1 and 21.2 lymph nodes, respectively, but the authors did not clarify whether both sets of dissections were performed by the same individuals. If manual dissections had been carried out by less experienced individuals then it is possible that this may have also affected the numbers of nodes harvested.
Metastatic incidence refers to the proportion of lymph nodes which contain tumour deposits. A decrease in metastatic incidence after the use of lymph node revealing solutions has been reported. Saleki and Haeri attributed significance to this finding, stating it to be due to the overall greater number of lymph nodes harvested after secondary dissection. In contrast, five studies showed an increase in metastatic incidence, but not always with significance.
Upstaging refers to an upwards change in pathological staging, which may then alter patient treatment if there is a shift from node-negative (pN0) to node-positive (pN1 or pN2). This is because node-positive patients receive chemotherapy, while node-negative patients may not.
Nine studies reported upstaging after the use of lymph node revealing solutions, ranging from 2.4% to 33% ( Table 2 ). Six of these claimed the finding to be significant, in that upstaging from Dukes' B to Dukes' C was reported, prompting adjuvant therapy. However, this may not have been a correct assumption because most of these studies had questionable underlying primary manual dissection practice with fewer than the recommended minimum of 12 lymph nodes found on average (range 2.94–7.3). These studies were therefore more likely to identify upstaging once a lymph node revealing solution had been applied. It is likely that upstaging would have been insignificant, or not present at all, had there been optimal primary manual dissection. In one study by Koren et al, there was upstaging in 10 cases, and a further eight cases had the staging changed from Nx to N0, suggesting an underlying deficit in primary manual dissection technique. The case upstaged by Brown et al was a soft tissue metastasis which the authors suggested may have been artefactual. The evidence in the literature is therefore questionable.
Multiple studies have demonstrated smaller sized lymph nodes after lymph node revealing solutions are used ( Table 3 ). Some of the more recent studies using GEWF have assessed and attributed statistical significance to this. Brown et al found that 83% of additional lymph nodes were ≤2 mm in size. Where GEWF is used this may be due to the white colour of lymph nodes which facilitates detection. There is ongoing debate regarding the clinical significance of CRC metastases in small lymph nodes. Dhar et al concluded that metastatic lymph node size is a strong prognostic variable in CRC, using two sample log rank testing to demonstrate that the prognostic impact decreased when lymph nodes were more than 10 mm in diameter. Dhar et al did concede that their findings needed to be confirmed with a larger study before clinical application. In another recent study, Märkl et al concluded that 'minute lymph nodes [<1 mm] have virtually no role in correct histopathological lymph node staging'. They did however agree that the detection of relatively small lymph nodes (1–5 mm) was an important factor for exact lymph node staging and was prognostically relevant, with an association between a high number of harvested lymph nodes and a favourable outcome in colon carcinoma.
It is important to consider whether finding a greater number of smaller lymph nodes has the potential to change patient management. If the only significant finding is a greater number of smaller tumour-free lymph nodes, then the patient will remain node-negative and there will be no change in treatment. There will be no benefit to the patient but there will be a cost to the laboratory, both in terms of increased turnaround times and finances.
If metastases are prevalent in larger lymph nodes (ie, >5 mm), then they should be identified by manual dissection, providing the dissector is adequately experienced. If this is the case, then one might argue that the use of lymph node revealing solutions is not necessary. It may be that education is as important a tool as is the use of adjunct chemicals, but currently there remains a lack of evidence to prove or disprove this.
Review of the Literature
Number of Lymph Nodes Retrieved
The most commonly described benefit of using lymph node revealing solutions is the pure increase in the numbers of lymph nodes harvested, many of which are of a smaller size than might be identified by manual dissection. Studies have shown a variable increase in harvested lymph nodes. In one study, a mean harvest of 76.4 and 73.7 lymph nodes was seen after application of alcohol in colonic and rectal resections, respectively. In the same study, a secondary manual dissection identified a mean of 18.1 and 21.2 lymph nodes, respectively, but the authors did not clarify whether both sets of dissections were performed by the same individuals. If manual dissections had been carried out by less experienced individuals then it is possible that this may have also affected the numbers of nodes harvested.
Metastatic Incidence and Upstaging
Metastatic incidence refers to the proportion of lymph nodes which contain tumour deposits. A decrease in metastatic incidence after the use of lymph node revealing solutions has been reported. Saleki and Haeri attributed significance to this finding, stating it to be due to the overall greater number of lymph nodes harvested after secondary dissection. In contrast, five studies showed an increase in metastatic incidence, but not always with significance.
Upstaging refers to an upwards change in pathological staging, which may then alter patient treatment if there is a shift from node-negative (pN0) to node-positive (pN1 or pN2). This is because node-positive patients receive chemotherapy, while node-negative patients may not.
Nine studies reported upstaging after the use of lymph node revealing solutions, ranging from 2.4% to 33% ( Table 2 ). Six of these claimed the finding to be significant, in that upstaging from Dukes' B to Dukes' C was reported, prompting adjuvant therapy. However, this may not have been a correct assumption because most of these studies had questionable underlying primary manual dissection practice with fewer than the recommended minimum of 12 lymph nodes found on average (range 2.94–7.3). These studies were therefore more likely to identify upstaging once a lymph node revealing solution had been applied. It is likely that upstaging would have been insignificant, or not present at all, had there been optimal primary manual dissection. In one study by Koren et al, there was upstaging in 10 cases, and a further eight cases had the staging changed from Nx to N0, suggesting an underlying deficit in primary manual dissection technique. The case upstaged by Brown et al was a soft tissue metastasis which the authors suggested may have been artefactual. The evidence in the literature is therefore questionable.
Does Lymph Node Size Matter?
Multiple studies have demonstrated smaller sized lymph nodes after lymph node revealing solutions are used ( Table 3 ). Some of the more recent studies using GEWF have assessed and attributed statistical significance to this. Brown et al found that 83% of additional lymph nodes were ≤2 mm in size. Where GEWF is used this may be due to the white colour of lymph nodes which facilitates detection. There is ongoing debate regarding the clinical significance of CRC metastases in small lymph nodes. Dhar et al concluded that metastatic lymph node size is a strong prognostic variable in CRC, using two sample log rank testing to demonstrate that the prognostic impact decreased when lymph nodes were more than 10 mm in diameter. Dhar et al did concede that their findings needed to be confirmed with a larger study before clinical application. In another recent study, Märkl et al concluded that 'minute lymph nodes [<1 mm] have virtually no role in correct histopathological lymph node staging'. They did however agree that the detection of relatively small lymph nodes (1–5 mm) was an important factor for exact lymph node staging and was prognostically relevant, with an association between a high number of harvested lymph nodes and a favourable outcome in colon carcinoma.
It is important to consider whether finding a greater number of smaller lymph nodes has the potential to change patient management. If the only significant finding is a greater number of smaller tumour-free lymph nodes, then the patient will remain node-negative and there will be no change in treatment. There will be no benefit to the patient but there will be a cost to the laboratory, both in terms of increased turnaround times and finances.
If metastases are prevalent in larger lymph nodes (ie, >5 mm), then they should be identified by manual dissection, providing the dissector is adequately experienced. If this is the case, then one might argue that the use of lymph node revealing solutions is not necessary. It may be that education is as important a tool as is the use of adjunct chemicals, but currently there remains a lack of evidence to prove or disprove this.