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Lymphadenectomy of colorectal cancer is a decisive factor for the prognostic and therapeutic staging of the patient. For over 15 years, we have asked ourselves if the minimum number of 12 examined lymph nodes LNs was sufficient for the prevention of understaging. The debate is certainly still open if we consider that a limit of 12 LNs is still not the gold standard mainly because the research methodology of the first studies has been criticized.
It should however be noted that both the pressing nature of the debate and the dissemination of guidelines have been responsible for a trend that has allowed for a general increase in the number of LNs examined. There are different variables that can affect the retrieval of LNs.
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Some, like the surgeon, the surgery, and the pathology exam, are without question modifiable; however, other both patient and disease-related variables are non-modifiable and pose the question of whether the minimum number of examined LNs must be individually assigned. The lymph nodal ratio, the sentinel LNs and the study of the biological aspects of the tumor could find valid application in this field in the near future.
Core tip: Lymphadenectomy of colorectal cancer is a decisive factor for the prognostic staging of the patient. A limit of 12 lymph nodes LNs is still not the gold standard and accessible only in highly specialized centers. There are different variables that can affect the retrieval of LNs; some are non-modifiable and pose the question of whether the minimum number of examined LNs must be individually assigned.
In , Curti et al[ 1 ] stressed that continually talking about the lymphadenectomy of colorectal cancer makes for incredibly monotonous reading.
In fact, even though it has been proven that the excision of lymph nodes LNs in colorectal cancer is a crucial measure, in the last decade the problem has mainly shifted its focus to the physical dimensions of the lymph nodal excision and, more specifically, to the number of LNs to be removed.
Even if in this area there are precise indications, in reality, they are not always respected due to, above all else, the large number of variables that can interfere with the sampling of the LNs. Actually, this is not the case, since as we shall see, the lack of reliable data makes the current staging systems inadequate. In addition to its accuracy in staging, the LNs excision also seems to be an independent prognostic factor.
Many case-study reviews[ 3 - 5 , 10 , 11 , 14 , 19 , 20 , 24 - 28 , 35 , 40 - 49 ], particularly in patients with stage II, report a directly proportional relationship between the number of LNs removed and survival. In this regard, it seems appropriate here to refer to the systematic review of Chang et al[ 24 ] who report that in 16 of 17 studies the increased survival of patients with stage II colon cancer was associated with increased numbers of LNs evaluated.
The most likely explanation is that the higher the number of LNs examined the better select the group of node-negative patients with a better prognosis for which surgery alone should be curative.
Other authors[ 1 , 21 , 40 , 50 ], however, believe that in patients with more advanced stages, the lymphadenectomy can be therapeutic both by improving tumor clearance by the surgeon and by reducing the metastatic spread through lymphatic drainage. Not all authors agree with this latter view[ 5 , 11 ].
Last but not least, it must be noted that organizations such as the American College of Surgeons, the ASCO, and the National Quality Forum consider the entity of the lymphadenectomy as a way to gauge the quality of a center dealing with this type of pathology[ 51 - 55 ]. Concerning this issue, not all are in agreement mainly because the number of LNs removed may not reflect the quality of the surgeon or the pathologist but, as we shall see later, may be tied to unchangeable factors inherent in the patient or the tumor[ 6 , 50 ].
Many authors[ 17 , 27 , 28 , 56 ] claim that in clinical practice there should be no set limit to the number of LNs examined since in addition to survival, as has already been mentioned, there is a direct correlation between the number of examined LNs and the number of LNs with metastasis[ 4 , 14 , 24 , 28 , 57 - 59 ]. However, in light of this observation, we have to ask ourselves what the minimum number of LNs is, beyond which there is no change in the staging if not within acceptable limits.
In light of this, the number of LNs to be sampled still varies widely even though it has been discussed for over 20 years. In this regard, what Stocchi et al[ 41 ] have recently reported seems paradigmatic. He claims that, considering only patients treated for stage II colon cancer, the examination of at least 12 LNs is associated with an improvement in results; this improvement reduces if a smaller sample of LNs get examined, but it does not increase with a larger sample of LNs.
The debate is certainly still open if we consider that a limit of 12 LNs is, as of today, still not the gold standard mainly because the research methodology of the first studies[ 40 , 63 , 64 ], which do not go beyond a level of III or IV and a grade C recommendation, has been criticized[ 6 , 51 ]. This confusion is also documented by McDonald et al[ 6 ] who, citing 10 observational studies that analyzed more than patients, points out that not only is there no agreement on what the LN cut-off point should be, but that in a wide range of LNs examined between 6 and 21 the actual cut-off point fluctuated.
This range is similar to the one reported by Valsecchi et al[ 21 ] between 6 and 17 and lower than the one reported by Noura et al[ 42 ] between 6 and Gelos et al[ 78 ], however, focuse on yet another aspect, arguing that in patients with a malignancy at an earlier stage which can lead to a lower immune response, it is likely that we can settle for a sample of less than 12 LNs.
It should however be noted that both the pressing nature of the debate and the dissemination of guidelines have been responsible for a trend that, over the years, has allowed for a general increase in the number of LNs examined, thus enabling the U. This, however, is probably not the case in smaller hospitals[ 9 , 21 ].
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Ideally, the surgeon should remove all the LNs pertaining to the tumor and the pathologist should sample and examine them thoroughly. In our opinion, all the variables, modifiable and unmodifiable, that can affect lymph nodal sampling should be examined so as to make the work of both the surgeon and of the pathologist more efficient. Indeed other authors consider this correlation inconsistent[ 8 , 19 , 22 , 53 , 78 , 84 - 86 ] as it does not record statistical differences related to surgeon expertise or between colorectal surgeons and general surgeons, thus giving other authors[ 9 , 87 , 88 ] the opportunity to dwell, instead, on the importance of an educational strategy that allows for a more accurate surgical technique.
Whether the greater length of the intestine removed can determine more lymph nodal sampling is, in fact, a matter of controversy. While some authors lean toward this hypothesis[ 19 , 21 , 78 ], others refute it completely[ 90 ]. Although, as of present, literature has not offered conclusive data as to whether emergency surgeries are responsible for limited resections and hence smaller numbers of collected LNs[ 19 , 40 , 56 , 86 ], more reliable data is available with regards to the influence of laparoscopic surgery on lymph nodal sampling, whose efficacy has been questioned.
More significantly, a recent meta-analysis[ ] of 24 randomized trials has shown no significant differences between the two approaches concerning the number of LNs examined. On the contrary, Lujan et al[ ] has reported advantages in favor of laparoscopic surgery with regards to the number of LNs sampled in patients suffering from rectal cancer Only prospective or prospective randomized trials in over patients.
The possibility of having more time may also be useful for the implementation of procedures which have been widely recommended[ 7 , 27 , 30 , 40 ].
Colorectal cancer and lymph nodes: The obsession with the number 12
Such procedures include the fat clearance technique or the intra-arterial injection of blue methylene, among others, which seem to improve performance.
However, in addition to being costly[ 11 , 23 , 27 , 60 ], these procedures are difficult to carry out in centers with a high case volume[ 3 , 23 ].
Patient-related: The patient-related variables are among those for which there is less debate and difference of opinion. Among the hypotheses put forth, we must remember that surgery performed on a patient of advanced age cannot be extensive because of the presence of comorbidities[ 3 , 10 , 40 ], in addition to the physiological involution of LNs[ 10 , 40 , 56 ] and the weaker response of the immune system[ 41 ].
Similarly, most authors[ 19 , 22 , 36 , 85 , 90 , ], with regards to gender, do not report a different LN retrieval while only some[ 60 , 79 , ] mention greater sampling in females.
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Not all authors, on the other hand, are in agreement on the role that obesity may have during lymphadenectomy; some authors[ 5 , ], in fact, have shown either a higher LN retrieval in non-obese patients or a lower one in patients with high body mass index BMI , probably due to the more difficult surgical dissection[ 9 , 40 , 51 , 84 ].
Kuo et al[ 5 ], which refer in his experience as the BMI is associated with LNs harvest, highlights that the larger LN retrieval in non-obese patients is due to a bigger number of right colon cancers. In fact many authors do not report such a correlation[ 9 , 22 , 61 , 84 ]. Disease-related: Also with regards to the unchangeable disease-related variables, the literature is mostly consistent.
All authors, in fact, agree that it is more difficult to achieve the target of 12 LNs when the tumor is located in the rectum, possibly due to the smaller size of the LNs, in spite of the higher percentage of malignant nodes retrieved[ 3 , 53 ]. With regards to the colon, the number of LNs sampled is definitely higher in the right colon[ 3 , 5 , 6 , 10 , 18 , 21 , 22 , 25 , 36 , 41 , 44 , 52 , 60 , 61 , 78 , 80 , 84 , , ] either because of the greater length of the mesentery root[ 5 , 90 ] or due to a different embryological development that would ensure a greater number of LNs[ 78 ].
Tumor characteristics have often been thought to have an effect on lymph nodal sampling; the greater the size and the more advanced the tumor staging T and grading , the greater the number of LNs retrieved[ 9 , 10 , 21 , 22 , 25 , 31 , 78 , 86 , ], this probably due either to a greater immune response[ 78 ] or to more aggressive surgery[ 9 , 10 ].
When we consider, instead, the non-advanced tumors interesting is that recently report by Benhaim et al[ 99 ], the first in the literature, that determine the total number of LNs examined after colectomy for an endoscopically removed malignant polyp.
In these patients the mean number of LNs examined was significantly lower compared to both patients operated for colon cancer at any stage It is also generally agreed[ 3 , 56 , 80 , 86 , , ] that pre-operative radiotherapy is responsible for either a minor, absent, or at best widely variable lymph nodal sampling, irrespective of the characteristics of the patients or treatment[ 17 ].
Evans et al[ 86 ], Deodhar et al[ 3 ], Tekkis et al[ 56 ] therefore refer to an average lymph nodal sampling of 7, 9.
This appears to be due to inflammatory post-radiotherapy processes which cause stromal fibrosis of the LNs and of their subsequent reduction in size[ 6 , 17 , 67 ]. Rullier et al[ ] report that for every Gy of radiation, the sampled LNs number will be less than 0. It is perhaps interesting to note that, in this case, the reduction in the number of sampled LNs, although oncologically favorable does not affect the survival rate but rather must be viewed as a positive response to neo-adjuvant treatment[ 6 , - ].
This has led some authors[ 17 ] to conclude that the limit of 12 LNs is unrealistic for the stage of rectal cancer of patients who are treated with neoadjuvant therapy. The seventh edition of the AJCC classification[ 2 ], as mentioned previously, subdivides patients treated for colorectal cancer into prognostic categories according to the number of metastatic LNs.
However, not all authors who have written on the subject agree[ 6 , 43 , 49 ]. The LNR, independent of the number of LNs sampled, is also justified since, taken with the AJCC classification, it would allow us to sub-divide, according to the risk involved, stage III patients reducing the excessive prognostic heterogeneity[ 12 , 16 , 45 ].
In light of this, reviewing and taking into consideration the work of Bamboat et al[ 8 ], Qiu et al[ 12 ], Song et al[ 13 ], and Greenberg et al[ ] in , the LNR seems to be an independent prognostic factor in colorectal cancer, superior to the classification based only on N stage number of positive modes.
Conversely, Noura et al[ 42 ] only one year before published an interesting and somewhat more cautious editorial. In fact, the author reported that even though the LNR seemed to be a more reliable prognostic factor, its validity, in actuality, could not be completely agreed upon.
In fact, clinical records were very different, randomized and multi-centric studies were lacking, and, most importantly, a uniformly valid cut-off was missing.
Despite the fact that numerous authors have expressed their opinions on the number of LNs sampled, it can be gathered that the number is between 6 and 40[ 42 ]. Even if the surgeon and pathologist, as variables in the equation, could improve simply by standardizing surgical technique and by increasing the amount of time dedicated to this procedure, the other, more important variables[ 22 , 31 , ], namely patient and cancer-related, are not as easily modifiable.
It is with these latter two variables in mind that we still pose the question whether it is possible, as we hope, to establish a universally valid cut-off node for all patients or whether it should instead be varied according to individual cases[ 6 , 78 ].
Today, a valid perspective is still necessary for the identification of the sentinel LNs at least 3 [ ]. The identification of the sentinel LNs, actually still remains a controversy among those authors who consider the mesenteric lymph drainage, especially in the rectum, too complicated[ 32 , 40 ], and the majority of authors who, on the other hand, maintain that an aberrant lymphatic drainage occurs only in a small percentage of cases[ 27 , 29 , 33 , 34 ].
As certainly interesting, the biological aspects of the tumor still remain the subject of speculation.
Some authors suggest that reduced survival is not necessarily due to an inappropriate dissection performed by the surgeon and the pathologist, but may be linked to a cancer that is quite virulent and is hence responsible for a low immune response from the patient[ 35 , 40 , 57 , ]. Not coincidentally, these malignancies are located in the right colon[ 41 , 44 , ], where, as mentioned, more LNs are found. As has already been pointed out, the obsession with the number 12 has its origins in studies which lack clear statistical evidence.
Just as Curti et al[ 1 ] asserted that, as of , not even a single prospective study had been published, authors still today are calling for prospective controlled studies that are, without question, difficult to predict both for a number of ethical reasons and for the sheer volume of clinical records.
Hence, obtaining reliable data that would allow us to go beyond this obsession with the number 12 will not be easy.
National Center for Biotechnology Information , U. Journal List World J Gastroenterol v. World J Gastroenterol. Published online Feb Author information Article notes Copyright and License information Disclaimer. Author contributions: Li Destri G, Di Carlo I, Scilletta R, Scilletta B and Puleo S designed the research, analysed the literature, wrote and revised the paper; all authors have approved the final version to be published.
All rights reserved. This article has been cited by other articles in PMC. Abstract Lymphadenectomy of colorectal cancer is a decisive factor for the prognostic and therapeutic staging of the patient.
Table 1 Minimum lymph node sampling recommended for a correct staging. Open in a separate window. LN: Lymph node. Table 4 Lymph node sampling in laparoscopic vs open approaches. Unmodiafiable factors Patient-related: The patient-related variables are among those for which there is less debate and difference of opinion.
References 1. Colorectal carcinoma: is lymphadenectomy useful. Dig Surg.
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