Supplementary Figure 1 from Preparing the “Soil”: The Primary Tumor Induces Vasculature Reorganization in the Sentinel Lymph Node before the Arrival of Metastatic Cancer Cells
Chao‐Nan QianBree D. BerghuisGalia TsarfatyMaryBeth BruchEric J. KortJon DitlevIlan TsarfatyEric HudsonDavid G. JacksonDavid PetilloJindong ChenJames H. ResauBin Tean Teh
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Supplementary Figure 1 from Preparing the “Soil”: The Primary Tumor Induces Vasculature Reorganization in the Sentinel Lymph Node before the Arrival of Metastatic Cancer CellsKeywords:
Primary tumor
Primary (astronomy)
The lymphatic vasculature drains lymph fluid from the tissue spaces of most organs and returns it to the blood vasculature for recirculation. Before reaching the circulatory system, antigens and pathogens transported by the lymph are trapped by the lymph nodes. As proposed by Florence Sabin more than a century ago and recently validated, the mammalian lymphatic vasculature has a venous origin and is derived from primitive lymph sacs scattered along the embryonic body axis. Also as proposed by Sabin, it has been generally accepted that lymph nodes originate from those embryonic primitive lymph sacs. However, we now demonstrate that the initiation of lymph node development does not require lymph sacs. We show that lymph node formation is initiated normally in E14.5 Prox1-null mouse embryos devoid of lymph sacs and lymphatic vasculature, and in E17.5 Prox1 conditional mutant embryos, which have defective lymph sacs. However, subsequent clustering of hematopoietic cells within these developing lymph nodes is less efficient.
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<p>Table S2. Differentially activated pathways in TH1, TH5 and TH6 case. In TH1, TH5 and TH6 case, the pathway enrichment test was performed between two lymph nodes (4L and 4R) vs. 7 lymph node, between two lymph nodes (7 and 4L) vs. 11Rs lymph node & primary, and between three lymph nodes vs. primary, respectively. Significant pathways were not found in other cases.</p>
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British Journal of Cancer (2011) 104, 221–222. doi:10.1038/sj.bjc.6606000 www.bjcancer.comPublished online 23 November 2010& 2011 Cancer Research UKSir,We read with interest the paper by Polterauer et al (2010) inwhich they evaluated the prognostic value of lymph node density(LND) in patients with lymph node-positive cervical cancer. LNDis defined as the ratio of the number of metastatic lymph nodesto the total number of lymph nodes removed. They showed thatLND410% is associated with an impaired disease-free and overallsurvival. Lymph node involvement and lymph vascular spaceinvolvement have always been noted to be a poor prognostic factorin cancer of the cervix (Pecorelli, 2006), and thus this confirms thefact that the higher the number of lymph nodes involved,the worse the prognosis of the patient becomes. The benefit ofusing LND could be that it also incorporates the extent of surgicalstaging. Indeed, it is probably true that when you perform acomplete lymph node dissection instead of a sampling you havemore chance of finding all involved lymph nodes. However, thereis more to it than positive lymph nodes and surgical skills.Although the authors gave the mean/median number ofremoved lymph nodes and positive lymph nodes for all patients,we were not able to discern this information for the LNDp10% orLND410% group separately. We believe that this information ispivotal in a study that examines the ratio of both parameters. In aratio, both the numerator and denominator have an equal role. Theauthors state that they performed a systemic lymphadenectomy inall patients. This means that the mean/median number of removedlymph nodes cannot be statistically different in both groups. As aconsequence, only the denominator will become important, andthus the number of positive lymph nodes will become theprognostic factor. If for any reason the total number of lymphnodes removed in both groups is different, then one must questionthe reasons why. Did the surgeon stop the operation prematurelybecause during the operation he/she discovered bulky involvedlymph nodes? This would make a complete systemic lymphade-nectomy redundant, as the patient is already known to be lymphnode positive based on these few lymph nodes. This is generallyaccepted as an indication for (chemo-)radiotherapy, and thecombination of a radical surgery and pelvic (chemo-)radiotherapywill increase therapy-related morbidity (Quinn et al, 2006). Maybethe pathologist stopped looking intensively for other lymph nodesbecause he/she already found several positive lymph nodes.Second, with respect to the technique used, they referred to aprevious study in which a laparoscopic pelvic lymph node stagingwas described (Polterauer et al, 2008). In this study, patients wereincluded between 1995 and 2007 and, remarkably, the mediannumber of lymph nodes was 15, being more than 3 lymph nodesless than in the present study. Does this implicate a learning curverelated to the laparoscopic technique used? If yes, once more asurgical bias is introduced.Third, we question the cutoff value and how it was established.The authors mentioned that this was based on preliminary datafrom a study by Ooki et al (2007). We wonder how welloesophageal cancer can be compared with cervical cancer. Bothorgans are located in completely different anatomic regions, with adifferent lymph vessel drainage system and lymph node distribu-tion. Did the authors try different cutoff points or was the 10%cutoff the only value examined? If the authors tried different cutoffpoints, one could argue that the authors should have used anindependent validation set to validate this cutoff point.Fourth, with a median of 18.5 lymph nodes (range 12–27),Polterauer et al demonstrated that they routinely performedcomplete lymph node dissections. As the ratio of the mediannumber of involved lymph nodes (n¼2) to the median number ofremoved lymph nodes (n¼18.5) was 10.8%, removing one or twolymph nodes would more or less determine whether the patientbelonged to the category of patients with LNDp10% or LND410%. This would implicate that the surgeon could influence towhich prognostic group the patient will belong. After all, it sufficesto remove more lymph nodes to shift the patient from theLND410% group to the LNDp10% group. It is contradictory thatthe surgeon has to remove more ‘healthy’ lymph nodes to‘improve’ the prognosis of the patient. With more healthy lymphnodes the denominator will become bigger and thus the LNDsmaller. This strikes us as ironic.In conclusion, as LND is influenced by surgical technique,anatomic circumstances and the quality and accuracy of thepathological analysis, we believe that LND is not an objectiveparameter and should not influence the decision on what kind ofadjuvant treatment should be given to a patient. We believe thatthe number of positive lymph nodes is probably the true predictor,but as the number of patients in each of the different groups (1 vs 2vs 42) was low, the authors were unable to reach significance.Using a ratio solved this problem by creating two arbitrary groupsof patients and by using denominators that enlarged the differencePublished online 23 November 2010 between the numerators.*Correspondence: Dr T Van Gorp; E-mail: toon.van.gorp@mumc.nl
Lymphadenectomy
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This study investigates the relationship between the number of recovered lymph nodes and lymph node metastases in colorectal resection specimens. All of the slides from 2427 pT3 colorectal resection specimens from patients operated on at William Beaumont Hospital during the 45 years from 1955 through 2000 were reviewed. Lymph node metastases were present in 333 of 1499 (22.2%) specimens with fewer than 15 recovered lymph nodes, compared with 789 of 928 (85.0%) specimens with 15 or greater recovered lymph nodes (p <0.01). The proportion of lymph node metastases increased as a function of the number of recovered lymph nodes (p <0.01). Similarly, in patients without lymph node metastases, survival increased as a function of the number of recovered lymph nodes. Among these patients, the 5-year overall survival rate was 62.2% among patients with seven or fewer recovered lymph nodes and 75.8% among patients with 18 or more recovered lymph nodes (p = 0.018). Statistical analysis found the predictive probability of identifying the single lymph node metastasis in a theoretical specimen with a single lymph node metastasis is 0.25 if 12 lymph nodes are recovered and 0.46 if 18 lymph nodes are recovered. The predictive probability increased as the number of recovered lymph nodes increased, suggesting there is no minimum number that reliably or accurately stages all patients. Thus, all palpable lymph nodes should be recovered, including those that are 1 or 2 mm.
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Log-rank test
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Lymph node metastases are important determinants in the prognosis of primary colorectal cancer. Although it has been established that enlarged, palpable lymph nodes contain metastases in less than half of the cases, no definitive data concerning the incidence of metastases in lymph nodes measuring 5 mm or less are available. We treated the surgical specimens of 52 consecutive patients who had colon cancer with a lymph node clearance technique at the Roswell Park Memorial Institute, Buffalo. We found 2699 lymph nodes in the 52 specimens, with a mean of 52 lymph nodes per specimen (range, five to 151). Sixty-four lymph nodes were found with metastases in 21 (40%) of the 52 patients. Fifty-nine of 64 of the lymph nodes were reexamined and remeasured. Thirty-nine lymph node metastases measured less than 5 mm, 13 were between 5 and 10 mm, and eight were larger than 10 mm. We concluded that lymph node metastases in colon cancer occur most frequently in lymph nodes measuring less than 5 mm (small lymph nodes). The use of lymph node clearing techniques in surgical specimens improves detection of small lymph node metastases and thereby diminishes understaging.
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<p>Table S2. Differentially activated pathways in TH1, TH5 and TH6 case. In TH1, TH5 and TH6 case, the pathway enrichment test was performed between two lymph nodes (4L and 4R) vs. 7 lymph node, between two lymph nodes (7 and 4L) vs. 11Rs lymph node & primary, and between three lymph nodes vs. primary, respectively. Significant pathways were not found in other cases.</p>
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Recovery of pericolorectal lymph nodes from colectomy specimens has long been part of colorectal cancer staging. Recently, adjuvant therapy has been added for high stage carcinomas, providing further impetus for performing careful lymph node dissections. Pericolorectal lymph nodes were examined to determine if there has been a change over time in the number of lymph nodes recovered and proportion of specimens with pericolonic lymph node metastases from colorectal carcinoma resection specimens. Also, the authors attempted to establish a recommendation for a minimum number of lymph nodes that should be recovered before a colon can be considered free of metastases. Slides and reports of the first 20 consecutive pT3 colorectal carcinoma resections in each year from 1955 to 1995 at William Beaumont Hospital that did not have known metastases at the time of surgery were reviewed (750 specimens total). The mean number of lymph nodes recovered per specimen and incidence of detected lymph node metastases increased over the 41-year period, with the greatest increase occurring during 1992-1995. The greatest proportion of patients with lymph node metastases detected occurred in the 17 to 20 lymph nodes recovered per specimen group. Specimens with more than 20 lymph nodes did not have a higher proportion of lymph node metastases detected compared to specimens with 17 to 20 lymph nodes. Approximately 20% of the specimens with metastases had more than 17 lymph nodes recovered. These results suggest that pathologists should retrieve all the lymph nodes that can be recovered, but at least 17 lymph nodes should be recovered to insure accurate documentation of nodal metastases when present.
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