Get 20M+ Full-Text Papers For Less Than $1.50/day. Start a 14-Day Trial for You or Your Team.

Learn More →

Same Surgeon: Different Centre Equals Differing Lymph Node Harvest following Colorectal Cancer Resection

Same Surgeon: Different Centre Equals Differing Lymph Node Harvest following Colorectal Cancer... Hindawi Publishing Corporation International Journal of Surgical Oncology Volume 2011, Article ID 406517, 6 pages doi:10.1155/2011/406517 Research Article Same Surgeon: Different Centre Equals Differing Lymph Node Harvest following Colorectal Cancer Resection 1 2 3 4 4 M. D. Evans, S. Robinson, S. Badiani, A. Rees, J. D. Stamatakis, 3 5 S. S. Karandikar, and G. Langman Department of Surgery, Singleton Hospital, Sketty, Swansea SA2 8QA, UK Alexandra Hospital, Worcester Acute Hospital NHS Trust, Redditch B98 7UB, UK Department of Surgery, Heart of England Foundation NHS Trust, Birmingham B9 5SS, UK Princess of Wales Hospital, Bridgend CF31 1RQ, UK Department of Pathology, Heart of England Foundation NHS Trust, Birmingham B9 5SS, UK Correspondence should be addressed to S. S. Karandikar, sharad.karandikar@heartofengland.nhs.uk Received 17 August 2010; Accepted 12 January 2011 Academic Editor: Timothy M. Pawlik Copyright © 2011 M. D. Evans et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Introduction. The aim of this study was to examine the effect of surgeon relocation on lymph node (LN) retrieval in colorectal cancer (CRC) resection. Methods. The study population was 213 consecutive patients undergoing CRC resection by a single surgeon, at two units: unit one 110 operations (2002–2005) and unit two 103 (2005–2009). LN yields and case mix were compared. Results. Median LN harvests were significantly different between the two centres: unit 1: 13 nodes/patient and unit 2: 22 nodes/patient (P< .001). In unit one 42% of cases were LN positive and in unit two 48% (P = .398). There was no difference in case mix. Multivariate analysis identified unit (P< .001) and pathologist (P = .007) as independent predictors of harvest. Conclusions. A surgeon moving units can experience significantly different LN yield following CRC resection. Both units comply with national standards, but the “surgeon’s results” at the two units appear to be pathologist dependent. This has implications for nodal harvest as a surrogate marker of surgical quality. 1. Introduction of both the operating surgeon and reporting pathologist [7–11]. There is also interunit variability in the harvesting The identification of lymph node (LN) metastases following of LNs following CRC resection [7, 12, 13]. It is not colorectal cancer (CRC) resection is one of the critical clear, however, whether the interunit variability previously discriminators that influence the decision to use adjuvant observed is due to variations in patient characteristics, therapy. Examination of too few lymph nodes risks under surgical technique, or pathological technique. The aim of this staging a patient’s disease. Failure to identify nodal metas- study was therefore to compare the LN harvest and factors tases that exist may deprive the patient of adjuvant therapy influencing it in patients undergoing CRC resection by a and misinform them of their prognosis. Inaccurate staging single surgeon, in separate units, following relocation of the may also have an adverse effect on survival statistics for surgeon during the series. both node negative and node positive cases. LN harvest is increasingly being suggested as a surrogate marker of surgical quality in the treatment of CRC [1, 2]. National agencies 2. Patients and Methods and professional associations in the UK and USA have recommended that a minimum of 12 nodes/patient should The study population consisted of 213 patients undergoing be examined, with all units being expected to achieve this consecutive potentially curative CRC resection for adeno- level consistently [3–6]. carcinoma, operated on by a single consultant surgeon, in LN retrieval is dependent on variables that relate to two units, over a seven-year period. In unit one 110 cases patient characteristics, the operation, and the techniques were carried out between October 2002 and July 2005 and 2 International Journal of Surgical Oncology 103 cases in unit two between August 2005 and October 2009. Patients were identified from prospectively collected databases at the two centres. Individual pathology reports ∗ were retrieved from the hospital pathology database and reviewed. All cases were carried out by an open technique, and there was no change in surgical technique during the study period. All cases were either performed by the consul- tant surgeon or by a trainee under direct supervision of the surgeon. CRC screening was introduced into the second unit during the study period, and seven cases performed in this unit were screen detected. Pathological reporting of the resected specimens was performed by one of eleven consultant pathologists at the two units (three at unit one and eight at unit two). At the One Two second unit, five pathologists had reported more than five Unit specimens and the remaining three pathologists had reported less than five cases each. The results of the three pathologists Mann Whitney reporting less than five cases were therefore pooled, totalling P< .001 eight cases for analysis in this study. Figure 1: Boxplots of LN harvest at the two units. Grey boxes Both units had broadly similar pathological laboratory represent the interquartile range, black horizontal line within the standard operating policies for the retrieval of LNs from CRC grey box the median LN harvest, the and whiskers the range with specimens which consisted of fixation in formalin, cutting circles representing statistical outliers. through the mesenteric tissue in slices parallel to the bowel wall, followed by careful manual dissection of all LNs out of the specimen. Neither unit used fat clearing techniques. data were analysed using SPSS version 16.0 for Mac statistical Data recorded for each patient and compared between software (SPSS, Chicago, IL, USA). units included overall LN harvest and case mix assessed by comparison of patient age, site of operation (divided into right colon, left colon, and rectum), operative urgency 3. Results (elective or emergency), T stage (rectal cases treated with preoperative radiotherapy were excluded in analysis of this There were 110 cases carried out in unit one and 103 cases variable), and the use of neoadjuvant radiotherapy in rectal in unit two. Overall median LN harvest was significantly cancer. different between units, in unit one 13 nodes/patient (range 0–30, 95% C.I 11.7–14.0) and in unit two 22 nodes/patient Factors which may have influenced LN harvest (shown (range 4–102, 95% C.I 23.0–29.6), P< .001 (see Figure 1). in Table 3) in addition to unit of operation were examined Comparison of case mix, patient age, operative urgency, and with univariate analysis. Significant factors on univariate tumour T stage is presented in Table 1. Case mix according examination were then assessed with multivariate analysis. to tumour site was similar between units (Table 1). Lymph node harvests, according to tumour location in right colon, left colon, and rectum, were recorded and compared between units. 3.1. Comparison of LN Yield according to Colonic or Rectal The proportion of LN positive (Dukes’ C) cases was Tumour Location. Analysis of LN harvest according to compared between units and the LN harvest of LN positive whether the tumour was colonic (right and left combined) or and LN negative cases compared within the individual units. rectal demonstrated that colonic (unit one median 15 nodes The effect overall LN harvest had on rates of LN positive cases versus unit 2 median 18 nodes, P = .014) and rectal (unit one across the whole series was also examined. median 10 nodes versus unit two median 31 nodes, P< .001) tumours were higher in the second unit. Analysis of LN harvest according to tumour location demonstrated that LN harvests were significantly higher in left colonic and rectal 2.1. Statistical Analysis. Median values were used to compare tumours in the second unit, but identical in tumours of the all variables. Overall LN harvest between centres was com- right colon (Table 2). Intraunit analysis demonstrated that pared using the Mann-Whitney U test. Case mix between unit one had higher LN harvests in colonic cases (colon the units was compared with Mann-Whitney U test and Chi- median 15 nodes versus rectum median 10 nodes, P< .001), squared test, as appropriate. whereas, in unit two, higher LN harvests were observed in Factors influencing LN retrieval were examined with rectal cases (colon median 18 nodes versus rectum 31 nodes, Pearson’s correlation coefficient, Mann-Whitney U test, and P ≤ .001). Kruskal Wallis H-test as appropriate. The independent effect of variables that were significant on univariate analysis was assessed using multiple backward regression analysis. 3.2. Factors Influencing LN Retrieval. Speculative univariate Significance was assumed for all tests at the 5% level. The analysis of the factors that may have influenced overall LN Total LN harvest International Journal of Surgical Oncology 3 Table 1: Case mix between units. Unit 1 Unit 2 X Percentage of total cases Percentage of total cases P value 35% 40% Right colon P = .427 (38/110) (41/103) 20% 25% ∗∗ Left colon P = .360 (22/110) (26/103) Tumour location 45% 35% Rectum P = .153 (49/110) (36/103) 1% 0% Panproctocolectomy NA (1/110) Median patient age 72 71 P = .789 86% 90% Elective (95/110) (94/103) Operative urgency P = .373 14% 10% Emergency (15/110) (10/103) 21% 20% 1&2 (19/89) (17/84) ∗∗∗ Tstage P = .857 79% 79% 3&4 (71/89) (67/84) ∗∗ Right colon includes right hemicolectomy, extended right hemicolectomy, subtotal colectomy, and transverse colectomy. Left colon includes left hemicolectomy, sigmoid colectomy, and Hartmann’s procedure for colonic tumours and high anterior resection for colonic/rectosigmoid tumours. ∗∗∗ Rectums with preoperative radiotherapy excluded. Table 2: Lymph node harvest according to tumour location between units. Unit 1 Unit 2 P value Median LN harvest/patient Median LN harvest/patient (range) (range) Right colon 16 (5–26) 17 (5–47) .253 Left colon 15 (6–30) 21 (4–64) .023 Rectum (overall) 10 (0–22) 31 (5–102) <.001 11 (0–22) 25 (5–102) Rectum without preoperative radiotherapy <.001 n = 28 n = 17 7 (1–20) 41 (20–70) Rectum with preoperative radiotherapy <.001 n = 21 n = 19 harvest, at the two centres, demonstrated that, in addition to 3.4. Effect of LN Harvest on Identification of LN Metastases. The effect of LN harvest on the identification of LN the unit, significant variables for LN retrieval were T stage and reporting pathologist (Table 3). Age was not found to metastases is presented in Figure 2. Increased frequency of finding at least one metastatic node (Dukes’ C) was seen up be a significant variable (Pearson’s coefficient r =−0.048, to a harvest level of 36 nodes/patient. P = .487), Backward linear regression analysis showed that unit (P< .001) and reporting pathologist (P = .007) were independent significant variables. 4. Discussion Accurate histopathological staging of colorectal cancer 3.3. Proportion of Cases That Were Dukes’ C according to (CRC) is vital to identify patients with Dukes’ C disease Unit. In unit one 46/110 (42%) cases were LN positive for adjuvant chemotherapy. In addition, accurate staging and in unit two 49/103 (48%), x P = .398. In unit is imperative to provide patients with realistic prognostic one, the median LN harvest of patients who were LN information and to allow meaningful comparative audit negative was 11 nodes/patient and in those who were LN between units. This is particularly important as lymph positive was 15 nodes/patient, P = .004. In unit two the node (LN) harvests are increasingly being used as surrogate median LN harvest in patients who were node negative was markers of surgical quality in the treatment of bowel cancer 21 nodes/patient and in those who were node positive was [1, 2]. Previous studies have demonstrated that LN harvests 23 nodes/patient, P = .616. are dependent on numerous variables that relate to patient 4 International Journal of Surgical Oncology Table 3: Analysis of factors that may have influenced overall LN retrieval. Variable Number Median LN harvest P value Unit 1 110 13 Unit P< .001 Unit 2 103 22 Right colon 80 16 ∗∗ P = .761 Left colon 48 17 Operation type Rectal 85 16 Rectal with radiotherapy 40 16 P = .996 Rectal without radiotherapy 45 19 Elective 188 16 Operative urgency P = .299 Emergency 25 15 A45 12 ∗∗ Final Dukes’ stage P = .158 B72 16 C96 17 CR 7 7 114 9 ∗∗ Tstage P = .001 240 18 3 114 16 438 17 131 15 ∗∗ Reporting Pathologist Unit 1 P< .001 239 14 340 11 437 33 532 15 612 19 ∗∗ Reporting Pathologist Unit 2 P< .001 78 23 86 25 ∗∗∗ 9 824 Symptomatic 205 16 Clinical presentation P = .195 Screen detected (all unit 2) 8 19 ∗∗ ∗∗∗ Mann-Whitney U test. Kruskal- Wallis H test. Pooled results of 4 pathologists each reporting less than 5 cases. resection for colon and rectal cancer, despite no change >37 n = 22 in surgical technique, and with a similar case mix in 31–36 n = 8 terms of patient age, tumour location, and T stage. The implication of this finding is that the difference in LN 25–30 n = 19 retrieval between units relates to the pathological techniques, 19–24 as the surgical technique has been standardised by the n = 35 surgeon. 13–18 n = 55 Review of the standard operating policies of both lab- 7–12 n = 51 oratories showed no discernable difference in the methods of fixation or specimen dissection, which suggests that 0–6 n = 23 the differences must relate to the individual pathologist. Neither laboratory employed fat clearance techniques that 0 20 40 60 80 100 have previously been reported to increase both nodal yields Cases LN positive (%) and upstage tumours [14–17]. Fat clearance techniques have Figure 2: Lymph node harvest and percentage of cases of lymph not routinely been used in most centres, and we believe the node positive. methods used in this study are representative of practice across the UK. It has previously been reported that LN harvests follow- characteristics and the techniques of surgeon and pathologist ing rectal resection are lower than after colonic resection [7–11]. The present study has demonstrated that a surgeon [7, 8, 13, 18]. This may explain some of the lower LN harvest observed in unit one in this series, where proportionally relocating to a new unit may experience a dramatic and statistically significant increase in nodal yield following more rectal resections were performed. However, in unit two, LN harvest International Journal of Surgical Oncology 5 rectal cancer specimens had significantly higher LN yields References than colonic tumours. The use of preoperative radiotherapy [1] G.J.Chang,M.A.Rodriguez-Bigas,J.M.Skibber,and V. A. for rectal cancer in unit two was not associated with a Moyer, “Lymph node evaluation and survival after curative reduced lymphatic harvest, as has been previously widely resection of colon cancer: systematic review,” Journal of the reported [7, 8, 19, 20]. A possible explanation, for these National Cancer Institute, vol. 99, no. 6, pp. 433–441, 2007. apparent divergences from the norm, is that a pathologist [2] N. N. Baxter, “Is lymph node count an ideal quality indicator with a particular interest in rectal cancer specimens reported for cancer care?” Journal of Surgical Oncology, vol. 99, no. 4, most of the rectal cases in unit two. pp. 265–268, 2009. Another possible explanation for the observed difference [3] Improving Outcomes in Colorectal Cancer, Manual Update: in LN harvest between unit one and two is the separate NICE; 2004 June 2004. chronological time periods that the harvests cover, that is, [4] “Guideleines for the Management of Colorectal Cancer: The Association of Coloproctology of Great Britain and Ireland,” unit one years 2002–2005 and unit two years 2005–2009. During the latter period, national nodal harvests across [5] H. Nelson, N. Petrelli, A. Carlin et al., “Guidelines 2000 for the UK have improved [21]. However, local audit of LN colon and rectal cancer surgery,” Journal of the National Cancer harvesting at unit one, for resections between 1999 and 2004, Institute, vol. 93, no. 8, pp. 583–596, 2001. showed a median of 13 nodes/patient [8]. Reaudit of harvests [6] G. T. Williams, P. Quirke, and N. A. Shepherd, Dataset for at unit one for the period 2006-2007 showed that the median Colorectal Cancer, The Royal College of Pathologists, 2nd harvest was identical, at 13 nodes/patient [22]. edition, 2007. Higher LN harvests are associated with higher rates of [7]P.P.Tekkis, J. J. Smith, A. G. Heriot,A.W.Darzi,M.R. both node positive disease and improved survival [7, 8, 12, Thompson, and J. D. Stamatakis, “A national study on lymph 23–26]. In the present study, increased nodal yield at the node retrieval in resectional surgery for colorectal cancer,” second unit was associated with a trend towards a higher Diseases of the Colon and Rectum, vol. 49, no. 11, pp. 1673– proportion of cases being staged as Dukes’ C. Although the 1683, 2006. [8] M.D.Evans,K.Barton, A. Rees,J.D.Stamatakis, andS.S. difference was not statistically significant, it is possible that Karandikar, “The impact of surgeon and pathologist on lymph this represents a type II statistical error and that a larger data node retrieval in colorectal cancer and its impact on survival set may yield a statistically significant result. for patients with Dukes’ stage B disease,” Colorectal Disease, Whether 12 nodes per patient is an appropriate level vol. 10, no. 2, pp. 157–164, 2008. is controversial. It may be appropriate that the guidance [9] C.C.Thorn,N.P.Woodcock,N.Scott,C.Verbeke,S.B.Scott, should be revised so that as many nodes as possible should andN.S.Ambrose,“What factorsaffect lymph node yield in be examined [7, 23, 27]. This study supports the latter surgery for rectal cancer?” Colorectal Disease,vol. 6, no.5,pp. view with a higher proportion of cases being classified 356–361, 2004. as LN positive cases up to 36 nodes/patient. Our findings [10] P. M. Johnson,D.Malatjalian,G.A.Porteretal., “Adequacyof must, however, be interpreted with some caution as more nodal harvest in colorectal cancer: a consecutive cohort study,” Journal of Gastrointestinal Surgery, vol. 6, no. 6, pp. 883–890, pathologically advanced tumours have been associated with higher LN harvests [13]. The higher nodal harvest observed [11] J. B. Schofield, N. A. Mounter, R. Mallett, and N. Y. Haboubi, may therefore be a consequence of the disease severity, rather “The importance of accurate pathological assessment of than patients with lower LN yields having missed nodal lymph node involvement in colorectal cancer,” Colorectal metastases. Disease, vol. 8, no. 6, pp. 460–470, 2006. In this series, following multivariate analysis, unit of [12] D. F. H. Pheby, D. F. Levine, R. W. Pitcher, and N. A. operation and reporting pathologist were independently Shepherd, “Lymph node harvests directly influence the staging predictive of nodal harvest. Our finding that a surgeon work- of colorectal cancer: evidence from a regional audit,” Journal of ing at different sites can experience different nodal yields Clinical Pathology, vol. 57, no. 1, pp. 43–47, 2004. has been previously reported (Rieger et al. [28]), although [13] N. N. Baxter, D. J. Virnig, D. A. Rothenberger, A. M. Morris, J. Jessurun, and B. A. Virnig, “Lymph node evaluation in this series was smaller than our study and the results colorectal cancer patients: a population-based study,” Journal were not subjected to multi-variate analysis to determine of the National Cancer Institute, vol. 97, no. 3, pp. 219–225, if pathologist or unit were independently predictive of LN harvest. [14] N. Y. Haboubi, P. F. Schofield, P. Clark, and S. M. Kaftan, “The importance of combining xylene clearance and immunohis- tochemistry in the accurate staging of colorectal carcinoma,” 5. Conclusions Journal of the Royal Society of Medicine, vol. 85, no. 7, pp. 386– 388, 1992. This study has demonstrated that a single surgeon who [15] K. W. M. Scott and R. H. Grace, “Detection of lymph moves units, with no change in surgical technique and node metastases in colorectal carcinoma before and after fat similar case mix at the two units, can experience significantly clearance,” British Journal of Surgery, vol. 76, no. 11, pp. 1165– differing LN harvests following resection for CRC. These 1167, 1989. findings confirm that the pathologist is a critical determinant [16] S. J. Cawthorn, N. M. Gibbs, and C. G. Marks, “Clearance on the numbers of LNs harvested following resection for technique for the detection of lymph nodes in colorectal CRC. This has implications if LN harvest is used as a marker cancer,” British Journal of Surgery, vol. 73, no. 1, pp. 58–60, of “surgical quality.” 1986. 6 International Journal of Surgical Oncology [17] C. Vogel, T. Kirtil, F. Oellig, and M. Stolte, “Lymph node preparation in resected colorectal carcinoma specimens employing the acetone clearing method,” Pathology Research and Practice, vol. 204, no. 1, pp. 11–15, 2008. [18] M. A. Ostadi, J. L. Harnish, S. Stegienko, and D. R. Urbach, “Factors affecting the number of lymph nodes retrieved in colorectal cancer specimens,” Surgical Endoscopy and Other Interventional Techniques, vol. 21, no. 12, pp. 2142–2146, 2007. [19] R. E. Wijesuriya, K. I. Deen, J. Hewavisenthi, J. Balawardana, and M. Perera, “Neoadjuvant therapy for rectal cancer down- stages the tumor but reduces lymph node harvest signifi- cantly,” Surgery Today, vol. 35, no. 6, pp. 442–445, 2005. [20] N. N. Baxter, A. M. Morris, D. A. Rothenberger, and J. E. Tepper, “Impact of preoperative radiation for rectal cancer on subsequent lymph node evaluation: a population-based analysis,” International Journal of Radiation Oncology Biology Physics, vol. 61, no. 2, pp. 426–431, 2005. [21] J. J. Smith, J. Cornish, P. P. Tekkis, and M. R. Thompson, “Quality Improvement and Open Reporting: The Association of Coloproctology of Great Britain and Ireland,” The National Bowel Cancer Audit Report 2007. [22] J. Stamatakis, J. Smith, M. Evans, and J. Davies, “3rd Bowel Cancer Audit Report April 2005-March 2007,” Cancer Services Co-ordinating Group, 2008. [23] N. S. Goldstein, W. Sanford, M. Coffey, and L. J. Layfield, “Lymph node recovery from colorectal resection specimens removed for adenocarcinoma: trends over time and a recom- mendation for a minimum number of lymph nodes to be recovered,” American Journal of Clinical Pathology, vol. 106, no. 2, pp. 209–216, 1996. [24] R. S. Swanson, C. C. Compton, A. K. Stewart, and K. I. Bland, “The prognosis of T3N0 colon cancer is dependent on the number of lymph nodes examined,” Annals of Surgical Oncology, vol. 10, no. 1, pp. 65–71, 2003. [25] T. E. Le Voyer, E. R. Sigurdson, A. L. Hanlon et al., “Colon cancer survival is associated with increasing number of lymph nodes analyzed: a secondary survey of intergroup trial INT- 0089,” Journal of Clinical Oncology, vol. 21, no. 15, pp. 2912– 2919, 2003. [26] M. Prandi, R. Lionetto, A. Bini et al., “Prognostic evaluation of stage B colon cancer patients is improved by an adequate lymphadenectomy: results of a secondary analysis of a large scale adjuvant trial,” Annals of Surgery, vol. 235, no. 4, pp. 458– 463, 2002. [27] G. Cserni, V. Vinh-Hung, and T. Burzykowski, “Is there a min- imum number of lymph nodes that should be histologically assessed for a reliable nodal staging of T3NOMO colorectal carcinomas?” Journal of Surgical Oncology, vol. 81, no. 2, pp. 63–69, 2002. [28] N. A. Rieger,F.S.Barnett,J.W.E.Moore et al., “Quality of pathology reporting impacts on lymph node yield in colon cancer,” Journal of Clinical Oncology, vol. 25, no. 4, p. 463, 2007, author reply -4. MEDIATORS of INFLAMMATION The Scientific Gastroenterology Journal of World Journal Research and Practice Diabetes Research Disease Markers Hindawi Publishing Corporation Hindawi Publishing Corporation Hindawi Publishing Corporation Hindawi Publishing Corporation Hindawi Publishing Corporation http://www.hindawi.com Volume 2014 http://www.hindawi.com Volume 2014 http://www.hindawi.com Volume 2014 http://www.hindawi.com Volume 2014 http://www.hindawi.com Volume 2014 International Journal of Journal of Immunology Research Endocrinology Hindawi Publishing Corporation Hindawi Publishing Corporation http://www.hindawi.com Volume 2014 http://www.hindawi.com Volume 2014 Submit your manuscripts at http://www.hindawi.com BioMed PPAR Research Research International Hindawi Publishing Corporation Hindawi Publishing Corporation http://www.hindawi.com Volume 2014 http://www.hindawi.com Volume 2014 Journal of Obesity Evidence-Based Journal of Journal of Stem Cells Complementary and Ophthalmology International Alternative Medicine Oncology Hindawi Publishing Corporation Hindawi Publishing Corporation Hindawi Publishing Corporation Hindawi Publishing Corporation Hindawi Publishing Corporation http://www.hindawi.com Volume 2014 http://www.hindawi.com Volume 2014 http://www.hindawi.com Volume 2014 http://www.hindawi.com Volume 2014 http://www.hindawi.com Volume 2014 Parkinson’s Disease Computational and Behavioural Mathematical Methods AIDS Oxidative Medicine and in Medicine Research and Treatment Cellular Longevity Neurology Hindawi Publishing Corporation Hindawi Publishing Corporation Hindawi Publishing Corporation Hindawi Publishing Corporation Hindawi Publishing Corporation http://www.hindawi.com Volume 2014 http://www.hindawi.com Volume 2014 http://www.hindawi.com Volume 2014 http://www.hindawi.com Volume 2014 http://www.hindawi.com Volume 2014 http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png International Journal of Surgical Oncology Hindawi Publishing Corporation

Same Surgeon: Different Centre Equals Differing Lymph Node Harvest following Colorectal Cancer Resection

Loading next page...
 
/lp/hindawi-publishing-corporation/same-surgeon-different-centre-equals-differing-lymph-node-harvest-0ARVNbKOf8
Publisher
Hindawi Publishing Corporation
Copyright
Copyright © 2011 M. D. Evans et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
ISSN
2090-1402
eISSN
2090-1410
DOI
10.1155/2011/406517
Publisher site
See Article on Publisher Site

Abstract

Hindawi Publishing Corporation International Journal of Surgical Oncology Volume 2011, Article ID 406517, 6 pages doi:10.1155/2011/406517 Research Article Same Surgeon: Different Centre Equals Differing Lymph Node Harvest following Colorectal Cancer Resection 1 2 3 4 4 M. D. Evans, S. Robinson, S. Badiani, A. Rees, J. D. Stamatakis, 3 5 S. S. Karandikar, and G. Langman Department of Surgery, Singleton Hospital, Sketty, Swansea SA2 8QA, UK Alexandra Hospital, Worcester Acute Hospital NHS Trust, Redditch B98 7UB, UK Department of Surgery, Heart of England Foundation NHS Trust, Birmingham B9 5SS, UK Princess of Wales Hospital, Bridgend CF31 1RQ, UK Department of Pathology, Heart of England Foundation NHS Trust, Birmingham B9 5SS, UK Correspondence should be addressed to S. S. Karandikar, sharad.karandikar@heartofengland.nhs.uk Received 17 August 2010; Accepted 12 January 2011 Academic Editor: Timothy M. Pawlik Copyright © 2011 M. D. Evans et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Introduction. The aim of this study was to examine the effect of surgeon relocation on lymph node (LN) retrieval in colorectal cancer (CRC) resection. Methods. The study population was 213 consecutive patients undergoing CRC resection by a single surgeon, at two units: unit one 110 operations (2002–2005) and unit two 103 (2005–2009). LN yields and case mix were compared. Results. Median LN harvests were significantly different between the two centres: unit 1: 13 nodes/patient and unit 2: 22 nodes/patient (P< .001). In unit one 42% of cases were LN positive and in unit two 48% (P = .398). There was no difference in case mix. Multivariate analysis identified unit (P< .001) and pathologist (P = .007) as independent predictors of harvest. Conclusions. A surgeon moving units can experience significantly different LN yield following CRC resection. Both units comply with national standards, but the “surgeon’s results” at the two units appear to be pathologist dependent. This has implications for nodal harvest as a surrogate marker of surgical quality. 1. Introduction of both the operating surgeon and reporting pathologist [7–11]. There is also interunit variability in the harvesting The identification of lymph node (LN) metastases following of LNs following CRC resection [7, 12, 13]. It is not colorectal cancer (CRC) resection is one of the critical clear, however, whether the interunit variability previously discriminators that influence the decision to use adjuvant observed is due to variations in patient characteristics, therapy. Examination of too few lymph nodes risks under surgical technique, or pathological technique. The aim of this staging a patient’s disease. Failure to identify nodal metas- study was therefore to compare the LN harvest and factors tases that exist may deprive the patient of adjuvant therapy influencing it in patients undergoing CRC resection by a and misinform them of their prognosis. Inaccurate staging single surgeon, in separate units, following relocation of the may also have an adverse effect on survival statistics for surgeon during the series. both node negative and node positive cases. LN harvest is increasingly being suggested as a surrogate marker of surgical quality in the treatment of CRC [1, 2]. National agencies 2. Patients and Methods and professional associations in the UK and USA have recommended that a minimum of 12 nodes/patient should The study population consisted of 213 patients undergoing be examined, with all units being expected to achieve this consecutive potentially curative CRC resection for adeno- level consistently [3–6]. carcinoma, operated on by a single consultant surgeon, in LN retrieval is dependent on variables that relate to two units, over a seven-year period. In unit one 110 cases patient characteristics, the operation, and the techniques were carried out between October 2002 and July 2005 and 2 International Journal of Surgical Oncology 103 cases in unit two between August 2005 and October 2009. Patients were identified from prospectively collected databases at the two centres. Individual pathology reports ∗ were retrieved from the hospital pathology database and reviewed. All cases were carried out by an open technique, and there was no change in surgical technique during the study period. All cases were either performed by the consul- tant surgeon or by a trainee under direct supervision of the surgeon. CRC screening was introduced into the second unit during the study period, and seven cases performed in this unit were screen detected. Pathological reporting of the resected specimens was performed by one of eleven consultant pathologists at the two units (three at unit one and eight at unit two). At the One Two second unit, five pathologists had reported more than five Unit specimens and the remaining three pathologists had reported less than five cases each. The results of the three pathologists Mann Whitney reporting less than five cases were therefore pooled, totalling P< .001 eight cases for analysis in this study. Figure 1: Boxplots of LN harvest at the two units. Grey boxes Both units had broadly similar pathological laboratory represent the interquartile range, black horizontal line within the standard operating policies for the retrieval of LNs from CRC grey box the median LN harvest, the and whiskers the range with specimens which consisted of fixation in formalin, cutting circles representing statistical outliers. through the mesenteric tissue in slices parallel to the bowel wall, followed by careful manual dissection of all LNs out of the specimen. Neither unit used fat clearing techniques. data were analysed using SPSS version 16.0 for Mac statistical Data recorded for each patient and compared between software (SPSS, Chicago, IL, USA). units included overall LN harvest and case mix assessed by comparison of patient age, site of operation (divided into right colon, left colon, and rectum), operative urgency 3. Results (elective or emergency), T stage (rectal cases treated with preoperative radiotherapy were excluded in analysis of this There were 110 cases carried out in unit one and 103 cases variable), and the use of neoadjuvant radiotherapy in rectal in unit two. Overall median LN harvest was significantly cancer. different between units, in unit one 13 nodes/patient (range 0–30, 95% C.I 11.7–14.0) and in unit two 22 nodes/patient Factors which may have influenced LN harvest (shown (range 4–102, 95% C.I 23.0–29.6), P< .001 (see Figure 1). in Table 3) in addition to unit of operation were examined Comparison of case mix, patient age, operative urgency, and with univariate analysis. Significant factors on univariate tumour T stage is presented in Table 1. Case mix according examination were then assessed with multivariate analysis. to tumour site was similar between units (Table 1). Lymph node harvests, according to tumour location in right colon, left colon, and rectum, were recorded and compared between units. 3.1. Comparison of LN Yield according to Colonic or Rectal The proportion of LN positive (Dukes’ C) cases was Tumour Location. Analysis of LN harvest according to compared between units and the LN harvest of LN positive whether the tumour was colonic (right and left combined) or and LN negative cases compared within the individual units. rectal demonstrated that colonic (unit one median 15 nodes The effect overall LN harvest had on rates of LN positive cases versus unit 2 median 18 nodes, P = .014) and rectal (unit one across the whole series was also examined. median 10 nodes versus unit two median 31 nodes, P< .001) tumours were higher in the second unit. Analysis of LN harvest according to tumour location demonstrated that LN harvests were significantly higher in left colonic and rectal 2.1. Statistical Analysis. Median values were used to compare tumours in the second unit, but identical in tumours of the all variables. Overall LN harvest between centres was com- right colon (Table 2). Intraunit analysis demonstrated that pared using the Mann-Whitney U test. Case mix between unit one had higher LN harvests in colonic cases (colon the units was compared with Mann-Whitney U test and Chi- median 15 nodes versus rectum median 10 nodes, P< .001), squared test, as appropriate. whereas, in unit two, higher LN harvests were observed in Factors influencing LN retrieval were examined with rectal cases (colon median 18 nodes versus rectum 31 nodes, Pearson’s correlation coefficient, Mann-Whitney U test, and P ≤ .001). Kruskal Wallis H-test as appropriate. The independent effect of variables that were significant on univariate analysis was assessed using multiple backward regression analysis. 3.2. Factors Influencing LN Retrieval. Speculative univariate Significance was assumed for all tests at the 5% level. The analysis of the factors that may have influenced overall LN Total LN harvest International Journal of Surgical Oncology 3 Table 1: Case mix between units. Unit 1 Unit 2 X Percentage of total cases Percentage of total cases P value 35% 40% Right colon P = .427 (38/110) (41/103) 20% 25% ∗∗ Left colon P = .360 (22/110) (26/103) Tumour location 45% 35% Rectum P = .153 (49/110) (36/103) 1% 0% Panproctocolectomy NA (1/110) Median patient age 72 71 P = .789 86% 90% Elective (95/110) (94/103) Operative urgency P = .373 14% 10% Emergency (15/110) (10/103) 21% 20% 1&2 (19/89) (17/84) ∗∗∗ Tstage P = .857 79% 79% 3&4 (71/89) (67/84) ∗∗ Right colon includes right hemicolectomy, extended right hemicolectomy, subtotal colectomy, and transverse colectomy. Left colon includes left hemicolectomy, sigmoid colectomy, and Hartmann’s procedure for colonic tumours and high anterior resection for colonic/rectosigmoid tumours. ∗∗∗ Rectums with preoperative radiotherapy excluded. Table 2: Lymph node harvest according to tumour location between units. Unit 1 Unit 2 P value Median LN harvest/patient Median LN harvest/patient (range) (range) Right colon 16 (5–26) 17 (5–47) .253 Left colon 15 (6–30) 21 (4–64) .023 Rectum (overall) 10 (0–22) 31 (5–102) <.001 11 (0–22) 25 (5–102) Rectum without preoperative radiotherapy <.001 n = 28 n = 17 7 (1–20) 41 (20–70) Rectum with preoperative radiotherapy <.001 n = 21 n = 19 harvest, at the two centres, demonstrated that, in addition to 3.4. Effect of LN Harvest on Identification of LN Metastases. The effect of LN harvest on the identification of LN the unit, significant variables for LN retrieval were T stage and reporting pathologist (Table 3). Age was not found to metastases is presented in Figure 2. Increased frequency of finding at least one metastatic node (Dukes’ C) was seen up be a significant variable (Pearson’s coefficient r =−0.048, to a harvest level of 36 nodes/patient. P = .487), Backward linear regression analysis showed that unit (P< .001) and reporting pathologist (P = .007) were independent significant variables. 4. Discussion Accurate histopathological staging of colorectal cancer 3.3. Proportion of Cases That Were Dukes’ C according to (CRC) is vital to identify patients with Dukes’ C disease Unit. In unit one 46/110 (42%) cases were LN positive for adjuvant chemotherapy. In addition, accurate staging and in unit two 49/103 (48%), x P = .398. In unit is imperative to provide patients with realistic prognostic one, the median LN harvest of patients who were LN information and to allow meaningful comparative audit negative was 11 nodes/patient and in those who were LN between units. This is particularly important as lymph positive was 15 nodes/patient, P = .004. In unit two the node (LN) harvests are increasingly being used as surrogate median LN harvest in patients who were node negative was markers of surgical quality in the treatment of bowel cancer 21 nodes/patient and in those who were node positive was [1, 2]. Previous studies have demonstrated that LN harvests 23 nodes/patient, P = .616. are dependent on numerous variables that relate to patient 4 International Journal of Surgical Oncology Table 3: Analysis of factors that may have influenced overall LN retrieval. Variable Number Median LN harvest P value Unit 1 110 13 Unit P< .001 Unit 2 103 22 Right colon 80 16 ∗∗ P = .761 Left colon 48 17 Operation type Rectal 85 16 Rectal with radiotherapy 40 16 P = .996 Rectal without radiotherapy 45 19 Elective 188 16 Operative urgency P = .299 Emergency 25 15 A45 12 ∗∗ Final Dukes’ stage P = .158 B72 16 C96 17 CR 7 7 114 9 ∗∗ Tstage P = .001 240 18 3 114 16 438 17 131 15 ∗∗ Reporting Pathologist Unit 1 P< .001 239 14 340 11 437 33 532 15 612 19 ∗∗ Reporting Pathologist Unit 2 P< .001 78 23 86 25 ∗∗∗ 9 824 Symptomatic 205 16 Clinical presentation P = .195 Screen detected (all unit 2) 8 19 ∗∗ ∗∗∗ Mann-Whitney U test. Kruskal- Wallis H test. Pooled results of 4 pathologists each reporting less than 5 cases. resection for colon and rectal cancer, despite no change >37 n = 22 in surgical technique, and with a similar case mix in 31–36 n = 8 terms of patient age, tumour location, and T stage. The implication of this finding is that the difference in LN 25–30 n = 19 retrieval between units relates to the pathological techniques, 19–24 as the surgical technique has been standardised by the n = 35 surgeon. 13–18 n = 55 Review of the standard operating policies of both lab- 7–12 n = 51 oratories showed no discernable difference in the methods of fixation or specimen dissection, which suggests that 0–6 n = 23 the differences must relate to the individual pathologist. Neither laboratory employed fat clearance techniques that 0 20 40 60 80 100 have previously been reported to increase both nodal yields Cases LN positive (%) and upstage tumours [14–17]. Fat clearance techniques have Figure 2: Lymph node harvest and percentage of cases of lymph not routinely been used in most centres, and we believe the node positive. methods used in this study are representative of practice across the UK. It has previously been reported that LN harvests follow- characteristics and the techniques of surgeon and pathologist ing rectal resection are lower than after colonic resection [7–11]. The present study has demonstrated that a surgeon [7, 8, 13, 18]. This may explain some of the lower LN harvest observed in unit one in this series, where proportionally relocating to a new unit may experience a dramatic and statistically significant increase in nodal yield following more rectal resections were performed. However, in unit two, LN harvest International Journal of Surgical Oncology 5 rectal cancer specimens had significantly higher LN yields References than colonic tumours. The use of preoperative radiotherapy [1] G.J.Chang,M.A.Rodriguez-Bigas,J.M.Skibber,and V. A. for rectal cancer in unit two was not associated with a Moyer, “Lymph node evaluation and survival after curative reduced lymphatic harvest, as has been previously widely resection of colon cancer: systematic review,” Journal of the reported [7, 8, 19, 20]. A possible explanation, for these National Cancer Institute, vol. 99, no. 6, pp. 433–441, 2007. apparent divergences from the norm, is that a pathologist [2] N. N. Baxter, “Is lymph node count an ideal quality indicator with a particular interest in rectal cancer specimens reported for cancer care?” Journal of Surgical Oncology, vol. 99, no. 4, most of the rectal cases in unit two. pp. 265–268, 2009. Another possible explanation for the observed difference [3] Improving Outcomes in Colorectal Cancer, Manual Update: in LN harvest between unit one and two is the separate NICE; 2004 June 2004. chronological time periods that the harvests cover, that is, [4] “Guideleines for the Management of Colorectal Cancer: The Association of Coloproctology of Great Britain and Ireland,” unit one years 2002–2005 and unit two years 2005–2009. During the latter period, national nodal harvests across [5] H. Nelson, N. Petrelli, A. Carlin et al., “Guidelines 2000 for the UK have improved [21]. However, local audit of LN colon and rectal cancer surgery,” Journal of the National Cancer harvesting at unit one, for resections between 1999 and 2004, Institute, vol. 93, no. 8, pp. 583–596, 2001. showed a median of 13 nodes/patient [8]. Reaudit of harvests [6] G. T. Williams, P. Quirke, and N. A. Shepherd, Dataset for at unit one for the period 2006-2007 showed that the median Colorectal Cancer, The Royal College of Pathologists, 2nd harvest was identical, at 13 nodes/patient [22]. edition, 2007. Higher LN harvests are associated with higher rates of [7]P.P.Tekkis, J. J. Smith, A. G. Heriot,A.W.Darzi,M.R. both node positive disease and improved survival [7, 8, 12, Thompson, and J. D. Stamatakis, “A national study on lymph 23–26]. In the present study, increased nodal yield at the node retrieval in resectional surgery for colorectal cancer,” second unit was associated with a trend towards a higher Diseases of the Colon and Rectum, vol. 49, no. 11, pp. 1673– proportion of cases being staged as Dukes’ C. Although the 1683, 2006. [8] M.D.Evans,K.Barton, A. Rees,J.D.Stamatakis, andS.S. difference was not statistically significant, it is possible that Karandikar, “The impact of surgeon and pathologist on lymph this represents a type II statistical error and that a larger data node retrieval in colorectal cancer and its impact on survival set may yield a statistically significant result. for patients with Dukes’ stage B disease,” Colorectal Disease, Whether 12 nodes per patient is an appropriate level vol. 10, no. 2, pp. 157–164, 2008. is controversial. It may be appropriate that the guidance [9] C.C.Thorn,N.P.Woodcock,N.Scott,C.Verbeke,S.B.Scott, should be revised so that as many nodes as possible should andN.S.Ambrose,“What factorsaffect lymph node yield in be examined [7, 23, 27]. This study supports the latter surgery for rectal cancer?” Colorectal Disease,vol. 6, no.5,pp. view with a higher proportion of cases being classified 356–361, 2004. as LN positive cases up to 36 nodes/patient. Our findings [10] P. M. Johnson,D.Malatjalian,G.A.Porteretal., “Adequacyof must, however, be interpreted with some caution as more nodal harvest in colorectal cancer: a consecutive cohort study,” Journal of Gastrointestinal Surgery, vol. 6, no. 6, pp. 883–890, pathologically advanced tumours have been associated with higher LN harvests [13]. The higher nodal harvest observed [11] J. B. Schofield, N. A. Mounter, R. Mallett, and N. Y. Haboubi, may therefore be a consequence of the disease severity, rather “The importance of accurate pathological assessment of than patients with lower LN yields having missed nodal lymph node involvement in colorectal cancer,” Colorectal metastases. Disease, vol. 8, no. 6, pp. 460–470, 2006. In this series, following multivariate analysis, unit of [12] D. F. H. Pheby, D. F. Levine, R. W. Pitcher, and N. A. operation and reporting pathologist were independently Shepherd, “Lymph node harvests directly influence the staging predictive of nodal harvest. Our finding that a surgeon work- of colorectal cancer: evidence from a regional audit,” Journal of ing at different sites can experience different nodal yields Clinical Pathology, vol. 57, no. 1, pp. 43–47, 2004. has been previously reported (Rieger et al. [28]), although [13] N. N. Baxter, D. J. Virnig, D. A. Rothenberger, A. M. Morris, J. Jessurun, and B. A. Virnig, “Lymph node evaluation in this series was smaller than our study and the results colorectal cancer patients: a population-based study,” Journal were not subjected to multi-variate analysis to determine of the National Cancer Institute, vol. 97, no. 3, pp. 219–225, if pathologist or unit were independently predictive of LN harvest. [14] N. Y. Haboubi, P. F. Schofield, P. Clark, and S. M. Kaftan, “The importance of combining xylene clearance and immunohis- tochemistry in the accurate staging of colorectal carcinoma,” 5. Conclusions Journal of the Royal Society of Medicine, vol. 85, no. 7, pp. 386– 388, 1992. This study has demonstrated that a single surgeon who [15] K. W. M. Scott and R. H. Grace, “Detection of lymph moves units, with no change in surgical technique and node metastases in colorectal carcinoma before and after fat similar case mix at the two units, can experience significantly clearance,” British Journal of Surgery, vol. 76, no. 11, pp. 1165– differing LN harvests following resection for CRC. These 1167, 1989. findings confirm that the pathologist is a critical determinant [16] S. J. Cawthorn, N. M. Gibbs, and C. G. Marks, “Clearance on the numbers of LNs harvested following resection for technique for the detection of lymph nodes in colorectal CRC. This has implications if LN harvest is used as a marker cancer,” British Journal of Surgery, vol. 73, no. 1, pp. 58–60, of “surgical quality.” 1986. 6 International Journal of Surgical Oncology [17] C. Vogel, T. Kirtil, F. Oellig, and M. Stolte, “Lymph node preparation in resected colorectal carcinoma specimens employing the acetone clearing method,” Pathology Research and Practice, vol. 204, no. 1, pp. 11–15, 2008. [18] M. A. Ostadi, J. L. Harnish, S. Stegienko, and D. R. Urbach, “Factors affecting the number of lymph nodes retrieved in colorectal cancer specimens,” Surgical Endoscopy and Other Interventional Techniques, vol. 21, no. 12, pp. 2142–2146, 2007. [19] R. E. Wijesuriya, K. I. Deen, J. Hewavisenthi, J. Balawardana, and M. Perera, “Neoadjuvant therapy for rectal cancer down- stages the tumor but reduces lymph node harvest signifi- cantly,” Surgery Today, vol. 35, no. 6, pp. 442–445, 2005. [20] N. N. Baxter, A. M. Morris, D. A. Rothenberger, and J. E. Tepper, “Impact of preoperative radiation for rectal cancer on subsequent lymph node evaluation: a population-based analysis,” International Journal of Radiation Oncology Biology Physics, vol. 61, no. 2, pp. 426–431, 2005. [21] J. J. Smith, J. Cornish, P. P. Tekkis, and M. R. Thompson, “Quality Improvement and Open Reporting: The Association of Coloproctology of Great Britain and Ireland,” The National Bowel Cancer Audit Report 2007. [22] J. Stamatakis, J. Smith, M. Evans, and J. Davies, “3rd Bowel Cancer Audit Report April 2005-March 2007,” Cancer Services Co-ordinating Group, 2008. [23] N. S. Goldstein, W. Sanford, M. Coffey, and L. J. Layfield, “Lymph node recovery from colorectal resection specimens removed for adenocarcinoma: trends over time and a recom- mendation for a minimum number of lymph nodes to be recovered,” American Journal of Clinical Pathology, vol. 106, no. 2, pp. 209–216, 1996. [24] R. S. Swanson, C. C. Compton, A. K. Stewart, and K. I. Bland, “The prognosis of T3N0 colon cancer is dependent on the number of lymph nodes examined,” Annals of Surgical Oncology, vol. 10, no. 1, pp. 65–71, 2003. [25] T. E. Le Voyer, E. R. Sigurdson, A. L. Hanlon et al., “Colon cancer survival is associated with increasing number of lymph nodes analyzed: a secondary survey of intergroup trial INT- 0089,” Journal of Clinical Oncology, vol. 21, no. 15, pp. 2912– 2919, 2003. [26] M. Prandi, R. Lionetto, A. Bini et al., “Prognostic evaluation of stage B colon cancer patients is improved by an adequate lymphadenectomy: results of a secondary analysis of a large scale adjuvant trial,” Annals of Surgery, vol. 235, no. 4, pp. 458– 463, 2002. [27] G. Cserni, V. Vinh-Hung, and T. Burzykowski, “Is there a min- imum number of lymph nodes that should be histologically assessed for a reliable nodal staging of T3NOMO colorectal carcinomas?” Journal of Surgical Oncology, vol. 81, no. 2, pp. 63–69, 2002. [28] N. A. Rieger,F.S.Barnett,J.W.E.Moore et al., “Quality of pathology reporting impacts on lymph node yield in colon cancer,” Journal of Clinical Oncology, vol. 25, no. 4, p. 463, 2007, author reply -4. MEDIATORS of INFLAMMATION The Scientific Gastroenterology Journal of World Journal Research and Practice Diabetes Research Disease Markers Hindawi Publishing Corporation Hindawi Publishing Corporation Hindawi Publishing Corporation Hindawi Publishing Corporation Hindawi Publishing Corporation http://www.hindawi.com Volume 2014 http://www.hindawi.com Volume 2014 http://www.hindawi.com Volume 2014 http://www.hindawi.com Volume 2014 http://www.hindawi.com Volume 2014 International Journal of Journal of Immunology Research Endocrinology Hindawi Publishing Corporation Hindawi Publishing Corporation http://www.hindawi.com Volume 2014 http://www.hindawi.com Volume 2014 Submit your manuscripts at http://www.hindawi.com BioMed PPAR Research Research International Hindawi Publishing Corporation Hindawi Publishing Corporation http://www.hindawi.com Volume 2014 http://www.hindawi.com Volume 2014 Journal of Obesity Evidence-Based Journal of Journal of Stem Cells Complementary and Ophthalmology International Alternative Medicine Oncology Hindawi Publishing Corporation Hindawi Publishing Corporation Hindawi Publishing Corporation Hindawi Publishing Corporation Hindawi Publishing Corporation http://www.hindawi.com Volume 2014 http://www.hindawi.com Volume 2014 http://www.hindawi.com Volume 2014 http://www.hindawi.com Volume 2014 http://www.hindawi.com Volume 2014 Parkinson’s Disease Computational and Behavioural Mathematical Methods AIDS Oxidative Medicine and in Medicine Research and Treatment Cellular Longevity Neurology Hindawi Publishing Corporation Hindawi Publishing Corporation Hindawi Publishing Corporation Hindawi Publishing Corporation Hindawi Publishing Corporation http://www.hindawi.com Volume 2014 http://www.hindawi.com Volume 2014 http://www.hindawi.com Volume 2014 http://www.hindawi.com Volume 2014 http://www.hindawi.com Volume 2014

Journal

International Journal of Surgical OncologyHindawi Publishing Corporation

Published: Mar 17, 2011

References