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Lymph node yield in rectal cancer surgery: Effect of preoperativechemoradiotherapy

B. Morcos a,*, B. Baker a, M. Al Masri a, H. Haddad b, S. Hashem c

a Department of Surgery and Surgical Oncology, King Hussein Cancer Center, Amman, Jordanb Department of Pathology, King Hussein Cancer Center, Amman, Jordan

c Department of Radiation Oncology, King Hussein Cancer Center, Amman, Jordan

Accepted 22 December 2009

Abstract

Aim: Adequate lymph node resection in rectal cancer is important for staging and local control. This study aims to verify the effect of neo-adjuvant chemoradiation, as well as some clinicopathological features, on the yield of lymph nodes in rectal carcinoma.Methods: Data on consecutive patients who had total mesorectal excision for rectal adenocarcinoma at a single cancer center between Jan-uary 2003 and July 2008 were reviewed. No patient had any prior pelvic surgery or radiotherapy. Patients had neoadjuvant chemoradio-therapy if they were stage II or III.Results: A total of 116 patients were included. The mean age was 53 years (range 29e83). Fifty-nine patients (51%) received neoadjuvanttherapy before resection. The mean number of lymph nodes removed was 18 (range 4e67) per specimen. There was less lymph node yieldin patients who received neoadjuvant therapy (16 vs. 19, p ¼ 0.008). Only 64% of patients who had preoperative therapy had 12 lymphnodes or more in the specimen as opposed to 88% of those who had surgery upfront ( p ¼ 0.003). Other factors associated with lower lymphnode yield included: female sex ( p ¼ 0.03) and tumour location in the lower rectum ( p ¼ 0.002). Age, tumour stage and grade, type ofoperation and surgical delay did not affect the number of lymph nodes removed.Conclusion: Preoperative chemoradiotherapy for rectal cancer results in reduction in lymph node yield. Female sex and lower rectal tu-mours are also associated with retrieval of fewer lymph nodes.� 2009 Elsevier Ltd. All rights reserved.

Keywords: Lymph nodes; Rectal cancer; Neoadjuvant; Chemoradiation

Introduction

Pathological staging of colorectal cancer requires ade-quate resection of the tumour with the regional lymph no-des. In rectal carcinoma, this is achieved by totalmesorectal excision (TME). Inadequate lymph node re-moval may result in understaging.

The National Cancer Institute (NCI) recommends that atleast 12 lymph nodes are removed for adequate staging ofcolorectal cancer.1 This is in accordance with the recom-mendations of the World Congress of Gastroenterologyheld in Sydney in 1990.2 Removal of fewer lymph nodes

* Correspondence to: B. Morcos, King Hussein Cancer Center, P.O. Box

1269, Al-Jubeiha, Amman 11941, Jordan. Tel.: þ962 796756432; fax:

þ962 5353001.

E-mail address: bmorcos@doctor.com (B. Morcos).

0748-7983/$ - see front matter � 2009 Elsevier Ltd. All rights reserved.

doi:10.1016/j.ejso.2009.12.006

Please cite this article in press as: Morcos B, et al., Lymph node yield in rectal ca

(2010), doi:10.1016/j.ejso.2009.12.006

results in understaging, and some patients who would ben-efit from receiving adjuvant therapy, therefore, would notbe offered any.1 Removal of fewer lymph nodes is alsoassociated with a poorer survival and higher rates of localrecurrence.3e6 This is especially important for rectal can-cer, as local recurrence is associated with significantmorbidity.

Preoperative radiotherapy is thought to decrease thelymph node yield after surgical excision.7e10 This is prob-ably caused by the immune response and fibrosis in lymphnodes exposed to radiotherapy, which results in diminu-tion in their size, making their identification in the pathol-ogy specimen difficult. This study aims to look at theeffect of preoperative chemoradiotherapy (CRT) on thenumber of lymph nodes retrieved in the mesorectalspecimen. Other clinicopathological factors are alsostudied.

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Patients and methods

Patient population

Data on all patients who had resection of rectal adeno-carcinoma at a single cancer center were retrospectively re-viewed. During the period from January 2003 to July 2008a total of 134 cases met the inclusion criteria for this study.Their surgery was performed at the center by one of foursurgeons who had previous training in proper rectal cancersurgery. All the patients had curative or potentially curativeTME. Eighteen patients were excluded from the study be-cause of previous pelvic surgery or radiotherapy. Fifteenpatients had previous pelvic radiotherapy and 3 patientshad pelvic surgery. The remaining 116 patients constitutedthe study population.

Treatment

Table 1

Clinicopathological features of 116 patients.

Feature Surgery only

no. (%)

Neoadjuvant

no. (%)

Total no.

(%)

Age

<50 years 25 (44%) 25 (42%) 50 (43%)

>50 years 32 (56%) 34 (58%) 66 (57%)

Gender

Male 28 (49%) 33 (56%) 61 (53%)

Female 29 (51%) 26 (44%) 55 (47%)

Tumour Site

Upper (>10 cm) 18 (32%) 3 (5%) 21 (18%)

Middle (6e10 cm) 19 (33%) 27 (46%) 46 (40%)

Lower (<6 cm) 20 (35%) 29 (49%) 49 (42%)

Tumour Grade

Well-Moderately

differentiated

53 (93%) 52 (88%) 105 (91%)

Poor-Undifferentiated,

Signet ring

4 (7%) 7 (12%) 11 (9%)

T stage (pT)a

T1 2 (4%) 0 (0%) 2 (2%)

All patients had preoperative metastatic workup; includ-ing chest and abdomen CT scans, as well as a pelvic MRIstudy for local disease staging. Endorectal ultrasound wasnot used as it was unavailable at our institute. Patientswith stage I disease had primary surgery. Patients whohad stage II or III disease and whose tumours were lowerthan 12 cm from the anal verge received neoadjuvantCRT. The treatment was given according to Bosset regi-men. Patients received a total of 45 Gy in 25 fractionsover a 5-week period, together with a combination of5-Flurouracil and folinic acid in weeks one and five. All pa-tients continued the treatment uninterrupted. About 6e8weeks after finishing the CRT, patients underwent surgery.The type of surgery depended on the level of the tumour. Ifit was not possible to preserve the sphincter, abdominoper-ineal resection (APR) was performed. Otherwise, low ante-rior resection (LAR) was done. In all cases TME wasperformed. High ligation of the inferior mesenteric arterywas not routinely undertaken unless there were enlargedapical lymph nodes. A pathologist meticulously dissectedand retrieved the mesorectal lymph nodes. No other methodfor retrieval was used.

T2 19 (37%) 2 (4%) 21 (20%)

T3 24 (47%) 43 (81%) 67 (64%)

T4 6 (12%) 8 (15%) 14 (14%)

Type of Surgery

Statistical analysis LAR 44 (77%) 50 (85%) 94 (81%)

APR 13 (23%) 9 (15%) 22 (19%)

Preoperative Chemoradiation

Yes e 59 (100%) 59 (51%)

No 57 (100%) e 57 (49%)

Elapsed time between CRT and Surgeryb

<6 weeks e 13 (23%) e

6e8 weeks e 16 (29%) e>8 weeks e 27 (48%) e

LAR, Low Anterior Resection; APR, Abdominoperineal Resection.a Data missing for 12 patients.b Data missing for 3 patients.

The effect of CRT on lymph node yield was evaluated.The association was tested using the Wilcoxon test or theKruskaleWallis test. Multivariate analysis was performedusing ANCOVA on the log transformation of the numberof lymph nodes removed. Univariate and multivariate anal-yses were also performed on other clinicopathological fac-tors including: age, sex, T stage, grade and level of tumour,type of the surgery and timing of the operation after finish-ing CRT.

Please cite this article in press as: Morcos B, et al., Lymph node yield in rectal ca

(2010), doi:10.1016/j.ejso.2009.12.006

Results

Clinicopathological variables

The clinicopathological features are shown in Table 1.Out of the 116 patients, 61 were men and 55 were womenwith a mean age of 53 years (range 29e83). A little overhalf of the patients were over 50 years of age. All the tumourswere adenocarcinomas and most of them were well or mod-erately differentiated (91%). Of the patients with a known pTstage, there was a predominance of T3 tumours (64%); theother stages were much less represented. Most tumourswere in the lower two thirds of the rectum (82%).

The majority of the study population had sphincter spar-ing surgery. APR was performed in 19% of patients only.Fifty-nine patients (51%) had neoadjuvant CRT. The timeelapsed between the completion of the CRT and the surgeryranged between 8 and 11 weeks in 48% of patients, al-though our target was 6e8 weeks. Only one patient hada delay of more than 11 weeks. The rest of the patientshad their operations done before that.

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Neoadjuvant therapy and lymph node yield

We looked at the number of lymph nodes removed withthe specimens. The mean number in this series was 18(range 4e67). Patients receiving preoperative CRT hada lower number of lymph nodes retrieved than those whohad surgery upfront (16 vs. 19, p ¼ 0.004), as shown inTable 2. If we consider the number of lymph nodes requiredfor adequate staging, only 64% of patients receiving neoad-juvant therapy had 12 or more lymph nodes removed, incomparison to 88% for those having no preoperative ther-apy ( p ¼ 0.003), indicating that a higher proportion ofpatients who received neoadjuvant CRT would be consid-ered as having ‘inadequate’ resection.

Other factors

Other factors that were associated with a lower yield oflymph nodes included female sex and tumour location inthe lower rectum. Multivariate analysis of the data alsoshowed a significant association with the above-mentionedfactors (Table 3). Patient age, tumour grade, T stage andtype of surgery (APR vs. LAR) had no impact on lymph

Table 2

Factors influencing LN yield (Univariate Analysisa).

Feaure LN 95% CI P value

Age

<50 years 18 (15.3e21.2) 0.77

>50 years 17 (15.5e18.3)

Gender

Male 19 (16.8e21.5) 0.03

Female 16 (13.8e17.5)

Tumour Site

Upper (>10 cm) 23 (18.3e27.7) 0.00

Middle (6e10 cm) 15 (13.3e17.2)

Lower (<6 cm) 17 (15.1e19.5)

Tumour Grade

Well-Moderately differentiated 17 (15.5e18.5) 0.11

Poor-Undifferentiated, Signet ring 23 (15.6e29.4)

T stage (pT)b

T1 12 (2.0e21.0) 0.60

T2 18 (4.2e20.9)

T3 17 (15.5e19.0)

T4 16 (2.9e18.7)

Type of Surgery

LAR 18 (15.9e19.5) 0.73

APR 17 (14.5e19.0)

Preoperative Chemoradiation

Yes 16 (13.7e17.9) 0.00

No 19 (17.0e21.3)

Elapsed time between CRT and Surgeryc

<6 weeks 15 (10.7e18.9) 0.95

6e8 weeks 15 (11.6e19.1)

>8 weeks 17 (13.2e20.5)

LN, lymph node mean; LAR, Low Anterior Resection; APR, Abdomino-

perineal Resection; CI, Confidence Interval.a P values are based on nonparametric tests (Wilcoxon/KruskaleWallis).b Data missing for 12 patients.c Data missing for 3 patients.

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node yield. Timing of surgery anytime after 3 weeks of fin-ishing CRT resulted in similar numbers of lymph nodesretrieved.

Discussion

Adequate lymph node dissection

Adequate dissection of mesenteric lymph nodes in colo-rectal cancer is very important.1 On the one hand, it pro-vides adequate staging of the tumour, thus allowingproper prognostication and affects the decision to receiveeffective adjuvant treatment.3,4,6 It has been shown thatthe greater the number of lymph nodes removed, the higherthe possibility of finding involved ones.11,12 On the otherhand, adequate resection of lymph nodes improves localcontrol, decreases the incidence of local recurrence12,13

and improves survival.14e16

The number of lymph nodes that should be removed inorder to be considered adequate is not universally agreedupon. Various authors have suggested numbers rangingfrom 7 to 20, based on their individual series.6,17e20 In1990, the World Congress of gastroenterology in Sydneyrecommended that 12 lymph nodes should be removed.2

The NCI also used the12 lymph node guideline.1 The lastedition of TNM classification of the American Joint Com-mittee on Cancer states that ‘‘It is important to obtain 7e14lymph nodes in radical colon and rectum resection.’’21

Neoadjuvant therapy and lymph node yield

Most studies included colon and rectal cancer together.We only studied patients with rectal cancer. In our series,the mean number of lymph nodes removed was 18. In thosewho had surgery without preoperative CRT, that numberwas 19. This compares favorably with other series that re-vealed average numbers of lymph nodes removed between5 and 16.8,10,14,15,22e26 In these series, most patientshad < 12 lymph nodes removed. The percentage of patientswho had �12 lymph nodes removed ranged between 12.7%

Table 3

Factors influencing LN yield (Multivariate Analysisa).

Variableb LN 95% CI P value

Gender

Male 19 (16.8e21.5) 0.04

Female 16 (13.8e17.5)

Tumour site

Upper (>10 cm) 23 (18.3e27.7) 0.01

Middle (6e10 cm) 15 (13.3e17.2)

Lower (<6 cm) 17 (15.1e19.5)

Neoadjuvant therapy

Yes 16 (13.7e17.9) 0.01

No 19 (17.0e21.3)

LN, lymph node mean; CI, Confidence interval.a Based on ANCOVA model.b Only significant variables are shown.

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and 45%.8,22,23,26 In our series 76% of the patients had �12lymph nodes removed. For those who had surgery upfront,the figure was 88%.

The number of lymph nodes removed in rectal cancer de-pends on 3 main factors. The first factor is the surgeon and hisability to perform an adequate TME. A proper TME removesthe whole regional lymph node-bearing region of the tumour.The second factor is the pathologist; the more meticulous thepathological dissection of the mesorectal specimen thehigher the possibility of finding lymph nodes.27,28 It is worthnoting that two thirds of metastatic lymph nodes are less that5 mm in diameter.29 Those lymph nodes might not be de-tected if not looked for diligently. The third factor is relatedto patients’ physical and anatomic differences. These threefactors would explain the variations in lymph node numbersnoted in different studies.

The effect of neoadjuvant therapy in rectal cancer hasbeen suggested by some studies. The Dutch TME trial,which randomized patients to receive preoperative shortcourse radiotherapy followed by TME surgery or TME sur-gery only, found a significant difference in the number oflymph nodes retrieved.7 There were 7.7 lymph nodes re-trieved in patients who received preoperative radiotherapyin contrast to 9.7 lymph nodes in those who had surgery up-front. Other studies on preoperative radiotherapy reachedsimilar conclusions.8e10 In our study we aimed to look atthe effect of combination chemotherapy and radiotherapy.

In a German study,30 Wichmann compared patients whohad primary surgery and those who had CRT before sur-gery. There was a significant difference in the number oflymph nodes retrieved between the two groups (19.1 forsurgery only vs. 13.6 for preoperative therapy). Anotherstudy from France had a similar outcome (17 vs 13, respec-tively).26 In our series, there was a significant difference be-tween the numbers of lymph nodes retrieved in both groups(19 vs 16). The studies on preoperative radiotherapy andthose on preoperative combination CRT are consistent inthis regard and show relatively similar results. Hence, wecan deduce that radiotherapy is the main cause for the re-duction in the number of lymph nodes. The effect of che-motherapy is not clear, but is probably minor.

In the Swiss study, Sermier has concluded that the impactof preoperative radiotherapy on the yield of lymph nodes istime-dependent.25 The authors admit, however, that the re-gression analysis in their study was greatly influenced by 5 pa-tients who underwent APR for recurrent anal cancer more than5 months after the end of radiotherapy. In our series, surgerydone anytime after 3 weeks had the same impact on lymphnode yield. This indicates that the effect of radiotherapy in re-ducing lymph node yield is in the first few weeks of therapy.

Other factors

Age did not have a significant effect on lymph nodeyield. Other studies, however, have found higher lymphnode yield in younger patients.8,22,23 In our series, male

Please cite this article in press as: Morcos B, et al., Lymph node yield in rectal ca

(2010), doi:10.1016/j.ejso.2009.12.006

sex was associated with a higher number of lymph nodes.The effect of sex on lymph node number is not consistentin the literature.8,22,24 Tumours in the upper rectum are as-sociated with a higher number of lymph nodes than those inthe mid and lower rectum. Thorn24 found a higher numberof lymph nodes in mid rectal tumours on univariate, but notmultivariate, analysis. Pathological T stage and grade, inthe present study, were not significant factors. Some stud-ies,8,26 but not others,10,22,24 agree with our conclusion.The type of surgery (APR vs. LAR) had no effect on lymphnode yield either. This is expected since the lymph node-bearing tissues: the mesorectum and inferior mesenteric ar-tery stalk, are similarly removed in both operations.

Conclusion

In conclusion, preoperative CRT is associated with a re-duction in the yield of lymph nodes in rectal cancer surgery.This is mainly related to radiotherapy, which exerts its’ ef-fects on the lymph nodes within the first few weeks of ther-apy. Other factors, such as sex and the level of the tumour,may also affect lymph node yield. All of these factorsshould be taken into consideration when evaluating the ad-equacy of lymph node resection in rectal carcinoma.

Conflict of interest statement

The authors have no conflict of interest to disclose.

References

1. Nelson H, Petrelli N, Carlin A, et al. Guidelines 2000 for colon and

rectal cancer surgery. J Natl Cancer Inst 2001;93:583–96.

2. Fielding LP, Arsenault PA, Chapuis PH, et al. Clinicopathological

staging for colorectal cancer: an International Documentation System

(IDS) and an International Comprehensive Anatomical Terminology

(ICAT). J Gastroenterol Hepatol 1991;6:325–44.

3. Cianchi F, Palomba A, Boddi V, et al. Lymph node recovery from co-

lorectal tumour specimens: recommendation for a minimum number

of lymph nodes to be examined. World J Surg 2002;26:384–9.

4. Pocard M, Panis Y, Malassagne B, et al. Assessing the effectiveness of

mesorectal excision in rectal cancer: prognostic value of the number of

lymph nodes found in resected specimens. Dis Colon Rectum 1998;41:

839–45.

5. Goldstein NS. Lymph node recoveries from 2427 pT3 colorectal re-

section specimens spanning 45 years: recommendations for a minimum

number of recovered lymph nodes based on predictive probabilities.

Am J Surg Pathol 2002;26:179–89.

6. Tepper JE, O’Connell MJ, Niedzwiecki D, et al. Impact of number of

nodes retrieved on outcome in patients with rectal cancer. J Clin Oncol

2001;19:157–63.

7. Marijnen CA, Nagtegaal ID, Klein Kranenbarg E, et al. No downstag-

ing after short-term preoperative radiotherapy in rectal cancer patients.

J Clin Oncol 2001;19:1976–84.

8. Baxter NN, Morris AM, Rothenberger DA, et al. Impact of preoperative

radiation for rectal cancer on subsequent lymph node evaluation: a pop-

ulation-based analysis. Int J Radiat Oncol Biol Phys 2005;61:426–31.

9. Nagtegaal ID, van de Velde CJ, van der Worp E, et alCooperative Clin-

ical Investigators of the Dutch Colorectal Cancer Group. Macroscopic

evaluation of rectal cancer resection specimen: clinical significance of

the pathologist in quality control. J Clin Oncol 2002;20:1729–34.

ncer surgery: Effect of preoperative chemoradiotherapy, Eur J Surg Oncol

ARTICLE IN PRESS

5B. Morcos et al. / EJSO xx (2010) 1e5

10. Maschuw K, Kress R, Ramaswamy A, et al. Short-term preoperative

radiotherapy in rectal cancer patients leads to a reduction of the detect-

able number of lymph nodes in resection specimens. Langenbecks

Arch Surg 2006;391:364–8.

11. Scott KW, Grace RH. Detection of lymph node metastases in colorec-

tal carcinoma before and after fat clearance. Br J Surg 1989;76:

1165–7.

12. Hernanz F, Revuelta S, Redondo C, Madrzo C, Castillo J, Gomez-

Fleitas M. Colorectal adenocarcinoma: quality of the assessment of

lymph node metastases. Dis Colon Rectum 1994;37:373–6.

13. Mukai M, Sato S, Nishida T, et al. Selection criteria for high risk and

low risk groups of recurrence and metastasis in patients with primary

colorectal cancer. Oncol Rep 2003;10:1753–8.

14. Luna-Perez P, Rodriguez-Ramirez S, et al. Prognostic significance of

retrieved lymph nodes per specimen in resected rectal adenocarcinoma

after preoperative chemoradiation therapy. Arch Med Res 2003;34:

281–6.

15. Caplin S, Cerottini JP, Bosman FT, et al. For patients with Dukes’

B (TNM Stage II) colorectal carcinoma, examination of six or

fewer lymph nodes is related to poor prognosis. Cancer 1998;83:

666–72.

16. Hsiang-Lin T, Chien-Yu L, Jan-Sing H, et al. The prognostic signifi-

cance of total lymph node harvest in patients with T2e4N0M0 colorec-

tal cancer. J Gastrointest Surg 2007;11:660–5.

17. Goldstein NS, Sanford W, Coffey M, Layfield LJ. Lymph node re-

covery from colorectal resection specimens removed for adenocarci-

noma. Trends over time and a recommendation for a minimum

number of lymph nodes to be recovered. Am J Clin Pathol 1996;

106:209–16.

18. Wong JH, Severino R, Honnebier MB, Tom P, Namiki TS. Number of

nodes examined and staging accuracy in colorectal carcinoma. J Clin

Oncol 1999;17:2896–900.

Please cite this article in press as: Morcos B, et al., Lymph node yield in rectal ca

(2010), doi:10.1016/j.ejso.2009.12.006

19. Swanson RS, Compton CC, Stewart AK, et al. The prognosis of T3N0

colon cancer is dependent on the number of lymph nodes examined.

Ann Surg Oncol 2003;10(1):65–71.

20. Sarli L, Bader G, Iusco D, et al. Number of lymph nodes examined

and prognosis of TNM stage II colorectal cancer. Eur J Cancer2004;41:272–9.

21. American Joint Committee on Cancer. Colon, rectum. In: AJCC can-

cer staging manual. 6th ed. New York, NY: Springer; 2002.

22. Wright FC, Law CHL, Last L, et al. Lymph node retrieval and assess-

ment in stage II colorectal cancer: a population-based study. Ann Surg

Oncol 2003;10(8):903–9.

23. Edler D, Oehrling K, Hallstroem M, et al. The number of analyzed

lymph nodes e a prognostic factor in colorectal cancer. Acta Oncol

2007;46:975–81.

24. Thorn CC, Woodcock NP, Scott N, et al. What factors affect lymph

node yield in surgery for rectal cancer? Colorectal Dis 2004;6:356–61.

25. Sermier A, Gervaz P, Egger JF, et al. Lymph node retrieval in abdom-

inoperineal surgical specimen is radiation time-dependent. World J

Surg Oncol 2006;4:29.

26. Rullier A, Laurent C, Capdepont M, et al. Lymph nodes after preop-

erative chemoradiotherapy for rectal carcinoma: number, status, and

impact on survival. Am J Surg Pathol 2008;32:45–50.

27. Scott K, Grace R. Detection of lymph node metastases in colorectal

carcinoma before and after fat clearance. Br J Surg 1989;76:1165–7.

28. Hida J, Mori N, Kubo R, et al. Metastases from carcinoma of the colon

and rectum detected in small lymph nodes by the clearing method.

J Am Coll Surg 1994;178:223–8.

29. Herrera-Ornelas L, Justiniano J, Castillo N, et al. Metastases in small

lymph nodes from colon cancer. Arch Surg 1987;122:1253–9.

30. Wichmann MW, Muller C, Meyer G, et al. Effect of preoperative ra-

diochemotherapy on lymph node retrieval after resection of rectal can-

cer. Arch Surg 2002;137:206–10.

ncer surgery: Effect of preoperative chemoradiotherapy, Eur J Surg Oncol