Journal of Surgical Research 146, 11–15 (2008)

Prognostic Significance of Lymph Node Metastases and Ratio inEsophageal Cancer1

Matthew Wilson, B.A.,* Ernest L. Rosato, M.D.,* Karen A. Chojnacki, M.D.,* Inna Chervoneva, Ph.D.,†John C. Kairys, M.D.,* Herbert E. Cohn, M.D.,* Francis E. Rosato, Sr., M.D.,* and Adam C. Berger, M.D.*,2

*Department of Surgery, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA; and †Division of Biostatistics, KimmelCancer Center, Thomas Jefferson University, Philadelphia, PA

Submitted for publication January 8, 2007

doi:10.1016/j.jss.2007.07.028

Background. The incidence of carcinoma of the dis-tal esophagus and GE junction is rapidly increasing. Alarge single-center experience was reviewed to deter-mine the impact of lymph node positivity and ratio onsurvival.

Methods. All patients undergoing esophagogastrec-tomy at Thomas Jefferson University Hospital be-tween January 1994 and December 2004 were re-viewed. Univariate and multivariate analyses wereperformed using log-rank and Cox proportional haz-ard models, and survival curves were estimated usingthe Kaplan-Meier method.

Results. Of 173 patients with invasive cancer, 123(71%) underwent preoperative chemoradiation ther-apy. The largest number of patients (45%) had adeno-carcinoma of the GE junction; 29% of patients hadesophageal adenocarcinoma while 14% had squamouscell cancer of the esophagus. Perioperative mortalitywas 5.7%. Median overall survival of the entire groupwas 22 months and 5-year overall survival was 27%.The most significant prognostic factor for overall sur-vival was the presence of positive LN (P � 0.01). Addi-tionally, patients with zero involved LN had a 5-yearsurvival of 34%, while patients with 1 to 3 positive LNand >3 positive LN had 5-year survival of 27% and 9%,respectively (P � 0.01). Finally, an increasing ratio ofpositive to examined LN was linearly associated witha worsening 5-year survival, (P � 0.153).

Conclusions. Increasing number of positive LN inpatients with esophageal cancer and increasing ra-tio of metastatic to examined LN portend a poor

1 Presented at the 2nd Annual Academic Surgical Congress (Asso-ciation for Academic Surgery), Phoenix, AZ, February 6–9, 2007.

2 To whom correspondence and reprint requests should be ad-dressed at Department of Surgery, Kimmel Cancer Center, ThomasJefferson University, 1100 Walnut Street, MOB, Suite 500, Phila-

delphia, PA 19107; E-mail: adam.berger@jefferson.edu.

11

prognosis. These factors should play an importantrole in determining which patients receive adjuvanttherapy. © 2008 Elsevier Inc. All rights reserved.

Key Words: esophageal cancer; lymph nodes; lymphnode ratio; prognosis.

INTRODUCTION

While uncommon in the United States, cancer of theesophagus is one of the most deadly malignancies inhumans and is increasing in frequency. In 2005, it wasestimated that 14,520 new cases were diagnosed with13,570 deaths from the disease. The incidence of esoph-ageal cancer is higher among Caucasians than amongall other ethnic groups and higher among men thanwomen. The overall 5-year survival, as determined be-tween 1995 and 2000, is 14% [1].

Surgical resection is the preferred approach for de-finitive treatment of this type of cancer, but increas-ingly physicians are using preoperative regimens com-bining chemotherapy and radiation to downstageprimary tumors both to increase the likelihood ofachieving complete resection and to prolong survival[2]. Randomized trials examining this treatment haveyielded mixed results; only one phase III trial hasshown increased survival using neoadjuvant therapy,while several others failed to show an increased sur-vival when compared with surgical resection alone [3].

Current research trends include examining treat-ment outcomes and prognostic factors for survival. Hof-stetter et al. have reported that patient survival hasincreased over time, likely due to improvements inpreoperative staging and advances in surgical tech-nique; the use of preop chemoradiation was found to bethe most significant factor in achieving a complete

resection of the tumor [4]. Berger et al. examined re-

0022-4804/08 $34.00© 2008 Elsevier Inc. All rights reserved.

12 JOURNAL OF SURGICAL RESEARCH: VOL. 146, NO. 1, MAY 1, 2008

sponse to neoadjuvant therapy in relation to survival,and found that a complete response to the therapy wasassociated with a 5-year survival of 48% comparedwith 15% for patients whose tumor was not responsiveto therapy; even down-staging the primary tumor tostage I increases overall survival to 34% [2].

The presence of lymph node metastasis (LNM) hasbeen demonstrated to be one of the most significantprognostic factors. Earlier studies have reported sig-nificant differences among patients with differentnumbers of LNM, all following a general trend of in-creasing positive nodes leading toward a worse prog-nosis [5–7]. Lymph node ratio has also been investi-gated as a prognostic indicator but its significance isless clear. Previous authors have shown that increas-ing LNR was associated with increased mortality,however there is disagreement of what ratios aresignificant [6, 7]. Eloubeidi reported that an overallincreasing ratio was inversely related to outcome [8].

The goal of this study was to examine a large data-base of patients undergoing esophagectomy to deter-mine the impact of increasing numbers of pathologi-cally confirmed positive LN and LN ratio on survival inpatients undergoing esophagectomy for cancer of theesophagus, GE junction, and gastric cardia.

MATERIALS AND METHODS

All patients undergoing esophagogastrectomy for esophageal can-cer or proximal gastric cancer at Thomas Jefferson University Hos-pital (TJUH) between January 1994 and December 2005 were ret-rospectively reviewed. The total number of patents identified was173; patients with high grade dysplasia were eliminated from thesurvival analysis. Although 173 patients with invasive cancer metthe criteria to be included in the study sample, the multivariateanalyses included a subset of 144 patients with complete recordswith respect to all known risk factors and complete lymph nodeinformation.

Patient medical records were examined and the information en-tered into a database with the approval of the TJUH InstitutionalReview Board. Data collected included: preoperative factors (age,co-morbidities, extent of symptoms, presence of Barrett’s esophagus,and imaging studies), treatment factors (chemotherapy drugs, radi-ation dosage, weight loss, and need for preoperative nutritionalsupport), tumor factors (histology, clinical and pathologic staging,and completeness of resection – R0, R1, or R2), and operative andhospital factors (type of operation, blood loss, type of conduit, type ofanastomosis, and complications), tumor recurrence (date and loca-tion), and long term survival.

All patients were staged both pre- and postoperatively accordingto the classification scheme of the American Joint Committee forCancer Staging 6th edition. Patients were clinically staged using CTscan and endoscopic ultrasound (EUS), when available. Patientswithout residual, viable tumor cells present in the surgical speci-mens (T0N0M0, stage 0-Rx) were regarded as having pathologiccomplete response (pCR). Patients with minimal residual tumor(T1N0M0) were classified as down-staged (stage 1-Rx). Follow-updata were obtained from patient charts, tumor registry, and refer-ring physicians. Numerous patients were treated at outside institu-tions and only underwent surgery at TJUH. For these patients,initial clinical stage information was often missing.

Most patients receiving induction chemoradiation received a com-

bination of 5-FU and a platinum based agent, such as cisplatin or

carboplatin. The standard dose of radiation, given concurrently withchemotherapy, was 45Gy. Thirty-six patients were treated under aphase I/II protocol at TJU combining 5FU, carboplatin, paclitaxel,and 45Gy of radiation [9]. The patients were given a 4 to 6 wk restperiod before definitive resection. During this period the patientswere often restaged using CT and EUS.

The overall survival was evaluated using the Kaplan-Meier esti-mator and the log-rank test for univariate analyses and Cox propor-tional hazards model for multivariate analyses. The Cox modelscontrolled for all known risk factors including age, pathologicalstage, length of stay, induction chemotherapy, type of surgery, andtumor location (stratification variable), the total number of lymphnodes, and N stage. Separate Cox models were fitted with addingeither an indicator of more than three positive lymph nodes orindicators of �25% and �50% positive lymph nodes. The primaryanalysis of lymph node positivity and lymph node ratio was based onpathologic staging information and not preoperative staging infor-mation. Proportional hazards assumptions were based on the corre-sponding tests [10]. Statistical analyses were performed in SAS (SASInstitute, Cary, NC) and S-Plus (Insightful, Seattle, WA).

RESULTS

There were 93 men and 30 women, ranging in agefrom 37 to 86 y (mean 62 y). Eighty-nine percent ofpatients were Caucasian (n � 110). Seventy-two per-cent of patients had a smoking history (n � 88). Themajority of patients (n � 123, 71%) underwent induc-tion chemoradiation. Of these patients, 26 (21.1%) hada pathologic complete response and 42 (34.1%) weredown-staged.

The operative technique was dictated by the locationof the tumor as well as surgeon preference. Table 1illustrates that the majority of patients (46%) under-went a transhiatal esophagectomy. However, approxi-mately 54% underwent some type of transthoracic ap-proach. There did appear to be a difference in survivalbased on the type of resection used. Patients who un-derwent 3-hole esophagectomy had significantly bettersurvival than those undergoing transhiatal (P � 0.044)and also better survival than those undergoing Ivor-Lewis esophagectomy (P � 0.052). This, however, didnot appear to be a function of lymph node harvest. Theaverage number of lymph nodes harvested in the3-hole group was 9.6, which was higher than thoseundergoing transhiatal approaches (mean � 6.4) butlower than those undergoing Ivor-Lewis esophagecto-mies (mean � 12.0).

TABLE 1

Operative Techniques

ProcedureNo. of patients

(n � 173)Overall

percentage, %

Ivor-Lewis 53 30.6Transhiatal 80 46.23-Hole 34 19.7Thoracoabdominal 1 0.6

Thoracoscopic 3-Hole 5 2.9

13WILSON ET AL.: IMPORTANCE OF LYMPH NODE NUMBER AND RATIO IN ESOPHAGEAL CANCER

There was no difference in the number of lymphnodes examined depending on whether patients did ordid not receive preoperative chemoradiation therapy(CRT) (median equals 6 versus 7 LN, P � 0.99).

Most patients presented with advanced disease, stageII to IV, (n � 117, 67.6%), half of whom had stage IIIdisease (n � 59) (Table 2). Most patients were clinicallystaged using CT, and 56 (28.9%) patients also under-went staging with EUS. Of the patients treated withinduction CRT, 98 had stage II or III disease (77.2%). Alarge portion (n � 25, 37.3%) of the patients not treatedwith neoadjuvant therapy had stage 0 or I disease.

The vast majority of patients had adenocarcinomas(80.3%), which occurred in the distal esophagus (n �45, 32.4%), GE junction (n � 62, 44.6%), and gastriccardia (n � 26, 15%) (Table 3). Tumor location wasmore varied than histological type. The majority of thetumors arose in the distal portions of the esophagusand into the proximal stomach. Specifically, 126 tu-mors (73%) were found in either the distal third or atthe GE junction (Table 4).

Follow-up ranged from 1 to 128 mo (median � 18mo). Overall, the median survival for the group was 22months and the 5-year overall survival rate was 27.1%.There was no significant difference in survival for pa-tients receiving induction chemoradiation versus sur-gery alone (P � 0.244), however, tumor response tochemoradiation was an important prognostic factor.The overall survival rate for patients with a pCR was38.8% with a median survival of 27.6 mo comparedwith 27.2% and 18.4 mo for non-pCR patients (P �0.118). Pathologic tumor stage was a significant pre-

TABLE 2

Initial Clinical Diagnosis

Stage, TNMNo. of patients

(n � 173) Percentage, %

0, Cis 8 4.6I, T1N0M0 17 9.8IIa, T2–3, N0M0 42 24.3IIb, T1–2, N1M0 5 2.9III, T3N1M0 59 34.1IV, M1a 11 6.4Unknown 31 17.9

TABLE 3

Histology

Histologic diagnosisNo. of patients

(n � 173)Overall

percentage, %

Adenocarcinoma 139 80.3Squamous cell carcinoma 31 17.9High grade dysplasia 1 0.5

Other/unknown 2 1.2

dictor of survival in the univariate analysis (P �0.037). However, this factor was not significant in themultivariate model because of the dramatic signifi-cance of lymph node positivity (a major component ofpathologic stage grouping).

Nodal metastasis were found in 38.2% of the patients(n � 66) and played a role in overall survival; patientswithout nodal involvement had a median survival 27mo versus 16.1 mo for node positive patients (P �0.010). In the initial analysis of lymph node positivity,a dichotomized cutoff of � or �3 was determined tobe a statistically significant predictor of overall sur-vival by univariate and multivariate analysis (P �0.021, HR � 2.29). We then analyzed the lymph nodesin a manner similar to that used by the AJCC for coloncancer; that is LNM � 0, LNM � 1 to 3, and LNM � 4or more. In this manner, patients with zero involvedLN had a 5-year survival of 34.1%, while patients with1 to 3 positive LN and �3 positive LN had 5-yearsurvival of 27% and 9%, respectively (P � 0.010 for thisgroup). Figure 1 presents the Kaplan-Meier survivalcurves for the groups of patients with zero, 1 to 3, and�3 positive lymph nodes. The difference in survivalamong these three groups was significant (P � 0.010).

Finally, we examined the impact of an increasing

TABLE 4

Tumor Location

LocationNo. of patients

(n � 173)Overall

percentage, %

Proximal 3 1.7Middle 17 9.8Distal 58 33.5GE-junction 68 39.3Cardia 27 15.6

FIG. 1. Kaplan-Meier curve demonstrating overall survival forpatients by lymph node category. (Color version of figure is available

online.)

14 JOURNAL OF SURGICAL RESEARCH: VOL. 146, NO. 1, MAY 1, 2008

LNR. The proportion of positive lymph nodes was an-alyzed by the following categories: zero, �25%, �25%but �50%, and �50%. The difference in survivalamong these four groups was not significant (P �0.153), but there were some important differences be-tween the groups as outlined in Table 5. CorrespondingKaplan-Meier survival curves are shown in Fig. 2.

DISCUSSION

Surgical resection remains the treatment of choicefor esophageal cancer. Despite improvements in oper-ative technique and advances in tumor staging, overallsurvival is still poor [11, 12]. Current attempts arebeing made to improve survival by using combinationsof treatments in a multi-modality approach. Chemo-therapy, radiation, and surgical resection are oftenused in conjunction to diminish recurrence. Most often,neoadjuvant therapy is prescribed; when chemoradia-tion is given prior to surgery it tends to be better

TAB

Surviv

n

Median surviva

Kaplan-Meierestimate

LN � category0 LN� 81 271–3 LN� 36 22�3 LN� 27 12

% LN � category0 LN� 81 270%–25% 22 1925%–50% 19 22�50% 22 9

FIG. 2. Kaplan-Meier curve demonstrating overall survival forpatients by lymph node ratio category. (Color version of figure is

available online.)

tolerated than when given postoperatively. In addition,administration prior to surgery allows chemotherapeu-tics and radiation access to the tumor with its bloodsupply intact. Despite the promise shown in manyphase II trials, for the most part neoadjuvant therapyhas not held up under phase III trial conditions.

The main goal of this study was to examine to utilityof the number of lymph node metastasis and the ratioof positive lymph nodes to excised lymph nodes asprognostic factors in survival of patients with tumorsof the esophagus, GE junction. and gastric cardia.

Consistent with previously reported data, the num-ber of LN metastasis proved to be an important indi-cator of survival. According to our findings, patientswith more than 3 LNM fared worse than patients with3 or fewer LNM. Other authors examining LNM havefound that less than 5 LNM compared with 5 or moreLNM to be a significant cutoff [7, 8]. However, thosestudies included mostly squamous cell carcinoma pa-tients, whereas our study concerned predominantly(81.4%) adenocarcinoma patients, the predominanttype in the Western hemisphere [13]. This discrepancymay reflect a difference in the behavior of the histolog-ical types. Nigro et al. reported less than 4 versus 4 ormore LNM as significant in a study including onlyadenocarcinoma patients, but that data were collectedon a much smaller patient population (n � 44) anddealt only with transmural tumors [6].

Lymph node ratio examination did not reach signif-icance in our study. However, Table 5 demonstratesthat increasing LNR may be associated with worseningsurvival. This observation has been previously re-ported for other malignancies, such as colon cancer, butnot in esophageal cancer [14]. We were able to eluci-date differences in survival of patients based upon thecategorization of their LNR as zero, less than 0.25, 0.26to 0.50, and greater than 0.51, an observation not pre-viously reported. Eloubeidi reported a similar finding;that increasing LNR was associated with a poorer

5

Data

e (months)

P-value 5-year survival

5% confidence limits

wer Upper

0 36 0.01 34.1%3 43 26.8%6 22 9.4%

0 36 0.153 34.1%6 24 24%9 36 20%4 15 15%

LE

al

l tim

9

Lo

21

21

prognosis [8]. Other authors have had differing cutoff

15WILSON ET AL.: IMPORTANCE OF LYMPH NODE NUMBER AND RATIO IN ESOPHAGEAL CANCER

points for LNR. Bollschweiler et al. reported that LNRonly became significant if it exceeded 0.20 (P � 0.01)and Nigro et al. showed patients with a LNR �0.1fared significantly better than those who had a LNR�0.1 [6, 7]. These two studies, when compared with thecurrent study, removed a large number of nodes (aver-age 26.4 and 51, respectively versus 8.6), which mayhave artificially lowered the observed ratio. We feelthat using these cutoff points will be easier to remem-ber and use since they are based on 25%, 50%, and 75%points. Although this factor did not reach statisticalsignificance in our study, most likely due to the smallnumber of patients per group with �20 patients perpositive lymph node grouping; larger studies will needto be done to confirm this.

One concern is that it may be difficult to assess thelymph node ratio after chemoradiation because thenumber of lymph nodes examined is often decreased.However, when we evaluated the number of lymphnodes examined in the patients who received neoadju-vant chemoradiation, there was no difference betweenthese patients and those who did not receive neoadju-vant therapy (n � 6 versus 7, P � 0.99). Further inves-tigation should examine the locations of the nodes priorto removal and compare that data with the LNR to seeif a positive node at one anatomical site differs from apositive node at another site in terms of survival rela-tive to the tumor location. Unfortunately, we wereunable to examine the exact locations of lymph nodemetastases in this study due to its retrospective na-ture. We chose to include gastric cardia tumors withGE junction and esophageal tumors because they wereall treated with esophagogastrectomy with similarlymph node stations being removed.

Our experience shows that the number of positivelymph nodes and the ratio of positive lymph nodes toexamined lymph nodes are significant prognostic fac-tors for esophageal carcinoma. When the AJCC nextrevises the TNM staging scheme, these two factorsshould be incorporated, thereby giving a more completepicture of a particular patient’s disease state to guide

clinical decision making.

ACKNOWLEDGMENTS

MW’s research was supported by the following NIH grant: Short-Term Training Program in Translational Cancer Research, CA069277.

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