iven

apUnivg M

latiicalThenowedn=e-frCox regression to identify independent prognostic factors. Result: Five-year dis-

International Journal of Gynecology and Obstetrics 116 (2012) 4346

Contents lists available at SciVerse ScienceDirect

International Journal of Gy

.ethe need for postoperative radiation. Sakuragi [3] summarized thatthe median or mean number of pelvic lymph nodes removed at lym-phadenectomy varied among studies, from 13 to 56. In the EORTC-GCG study, removal of more than 11 pelvic nodes was suggested asone of the quality indicators for pelvic lymphadenectomy [4]. Howev-er, the relationship between the number of nodes removed and thenumber of positive nodes has not been discussed in previous reports.Moreover, the association between the number of nodes removedand disease-free survival is still debatable. Pieterse et al. [5] foundthat a higher number of nodes removed had a positive impact on sur-vival only in patients with positive lymph nodes. This result was in-

Following approval by the Research Ethics Committee, the medicalrecords of cervical cancer patients who had undergone RHPL atChiang Mai University Hospital between January 25, 2002, andDecember 26, 2008, were reviewed. All patients who had had atleast 11 pelvic nodes removed were included in the study. The patientswhose operative schedule was more than 1 month from the rst visitreceived neoadjuvant chemotherapywith cisplatin. The systematic pel-vic lymphadenectomy in the studywas carried out by removing all fattytissue along both sides of the common iliac, external iliac, and internaliliac vessels, and also the fatty tissue inside the obturator fossa. Para-consistent with the recent study by Shah ethatmore extensive lymphadenectomywas a

Corresponding author at: Division of Gynecologic Onrics and Gynecology, Faculty of Medicine, Chiang MaiThailand. Tel.: +66 1 9933909; fax: +66 53 946112.

E-mail address: psuprase@mail.med.cmu.ac.th (P. Su

0020-7292/$ see front matter 2011 International Feddoi:10.1016/j.ijgo.2011.08.001issue around the uterineelvic node metastasis isand also an indicator of

cervical cancer patients who underwent RHLP.

2. Materials and methods

cervix and the upper vagina. The status of pone of the most important prognostic factorssystematic lymphadenectomy is to idthat have been transported to the lymp 2011 International Federation of Gynecology and Obstetrics. Published by Elsevier Ireland Ltd. All rights reserved.

1. Introduction

Radical hysterectomy and pelvic lymphadenectomy (RHPL) are thestandard treatment for early-stage cervical cancer [1, 2]. The goal of a

entify and remove tumor cellshatic t

survival in patients without nodal metastasis. However, this was notthe case in patients with positive lymph nodes. With these conictingresults, the present retrospective study was conducted to examine theassociation between the number of pelvic nodes removed and the dis-ease-free survival and number of positive pelvic nodes in early-stageinvolvement were considered separately, the 5-year disease-free survival in all groups was not signicantlydifferent. At multivariate analysis, the number of pelvic nodes removed was not an independent prognosticfactor. Conclusion: The number of pelvic nodes removed was not associated with 5-year disease-free survivalor number of positive pelvic nodes.Pelvic lymphadenectomyPelvic node removalRadical hysterectomyease-free survival was not signicantly different among the 4 groups. When patients with and without nodalDisease-free survival (n=68). The 5-year diseasfactors were analyzed usingCLINICAL ARTICLE

Pelvic node removal and disease-free survradical hysterectomy and pelvic lymphad

Prapaporn Suprasert a,, Kittipat Charoenkwan a, Sura Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Chiang Maib Division of Gynecologic Pathology, Department of Pathology, Chiang Mai University, Chan

a b s t r a c ta r t i c l e i n f o

Article history:Received 18 April 2011Received in revised form 31 July 2011Accepted 1 August 2011

Keywords:Cervical cancer

Objective: To examine the resurvival in early-stage cervnectomy (RHPL). Methods:who had at least 11 pelvicDecember 2008 were revieremoved: 1120 nodes (

j ourna l homepage: wwwt al. [6], which revealedssociatedwith improved

cology, Department of Obstet-University, Chiang Mai 50200,

prasert).

eration of Gynecology and Obstetrics.al in cervical cancer patients treated withectomy

an Khunamornpong b

ersity, Chang Mai, Thailandai, Thailand

onship between the number of pelvic nodes removed and 5-year disease-freecancer patients who underwent radical hysterectomy and pelvic lymphade-medical records of 826 cervical cancer patients who underwent RHPL and

des removed at Chiang Mai University Hospital between January 2002 and. The patients were divided into 4 groups according to the number of nodes243); 2130 nodes (n=344); 3140 nodes (n=171); and41 nodesee survival of patients in each group was compared. The clinicopathological

necology and Obstetrics

l sev ie r .com/ locate / i jgoaortic lymphadenectomy was performed only when gross metastasisto the common iliac nodes or para-aortic nodes was suspected. All sur-gical specimens were examined by gynecologic pathologists. Allresected lymph nodeswere carefully dissected off surrounding fatty tis-sue before being xed in formalin. The number of lymph nodesobtained from each group was initially recorded. All lymph nodeswere submitted in entirety for tissue processing and preparation of

Published by Elsevier Ireland Ltd. All rights reserved.

histologic slides. The nal number of lymph nodes resected in eachcase was obtained after verication by microscopic examination of thehistologic slides.

The patients received adjuvant concurrent platinum-based che-moradiation when the pathological report revealed at least one ofthe high risk factors, consisting of positive lymph nodes, positive para-metrium, or positive surgical margins. In addition, if two intermediaterisk factors including deep cervical stromal invasion and positive lym-phovascular space invasion (LVSI) were found, chemoradiation wasoffered. For the patients with positive LVSI as the only risk factor iden-tied, adjuvant treatment with cisplatin was given. The high-risk pa-tients with impaired renal function received radiation alone insteadof concurrent chemoradiation. After completion of treatment, patientswere followed up regularly. Treatment failure was dened either bypathological proof of recurrence or by imaging showing the regrowthof a tumor or an enlargement of lymph nodes. Disease-free survivalwas dened as a period of time between the month of operation andthe month of tumor recurrence or last follow-up.

To identify the effect of the extent of lymphadenectomy on thenumber of positive pelvic nodes and disease-free survival, the studiedpatients were categorized into 4 groups according to the total numberof nodes removed: 1120 nodes; 2130 nodes; 3140 nodes; and41nodes. The number of positive nodes and other factors in each groupwere compared using the 2 test. ANOVA was used to compare themean ages of the patients in the 4 groups. Descriptive data are pre-sented as mean (range) and discrete data are reported as number andpercentage. Five-year disease-free survival was calculated using the

Kaplan-Meier method and was compared between the groups usingthe log rank test. Moreover, separate analysis was performed forlymph node positive and node negative patients. Multivariate analysiswas carried out using a Cox proportional hazards regression model toidentify the independent prognostic factors. Statistical analysiswas per-formed using SPSS for Windows (SPSS, Chicago, IL, USA). Pb0.05 wasconsidered statistically signicant.

3. Results

During the study period, 843 patients with stage IAIIA cervicalcancer underwent RHPL. Seventeen patients were excluded becausethe number of pelvic nodes removed was less than 11, leaving 826patients whose records were reviewed. The demographic dataaccording to the number of pelvic nodes removed are shown inTable 1. Most patients had 2130 nodes removed (n=344) followedby 1120 nodes (n=243), 3140 nodes (n=171), and more than 40nodes (n=68). The mean number of nodes removed was 26 (range,1189). The mean age of the patients was 45 years (range, 1975).

The clinical and pathological data among the 4 groups were notsignicantly different for mean age, stage, histology, tumor grade,positive parametrium, positive vaginal margin, deep stromal inva-sion, positive pelvic nodes, and treatment. For those with pelvicnode metastasis, the mean number of positive nodes was 2 (range,121). Of the 126 patients with positive pelvic nodes, 59 (46.8%)had a single positive node and the distribution of patients with singlenodemetastasis was not signicantly different among the groups. The

Table 1Demographic data stratied by the number of pelvic nodes removed a.

Clinical data No. of pelvic nodes removed Total no.of patients

P value

1120 2130 3140 N40

No. of patients 243 344 171 68 826Mean age, y 45.6 45.1 44.8 43.6 45.1 0.280StageIA 6 (0.7) 16 (1.9) 9 (1.1) 1 (0.1) 32 (3.9) 0.676IA1 5 (0.6) 9 (1.1) 0 (0) 1 (0.1) 15 (1.8)

2253

2272

1

913474125

1

16178

212912

asio

44 P. Suprasert et al. / International Journal of Gynecology and Obstetrics 116 (2012) 4346IA2 9 (1.1)IB1 168 (20.3)IB2 29 (3.5)IIA 26 (3.1)

HistologySquamous 160 (19.4)Adeno 55 (6.7)Adenosquamous 13 (1.6)Neuroendocrine 11 (1.3)Other 4 (0.5)

Tumor gradeI 53 (6.4)II 105 (12.7)III 35 (4.2)Unknown 50 (6.1)

Positive pelvic lymph nodes 48 (5.8)Percentage of positive pelvic lymph nodes in each group 19.8No. of patients with single node positive 24 (50.0)Positive parametrium 38 (4.6)Positive vaginal marginInvasive 7 (0.8)HSIL 15 (1.8)DSI 106 (12.9)Positive LVSI 125 (15.2)

Neoadjuvant chemotherapy 67 (8.1)TreatmentRHPL 136 (16.5)RHPL+RT 19 (2.3)RHPL+CCRT 72 (8.7)RHPL+chemotherapy 16 (1.9)

Recurrence 17 (2.1)

Abbreviations: HSIL, high-grade squamous intraepithelial lesion; DSI, deep stromal invlymphadenectomy; RT, radical therapy; CCRT, concurrent chemoradiation.

a Values are given as number (percentage) unless otherwise given.8 (1.0) 3 (0.4) 1 (0.1) 21 (2.5)3 (27.0) 119 (14.4) 47 (5.7) 557 (67.4)0 (6.1) 20 (2.4) 10 (1.2) 109 (13.2)8 (4.6) 20 (2.4) 8 (1.0) 92 (11.1)

8 (27.6) 119 (14.4) 45 (5.4) 552 (66.8) 0.8666 (9.2) 33 (4.0) 18 (2.2) 182 (22.0)1 (2.5) 9 (1.1) 3 (0.4) 46 (5.6)9 (1.1) 6 (0.7) 0 (0) 26 (3.1)0 (1.2) 4 (0.5) 2 (0.2) 20 (2.4)

5 (11.5) 35 (4.2) 16 (1.9) 199 (24.1) 0.6713 (16.1) 72 (8.7) 29 (3.5) 339 (41.1)5 (5.5) 31 (3.8) 8 (1.0) 119 (14.4)0 (8.5) 33 (4.0) 15 (1.8) 168 (20.4)8 (5.8) 24 (2.9) 6 (0.7) 126 (15.3)4.0 14.0 8.8 15.3 0.0851 (44.7) 12 (50.0) 2 (33.3) 59 (46.8) 0.2374 (6.5) 20 (2.4) 6 (0.7) 118 (14.3) 0.319

0 (1.2) 7 (0.8) 1 (0.1) 25 (3.0) 0.0695 (0.6) 10 (1.2) 3 (0.4) 33 (4.0)7 (20.3) 81 (9.8) 32 (3.9) 386 (46.8) 0.6761 (20.8) 80 (9.7) 32 (3.9) 408 (49.7) 0.8147 (10.5) 49 (5.9) 21 (2.5) 224 (27.1) 0.730

3 (25.8) 104 (12.6) 42 (5.1) 495 (59.9) 0.6835 (3.0) 12 (1.5) 2 (0.2) 58 (7.0)2 (11.1) 43 (5.2) 21 (2.5) 228 (27.6)4 (1.7) 12 (1.5) 3 (0.4) 45 (5.4)2 (2.7) 16 (1.9) 6 (0.7) 61 (7.4) 0.636

n; LVSI, lymphovascular space invasion; RHPL, radical hysterectomy and pelvic node

patient who demonstrated the highest number of positive pelvic

itive nodes in a group of patients with less than 10 nodes removed.This might be explained by the inclusion of patients who only

Fig. 1. Disease-free survival (DFS) stratied by the number of pelvic nodes removed(mean, 43 months; median, 46 months; range, 1105 months).

Fig. 3. Disease-free survival (DFS) stratied by the number of pelvic nodes removedin patients with negative lymph nodes (mean, 43 months; median, 46 months; range,1105 months).

45P. Suprasert et al. / International Journal of Gynecology and Obstetrics 116 (2012) 4346nodes (n=21) was 45 years old. She presented with stage IB2 cancerwith an initial tumor size measuring approximately 5 cm. She re-ceived 1 cycle of cisplatin before undergoing RHPL and para-aorticnode sampling. The nal pathology revealed moderately differentiat-ed squamous cell carcinoma. The tumor had invaded the outer thirdof cervical stroma and showed positive LVSI without para-aorticnode involvement. The total number of nodes removed in this patientwas 32. She received adjuvant concurrent chemoradiation. However,distant recurrence in her left supraclavicular lymph node, lungs, andbrain was found at 12 months after completing treatment. The patientdied from her disease 2 months after the diagnosis of recurrence.

The mean follow-up time was 43 months and the recurrence ratefor the entire cohort of 826 patients was 7.4%, with no signicant dif-ference among the 4 groups. The 5-year disease-free survival amongthe 4 groups ranged from 89.7%96.6% (Fig. 1), and was not signi-cantly different. According to subgroup analysis based on nodal sta-tus, the 5-year disease-free survival ranged from 80.9%83.3% inpatients with positive nodes (Fig. 2) and 90.2%97.8% in those withnegative nodes (Fig. 3). There was no signicant association betweenthe number of resected pelvic nodes and the 5-year disease-free sur-vival, regardless of nodal status. Cox regression analysis for disease-free survival was carried out by incorporating the possible prognosticfactors, as given in Table 2. Thenumber of pelvic nodes removedwas notFig. 2. Disease-free survival (DFS) stratied by the number of pelvic nodes removedin patients with positive lymph nodes (mean, 43 months; median, 46 months; range,1105 months).an independent prognostic factor (P=0.402), while nonsquamous cellcarcinoma (P=0.001), stage IB2-IIA (P=0.002), poorly differentiatedtumor grade (P=0.001), positive pelvic node (P=0.001), vaginal mar-gin involvement (P=0.034), and LVSI (P=0.009) were independentprognostic factors.

4. Discussion

Systematic pelvic lymphadenectomy is an important part of surgi-cal treatment for early-stage cervical cancer. The mean or mediannumber of pelvic nodes removed varied from 1365 in previousreports [3, 7]. The variation in number of nodes removed dependedon several factors, including anatomy of the patient, status of localinammation, extent of surgery, processing of the specimen, and itsexamination by the pathologist [3]. However, the EORTC-GCG studyinto quality indicators for RHPL found that more than 90% of patientswho underwent pelvic lymphadenectomy had over 11 nodes re-moved [4]. In the present study, the mean number of nodes removedwas 26 and 97.5% of patients had more than 11 nodes removed.

The number of positive pelvic nodes was not signicantly differentamong the 4 groups. This result did not corresponded to that of thestudy by Pieterse et al. [5], who reported the highest incidence of pos-Table 2Cox regression analysis of the effect of prognostic factors on disease-free survival.

Factors Hazardratio

95% condenceinterval

P value

Neoadjuvant chemotherapy setting (nonevs received)

1.356 0.7192.557 0.348

Adjuvant treatment setting (none vs received) 0.809 0.3831.706 0.577Number of pelvic nodes removed (compared4 groups)

1.135 0.8441.525 0.402

Histology (SCCA vs non-SCCA) 2.827 1.5565.138 0.001Stage (IA-IB1-IB2-IIA) 2.620 1.4304.801 0.002Grade (I and II vs III) 2.672 1.4824.816 0.001Lymph node (negative vs positive) 3.117 1.5556.247 0.001Parametrium (negative vs positive) 0.757 0.3591.599 0.466Vaginal margin (negative vs positive) 1.773 1.0443.011 0.034DSI (inner and middle vs outer) 1.280 0.6502.517 0.475LVSI (negative vs positive) 2.742 1.2925.819 0.009

Abbreviations: SCCA, squamous cell carcinoma; DSI, deep stromal invasion; LVSI,lymphovascular space invasion.

underwent node sampling in their series. The lowest number ofnodes removed in that study was 1 in the negative node group and4 in the positive node group, while the present study only includedpatients who had at least 11 nodes removed to ensure adequate pel-vic node dissection. However, in the present study, the number of pel-

Acknowledgment

The National Research University Project under Thailand's Ofceof Higher Education Commission and Chiang Mai University providednancial support.

46 P. Suprasert et al. / International Journal of Gynecology and Obstetrics 116 (2012) 4346Recent publications have demonstrated that higher numbers ofresected lymph nodes were associated with better survival in patientswith various types of cancer, including breast, lung, colon, and endo-metrial cancers. These ndings suggest that extensive lymphadenect-omy may have a therapeutic impact [8-16]. Conversely, the benet ofthis is still debated in early-stage cervical cancer. Pieterse et al. [5]studied the number of pelvic lymph nodes removed in 467 early-stage cervical cancer patients who underwent radical hysterectomy.They concluded that there was no relationship between the largernumbers of nodes removed with either cancer-specic survival ordisease-free survival in patients with negative nodes. However, in pa-tients with positive pelvic nodes, they found a signicant relationshipbetween the number of lymph nodes removed and disease-free sur-vival, but no such relationship for cancer-specic survival. This resultis in contrast to the study by Shah et al. [6]. They analyzed the data for5522 early-stage cervical cancer patients from the Surveillance, Epi-demiology, and End Results (SEER) database and reported that thehigher number of pelvic nodes removed was associated with im-proved survival in patients with negative nodes, but not in thosewith positive nodes. In the present study, we did not nd a signicantimprovement in disease-free survival associated with the number ofresected nodes, regardless of nodal metastasis status. This resultwas conrmed using a Cox regression model to analyze potentialprognostic variables. From the analysis, the number of pelvic nodesremoved was not associated with disease-free survival. The strongestindependent prognostic factor in the present study was status oflymph node involvement, followed by nonsquamous cell carcinoma,presence of LVSI, poorly differentiated tumor grade, more advancedstage, and vaginal margin. These data correspond with previous re-ports [17-19]. However, parametrial invasion was not found to bean independent prognostic factor in the present study. This resultwas conrmed by Yuan et al. [20] who analyzed over 1000 cervicalcancer patients who underwent radical hysterectomy; multivariateanalysis in that study revealed that parametrial invasion was notthe important prognostic factor.

For patients with positive pelvic nodes, the nonsignicant differ-ence in disease-free survival among the study groups could beexplained by the comparable distribution of single node metastasisin each group. Sakuraki et al. [21] suggested that survival among sin-gle node positive patients was similar to that among node negativepatients.

The strength of the present study is its large sample size. In addi-tion, all participants were recruited from a single institution, whichmeant uniform treatment guidelines and surgical technique. Further-more, all specimens were examined by gynecologic pathologists. Ofnote, the limitations of the study include its retrospective natureand lack of information on cancer-specic survival.

In conclusion, the number of pelvic nodes removed was not asso-ciated with disease-free survival regardless of whether the patienthad pelvic node metastasis. Furthermore, positive pelvic node in-volvement was not signicantly associated with the number ofnodes removed. In our opinion, for standard pelvic lymphadenect-omy, a total of more than 10 nodes should be removed.Conict of interest

The authors declare that there are no conicts of interest

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Pelvic node removal and disease-free survival in cervical cancer patients treated withradical hysterectomy and pelvic lymphadenectomy1. Introduction2. Materials and methods3. Results4. DiscussionAcknowledgmentReferences