05 (2007) 604–608www.elsevier.com/locate/ygyno

Gynecologic Oncology 1

Pelvic and aortic lymph node metastasis in epithelial ovarian cancer

Augusto Pereira a, Javier F. Magrina b,⁎, Victoria Rey c, Manuel Cortes d, Paul M. Magtibay b

a Division of Gynecologic Surgery, General Hospital of Defense, San Fernando Cadiz, Spainb Division of Gynecologic Surgery, Mayo Clinic, 13400 East Shea Boulevard, Scottsdale, AZ 85259, USA

c Division of Gynecologic Surgery, Virgen Macarena Hospital, Seville, Spaind Division of Preventive Medicine, General Hospital of Defense, Zaragoza, Spain

Received 6 September 2006Available online 23 February 2007

Abstract

Objective. The appropriate management of advanced ovarian cancer has been controversial in recent years. There are no adequate data aboutthe importance of lymphadenectomy and the appropriate sites for lymph node assessment. We sought to evaluate the distribution, size, and numberof pelvic and aortic lymph node metastases in patients with epithelial ovarian carcinoma.

Methods. Retrospective chart review of 116 patients with stage IIIC or IV epithelial ovarian carcinoma treated at Mayo Clinic who underwentsystematic bilateral pelvic and aortic lymphadenectomy between 1996 and 2000.

Results. Eighty-six (78%) of 110 patients who underwent pelvic lymphadenectomy were found to have nodal metastases in 422 (16%) of2705 pelvic nodes that were removed. Eighty-four (84%) of 100 patients had documented aortic lymph node metastases in 456 (35%) of 1313aortic nodes that were removed. Fifty-five (59%) of 94 patients had bilateral metastatic pelvic and aortic lymph nodes and bilateral aorticlymphadenectomy was conducted in 53 (72%) of 74 patients. The most representative group for detection of nodal metastases was the aorticgroup (83%) followed by the external iliac group (59%) and the obturator nodes (53%). There was no significant difference between the meansize of positive (1.8 cm) and negative nodes (1.6 cm). Thirty-seven patients had unilateral tumor, and 1 patient (7%) had contralateral nodemetastasis.

Conclusion. The incidence of positive nodes bilaterally and positive high aortic nodes indicates the need for bilateral pelvic and aortic nodedissection (extending above the inferior mesenteric artery) in all patients regardless of laterality of the primary tumor.© 2007 Elsevier Inc. All rights reserved.

Keywords: Aortic lymphadenectomy; Aortic lymph node; Epithelial ovarian cancer; Pelvic lymphadenectomy; Pelvic lymph node

Introduction

Bilateral pelvic and aortic lymphadenectomy is an importantcomponent of the surgical staging for epithelial ovarian car-cinoma (EOC) to determine the nodal extension of disease [1].The presence of pelvic or aortic metastatic nodes was classifiedin 1985 as stage IIIC cancer by the International Federation ofGynecology and Obstetrics (FIGO).

Abbreviations: EOC, epithelial ovarian carcinoma; FIGO, InternationalFederation of Gynecology and Obstetrics.⁎ Corresponding author.E-mail address: jmagrina@mayo.edu (J.F. Magrina).

0090-8258/$ - see front matter © 2007 Elsevier Inc. All rights reserved.doi:10.1016/j.ygyno.2007.01.028

The aim of this study was to evaluate the distribution, size,and number of pelvic and aortic lymph node metastases inpatients with EOC.

Materials and methods

A retrospective review of the medical records of our tertiary care academicmedical center, Mayo Clinic, Scottsdale, Arizona, was conducted for the periodbetween 1996 and 2000 to identify all patients with primary EOC who werediagnosed with positive retroperitoneal lymph nodes (stage IIIC or IV) andtreated primarily surgically. Approval for this study was granted by the MayoFoundation Institutional Review Board.

Information was abstracted about the extent of disease, histologic grade, andtype of procedure. Collected data included each patient's age, tumor grade andtype, FIGO staging, nodal status, number of pelvic and aortic lymph nodesremoved, number of metastatic lymph nodes, size of metastatic and benignnodes, and distribution of metastatic lymph nodes.

Table 2Pelvic and aortic node involvement a

Lymphadenectomy No. % Mean nodesremoved, no.

605A. Pereira et al. / Gynecologic Oncology 105 (2007) 604–608

Statistical analysis was performed using χ2 analysis (to determine therelationship between lymph node status and other disease variables), theStudent's t test (to compare the means), and the Levene test for equality ofvariances. P values of less than .05 were considered statistically significant.

Pelvic Aortic Pelvic Aortic

Positive Negative 13 14 29.2 7.0Negative Positive 21 22 20.1 15.4Positive Positive 57 61 29.2 13.8Negative Negative 3 3 13.0 14.0

a N=94 patients.

Results

The records search identified 116 patients with EOC. Pelvicand aortic lymphadenectomy was performed in 94 patients,pelvic lymphadenectomy alone in 16, and aortic lymphade-nectomy alone in 6. Histologic grade of differentiation wasdescribed as Broder tumor grade 1 to 4. Thirty-six patients withclinically early peritoneal disease underwent full surgicalstaging, whereas 80 patients with clinically advanced peritonealdisease underwent full surgical debulking.

The mean age of the patients was 61.8 years (range, 24–87years). The distribution of patients by age, histologic type,stage, and tumor grade is summarized in Table 1.

Distribution and number of metastatic pelvic and aortic nodes

Data about pelvic lymphadenectomy were available for 110patients. Pelvic nodal metastases were documented in 86patients (78%). Of 2705 pelvic nodes removed, 422 (16%)

Table 1Distribution of patients by age, histologic type, stage, and tumor grade

Age, years a

Range No. (%)

20–29 1 (1)30–39 2 (2)40–49 15 (14)50–59 25 (23)60–69 32 (29)70–79 32 (29)≥80 2 (2)

Histologic findings b

Type No. (%)

Serous 76 (66)Mucinous 2 (2)Endometrioid 13 (11)Clear cell 1 (1)Brenner 2 (2)Undifferentiated 7 (6)Mixed 12 (10)Unclassified 3 (2)

Stage b No. (%)

Stage IIIC 85 (73)Stage IV 31 (27)

Grade b No. (%)

1 0 (0)2 3 (3)3 50 (43)4 63 (54)a N=109. (Data about the ages of 7 of the 116 total patients were not

available.)b N=116.

contained metastatic disease. The mean number of pelvic nodesremoved was 24.6 (range, 2–80), and the mean number ofmetastatic nodes removed was 3.8 (range, 1–23).

Data about aortic lymphadenectomy were available for 100patients. Aortic lymph node metastases were documented in 84patients (84%). Of 1313 aortic lymph nodes removed, 456(35%) were positive. The mean number of aortic nodes removedwas 13.1 (range, 1–55), and the mean number of aortic nodesremoved was 4.6 (range, 1–29).

The mean number of pelvic and aortic nodes removed was37.7 (range, 2–123), and the mean number of metastatic pelvicand aortic nodes removed was 8.4 (range, 1–42). Aortic lymphnode metastases (35%) were twice as common as pelvic nodaldisease (16%) (P<.001).

Data from pelvic and aortic lymphadenectomy wereavailable for 94 patients (Table 2). Three patients with negativepelvic and aortic lymph nodes also had positive intestinalmesenteric nodes and are included as stage IIIC. Most patients(61%) had positive pelvic and aortic nodes, 22% had negativepelvic but positive aortic nodes, and 14% had positive pelvicbut negative aortic nodes.

Bilateral metastatic pelvic lymph nodes were documented in55 (59%) of 94 patients with bilateral pelvic and aortic lympha-denectomy. Of 74 patients with bilateral aortic lymphadenect-omy, 53 (72%) had positive right aortic nodes and 49 (66%) hadpositive left aortic nodes. The distribution of pelvic nodemetastasis by affected lymphatic group is summarized in Table 3.

The distribution of aortic lymph node metastasis in relationto the inferior mesenteric artery was available for 17 patients.These findings are summarized in Table 4.

Size of metastatic lymph nodes

The mean size of 35 metastatic lymph nodes from 29 patientswas 1.8 cm (range, 0.2–5 cm). This size was similar to the mean

Table 3Location of lymph node metastases in patients with pelvic lymphadenectomy a

Lymphatic group Positive lymph node group

No. %

External iliac (n=88) 52 59Obturator (n=88) 47 53Common iliac (n=73) 33 45Presacral (n=15) 7 47Internal iliac (n=41) 13 32a N=110 patients.

Table 4Distribution of aortic node metastases in relation to inferior mesenteric artery a

Aortic node site IMA

Low High No. %

Negative (n=8) Positive 3 37.5Positive (n=11) Positive 8 72.7Positive (n=6) Negative 1 16.6

IMA, inferior mesenteric artery.a N=17 patients.

Table 5Distribution of positive and negative lymph nodes by size

Size, cm LN, no.(N=87)

Positive LN(n=35)

Negative LN(n=52)

No. % No. %

0.2–0.9 12 4 33 8 671–1.9 30 6 20 24 802–2.9 30 15 50 15 503–3.9 10 6 60 4 404–5 5 4 80 1 20

LN, lymph nodes.

606 A. Pereira et al. / Gynecologic Oncology 105 (2007) 604–608

size (1.6 cm) of 52 benign lymph nodes (range, 0.2–5 cm).There was no statistically significant association between themean size of positive and negative nodes (P= .61). Thedistribution of the metastatic and benign lymph nodes by sizeis summarized in Table 5. As nodal size increased, so did thesize of the metastases.

Distribution of positive nodes in patients with unilateral EOC

Thirty-seven patients with positive retroperitoneal nodes hadunilateral EOC, right-sided in 14 (42%) and left-sided in 19(58%) after exclusion of 4 patients with microscopic contral-ateral ovarian metastases. Pelvic lymphadenectomy was con-ducted in 31 patients and aortic lymphadenectomy in 27.Nineteen patients (61%) had positive pelvic nodes and 22 (81%)had positive aortic nodes.

Of 14 patients with bilateral pelvic lymphadenectomy andunilateral EOC, 7 patients (50%) had ipsilateral pelvic nodalinvolvement, 6 (43%) had bilateral nodal involvement, and 1(7%) had contralateral positive nodes.

Of 15 patients with bilateral aortic lymphadenectomy, 8(53%) had ipsilateral aortic nodal involvement, 6 (40%) hadbilateral positive nodes, and 1 (7%) had contralateral positivenodes.

Discussion

A normal adult body contains between 400 and 450 lymphnodes, most of which (≥250) are located in the abdomen andpelvis [2]. About 81 lymph nodes (range, 49–128) aredistributed between the pelvis (50) and the aortic area (31) [3].

Ferraris et al. [4] considered a systematic lymphadenectomyin cervical cancer when at least 20 positive pelvic lymph nodeswere collected, a selective lymphadenectomy for fewer than 20nodes, and a node biopsy for fewer than 5 nodes [4,5]. Theprevalence of lymph node positivity is closely dependent notonly on the number of lymph nodes removed but also on thenumber that is properly processed [6]. For purposes ofdocumenting nodal metastases in EOC, our findings indicatethat about 25 pelvic lymph nodes and 13 aortic lymph nodes areadequate. This overall number of affected lymph nodesrepresents 8% of the total lymph nodes of the body (38 aorticand pelvic nodes of 450 total body lymph nodes), 15% of theabdominal and pelvic lymph nodes (38 aortic and pelvic nodesof 250 abdominal lymph nodes), 50% of the pelvic lymph nodes(25 of 50 pelvic nodes), and 42% of the aortic lymph nodes (13aortic nodes of 31 total aortic lymph nodes).

The dissemination of malignant cells in EOC occurs in 2ways: exfoliation and peritoneal implantation or retroperitoneallymphatic drainage of the ovary, the latter increasing as thedisease spreads intraperitoneally [7]. For instance, in clinicalstage I ovarian cancer, the percentage of pelvic and aorticlymph node metastases has been reported to be 8% to 15% and5% to 24%, respectively. In peritoneally advanced ovariancarcinoma, retroperitoneal nodal involvement has beenreported to be 55% to 75% [8,9]. In EOC patients dyingfrom the disease, 48% to 70% have documented lymph nodeinvolvement [10,11].

We, like others [12], have observed a higher rate of positiveaortic nodes (84%) than pelvic node metastases (78%) in EOCpatients. Plentl and Friedman [13] described 3 major diffusionlymphatic routes for EOC: (1) along the ovarian vessels throughthe infundibulopelvic ligament to the aortic area, terminating atthe vena cava on the right side and between the aortic and renalvessels on the left side, and draining medially into theparaaortic, intercaval aortic, and paracaval lymph nodes [14];(2) through the broad ligament and parametrial lymphaticchannels to the interiliac and upper gluteal lymph nodes; and (3)by an accessory route along the round ligament to the externaliliac and inguinal lymph nodes.

Aortic nodal metastases are commonly understood as theinitial route for the spread of EOC, with the pelvic nodesconstituting a second metastatic site and the inguinal nodes atertiary disseminating site. However, in our study, 14% ofpatients had negative aortic nodes but positive pelvic nodes, and22% of patients had negative pelvic nodes but positive aorticnodes, which indicates that this assumption may not prove truefor all patients. Additionally, inguinal node involvementappears to be extremely infrequent even in patients with pelvicand aortic node metastases, as demonstrated by our finding thatno patient in this series with positive pelvic and aortic nodes hadinguinal lymph node involvement. Instead, it appears to be alate manifestation or an infrequent occurrence of EOC (none ofour 94 patients was affected).

Onda et al. [15] described the distribution of pelvic and aorticnode metastases in EOC and concluded that essential sites forlymph node sampling were the high aortic nodes (above theinferior mesenteric artery), the internal and external iliac nodes,and the obturator lymph nodes. The reported incidence ofpositive high aortic nodes is 58% to 79% and of the lower aorticnodes (below the inferior mesenteric artery), 33% to 71%[15,16]. In our study, we searched the distribution of lymph

607A. Pereira et al. / Gynecologic Oncology 105 (2007) 604–608

node metastases in the 12 pelvic areas by their anatomicalrelation to the arterial blood supply [17] (common iliac, externaliliac, internal iliac, obturator, parametrial, and right and leftaortic nodes). Our review indicated that the most representativegroups for detection of nodal metastases, by order of frequency,are the aortic nodes (83%), in particular the high nodes (65%),followed by the external iliac group (59%), the low aortic nodes(53%), and the obturator nodes (53%). The aortic nodes weretwice as likely as the pelvic nodes to contain metastases (35% vs16%). These findings are in agreement with earlier reportedfindings.

In regard to contralateral metastatic disease in patients withunilateral EOC, Benedetti-Panici et al. [8] initially indicated thatthe lymphatic spread was ipsilateral and that ipsilateral pelvicand aortic node dissection was therefore appropriate for staging.However, contralateral nodal involvement in EOC patients withunilateral clinical stage I disease has been reported to occur in asmany as 30% of patients [15,16,18,19]. More recent reports [20]have suggested that bilateral pelvic and aortic lymphadenect-omy should be undertaken for adequate retroperitoneal stagingin the presence of unilateral EOC.

Ipsilateral lymphadenectomy is also inadequate in patientswith unilateral EOC, clinical stage II to IV [21]. In patients withunilateral EOC and clinical stage III, ipsilateral lymphadenect-omy has been documented in only 40% of patients withretroperitoneal nodal involvement; the rest have contralateral orbilateral disease. Our results confirm similar findings. Ipsilateralsampling in unilateral EOC may result in understaging in aorticlymphadenectomy by 7% to 16% and in pelvic lymphadenect-omy by 0% to 7% [16].

Normal lymph node size varies from a few millimeters to2.5 cm in diameter. We observed a 2-mm difference betweenthe mean size of benign and metastatic lymph nodes, with thesize not correlating with the presence of metastatic disease. Asnodal size increases, so does the likelihood of metastatic EOC.For nodes of less than 2 cm, the likelihood of metastasis was24%, for those of 2 to 4 cm, 52.5%, and for nodes larger than4 cm, 80%. This finding is in agreement with those of previousreports [21–23], indicating that intraoperative assessment ofretroperitoneal lymph nodes by palpation is incorrect in 33%to 60% of patients. Eisenkop and Spirtos [24] identified 31.1%of positive nodes by palpation, 26.2% by visual inspection,and 42.6% by dissection, which indicates that surgicaldissection is necessary for full documentation of nodal disease.In our study, selecting only those nodes greater than 2 cm forremoval would not have detected 24% of patients with positivenodes.

EOC has a predisposition to disseminate to retroperitonealpelvic and aortic nodes compared with other gynecologicmalignancies, with an especially high predilection for the aorticnodes. Patients with EOC thus appear to require pelvic andaortic lymphadenectomy for full documentation of disease.

Acknowledgment

Editing, proofreading, and reference verification wereprovided by the Section of Scientific Publications, Mayo Clinic.

References

[1] Webb MJ, Wilson TO. Surgery of the ovaries. In: Webb MJ, editor. MayoClinic manual of pelvic surgery. Philadelphia: Lippincott Williams &Wilkins; 2000. p. 87–92.

[2] Gabella G, Anderson R, Dussek J, Evans S, Marston A, Perry M.Cardiovascular system. In: Williams PL, Bannister LH, Berry MM, CollinsP, Dyson M, Dussek JE, Ferguson MWJ, editors. Gray's anatomy: theanatomical basis of medicine and surgery. 38th ed. New York: ChurchillLivingstone; 1999. p. 1451–626.

[3] Panici PB, Scambia G, Baiocchi G, Matonti G, Capelli A, Mancuso S.Anatomical study of para-aortic and pelvic lymph nodes in gynecologicmalignancies. Obstet Gynecol 1992;79:498–502.

[4] Ferraris G, Lanza A, D'Addato F, Valli M, Re A, Bellino R, et al.Techniques of pelvic and para-aortic lymphadenectomy in the sur-gical treatment of cervix carcinoma. Eur J Gynaecol Oncol 1988;9:83–6.

[5] di Re F, Baiocchi G, Fontanelli R, Grosso G, Cobellis L, Raspagliesi F,et al. Systematic pelvic and paraaortic lymphadenectomy for advancedovarian cancer: prognostic significance of node metastases. GynecolOncol 1996;62:360–5.

[6] Carnino F, Fuda G, Ciccone G, Iskra L, Guercio E, Dadone D, et al.Significance of lymph node sampling in epithelial carcinoma of the ovary.Gynecol Oncol 1997;65:467–72.

[7] Ozols RF, Rubin SC, Thomas GM, Robboy SJ. Epithelial ovariancancer. In: Hoskins WJ, Perez CA, Young RC, editors. Principles andpractice of gynecologic oncology. 2nd ed. Philadelphia: Lippincott-Raven; 1997. p. 919–86.

[8] Benedetti-Panici P, Greggi S, Maneschi F, Scambia G, Amoroso M, RabittiC, et al. Anatomical and pathological study of retroperitoneal nodes inepithelial ovarian cancer. Gynecol Oncol 1993;51:150–4.

[9] Di Re F, Baiocchi G. Value of lymph node assessment in ovarian cancer:status of the art at the end of the second millennium. Int J Gynecol Cancer2000;10:435–42.

[10] Dvoretsky PM, Richards KA, Angel C, Rabinowitz L, Stoler MH,Beecham JB, et al. Distribution of disease at autopsy in 100 women withovarian cancer. Hum Pathol 1988;19:57–63.

[11] Vinokurov VL, Irzhanov SI, Zel'dovich DR, Chepik OF. Patterns in themetastasis of malignant ovarian tumors based on autopsy data [Russian].Vopr Onkol 1985;31:62–9.

[12] Rose PG, Piver MS, Tsukada Y, Lau TS. Metastatic patterns in his-tologic variants of ovarian cancer: an autopsy study. Cancer 1989;64:1508–13.

[13] Plentl AA, Friedman EA. Lymphatic system of the female genitalia: themorphologic basis of oncologic diagnosis and therapy. Major Probl ObstetGynecol 1971;2:1–223.

[14] Eichner E, Bove ER. In vivo studies on the lymphatic drainage of thehuman ovary. Obstet Gynecol 1954;3:287–97.

[15] Onda T, Yoshikawa H, Yokota H, Yasugi T, Taketani Y. Assessment ofmetastases to aortic and pelvic lymph nodes in epithelial ovarian carci-noma: a proposal for essential sites for lymph node biopsy. Cancer 1996;78:803–8.

[16] Tsumura N, Sakuragi N, Hareyama H, Satoh C, Oikawa M, Yamada H,et al. Distribution pattern and risk factors of pelvic and para-aortic lymphnode metastasis in epithelial ovarian carcinoma. Int J Cancer 1998;79:526–30.

[17] Mlyncek M. Pelvic and paraaortic lymphadenectomy in gynecologiconcology. J Pelvic Surg 1999;5:335–47.

[18] Cass I, Li AJ, Runowicz CD, Fields AL, Goldberg GL, LeuchterRS, et al. Pattern of lymph node metastases in clinically unilateral stageI invasive epithelial ovarian carcinomas. Gynecol Oncol 2001;80:56–61.

[19] Petru E, Lahousen M, Tamussino K, Pickel H, Stranzl H, Stettner H, et al.Lymphadenectomy in stage I ovarian cancer. Am J Obstet Gynecol 1994;170:656–62.

[20] Ayhan A, Gultekin M, Taskiran C, Celik NY, Usubutun A, Kucukali T,et al. Lymphatic metastasis in epithelial ovarian carcinoma with respectto clinicopathological variables. Gynecol Oncol 2005;97:400–4.

608 A. Pereira et al. / Gynecologic Oncology 105 (2007) 604–608

[21] Wu PC, Qu JY, Lang JH, Huang RL, Tang MY, Lian LJ. Lymph nodemetastasis of ovarian cancer: a preliminary survey of 74 cases oflymphadenectomy. Am J Obstet Gynecol 1986;155:1103–8.

[22] Knapp RC, Friedman EA. Aortic lymph node metastases in early ovariancancer. Am J Obstet Gynecol 1974;119:1013–7.

[23] Piver MS, Barlow JJ, Lele SB. Incidence of subclinical metastasis in stageI and II ovarian carcinoma. Obstet Gynecol 1978;52:100–4.

[24] Eisenkop SM, Spirtos NM. The clinical significance of occult macro-scopically positive retroperitoneal nodes in patients with epithelial ovariancancer. Gynecol Oncol 2001;82:143–9.