Pattern of Lymph Node Metastases in Clinically Unilateral Stage I Invasive Epithelial Ovarian Carcinomas

Gynecologic Oncology 80, 56 – 61 (2001) doi:10.1006/gyno.2000.6027, available online at http://www.idealibrary.com on

Pattern of Lymph Node Metastases in Clinically Unilateral Stage I Invasive Epithelial Ovarian Carcinomas 1,2 Ilana Cass, M.D.,* ,3 Andrew J. Li, M.D.,* Carolyn D. Runowicz, M.D.,† Abbie L. Fields, M.D.,† Gary L. Goldberg, M.D.,† Ronald S. Leuchter, M.D.,* Leo D. Lagasse, M.D.,* and Beth Y. Karlan, M.D.* *Cedars–Sinai Medical Center and UCLA School of Medicine, Los Angeles, California 90048; and †Albert Einstein College of Medicine and Montefiore Medical Center, Bronx, New York 10461 Received May 26, 2000; published online December 5, 2000

INTRODUCTION

Purpose. There is controversy regarding the pattern of lymphatic spread in unilateral stage I invasive ovarian carcinomas. The purpose of this study is to describe the incidence and distribution of lymph node (LN) metastases in ovarian carcinomas clinically confined to one ovary. Methods. Ninety-six patients with disease visibly confined to one ovary were identified. Pathology reports were reviewed to identify metastatic LN involvement, number of involved nodes, and their locations. Patients with gross disease in the pelvis or abdomen or those who had grossly positive LNs removed for debulking were excluded from this review. Results. Fourteen of ninety-six patients (15%) had microscopically positive LNs on pathologic review. All of these 14 patients had grade 3 tumors. Grade 3 tumors were more commonly seen in LN-positive versus LN-negative patients (P < 0.001). Pelvic nodes were positive in 7 patients (50%), paraaortic nodes in 5 patients (36%), and both in 2 patients (14%). Forty-two patients had LN sampling only on the side ipsilateral to the neoplastic ovary, 4 of whom (10%) had LN metastases. Fifty-four patients had bilateral sampling performed, 10 of whom (19%) had LN metastases. Of these 10 patients, isolated ipsilateral LN metastases were seen in 5 (50%) cases. Isolated contralateral LN metastases were seen in 3 (30%) cases, and bilateral metastases were seen in 2 (20%). Conclusions. In this cohort of patients with clinical stage I ovarian carcinoma with disease limited to one ovary, bilateral LN sampling increased the identification of nodal metastases. Ipsilateral sampling may result in the understaging of patients. Bilateral pelvic and paraaortic LN sampling is recommended to accurately stage ovarian carcinoma. © 2001 Academic Press Key Words: epithelial ovarian carcinoma; lymph node metastasis.

In 1985 the International Federation of Gynecologists and Obstetricians (FIGO) modified the staging for ovarian carcinoma in part to reflect the prognostic significance of metastatic spread to the pelvic or paraaortic lymph nodes (LNs) [1]. In disease confined to one or both ovaries, positive nodes result in an upstaging from stage I to stage IIIC. Some authors have challenged the wisdom of the categorization of patients with large (⬎2 cm) intraabdominal metastases along with those that have documented retroperitoneal disease [2, 17]. The 5-year survival decreases from ⬎90% for patients with disease limited to the ovaries to 46 – 60% when retroperitoneal extension is found, thereby justifying more aggressive adjunctive treatment [3, 4]. Surgical morbidity ascribed to LN evaluation includes lymphocyst formation, nerve and vessel injury, and increased operating time and blood loss. Furthermore, the incidence of retroperitoneal metastases has been reported to be relatively low in apparent stage I carcinomas [5–10]. Thus, many gynecologic oncologists perform only selective ipsilateral retroperitoneal sampling when disease is grossly confined to one ovary. Benedetti-Panici et al. concluded from their review of six patients that ipsilateral LN evaluation was adequate for clinical stage IA disease [6]. However, there are case reports in the literature that describe isolated contralateral extension [3, 7, 11, 15]. While these data argue for the need for bilateral sampling in apparent early-stage disease, no studies to date clearly describe the situation for carcinomas that appear to be clinically limited to one ovary. The purpose of this study was to evaluate the incidence and distribution of LN metastases in patients with clinical stage I epithelial ovarian carcinomas with disease visibly confined to one ovary.

1

This work was supported by the Cedars–Sinai Research for Women’s Cancers. 2 Presented at the 31st Annual Meeting of the Society of Gynecologic Oncologists, San Diego, California, February 2–5, 2000. 3 To whom correspondence should be addressed at the Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Cedars–Sinai Medical Center, 8700 Beverly Boulevard, Suite 160W, Los Angeles, CA 90048. Fax: (310) 423-0140. 0090-8258/01 $35.00 Copyright © 2001 by Academic Press All rights of reproduction in any form reserved.

MATERIALS AND METHODS A retrospective review of the medical records of all patients evaluated at the Cedars–Sinai Medical Center and the Albert Einstein College of Medicine/Montefiore Medical Center with 56

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LN METASTASES IN UNILATERAL STAGE I OVARIAN CARCINOMAS

TABLE 1 Relative Frequency of Histologic Type and Surgical Stage

A P value less than 0.05 was considered to be statistically significant.

Stage

Serous Endometrioid Clear cell Mucinous Mixed Small cell Transitional Brenner

RESULTS

I

II

IIIA

IIIB

IIIC

Total

8 14 16 14 4 0 2 1

5 6 1 0 0 0 0 0

7 1 1 2 0 0 0 0

0 0 0 0 0 0 0 0

8 2 2 0 1 1 0 0

28 23 20 16 5 1 2 1

ovarian carcinoma from January 1986 through December 1998 was performed. One thousand one hundred patients with invasive epithelial carcinomas were identified; those with ovarian carcinomas of low malignant potential were excluded. Of these patients, 96 were found to have disease visibly confined to one ovary at the time of staging laparotomy. All of these patients underwent surgical staging that included bilateral salpingooophorectomy, omentectomy, and LN sampling by a gynecologic oncologist. Peritoneal biopsies were obtained at the surgeon’s discretion. Records that described gross disease in the abdomen or pelvis and palpable or enlarged LNs suspicious for metastasis were excluded from further review. Operative and pathology reports were reviewed to ascertain metastatic LN involvement, number of involved nodes, and their anatomic locations. Information regarding the macroscopic appearance of the ovarian tumors, the presence of ascites, and whether random peritoneal biopsies were obtained was recorded. Postsurgical chemotherapy was recommended when appropriate depending on the clinical and histopathological findings. A standard platinum-based combination regimen was used for the vast majority of patients requiring adjuvant treatment. LN evaluation, in the absence of clinically evident metastatic disease, involved ipsilateral or bilateral sampling from the pelvic and/or paraaortic regions at the surgeon’s discretion. Pelvic sampling included removal of lymphatic and fatty tissue from the common, external, and internal iliac vessels and obturator vessels. Paraaortic dissection included sampling of the right- and left-sided anatomic aortic nodal groups from the bifurcation of the aorta to the reflection of the duodenum or to the origin of the renal arteries. Right-sided LN sampling encompassed tissue from the right paracaval, precaval, and aortocaval nodal groups. Left-sided sampling included left paraaortic and preaortic nodal groups. Multiple serial pathological sections were cut on all LNs submitted at the time of surgery to detect microscopic metastases, and were reviewed by two independent pathologists. The ␹ 2 test and the Mann–Whitney rank sum test were used to assess differences in clinical and histological characteristics.

Ninety-six patients had clinical unilateral stage I disease confined to one ovary at the time of surgery. However, after histopathologic review, 12 patients were advanced to FIGO stage II for microscopic extension to the fallopian tubes and/or uterus. Eleven patients were upstaged to IIIA for microscopic metastases outside the pelvis. The 14 patients upstaged to stage IIIC did so on the basis of microscopic LN metastases alone. The distribution of histology and stage is shown in Table 1. A variety of epithelial histologies were represented. Overall, serous was the most common histology (29%), followed by endometrioid (24%), clear cell (21%), and mucinous (17%). Among surgical stage I disease, clear cell was the most common histology (16/59, or 27%), followed by endometrioid and mucinous (14/59, or 24%). Serous histology was the most common among patients with stage IIIC disease (8/14 or 57%), followed by endometrioid and clear cell (2/14, or 14%). No mucinous tumors were seen in patients with positive lymph nodes. There were no statistical differences seen within those patients with serous or mucinous histology and stage of disease. Table 2 describes the distribution of grade of carcinoma and stage. The largest proportion of tumors was of high grade (43/96 or 45%). For surgical stage I, grades 1, 2, and 3 were equally represented (respectively, 20, 19, and 20 of 59). For stage IIIC, only grade 3 tumors were seen (14/14). Grade 3 tumors were more commonly seen in LN-positive versus LNnegative patients (P ⬍ 0.001). The incidence of paraaortic and pelvic nodal metastases is summarized in Table 3. Fourteen of ninety-six patients (15%) had microscopically positive LNs on pathologic review. Fortytwo patients had LN sampling only on the side ipsilateral to the neoplastic ovary, 4 of whom (10%) had LN metastases. Fiftyfour patients had bilateral sampling, 10 of whom (19%) had LN metastases. Pelvic nodes were positive in 7 (50%), paraaortic nodes in 5 (36%), and both in 2 (12%). The distribution of LN metastases in the 10 patients who underwent bilateral LN sampling was examined. Isolated ipsilateral LN metastases were seen in 5 of 10 cases and bilateral

TABLE 2 Relative Frequency of Grade and Surgical Stage Stage Grade

I

II

IIIA

IIIB

IIIC

1 2 3

20 19 20

1 7 4

3 3 5

0 0 0

0 0 14

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CASS ET AL.

TABLE 3 Incidence of Paraaortic and Pelvic Node Metastases Pelvic (n ⫽ 7)

Right tumor Left tumor

Paraaortic (n ⫽ 5)

Pelvic and PA (n ⫽ 2)

Right

Left

Bilateral

Right

Left

Right

Left

2 0

1 2

1 1

3 0

1 1

1 1

0 0

metastases were seen in 2 of 10 cases. Isolated contralateral LN metastases were seen in 3 of 10 cases. Of the 3 patients with isolated contralateral metastases, one involved both the paraaortic and pelvic nodes; one involved solely the pelvic nodes; and one involved solely the paraaortic nodes. No statistically significant differences were seen in mean ovarian volumes between patients with solely ipsilateral LN metastases and those with either bilateral or isolated contralateral LN metastases (550.7 cm 3 vs 668.6 cm 3). Factors relevant to apparent lymph drainage across the midline were considered. Of the five patients with contralateral lymph node metastases, two had microscopic metastases in the contralateral ovary and one had ascites. The remaining two patients had benign contralateral ovaries and peritoneal biopsies after histopathologic review and negative washings, although both patients had ovarian surface involvement. These data are summarized in Table 4. The mean number of retrieved nodes was determined from pathology reports and summarized in Table 5: 10.2 ⫾ 9.4 pelvic and 4.7 ⫾ 3.4 paraaortic nodes were sampled in patients with metastatic disease; 5.7 ⫾ 4.0 pelvic and 2.4 ⫾ 2.1 paraaortic nodes were sampled in patients without metastases. Overall, 6.4 pelvic and 2.9 paraaortic nodes were sampled in this cohort of patients. No statistically significant differences were identified in the number of nodes retrieved between patients with and without metastatic nodes.

Kaplan–Meier survival curves for overall survival are represented in Fig. 1. The median survival was 4.1 years for patients surgically staged I to IIIA and 2.0 years for patients surgically staged IIIC. No statistical differences in survival were seen between LN-positive and LN-negative patients, although our numbers are small. Review of operative reports of patients who had lymph node sampling revealed no nerve or vessel injury or significant blood loss associated with LN evaluation in this study. DISCUSSION Lymphatic drainage of the ovary is known to follow the gonadal blood supply. The dominant lymph channels coalesce in the infundibulopelvic ligament, where they travel with the pampiniform plexus of the ovarian veins, and then drain into the inferior pole of the kidney and move medially into the paraaortic and precaval LNs [6, 12]. An ancillary lymphatic pathway from the hilus of the ovary traverses the broad ligament draining into the obturator, external, and common iliac nodes [11, 13]. The pattern of LN spread in ovarian cancer has long been an area of interest. In 1985 the staging of ovarian cancer by FIGO was modified to incorporate the more aggressive biologic behavior associated with LN spread. Autopsy studies performed in patients who died of advanced epithelial ovarian carcinoma

TABLE 4 Histopathology of 14 Patients with LN Metastases Tumor site

Tumor surface

Washings

Adhesions

LN location

Contralateral ovary

Peritoneal biopsies

Right Right Right Left Left Right Right Right Right Right Right Left Left Left

Excrescence Smooth Excrescence Smooth Rupture Excrescence Smooth Smooth Rupture Excrescence Smooth Smooth Excrescence Smooth

Negative Negative Ascites Ascites Negative Negative Negative Negative Negative Negative Ascites Negative Negative Ascites

None None None Present None Present None Present None None None Present None None

L PA L pelvic B pelvic B pelvic R pelvic/PA R pelvic R PA R PA R PA R PA R pelvic L PA L PA L pelvic

Benign Metastasis Metastasis Benign Benign Benign Benign Benign Benign Benign Metastasis Benign Benign Benign

Negative Not done Negative Not done Negative Negative Not done Metastasis Metastasis Not done Metastasis Metastasis Negative Not done

LN METASTASES IN UNILATERAL STAGE I OVARIAN CARCINOMAS

TABLE 5 Number of Sampled Nodes

No. pelvic No. PA

LN ⫹

LN ⫺

Total

10.2 ⫾ 9.4 4.7 ⫾ 3.4

5.7 ⫾ 4.0 2.4 ⫾ 2.1

6.4 ⫾ 5.5 2.9 ⫾ 2.5

have described an 80% incidence of pelvic and paraaortic LN involvement [14]. In 1974, Knapp and Friedman described a 19% incidence of paraaortic LN spread in clinical stage I disease, which they suggested was the dominant lymphatic

FIG. 1.

59

pathway of the ovary [12]. Subsequent clinical studies of patients with stage I–III disease have confirmed the importance of both pelvic and paraaortic lymphatic drainage pathways, with some debate as to the most common site of LN involvement in ovarian carcinoma. Burghardt et al. performed paraaortic and pelvic lymphadenectomies in 105 patients and found an equal distribution of paraaortic and pelvic metastases [8]. In a smaller cohort of patients, Petru et al. found a higher prevalence of pelvic LN metastases, but more patients had pelvic than paraaortic lymphadenectomies [3]. Onda et al. [15] and Benedetti-Panici et al. [6] performed extensive pelvic and paraaortic lymphadenectomies on patients and found that the

Kaplan–Meier survival curves of LN-positive and LN-negative patients.

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CASS ET AL.

pre- or paraaortic nodes were the most common site of metastases. The incidence of occult LN metastases in clinical stage I disease varies in the literature from 4 to 27% [3, 6, 8 –10, 16]. Many authors suggest that the detection of metastatic disease varies with the type of surgical procedure. Di Re et al. defined a lymphadenectomy as yielding at least 20 nodes, and a LN sampling yielding between 5 and 20 nodes [5]. Although the highest incidence of LN metastases has been described in articles that used LN sampling [9, 10], patient numbers were very small in these reports. Larger studies with more stringent criteria for stage I disease have described LN metastases in 13–24% of patients who underwent lymphadenectomy [12]. The 15% incidence from the present series of patients with apparent unilateral stage I disease who had LN sampling is consistent with these reports. In this study, LN evaluation was considered a sampling procedure. Our findings are consistent with the correlation of histopathologic prognostic factors and LN involvement. Serous tumors with high nuclear grade had a statistically significant higher incidence of LN metastases, as described by others in the literature [6, 7, 9, 10, 17]. While none of the mucinous or low to moderate grade tumors demonstrated metastatic lymph nodes, our numbers are too small to recommend exclusion of lymph node sampling as part of surgical staging in these subsets of patients. Furthermore, the accuracy of grade may not be confirmed by frozen section diagnosis at the time of laparatomy. No statistical differences in survival were seen between our cohort of LN-positive and LN-negative patients. While median survival for stage IIIC patients was half that of patients staged I to IIIA, small numbers and limited follow-up likely contributed to the lack of statistical findings. The current study attempts to address the specific question of laterality of LN metastases in clinically unilateral stage I ovarian carcinoma. This retrospective review represents one of the largest groups of patients with uniform surgical entry criteria. Patients with gross disease in the pelvis or abdomen or with grossly positive LNs were excluded from this review. Although the numbers in this review are small, our findings are similar to those of Wu et al., Petru et al., Onda et al., and Walter et al., who suggest that isolated contralateral LN metastases occur not uncommonly [3, 7, 11, 15]. The cumulative occurrence of isolated contralateral LN metastases in the literature, including this study, is limited: 11 of 32 (34%) cases in patients with unilateral ovarian tumors (Table 6). The majority of these patients were noted to have early-stage disease without gross LN involvement [2, 3]. Yet these retrospective studies may be limited due to investigator bias; bilateral LN sampling may have been performed because of clinical suspicion of metastases not described in the operative reports. However, bilateral sampling is standard practice for some of the gynecologic oncologists at our institutions. The frequency of contralateral LN metastases in the present

TABLE 6 Summary of Literature Regarding Positive Isolated Contralateral Nodes Author

No. cases

Tumor site

Site of LN metastasis

Wu et al. [7]

3 of 6

Petru et al. [3] Walter and Magrina [11] Onda et al. [15] Cass et al.

1 1 1 5

Left Left Left Unspecified Left Right Right Left Right Right Left

Right Right Right Contralateral Right PA/pelvic Left pelvic L PA R PA/pelvic L Pelvic Bilateral pelvic Bilateral pelvic

of of of of

6 1 9 10

study (5 of 10 cases) supports the recommendation of the authors that bilateral LN evaluation is required in early-stage, apparently localized disease, which is consistent with the FIGO staging guidelines as well as the Gynecologic Oncology Group’s ovarian cancer surgical procedure [18]. These findings are in contrast with the conclusions of Benedetti-Panici et al., who found isolated ipsilateral pelvic LN involvement in three of six patients with unilateral disease confined to the pelvis [6]. The pattern of LN spread in disease confined to one ovary is unclear. There are a limited number of cases in the literature that describe the distribution and frequency of LN metastases in unilateral ovarian cancer. Given that 2 of 10 patients with apparent unilateral disease had bilateral LN metastases, and 3 of 10 had isolated contralateral metastases, our study supports the premise that lymph channels from the ovary do not solely drain to the ipsilateral nodes. Careful sampling and pathologic review of the contralateral ovary and abdominal peritoneum, even when clinically benign, are mandatory to identify occult metastatic disease. Bilateral LN sampling significantly increased the identification of nodal metastases and appropriately upstaged patients’ disease. We have shown that bilateral LN sampling increased the yield of LN metastases, 19% versus 10%. The literature suggests that lymphadenectomy may be superior to sampling to detect LN metastases [4, 17]. The role of bilateral lymphadenectomy in apparent unilateral stage I ovarian cancer should be evaluated in future prospective trials to determine the true incidence of LN involvement. Ongoing studies at our institution are examining lymphatic mapping with isosulfan blue in apparent early-stage ovarian carcinoma. ACKNOWLEDGMENTS The authors thank Fernando Otero, M.D., Joan Jones, M.D., and Denise Barbuto, M.D., for their contributions to this article.

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