Ultrastaging of negative pelvic lymph nodes to decrease the true prevalence of isolated paraaortic dissemination in endometrial cancer

https://doi.org/10.1016/j.ygyno.2019.05.008Get rights and content

Highlights

  • Ultrastaging pelvic lymph nodes in isolated paraaortic disease can identify occult metastasis.

  • Ultrastaging identified pelvic disease in 30% of patients with “isolated” paraaortic metastasis.

  • The prevalence of true isolated paraaortic metastasis is 1.8%.

Abstract

Objective

This study aimed to determine the prevalence of occult pelvic lymph node metastasis in patients with endometrial cancer (EC) with isolated paraaortic dissemination who underwent pelvic and paraaortic lymphadenectomy.

Methods

From 2004 to 2008, patients undergoing surgery for EC at our institution were prospectively treated according to a validated surgical algorithm relying on intraoperative frozen section. For the current study, we re-reviewed pathologic slides obtained at the time of diagnosis and performed ultrastaging of all negative pelvic lymph nodes to assess the prevalence of occult pelvic lymph node metastasis.

Results

Of 466 patients at risk for lymphatic dissemination, 394 (84.5%) underwent both pelvic and paraaortic lymphadenectomy. Of them, 10 (2.5%) had isolated paraaortic metastasis. Pathologic review of hematoxylin-eosin–stained slides identified 1 patient with micrometastasis in 1 of 18 pelvic lymph nodes removed. Ultrastaging of 296 pelvic lymph nodes removed from the 9 other patients (median [range], 32 [20–50] nodes per patient) identified 2 additional cases (1 with micrometastasis and 1 with isolated tumor cells), for a total of 3/10 patients (30%) having occult pelvic dissemination.

Conclusions

Ultrastaging and pathologic review of negative pelvic lymph nodes of patients with presumed isolated paraaortic metastasis can identify occult pelvic dissemination and reduce the prevalence of true isolated paraaortic disease. In the era of the sentinel lymph node (SLN) algorithm for EC staging, which incorporates ultrastaging of the SLNs removed, these findings demonstrate that use of the SLN algorithm can further mitigate the concern of missing cases of isolated paraaortic dissemination.

Introduction

Many patients with endometrial cancer (EC) presumed to be confined to the uterus actually have extrauterine disease [1]. Thus, in 1988 the International Federation of Gynecology and Obstetrics introduced the concept of surgical staging for EC, which replaced the clinical staging adopted in 1971 [2,3]. Comprehensive surgical staging includes hysterectomy, bilateral salpingo-oophorectomy, pelvic washing, and pelvic and paraaortic lymphadenectomy [4]. However, after >25 years the therapeutic role of lymphadenectomy is still under debate, and consensus is lacking among gynecologic oncologists on the extent of surgical staging [[5], [6], [7], [8]]. This controversy is mainly due to the results of 2 large, prospective trials comparing the addition of pelvic lymphadenectomy versus hysterectomy and bilateral salpingo-oophorectomy alone which failed to demonstrate survival benefits [9,10].

Therefore, the use of sentinel lymph node (SLN) mapping in EC has gained acceptance among gynecologists and is supported by numerous prospective and retrospective studies that observed low false-negative rates (<5%) and high negative predictive values (>95%) [11,12]. SLN mapping has revolutionized the staging process in presumed early-stage disease, largely replacing systematic pelvic and paraaortic lymphadenectomy in some institutions. Among the different techniques proposed for SLN mapping in EC, the use of cervical injection with indocyanine green is preferred [8,13] and has been recently recommended by a consensus of the Society of Gynecologic Oncology [14].

Despite the literature supporting the use of SLN, a main concern and criticism of SLN mapping using cervical dye injection is that it does not adequately map the paraaortic area and may potentially miss instances of isolated paraaortic disease [15]. The overall frequency of paraaortic lymph node dissemination has been described as between 0% and 17% [16]. Kumar at al [17] demonstrated that in the presence of pelvic metastasis, 51% of patients had paraaortic lymph node dissemination, whereas in the absence of pelvic metastasis, only 3% had isolated paraaortic lymph node dissemination [17]. Similarly, other studies and reviews have shown that the risk of isolated paraaortic node metastasis ranges from 1% to 5% [17,18].

A key component of the SLN algorithm proposed in the National Comprehensive Cancer Network guidelines for EC [19] is enhanced pathologic examination, also known as ultrastaging. This technique consists of evaluation for the presence of micrometastasis (tumor clusters >0.2–2.0 mm) and isolated tumor cells (single tumor cells or tumor clusters ≤0.2 mm) by immunohistochemistry (IHC) in lymph nodes that are negative at initial examination performed using hematoxylin-eosin (H&E) staining [20,21]. Ultrastaging was found to identify occult paraaortic metastasis in 73% of patients identified as being positive for pelvic node metastasis and negative for paraaortic node metastasis [22]. However, the prevalence of occult pelvic lymph node metastasis in patients with isolated paraaortic disease remains unexplored.

In the current study, we aimed to investigate whether pathologic review followed by ultrastaging of negative pelvic lymph nodes of patients with presumed isolated paraaortic disease could identify occult pelvic metastasis and decrease the prevalence of true isolated paraaortic disease.

Section snippets

Methods

This study was approved by the Mayo Clinic Institutional Review Board. The study cohort was identified by retrospectively searching our patient database for the records of consecutive patients who underwent surgical staging of EC at Mayo Clinic, Rochester, Minnesota, from January 2004 through December 2008 and who had not denied research authorization. Patients who received neoadjuvant therapy, had invasive synchronous cancer, or had stage IV disease were subsequently excluded. During this time

Results

From January 2004 to December 2008, 790 patients with EC were treated surgically at our institution and had research authorization; of these, 99 met the initial exclusion criteria and 225 were excluded because of low risk of lymphatic dissemination (Fig. 1). Among the 466 patients who were at risk for lymphatic dissemination and were candidates for complete lymphadenectomy, 28 had pelvic lymphadenectomy, 1 had paraaortic lymphadenectomy, and 394 (84.5%) had both; the other 43 had neither pelvic

Discussion

To our knowledge, this is the first study demonstrating that pathologic review and ultrastaging of pelvic lymph nodes of patients with isolated paraaortic dissemination can identify low-volume metastases that were not detected by routine pathologic examination at the time of diagnosis. In particular, with pathologic review and ultrastaging we detected low-volume metastases in the pelvic lymph nodes of 30% of patients with presumed “negative” pelvic lymph nodes and isolated paraaortic

Funding

This work was supported by the Small Grant Program, Mayo Clinic, Rochester, Minnesota. This publication was made possible by CTSA Grant Number UL1 TR000135 from the National Center for Advancing Translational Sciences (NCATS), a component of the National Institutes of Health (NIH). Its contents are solely the responsibility of the authors and do not necessarily represent the official view of NIH. Drs Leitao and Abu-Rustum are funded in part by the NIH/NCI Memorial Sloan Kettering Cancer Center

Role of the funding source

The funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Author contributions

Conceived and designed the study: Francesco Multinu, Jvan Casarin, Andrea Mariani.

Collected the data: Francesco Multinu, Jvan Casarin, Serena Cappuccio, Stefano Angioni, Gavino Faa, Andrea Mariani, Gary L. Keeney.

Contributed data or analysis tools: Francesco Multinu, Jvan Casarin, Andrea Mariani, Amy L. Weaver, Michaela E. McGree.

Writing, review and editing: Francesco Multinu, Jvan Casarin, Serena Cappuccio, Andrea Mariani, Mario M. Leitao Jr., Nadeem R. Abu-Rustum, Stefano Angioni, Gavino Faa,

Declaration of Competing Interest

All authors report no potential conflicts of interest. Jvan Casarin, MD, is a research fellow supported by University of Insubria, Varese, Italy, and Fondo Miglierina, Provincia di Varese, Italy.

References (33)

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