Low-volume disease in endometrial cancer: The role of micrometastasis and isolated tumor cells

Highlights

• Sentinel node mapping improves detection of stage IIIC endometrial cancer.

• Patients at low risk of lymphatic spread are more likely to be diagnosed with low volume disease.

• Patients with micrometastasis in sentinel nodes should be receive adjuvant treatment.

• Patients with isolated tumor cells in sentinel nodes deserve to be treated on the basis of uterine factors.

Abstract

Nodal assessment represents an integral part of staging procedure for endometrial cancer. The widespread diffusion of sentinel node mapping determinates a phenomenon of migration from stage I to stage III disease, especially for low-risk endometrial cancer patients. The adoption of sentinel node mapping and pathological ultrastaging increase the detection of low volume disease (i.e., micrometastasis and isolated tumor cells), being low volume disease detected in >30% of patients with positive nodes. The prognostic role of low volume disease is discussed as well as the possible adjuvant strategies for patients diagnosed with micrometastasis and isolated tumor cells. The role of further prospective treatments in endometrial cancer, including molecular and genetic profiling, is critically reviewed.

Introduction

Endometrial cancer (EC) is the most common gynecological malignancy in developed countries, with >55,000 new cases diagnosed every year in the United States (U.S.) [1,2]. EC incidence is increasing: in the U.S. its incidence has increased of >20,000/year cases from 2007 to 2017 [[1], [2], [3]], and the Centers for Disease Control and Prevention (CDC) estimates that uterine cancer death rates increased approximately 1.1% per year in the U.S. [4].

Surgery represents the main step of the treatment for EC [4,5]. Hysterectomy (with or without salpingo-oophorectomy) allows tumor removal and can be useful to tailor adjuvant treatments. The role of retroperitoneal staging is still debated [4,5]. In 1988, the International Federation of Gynecology and Obstetrics (FIGO) introduced the concept of surgical staging for EC [6]. In 2005, the American College of Obstetricians and Gynecologists (ACOG) recommended surgical staging as an important part of EC management [7]. In 2015, the last practice bulletin published by the committee ACOG in association with Society of Gynecologic Oncology (SGO) recommended the importance of retroperitoneal staging, reporting that “the initial management of endometrial cancer should include comprehensive surgical staging” [8]. However, randomized controlled trials failed to demonstrate the therapeutic role of lymphadenectomy in EC [9,10]. The cumulative results of these trials showed that the execution of lymphadenectomy increases the risk of developing postoperative morbidity (including lymphoceles, lymphoedema and lymphorrhagia) without significant impacts on oncologic outcomes [9,10]. In the recent years several publications showed that sentinel node mapping is an effective method to identify disease harboring in the lymph nodes, which may allow us to avoid the performance of lymphadenectomy [[11], [12], [13], [14], [15], [16], [17], [18], [19], [20]].

The most recent guidelines published by the National Comprehensive Cancer Network (NCCN introduced), with a level IIB evidence, acknowledge the concept of sentinel node mapping, stating that “The role of sentinel node mapping in endometrial carcinoma is under evaluation, sentinel node mapping can be considered for the surgical staging of apparent uterine-confined malignancy when there is no metastasis demonstrated by imaging studies or no obvious extra-uterine disease at exploration” [21]. To date, several retrospective experiences underline that sentinel node mapping upholds oncologic results of standard lymphadenectomy, minimizing surgery-related morbidity [[11], [12], [13], [14], [15], [16], [17], [18], [19], [20]]. Furthermore, pathological ultrastaging of sentinel nodes result in a more sensitive and accurate identification of lymphatic disease in comparison to standard lymphadenectomy [[22], [23], [24]]. In fact, the adoption of sentinel node mapping allows to identify low volume disease (i.e., micrometastasis and isolated tumor cells) not detectable via conventional examinations. However, the prognostic value and therapeutic implications related of the detection of low volume disease in EC is still controversial [[25], [26], [27]]. Here, we sought to review the current evidence regarding the importance of pathological ultrastaging, and the role of micrometastasis and isolated tumor cells in EC. Further perspective in EC managements are discussed as well.