Stage I, grade 3 endometrioid adenocarcinoma of the endometrium: An analysis of clinical outcomes and patterns of recurrence

doi:10.1016/j.ygyno.2009.10.043

Gynecologic Oncology

Volume 116, Issue 1, January 2010, Pages 10-14

https://doi.org/10.1016/j.ygyno.2009.10.043 Get rights and content

Abstract

Objective

To study patterns of recurrence and survival outcomes in patients with surgical stage I, grade 3 endometrioid adenocarcinoma of the endometrium (EA) treated with various treatment modalities.

Methods

A retrospective multi-institutional study of surgical stage I, grade 3 EA patients diagnosed between1988 and 2006 was performed. Demographic, clinicopathologic, treatment and outcome data were collected. After surgery, patients were treated with either observation or radiotherapy (vaginal brachytherapy, whole pelvic or both).

Results

One hundred seventy-six patients were collected with a median age of 68 years. Twenty-six (15%) were stage IA, 96 (54%) IB and 54 (31%) IC. Sixty-one patients (35%) had lymphovascular space invasion (LVSI) and a mean of 18.9 lymph nodes (LNs) was removed. Seventy-eight patients (44%) were observed while 98 (56%) were treated with radiotherapy, the majority (n = 51) receiving brachytherapy. After a median follow-up of 58 months, 20 recurrences (11%) were noted. Ninety percent of recurrences occurred in Stage IB/IC patients. The median time to recurrence was 22.5 months (5–74.5) and 80% of recurrences were extra-pelvic. There was no significant difference in recurrence based upon treatment modality or LVSI. Majority of recurrences were not salvaged as 75% (12/16) died of their disease with a median time of recurrence to death of 8 months.

Conclusions

Patients with stage IB/IC, grade 3 endometrioid adenocarcinoma have a significant risk for extra-pelvic recurrence. Most patients will not be salvaged and will succumb to their disease, suggesting that current loco-regional adjuvant treatment strategies are not optimal and evaluation of more systemic therapies is warranted.

Introduction

Endometrial carcinoma is the most common gynecologic malignancy in the United States. In 2008, over 40,000 women were diagnosed with endometrial cancer and an estimated 7500 died from their disease [1]. Initial management is surgical, with hysterectomy, bilateral salpingo-oopherectomy and lymph node assessment [2]. Recommendations for adjuvant treatment (either radiation or adjuvant chemotherapy with or without radiation) are usually reserved for those women with a moderate to high risk for recurrence, including those patients with extrapelvic disease [3], [4], [5], [6], [7].

Most patients present with early-stage, low-grade (grade 1) disease and experience 5-year survival rates approaching 80–90% [8], [9], [10]. However, a subgroup of patients will present with grade 3 disease, a distinct, more biologically aggressive endometrioid subtype which has a higher risk of both locoregional and distant relapse and poorer survival outcomes. There are several studies suggesting that histologic grade is one of the most important prognostic factors for recurrence and outcomes in patients with early-stage endometrial cancer. Fujimoto et al. demonstrated that patients with stage I–III, grade 3 disease experienced higher locoregional recurrence rates than patients with lower grade, similarly staged disease [11]. Grigsby et al. reported 5-year progression-free survival rates for grade 3 tumors with superficial and deep myometrial invasion of 69% and 42%, respectively, compared with 70% to 95% for the other stage I subgroups [12]. Furthermore, Creutzberg et al. confirmed that grade 3 endometrioid histology was one of the most adverse prognostic factors for recurrence, with a HR of 5.4 [13]. These studies cumulatively demonstrate that patients with early-stage, grade 3 endometrioid adenocarcinoma of the endometrium have poorer outcomes than those with early-stage, lower grade disease. However, little is still understood about the clinical behavior and optimal treatment strategies for women with stage I, grade 3 disease. Specifically, patterns of recurrence have not been well-defined in patients with comprehensively staged grade 3 disease. Therefore, the primary objectives of our study were to identify the patterns of recurrence and determine if clinical outcomes of women with surgical stage I, grade 3 endometrial cancer vary by treatment modality. A secondary objective was to determine the survival outcomes of patients with locoregional versus distant recurrences.

Section snippets

Methods and materials

A multi-institutional retrospective study was performed involving 5 academic centers: Cleveland Clinic, Cleveland, OH; University Hospitals at Case Medical Center, Cleveland, OH; Ohio State University Medical Center, Columbus, OH; University of Oklahoma Health Sciences Center, Oklahoma City, OK; and Duke University Medical Center, Durham, NC. Tumor registry and pathology databases were used to identify all women with stage I, grade 3 endometrioid adenocarcinoma of the endometrium diagnosed

Results

A total of 176 patients were identified. Patient characteristics and surgicopathologic data are described in Table 1. The median age of this group was 68 years (range 35–93 years) and the majority of patients were Caucasian (86%). Twenty-six women (15%) were diagnosed with stage IA, 96 (54%) with IB and 54 (31%) with IC disease. Sixty-one patients (35%) were noted to have lymphovascular space invasion (LVSI) with a mean tumor size of 4.1 cm and a mean of 18.9 lymph nodes (LNs) removed per

Discussion

In this multi-institutional retrospective analysis, we present the largest series of patients with early-stage, grade 3 endometrioid adenocarcinoma of the endometrium and define the patterns of recurrence and survival outcomes for this subgroup. The overall recurrence rate for surgical stage IA-IC patients was 8–13%. Patients with stage IB/IC disease had a significant risk for extra-pelvic recurrence and most were not salvaged and succumbed to their disease. Furthermore, on multivariate

Conflict of interest statement

No conflicts of interest are noted for any author.

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Absence of prognostic value of lymphovascular space invasion in patients with endometrial cancer and negative sentinel lymph nodes
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In addition studies evaluated the prognostic value of LVSI in patients with negative lymph nodes but came to different conclusions [10–18]. Only 5 of these studies included patients with negative nodes in cohorts that were completely staged, using either sentinel lymph node (SLN) or complete lymph node dissection (LND), but did not compare between the two techniques [10,11,14–16]. SLN mapping has emerged in the past two decades as an alternative procedure to LND and is associated with less morbidity while preserving and maybe improving staging information [19–23].
To evaluate if the prognostic value of lymphovascular space invasion (LVSI) is different in endometrial cancer patients with negative lymph nodes following sentinel lymph node (SLN) mapping or lymph node dissection (LND) as staging procedure.
A retrospective study of 510 patients diagnosed with endometrial carcinoma in our institution between 2007 and 2014. We excluded patients that were diagnosed with positive nodes (Stage IIIc). We compared patients' characteristics and survival outcomes as function of their LVSI status (positive LVSI vs negative LVSI subgroups) in each cohort separately.
413 patients met the inclusion criteria, out of whom 239 underwent SLN and 174 patients underwent LND only. In the SLN group, life table analysis showed 5-year OS and PFS of 80% and 72% in patients with LVSI compared to 96%, and 93% without LVSI. Same trend was observed among patients with LND with 5-year OS and PFS of 74% and 64% in patients with LVSI compared to 97%, and 90% without LVSI. On multivariable analysis, adjusted for age, FIGO stage, grade and maximal tumor size, the favorable survival of negative LVSI remained only in the LND cohort (SLN cohort: HR 1.2, CI [0.3–4.0], P = 0.8 and HR 1.7, CI [0.7–4.3], p = 0.2 for OS and PFS, respectively; LND cohort: HR 3.1, CI [1.4–6.5], p < 0.001 and HR 2.5, CI [1.2–4.9], p = 0.01 for OS and PFS, respectively).
The prognostic value of LVSI disappears when patients undergo staging with SLN and are found to have negative nodes in contrast to those who have undergone LND. Future studies should confirm our observation on patients with negative sentinel nodes, and plan on tailoring adjuvant treatment to this specific subgroup.
Unique prognostic features of grade 3 endometrioid endometrial carcinoma: Findings from 101 consecutive cases at a Japanese tertiary cancer center
2021, Taiwanese Journal of Obstetrics and Gynecology
The prognosis of and optimal treatment for grade 3 endometrioid endometrial carcinoma (G3EEC) currently remain unclear. This study aimed to clarify the baseline recurrence risk in patients with early-stage (stage I–II) G3EEC without adjuvant therapy and the prognosis of patients with advanced-stage (stage III–IV) G3EEC.
A total of 101 patients with pathologically confirmed G3EEC from 1997 to 2018 were identified. Their clinicopathological characteristics and survival outcomes were reviewed retrospectively. Disease-free survival and overall survival values were estimated according to the Kaplan–Meier method and compared using a log-rank test.
Recurrence was observed in eight (13%) of 63 patients with early-stage G3EEC, none of whom had received adjuvant therapy. The 5-year disease-free survival and 5-year overall survival rates for these patients were 86.7% and 96.4%, respectively. Recurrence was also observed in 12 (41%) of 29 patients with stage III G3EEC. The 5-year overall survival rates for stage III patients who underwent adjuvant chemotherapy and adjuvant radiotherapy were 85.6% and 42.9%, respectively. The 3-year overall survival rate among stage IVB patients was only 12.7% despite multidisciplinary treatment provision.
Our study newly demonstrates that patients with early-stage G3EEC have a favorable prognosis and a low recurrence rate in the absence of adjuvant therapy. In patients with stage III G3EEC, adjuvant chemotherapy was more beneficial than adjuvant radiotherapy. The poor prognosis of patients with stage IV G3EEC indicates the need for more effective treatments. Unique therapeutic approaches based on staging are recommended for treatment of G3EEC.
Clinicopathological significance of PSF3 expression in uterine endometrial carcinomas
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However, for patients between these 2 groups, treatment performance is sometimes not as good as would be expected [20,21]. Therefore, it is anticipated that identification of suitable histopathologic biomarkers would allow clinicians to distinguish patients who need appropriate therapy to improve their outcome [19,22]. In this study, we showed that high expression of PSF3 was associated with poor clinical outcomes in all types of ECs as well as in patients with FIGO stages I and II.
PSF3 (Partner of SLD Five 3) is a member of the heterotetrameric complex termed GINS. Previous studies have shown that PSF3 is up-regulated in several cancers and is associated with tumor malignancy. However, the clinicopathological significance of PSF3 expression in endometrial lesions is still poorly understood. To investigate whether PSF3 could serve as a useful biomarker for endometrial carcinomas, we performed immunohistochemical analysis of PSF3 expression. In 155 cases of endometrial carcinomas (ECs), the mean tumor proportion score of PSF3 expression was 30.7% in G1 endometrioid carcinoma, 55.0% in G2 endometrioid carcinoma, 59.0% in G3 endometrioid carcinoma, and 58.9% in nonendometrioid carcinomas. In 25 cases of atypical hyperplasia, the mean tumor proportion score of PSF3 expression was significantly lower (10.4%). High expression of PSF3 was associated with more advanced pathologic T stage (P = .000), lymphatic invasion (P = .001), and poor clinical outcomes such as shorter relapse-free survival (P = .000) and overall survival (P = .001). When we compared the immunostaining of PSF3 and Ki-67, the proportions of PSF3-positive cells in tumor epithelial cells were comparable to those of Ki-67–positive cells. However, PSF3-positive cells were selectively found in tumor cells, whereas Ki-67–positive cells were also found in tumor stromal cells. These results demonstrated that PSF3 immunostaining was valuable as a histopathologic marker for differential diagnosis between atypical hyperplasia and ECs, for tumor histologic grading, and for determining a patient's prognosis. PSF3 may play a crucial role in tumor progression in EC.
Pros and cons of vaginal brachytherapy after external beam radiation therapy in endometrial cancer
2016, Gynecologic Oncology
A large number of studies have looked at the role of radiation therapy in the treatment of endometrial cancer. One particular radiation strategy in common practice is the use of adjuvant external beam (EB) radiotherapy followed by vaginal brachytherapy (VB). While the addition of VB to EB provides a theoretical benefit of a localized boost with higher focused dose to an area of potentially high recurrence risk, a randomized clinical trial to compare outcomes and toxicities of EB + VB vs. EB alone is lacking. The goal of this review is to present the current data for and against the use of this combined radiation modality and to provide some preliminary evidence regarding which patient populations may be most likely to benefit.
Staging for endometrial cancer: The controversy around lymphadenectomy - Can this be resolved?
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Endometrial cancer remains the most common malignancy of the female genital tract. Lymph node metastasis is one of the most important prognostic factors, and stratification into pelvic lymph node invasion (stage IIIC1) and para-aortic lymph node invasion (stage IIIC2) improved the predictive value of the 2009 International Federation of Gynecology and Obstetrics (FIGO) classification.
Radiological examination methods such as magnetic resonance imaging and positron emission tomography–computed tomography do not have good-enough sensitivity to avoid lymphadenectomy for the assessment of lymph node invasion. Prediction scores are becoming increasingly valuable to exclude lymph node metastasis in low-risk groups, and biomarkers could help to identify patients with high-risk lymph node metastatic probability.
The therapeutic role of lymph node dissection remains a matter of debate. Several end points can be considered to evaluate the opportunity of lymphadenectomy in endometrial cancer.
First, we compare survival according to the realization, the extent, and the numbers of nodes removed during lymphadenectomy. Second, we assess the opportunity of lymphadenectomy in order to tailor adjuvant treatment modalities. Third, we analyze the surgical complication rate after pelvic lymphadenectomy.
A suggested modification to FIGO stage i endometrial cancer
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Citation Excerpt :
Previous studies evaluating LVSI have shown mixed results. Rasool et al. examined 147 patients with endometrial cancer and found that LVSI was not predictive of recurrence or poor outcomes [6], whereas Gadducci et al. found that LVSI was associated with distant, hematogenous failures [7]. In a multivariate analysis performed by Kondalsamy-Chennakesavan et al. to predict the risk of relapse, LVSI was an independent prognostic factor [8].
FIGO stage I endometrial cancers are divided into two substages, regardless of the presence or absence of lymphovascular space invasion (LVSI). The aim of this study was to investigate whether stratification based on the LVSI status would better predict mortality.
Using a multicentric database, we identified patients who underwent endometrial cancer operations between 2000 and 2010. The staging performance was quantified with respect to discrimination.
The study cohort included 508 patients (198 with LVSI-positive tumors and 310 with LVSI-negative tumors). The survival difference between the stage I patients with LVSI-positive and LVSI-negative tumors was highly significant (81% and 97%, respectively P = .009), whereas the difference between the stage I patients with tumors invading greater or less than half of the myometrium was not (87% and 96%, respectively P = 0.09). The 5-year OS rates for the patients with LVSI-negative tumors invading less than half of the myometrium, with LVSI-negative tumors invading more than half of the myometrium and with LVSI-positive invading more than or less than half of the myometrium were 98%, 95%, and 81%, respectively (P = .03). Separating the LVSI-negative and LVSI-positive tumors would improve discrimination (concordance index, 77% vs. 75%, respectively, using the actual staging system).
A LVSI-positive status has a significantly worse prognosis. In this study, the distinction by LVSI status appears to be more relevant than the distinction between stages IA and IB for predicting survival in stage I endometrial cancer. This difference in prognosis would favor restaging these two entities.

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Stage I, grade 3 endometrioid adenocarcinoma of the endometrium: An analysis of clinical outcomes and patterns of recurrence

Abstract

Objective

Methods

Results

Conclusions

Introduction

Section snippets

Methods and materials

Results

Discussion

Conflict of interest statement

Int. J. Radiat. Oncol. Biol. Phys.

Obstet. Gynecol.

Gynecol. Oncol.

Int. J. Radiat. Oncol. Biol. Phys.

Int. J. Radiat. Oncol. Biol. Phys.

Int. J. Radiat. Oncol. Biol. Phys.

Gynecol. Oncol.

Int. J. Radiat. Oncol. Biol. Phys.

Gynecol. Oncol.

Gynecol. Oncol.

Cancer statistics, 2008

CA Cancer J. Clin

Clinical management guidelines for obstetrician-gynecologists, number 65, August 2005: management of endometrial cancer

Obstet. Gynecol.