Management of Early Stage, High-Risk Endometrial Carcinoma: Preoperative and Surgical Considerations

Endometrial cancer is the most common gynecologic malignancy in the developed world. Most cases are diagnosed at an early stage and have low-grade histology, portending an overall excellent prognosis. There exists a subgroup of patients with early, high-risk disease, whose management remains controversial, as current data is clouded by inclusion of early stage tumors with different high-risk features for recurrence, unstandardized protocols for surgical staging, and an evolving staging system by which we are grouping these patients. Here, we present preoperative and intraoperative considerations that should be taken into account when planning surgical management for this population of patients.

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Unique Molecular Features in High-Risk Histology Endometrial Cancers

Cancers ◽

10.3390/cancers11111665 ◽

2019 ◽

Vol 11 (11) ◽

pp. 1665 ◽

Cited By ~ 3

Author(s):

Pooja Pandita ◽

Xiyin Wang ◽

Devin E. Jones ◽

Kaitlyn Collins ◽

Shannon M. Hawkins

Keyword(s):

Endometrial Cancer ◽

High Risk ◽

Early Stage ◽

Standard Of Care ◽

The United States ◽

Model Systems ◽

Low Grade ◽

Cell Of Origin ◽

Molecular Features ◽

The Impact

Endometrial cancer is the most common gynecologic malignancy in the United States and the sixth most common cancer in women worldwide. Fortunately, most women who develop endometrial cancer have low-grade early-stage endometrioid carcinomas, and simple hysterectomy is curative. Unfortunately, 15% of women with endometrial cancer will develop high-risk histologic tumors including uterine carcinosarcoma or high-grade endometrioid, clear cell, or serous carcinomas. These high-risk histologic tumors account for more than 50% of deaths from this disease. In this review, we will highlight the biologic differences between low- and high-risk carcinomas with a focus on the cell of origin, early precursor lesions including atrophic and proliferative endometrium, and the potential role of stem cells. We will discuss treatment, including standard of care therapy, hormonal therapy, and precision medicine-based or targeted molecular therapies. We will also discuss the impact and need for model systems. The molecular underpinnings behind this high death to incidence ratio are important to understand and improve outcomes.

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Racial Differences in Oncogene Mutations Detected in Early-Stage Low-Grade Endometrial Cancers

International Journal of Gynecological Cancer ◽

10.1097/igc.0b013e31826b1110 ◽

2012 ◽

Vol 22 (8) ◽

pp. 1367-1372 ◽

Cited By ~ 13

Author(s):

Michele L. Cote ◽

Govindaraja Atikukke ◽

Julie J. Ruterbusch ◽

Sara H. Olson ◽

Shawnita Sealy-Jefferson ◽

...

Keyword(s):

African American ◽

Endometrial Cancer ◽

Endometrial Carcinoma ◽

African American Women ◽

Racial Differences ◽

Early Stage ◽

Fisher Exact Test ◽

Low Grade ◽

Urban Hospital ◽

American Women

ObjectiveTo describe the pattern and frequency of oncogene mutations in white and African American women with endometrial cancer and to determine if racial differences in oncogene mutations exist among women with pathologically similar tumors.MethodsPatients with endometrial cancer from a large urban hospital were identified through medical records, and representative formalin-fixed paraffin-embedded tumor blocks were retrieved. The study sample included 150 patients (84 African Americans) who underwent total abdominal hysterectomy for endometrial cancer. The Sequenom MassARRAY system and the OncoCarta Assay version 1.0 (Sequenom) were used to test for 238 mutations in 19 common oncogenes. The χ2test and the Fisher exact test were used to assess differences in distribution of variables by race and oncogene mutation status.ResultsThere were 20 mutations identified in 2 oncogenes (PIK3CAandKRAS) in tumors from 19 women (12.7%). Most of the mutations were found inPIK3CA(16/20). Thirteen percent of endometrioid tumors harbored mutations (11PIK3CAand 2KRAS) as did 29% of the malignant mixed Mullerian tumors (3PIK3CAand 1KRAS). There were no observed mutations in serous, clear cell, or mucinous tumor types. Among low-grade endometrioid cancers, tumors from African American patients were significantly associated with harboring either aKRASorPIK3CAmutation (P= 0.04), with 7PIK3CAmutations and all 4KRASmutations identified in African American women.ConclusionsThis study provides preliminary evidence that oncogene mutation frequency of some subtypes of histologically similar endometrial carcinoma differ by race. Additional studies are needed to further explore this phenomenon in patients with endometrial carcinoma.

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A Deceptive Spread: Myoinvasion of Endometrial Carcinoma Imitating Adenoma Malignum

International Journal of Surgical Pathology ◽

10.1177/1066896919886113 ◽

2019 ◽

Vol 28 (3) ◽

pp. 284-286

Author(s):

Pratik Q. Deb ◽

Jenna Z. Marcus ◽

Yasmin Abedin ◽

Debra S. Heller

Keyword(s):

Endometrial Carcinoma ◽

Early Stage ◽

Current Treatment ◽

Cervical Adenocarcinoma ◽

Low Grade ◽

Endometrioid Carcinoma ◽

Simultaneous Presence ◽

Cervical Stroma ◽

Adenoma Malignum ◽

Developed World

Endometrioid type of endometrial carcinoma is the most common form of uterine malignancy. The majority of patients in the developed world present with the low-grade, low-stage type of this malignancy. The current treatment of early-stage endometrioid carcinoma provides most patients with a favorable outcome. One of the important factors that determine the outcome of early-stage endometrial carcinoma is the involvement of cervical stroma. One of the very rare forms of cervical stromal involvement by endometrioid carcinoma is termed “adenoma malignum type” invasion due to its similarity to the infamously deceptive type of cervical adenocarcinoma called adenoma malignum. Since adenoma malignum is often discovered incidentally, finding adenoma malignum type of myoinvasion may deceive a pathologist to diagnose the simultaneous presence of endometrial carcinoma and adenoma malignum in the same patient as 2 separate entities. Also, this type of myoinvasion may be missed altogether for its subtle nature. In this article, we report a case of low-grade, low-stage endometrioid carcinoma with adenoma malignum type of myoinvasion. We have pointed out the subtle nature of this lesion and the important features to remember to successfully identify it.

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Ovarian conservation for young women with early-stage low-grade endometrial cancer: A proposal for a two-step approach

American Journal of Obstetrics and Gynecology ◽

10.1016/j.ajog.2020.12.1213 ◽

2021 ◽

Author(s):

Koji Matsuo ◽

Rachel S. Mandelbaum ◽

Shinya Matsuzaki ◽

Maximilian Klar ◽

Lynda D. Roman ◽

...

Keyword(s):

Endometrial Cancer ◽

Young Women ◽

Early Stage ◽

Low Grade ◽

Ovarian Conservation

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Defining optimal adjuvant treatment for high-risk early-stage endometrial cancer

Gynecologic Oncology ◽

10.1016/s0090-8258(21)00877-5 ◽

2021 ◽

Vol 162 ◽

pp. S123-S124

Author(s):

Olivia Khouri ◽

Anne Van Arsdale ◽

Nicole Vilardo ◽

Divya Gowthaman ◽

Gregory Gressel ◽

...

Keyword(s):

Endometrial Cancer ◽

High Risk ◽

Adjuvant Treatment ◽

Early Stage ◽

Early Stage Endometrial Cancer

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Lymphadenectomy in Early-Stage Intermediate-/High-Risk Endometrioid Endometrial Cancer: Clinical Characteristics and Outcomes in an Australian Cohort

International Journal of Gynecological Cancer ◽

10.1097/igc.0000000000001039 ◽

2017 ◽

Vol 27 (7) ◽

pp. 1379-1386 ◽

Cited By ~ 1

Author(s):

Rhonda Farrell ◽

Suzanne C. Dixon ◽

Jonathan Carter ◽

Penny M. Webb

Keyword(s):

Overall Survival ◽

Endometrial Cancer ◽

High Risk ◽

Adjuvant Treatment ◽

Cox Regression ◽

Early Stage ◽

Cox Regression Analysis ◽

Cancer Study ◽

Stage Ib ◽

Australian Cohort

ObjectiveThe role of lymphadenectomy (LND) in early-stage endometrial cancer (EC) remains controversial. Previous studies have included low-risk patients and nonendometrioid histologies for which LND may not be beneficial, whereas long-term morbidity after LND is unclear. In a large Australian cohort of women with clinical early-stage intermediate-/high-risk endometrioid EC, we analyzed the association of LND with clinicopathological characteristics, adjuvant treatment, survival, patterns of disease recurrence, and morbidity.Materials and MethodsFrom a larger prospective study (Australian National Endometrial Cancer Study), we analyzed data from 328 women with stage IA grade 3 (n = 63), stage IB grade 1 to 3 (n = 160), stage II grade 1 to 3 (n = 71), and stage IIIC1/2 grade 1 to 3 (n = 31/3) endometrioid EC. Overall survival (OS) was estimated using Kaplan-Meier methods. The association of LND with OS was assessed using Cox regression analysis adjusted for age, stage, grade, and adjuvant treatment. The association with risk of recurrent disease was analyzed using logistic regression adjusted for age, stage, and grade. Morbidity data were analyzed using χ2 tests.ResultsMedian follow-up was 45.8 months. Overall survival at 3 years was 93%. Lymphadenectomy was performed in 217 women (66%), 16% of this group having positive nodes. Median node count was 12. There were no significant differences in OS between LND and no LND groups, or by number of nodes removed. After excluding stage IB grade 1/2 tumors, there was no association between LND and OS among a “high-risk” group of 190 women with a positive node rate of 24%. However, a similar cohort (n = 71) of serous EC in the Australian National Endometrial Cancer Study had improved survival after LND. Women who underwent LND had significantly higher rates of critical events (5% vs 0%, P = 0.02) and lymphoedema (23% vs 4%, P < 0.0001).ConclusionsIn this cohort with early-stage intermediate-/high-risk endometrioid EC, LND did not improve survival but was associated with significantly increased morbidity.

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Isolated vulvar metastasis after robot-assisted laparoscopic hysterectomy for low grade, early stage endometrial cancer: a case report and review of the literature

European Journal of Gynaecological Oncology ◽

10.31083/j.ejgo.2021.03.2254 ◽

2021 ◽

Vol 42 (3) ◽

pp. 418

Keyword(s):

Endometrial Cancer ◽

Case Report ◽

Early Stage ◽

Laparoscopic Hysterectomy ◽

Low Grade ◽

Review Of The Literature ◽

Robot Assisted ◽

Early Stage Endometrial Cancer

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Redefining Stage I Endometrial Cancer: Incorporating Histology, a Binary Grading System, Myometrial Invasion, and Lymph Node Assessment

International Journal of Gynecological Cancer ◽

10.1097/igc.0b013e3182a5055e ◽

2013 ◽

Vol 23 (9) ◽

pp. 1620-1628 ◽

Cited By ~ 14

Author(s):

Joyce N. Barlin ◽

Robert A. Soslow ◽

Megan Lutz ◽

Qin C. Zhou ◽

Caryn M. St. Clair ◽

...

Keyword(s):

Endometrial Cancer ◽

Myometrial Invasion ◽

Staging System ◽

Stage I ◽

Low Grade ◽

List Type ◽

High Grade ◽

High Grade Carcinoma ◽

Concordance Probability ◽

Grade 3

ObjectiveWe propose a new staging system for stage I endometrial cancer and compare its performance to the 1988 and 2009 International Federation of Gynecology and Obstetrics (FIGO) systems.MethodsWe analyzed patients with 1988 FIGO stage I endometrial cancer from January 1993 to August 2011. Low-grade carcinoma consisted of endometrioid grade 1 to grade 2 lesions. High-grade carcinoma consisted of endometrioid grade 3 or nonendometrioid carcinomas (serous, clear cell, and carcinosarcoma). The proposed system is as follows:IA. Low-grade carcinoma with less than half myometrial invasionIA1: Negative nodesIA2: No nodes removedIB. High-grade carcinoma with no myometrial invasionIB1: Negative nodesIB2: No nodes removedIC. Low-grade carcinoma with half or greater myometrial invasionIC1: Negative nodesIC2: No nodes removedID. High-grade carcinoma with any myometrial invasionID1: Negative nodesID2: No nodes removedResultsData from 1843 patients were analyzed. When patients were restaged with our proposed system, the 5-year overall survival significantly differed (P < 0.001): IA1, 96.7%; IA2, 92.2%; IB1, 92.2%; IB2, 76.4%; IC1, 83.9%; IC2, 78.6%; ID1, 81.1%; and ID2, 68.8%. The bootstrap-corrected concordance probability estimate for the proposed system was 0.627 (95% confidence interval, 0.590–0.664) and was superior to the concordance probability estimate of 0.530 (95% confidence interval, 0.516–0.544) for the 2009 FIGO system.ConclusionsBy incorporating histological subtype, grade, myometrial invasion, and whether lymph nodes were removed, our proposed system for stage I endometrial cancer has a superior predictive ability over the 2009 FIGO staging system and provides a novel binary grading system (low-grade including endometrioid grade 1–2 lesions; high-grade carcinoma consisting of endometrioid grade 3 carcinomas and nonendometrioid carcinomas).

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Undifferentiated endometrial carcinoma: a National Cancer Database analysis of prognostic factors and treatment outcomes

International Journal of Gynecological Cancer ◽

10.1136/ijgc-2019-000465 ◽

2019 ◽

Vol 29 (7) ◽

pp. 1126-1133

Author(s):

Mariam AlHilli ◽

Paul Elson ◽

Lisa Rybicki ◽

Sudha Amarnath ◽

Bin Yang ◽

...

Keyword(s):

Endometrial Cancer ◽

Prognostic Factors ◽

Adjuvant Therapy ◽

Endometrial Carcinoma ◽

Treatment Outcomes ◽

Survival Data ◽

Early Stage ◽

National Cancer Database ◽

Early Stage Disease ◽

Prognostic Groups

BackgroundUndifferentiated endometrioid endometrial carcinoma of the uterus is a rare, highly aggressive, and under-recognized subtype of endometrial cancer.ObjectiveThis study evaluates survival, prognostic factors for survival, and treatment outcomes associated with undifferentiated endometrial cancer.MethodsThe National Cancer Database was queried to identify patients with undifferentiated endometrial cancer who underwent definitive primary surgical treatment. Patients with all other histologic subtypes or incomplete treatment data were excluded. Univariable and multivariable Cox proportional hazards analyses were used to determine independent prognostic factors for survival. Points for each prognostic factor were assigned from regression coefficients in the final multivariable model and summed for a total score. Recursive partitioning analysis was used to determine cut-offs in the score to identify unique prognostic groups.ResultsAmong 349 404 women diagnosed with endometrial cancer from 2004 to 2013, 3994 (1.1%) met the criteria for diagnosis of undifferentiated endometrial cancer and 3486 had survival data. Median age at diagnosis was 65 years (interquartile range (IQR) 57–74) and 58% of patients had early stage disease. Median interval from diagnosis to surgery was 3.7 weeks (IQR 2.0–5.7). Five year overall survival was 57% (standard error (SE) 1%). Stage was the strongest predictor of survival, with a 15–20% decrement in 5 year survival for each advance in stage. Stage, age, race, and presence of comorbidities were independent predictors of survival and were used to categorize patients into five prognostic groups. Adjuvant therapy was associated with improved survival across most disease stages and prognostic groups. Multimodal adjuvant therapy was superior to unimodal treatment particularly in advanced stage unfavorable and very unfavorable groups.ConclusionIn women with undifferentiated endometrial cancer, survival is primarily driven by stage. Despite the poor overall prognosis of undifferentiated endometrial cancer, multimodal adjuvant therapy is a key component of treatment.

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