Endometrial Cancer Characteristics and Risk of Recurrence

The Role of Epigenetic Silencing of MLH1

Lindsay E. Borden, MD; Tonja M. Locklear, PhD; Douglas J. Grider, MD; Janet L. Osborne, MD; Erin J. Saks, MD; Fidel A. Valea, MD; David A. Iglesias, MD

Disclosures

Am J Clin Pathol. 2022;157(1):90-97.

Abstract and Introduction

Abstract

Objectives: To describe clinicopathologic characteristics and survival outcomes of endometrial adenocarcinomas stratified by mismatch repair (MMR) status.

Methods: Single-institution, retrospective study of all women with endometrioid adenocarcinomas treated from January 2012 through December 2017. Patients were categorized into one of three groups based on MMR testing: intact MMR expression (MMR+), probable MMR mutation (MMR–), or MLH1 hypermethylation (hMLH1+). Demographics, pathologic characteristics, recurrence rates, and survival differences were analyzed.

Results: In total, 316 women were included in the analysis: 235 (74.4%) patients in the MMR+ group, 10 (3.1%) in the MMR– group, and 71 (22.5%) in the hMLH1+ group. Patients with hMLH1+ were significantly older, exhibited higher-grade histology and presence of lymphovascular space invasion, and were more likely to have received adjuvant treatment. The early stage hMLH1+ patients were more likely to recur (15.3% hMLH1+ vs 2.3% MMR+ vs 12.5% MMR–, P < .001). Hypermethylation remained a significant predictor of recurrence in multivariable analysis (odds ratio, 5.09; 95% confidence interval [CI], 1.54–16.86; P = .008). Recurrence-free survival was significantly reduced in early stage hMLH1+ (hazard ratio, 7.40; 95% CI, 2.80–21.62; P < .001).

Conclusions: Women with hMLH1+ endometrial cancer have worse prognostic features and recur more frequently, even in patients traditionally considered low risk for recurrence.

Introduction

Endometrial cancer is the most common gynecologic malignancy in the United States, with 61,880 estimated new cases in 2019 and 12,160 estimated deaths.^[1] Approximately 3% to 5% of endometrial cancers may be attributable to Lynch syndrome, characterized by a deleterious germline mutation in a gene coding for mismatch repair (MMR) proteins, which results in an increased lifetime risk of endometrial, colon, and breast cancers, as well as other malignancies.^[2] Identification of these higher-risk patients and families has the advantage of allowing for appropriate patient counseling and informing decisions related to cancer screening, possible risk reduction strategies, and therapeutic options. Historically, higher-risk individuals who would be candidates for germline genetic testing were identified based on the patient's personal and family history. However, given the concern for possibly missing a proportion of at-risk individuals and their families based on history alone, many centers have adopted universal tumor-based screening of patients diagnosed with endometrial and/or colon cancers. MMR testing is a critical step in the identification of the Lynch syndrome proband and sporadic microsatellite-unstable endometrial carcinomas. The current study focuses on the clinical characteristics and survival outcomes of sporadic high microsatellite instability (MSI-H) endometrial carcinomas secondary to hypermethylation of the MLH1 promoter (hMLH1+) region resulting in epigenetic silencing of the MLH1 and PMS2 genes.

Further understanding of the characteristics and behaviors of these tumors is necessary given the introduction and emphasis of personalized cancer care. This study aims to describe the unique characteristics and long-term outcome data of a cohort of hMLH1+ tumors and compare them with tumors with intact MMR expression (MMR+) and germline-deficient MMR expression (MMR–).

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Table 1. Demographic, Pathologic, and Adjuvant Data of Endometrioid Endometrial Adenocarcinomas, Categorized by Mismatch Repair Status
Characteristic	MMR+ (n = 235)	MMR– (n = 10)	hMLH1+ (n = 71)	P Value^a
Age at surgery, mean, y	60.7	57.1	66.9	<.001^b
BMI, mean, kg/m²	37.1	33.8	34.0	.0532^b
BMI, No. (%)				.0102
<25	18 (7.7)	3 (30)	4 (5.6)
25–29.99	35 (14.9)	0 (0)	14 (19.7)
30–34.99	53 (22.6)	2 (20)	27 (38.0)
≥35	129 (54.9)	5 (50)	26 (36.6)
Race, No. (%)				.0852
White	219 (93.2)	8 (80.0)	61 (85.9)
Black	11 (4.7)	2 (20.0)	6 (8.5)
Other	5 (2.3)	0 (0)	4 (5.6)
Tobacco use,^c No. (%)				.1124
No	165 (70.8)	6 (60.0)	58 (81.7)
Yes	68 (29.2)	4 (40.0)	13 (18.3)
Grade,^d No. (%)				.0001
1	172 (73.2)	7 (70.0)	32 (45.1)
2	53 (22.6)	2 (20.0)	28 (39.4)
3	10 (4.3)	1 (10.0)	11 (15.5)
Depth of invasion, No. (%)				.1440
None	43 (18.3)	3 (30.0)	11 (15.5)
<50%	135 (57.5)	4 (40.0)	33 (46.5)
>50%	57 (24.3)	3 (30.0)	27 (38.0)
LVSI,^d No. (%)				.0071
Absent	211 (91.0)	8 (80.0)	54 (77.1)
Present	21 (9.1)	2 (20.0)	16 (22.9)
Stage, No. (%)				.1407
I	209 (88.9)	8 (80.0)	57 (80.3)
II	5 (2.1)	0 (0)	2 (2.8)
III	16 (6.8)	1 (10.0)	11 (15.5)
IV	5 (2.1)	1 (10.0)	1 (1.4)
Lymph node status,^e No. (%)				.0694
Negative	176 (94.6)	8 (88.9)	56 (86.2)
Positive	10 (5.4)	1 (11.11)	9 (13.9)
Adjuvant treatment, No. (%)				.0153
Yes	62 (26.4)^f	4 (40.0)	31 (43.7)
None	173 (73.6)^g	6 (60.0)	40 (56.3)
Type of adjuvant treatment, No. (%)	(n = 59)	(n = 4)	(n = 31)	.4090
Chemotherapy alone	9 (15.3)^h	2 (50.0)	4 (12.9)
Chemo + radiation	14 (23.7)	1 (25.0)	8 (25.8)
Radiation alone	36 (61.0)^h	1 (25.0)	19 (61.3)^h

BMI, body mass index; hMLH1+, hypermethylation of MLH1 promoter; LVSI, lymphovascular space invasion; MMR+, intact mismatch repair expression; MMR–, probable MMR mutation.
^aFisher-Freeman-Halton test.
^bKruskal-Wallis test.
^cTwo patients had missing data.
^dFour patients had missing data.
^eFifty-six patients had missing data.
^fThree received additional neoadjuvant chemotherapy, and three patients received hormonal treatment only.
^gOne received neoadjuvant radiation treatments.
^hTwo also received hormonal treatment.

Table 2. Early vs Advanced Stage Recurrence Rate Among Mismatch Repair Groups
Characteristic	MMR+, No. (%)	MMR–, No. (%)	hMLH1+, No. (%)	P Value^a
Stage I/II	(n = 214)	(n = 8)	(n = 59)
Recurrence				<.001
None	209 (97.7)	7 (87.5)	50 (87.7)
Yes	5 (2.3)	1 (12.5)	9 (15.3)
Isolated vaginal	3		3
Pelvic	1	1	2
Nodal
Distant	1		4
Stage III/IV	(n = 21)	(n = 2)	(n = 12)
Recurrence				1.00
None	16 (76.2)	2 (100)	10 (83.3)
Yes	5 (23.8)	0 (0)	2 (16.7)
Isolated vaginal
Pelvic
Nodal	1		1
Distant	4		1

hMLH1+, hypermethylation of MLH1 promoter; MMR+, intact mismatch repair expression; MMR–, probable MMR mutation.
^aFisher exact test.

Table 3. Adjusted Odds Ratios for Recurrence
Predictor	OR (95% CI)	P Value^a
MMR group
hMLH1+ vs MMR+	5.092 (1.538–16.860)	.008
MMR– vs MMR+	6.622 (0.598–73.348)	.123
Age	1.061 (1.002–1.122)	.041
Grade	1.349 (0.561–3.240)	.504
LVSI (present)	5.601 (1.096–28.629)	.039
Adjuvant treatment (no)	1.831 (0.429–7.811)	.414
	c = .792

CI, confidence interval; hMLH1+, hypermethylation of MLH1 promoter; LVSI, lymphovascular space invasion; MMR+, intact mismatch repair expression; MMR–, probable MMR mutation; OR, odds ratio.
^aMultiple logistic regression.

Table 4. Risk Stratification to Evaluate Recurrence Rate Among Mismatch Repair Groups
Characteristic	MMR+, No. (%)	MMR–, No. (%)	hMLH1+, No. (%)	P Value^a
Low risk^b	(n = 40)	(n = 3)	(n = 9)
Recurrence				.23
Yes	0 (0)	0 (0)	1 (11.1)
None	40 (100)	3 (100)	8 (88.9)
Low-intermediate risk^c	(n = 144)	(n = 4)	(n = 31)
Recurrence				.03
Yes	3 (2.1)	0 (0)	4 (12.9)
None	141 (97.9)	4 (100)	27 (87.1)
High-intermediate risk^d	(n = 30)	(n = 1)	(n = 19)
Recurrence				.04
Yes	2 (6.7)	1 (100)	4 (21.1)
None	28 (93.3)	0 (0)	15 (78.9)

hMLH1+, hypermethylation of MLH1 promoter; MMR+, intact mismatch repair expression; MMR–, probable MMR mutation.
^aFisher-Freeman-Halter test.
^bLow risk = grade 1 or 2 histology, no myometrial invasion.
^cLow-intermediate risk = patients who fit criteria for neither low risk nor high-intermediate risk.
^dHigh-intermediate risk = one or more of the following risk factors: grade 2 or 3 histology, more than 50% depth of invasion, or presence of lymphovascular space invasion. Patients younger than 50 years need all three risk factors, patients aged between 50 and 69 years need two risk factors, and patients aged 70 years and older need only one risk factor.