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Original Research ajog.


Preoperative predictors of endometrial cancer at time of
hysterectomy for endometrial intraepithelial neoplasia
or complex atypical hyperplasia
Monica Hagan Vetter, MD; Blair Smith, MD; Jason Benedict, MS; Erinn M. Hade, PhD; Kristin Bixel, MD; Larry J. Copeland, MD;
David E. Cohn, MD; Jeffrey M. Fowler, MD; David O’Malley, MD; Ritu Salani, MD, MBA; Floor J. Backes, MD

BACKGROUND: Endometrial intraepithelial neoplasia, also known as the time of hysterectomy was developed using logistic regression with 5-
complex atypical hyperplasia, is a precancerous lesion of the endometrium fold cross-validation.
associated with a 40% risk of concurrent endometrial cancer at the time of RESULTS: Of the 1055 charts reviewed, 169 patients were eligible and
hysterectomy. Although a majority of endometrial cancers diagnosed at included. Of these patients, 87 (51.5%) had a final diagnosis of endo-
the time of hysterectomy for endometrial intraepithelial neoplasia are low metrial intraepithelial neoplasia/other benign disease, whereas 82
risk and low stage, approximately 10% of patients ultimately diagnosed (48.5%) were ultimately diagnosed with endometrial cancer. No medical
with endometrial cancers will have high-risk disease that would warrant comorbidities were found to be strongly associated with concurrent
lymph node assessment to guide adjuvant therapy decisions. Given these endometrial cancer. Patients with endometrial cancer had a thicker
risks, some physicians choose to refer patients to a gynecologic oncologist average endometrial stripe compared to the patients with no endometrial
for definitive management. Currently, few data exist regarding preoper- cancer at the time of hysterectomy (15.7 mm; standard deviation, 9.5)
ative factors that can predict the presence of concurrent endometrial versus 12.5 mm; standard deviation, 6.4; P ¼ .01). An endometrial stripe
cancer in patients with endometrial intraepithelial neoplasia. Identification of 2 cm was associated with 4.0 times the odds of concurrent endo-
of these factors may assist in the preoperative triaging of patients to metrial cancer (95% confidence interval, 1.5e10.0), controlling for age. In
general gynecology or gynecologic oncology. all, 87% of endometrial cancer cases were stage T1a (Nx or N0).
OBJECTIVE: To determine whether preoperative factors can predict the Approximately 44% of patients diagnosed with endometrial cancer and an
presence of concurrent endometrial cancer at the time of hysterectomy in endometrial stripe of 2 cm met the “Mayo criteria” for indicated lym-
patients with endometrial intraepithelial neoplasia; and to describe the phadenectomy compared to 22% of endometrial cancer patients with an
ability of preoperative characteristics to predict which patients may be at a endometrial stripe of <2 cm.
higher risk for lymph node involvement requiring lymph node assessment CONCLUSION: Endometrial stripe thickness and age were the stron-
at the time of hysterectomy. gest predictors of concurrent endometrial cancer at time of hysterectomy
MATERIALS AND METHODS: We conducted a retrospective for endometrial intraepithelial neoplasia. Referral to a gynecologic
cohort study of women undergoing hysterectomy for pathologically oncologist may be especially warranted in endometrial intraepithelial
confirmed endometrial intraepithelial neoplasia from January 2004 to neoplasia patients with an endometrial stripe of 2 cm given the
December 2015. Patient demographics, imaging, pathology, and out- increased rate of concurrent cancer and potential need for lymph node
comes were recorded. The “Mayo criteria” were used to determine assessment.
patients requiring lymphadenectomy. Unadjusted associations between
covariates and progression to endometrial cancer were estimated by 2- Key Words: endometrial cancer, endometrial hyperplasia, endometrial
sample t-tests for continuous covariates and by logistic regression for intraepithelial neoplasia, endometrial stripe, precancerous lesion, trans-
categorical covariates. A multivariable model for endometrial cancer at vaginal pelvic ultrasound

E ndometrial intraepithelial neoplasia

(EIN), formally known as complex
atypical hyperplasia (CAH), is a prema-
of clinical significance because of an
approximately 40% risk of progression to
endometrial cancer (EC).1e3 Further-
hysterectomy, with or without bilateral
salpingo-oophorectomy. This treatment
protocol allows for full pathologic evalu-
lignant lesion of the endometrium that is more, the prevalence of concurrent EC in ation and assessment of concurrent can-
patients diagnosed with EIN undergoing cer, and provides definitive therapy.4,9
hysterectomy approaches 43%.4 Risk Nonsurgical management may be
Cite this article as: Vetter MH, Smith B, Benedict J, et al.
Preoperative predictors of endometrial cancer at time of factors for the development of EIN appropriate for patients desiring future
hysterectomy for endometrial intraepithelial neoplasia or include obesity, anovulation, nulliparity, fertility or for those patients with
complex atypical hyperplasia. Am J Obstet Gynecol and diabetes.5,6 A diagnosis of EIN can be comorbidities precluding surgical
2020;222:60.e1-7. made by outpatient endometrial biopsy management.10
0002-9378/$36.00 or by dilation and curettage, with or The majority of EIN patients
ª 2019 Elsevier Inc. All rights reserved. without hysteroscopy.7,8 Given the high ultimately diagnosed with EC will
risk of concurrent cancer and the risk of have early stage, low-risk disease.
progression, the standard treatment of However, approximately 12% will have
EIN is surgical management with high-grade tumors with deep

60.e1 American Journal of Obstetrics & Gynecology JANUARY 2020 GYNECOLOGY Original Research

second surgery based on intra-

AJOG at a Glance operative frozen section, final pa-
Why was this study conducted? thology diagnosis, and/or provider
To determine whether there are preoperative predictors of concurrent uterine choice. Patients with no preoperative
adenocarcinoma at time of hysterectomy for endometrial intraepithelial imaging or those who had undergone
neoplasia, and need for lymph node assessment at time of surgical management. prehysterectomy endometrial ablation
were excluded. Patient demographics,
Key findings imaging results, pathologic data, and
Both preoperative endometrial stripe thickness and smoking status predicted the outcomes were recorded from the
presence of concurrent cancer at time of hysterectomy for endometrial intra- medical record.
epithelial neoplasia. Endometrial stripe thickness of 2 cm was associated with a We used the widely accepted “Mayo
4-fold increase in odds of concurrent cancer compared to endometrial stripe criteria” to calculate for whom a
thickness of <2 cm. In all, 44% of patients with an endometrial stripe of 2 cm lymph node dissection would be rec-
met clinical criteria for lymph node assessment. ommended.15 The Mayo criteria
recommend a lymph node dissection
What does this add to what is known? for patients with the following: grade
This study suggests that referral to gynecologic oncology may be warranted for 1 or grade 2 endometrioid adenocar-
patients with endometrial intraepithelial neoplasia, especially if endometrial cinoma 2 cm and >50% myometrial
stripe thickness is 2 cm, given the increased rate of concurrent cancer and the invasion, any grade 3 endometrioid
potential need for lymph node assessment. adenocarcinomas, and all non-
endometrioid adenocarcinomas (se-
rous, clear cell, mixed, carcinosar-
myometrial invasion and a 3e7% risk suspicious feature as important in the coma). Descriptive statistics (counts,
of lymph node involvement.4,11e13 prediction of underlying cancer risk, frequency, mean, and standard devia-
Although the comprehensive surgical with the highest risk in patients assigned tion) were reported. Initial associa-
staging with lymph node assessment via the designation of EIN suspicious.16 tions with progression to EC were
full lymphadenectomy or sentinel However, few data exist on the impact made by 2-sample t tests for contin-
lymph node approach for all patients of objective preoperative factors that uous covariates and by the estimation
with EIN would result in overtreatment may be used to predict the risk of un- of odds ratios (OR), and 95% confi-
in a large proportion of patients, there derlying EC. dence intervals (CI), for categorical
remains a subset of patients for whom The primary purpose of this study covariates. A predictive multivariable
lymph node assessment as a guide to was to determine whether preoperative logistic model for progression to EC
adjuvant therapy is beneficial in factors, including imaging and patient was developed by forward selection of
reducing the risk of over- or under- characteristics, can predict the pres- covariates with crude association at
treatment. In addition, hysterectomy ence of concurrent EC at the time of the 10% level and 5-fold cross-
results in disruption of the lymphatic hysterectomy in patients diagnosed validation. Model discrimination was
channels, making sentinel lymph node with EIN. A secondary outcome was assessed by the area under the receiver
assessment impossible to perform after to describe the ability of preoperative operating characteristic curve (AUC),
hysterectomy, in the event of an EC characteristics to predict which pa- and model calibration was assessed
diagnosis on intraoperative or final pa- tients may require a lymph node using the HosmerLemeshow
thology. This fact has resulted in dissection. goodness-of-fit test. The associations
ongoing discussions about whether or between the Mayo criteria and either
not a referral to a gynecologic oncolo- Materials and Methods LND, lymphadenectomy, or EMS
gist is warranted in all cases of EIN.14 After obtaining institutional review thickness were assessed using the
Given the challenging management board approval, a retrospective chart Fisher exact test. All reported P values
decisions associated with EIN, interest review was performed, encompassing are 2 sided. Data were analyzed in
exists in identifying factors that may all patients undergoing hysterectomy Stata version 15.1 (StataCorp, College
improve preoperative risk prediction of and bilateral salpingo-oophorectomy Station, TX).
EC. Previous studies have identified for confirmed EIN at The Ohio
sampling method as being associated State University from January 2004 to Results
with EC risk, with EIN diagnosed on December 2015. Confirmation of an In total, 169 individuals were eligible to
office biopsy alone being more strongly EIN diagnosis by an Ohio State Uni- be included in the study. EIN was diag-
associated with EC on follow-up.15,16 A versity pathologist was required for nosed by endometrial biopsy in 44% of
retrospective study identified pathologic inclusion. Lymph node assessment the patients, whereas EIN was initially
characteristics such as extent of EIN or was performed either at the time of diagnosed by dilation and curettage in
involvement of a polyp or other primary surgery or, in rare cases, in a 56% of the patients. In all, 73 patients

JANUARY 2020 American Journal of Obstetrics & Gynecology 60.e2

Original Research GYNECOLOGY

Baseline patient characteristics by final pathology diagnosis at time of hysterectomy
Endometrial cancer Benign Pathology Unadjusted OR Adjusted ORa
Characteristic (n ¼ 82), n (%) (n ¼ 87), n (%) (95% CI) (95% CI)
EMS thickness
<2 cm 59 (42.4) 80 (57.6) Reference Reference
2 cm 23 (76.7) 7 (23.3) 4.5 (1.8e11.1) 4.0 (1.6e10.1)
Smoking status
Never smoker 55 (52.9) 49 (47.1) Reference
Ever smoker 25 (41.7) 35 (58.3) 0.6 (0.3e1.2)
Age, y
50 23 (42.6) 31 (57.4) Reference Reference
51e64 39 (45.9) 46 (54.1) 1.1 (0.6e2.3) 1.2 (0.6e2.4)
65 20 (66.7) 10 (33.3) 2.7 (1.1e6.8) 2.3 (0.9e5.9)
Nonwhite 7 (53.8) 6 (46.2) Reference
White 75 (48.1) 81 (51.9) 0.8 (0.3e2.5)
Menopausal status
Premenopausal 25 (41.0) 36 (59.0) Reference
Postmenopausal 56 (52.8) 50 (47.2) 1.6 (0.9e3.0)
Not obese (<30) 14 (48.3) 15 (51.7) Reference
Obesed (30) 68 (48.6) 72 (51.4) 1.0 (0.5e2.3)
No 25 (44.6) 31 (55.4) Reference
Yes 57 (50.4) 56 (49.6) 1.3 (0.7e2.4)
No 58 (47.5) 64 (52.5) Reference
Yes 24 (51.1) 23 (48.9) 1.2 (0.6e2.3)
BMI, body mass index (kg/m2); CI, confidence interval; EC, endometrial cancer; EMS, endometrial stripe thickness; OR, odds ratio.
Adjusted odds ratio includes the variables in the final model only; b Smoking status has 5 missing values (2 in EC group and 3 in benign pathology group); c Menopausal status has 2 missing values
(1 in EC group and 1 in benign pathology group); d Obesity was defined as BMI 30.
Vetter et al. Predictors of cancer at time of surgical management of endometrial intraepithelial neoplasia. Am J Obstet Gynecol 2020.

(43%) had a final diagnosis of EIN; 82 those with EIN/other benign disease. maximum: 21.0, 64.3) for those pro-
(48%) were diagnosed with endometrial As women aged, they were more often gressing to EC and 41.5 (minimum,
cancer at the time of hysterectomy, diagnosed with EC (65 years vs 50 maximum: 19.9, 69.2) for those who
whereas 14 (8%) had other benign years: OR, 2.7; 95% CI, 1.1e6.8), P ¼ did not. The rate of hypertension,
disease. .08). In both groups, most patients diabetes, and breast cancer were similar
Demographics for the study popu- were of white race/ethnicity, were between the 2 groups.
lation are reported in Table 1 according postmenopausal, and had never used The final multivariable model
to final pathologic diagnosis. The hormone replacement therapy. The (Figure 1) found preoperative trans-
average age of patients diagnosed with most commonly noted medical co- vaginal ultrasound endometrial stripe
EC at the time of hysterectomy was 56 morbidity in both groups was obesity (EMS) and age group to be strongly
years (standard deviation [SD], 10.0), (83% in both groups). Median body associated with an increased odds of
compared to 54 years (SD, 10.0) for mass index was 39.5 (minimum, EC. The final predictive model had

60.e3 American Journal of Obstetrics & Gynecology JANUARY 2020 GYNECOLOGY Original Research

histology, grade 3, and was noted to have

an EMS of 13.5 mm prior to
Multivariable logistic regression model for endometrial cancer at time of
In the entire cohort, there was a
single recurrence after a median
follow-up of 2.4 years. This patient
had stage IA, grade I endometrioid EC
with negative lymphovascular space
invasion. She did not undergo lym-
phadenectomy and did not receive
adjuvant therapy. She was found to
have pelvic and nodal recurrences 12
months after hysterectomy. She
declined any additional therapy in
favor of hospice placement, and died
of disease within 2 months.

Principal findings
Our study demonstrates that patients
Vetter et al. Predictors of cancer at time of surgical management of endometrial intraepithelial neoplasia. Am J Obstet
Gynecol 2020. with a preoperative diagnosis of complex
endometrial hyperplasia and an EMS of
2 cm have 4.0 (95% CI: 1.6, 10.1) times
reasonable discrimination (AUC, 0.64; Approximately 24% (n ¼ 20) of EC the odds of endometrial cancer at the
95% CI, 0.56e0.72) and calibration patients underwent lymphadenectomy; time of hysterectomy, controlling for
(HosmerLemeshow goodness-of-fit 7 of these cases (35%) met Mayo age. Furthermore, 44% (n¼ 10) of pa-
test, P ¼ 0.41). Patients with EC at criteria. Of 82 patients with endome- tients with an EMS of 2 cm would have
the time of hysterectomy had an trial cancer, 23 (28%) met Mayo required lymph node dissection based
average EMS of 15.7 (SD, 9.5) mm criteria. Ten patients (44%) with an on Mayo criteria.
compared to those with EIN/other EMS of 2 cm met Mayo criteria on
benign disease 12.5 (SD, 6.4). Patients final pathology, compared to 13 pa- Clinical implications
with an EMS of 2 cm had 4.0 times tients (22%) with an EMS of <2 cm, Management of EIN continues to be a
the odds of concurrent EC (OR, 4.0; indicating that a lymph node dissec- complex issue, especially when deciding
95% CI, 1.6e10.1), controlling for age tion would be warranted. Of the pa- on referral to a gynecologic oncologist.
(Table 1). An increased odds of EC is tients with an EMS of 2 cm and EC Previous studies exploring the predic-
also suggested for those patients with diagnosis, 20 patients (87.0%) had tion of the risk of concurrent EC in pa-
increased age (65 years and older; grade 1, 2 patients (8.7%) had grade 2, tients with EIN have focused on factors
adjusted OR, 2.3, 95% CI, 0.9e5.9), and 1 patient (4.4%) had grade 3. Two such as sampling method and histologic
compared to patients 50 years and patients (8.7%) had nonendometrioid characteristics such as type and extent of
younger, controlling for EMS histology, 4 (17.4%) had >50% myo- EIN.16 For the first time, we have
(Table 1). metrial invasion, and 3 (13.0%) had demonstrated that the preoperative EMS
Table 2 describes the characteristics lymphovascular space invasion. determined by preoperative transvaginal
of patients who were diagnosed with There were 2 instances of stage III ultrasound is associated with increased
EC at the time of hysterectomy. The disease. One patient had a dediffer- odds of EC, while controlling for age.
majority of EC cases were early stage entiated carcinoma at the time of hys- These results may be particularly rele-
as defined as T1a (Nx or N0) (87%), terectomy and subsequently underwent vant to women and their gynecologists
and had low-risk pathologic features imaging, as she did not undergo lymph who are in settings that may be a distance
such as grade 1 disease (92%), endo- node assessment at the time of hyster- away from a gynecologic oncologist.
metrioid histology (96%), and lack of ectomy. Her imaging demonstrated Applying this assessment may assist in
lymphovascular space invasion (89%). lymphadenopathy that was biopsied and making the decision/plan for referral.
However, 10% of patients had >50% found to be consistent with metastatic Within the cohort diagnosed with
myometrial invasion; these patients disease. She then received systematic concurrent EC, the majority of cases
were considered to be stage IB or chemotherapy without complete lym- were early stage with low-risk patho-
higher. Of the EC cohort, 15% phadenectomy and had no evidence of logic features such as grade 1 or
received adjuvant therapy, most disease at 17 months. The other patient endometrioid histology. In fact, almost
commonly with vaginal brachytherapy. had stage IIIC disease of endometrioid half of these cases were confined to the

JANUARY 2020 American Journal of Obstetrics & Gynecology 60.e4

Original Research GYNECOLOGY

endometrium. There was a lower rate

of high-risk disease in our cohort
Clinicopathological characteristics of patients diagnosed with endometrial
(grade 2/3 disease or outer 50%
carcinoma at time of final pathology
myoinvasion) compared to those in
previously studied cohorts.4,17 This Characteristic Endometrial carcinoma (n ¼ 82), n (%)
may reflect demographic differences, Stage
such as a higher proportion of patients
IA 71 (86.6)
of white race/ethnicity and a higher
body mass index in our cohort, both IB 4 (4.9)
of which are associated with the II 5 (6.1)
development of type I endometrial III 2 (2.4)
cancers.18 Type I endometrial cancers
are most often estrogen dependent
and are associated with lower grades 1 75 (91.5)
and rates of myoinvasion, lympho- 2 4 (4.9)
vascular space invasion, and lymph 3 3 (3.7)
node involvement compared to type II
endometrial cancers.19 Histology
The major advantage in referring Endometrioid 79 (96.3)
patients with EIN to a gynecologic Mixed pattern 2 (2.4)
oncologist is the gynecologic oncolo- Dedifferentiated 1 (1.2)
gist’s ability to perform comprehensive
staging, including lymph node assess- LVSI
ment when needed. Although the Present 9 (11.0)
impact of routine lymphadenectomy on Absent 73 (89.0)
survival is controversial, the benefit of
Meets Mayo criteria 23 (28.0)
lymph node assessment lies within
determining which patients need adju- Underwent LND 20 (24.4)
vant therapy.20 Previously, full lym- Recurrence 1 (1.2)
phadenectomy was performed as part of LND, lymphadenectomy; LVSI, lymphovascular space invasion.
comprehensive surgical staging, but was Vetter et al. Predictors of cancer at time of surgical management of endometrial intraepithelial neoplasia. Am J Obstet
Gynecol 2020.
associated with increased lymphe-
dema.21 Interest then turned to defining
low-risk patients in whom full lymph
node dissection could be avoided. EC involves injecting the cervix with is to offer SLN dissection to all patients
Mariani et al defined a low-risk popu- indocyanine green a fluorescent dye, with EIN. This would allow for a less
lation consisting of patients with grade with or without a colorimetric dye or morbid, yet reliable, lymph node
1 or 2 endometrioid adenocarcinoma radioactive tracer, and has been shown assessment and avoidance of a second
with less than 50% myometrial invasion to be a reliable and safe alternative to surgical procedure and its associated
and a tumor <2 cm in diameter.19e22 A full lymphadenectomy, with a low risks in the event of an EC diagnosis.
prospective study using these criteria false-negative rate.23e27 It is important Based on our study, the risk of meeting
demonstrated a <1% risk of lymph to note that the ability to perform SLN Mayo criteria (indicating the need for
node involvement in these low-risk mapping in EC depends on intact, lymphadenectomy) in patients with
patients compared to 16% in those not unobstructed lymphatic channels EIN/CAH was 28%. SLN mapping
meeting the criteria. Notably, in our originating from the uterine corpus should be considered for all patients with
cohort, 44% of patients with an EMS of and cervix and cannot be performed EIN/CAH, especially for patients with an
2 cm would have required lymph after hysterectomy. EIN patients diag- endometrial stripe thickness of >2 cm
node dissection using the criteria nosed with EC with high-risk features on preoperative pelvic ultrasound.
described above. at the time of hysterectomy alone Knowledge of lymph node status in pa-
Most recently, sentinel lymph node would then subsequently require a full tients with high intermediate uterine risk
(SLN) mapping has been introduced lymphadenectomy. This results in the factors would allow a more tailored
into the surgical management of patient being exposed to additional recommendation for postoperative
endometrial cancer, with the intention anesthesia risks and surgical risks therapy or surveillance, with possible
to reduce morbidity associated with a associated with lymphadenectomy. omission of external beam radiation
full lymphadenectomy (eg, lymphe- One alternative approach to manage- therapy and/or chemotherapy for pa-
dema, lymphocele). SLN mapping in ment of EIN in the era of SLN mapping tients at low risk for recurrence.28,29

60.e5 American Journal of Obstetrics & Gynecology JANUARY 2020 GYNECOLOGY Original Research

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28. Nout RA, Smit VT, Putter H, et al. Vaginal randomised, phase 3 trial. Lancet Oncol Biostatistics (Mr Benedict and Dr Hade), Department of
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open-label, non-inferiority, randomised trial. From the Division of Gynecologic Oncology (Drs Vetter, accepted Aug. 3, 2019.
Lancet 2010;375:816–23. Bixel, Copeland, Cohn, Fowler, O’Malley, Salani, and The authors report no conflicts of interest.
29. de Boer SM, Powell ME, Mileshkin L, et al. Backes), Department of Obstetrics/Gynecology, The Ohio These findings were presented in part at the 2017
Adjuvant chemoradiotherapy versus radio- State University College of Medicine, Columbus, OH; Di- Society of Gynecologic Oncology Winter Meeting in
therapy alone for women with high-risk endo- vision of Gynecologic Oncology (Dr Smith), Department of Breckenridge, CO, Jan. 26e28, 2017.
metrial cancer (PORTEC-3): final results of an Obstetrics/Gynecology, University of MissourieKansas Corresponding author: Floor Backes, MD. Floor.
international, open-label, multicentre, City School of Medicine, Kansas City, MO; Center for

60.e7 American Journal of Obstetrics & Gynecology JANUARY 2020