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Endometrial carcinoma risk among women diagnosed with
endometrial hyperplasia: the 34-year experience in a large
health plan
JV Lacey Jr*
,1
, OB Ioffe
2
, BM Ronnett
3
, BB Rush
4
, DA Richesson
1
, N Chatterjee
5
, B Langholz
6
, AG Glass
4
and
ME Sherman
1
1
Hormonal and Reproductive Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD, USA;
2
Department of Pathology, University of Maryland Medical Center, Baltimore, MD, USA;
3
Department of Pathology, The Johns Hopkins Medical
Institutions, Baltimore, MD, USA;
4
Kaiser Permanente Center for Health Research, Portland, OR, USA;
5
Biostatistics Branch, Division of Cancer
Epidemiology and Genetics, National Cancer Institute, Rockville, MD, USA;
6
Division of Biostatistics, Department of Preventive Medicine, Keck School of
Medicine of the University of Southern California, Los Angeles, CA, USA
Classifying endometrial hyperplasia (EH) according to the severity of glandular crowding (simple hyperplasia (SH) vs complex
hyperplasia (CH)) and nuclear atypia (simple atypical hyperplasia (SAH) vs complex atypical hyperplasia (CAH)) should predict
subsequent endometrial carcinoma risk, but data on progression are lacking. Our nested case –control study of EH progression
included 138 cases, who were diagnosed with EH and then with carcinoma (1970–2003) at least 1 year (median, 6.5 years) later, and
241 controls, who were individually matched on age, date, and follow-up duration and counter-matched on EH classification. After
centralised pathology panel and medical record review, we generated rate ratios (RRs) and 95% confidence intervals (CIs), adjusted
for treatment and repeat biopsies. With disordered proliferative endometrium (DPEM) as the referent, AH significantly increased
carcinoma risk (RR ¼14, 95% CI, 5 – 38). Risk was highest 1– 5 years after AH (RR ¼48, 95% CI, 8–294), but remained elevated 5 or
more years after AH (RR ¼3.5, 95% CI, 1.0 –9.6). Progression risks for SH (RR ¼2.0, 95% CI, 0.9 –4.5) and CH (RR ¼2.8, 95% CI,
1.0–7.9) were substantially lower and only slightly higher than the progression risk for DPEM. The higher progression risks for AH
could foster management guidelines based on markedly different progression risks for atypical vs non-atypical EH.
British Journal of Cancer (2008) 98, 45 – 53. doi:10.1038/sj.bjc.6604102 www.bjcancer.com
Published online 20 November 2007
&2008 Cancer Research UK
Keywords: endometrial adenocarcinoma; uterine cancer; atypical hyperplasia; counter-matching; histopathology
Abnormal vaginal bleeding often prompts endometrial biopsy or
curettage to exclude endometrial carcinoma and endometrial
hyperplasia (EH), its precursor (Clark et al, 2002; Montgomery
et al, 2004). Endometrial hyperplasia is a pathologically hetero-
geneous diagnosis that ranges from histologically subtle and
spontaneously reversible proliferative lesions to incipient carcino-
ma (Montgomery et al, 2004; Mazur, 2005). To describe the risk of
subsequent carcinoma (Marsden and Hacker, 2001; McCluggage,
2006), the widely used World Health Organization (WHO) system
classifies biopsy diagnoses of EH according to the severity of
glandular crowding and the presence of nuclear atypia (Clark et al,
2006). Lesions showing minimal crowding are considered simple
hyperplasia (SH), whereas lesions showing greater crowding are
designated as complex hyperplasia (CH) (Zaino, 2000). Simple
hyperplasia and CH with nuclear atypia are designated as simple
atypical hyperplasia (SAH) and complex atypical hyperplasia
(CAH), respectively. Complex atypical hyperplasia is more
common than SAH and represents the most frequently identified
immediate precursor of endometrial carcinoma (Silverberg, 2000).
Distinguishing low-risk EH lesions that can be conservatively
managed with progestogen-based treatment plus surveillance from
higher-risk EH lesions that require immediate surgical treatment
has clinical implications (Clark et al, 2006; McCluggage, 2006;
Soslow, 2006). There is no consensus on the management of SH or
CH (Clark et al, 2006), which make up most EH diagnoses, but
these lesions are thought to pose only modest risk of progression
to carcinoma (Marsden and Hacker, 2001; Montgomery et al,
2004). In contrast, hysterectomy is generally recommended for
women with SAH or CAH because of a high probability of
underlying carcinoma when AH is diagnosed (ACOG, 2005).
Approximately 20 200 women in the United States who undergo
hysterectomy receive a primary hospital discharge diagnosis of EH
each year (Keshavarz et al, 2002), but progression risks for EH
have not been accurately characterised in rigorous population-
based studies (Silverberg, 2000). Current management of EH relies
on largely historical data from studies that lacked adequate control
Received 24 July 2007; revised 14 October 2007; accepted 22 October
2007; published online 20 November 2007
*Correspondence: Dr JV Lacey, Division of Cancer Epidemiology and
Genetics, National Cancer Institute, 6120 Executive Blvd, MSC 7234,
Rockville, MD 20852-7234, USA;
E-mail: jimlacey@nih.gov
British Journal of Cancer (2008) 98, 45 – 53
&
2008 Cancer Research UK All rights reserved 0007 – 0920/08
$
30.00
www.bjcancer.com
Clinical Studies
groups (Kurman et al, 1985; Feldman et al, 1995; Terakawa et al,
1997; Tabata et al, 2001; Horn et al, 2004; Baak et al, 2005) and
were limited by sample size (Feldman et al, 1995; Tabata et al,
2001), short follow-up (Feldman et al, 1995; Terakawa et al, 1997;
Tabata et al, 2001), suboptimal statistical methods (Kurman et al,
1985; Pettersson et al, 1985; Feldman et al, 1995; Terakawa et al,
1997; Tabata et al, 2001; Horn et al, 2004), and minimal clinical
and treatment information (Kurman et al, 1985; Pettersson et al,
1985; Terakawa et al, 1997; Tabata et al, 2001; Horn et al, 2004).
Endometrial hyperplasia diagnoses can misclassify disease severity
because of biopsy sampling errors (Zaino, 2000; Trimble et al,
2006; Zaino et al, 2006) or the community pathologists’ reported
tendency to overestimate lesion severity (Silverberg, 2000).
Accurate and precise estimates of endometrial carcinoma risk
after an EH diagnosis are needed to develop evidence-based
management guidelines. Therefore, we conducted a nested case –
control study of EH progression risk.
MATERIALS AND METHODS
Study setting
The Kaiser Permanente Center for Health Research (KPCHR) is the
research arm of the Kaiser Permanente Northwest (KPNW) pre-
paid health plan (Wagner et al, 2005). Since the early 1940s, the
KPNW has provided essentially all health care to its members, who
are drawn from the Portland OR metropolitan area. We described
previously our study design and methods in detail (Lacey,
submitted).
Unique KPNW identification numbers allow linkage across
computerised administrative, surgical, pharmacy, tissue archive,
and tumour registry databases. The tumour registry captures 95 –
98% of all newly diagnosed cancers among KPNW members. The
KPNW Department of Pathology annually diagnoses approxi-
mately 50 endometrial carcinomas and interprets 1100 endometrial
biopsies, 8% of which are reported as EH.
Cases
Using these databases, we identified 188 potential cases: women
who received a diagnosis of incident EH on biopsy or curettage,
followed by a diagnosis of incident endometrial carcinoma at least
1 year later, between 1 August 1970 and 31 December 2003. To
capture as many potential progression cases as possible, we also
included 41 women with an index biopsy diagnosed as non-
atypical EH (SH or CH) who received a diagnosis of CAH at
hysterectomy at least 1 year later. We henceforth refer to biopsy or
curettage as biopsy (Shutter and Wright, 2005) and to the initial
diagnosis of EH as the index biopsy.
Slide review
We retrieved all pathology slides and reports for all index biopsies,
follow-up biopsies, and hysterectomy procedures. One pathologist
(MES) initially reviewed all slides, assigned a WHO classification,
and selected one representative slide for each specimen. Two
gynaecologic pathologists (BMR and OBI), who were masked to all
specimen data except patient age and accession date, then
independently classified the selected slides according to agreed-
upon WHO nomenclature (Kurman et al, 1985). We assigned a
panel diagnosis for each specimen based on exact agreement
between at least two of the three pathologists. When all three
reviewers disagreed, the first review diagnosis (MES’s) became the
panel diagnosis. Panel diagnoses were inactive endometrium;
atrophy; polyp; secretory endometrium (SEM); proliferative
endometrium (PEM); disordered proliferative endometrium
(DPEM); SH; CH; AH (SAH or CAH); EH, not otherwise specified
(NOS); or carcinoma. For analysis, we combined inactive, atrophy,
polyp, SEM, and PEM into ‘negative’ and considered DPEM to
represent equivocal EH (Silverberg, 2000; Mazur, 2005; McCluggage,
2006).
We excluded eight potential cases with miscoded original
diagnoses of EH (N¼6) or cancer (N¼2) and seven cases whose
panel diagnosis did not confirm their original end point diagnosis
of CAH or carcinoma at hysterectomy. Of the remaining 214
potential cases, 138 (65.4%) with index biopsy panel diagnoses of
DPEM (N¼33), SH (N¼42), CH (N¼21), or AH (N¼42) were
eligible. This included 28 cases whose original index biopsy was
downgraded by the panel but who had a subsequent biopsy that
met all eligibility criteria. The 76 ineligible cases had index
biopsies with panel diagnoses of inactive (N¼14), atrophy (N¼8),
polyp (N¼4), SEM (N¼8), PEM (N¼22), or carcinoma (N¼13);
or their slides were unsatisfactory (N¼7) or unavailable (N¼1)
for review. Of the eligible cases, 127 clinically progressed from EH
to carcinoma and 11 clinically progressed to AH at hysterectomy
(Supplementary Table 1).
Controls
For each case, we constructed a risk set of individually matched
potential controls: all KPNW members with an index biopsy
diagnosis of incident EH who remained at risk (i.e. no
hysterectomy or uterine carcinoma) for at least as long as the
progression interval of the case to whom they were matched. Each
control within each risk set was matched to that risk set’s case on
age at (±1 year) and date of (±1 year) index biopsy and assigned
a matched censoring date based on the case’s progression interval.
When necessary, we relaxed the date- and age-matching criteria
in successive 1-year intervals, up to 5 years, to populate risk sets
that were initially empty. To avoid selecting controls who were
diagnosed with endometrial carcinoma shortly after their matched
censoring date, we required each potential control to remain at
risk for one additional year after her matched censoring date.
Therefore, the controls who were eligible to be selected had all
been diagnosed with EH at the same age and date as the cases and
had the same duration of at-risk follow-up as the cases.
Almost three-quarters of all EH diagnoses at the KPNW are SH
(Lacey JV Jr, unpublished observation). Random selection of
controls would have led to underrepresentation of patients who
had CH or AH, especially in risk sets for older cases or cases with
longer progression intervals. To avoid this potential limitation,
we selected controls via counter-matching, a form of weighted
random sampling (Lacey, submitted). Counter-matching (Langholz
and Clayton, 1994) oversamples controls with rare values of a
proxy exposure that is known for the entire cohort. Detailed
exposures are then determined for the selected controls, rather
than the entire cohort. The correlated proxy and detailed
exposures increase statistical power while reducing data collection
burdens (Cologne et al, 2004). Our proxy exposure was the original
KPNW index biopsies diagnoses. We selected cases and controls
based on those EH diagnoses (and thus all 229 potential cases
could serve as controls for other eligible cases). Our detailed
exposure was the pathology panel review diagnosis, which was
used in our statistical analysis.
The 138 risk sets (one per eligible case) had 5891 total potential
controls (mean ¼42.7 controls per risk set; range ¼4 –123) who
represented 2946 unique patients because controls could appear in
multiple risk sets. To counter-match, we needed to know the
original EH classifications for all 5891 potential controls. The
KPNW pathology database recorded EH diagnoses, but EH
classifications – SH, CH, or AH – were only available in the
pathology reports. Reviewing 5891 pathology reports was
impractical, so we used batch-quota sampling (Langholz, 2006)
to review batches of pathology reports from each risk set to
determine frequencies of SH, CH, and AH. We translated EH
terminology used before 1995 (Silverberg, 2000) into WHO
Progression of endometrial hyperplasia to carcinoma
JV Lacey Jr et al
46
British Journal of Cancer (2008) 98(1), 45 – 53 &2008 Cancer Research UK
Clinical Studies
nomenclature as needed (e.g., ‘mild’ to SH, ‘moderate’ or
‘adenomatous’ to CH, and ‘severe’ to AH). We reviewed 3182
(54%) potential controls’ pathology reports: 2230 were SH (70%;
includes 26 DPEM and 54 EH, NOS), 666 were CH (21%), and 153
were AH (5%; includes 10 SAH and 46 AH, NOS). We excluded 133
(4.2%) potential controls whose reports were miscoded as EH.
We selected three counter-matched controls from each eligible
case’s risk set. First, we chose two controls whose index biopsy
original EH classification differed from the case’s index biopsy
original EH classification (e.g., if the case had CH, we chose one
control who had SH and one control who had AH). Then,
regardless of the case’s original EH classification, we chose a third
control who had AH. We intentionally oversampled controls with
AH because we expected our pathology panel to downgrade many
of those original AH diagnoses. If a risk set did not contain the
desired AH control(s), we substituted a control originally classified
as CH for the desired AH control. We selected 413 potential
controls (one case had only two controls): 129 SH (31%), 153 CH
(37%), and 131 AH (32%).
Control slide review
Our pathology panel review of controls’ slides employed the same
protocol that was used for cases. Nine (2%) index biopsy slides
were unavailable or unsatisfactory. Of the 404 (98%) controls
whose slides were reviewed, 160 (39%) were ineligible because
their index biopsies had final pathology panel diagnoses of
negative (inactive, N¼44; atrophic, N¼7; polyp, N¼2; SEM,
N¼24; PEM, N¼83) or carcinoma (N¼3). The 241 controls
(58%) with index biopsy final diagnoses of DPEM (N¼97; 24%),
SH (N¼67; 16%), CH (N¼43; 10%), or AH (N¼34; 8%) were
eligible (Figure 1).
Medical record review
We used a standardised abstract form to extract demographic
characteristics, height and weight, reproductive and pregnancy
history, other health factors, use of exogenous hormones, and
treatment for EH. Risk factors were generally assessed at the time
of index biopsy. We supplemented medical record data with
computerised linkage to outpatient pharmacy data available after
1986. By 1993, 93–97% of KPNW members had pharmacy benefits
at KPNW-operated pharmacies.
Statistical analysis
Conditional logistic regression generated rate ratios (RRs) and
95% confidence intervals (CIs) to estimate the relative risk of being
diagnosed with carcinoma after a diagnosis of EH. Risk estimates
were based on the panel diagnoses of EH type, with DPEM as the
reference group.
To assess confounding, we examined associations between EH
type at index biopsy (Table 1) and endometrial carcinoma risk
factors from the medical record data (see Table 2 for variables and
categories). Only body mass index (BMI; o25, 25 – 34,
X35 kg m
2
) and repeat biopsies (any within first 6 months, any
subsequent follow-up biopsy, or none) were statistically signifi-
cantly associated with both EH type and case – control status.
Because of its clinical importance, we also adjusted for treatment
(progestogen-based, other types, or none), even though treatment
was similar for cases and controls (Table 1). Final regression
models included sampling weights for both the batch-quota and
counter-matched sampling (which were included as an offset in
standard conditional logistic regression; Langholz, 2007) and were
adjusted for age (in 1-year intervals), date (in 1-year intervals),
duration of follow-up (in days), repeat biopsies, BMI, and
treatment. Negative confounding by BMI and positive confounding
by repeat biopsies essentially balanced out each other, while
adjustment for treatment had minimal influence on the risk
estimates.
Human subjects
The KPCHR’s Research Subjects Protection Office and the National
Cancer Institute’s Special Studies IRB approved this study.
Role of the funding source
The funding source did not play a role in the study design;
collection, analysis, or interpretation of data; manuscript writing;
or decision to submit the manuscript for publication.
RESULTS
Of the 127 cases diagnosed with endometrial carcinoma, 121 (95%)
were endometrioid adenocarcinomas, five were clear cell carcinomas
(4%), and one was a mucinous carcinoma (1%). Eighty-two
percent were well differentiated and 11% had spread beyond the
uterus.
Age, date, and length of progression interval were similar among
eligible cases and controls, as expected from our matched design
(Table 1). The overall median age at the time of index biopsy was
52 years. Median ages at the time of index biopsy were similar
between cases and controls for each EH classification (data not
shown).
The median interval between index biopsy and diagnosis of
carcinoma was 6.7 years (range, 1 – 24.5). Cases’ intervals were
longer for DPEM (10.4 years) and SH (8.6 years) than for CH and
AH. For each EH classification, some cases had progression
intervals longer than 10 years.
Three-fourths of cases and a slightly higher percentage of
controls had at least one follow-up biopsy after the index biopsy
but before the biopsy that prompted hysterectomy. Controls were
twice as likely as cases to have had follow-up biopsies within 6
months of the index biopsy. However, total mean (2.2) and median
(2) numbers of biopsies were similar. Over 80% of both groups
received progestogen-based treatment during follow-up, including
similar proportions of oral and injectable progestogens.
Age at menarche, parity, menopausal status, age at menopause,
and smoking were similar between cases and controls (Table 2).
Cases were significantly more likely than controls to have
higher BMI and a history of irregular menses or diabetes
before their index biopsy. Morbid obesity (BMIX40 kg m
2
) was
present in 21% of cases and 15% of controls. Oral contraceptive
use and menopausal hormone therapy use were less common in
cases than in controls. Approximately 60% of both cases and
controls were pre- or perimenopausal at the time of their index
biopsy.
Women diagnosed with EH were significantly more likely
(RR ¼4.0, 95% CI, 2.0 – 7.7) than women diagnosed with DPEM to
be subsequently diagnosed with carcinoma (Table 3). Increasing
severity of EH was associated with a nearly exponential increase in
progression risk. The RRs for SH and CH were 2.0 (95% CI, 0.92 –
4.5) and 2.8 (95% CI, 1.0–7.9), respectively, whereas the risk of
carcinoma was over 10 times higher after an index biopsy of AH
(RR ¼14.2, 95% CI, 5.3–38.0).
To improve the statistical precision of risk estimates by time
interval since index biopsy, we expanded the reference group to
include DPEM or SH (Table 4). Progression risks for AH were
higher within 5 years of index biopsy (RR ¼48, 95% CI, 8 – 294)
than after 5 or more years of follow-up (RR ¼3.5, 95% CI, 1.3 –
9.6); the CIs for these risk estimates barely overlapped. A diagnosis
of CH did not significantly increase risk of carcinoma within or
after 5 years.
Progression of endometrial hyperplasia to carcinoma
JV Lacey Jr et al
47
British Journal of Cancer (2008) 98(1), 45 – 53&2008 Cancer Research UK
Clinical Studies
Other analyses
Results did not change after also adjusting for the number of
progestogen prescriptions; restricting analyses to women with
documented pharmacologic treatment or women who were
postmenopausal or over 50 years of age at the time of index
biopsy; or excluding the eight cases and one control who used
tamoxifen before or during follow-up or the 11 cases (and their
18 matched controls) whose clinical end point was AH at
hysterectomy.
Potential cases (N=229)
Diagnosed with EH or DPEM and then diagnosed with carcinoma (N=188)
or CAH at hysterectomy (N=41) at least 1 year later
Based on NCI microscopic review, one representative slide chosen from each
accession/procedure
Independent review by two pathologists to establish panel diagnosis
Based on NCI microscopic review, one representative slide chosen from
each accession/procedure
Independent review by two pathologists to establish panel diagnosis
Eligible cases
N=138
Eligible
cases
N=138
Eligible
controls
N=241
Excluded:
Original index biopsy diagnosis was not EH or DPEM (N=6)
Original end point was not carcinoma or CAH (N=9)
Analytic population
Potential controls (N=5 891)
Diagnosed with EH and then no uterine cancer or hysterectomy for
intervals equal to the progression intervals of the cases
1. Individually matched to eligible cases on age at and date of index biopsy
plus duration of progression interval
2. Batch-quota sampling: N=3 182 controls
3. Select three counter-matched controls per case: N=413 selected
controls
Control selection:
Assemble risk sets for
each eligible case
Ineligible cases:
Index biopsy was negative (N=55)
Index biopsy was cancer (N=13)
Final diagnosis could not be assigned (N=8)
Ineligible controls:
Index biopsy was negative (N=160)
Index biopsy was cancer (N=3)
Final diagnosis could not be assigned (N=9)
Figure 1 Identification, assessment, and eligibility status of potential cases and potential controls.
Progression of endometrial hyperplasia to carcinoma
JV Lacey Jr et al
48
British Journal of Cancer (2008) 98(1), 45 – 53 &2008 Cancer Research UK
Clinical Studies
Analyses that successively excluded risk sets with short
progression intervals revealed the same pattern of risks. The RRs
for SH, CH, and AH were 1.9, 2.8, and 14.6, respectively, after
excluding progression intervals less than 2 years; 1.8, 1.9, and 9.8,
respectively, after excluding progression intervals less than 3 years;
and 1.6, 1.8, and 6.6, respectively, after excluding progression
intervals less than 4 years. None of these RRs for SH or CH were
statistically significant, whereas all of these RRs for AH were
statistically significant (data not shown).
Progression risks were somewhat higher among women who had
one or more follow-up biopsies. Many cases and controls had
repeat biopsies within 3 or 6 months of their index biopsy; when
risk was based on the most severe panel diagnosis for any biopsy
within the first 3 or 6 months of follow-up, results did not
materially change (data not shown).
DISCUSSION
Rigorous estimates of progression risks for EH could foster
improved clinical management of abnormal vaginal bleeding.
Numerous methodologic deficiencies limit the available data on
progression. In our analysis, biopsy diagnoses of SH and CH did
not substantially increase the risk of progression to carcinoma
compared with DPEM. Thus, DPEM, SH, and CH seem to be
low-risk lesions that may be amenable to attempts at conservative
management with close surveillance. Progression risks for AH
were substantially elevated and remained increased for years.
Our findings support the development of a simplified, potentially
dichotomous, pathologic classification that would differentiate
non-atypical EH from AH.
Risk of carcinoma after AH was markedly higher 1–5 years after
index biopsy and remained significantly elevated well after 5 years.
Most of the women who received a panel diagnosis of AH in our
study were later diagnosed with carcinoma. In previous studies, up
to 50% of women who received biopsy diagnoses of AH had occult
endometrial carcinoma when hysterectomy was performed soon
thereafter (Silverberg, 2000; Valenzuela et al, 2003; Shutter and
Wright, 2005; Trimble et al, 2006). To minimise including such
patients, we excluded cases diagnosed with carcinoma within 1
year of an EH diagnosis, performed a centralised pathology review
and excluded cases and controls whose index biopsies were
upgraded from EH to carcinoma, and demonstrated robust results
in sensitivity analyses that successively excluded risk sets of cases
diagnosed within 2, 3, or 4 years of their index biopsies. Our
average clinical progression interval was 6 years. Biopsy sampling
error and variable timing of repeat biopsies make it difficult to
establish exact progression times or distinguish true progression
from persistence of undetected, early-stage occult carcinoma
(Silverberg, 2000). Nonetheless, women with long intervals
between diagnosis of AH and carcinoma probably represent true
examples of progression.
Of the 25 potential cases whose index biopsies were originally
diagnosed as AH, our pathology panel reclassified 28% as
Table 1 Follow-up characteristics of eligible cases and eligible controls
Cases (N¼138) Controls (N¼241)
a
P-value
Age at EH diagnosis (years)
o44 28 (20%) 53 (22%) 0.99
45 – 48 28 (20%) 54 (22%)
49 – 52 26 (19%) 40 (17%)
53 – 58 29 (21%) 51 (21%)
59 or older 27 (20%) 43 (18%)
Mean (years) 52.1 51.5
Median year at EH diagnosis (range) 1989 (1971 – 2001) 1989 (1972 – 2002)
Age at carcinoma diagnosis or censoring (years) 0.82
o50 20 (15%) 46 (19%)
50 – 54 33 (24%) 52 (22%)
55 – 59 25 (18%) 42 (17%)
60 – 67 29 (21%) 54 (22%)
68 or older 31 (22%) 47 (20%)
Median follow-up interval (years) 6.7 (1.0 – 24.5) 6.4 (1.0 – 24.5) 0.62
By final diagnosis of EH
DPEM 10.4 (1.3 – 24.5) 5.9 (1.0 – 23.4)
SH 8.6 (1.0 – 22.1) 6.7 (1.0 – 24.5)
CH 5.9 (1.6 – 18.3) 6.7 (1.2 – 24.5)
AH 4.4 (1.0 – 18.3) 6.7 (1.0 – 23.4)
Follow-up biopsies
At least one 104 (75%) 207 (86%) 0.02
At least one within 1st 6 months 31 (22%) 128 (53%) 0.01
Median number (range) 2 (0 – 12) 2 (0 – 13)
Mean among women with at least 1 2.9 2.5 0.41
Treatment during progression interval
Any progestogen 118 (86%) 222 (92%) 0.17
Oral
b
99 (72%) 208 (86%) 0.13
Intramuscular
b
29 (21%) 42 (17%) 0.75
AH ¼atypical hyperplasia; CH ¼complex hyperplasia; DPEM ¼disordered proliferative endometrium; EH ¼endometrial hyperplasia; SH ¼simple hyperplasia. w
2
Likelihood
ratio P-values from conditional logistic regression analysis, adjusted for age at index biopsy, date of index biopsy, duration of follow-up, and weighted based on the batch-quota
and counter-matched sampling. For progression interval and follow-up biopsies, P-value is from t-tests.
a
Four hundred and thirteen controls were originally matched to cases on
age at EH diagnosis, date of EH diagnosis, and duration of follow-up, based on the original community diagnoses of EH. Because the 172 controls who were ineligible based on
the pathology panel diagnoses are not included above, the distribution of age, date, and follow-up interval among the 241 eligible controls above differs slightly from the
distribution among all 413 potential controls.
b
Not mutually exclusive.
Progression of endometrial hyperplasia to carcinoma
JV Lacey Jr et al
49
British Journal of Cancer (2008) 98(1), 45 – 53&2008 Cancer Research UK
Clinical Studies
carcinoma, confirmed 24% as AH, and downgraded the severity of
44% to SH, CH, DPEM, or negative. These results resemble
findings from a recent Gynecologic Oncology Group (GOG) study
of 289 patients who underwent hysterectomy within 12 weeks of
receiving a community-based biopsy diagnosis of AH (Trimble
et al, 2006). The GOG pathology panel upgraded 29% of AH
Table 2 Selected descriptive and clinical factors
Cases (N¼138) Controls (N¼241)
N%N%P-value
Age at menarche (years) 0.35
o12 21 15.2 42 17.4
12 – 13 61 44.2 107 44.4
14 or older 28 20.3 40 16.6
Ever sought treatment for irregular menses 0.007
Yes 70 50.7 111 46.1
No 2 1.5 24 10.0
Number of pregnancies 0.02
0 21 15.2 31 12.9
1 15 10.9 22 9.1
2 – 3 56 40.6 109 45.2
4+ 46 33.3 79 32.8
Number of live births 0.51
0 – 1 30 21.7 37 15.4
2 – 3 64 46.4 122 50.6
4+ 44 31.9 82 34.0
BMI at index biopsy (kg m
2
)0.005
o25 26 18.8 70 29.1
25 – 29 32 23.2 45 18.7
30 – 34 23 16.7 41 17.0
35 – 39 26 18.8 24 10.0
40+ 29 21.0 36 14.9
Menopausal status at index biopsy 0.59
Pre- or perimenopausal 82 59.4 151 62.7
Postmenopausal 54 39.1 82 34.0
Age at menopause p45 years 6 4.4 12 5.0
Age at menopause 46 – 52 years 28 20.3 40 16.6
Age at menopause 53+ years 16 11.6 24 10.0 0.62
a
Ever diagnosed with diabetes 0.03
Yes 34 24.6 40 16.6
No 81 58.7 168 69.7
Personal history of cancer 0.70
Yes 16 11.6 19 7.9
No 113 81.9 196 81.3
Smoking status at index biopsy 0.88
Never 77 55.8 133 55.2
Former 36 26.1 55 22.8
Current 19 13.8 32 13.3
Oral contraceptive use before index biopsy 0.08
Ever 28 20.3 84 34.9
Never 98 71.0 131 54.4
Menopausal hormone therapy use o0.0001
At index biopsy
Never 89 64.5 71 29.5
Former 15 10.9 54 22.4
Current 25 18.1 75 31.1
At diagnosis/censoring o0.0001
Never 53 38.4 4 1.7
Former 50 36.2 102 42.3
Current 31 22.5 122 50.6
BMI ¼body mass index. Missing values are not shown. P-values are w
2
likelihood ratio P-values from conditional logistic regressions, adjusted for age at index biopsy, date of index
biopsy and duration of follow-up, and weighted based on the batch-quota and counter-matched sampling.
a
w
2
P-value for age at menopause.
Progression of endometrial hyperplasia to carcinoma
JV Lacey Jr et al
50
British Journal of Cancer (2008) 98(1), 45 – 53 &2008 Cancer Research UK
Clinical Studies
diagnoses to carcinoma, confirmed 40% as AH, and downgraded
26% to less-severe lesions. Hysterectomy revealed invasive
carcinoma in 19% of the GOG patients whose original diagnoses
were downgraded. In our study, 29% of potential cases – all of
whom were later diagnosed with carcinoma – had index biopsies
that the panel downgraded to negative. Although AH may be
overdiagnosed in community settings (Silverberg, 2000), sampling
errors and interpretive challenges commonly beset endometrial
biopsy diagnoses.
All patients in our study had at least one endometrial biopsy that
was originally classified as EH or DPEM. Most of them received
repeat biopsies and progestogen therapy. Approximately 75% of
the endometrial carcinomas diagnosed at KPNW between 1970 and
2003 occurred among women who either had no earlier EH or
underwent hysterectomy within weeks or months after an EH
diagnosis. The well-differentiated stage 1 endometrioid carcinomas
(Bokhman, 1983) that formed the majority of our case group are
typical of most endometrial carcinomas diagnosed in Europe and
North America (Amant et al, 2005). Our case patients presumably
had a similar clinical course as women whose carcinomas are not
preceded by a diagnosis of EH. Our results can be generalised to
women who have received biopsy-based diagnoses of EH, who do
not undergo hysterectomy for at least 1 year, and who receive
management and follow-up in accord with community standards.
High BMI, a history of menstrual irregularities, and less
exogenous hormone use were more common in cases than in
controls. Statistical adjustment for treatment and minor differ-
ences in the repeat biopsies did not substantially affect progression
risks, but it remains possible that residual differences contributed
to our observations. Varied approaches to clinical follow-up of EH
contribute to the inherent difficulties of assessing progression risk
(Zaino, 2000). Our results caution that, even with contemporary
treatment and surveillance (Montgomery et al, 2004; Karamursel
et al, 2005; McCluggage, 2006), increased risk may persist for many
years after EH is diagnosed.
Our analysis could theoretically underestimate true progression
risk for non-atypical EH if the EH lesions that were treated with
hysterectomy within 1 year (whom we excluded) were markedly
more aggressive than those that were included in our analysis, but
this seems unlikely. The nearly identical progression intervals
Table 3 Relative risk of being diagnosed with endometrial carcinoma 1 or more years after a diagnosis of EH
Cases Controls
Pathology panel diagnosis
for index biopsy N%N% Rate ratio
a
95% CI Rate ratio
b
95% CI
DPEM 33 23.9 97 40.3 1.0 Ref. 1.0 Ref.
Any EH 105 76.1 144 59.7 3.4 1.9 – 6.0 4.0 2.0 – 7.7
Non-atypical EH 62 44.9 110 45.6 2.0 1.1 – 3.8 2.2 1.1 – 4.7
SH 41 29.7 67 27.8 1.9 0.96 – 3.9 2.0 0.92 – 4.5
CH 21 15.2 43 17.8 2.2 0.91 – 5.3 2.8 1.0 – 7.9
AH 43 31.2 34 14.1 9.9 4.3 – 23.1 14.2 5.3– 38.0
AH ¼atypical hyperplasia; CH ¼complex hyperplasia; CI ¼confidence interval; DPEM ¼disordered proliferative endometrium; EH ¼endometrial hyperplasia; SH ¼simple
hyperplasia. DPEM is the reference group for all rate ratios. SH includes one case and two controls diagnosed with ‘EH, not otherwise specified’.
a
Rate ratios are based on
conditional logistic regression analysis adjusted for age at index biopsy, date of index biopsy, interval between EH and carcinoma, and weighted based on the batch-quota and
counter-matched sampling. All controls were diagnosed with EH at the same age and date as the cases and remained at risk (i.e., no hysterectomy or uterine cancer) for at least
as long as the progression interval of the cases.
b
Rate ratios are also adjusted for body mass index (BMI) at the time of EH diagnosis (o25, 25– 34, X35 kg m
2
), progestogen-
based treatment for EH (any progestogen-based treatment, other treatment, or no treatment), and follow-up biopsies (any biopsy taken within 6 months of the index biopsy, any
subsequent follow-up biopsy, or none).
Table 4 Relative risk of being diagnosed with endometrial carcinoma 1 or more years after a diagnosis of EH, stratified by time interval between EH and
carcinoma
Follow-up interval
a
1 – 4.9 years
b
5 or more years
c
Pathology panel diagnosis
for index biopsy Cases Controls RR
d
95% CI Cases Controls RR
d
95% CI
DPEM 12 44 1.0 Ref. 21 53 1.0 Ref.
SH 12 31 29 36
CH 9 13 3.2 0.5 – 22.2 12 30 1.1 0.4 – 3.2
AH 24 14 48.0 7.8 – 294.2 19 20 3.5 1.3 – 9.6
AH ¼atypical hyperplasia; CH ¼complex hyperplasia; CI ¼confidence interval; DPEM ¼disordered proliferative endometrium; EH ¼endometrial hyperplasia; RR ¼rate ratio;
SH ¼simple hyperplasia. DPEM or SH is the reference group for all RRs. SH includes one case and two controls diagnosed with ‘EH, not otherwise specified’. All controls were
diagnosed with EH at the same age and date as the cases and remained at risk (i.e., no hysterectomy or diagnosis of uterine cancer) for at least as long as the progression interval
of the cases.
a
Interval between index biopsy and diagnosis of carcinoma (cases) or matched censoring date (controls). The minimum follow-up interval for all cases and controls
was 1 year.
b
Restricted to the 57 cases who were diagnosed with carcinoma between 1 and 4.9 years after their diagnosis of EH, plus the 102 controls who were individually
matched to these cases on age at EH diagnosis, date of EH diagnosis, and duration of follow-up. See the Materials and Methods section for additional details.
c
Restricted to the 81
cases who were diagnosed with carcinoma 5 or more years after their diagnosis of EH, plus the 139 controls who were individually matched to these cases on age at EH
diagnosis, date of EH diagnosis, and duration of follow-up. See the Materials and Methods section for additional details.
d
Rate ratios are based on conditional logistic regression
analysis adjusted for age at the time of index biopsy, date of index biopsy, interval between EH and carcinoma, body mass index (BMI) at the time of EH diagnosis (o25, 25 – 34,
X35 kg m
2
), progestogen-based treatment for EH (any progestogen-based treatment, other treatment, or no treatment), and follow-up biopsies (any biopsy taken within 6
months of the index biopsy, any subsequent follow-up biopsy, or none), and weighted based on the batch-quota and counter-matched sampling.
Progression of endometrial hyperplasia to carcinoma
JV Lacey Jr et al
51
British Journal of Cancer (2008) 98(1), 45 – 53&2008 Cancer Research UK
Clinical Studies
across categories of original EH diagnoses suggest that those
classifications did not predict subsequent clinical behaviour of
non-atypical EH. There were no substantial differences in clinical
or patient characteristics at the time of index biopsy that could
have been used to reliably identify high-risk SH or CH patients.
Cases and controls came from one health plan and likely received
similar clinical care after their EH diagnoses. Therefore, the
experience of women diagnosed with SH or CH in our study is
likely representative of the general population of women with non-
atypical EH.
Our study design represents an improvement over previous
studies that lacked control groups (Kurman et al, 1985; Lindahl
and Willen, 1994; Terakawa et al, 1997; Tabata et al, 2001; Horn
et al, 2004; Baak et al, 2005), included few women with EH who
developed carcinoma (Kurman et al, 1985; Feldman et al, 1994;
Lindahl and Willen, 1994; Horn et al, 2004; Baak et al, 2005) or
relied on short follow-up (Terakawa et al, 1997; Tabata et al, 2001).
Previous studies expressed risk as crude percentages – e.g., 20% of
patients with non-atypical AH (Ferenczy and Gelfand, 1989) or
29% of patients with AH (Kurman et al, 1985) progress to cancer –
rather than population-based rate ratios. In our study, 2, 9, and
14% of all women with original community diagnoses of SH, CH,
and AH, respectively, were subsequently diagnosed with endo-
metrial carcinoma. Using the pathology panel diagnoses, the
cumulative probabilities of progression for SH, CH, and AH were
10, 10, and 40%, respectively. Therefore, previous estimates of
carcinoma risk based on consensus diagnoses of SH, CH, and AH
(Kurman et al, 1985; Ferenczy and Gelfand, 1989; Montgomery
et al, 2004; Horn et al, 2007) may require revision. Our findings
reaffirm the need to improve the sensitivity and specificity of AH
diagnoses (Soslow, 2006) and efficiently identify the rare non-
atypical EH lesions that are likely to progress. Modern outpatient
biopsy techniques achieve over 90% sensitivity for detecting
carcinoma (Dijkhuizen et al, 2000), but better endometrial
assessment (Zaino, 2000), histopathologic classifications (Mutter,
2002), and candidate molecular markers (Mutter, 2000) deserve
further study.
Our study used one large, essentially population-based health
plan with linked data covering 34 years. We reviewed all available
pathology from patients with a full range of EH and DPEM and
accounted for clinical follow-up, repeat biopsies, and specific
treatments. However, few women with panel-confirmed AH had
extended follow-up. Our analysis captured clinical progression in
the context of contemporary clinical management (Ferenczy and
Gelfand, 1989; Randall and Kurman, 1997; Marsden and Hacker,
2001; Montgomery et al, 2004; Clark et al, 2006; McCluggage,
2006), rather than natural history. Repeated sampling, treatment,
and censoring may have affected the absolute risk of carcinoma in
our study population compared with untreated women, but our
rate ratios are likely unbiased.
In conclusion, the risk that a woman who receives a biopsy
diagnosis of AH will progress to carcinoma is high during early
and long-term follow-up. The overall progression risks for SH and
CH are lower than previously reported, but a small percentage
of these patients progress to carcinoma despite conventional
clinical follow-up. On the basis of these findings, a dichotomous
classification of non-atypical EH vs atypical EH, along with refined
detection and classification of endometrial carcinoma precursors,
could improve clinical management of abnormal vaginal bleeding.
ACKNOWLEDGEMENTS
We thank Stella Munuo, MSc, and Ruth Parsons, BA, at IMS Inc.,
for data management. We thank J Danny Carreon, MPH, at the
Division of Cancer Epidemiology and Genetics, NCI, for technical
assistance. We thank Kris Bennett, Chris Eddy, BS, Beverly
Battaglia, and the rest of the KPCHR staff. The National Cancer
Institute’s Intramural Research Program (Division of Cancer
Epidemiology and Genetics) funded this study.
Supplementary Information accompanies the paper on British
Journal of Cancer website (http://www.nature.com/bjc)
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