Evaluation of the endometrium for malignant or

premalignant disease
Author
Sarah Feldman, MD, MPH Section Editors
Deborah Levine, MD
Barbara Goff, MD
Robert L Barbieri, MD Deputy Editor
Sandy J Falk, MD

Last literature review version 17.1: January 2009 | This topic last updated: February 2,
2009 (More)

INTRODUCTION Evaluation of the endometrium is the key component in the diagnostic

evaluation of women suspected of endometrial cancer or a premalignant endometrial lesion. An
endometrial sampling procedure is the gold standard for diagnostic evaluation of women with
abnormal uterine bleeding in whom endometrial hyperplasia or carcinoma is a possibility (show
table 1). (See "Endometrial sampling procedures").

INVASIVE METHODS

Endometrial biopsy The development of equipment and techniques for office-based

endometrial biopsy has generally replaced the need for diagnostic dilation and curettage (D & C)
performed in the hospital [1] . Advantages of office biopsy include: It can be done with minimal
to no cervical dilation. Anesthesia is generally not required. The cost is approximately one-tenth
of a hospital D & C.

There is an excellent correlation between the histopathology of endometrial specimens taken by

biopsy instruments in the office and D & C [2-4] . However, when less than 50 percent of the
endometrium is affected, the malignancy can be missed (show table 2). Despite some

limitations, numerous studies have shown that the endometrium is usually adequately sampled
with biopsy techniques:

(1) A meta-analysis of 39 studies involving 7914 women compared the results of endometrial
sampling with histopathology at D & C, hysteroscopy, and/or hysterectomy [5] . The significant
findings from this analysis were: Pipelle sampling was more sensitive for the detection of
endometrial cancer and atypical hyperplasia than all other sampling devices. The detection rates
for endometrial cancer (by Pipelle) in postmenopausal and premenopausal women were 99.6 and
91 percent, respectively. The detection rate for atypical hyperplasia was 81 percent.

The specificity for all devices was 98 to 100 percent. Fewer than 5 percent of patients had an
insufficient or no sample.

(2) Another meta-analysis assessed the accuracy of outpatient endometrial biopsy in the
diagnosis of endometrial cancer [6] . The posttest probability of endometrial cancer after a
positive test was 82 percent (95% CI, 60 to 93 percent), and after a negative test it was 0.9
percent (95% CI, 0.4 to 2.4 percent). In this analysis, 15 percent (138 of 945) of specimens were
inadequate (no sample or insufficient tissue for assessment) and one case of cancer was
subsequently found among these patients.

All sampling devices perform better when pathology is global rather than focal; this has been
demonstrated repeatedly in multiple studies. As an example, the importance of the volume of
disease was illustrated in a study of 65 patients with known cancer who underwent Pipelle biopsy
prior to hysterectomy [7] . Endometrial sampling was most reliable when at least one-half of the
endometrium was affected by disease. Five patients had tumors present only in an endometrial
polyp.

For this reason, additional endometrial assessment should be performed if abnormal uterine
bleeding persists after a "benign" endometrial biopsy [8] . Benign endometrial histology includes
atrophy (absence of a hormonal effect), proliferative endometrium (estrogen effect), secretory
endometrium (progestin effect), disordered or dyssynchronous endometrium (implies irregular
shedding of the endometrium secondary to unopposed estrogen), and endometritis. Further
endometrial assessment should also be considered when the endometrial biopsy is
nondiagnostic, but a high suspicion of cancer remains [9] . Nondiagnostic biopsies may be
associated with polyps, fibroids, endometrial cancer or other lesions occupying an area of the
uterus that was not sampled. Additional endometrial assessment may include a combination of
repeat endometrial biopsy or D & C hysteroscopy combined with transvaginal ultrasonography
(TVUS) with or without sonohysterography.

If endometrial biopsy does not yield sufficient tissue for pathological diagnosis, then the clinical
setting should dictate further management. We suggest TVUS if the woman is postmenopausal
and the bleeding has not been persistent; a thin endometrial stripe in this setting is most
consistent with atrophy and does not require further invasive studies. A thick endometrial stripe,
persistent bleeding, or bleeding in a post or perimenopausal woman should be followed by
additional endometrial sampling, such as hysteroscopy with curettage.

The diagnosis of early grade endometrial cancer by pathologic evaluation is sometimes

controversial, as the distinction between high grade precancers and cancer may be unclear, and
different examiners may have different opinions regarding the diagnosis. If there is a
management decision that may be affected by this distinction, additional slide review or
additional markers may be requested.

Dilation and curettage As discussed above, endometrial biopsy in the office has generally
replaced diagnostic D & C, but there is still a role for this procedure for some women. Indications
for diagnostic D & C include: When a patient is not able to tolerate an office endometrial biopsy
(eg, due to pain or anxiety) After a nondiagnostic office biopsy in women who are at high risk of
endometrial carcinoma After benign histology on office biopsy in women who have persistent
abnormal uterine bleeding When there is insufficient tissue for analysis on office biopsy When
cervical stenosis prevents the completion of an office biopsy When a concomitant operative
procedure, such as laparoscopy, is deemed necessary

(See "Dilation and curettage").

Hysteroscopy Hysteroscopy provides direct visualization of the endometrial cavity, thereby

allowing targeted biopsy or excision of lesions identified during the procedure. However,
hysteroscopy requires more skill and is more costly and invasive than most other modalities of
endometrial assessment [9] . (See "Overview of hysteroscopy").

Patients who have one of the indications above and who proceed to diagnostic D & C should also
be consented for diagnostic hysteroscopy at the same time. Multiple studies have shown that
hysteroscopy can aid in the detection of focal lesions of the endometrial lining which may be
missed by D & C alone [10,11] . However, in one large study of 1286 women, endometrial cancer
was missed in 10 women (34.5 percent) using hysteroscopy alone. Therefore, for women at risk
for endometrial cancer, we advise performing BOTH procedures (visualization and biopsy). Small
polyps can usually be removed at the same time.

The decision as to whether to perform a diagnostic hysteroscopy in the operating room or in the
office depends upon provider preference and equipment, the indications for the procedure, and
patient comfort/preference. The option of operative/therapeutic hysteroscopy should also be

discussed with the patient. Because therapeutic hysteroscopy involves greater risk than
diagnostic hysteroscopy [12] , its use should be reserved for women at low risk of endometrial
cancer, and in whom the value of hysteroscopic resection of a lesion is clear (ie, heavy bleeding
in a premenopausal woman who desires to maintain her fertility).

Patients in whom a diagnosis of cancer is possible should have a diagnostic procedure followed
by definitive treatment.

In women at risk for cancer, the risk of possible cancer dissemination due to intraperitoneal
spillage of the endometrial cells is discussed below. (See "Risk of tumor dissemination" below).

NONINVASIVE METHODS The discussion below applies to use of noninvasive imaging

techniques to evaluate the endometrium in women with AUB.

Transvaginal ultrasound

Postmenopausal women Transvaginal ultrasound (TVUS) is used to evaluate the endometrium,

as well as the entire pelvis, noninvasively. Scanning the uterus in a sagittal view, double wall
endometrial thickness is measured in an anteroposterior dimension from one basalis layer to the
other, excluding any fluid within the cavity.

In women with postmenopausal bleeding, an endometrial thickness of less than 5 mm is

associated with a low risk of endometrial disease [13,14] . Cancer becomes increasingly more
frequent relative to benign disease as the endometrial thickness approaches 20 mm, which was
the mean endometrial thickness in 759 women with endometrial cancer in one study [14] .
Thickness measurements are applicable when the endometrium is homogeneous. Any focal
endometrial lesion requires biopsy.

The American College of Obstetricians and Gynecologists and the Society of Radiologists advise
that either TVUS or endometrial biopsy are effective as a first diagnostic step in women with
postmenopausal bleeding [15,16] . Both diagnostic modalities have similar sensitivity for
detecting endometrial carcinoma.

This conclusion was supported by a literature review including data from almost 6000 women,
which found that the probability of cancer in a postmenopausal woman with vaginal bleeding and
a 10 percent pretest probability of endometrial cancer (the average risk associated with
postmenopausal bleeding) was 1 percent following a normal (<5 mm endometrial thickness)

TVUS [17] . Given this low risk of endometrial cancer, the authors suggested that endometrial
sampling might be unnecessary in women with a negative sonogram.

However, two other meta-analyses came to a different conclusion. One such meta-analysis with
nine studies (3483 women without endometrial cancer and 380 with the disease) found that the
detection rate for endometrial cancer varied according to the criteria for judging the endometrial
thickness as abnormal [18] . The detection rate was 63 percent (95% CI 58-69) when considering
an endometrial thickness that resulted in a false positive rate of only 10 percent; however, the
detection rate increased to 96 percent (95% CI 94-98) if a false positive rate of 50 percent was
considered acceptable. The authors concluded that even with a lower threshold for calling results
suspicious, 4 percent of endometrial cancers would be missed; thus, further invasive diagnostic
testing was indicated in all symptomatic women with a "thin" endometrial thickness. They also
noted that median endometrial thickness varied among centers such that 5 mm may not be a
universally reliable threshold. The other systematic review consisted of 57 studies with 9031
patients [19] . Only four studies used the 5 mm cut-off level, which was the best-quality
criteria. Using the pooled estimates from these four studies only, a positive test result raised the
probability of carcinoma from 14 to 31 percent, while a negative test reduced it to 2.5 percent.
The authors concluded that a negative result ( 5 mm) usually excluded endometrial pathology,
but ultrasound measurement of endometrial thickness alone could not be used to reliably
exclude cancer.

As noted above, most clinical investigators have used either 4 or 5 mm as the threshold for
further assessment. A detailed discussion of choosing an approach to postmenopausal bleeding
can be found separately. (See "The evaluation and management of uterine bleeding in
postmenopausal women").

Premenopausal women In contrast to postmenopausal women, the utility of TVUS for

excluding endometrial abnormalities in premenopausal women has not been established
[20,21] . In one study of 200 premenopausal women with AUB, 16 of 80 women (20 percent) with
an endometrial stripe <5 mm were subsequently found to have an endometrial polyp or
submucosal leiomyoma as the source of their bleeding [21] .

In premenopausal women, TVUS should be performed on day 4, 5, or 6 of the bleeding cycle,

when the endometrium is expected to be its thinnest (in reproductive age women normal
endometrial thickness in the proliferative phase is 4 to 8 mm and in the secretory phase 8 to 14
mm [9] ) (show ultrasound 1) [22] . There is no standard threshold for abnormal endometrial
thickness in premenopausal women. Further evaluation should be based on the clinical situation,
including persistent abnormal bleeding not responsive to medical management or suspicion of a
structural abnormality, such as a polyp, which might require removal.

Women on HRT TVUS does NOT appear to be a useful screening tool for excluding endometrial
hyperplasia/cancer in women on estrogen replacement therapy (ERT) that is unopposed or given

with cyclic progesterone [23,24] . Thickness thresholds are not well established for such women;
as a result, endometrial sampling is still the gold standard to exclude endometrial hyperplasia
and/or carcinoma.

For women on HRT therapy, TVUS should be obtained only for standard clinical indications, such
as to assess adnexal pathology, or if abnormal bleeding occurs and an endometrial biopsy
cannot be easily obtained. In the case of abnormal bleeding in women on cyclic progesterone, it
is best to obtain the TVUS early in cycle, when the endometrium is expected to be at its thinnest.
Persistent bleeding always requires endometrial biopsy regardless of ultrasound findings. We tell
patients that bleeding is common when ERT is initiated and should decrease over time. If it does
not, and if it becomes heavier, or bleeding occurs after a long period of no bleeding, then a
biopsy is indicated.

Women on tamoxifen Women on tamoxifen, both for treatment and prevention of breast
cancer, are known to have thickened endometrial stripes. The appearance can be cystic on TVUS
due to reactivation of foci of adenomyosis. There is no clear cut-off for normal versus
pathological endometrial thickness in these patients. In general, we do not feel there is a role for
baseline endometrial assessment, but women should have an endometrial biopsy if any
abnormal bleeding occurs, as tamoxifen confers a slight increase in endometrial cancer risk
(roughly 1/1000). Since tamoxifen is associated with formation of endometrial polyps,
sonohysterography can be helpful in these women to identify those with focal disease that would
be better triaged to hysteroscopy rather than blind biopsy.

Asymptomatic women with endometrial thickening or fluid A thickened endometrium or fluid

within the endometrial cavity can be an incidental finding on an ultrasound examination
performed for an indication other than evaluation of the endometrium. Further evaluation of the
endometrium in these women is sometimes indicated. Postmenopausal women The criteria for
a thickened endometrium necessitating intervention in postmenopausal women without any
uterine bleeding (not even one spot of blood) have not been established. A well-designed
decision analysis calculated that postmenopausal women without uterine bleeding who had an
endometrial thickness >11 mm had an endometrial cancer risk of 6.7 percent, which is similar to
that in postmenopausal women with bleeding and endometrial thickness >5 mm; the risk of
endometrial cancer was less than 0.002 percent at endometrial thickness 11 mm [25] . Based
on this analysis, we suggest sampling the endometrium of postmenopausal women without
uterine bleeding who have an endometrial thickness >11 mm.

We also sample postmenopausal women without uterine bleeding with lesser degrees of
endometrial thickening if they have endometrial fluid. In most of these women, endometrial fluid
is related to cervical stenosis [26-28] . Observational studies have consistently found that
asymptomatic postmenopausal women with endometrial fluid and an endometrial thickness less
than 3 mm do not have endometrial cancer or hyperplasia [26,28-31] . However, there is an
increasing risk of endometrial cancer in women with endometrial fluid and endometrial
thickening >3 mm; therefore, we biopsy these women.

Pelvic pain, a common reason for pelvic imaging, is not an indication for endometrial sampling in
the absence of abnormal uterine bleeding or suspicious sonographic findings. Premenopausal
women In asymptomatic premenopausal women, endometrial thickness alone is not an
indication for biopsy. Endometrial evaluation should be based on a combination of factors (show
table 1), including cervical cytology results showing glandular abnormalities or endometrial cells,
a chronic history of estrogen excess or anovulation (polycystic ovary syndrome), as well as
endometrial thickness. (See "Premenopausal women" above and see "Terminology and
evaluation of abnormal uterine bleeding in premenopausal women").

Saline infusion sonography Saline infusion sonography (also called sonohysterography) is an

imaging technique in which sterile saline is instilled into the endometrial cavity and TVUS is
performed. This procedure allows for careful architectural evaluation of the uterine cavity to
detect small lesions (eg, polyps or small submucous fibroids) which may be missed on TVUS or
by blind endometrial sampling. In one study, as an example, the sensitivity and specificity of
saline infusion sonography for detection of polyps were significantly higher than for TVUS alone
(93 and 94 for SIS versus 75 and 76 percent for TVUS) [32] . (See "Saline infusion
sonohysterography").

The disadvantage of saline infusion sonography is that no tissue is obtained for histological
diagnosis and it can be uncomfortable. The lack of histologic material for diagnosis was
addressed in another study that performed both endometrial biopsy and saline infusion
sonography in 113 women age 25 to 69 years with persistent AUB who subsequently underwent
hysteroscopy/curettage or hysterectomy [33] . The sensitivity, specificity, positive and negative
predictive values of biopsy/saline infusion sonography were 97, 70, 82, and 94 percent,
respectively. False positive results were due to intrauterine debris, blood clot, thickened
endometrial folds, and misidentified endometrial fragments. The combined technique of blind
biopsy and saline infusion sonography permitted diagnosis of the cause of abnormal uterine
bleeding in most women, without the need for more invasive procedures such as hysteroscopy
[34] . A subsequent meta-analysis came to this same conclusion [35] . The combined technique
is most useful in women with a symmetrically thickened endometrium. If saline infusion
sonography shows a focal lesion, hysteroscopy should be considered.

In randomized trials, outpatient hysteroscopy was associated with more pain than saline infusion
sonography [36-38] .

As with hysteroscopy, dissemination of cancer is a theoretical concern. (See "Risk of tumor

dissemination" below).

In summary, because of the lack of a definitive diagnosis, the potential discomfort of the
procedure, and the cost, we feel saline infusion should not be used for primary evaluation of

abnormal bleeding, but only in cases in which a diagnosis is unclear after biopsy, and for whom
there is a relative contraindication to proceeding to D & C/hysteroscopy.

RISK OF TUMOR DISSEMINATION One concern with hysteroscopy and saline infusion
sonography is that fluid flushed from the endometrial cavity through the fallopian tubes can
contain endometrial cells, some of which remain viable [39-51] . (See "Overview of
hysteroscopy" and see "Saline infusion sonohysterography").

The presence of tumor cells in peritoneal washings changes the stage of a woman with
endometrial cancer to at least stage IIIA (show table 4). However, a meta-analysis of
observational studies reported no significant difference in the frequency of positive peritoneal
cytology in women with endometrial carcinoma who had or had not undergone diagnostic
hysteroscopy (OR 1.64, 95%CI 1.0-28) [51] .

The clinical significance of iatrogenic upstaging is not known, as transport of these cells does not
necessarily result in implantation and persistence. In the few studies that have reported longterm follow-up, there was no detriment to survival associated with pre-staging
hysterosalpingography (with confirmed intraperitoneal spill) [52] or hysteroscopy [53] . Further
study is needed to clarify the clinical impact of tumor cell dissemination.

INFORMATION FOR PATIENTS Educational materials on this topic are available for patients.
(See "Patient information: Endometrial cancer diagnosis and staging" and see "Patient
information: Abnormal uterine bleeding"). We encourage you to print or e-mail these topics, or to
refer patients to our public web site www.uptodate.com/patients, which includes these and other
topics.

SUMMARY AND RECOMMENDATIONS

Initial evaluation Endometrial biopsy is preferable to ultrasound as the initial test for women
with abnormal uterine bleeding due to its high sensitivity, low complication rate, and low cost.
Endometrial biopsy is a more cost-effective initial approach than ultrasound when the prevalence
of endometrial carcinoma is at least 15 percent [54] .

TVUS is an acceptable alternative initial test in postmenopausal women who cannot tolerate
office biopsy, or in women who need concurrent evaluation of the adnexae. A summary of the
literature suggests that using an endometrial cutoff of <4 mm would yield a false negative rate
for endometrial cancer of 0.25 to 0.5 percent [55] , which compares favorably with the false
negative rate reported for endometrial biopsy.

Endometrial biopsy is required for histological diagnosis if the endometrium is not adequately
visualized, the stripe is 4 mm (focal or global), and in women with persistent bleeding
[14,55,56] . Blind biopsy is most accurate in women with a globally thickened endometrium;
visually directed sampling (ie, hysteroscopy) is preferable for women with focal abnormalities.

Evaluation of persistent bleeding Persistent abnormal bleeding in peri- or post-menopausal

women is worrisome even with a benign or negative initial evaluation. Two studies have followed
patients with a negative initial biopsy, and found up to 20 percent of the patients were
eventually diagnosed with either complex atypical hyperplasia or cancer [57,58] .

Persistent bleeding is worrisome even when the endometrial thickness is <4 mm [14,59,60] ,
particularly if there are other risk factors for endometrial cancer (show table 1 and show table 3).
Endometrial cancer can still occur in this setting since serous carcinoma of the endometrium may
arise from atrophic endometrium [61] . Therefore, further diagnostic evaluation is indicated.
Depending upon the prior evaluation, a combination of repeat endometrial biopsy or D & C
hysteroscopy combined with transvaginal sonohysterography or ultrasonography should be
pursued.

Evaluation for a nonendometrial source of bleeding, such as fallopian tube or ovarian cancer,
should also be pursued.

Women who should undergo evaluation for endometrial hyperplasia

or endometrial cancer
Over age 40 years with abnormal uterine bleeding
Under age 40 years with abnormal uterine bleeding and risk factors (eg,
chronic anovulation, obesity, tamoxifen diabetes, family history of
endoemtrial/ovarian/breast/colon cancer)
Failure to respond to medical treatment of abnormal uterine bleeding

Women with uterus in situ receiving unopposed estrogen replacement therapy

Presence of atypical glandular cells on cervical cytology
Presence of endometrial cells on cervical cytology in a woman 40 years of age
Women with hereditary nonpolyposis colorectal cancer
False negative endometrial biopsy in women
with endometrial cancer undergoing
hysterectomy
Percent of
Number Cancer
endometrial cavity
of
missed on
affected by disease
patients sampling
Less than 5
3
3
5 to 25
12
4
26 to 50
20
4
over 50
30
0
Adapted from Guido, RS, Kanbour,
A, Ruhn, M, Christopher son, WA. J
Reprod Med . 1995; 40:553

Risk factor for endometrial cancer

Increasing age
Unopposed estrogen therapy
Late menopause (after age 55)
Nulliparity
Polycystic ovary syndrome (chronic
anovulation)
Obesity
Diabetes mellitus
Hereditary nonpolyposis colorectal
cancer
Tamoxifen therapy
Early menarche
Estrogen secreting tumor
Family history of endometrial, ovarian,
breast, or colon cancer
NA: RR not available.

Relative risk
(RR)
NA
2 to 10
2
2
3
2 to 4
2
22 to 50
percent
lifetime risk
2/1000
NA
NA
NA

Adapted from data in Smith, RA, von Eschenbach, AC, Wender, R, et al. American Cancer Society
Guidelines for Early Endometrial Cancer Detection: Update 2001.