International Journal of Gynecological Pathology

29:4450, Lippincott Williams & Wilkins, Baltimore

r 2009 International Society of Gynecological Pathologists

Original Article

Chronic Endometritis: A Combined Histopathologic

and Clinical Review of Cases From 2002 to 2007

Matthew Smith, M.D.,Kori A. Hagerty, M.D., Betty Skipper, Ph.D.,

and Therese Bocklage, M.D.

Summary: Chronic plasmacytic endometritis (CPE) is an infectious or reactive process

with multiple etiologies. The lesion is reportedly often associated with pelvic
inammatory disease and intermenstrual bleeding. However, the clinical signicance
of the diagnosis when found incidentally and whether particular pathologic ndings are
associated with clinically important CPE have not been evaluated. We reviewed 105
chronic endometritis cases that had been diagnosed earlier and 130 controls to examine
the pathologic and clinical associations in a diverse population. A pathology database
was searched for endometrial biopsies diagnosed as CPE, and 105 cases were found.
Systematic randomized sampling identied 130 control cases (biopsies not diagnosed as
CPE). Slides were carefully reviewed to assess 10 histopathologic features. Clinical
records were reviewed for 15 clinical parameters. Analysis was performed using w2 tests
and SAS software. Few patients (3%) received antibiotics or further clinical intervention
after the diagnosis of CPE was rendered. The clinical data trended toward fewer
menstrual abnormalities as plasma cells increased. The intensity of inammation
showed no association with patient age or symptom duration. Evaluation of controls
revealed 17 cases with missed diagnosis of CPE, representing an overall 16%
underdiagnosis rate. In CPE, there are no specic clinical features that correlate with
the intensity of pathologic ndings; the most specic histologic feature is the presence of
plasma cells, and it is predominantly identied in weakly proliferative endometrium.
There is a clinically insignicant 16% pathologic underdiagnosis rate. In contrast to the
ndings of past studies, only a small percentage of patients had pelvic inammatory
disease (4%). Key Words: Chronic endometritisPlasma cellsPlasmacyticPelvic
inammatory diseaseEndometrial inammation.

Chronic plasmacytic endometritis (CPE) is con-
sidered an infectious or reactive process. Commonly
cited causes include transvaginal infection, intrauter-
ine devices (IUDs), submucosal leiomyoma, and
From the Department of Pathology (M.S., T.B.); Department of
Family and Community Medicine (B.S.), University of New
Mexico School of Medicine, Albuquerque, New Mexico; and
Department of Family Medicine (K.A.H.), Southern Regional
Area Health Education Center, Fayetteville, North Carolina.
Address correspondence and reprint requests to Therese
Bocklage MD, Department of Pathology, MSC08 46401 1,
University of New Mexico, Albuquerque, NM 87131. E-mail:
Tbocklage@salud.unm.edu.
endometrial polyp; in other words, almost any cause
of chronic irritation to the endometrium may result in
a chronic inammatory reaction (1). The histopatho-
logic diagnosis is characterized by endometrial
inammation rich in plasma cells with or without
accompanying acute inammation and lymphocytes
(2). Lymphocytes are a known normal component of
the endometrial stroma, whose number uctuates
with the phase of the cycle (3). However, in CPE their
numbers are increased (2). Although the diagnostic
criteria for signicant (eg, clinically signicant)
chronic endometritis remain controversial, it is
generally agreed that the presence of plasma cells

DOI: 10.1097/PGP.0b013e3181ae81bb 44
 CHRONIC ENDOMETRITIS 45

within the endometrial stroma is the most useful TABLE 1. Assessed clinical and histologic characteristics
histologic criterion for diagnosis (2). In addition to Clinical criteria Histological criteria
plasma cells, a variety of other features can alert the Age Phase of cycle
reviewing pathologist to the possible presence of Ethnicity Number of plasma cells
CPE. Disturbances in normal growth and matura- Metrorrhagia Lymphocytes
Lower abdominal pain Neutrophils
tion, supercial mucosal stromal edema, stromal Menorrhagia Macrophages
breakdown, and characteristic spindle cell alteration Menometrorrhagia Eosinophils
of the stroma are other morphologic changes that can Dysmenorrhea Spindled stroma
Duration of symptoms Epithelial changes
be seen with CPE (1,2). Menstrual status Vasculitis
There are few large (100 cases or more) published Pregnancy status Original diagnosis
studies statistically examining both the histopathol- Hormonal contraceptive use Amount of tissue
Form of treatment
ogy and clinical ndings of CPE in an ethnically Cultures performed
heterogeneous population. Evaluation of CPE in a History of pelvic inammatory
signicant Native American population has not disease
Resolution of symptoms
occurred. We hypothesized that thorough examina-
tion of the histopathologic ndings and clinical Clinical and histological criteria were collected on each specimen
and associated patient.
history of CPE would further elucidate its clinical
signicance and major histopathologic features, and
would provide information with regard to the most ensure that all fragments in the tissue section were
common associated or causative conditions. examined. Three levels were reviewed for each biopsy;
only 1 level was reviewed by the grid. Chi-square tests
were used to test for dierences between groups, and
the binomial distribution was used to calculate 95%
MATERIALS AND METHODS
condence limits for the undiagnosed CPE propor-
We undertook a retrospective chart and biopsy tion. SAS software was used for the analysis.
review that focused on the collection of clinical data
and the examination of endometrial tissue samples
obtained from patients seen at the University of New RESULTS
Mexico Health Sciences Center (Albuquerque, New
Mexico) between 2002 and 2007. A total of 235 The mean age of the patients was 46 years, with a
endometrial biopsies were culled from the les: 105 range between 21 and 86 years of age. There were no
women with a diagnosis of chronic endometritis age or ethnic dierences (Anglo, Hispanic, Native
matched to 130 women of similar age and menstrual American, other) related to the diagnosis of CPE
status without that diagnosis. The search was versus non-CPE. Overall results are listed in Table 2.
performed by using the surgical database software The largest dierence between the control and CPE
program Tamtron PowerPath (IMPAC Medical groups occurred among White, non-Hispanic women,
Systems, Inc. 2310 Corporate Circle, Suite 275 with 5% fewer such patients in the CPE group
Henderson, NV 89074) for endometrial biopsies. (P40.05). Premenopausal women represented the
Curettage specimens were not included. Patients were largest number of individuals (43%) in the overall
excluded if their biopsies were known to contain sample. Premenopausal women composed 34% of
hyperplasia or carcinoma. CPE cases, whereas menopausal and postmenopausal
The original diagnoses were made on the basis of made up 42% and 19%, respectively. Five percent of
the identication of stromal plasma cells. Subse-
quently, for this study, 1 senior pathologist assessed
biopsies for 11 histologic criteria, whereas 2 other TABLE 2. Overall study data
investigators reviewed patient charts for 15 clinical Control CPE
criteria (Table 1); collection of data and slide No. cases 130 105
examination occurred independently. The degree of Mean age (yr) 44 48
Mean degree of inammation None Moderate
plasmacytic inammation was determined as number Mean duration of symptoms (yr) o1 o1
of plasma cells per 40  high-power eld (HPF) Datable endometrium (%) 61 51
using an Olympus BX40 microscope. The pathologist Overall results for both CPE and control cases.
used a grid hand drawn on 1 level of each case so as CPE indicates chronic plasmacytic endometritis.

Int J Gynecol Pathol, Vol. 29, No. 1, January 2010

46 M. A. SMITH ET AL.
the patients had no veriable menstrual status. The
majority (80%) of the women in our study had been
pregnant twice or more. Of the entire study popu-
lation, 24% of the women had used exogenous
hormones (oral contraceptive pills, hormone replace-
ment therapy, etc) at the time of biopsy.
There were no signicant associations with regard
to the presence of neutrophils or eosinophils or the
presence or type of reactive epithelial change
(squamous metaplasia, tubal metaplasia, eosinophilic
syncytium, mixed metaplasia) with the degree of
chronic inammation. Histopathologic review re-
vealed a statistically signicant presence of spindled
stroma in cases with a high number of plasma cells
and a trend toward proportional increases in spind-
ling with higher degrees of inammation (Fig. 1).
Chronic endometritis was identied in a number of
cases (51%), with nonaltered endometrium of all
phases of the cycle, including secretory (Fig. 2).
Macrophages were also shown to be statistically
signicant in cases of endometritis, with a trend
toward higher numbers of macrophages with lower
numbers of plasma cells. Lymphocytes increased in
number as the plasma cell inltrate increased
(Po0.001). In cases of minimal-to-mild plasmacytic
inammation, there were 26 cases of mild lymphocy-
tic presence, 19 moderate, and 13 orid. Among CPE
cases with moderate or greater inammation, there
were 0 cases of no lymphocytic inammation, 9 cases
of mild inammation, 12 of moderate inammation,
and 21 of orid inammation. Most cases of CPE had
minimal (o10 per HPF) to moderate (20 to 50 per
HPF) numbers and fewer had orid (50 to 100 per
HPF) or extraorid amounts (4100 per HPF) (Fig. 2).
The degree of inammation was rst assessed by
FIG 1. Hematoxylin and eosin stained photograph showing
spindeled stroma in presence of chronic plasmacytic endometritis.
Int J Gynecol Pathol, Vol. 29, No. 1, January 2010
high-power microscopic review, and the case was
scored according to the most inamed area on the
slide. All cases contained at least 2 elds with plasma
cells present. Plasma cells were most noticeable
clustered around stromal vessels (Fig. 3) as opposed
to at or immediately below the endometrial surface.
Investigation into associated ndings showed that
cases involving hyperplasia, polyps, and carcinoma
made up less than 5% of cases, and showed no
statistically signicant association with degree of
chronic inammation. Of the specimens with secre-
tory stroma, 1 case had concurrent tubal metaplasia.
The remainder of cases in secretory phase did not
have abnormal epithelial changes. Five patients were
noted to have histologic evidence of a prior preg-
nancy; these patients were excluded from the study.
Examination of the control cases revealed 17 cases
(16%) of CPE that were not diagnosed as chronic
endometritis by the original reviewing pathologist
(Fig. 4). Of these, 5% of total control cases were of
moderate to extraorid inammation. This nding
of undiagnosed CPE was statistically signicant
(Po0.05) when compared with the CPE group, with
a condence interval of 0.02 to 0.12.
Only 3 patients received antibiotics after the
diagnosis of chronic endometritis was reported
(2.8%). These patients did not have clinical symp-
toms of fever, pain, or elevated white blood cell
counts to distinguish them clinically from nonspeci-
cally treated patients. The few patients treated did
not have CPE that was orid or extraorid in degree.
The duration and type of symptoms (menorrhagia,
menometrorrhagia, postmenopausal bleeding, etc)
did not dier statistically between CPE patients and
the age-matched control group (Fig. 5). Younger
patients (o45 y) did not dier in the range of
histopathologic features when compared with pa-
tients aged 45 years or above.
DISCUSSION
Our study conrmed that the reported histologic
features of CPE diagnosed earlier, including inam-
mation comprising plasma cells, lymphocytes, and
sometimes neutrophils and eosinophils; alterations in
proliferative or secretory phase pattern; and stromal
breakdown, are commonly observed in CPE (1,2). A
direct correlation in lymphocyte numbers with
plasma cell numbers is commonly observed, as is an
association with lymphoid follicles (1,2). In our
study, there was a greater propensity for plasma cells
 CHRONIC ENDOMETRITIS
FIG 2. Histogram of spectrum of chronic plasmacytic endometritis and number of cases by datability.
to aggregate around deeper stromal vessels than at
the endometrial surface, as has been reported earlier
(4,5). Our ndings share some similarities with an
earlier clinical review by Cadena et al. (6). However,
that study did not correlate histologic ndings with
clinical signs and symptoms. In addition, Cadena et
al. found that one third of their patients had pelvic
inammatory disease (PID) and 11% had an IUD.
These numbers are much higher than in our study,
and it is not clear why there is such a large dierence.
The dierence may be related to a lower rate of PID
and IUD placement in our patient population. New
methods of IUD placement and new devices may
diminish or abrogate an inammatory response. It is
also possible that the retrospective chart review
design of our study compromises some accuracy in
clinical data when the medical record is incomplete or
FIG 3. Hematoxylin and eosin stained photograph showing high
numbers of plasma cells clustered around stromal vessels.
47
incorrect. The records abstracted for this study were
those of an academic medical institutition with
electronic charting, and seemed to be complete. In
addition, the Cadena et al. study did not report a
possible miss rate of histologic diagnosis of chronic
endometritis, as our review does.
A recent study by Cicinelli et al. (7) suggests using a
triad of hysteroscopy, standard microbiology culture,
and endometrial biopsy to best assess for the presence
of CPE. This well-designed, prospective study re-
ported an 89% correlation of hysteroscopy (micro-
polyps, congestion, and edema) and histology for
CPE, coupled with a high microbiology culture rate
of 73%. In this study, the histologic criteria used for
the diagnosis of CPE are unclear. In addition, it is
likely that a high degree of inammation is necessary
for the development of micropolyps. As the presence
FIG 4. Histogram comparing chronic plasmacytic endometritis
(CPE) and controls by menstrual status and including number of
undiagnosed cases.
Int J Gynecol Pathol, Vol. 29, No. 1, January 2010
48 M. A. SMITH ET AL.

FIG 5. Histogram comparing chronic plasmacytic endometritis (CPR) and control cases by clinical symptoms.

of micropolyps was the largest factor in predicting a study by Cicinelli et al. (7) described a potential
diagnosis of CPE, it is likely that the population of signicant relationship with their triad of ndings
patients with CPE in this study makes up a smaller (positive culture, hysteroscopic features of CPE and
swath of the overall CPE population, comprising histologic evidence of CPE) and infertility. None of
only those patients with more orid inammation. By the patients in our study presented with this
contrast, our study consists of the entire histologic complaint, which again, was a notable dierence
spectrum of patients with CPE, including patients between Cicinellis patients and the current patient
with minimal inammation unlikely to result in group.
hysteroscopically identiable micropolyps. It would When comparing clinical history with histopathol-
be useful to determine whether patients with CPE of ogy, we found no association between the degree of
minimal degree correlate histologically with a lower inammation and age, the duration of symptoms and
rate of positive microbiology culture. age, or the types of symptoms and age (grouped as
Although current textbook descriptions state that o45 y and Z45 y). These ndings suggest that the
the endometrium is altered and not datable in the degree of chronic inammation may not directly
setting of CPE, we found that chronic endometritis impact symptoms, and are consistent with those of
was identied in a number of cases with nonaltered other studies (6,8). The lack of clear association is in
endometrium of all phases of the cycle, including
secretory (Fig. 6). This nding suggests that the
endometrial stroma and cycling is not always aected
to the point of disturbing the endometrial phase.
Although almost half the cases had stromal break-
down, the nding was not a signicant association,
though other studies suggest an inammatory rela-
tionship in such cases (5). In fact, few of the
histologic ndings track in a signicant fashion with
clinical features. This lack of correlation may be the
result of the variety of histologic ndings that may be
present, of which only 1, the presence of plasma cells,
is a key feature. Furthermore, despite a vigorous
semiquantitation of the plasma cells in our patients
biopsies, the number of these cells also does not
correlate with clinical features. The patients in this
FIG 6. Hematoxylin and eosin stained photograph showing
study showed the same clinical symptoms and clinical nonaltered proliferative endometrium in a case of chronic
history as the control group. The aforementioned plasmacytic endometritis.

Int J Gynecol Pathol, Vol. 29, No. 1, January 2010

 CHRONIC ENDOMETRITIS
accord with the earlier large study by Cadena et al.
(6) comprising 152 patients. The lack of any
association between distinct histologic features or
clinical symptoms and patient ethnicity is similar to
the ndings in the Cadena et al.s study.
The 16% calculated underdiagnosis rate is poten-
tially important. When adjusted for greater degrees of
inammation than the minimal criterion of rare
plasma cells, the rate decreases to 5%, which remains
a relatively high number of undetected CPE cases,
given the frequency of endometrial biopsies per-
formed. This rate is consistent with an earlier study
showing an underdiagnosis rate when examining
apparently normal proliferative tissues with methyl
green pyronin of 18% (5). The underdiagnosis rate is
most likely attributed to plasma cells being over-
looked. Our examination using a grid assured
complete, comprehensive review that is not normally
achieved in routine pathology practice. It would be
unusual for the original diagnosis pathologist to use
this technique, and this likely accounts for the
majority of underdiagnosed cases.
Interestingly, there was no association between
severity of histopathology and clinical treatment, and
only a few patients actually received antibiotic
therapy. Review of clinical documentation shows
that intervention (in terms of antibiotic therapy) was
rarely performed in reaction to the CPE diagnosis.
Treatment usually comprised surgical ablation, cur-
ettage, or simple hysterectomy. Thus, in the current
treatment setting, clinicians seem to nd it unneces-
sary to treat CPE patients with antibiotics, despite
the classic association of CPE with several bacterial
etiologies, including Neisseria gonorrhea, Chlamydia,
and Mycoplasma. Cicinelli et al. (7) found that in
addition to these bacteria, 70% of CPE cases resulted
from nongonococcal, nonchlamydial infections in-
cluding common bacteria such as Escherichia coli,
Streptococci, and Enterococcus faecalis. Our study
did not include bacterial cultures of the endometrial
biopsies, as it comprises a retrospective review, and
attempts to culture the endometrium require a special
approach not routinely undertaken at the time of
endometrial biopsy.
It is well known that there is an association
between PID and its associated organisms (Chlamy-
dia and Neisseria gonorrhea) (1,6,9). In young women
with clinical signs and symptoms of PID, clinicians
currently reexively treat with cefotetan and doxycy-
cline (10). As new information suggests that the
variety of possible etiological organism is broad, even
broad spectrum antibiotics would likely miss many of
49
the possible infectious causes of CPE. Additional
studies have shown that curettage and antibiotic
treatment decrease the degree of inammation in
cases of CPE (11,12). At our institution, treatment
performed on patients with CPE seems to be aimed at
addressing symptoms and not at a possible infectious
etiology, as only a small minority of clinicians
prescribed antibiotics after the diagnosis of CPE
was reported to them.
One of the goals of our study was to examine
whether a particular suite of histologic features
correlated with distinct clinical features. We did not
nd any such associations. A secondary goal was to
determine whether a critical threshold of histologic
features (either in number of features or intensity of
inammatory changes) predicted a particular clinical
presentation (such as fever, pain, other evidence of
PID). In our patient group, no set of histologic
features or degree of intensity of inammation
predicted a particular clinical presentation, a re-
sponse by the clinician to prescribe antibiotics, or
outcome. Currently, most cases of CPE are attributed
to PID, other common bacteria, polyps, past clinical
or surgical procedures, and the presence of IUDs
(2,9,10). The retrospective nature of our study
identied few cases where cultures were performed
coinciding with biopsies. Review of clinical histories
did not reveal any cases diagnosed by the clinicians as
PID, and only a single patient was noted to have an
IUD. Finally, the presence of polyps was rare and not
statistically signicant in comparison with the control
group.
In conclusion, the histologic diagnosis of chronic
endometritis comprises a variety of features and
varying degrees of intensity of inammation that do
not show any correlation with clinical features such
as type of symptoms, duration of symptoms, and
severity of symptoms. Premenopausal and postme-
nopausal women do not dier in the degree or type of
inammatory response that occurs in CPE. The
current patient population diers from the last large
patient cohort study in that there are no patients with
PID in the current patient group and only 1 patient
with an IUD. As few clinicians in this study treated
their patients with antibiotics, a miss-rate of up to
16% of cases may not be signicant, as such patients
were treated identically to those patients in whom a
diagnosis of chronic endometritis was rendered.
Microbiology cultures were not obtained in the
majority of the patients in this study; a recent study
in which such cultures were obtained (and found a
high rate of positivity and a high rate of infertility)
Int J Gynecol Pathol, Vol. 29, No. 1, January 2010
50 M. A. SMITH ET AL.
most likely included only patients who would qualify
as having orid or extraorid CPT, according to 1. Mod Pathol 2001;14:8779.
our criteria. It is unknown whether patients with
more minimal histologic examples of chronic endo-
metritis have a similar (90%) rate of positive
microbiology culture.
Acknowledgment: There was no pharmaceutical or indus-
trial support for this project.
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