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139
Does Hysteroscopy Facilitate Tumor Cell
Dissemination?
Incidence of Peritoneal Cytology from Patients with Early Stage Endometrial Carcinoma
following Dilatation and Curettage (D & C) versus Hysteroscopy and D & C
Andreas Obermair, M.D.1
Magda Geramou, M.D.1
Fatih Gucer, M.D.2
Ursula Denison, M.D.3
Anton H. Graf, M.D., Ph.D.4
Elisabeth Kapshammer, M.D.5
Walter Neunteufel, M.D.6
Inge Frech, M.D.7
Alexandra Kaider, M.Sc.8
Christian Kainz, M.D.1
for the Austrian Gynecologic
Oncology Study Group
1
Division of Gynecology, Department of Gynecology and Obstetrics, University Hospital of Vienna,
Vienna, Austria.
2
Department of Gynecology and Obstetrics, University Hospital of Graz, Graz, Austria.
3
Department of Gynecology and Obstetrics, General Hopital Wilhelminenspital, Vienna, Austria.
4
Department of Gynecology and Obstetrics, General Hospital Salzburg, Salzburg, Austria.
5
Department of Gynecology, Hospital Barmherzige
Schwestern, Linz, Austria.
6
Department of Gynecology and Obstetrics, General Hospital Dornbirn, Dornbirn, Austria.
7
Department of Gynecology and Obstetrics, Kaiser
Franz Josef Hospital, Vienna, Austria.
BACKGROUND. In several case reports, distension and irrigation of the uterine
cavity during fluid hysteroscopy was suspected to cause tumor cell dissemination
into the abdominal cavity in patients with endometrial carcinoma. It was the aim
of this study to compare the incidence of positive peritoneal cytology in patients
who underwent dilatation and curettage (D & C) with or without previous hysteroscopy.
METHODS. The authors conducted a multicentric, retrospective cohort analysis.
One hundred thirteen consecutive patients with endometrial carcinoma treated
between 1996 and 1997 were included. Endometrial carcinoma had to be limited to
the inner half or less than the inner half of the myometrium (pathologic Stage
IA,B). Positive peritoneal cytology was obtained during staging laparotomy. Patients underwent D & C either with or without prior diagnostic fluid hysteroscopy.
No selection or randomization was applied to the two groups. Positive peritoneal
cytology, defined as malignant or suspicious, was considered the primary statistical
endpoint.
RESULTS. Peritoneal cytology was suspicious or positive in 10 of 113 patients (9%).
The presence of suspicious or positive peritoneal cytology was associated with a
history of hysteroscopy (P 5 0.04) but not with myometrial invasion (P 5 0.57),
histologic subtype (P 5 1.00) or grade (r 5 0.16, P 5 0.10), or the time between D
& C and staging laparotomy (r 5 0.04, P 5 0.66).
CONCLUSIONS. Based on the limited extent of endometrial carcinoma in the current
analysis, our data strongly suggest dissemination of endometrial carcinoma cells
after fluid hysteroscopy. Determining whether a positive peritoneal cytology affects
the prognoses of patients without further evidence of extrauterine disease will
require longer follow-up. Cancer 2000;88:139 – 43.
© 2000 American Cancer Society.
KEYWORDS: endometrial carcinoma, peritoneal cytology, tumor cell dissemination,
hysteroscopy, dilatation and curettage.
8
Department of Computer Sciences/Biometrics,
University Hospital of Vienna, Vienna, Austria.
The authors acknowledge the contributions of
the following institutions and pathologists/cytologists: Department of Clinical Pathology/Gynecopathology, University Hospital of Vienna,
Vienna, Austria (G. Breitenecker, M.D.); Department of Gynecology and Obstetrics, University
Hospital of Graz, Graz, Austria (H. Pickel, M.D.);
Department of Clinical Pathology, General Hospital Wilhelminenspital Vienna, Vienna, Austria
(K. Kofler, M.D., and G. Rona-Selnic, M.D.); Department of Clinical Pathology, General Hospital
© 2000 American Cancer Society
Salzburg, Salzburg, Austria (O. Dietze, M.D.);
Hospital Barmherzige Schwestern Linz, Linz,
Austria (W. Sega, M.D.); Department of Clinical
Pathology, General Hospital Dornbirn, Dornbirn,
Austria (G. Breitfellner, M.D.); Department of
Clinical Pathology, Kaiser Franz Josef Hospital,
Vienna, Austria (M. Klimpfinger, M.D.).
Address for reprints: Andreas Obermair, M.D., Department of Gynecology and Obstetrics, University
Hospital of Vienna, Waehringer Guertel 18-20;
A-1090 Vienna, Austria.
Received April 8, 1999; revision received August 2,
1999; accepted August 2, 1999.
140
CANCER January 1, 2000 / Volume 88 / Number 1
P
atients with endometrial carcinoma commonly
present with abnormal uterine bleeding as a leading symptom.1,2 Endometrial carcinoma is usually diagnosed as an organ-confined disease, with 5-year
disease free survival rates of 90% and 80% for patients
with Stage IA and B disease, respectively.3 Although
there is some debate regarding whether a positive
peritoneal cytology worsens the prognosis in the absence of further extrauterine disease, patients with
organ-confined endometrial carcinoma who present
with malignant cells in the peritoneal washing have
to be classified as Stage IIIA according to the current International Federation of Gynecology and Obstretrics (FIGO) staging classification.4
In order to improve the sensitivity of dilatation
and curettage (D & C), hysteroscopy has been established as a feasible and widely accepted procedure for
the assessment of abnormal uterine bleeding within
the last decade.5–7 Though it is a common practice, the
role of hysteroscopy in diagnosing endometrial carcinoma is not yet established. An increasing number of
case reports assume abdominal dissemination of malignant cells during hysteroscopy in patients with endometrial carcinoma.8 –12 Until now, systematic investigation of tumor cell dissemination by hysteroscopy
has failed because of ethical reservations. Several authors have expressed the concern that distension and
irrigation of the uterine cavity with fluid media may
increase intrauterine pressure and thereby facilitate
the dispersion of malignant cells through the fallopian
tubes into the abdominal cavity. However, it has not
been clarified whether tumor cell dissemination is
more frequent when D & C is combined with hysteroscopy compared with D & C alone.
A search of the WINSPIRS MEDLINE database
(1985–1999) found no study that compared the incidence of positive peritoneal cytology in endometrial
carcinoma patients with or without previous hysteroscopy. Therefore, the aim of the current study was to
evaluate the incidence of positive peritoneal washings
in patients with early stage endometrial carcinoma in
the inner half or less than the inner half of the myometrium, and to compare these findings for patients
who underwent hysteroscopy plus D & C with those
for patients who only had D & C prior to surgical
staging.
MATERIALS AND METHODS
Patients
The authors conducted a multicentric, retrospective
chart review of all patients who underwent D & C with
or without prior diagnostic hysteroscopy as a single
procedure for abnormal uterine bleeding. Data for this
analysis were collected from 113 patients who had
undergone surgery for endometrial carcinoma between 1996 and 1997 at 7 Austrian hospitals. At all
participating institutions, patients with abnormal
uterine bleeding were diagnosed by D & C as well as by
means of a diagnostic hysteroscopy. However, due to
organizational circumstances (scheduling, equipment
problems), hysteroscopy was not performed in 39 of
113 cases. Patients were included if they had histologically proven endometrial carcinoma invading half or
less than half of the myometrium and evaluable peritoneal cytology. World Health Organization (WHO)
criteria were used for histologic classification. Surgery
records and histologic findings were used to determine the stage of disease according to the FIGO 1988
criteria.4
Treatment
All procedures were carried out under general anesthesia. The cervix was dilated sufficiently to Hegar size
6 in order to allow insertion of a standard 4-mm
telescope with a 5-mm diagnostic sheath. The uterine
cavity was generally distended with normal saline up
to a pressure of 150 mmHg, in order to allow full
inspection. All pathologic specimens were obtained
with a blind D & C, which was carried out after hysteroscopy. In cases of histologically verified endometrial carcinoma, the standard surgical procedure consisted of a total abdominal hysterectomy (TAH) with
bilateral oophorectomy (BSO). In patients with myometrial invasion of up to one-half of the inner myometrium, we do not perform lymph node dissection
on a routine basis, because positive pelvic lymph
nodes are present in 3– 6% of the patients.13 Nevertheless, in 3 patients with pathologic Stage IA and 18
patients with pathologic Stage IB, a pelvic lymph node
sampling was performed. Peritoneal cytology was obtained before hysterectomy by peritoneal washing of
the pouch of Douglas, using 100 –200 mL of sterile
saline. After centrifugation at 3000 g for 10 minutes,
the pellets were stained with May-Grünwald-Giemsa
and Papanicolaou stains. Peritoneal cytology was considered positive or suspicious regardless of the degree
of positive or suspicious cytology.
Statistical Methods
Peritoneal cytology was considered the primary statistical endpoint of this analysis. Frequency distributions
of ordered categoric variables were compared by
means of exact Wilcoxon rank sum tests. Correlation
between dichotomous variables were tested using
Fisher exact tests, and correlations between continous
or ordered categoric variables were estimated by the
Spearman rank correlation coefficient. Reported P values are two-sided and a P value , 0.05 was considered
Hysteroscopy and Endometrial Carcinoma/Obermair et al.
TABLE 1
Patients Characteristics
Peritoneal cytology
Negative
Suspicious
Malignant
Myometrial invasion
None
,50%
Histologic subtype
Endometrioid
Others
Grading
G1
G2
G3
Time between D & C
and TAH/BSO
(days) (Median;
quartiles)
All
patients
HSK 1 D & C
n 5 74
D&C
n 5 39
P value
103
5
5
65 (87.8%)
4 (5.4%)
5 (6.8%)
38 (97.5%)
1 (2.5%)
0
0.046a
20
93
12 (16.2%)
62 (83.8%)
8 (20.5%)
31 (79.5%)
0.609b
102
11
67 (90.5%)
7 (9.4%)
35 (89.7%)
4 (10.3%)
1.000c
56
41
11
37 (52.8%)
27 (38.6%)
6 (8.6%)
19 (50.0%)
14 (36.8%)
5 (13.2%)
0.666c
16 (8,27)
13 (8,27)
20 (11,26)
0.146
HSK: hysteroscopy; D & C: dilatation and curettage.
a
Exact Wilcoxon rank sum test (one-sided).
b
Exact Wilcoxon rank sum test (two-sided).
c
Fisher exact test.
significant. A one-sided Wilcoxon rank sum test was
performed to compare peritoneal cytology with the
application of hysteroscopy, because there is no rationale for increased tumor cell dissemination by D & C
alone compared with hysteroscopy followed by D & C.
RESULTS
Analysis was based on the data of 113 patients with
endometrial carcinoma who had D & C prior to TAH/
BSO. Seventy-four patients underwent a hysteroscopy
before D & C, and in 39 patients D & C was performed
without prior hysteroscopy.
The mean age of the patients was 64 years (range,
43– 86 years). Twenty patients were regarded as Stage
IA (tumor confined to the endometrium) and 93 as
Stage IB (tumor confined to the inner half of the
myometrium). Overall, we found peritoneal cytology
to be suspicious or positive in 10 of 113 cases (8.8%).
Patient characteristics showed that the patients were
similar with regard to pathologic stage, histologic type
and grade, and the time period between D & C and
TAH/BSO (Table 1). The presence of suspicious or
carcinoma cells within the peritoneal fluid was associated with a history of hysteroscopy (P 5 0.04) but not
with myometrial invasion (P 5 50.57), histologic subtype (P 5 1.00), grade (r 5 0.16, P 5 0.10), or the time
between D & C and staging laparotomy (r5 0.04, P 5
0.66).
141
Strong evidence for tumor cell dissemination was
also suspected in 1 case of a patient age 65 years with
an undifferentiated Stage IA endometrioid-type adenocarcinoma. During staging laparotomy, which was
performed 16 days (quartiles: 8, 27) after hysteroscopy
and D & C, we found not only positive peritoneal
cytology but also a single islet of carcinomatous tissue
on the surface of the uterine corpus. No other cases
with positive peritoneal cytology presented with visible carcinomatous tissue within the abdomen. The
clinical and histopathologic features of all patients
with positive peritoneal cytology are given in Table 2.
DISCUSSION
These data strongly suggest hysteroscopic tumor cell
dissemination of endometrial carcinoma cells in the
course of fluid hysteroscopy. In a retrospective chart
analysis of patients with endometrial carcinoma invading half or less than half of the myometrium
(pathologic Stage IA,B), we found positive peritoneal
washings to be significantly more frequent for patients
who underwent hysteroscopy before surgical staging
than for those who underwent D & C alone. Five of 113
patients with pathologic Stage IA,B endometrial carcinoma had suspicious cytology and an additional 5
patients had positive cytology. Four of the five patients
with suspicious cytology had had hysteroscopy prior
to surgical staging, whereas only one of those patients
was diagnosed by D & C alone. All of the five patients
with positive peritoneal cytology had had hysteroscopy prior to staging laparotomy. Analysis was restricted to patients with involvement of the inner half
of the myometrium, because the incidence of positive
peritoneal cytology is much higher in patients with
involvement of the outer half of the myometrium.14 In
patients in whom cancer was restricted to the inner
half of the myometrium, the finding of positive peritoneal cytology would therefore be much more indicative of tumor cell dissemination, compared with patients with involvement of the outer half of the
myometrium. Due to the multicentric design of this
study, the position of the tumor within the uterine
cavity and the presence of vascular space involvement
were not evaluated.
Although diagnostic hysteroscopy is widely used
for the diagnosis of endometrial hyperplasia or carcinoma, a clear statement of acceptance from a medical
point of view has not been issued regarding tumor cell
dissemination into the peritoneal cavity in association
with endometrial carcinoma.
The authors of various case reports discussed an
association between hysteroscopy and abdominal dissemination of malignant cells into the peritoneal cavity. Romano et al.8 reported a case of clinical Stage IA,
142
CANCER January 1, 2000 / Volume 88 / Number 1
TABLE 2
Clinical and Histologic Features of Patients with Positive Peritoneal Cytology
Patient
Initials
Age
(yrs)
HSK
Cytology
Myometrial
invasion
Histologic type
Grading
Time betw D & C 6 H
and laparoto (days)
1
2
3
4
5
6
7
8
9
10
SC
RO
BA
HO
DO
WU
DE
KA
BR
BE
70
56
60
61
78
67
77
46
72
75
Y
Y
Y
Y
Y
Y
Y
Y
Y
N
S
S
M
S
M
M
M
M
S
S
,50%
NONE
,50%
,50%
,50%
,50%
,50%
,50%
,50%
,50%
MMT
END
END
END
END
END
END
END
END
END
1
2
1
2
3
2
2
2
2
24
35
23
3
13
19
13
19
10
29
HSK: hysteroscopy; D & C: dilatation and curettage; Y: yes; N: no; S: suspicious; M: malignant; MMT: malignant mixed mesodermal tumor (Müller); END: endometrioid.
Grade 2 endometrial adenocarcinoma diagnosed by
hysteroscopy and endometrial biopsy. Positive cytology was found during surgical staging. Schmitz and
Nahhas9 reported a case of a patient age 63 years who
underwent hysteroscopy followed by D & C. Three
weeks later, malignant cells were found in pelvic
washings during laparotomy. Another case with Stage
IA Grade 1 adenocarcinoma of the endometrium has
been reported from our hospital.10 A hysteroscopy was
performed after peritoneal cytology had been obtained by peritoneal washing with saline. In contrast
to the first washing, a second peritoneal lavage that
was carried out immediately after hysteroscopy demonstrated positive cytology. Rose et al.12 reported a
case of a patient age 39 years with endometrial carcinoma that had been resected by hysteroscopy and
treated conservatively. Leveque et al.15 found a relatively high incidence of positive peritoneal cytology
(37%) in 19 patients with Stage IA–C endometrial carcinoma; they assumed that hysteroscopy, which had
been carried out in all 19 cases preoperatively, might
have been the reason for this.
All these authors speculate that saline irrigation of
the uterine cavity might cause dissemination of endometrial carcinoma cells through the fallopian tubes
into the peritoneal cavity. Although transtubal spill
seems likely, it is not fully clarified whether other
factors might play an additional role. Recently, Baker
and Adamson determined that 100 mmHg was the
median intrauterine perfusion pressure for spill of dye
from both tubes; no spill occurred at pressures ,70
mmHg.16 Although endometrial cells could not be
found before hysteroscopy, the incidence of endometrial cells in the peritoneal fluid was 65% after chromopertubation. Creasman et al.17 suggested that spill
might occur at a different anatomic site than the fallopian tube, as malignant cells were discovered in the
peritoneal cavity in 3 of 44 patients with endometrial
carcinoma. One of these three patients had had a
previous bilateral salpingectomy and two patients a
tubal ligation before hysterectomy.17 From all these
reports, it has not been proven that tumor cell dissemination is more common in cases in which D & C plus
hysteroscopy is performed compared with cases in
which D & C alone is performed.
Whether positive peritoneal cytology affects the
prognosis of patients with Stage I endometrial carcinoma is currently a subject of animated scientific discussion. Although some authors14,18 –20 have shown
that increasing concentrations of carcinoma cells in
peritoneal washings significantly shorten the time to
recurrence of disease, others have suggested that positive peritoneal cytology is prognostically irrelevant
unless extrauterine disease is present.21–23 Gucer et
al.24 report that previous hysteroscopy did not seem to
increase the risk of early recurrence in 25 patients with
and 55 patients without fluid hysteroscopy. In both
groups, only 1 recurrence could be observed after
median follow-up periods of 29 and 30 months, respectively. In the current investigation, we chose the
presence of malignant cells as the primary statistical
endpoint because it represented “advanced disease”
according to the current FIGO classification.4 For this
reason, and because of the short observation period,
the question of whether hysteroscopy affects the patients’ prognosis has not been addressed in this study
but will be a topic of further investigation.
In response to case reports and also our own
observations, we intended to compare the rate of positive peritoneal washings of patients with hysteroscopy before laparotomy with those of patients who did
not have hysteroscopy. Therefore, we initiated a retrospective chart analysis with peritoneal cytology as
the statistical endpoint. All hysteroscopies were per-
Hysteroscopy and Endometrial Carcinoma/Obermair et al.
formed with saline irrigation. ITo avoid positive results
due to involvement of the uterine serosa, only cases
with invasion of the inner half (or less than the inner
half) of the myometrium were selected. Patients with
involvement of the outer half of the myometrium, as
well as those with invasion of the uterine cervix or the
fallopian tube, were excluded.
In summary, our data strongly suggest hysteroscopic tumor cell dissemination of carcinoma cells via
fluid hysteroscopy. We found positive peritoneal cytology significantly more often for patients who underwent hysteroscopy before surgical staging than for
those who did not undergo hysteroscopy but only D &
C. An association between hysteroscopy and dispersion of tumor cells is therefore highly possible. Established prognostic factors, such as depth of myometrial
invasion, histologic subtype, grading, and the time
between D & C and TAH/BSO, were similar for patients with and without previous hysteroscopy. Nevertheless, the retrospective design of the study did not
permit a conclusive statement in this regard. For ethical reasons, it is difficult to tackle this question from
a prospective approach. Prospectively, it is suggested
that investigators pay close attention to peritoneal
cytology findings. Moreover, it would be of considerable interest to collect a much larger sample size to
verify the interesting phenomenon that we have reported in this article, so that final conclusions may be
drawn.
9.
10.
11.
12.
13.
14.
15.
16.
17.
18.
19.
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