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Malignant Uterine Tumors
Fig. 30.6 Same patient as in Fig. 30.5. Color Doppler sonography
demonstrates peripheral blood vessels.
Authors’ Experience
30
We conducted a study22to determine whether the protocol outlined above would be useful in the early detection of endometrial
carcinoma and, in positive cases, assessing the extent of myometrial invasion. A group of 750 postmenopausal women were examined by transvaginal sonography one day before a scheduled
hysterectomy, which was indicated for various gynecological condi-
tions. Thirty-five of the women had endometrial carcinoma.
Endometrial thickness. Ninety percent of the carcinomas showed
an endometrial (tumor) thickness greater than 10 mm (usually ⬎
20 mm). The endometrium in the remaining 10% was between 5
and 10mm thick. Endometrial thickness was less than 5 mm in
100% of the patients with an atrophic endometrium and in 73 %
with a normal endometrium. In approximately half of the carcinoma cases, the endometrium had either a hyperechoic or nonhomogeneous appearance at ultrasound.
Intrauterine fluid. While many studies have dealt with endometrial
thickness, little attention has been given to the presence of in-
trauterine fluid. It has been found, however, that the presence of in-
trauterine fluid correlates with a malignant process in the genital
tract arising from the uterine fundus, cervix, ovaries, or fallopian
Fig. 30.7 Same patient as in Figs. 30.5 and 30.6. A moderately high
RI (0.56) is recorded from the vessels in Fig. 30.6, consistent with a
benign process. An endometrial polyp was diagnosed at histological
examination.
tube. Whenever intrauterine fluid is detected, a detailed tumor
search should be initiated. We found that the presence of in-
trauterine fluid was associated with endometrial carcinoma in most
cases, although the absence of intracavitary fluid did not exclude a
malignant process.
Myometrial invasion. A subendometrial ring (halo) was visible in
87% of endometrial carcinomas, and interruption of the halo was a
sign of myometrial invasion. This invasion was classified as superficial in three cases and deep in 15 cases. The presence and depth of
myometrial invasion were accurately determined with ultrasound
(relative to histological findings) in 92 % of the carcinoma cases.
Tumorvessels. Areas of neovascularity could be detected in the endometrial carcinomas. The newly formed vessels were classified as
intratumoral (color pixels within the endometrium) or peritumoral
(color pixels bordering the endometrium). The blood flow velocity
in the intratumoral vessels was lower than in the peritumoral vessels (Figs. 30.8 and 30.9). Overall, 91% of the endometrial carcinomas displayed abnormal intratumoral and/or peritumoral blood
flow with low impedance values (RI = 0.42 ⫾ 0.02). The average RI
in the carcinoma vessels was significantly lower than in the endometrial vessels of patients with hyperplasia (Table 30.1).
292
Fig. 30.8 Color Doppler shows areas of intense neovascularization
within the myometrium, consistent with myometrial invasion by endometrial carcinoma.
Fig. 30.9 Same patient as in Fig. 30.8. Low impedance values
(RI = 0.32, PI = 0.38) are detected within the myometrium. Histology
confirmed invasive endometrial carcinoma.
Table 30.1 Flow detection, resistance index, and peak systolic velocity in relation to histological findings
Endometrial Carcinoma
Histology Number of
patients
Atrophic 10 0 0 – – – –
Normal 643 0 0 – – – –
Hyperplastic 62 5 8 0,65* 0,05 7,0* 2,1
Endometrial carcinoma 35 32 91 0.42* 0.02 17.1** 2.7
a
Statistically significant (p ⬍ 0.05)
b
Peak systolic velocity only in peritumoral vessels.
With permission from Kurjak A et al: Endometrial carcinoma in postmenopausal women: evaluation by transvaginal color Doppler ultrasonography. Am. J. Obstet.
Gynecol. 169 (1993) 1597 – 603.
Flow detection Resistance index Peak systolic velocity (cm/s)
Number % Mean SD Mean SD
Summary of the results. In this study the following features
were most strongly suggestive of endometrial carcinoma:
➤
Endometrial thickness greater than 5 mm
➤
Nonhomogeneous or hyperechoic endometrial structure
➤
Presence of intrauterine fluid
Review of the Literature
Transvaginal B-Mode and Doppler Sonography
The appearance of endometrial carcinoma at transvaginal ulMyometrial invasion was usually present when the subendometrial halo was interrupted. The intratumoral blood vessels showed a higher flow velocity than the peritumoral blood
vessels. The average RI in endometrial carcinoma was significantly lower than the RI in endometrial hyperplasia. This could
be an important criterion for differentiating the two conditions
in diagnostic practice.
Three cases could not be evaluated because the endometrium had been curetted a week before the ultrasound
examination and could not be assessed sonographically. This
shows that the sequence of diagnostic procedures is an important aspect that should always be considered if optimum sonographic results are to be achieved.
Three stage I endometrial carcinomas were asymptomatic
trasound has b een described in the literature
nonhomogeneous endometrial band. In advanced cases the
endometrium appears thickened, has an irregular structure,
shows inhomogeneous echogenicity, and is poorly delineated
from the myometrium (absence of the subendometrial halo).
The depth of myometrial invasion, which typically appears as a
hypoechoic area, can be determined accurately by transvaginal
sonography. However, endometrial hyperplasia cannot be distinguished from carcinoma by B-mode imaging alone, since
both conditions present with endometrial thickening
appears that diagnostic accuracy can be substantially improved by adding color and pulsed Doppler ultrasound, because most endometrial carcinomas exhibit abnormal blood
flow (tumor angiogenesis) with low impedance values
21
as a thickened,
2, 12, 36
2, 16
and were detected by following the above protocol, which is
based on increased endometrial thickness (⬎20 mm) and the
detection of intratumoral and/or peritumoral blood flow with
a low RI.
Follow-up study. In a more recent study at our department, Illjas et
16a
examined 288 postmenopausal women who underwent hys-
al.
terectomy for various indications (incontinence, prolapse, uterine
descent, leiomyomas). Fourteen endometrial carcinomas were de-
tected in postoperative histological examinations.
The diagnostic accuracy of transvaginal Doppler sonography in
this study was 93 %, as 13 of the 14 endometrial carcinomas were
detected with ultrasound prior to hysterectomy. Endometrial thickness was more than 10 mm in 36% of the patients with endometrial
carcinoma; it was between 6 and 10 mm in 57%. Only one patient
with endometrial carcinoma had an endometrial thickness equal to
5 mm. Areas of neovascularity were found in 93% of the patients.
The newly formed vessels were classified as intratumoral (color
pixels within the endometrium) or peritumoral (color pixels bordering the endometrium). The average resistance index was 0.39 ⫾
0.03 in the intratumoral vessels and 0.43 ⫾ 0.03 in the peritumoral
vessels. The RI values in the endometrial carcinomas were significantly lower than in the nine cases with endometrial hyperplasia
(RI = 0.64 ⫾ 0.05).
Angiogenesis and tumor grade. Abulafia et al.1evaluated angio-
genesis in endometrial hyperplasia and in stage I endometrial carcinoma and investigated the relationship between neoangiogenesis,
tumor grade, and the depth of tumor invasion. Three groups of
patients were examined: a control group of patients who under-
went hysterectomy for benign uterine changes (n = 19), patients
with endometrial hyperplasia (n = 24), and patients with stage I endometrial carcinoma (n = 34). All hysterectomy specimens were
stained immunohistochemically for factor VIII-related antigen,
which is a sensitive and specific marker for vascular endothelium.
Areas of endometrium with the deepest myometrial invasion or
with the highest grade of endometrial hyperplasia and highest angiogenic intensity were selected for examination.
Increased angiogenic intensity (based on microvessel counts)
was found in complex endometrial hyperplasia compared with
simple hyperplasia. Angiogenesis in stage Ia endometrial carcinoma was comparable to that found in complex endometrial hyperplasia. Angiogenesis in invasive endometrial carcinoma (stages Ib
and Ic) was more pronounced than in complex endometrial hyperplasia or stage Ia endometrial carcinoma. Higher tumor grades
were found to be directly correlated with angiogenic intensity. Due
to the limited number of patients with stage Ib and Ic endometrial
carcinoma, the depth of tumor invasion could not be analyzed independently of tumor stage. Despite this limitation, it was found
that angiogenesis increased with the depth of invasion and tumor
grade. This suggests that the extent of neovascularization in endometrial carcinoma is linked to the grade of tumor differentiation.
Gynecological Ultrasound
.It
.
293
Malignant Uterine Tumors
The key result of this study is that both endometrial hyperplasia and endometrial carcinoma have a rich vascular supply
and can therefore be detected with sensitive Doppler instruments. Also, the intensity of angiogenesis in stage I endometrial carcinomas shows a direct correlation with the
depth of tumor invasion and tumor grade.
Uterine artery PI. Bourne et al.2studied flow impedance in the
uterine arteries of women with endometrial carcinoma (n = 17),
women with normal endometrium (n = 85), and women receiving
hormonal therapy (n = 35). The authors defined an arbitrary cutoff
value of ⬍1.5 for the PI as a positive test result (Fig. 30.10). Using
this cutoff, they achieved a positive predictive value of 94 % and a
negative predictive value of 91% in women with postmenopausal
bleeding. Better predictive values could probably have been
achieved by sampling more specific vessels than the uterine artery,
such as the intratumoral and peritumoral vessels
the PI appears to be a less sensitive and specific impedance parame-
ter than the RI in the evaluation of tumor vessels.
RI in the arcuate and spiral arteries. Hata et al.
cantly lower resistance index (RI = 0.535 ⫾ 0.158) in the arcuate ar-
teries in 10 endometrial carcinomas than in the normal uterus
(RI = 0.767 ⫾ 0.75). The RI in this study was higher than the RI calculated in our studies because Hata et al. measured values in the ar-
30
cuate arteries whereas we sampled the spiral arteries. Also, the
study by Hata et al. was performed in only 10 cancer patients.
Merce et al.
compared their findings with 19healthy volunteers. The authors
used duplex sonography and sampled Doppler signals from both
uterine arteries and from the intramyometrial (radial and arcuate)
arteries. A significantly lower RI was found in the uterine and in-
tramyometrial arteries of women with abnormal endometrial findings, including two carcinomas, than in women with normal findings. The authors concluded that the RI of the intramyometrial
(radial and arcuate) arteries was a considerably more accurate and
specific indicator than the RI of the uterine arteries and was there-
fore a better predictor of positive findings.
Criteria for evaluating uterine vascularity. Aleem et al.
tempted to establish color and pulsed Doppler sonographic criteria
for evaluating uterine vascularity in postmenopausal women in
order to reduce the number of unnecessary dilation and curettage
procedures. The prospective study involved 42 postmenopausal
patients who were examined before undergoing fractional curet-
26
examined 45 patients with metrorrhagia and
18, 36
. Moreover,
16
found a signifi-
tage. Twenty patients had symptoms such as vaginal bleeding or an
enlarged uterus, and 22 patients were asymptomatic. The criteria
used to evaluate the endometrium were endometrial thickness
(cutoff value of 8 mm), rates of visualization, and the distribution
pattern of myometrial (peritumoral) and endometrial (in-
tratumoral) vessels, along with pulsatility and resistance indices.
Endometrial thickness was greater than 8 mm in all cases of endometrial carcinoma (14 of 14 cases), endometrial hyperplasia (8 of
8 cases), and one endometrial polyp. Endometrial thickness was
less than 8 mm in the nine patients with leiomyomas and in the
asymptomatic controls. The visualization rates of myometrial and
endometrial vessels in cases of endometrial carcinoma were 93%
and 43%, respectively, which were significantly higher than for
cases with benign endometrial changes. Dense vascularity was
found in 80% of the endometrial carcinomas, contrasting with the
“loose” vascularity that is more typical of endometrial hyperplasia.
Intratumoral vessels were seen in 43 % of the carcinoma patients
but in only 12% of the patients with endometrial hyperplasia. The
average PI and RI values for these vessels in cases of endometrial
carcinoma were 0.73 ⫾ 0.11 and 0.50 ⫾ 0.05, respectively.
Comments. Transvaginal color Doppler sonography appears to
be an effectivemethod of screening for endometrial carcinoma
and ovarian carcinoma in the same sitting. Hence, it can provide an important addition to oncological preventive medicine
in women. The use of this technique could also reduce the
number of dilation and curettage procedures, thereby reducing
the costs to payers and lowering the risks to patients.
Intra-arterial chemotherapy. Hata et al.
15a
used transvaginal
Doppler ultrasound and MRI to assess the efficacy of intraarterial chemotherapy for endometrial carcinoma. The RI in
the intratumoral vessels showed no correlation with the tumor
volume, but significant differences were measured between
the RI values before (mean = 0.58 ⫾ 0.15) and after (mean = 0.77
⫾ 0.13) intra-arterial chemotherapy. The authors’ conclusion is
that transvaginal color Doppler is a useful method for evaluat-
1a
at-
ing hemodynamic changes after intra-arterial chemotherapy
and can demonstrate the response of the endometrium to the
therapy.
Three-dimensional Sonography—New Discoveries
with a New Method?
294
Fig. 30.10 Same patient as in Figs. 30.8 and 30.9. A low RI (0.59) is
also found in the uterine arteries of this patient with invasive endometrial carcinoma. This finding indicates myometrial invasion.
Significance of endometrial volume. In a study by Hata et al.15,
3 D ultrasound was used to assess the significance of endometrial
volume in women with postmenopausal bleeding
dometrial volume in cases of endometrial carcinoma differed significantly from the volume of normal or hyperplastic endometria. A
cutoff volume of 13 ml was 100% sensitive in the diagnosis of carcinoma. There was only one false-positive result in a patient with endometrial hyperplasia, resulting in a specificity of 98.8 % and a posi-
tive predictive value of 91.7%. Endometrial volume correlated with
tumor grade: both the thickness and volume of the endometrium
were smaller in well-differentiated tumors than in moderately or
poorly differentiated tumors. Endometrial thickness and volume in
patients who subsequently had to undergo surgery were compared
with the depth of myometrial invasion and tumor stage. It was
found that the sonographically determined values for endometrial
volume and thickness rose with increasing depth of invasion. In addition, a relatively large primary tumor volume was found in
patients with advanced disease. Only patients with tumor volumes
greater than 25 ml were found to have positive pelvic lymph nodes
at operation. These findings agree with a previous study by Schink
34a
et al.
in which tumors smaller than 2.0 cm in diameter were as-
17a
. The en-
sociated with only a 4 % risk of lymph node involvement and a 98 %
five-year survival rate. Thus, tumor size has proved to be a significant prognostic factor that is independent of tumor grade and the
depth of myometrial invasion.
Malignant Uterine Tumors
Visualization of the uterine cavity. In a study published by BonillaMusoles et al.
women with postmenopausal bleeding were evaluated with 3 D ul-
trasound following distention of the uterine cavity with sterile saline solution. The results of 3 D hysterosonography were compared
with transvaginal sonography, transvaginal sonohysterography,
transvaginal color Doppler, and hysteroscopy. The results with
transvaginal 3 D sonography agreed with the findings obtained by
hysteroscopy. Thus, 3 D hysterosonography with a negative con-
trast medium appears to improve the visualization of the uterine
cavity and the evaluation of endometrial thickness and of myometrial and cervical invasion in patients with endometrial carcinoma.
1b
, endometrial thickness and homogeneity in 36
In our experience, the 3 D power Doppler mode is excellent for
evaluating the tortuous, thin-walled vessels that grow into the
uterine cavity and myometrium when an invasive cancer is
present (Fig. 30.
and sector image display options that are available (Fig. 30.
11). This is facilitated by the three-dimensional
12).
Indications. Three-dimensional sonography is currently used
for the following applications:
➤
Defining the complex vascular structures, which often appear fragmentary, in patients with endometrial carcinoma
(this may be facilitated by contrast enhancement)
➤
Determining the depth of invasion of endometrial carcinoma
(staging)
➤
Monitoring tumor response to chemotherapy and/or radiotherapy
17b
.
Fig. 30.11 Three-dimensional image of abnormal endometrial proliferation in a postmenopausal woman who had undergone fractional
curettage. Histopathological examination revealed endometrial carcinoma. Power Doppler demonstrates both peripheral and central
neovascularity. Careful e xamination of the posterior uterine wall
showed abnormal vessels in the inner portions of the myometrium,
consistent with superficial myometrial invasion.
Gynecological Ultrasound
Interpretation of 3 D information. Problems still exist in the in-
terpretation of 3 D power Doppler data. The examiner must be
familiar with the complexities of data processing for proper
digital manipulation of the 3 D display. It should also be realized that this data processing is very time-consuming and that
optimal, standardized software must be used to obtain reproducible results. Various parameters such as the pulse repetition frequency (PRF), wall filter setting, receiver gain, color priority, and frame rate must be optimized for the 3 D display. By
merely changing the color setting, the operator can radically
alter the quantitative results and the 3 D rendering of vascular
structures. We have found that information loss does not occur
with power Doppler imaging, even with a perpendicular
beam–vessel angle, and that very little decrease in color intensity occurs during diastole.
With the technology available today, the assessment of
vascular density with 3 D power Doppler ultrasound is a very
subjective matter. It is reasonable to expect that this problem
will be solved by integrated software that can perform 3 D
blood-flow measurements in tumors. The use of contrast
media may aid in the detection of very small tumor vessels and
thus improve the sensitivity and specificity of the method.
Comments. Three-dimensional ultrasound with a power
Doppler facility could play an important role in assessing the
depth of invasion of endometrial carcinoma. The ability to
simultaneously display areas of neovascularization in the en-
Fig. 30.12 The “niche display mode” portrays a slice from a three-dimensional image. Rotating and shifting the coordinate system is help-
ful in detecting irregular myometrial vessels that would indicate myometrial invasion. The stored image volume is subdivided into a series
of parallel slices, and the examiner can scroll through them to locate a
myometrial area with signs of neovascularization. This type of study
can accurately determine both the location and depth of myometrial
infiltration.
dometrium and myometrium increases diagnostic accuracy.
Because the method had a negative predictive value of 100% in
our studies
17b
, it could justify the election of less radical
surgery in patients who do not have deep myometrial invasion,
helping to reduce morbidity and lower costs in the health care
industry
13a
. Meanwhile, patients with a tumor stage that warrants a primary aggressive approach can be referred directly
for the appropriate treatment.
295
Malignant Uterine Tumors
Uterine Sarcoma
Uterine sarcoma is a rare tumor that accounts for only 1–3% of
all genital tract malignancies in women and from 3% to 7.4% of
malignant tumors of the uterine corpus
32
(Fig. 30.13). It is a rare
but extremely aggressive tumor that tends to metastasize
early, leading to death
9
. There are still many unanswered questions regarding this disease, and there is still no satisfactory
procedure for making an early and accurate diagnosis.
Moreover, it is expected that the incidence of uterine sarcomatous disease will rise in the near future as more gynecologists
opt for the conservative management of uterine leiomyomas
Authors’ Experience
In patients who were treated at our center for uterine sarcoma, all
documented findings including surgery reports and histological results were analyzed for this study. The RI in both uterine arteries,
the RI in the newly formed tumor vessels, and peak systolic velocity
were determined. To our knowledge, this is the largest clinical se-
ries of uterine sarcomas to be evaluated with Doppler ultrasound.
The data from eight patients with uterine sarcoma could be ana-
30
lyzed; 75% of the women were postmenopausal, and the most
frequent complaint was vaginal bleeding.
RI and peak systolic velocity. Irregular blood vessels were de-
tected in all sarcomas (100%), while tumor blood flow was detected
in only 30% of the myomas (Fig. 30.14). The RI values decreased
from the normal uterus to the myomatous uterus to the sarcomatous uterus. The mean RI in the sarcomas was 0.37 ⫾ 0.03
(Fig. 30.15). The peak systolic velocity also decreased from normal
to myomatous to sarcomatous uterus (16.8 ⫾ 6.4 cm/s in sar-
comas).
We studied tumor blood flow in both benign (myomas) and
malignant uterine tumors (sarcomas) in order to discover criteria
that might indicate a sarcoma and to improve the accuracy of ultrasound in differentiating between these tumors. Ultrasound in
patients with uterine sarcoma typically showed irregular, scattered,
small-caliber vessels with low impedance and low intratumoral and
peritumoral blood flow velocities. Additionally, both uterine arteries in sarcoma patients showed a low RI and a low peak systolic
velocity compared with women who had a normal or myomatous
uterus (Fig. 30.16).
Comments. There has been an urgent need for a diagnostic
method that can ensure the precise differentiation in vivo of
benign and malignant uterine tumors. Transvaginal color
Doppler sonography appears to have great potential in this regard.
27
.
Fig. 30.13 Nonhomogeneous uterine tumor in a postmenopausal
woman. The nonhomogeneity of the mass is caused by degenerative
changes and intratumoral hemorrhage.
Fig. 30.14 Same patient as in Fig. 30.13. Color Doppler image shows
numerous, irregularly distributed vessels consistent with a malignant
tumor.
296
Fig. 30.15 Same patient as in Figs. 30.13 and 30.14. Analysis of the
power Doppler waveform indicates a low RI (0.34).
Fig. 30.16 Same patient as in Figs. 30.13– 30.15. The low RI (0.54) in
the uterine ar tery is a sign of advanced uterine sarcoma.
Cervical Carcinoma
References
The uterine cervix varies considerably in size and thickness. It
occupies a larger portion of the uterus before menarche and
after menopause than in women of childbearing age. Visualization of the cervix with transvaginal ultrasound may prove
difficult if the probe is placed too close to the cervix. This problem is solved by withdrawing the probe slightly and by angling
it slightly backward in patients with an anteflexed uterus or
slightly forward in patients with a retroflexed uterus
13
.
Positioning the transducer. The success of color Doppler
sonography in the diagnosis of uterine malignancies does not
extend to cervical carcinoma. Hata et al.
16
were unable to detect abnormal blood flow signals in half of their cases, even in
patients with advanced cervical cancers. It is assumed that the
new blood vessels that form during the early stage of cervical
carcinoma are too small to be detected with current ultrasound
Conclusion
Transvaginal color Doppler sonography is a noninvasive procedure for evaluating the vascularity of uterine tumors. It can
be used in any given patient as often as desired. The ability to
display and analyze specific flow velocity waveforms will undoubtedly yield new data on normal and abnormal vascular
structures in and around tumors. With color Doppler ultrasound, we have a technology that may enable us to reliably
differentiate benign from malignant tumors in the foreseeable
future.
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298
Blood Flow Changes in Cervical Carcinoma Treated by
31
Primary Chemotherapy
C. Villena-Heinsen, A. K. Ertan, M. Holländer, and W. Schmidt
Treatment of Cervical Carcinoma
Tumor volume. In patients with cervical carcinoma, the tumor
volume has a critical impact on local tumor control, the incidence of distant metastases, the disease-free interval, and total
survival time
a poorer prognosis than women with smaller tumors at the
same FIGO (International Federation of Gynecologists and Obstetricians) stage
of only limited value as curative treatments
Cisplatin-based combination chemotherapy. Because stagespecific survival rates have not improved with traditional
treatment modalities during the past 40 years
perimentation is justified in an effort to improve treatment
outcomes in this population. Primary,cisplatin-based systemic
combination chemotherapy has shown high response rates be-
3
. Accordingly,patients with a “bulky” tumor have
6
. Both radiotherapy and surgical excision are
15
.
16
, clinical ex-
tween 60% and 100%
prolongation of disease-free interval (p = 0.009) and total sur-
vival (p = 0.05) in patients with a bulky tumor more than 4 cm
in diameter
intra-arterial chemotherapy
Intra-arterial chemotherapy. Bilateral, superselective intraarterial chemotherapywith cisplatin is done to achieve a maximum reduction in tumor size with minimum systemic toxicity,
the goal b eing to improve the operability of the tumor. Response to the therapy, as measured by a reduction in tumor
volume, was objectively and sequentially documented by
manual palpation, B-mode ultrasound, and MR imaging. The
progression of tumor markers was also documented.
17
. Good local control is achieved with primary
1, 17, 24
. Sardi et al. reported a significant
9, 18, 21
.
Gynecological Ultrasound
Assessing Treatment Response with Pulsed Color Doppler Sonography
Wealso studied pulsed color Doppler sonography in our search
for an additional indicator of treatment response. The goal of
our study was to evaluate the accuracy of this procedure in
monitoring the response of large cervical carcinomas to
neoadjuvant intra-arterial chemotherapy.
Authors’ Studies
Patients and Methods
Eight patients (7 premenopausal) between 32 and 54 years of
age (average 43 years) with a bulky tumor at clinical stage Ib2
to IIb were examined by color Doppler sonography immediately before their first and second chemotherapy cycles and
prior to operative treatment. A clinical and MRI assessment of
tumor size was also performed at these times. The examination protocol, equipment technology, and instrument settings
were standardized in this prospective study. The examinations
were performed with an Acuson 128 XP10 using a 5 MHz endovaginal probe and color Doppler system.
Parameters. The primary tumor was examined closely and systematically for blood vessels using color Doppler ultrasound.
The following parameters were documented in the tumor area:
➤
Number of sampled vascular segments
➤
Peak systolic blood flow velocity within the sampled vascular segments
➤
Mean resistance index (RI
segments
The RI
uterine arteries was also determined:
RI =
in the tumor-supplying vessels in the area of both
mean
peak systolic velocity—end-diastolic velocity
peak systolic velocity
mean
Treatment Regimen
Both uterine arteries were punctured and catheterized by the
transfemoral route using the Seldinger technique, and inflow
for the pending chemotherapy was confirmed by spiral CT.
Next, 25 mg of cisplatin was infused into the uterine artery for
two hours. This was repeated 24hours later.
Three weeks later, a second treatment cycle was performed
according to the same regimen.
After another three-week interval, a radical Wertheim–
Meigs operation was performed with para-aortic and paracaval lymph node sampling. Adjuvant radiotherapy was added
in some cases, depending on the definitive tumor histology.
) within the sampled vascular
299
Blood Flow Changes in Cervical Carcinoma Treated by Primary Chemotherapy
Results
Fig. 31.1 Pretherapeutic examination (before the first chemotherapy
cycle). Color Doppler image shows dense intratumoral vascularity in
the transverse scan.
31
Tumor volume. The mean tumor volume was 98 cm3before
treatment began (the smallest tumor volume was 36 cm
largest 203 cm
3
). All of the tumors responded to intra-arterial
3
, the
chemotherapy. The preoperative tumor volume after two cycles of intra-arterial chemotherapy was 46 cm
3
(15–83 cm3).
The average reduction in tumor volume was 51% (28–80%)
(p = 0.01). Three patients showed a partial remission (⬎50% reduction in tumor volume), and five showed a minor response
(⬍50% reduction in tumor volume). The reduction in tumor
volume was also clinically apparent in the eight patients.
The goal of improving operability was achieved in seven of
the eight patients. One patient, who had a stage T2b tumor
with an initial volume of 203 cm
3
, showed positive local response but developed fulminating, unilateral parametrial
spread to the pelvic wall. Surgical resection was withheld in
this case, therefore, and radiotherapy was administered.
SCC tumor marker. Four of eight patients showed an abnormally high level of serum SCC tumor marker before treatment.
The mean level was 5.1 ng/ml, the lowest level was 3.6 ng/ml,
and the highest was 6.4 ng/ml (normal serum level ⱕ 2.5 ng/
ml). All of the patients showed a fall of tumor marker level in
response to chemotherapy (p = 0.06). Only one of four patients
still had an abnormally high SCC level prior to surgery. After
surgery it returned to normal and remained there. Following
two cycles of intra-arterial chemotherapy, a positive correlation was found between the reduction in tumor volume and
the fall in tumor marker level (Spearman correlation coefficient r = 0.65; p = 0.08).
300
Fig. 31.2 A reduction of intratumoral vascularity is noted before the
second cycle of intra-arterial chemotherapy.
Fig. 31.3 A further decrease in vascularity is noted immediately
before surgery (3 weeks after the second chemotherapy cycle).
Intratumoral vascularity. A steady decrease was observed in
the number of vascular segments that could be defined and
sampled with Doppler ultrasound, the peak systolic flow
velocity,and the RI
. An average of 3.5 intratumoral vascular
mean
segments were sampled before treatment, compared with 3.2
before the second treatment cycle and 2.7 just before surgery.
This decrease was not statistically significant. A statistically
significant correlation was found between the reduction in
vessel count and the reduction in tumor volume following two
cycles of intra-arterial chemotherapy (p = 0.02). Figures
31.
1–31.3 document the decline of vascularity in response to
therapy.
Doppler parameters. The peak systolic flow velocity was 0.16,
0.14, and 0.13 m/s at the successive points in the study.
A corresponding pattern was seen for RI
, which was
mean
0.73 before treatment and 0.71 and 0.67 preoperatively. These
trends were not statistically significant.
The RI
in both uterine arteries showed very little change
mean
in response to therapy. The mean value for both arteries was
initially 0.79. It was still 0.79 before the second chemotherapy
cycle and 0.76 before surgery.
These Doppler parameters did not correlate with the therapeutic response measured by a reduction in tumor volume
and a fall of tumor marker levels. Table 31.
1 shows the prog-
ression of the mean values of the Doppler parameters during
the study.
Assessing Treatment Response with Pulsed Color Doppler Sonography
Table 31.1 Mean vessel counts and Doppler parameters found at
different examination times
Intratumoral vascularity Uterine arteries
max
RI
meanRImean
right
artery
,
RI
mean
left
artery
Before 1st chemo-
Vessel
count
V
(m/s)
3.5 0.16 0.73 0.79 0.79
therapy
Before 2nd
3.2 0.14 0.71 0.78 0.79
chemotherapy
Preoperative 2.7 0.13 0.67 0.75 0.78
Discussion
Value of Color Doppler Sonography in Monitoring
Treatment Response
Relatively little has been published on the use of color Doppler
sonography in evaluating treatment response. On the whole,
however, the procedure appears to be useful for this purpose.
Breast carcinoma. Kedar et al.
tween changes in tumor vascularity and changes in tumor size.
When a specially designed quantitative scoring system was applied in women with breast carcinoma
that color Doppler sonography was of value in predicting the
response of the cancer to primary (neoadjuvant) medical therapy.
8
found a strong correlation be-
4, 5
, it was concluded
Park et al.
14
compared the therapeutic response in 16
women with trophoblastic tumors with the S/D ratio in the
uterine arteries. Starting with similar initial values, the responders showed a significantly lower S/D ratio compared
,
with the nonresponders (p ⬍ 0.05).
Tepper et al.
tween serum
20
documented a strong inverse correlation be-
β-hCG and the intratumoral RI in three patients.
On the whole, these results support the usefulness, accuracy, and sensitivity of color Doppler sonography in evaluating treatment response.
Currently there are no reports in the international literature
on similar studies in patients with cervical carcinoma. Certainly there are no data on the use of color Doppler in evaluating response to intra-arterial chemotherapy.
Benign–Malignant Differentiation of Cervical
Lesions with Color Doppler
Some results have been published on the use of pulsed color
Doppler sonography in the benign–malignant discrimination
of cervical lesions
RI and PI in the uterine artery. Kurjak and his group11examined 89
patients with histologically proven cervical carcinoma and compared them with a control group of 24 healthy women. The descending branch of the uterine artery was examined with Doppler
ultrasound. The uterine artery could not be visualized in 18% of the
carcinoma patients and 17% of the controls. The RI was significantly
lower in the carcinoma patients than in the healthy women. The PI
in the carcinoma group was also lower than in the controls, but
statistical significance was borderline. The authors believe that this
new technique is less effective in evaluating cervical lesions than
ovarian tumors.
11, 19
.
Gynecological Ultrasound
Fibrocystic breast changes and nonpuerperal mastitis. Madjar
12
et al.
observed a measurable reduction of blood flow in hormonally treated fibrocystic breasts. The decrease in the mean
frequency shift detectable by CW Doppler and the sum of the
frequency shifts correlated with an improvement in subjective
complaints and palpable findings.
In another study, pulsed color Doppler sonography was
used in seven patients with nonpuerperal mastitis to evaluate
their response to treatment with antibiotics and bromocriptine. The peak systolic and end-diastolic flow velocities, which
initially were abnormally high compared with the contralateral breast, returned to normal in response to the medical
therapy
Trophoblastic tumors. Several groups of authors
2
.
7, 14, 20
investigated the value of color Doppler sonography in evaluating the
response of trophoblastic tumors to therapy. Hsieh et al.
7
compared 23 patients with trophoblastic tumors with a control
group of 55 nonpregnant women and 15 patients with a
treated trophoblastic tumor. The group with trophoblastic
tumors showed a significantly higher peak systolic flow velocity and significantly lower RI
in both uterine arteries (p ⬍
mean
0.0001). The peak systolic velocity fell significantly during
chemotherapy (p ⬍ 0.001). This decrease correlated with the
treatment response as measured by serum
β-hCG and B-mode
ultrasound.
. Sohn et al.19examined 33 women with cervical lesions (19
RI
min
malignant and 14 benign; four of the malignant lesions developed
before menopause). The authors did not specify the exact site at
which the RI was determined (intratumoral, intracervical, in the
uterine artery, etc.). The malignant cervical lesions showed a minimum RI (RI
)of55%⫾ 8 SD, while the RI
min
was 79 % ⫾ 11 SD. The premenopausal patients had a mean RI
for the benign lesions
min
min
of
58% ⫾ 9 SD. The RI values were approximately the same in the
group of premenopausal women with benign lesions and in the
group with malignant lesions. Marked differences were found,
however, between the group of postmenopausal women with
benign lesions and the group with malignant lesions. Based on
these results, the authors advocate the separate examination of
premenopausal and postmenopausal patients and state that RI
min
has potential value in the benign–malignant differentiation of cer-
vical lesions.
RI
mean
. The RI
in our study was significantly higher in in-
mean
tratumoral vessels and in both uterine arteries at all examination
times. The pretherapeutic intratumoral RI
mean pretherapeutic RI
preoperative intratumoral RI
for both uterine arteries was 0.765.
RI
mean
for both uterine arteries was 0.79. The
mean
was 0.67, and the preoperative
mean
was 0.73, and the
mean
We cannot directly compare the study results because the objective Doppler analyses were based on different parameters
such as RI
necological tumors, however, it appears that the RI
min
and RI
. By analogy with the results in other gy-
mean
min
in the
group of patients studied here is not significantly lower than
301