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Published online before print January 18, 2002, 10.1148/radiol.2223010035
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(Radiology 2002;222:640-644.)
© RSNA, 2002

Vascular and Interventional Radiology

Embolization of Bleeding Residual Uterine Vascular Malformations in Patients with Treated Gestational Trophoblastic Tumors1

Adrian K. P. Lim, BMedSci, BM, BS, FRCR, Roshan Agarwal, BSc, MB, BS, MRCP, Michael J. Seckl, MB, BS, PhD, FRCP, Edward S. Newlands, MB, BS, PhD, FRCP, Nigel K. Barrett, MB, BS, MRCP, FRCR and Adam W. M. Mitchell, MB, BS, FRCS, FRCR

1 From the Departments of Imaging (A.K.P.L., N.K.B., A.W.M.M.) and Oncology (R.A., M.J.S., E.S.N.), Hammersmith Hospitals NHS Trust, Charing Cross Hospital, Fulham Palace Rd, London W6 8RF, England. From the 2000 RSNA scientific assembly. Received November 29, 2000; revision requested January 11, 2001; revision received September 4; accepted September 18. Address correspondence to A.W.M.M. (e-mail: amitchell@hhnt.org).


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
PURPOSE: To retrospectively evaluate embolotherapy of bleeding residual uterine vascular malformations in patients with gestational trophoblastic tumors.

MATERIALS AND METHODS: Fourteen patients were treated over the past 20 years. Embolizations were performed with a common femoral artery approach. Duplex ultrasonography was performed before and after embolization to document the uterine vascularity. The technique and materials used for each embolization, control of hemorrhage, need for repeat embolization, complications, and outcome of subsequent pregnancies were assessed.

RESULTS: Hemorrhage was controlled in 11 of the 14 patients; two patients required hysterectomy and one required uterine artery ligation for failure to control hemorrhage after initial embolization. Six patients required repeat embolization for recurrence of bleeding. Therapeutic benefit and success were associated with the ability to selectively embolize the uterine artery and to achieve a greater than 80% reduction in vascular malformation size. Pulsatility indexes of the uterine arteries and endometrial encroachment were not predictive of recurrent hemorrhage. Two patients delivered a total of three full-term infants, one patient experienced a miscarriage, and another experienced a termination of pregnancy following embolotherapy. Pain requiring opiate analgesia was a frequent complication of treatment.

CONCLUSION: Selective uterine artery embolization is a safe and effective treatment for severe bleeding from residual uterine vascular malformations in patients with treated gestational trophoblastic tumors.

© RSNA, 2002

Index terms: Arteriovenous malformations, therapeutic embolization, 98.1264 • Arteriovenous malformations, uterine, 98.141, 854.3191 • Uterine neoplasms, 854.3191 • Uterus, hydatidiform mole, 854.3191


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Gestational trophoblastic disease is a rare complication of pregnancy that is classified histologically into complete and partial hydatidiform moles (1). Complete hydatidiform moles are the most common form of gestational trophoblastic disease, with a prevalence of 1–2 per 1,000 pregnancies in developed countries. Evacuation of the products of conception following a molar pregnancy is curative in most patients. However, approximately 10% of complete hydatidiform moles and 0.5% of partial hydatidiform moles undergo malignant transformation into an invasive mole, a choriocarcinoma, or, rarely, a placental site tumor, and require further treatment (1). These malignancies are collectively known as gestational trophoblastic tumors, and more than 90% of patients are cured with chemotherapy (2).

Gestational trophoblastic tumors are highly vascular and are associated with the formation of uterine vascular malformations. These vascular malformations persist in 10%–15% of patients, even after complete resolution of the tumor following chemotherapy (3). Overall, 1%–2% of these uterine vascular malformations cause vaginal or intraperitoneal hemorrhage, which can be life threatening (3,4). Hysterectomy and uterine artery ligation have traditionally been the treatments of choice for achieving hemostasis. However, the advent of uterine artery embolization has provided an alternative strategy for the treatment of these patients.

Our institution is one of two national referral centers in the United Kingdom for the treatment of patients with gestational trophoblastic tumors. The purpose of our study was to retrospectively evaluate our 20-year experience with uterine artery embolization in the treatment of bleeding from uterine vascular malformations in patients with gestational trophoblastic tumors. To our knowledge, this is the largest series to date on the treatment of vascular malformations associated with gestational trophoblastic tumors and includes six previously reported cases from our institution (4).


   MATERIALS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Patients
Our institutional review board did not require its approval or informed patient consent for this retrospective study. Between January 1978 and September 1999, 14 women (age range, 18–42 years) with gestational trophoblastic tumors were referred for embolization of vascular malformations following uterine hemorrhage that was unremitting despite chemotherapy. Of these 14 patients, one had choriocarcinoma. In the remaining patients, clinical diagnosis of gestational trophoblastic tumors was based on rising serum ß-human chorionic gonadotropin levels and an antecedent molar pregnancy (seven patients had complete hydatidiform moles, and six patients had partial hydatidiform moles). All patients required transfusions of 2–20 units of blood, and the presence of vascular malformations was confirmed angiographically prior to embolization. In addition, nine patients treated after 1990 were assessed with Doppler ultrasonography (US) by two experienced sonographers, and the uterine artery pulsatility index was measured before and after embolization (5). The presence or absence of endometrial encroachment, as defined by replacement of the echogenic endometrial stripe by serpentine hypoechoic structures that demonstrate vascularity, was also documented with color Doppler US.

Embolization Technique
Embolization was performed with a common femoral artery approach, and aortograms were obtained to outline the main blood supply to the vascular malformation from the uterine arteries (Fig 1). Each uterine artery was then selectively catheterized with a 5-F Glide catheter (Terumo Europe, Leuven, Belgium) (in the past 8 years only) and embolized with one to two bottles of polyvinyl alcohol particles 150–250 µm or 355–500 µm in diameter (Contour; Target Therapeutics, Fremont, Calif), the agent of choice as discussed later. Coils, gelatin sponges, or dura mater were used for embolization prior to 1980. Before the advent of the Glide catheter, any cobra-shaped catheter was used. Embolization was complete when maximal reduction in flow or stasis was visualized within the system. A final aortogram was obtained to assess the size of any residual vascular malformation. Superselective catheterization of the uterine arteries was not always possible, in which case the internal iliac artery or its main branches were embolized.



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  		Figure 1a. Digital subtraction angiograms show a uterine vascular malformation at embolization in a patient with a gestational trophoblastic tumor. The procedure was performed with a common femoral artery approach and a 5-F Glide catheter. (a) Posteroanterior projection of the flush aortogram demonstrates the main blood supply to the vascular malformation (open arrows) from the uterine arteries (solid arrows). (b) Right anterior oblique projection demonstrates selective catheterization of the right uterine artery. (c) Right anterior oblique projection demonstrates embolization of the vascular malformation. Catheter tip is in the right uterine artery. (d) Posteroanterior projection of the flush aortogram obtained after bilateral uterine artery embolization demonstrates complete obliteration of the vascular malformation.

 


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  		Figure 1b. Digital subtraction angiograms show a uterine vascular malformation at embolization in a patient with a gestational trophoblastic tumor. The procedure was performed with a common femoral artery approach and a 5-F Glide catheter. (a) Posteroanterior projection of the flush aortogram demonstrates the main blood supply to the vascular malformation (open arrows) from the uterine arteries (solid arrows). (b) Right anterior oblique projection demonstrates selective catheterization of the right uterine artery. (c) Right anterior oblique projection demonstrates embolization of the vascular malformation. Catheter tip is in the right uterine artery. (d) Posteroanterior projection of the flush aortogram obtained after bilateral uterine artery embolization demonstrates complete obliteration of the vascular malformation.

 


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  		Figure 1c. Digital subtraction angiograms show a uterine vascular malformation at embolization in a patient with a gestational trophoblastic tumor. The procedure was performed with a common femoral artery approach and a 5-F Glide catheter. (a) Posteroanterior projection of the flush aortogram demonstrates the main blood supply to the vascular malformation (open arrows) from the uterine arteries (solid arrows). (b) Right anterior oblique projection demonstrates selective catheterization of the right uterine artery. (c) Right anterior oblique projection demonstrates embolization of the vascular malformation. Catheter tip is in the right uterine artery. (d) Posteroanterior projection of the flush aortogram obtained after bilateral uterine artery embolization demonstrates complete obliteration of the vascular malformation.

 


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  		Figure 1d. Digital subtraction angiograms show a uterine vascular malformation at embolization in a patient with a gestational trophoblastic tumor. The procedure was performed with a common femoral artery approach and a 5-F Glide catheter. (a) Posteroanterior projection of the flush aortogram demonstrates the main blood supply to the vascular malformation (open arrows) from the uterine arteries (solid arrows). (b) Right anterior oblique projection demonstrates selective catheterization of the right uterine artery. (c) Right anterior oblique projection demonstrates embolization of the vascular malformation. Catheter tip is in the right uterine artery. (d) Posteroanterior projection of the flush aortogram obtained after bilateral uterine artery embolization demonstrates complete obliteration of the vascular malformation.

 
Outcomes
The reduction in the size of a vascular malformation following embolization was estimated by marking the area of pre- and postembolization "pathologic blood flow" at virtually the same phase on tracing paper and then transcribing it onto squared graph paper (A.K.P.L., A.W.M.M.). The percentage reduction in size was obtained by expressing the difference between the pre- and postembolization areas as a percentage of the preembolization area as previously reported (4). This method nullifies the effects of magnification and was chosen because the area is the only measurable parameter that allows comparison of old and new cases.

Data on the control of hemorrhage (based on the need for repeat embolization or surgical intervention) and data on conception following embolization were obtained retrospectively from the clinical notes (R.A.). Side effects, such as pain, infection, or systemic symptoms resulting from the procedure (and time to second embolization, if applicable), were also documented. A successful embolization was defined as a complete cessation of uterine hemorrhage such that any surgical procedures were avoided.

Statistical Analysis
Statistical Package for the Social Sciences 9.0 software (SPSS, Chicago, Ill) was used for statistical analyses. The Mann-Whitney U test was used for correlating percentage decrease in malformation size with successful outcomes. This test was also used for comparing pre- and postembolization pulsatility index values and decrease in malformation size with the need for repeat embolotherapy. Correlation of endometrial encroachment and the need for repeat embolization was performed by using the Fisher exact test.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
DISCUSSION
 REFERENCES
 
In 11 of the 14 patients (79%), initial control of uterine hemorrhage was achieved with embolization alone (Fig 2) (Table 1). Of the three patients in whom embolization was unsuccessful, two underwent hysterectomy, and one underwent uterine artery ligation. Six of the 11 patients (55%) in whom embolization was successful required repeat embolization for recurrent hemorrhage. One of these patients (patient 4) underwent embolization five times over a 9-year period and finally underwent hysterectomy, since further embolotherapy was contraindicated due to embolization-induced claudication prior to 1998.



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  		Figure 2. Outcomes of embolization. * = persistence of uterine hemorrhage following embolization.

 

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  		TABLE 1. Clinical and Embolization Details for All Patients

 
For the six patients who required repeat embolization, the median time to second embolization was 8 months (range, 1–36 months). There was no statistically significant correlation between percentage reduction in vascular malformation size and the need for repeat embolization (Mann-Whitney U test, P = .33) (Table 1). In patients requiring immediate surgery, however, only a 51%–63% (median, 55%) reduction in vascular malformation size had been achieved with embolization, compared with a reduction of 50%–100% (median, 98%) in the remainder of patients (Mann-Whitney U test, P = .04) (Table 1). In patients 1, 3, 4, and 5, selective uterine artery catheterization was not possible, so the main trunk or anterior branches of the internal iliac arteries were embolized. Selective uterine artery embolization was performed in the remaining patients. The agent used for embolization in each patient is shown in Table 1.

Nine of the 14 patients underwent Doppler US before and after embolization (Table 2). The median preembolization pulsatility index was 0.5 (range, 0.2–1.1), which was consistent with a low resistivity system. In three patients, the pulsatility index returned to normal (ie, >1.2) after embolization (5). There was no statistically significant association between the pre- or postembolization pulsatility index values and the need for repeat embolotherapy (Mann-Whitney U test, P = .22 and P = 1.0, respectively) (Table 2). Endometrial encroachment of blood vessels was also seen at US in five of nine patients (56%), but this was not predictive of recurrent hemorrhage (Fisher exact test, P = .52) (Table 2).


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  		TABLE 2. Pulsatility Index Values and Treatment Outcome in Patients Assessed with US

 
The main side effect of embolization was pelvic pain, requiring opiate and nonsteroidal analgesia. After the fifth embolization, patient 4 also developed buttock and lower-limb claudication, which resolved spontaneously over several months. No other side effects, either early or delayed, were documented as a result of the procedure.

Four patients conceived following embolization, two of whom delivered a total of three full-term infants. Of the remaining two patients, one had a termination, and the other had a miscarriage at 30 weeks.


   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
REFERENCES
 
Vascular malformations of the uterus are rare and potentially life-threatening lesions. They can be congenital or acquired following uterine surgery, maternal diethylstilbestrol exposure, and endometrial and cervical cancer (6). However, the most common cause is gestational trophoblastic tumors.

Uterine vascular malformations persist in 10%–15% of patients with gestational trophoblastic tumors, even after complete remission of the tumor following chemotherapy, and the malformations can bleed. Since the majority of such vascular malformations are supplied predominantly by the uterine arteries (7–9), arterial catheterization and embolization have been used as the first line of treatment for these patients at our center for the past 22 years.

In our series, therapeutic benefit and success were associated with the ability to selectively embolize the uterine artery and to achieve a greater than 80% reduction in vascular malformation size. In the three patients in whom initial hemorrhagic control was not achieved, there was only a 51%–63% reduction in overall vascular malformation size. All of these patients were treated prior to 1990, and selective uterine artery embolization was not possible.

Our data also show that these vascular malformations may recur, even following complete embolization, possibly due to the opening of collateral vessels. However, repeat embolotherapy can be successful in the treatment of these patients.

Uterine vascular malformations in gestational trophoblastic tumors have been shown to have a low pulsatility index (5,10) due to arteriovenous shunting. Eradication of vascular malformations with embolization would therefore be expected to lead to normalization of uterine artery pulsatility index values. However, low postembolization pulsatility index values would imply a persistent vascular malformation and, therefore, an increased risk of recurrent hemorrhage. In our series, the pulsatility index values returned to normal in only three of nine patients following embolization. This suggests that in most patients, functional vascular malformations not readily detectable with angiography persist. However, there was no statistically significant association between a low pulsatility index and recurrent hemorrhage in our study, possibly due to the small sample size.

There was also no statistically significant correlation between the percentage reduction in vascular malformation size and the need for repeat embolotherapy. This may be because the method used for estimating the reduction in vascular malformation size is based on a two-dimensional representation of a three-dimensional structure and does not fully reflect the size of the vascular malformation in the orthogonal plane.

The main and virtually only side effect of embolization in our study was pain, which was readily controlled with opiate and nonsteroidal analgesia. This is similar to other reported series of uterine artery embolization for disease processes unrelated to gestational trophoblastic tumors (11). Only one patient experienced buttock and lower-limb claudication, which resolved spontaneously and is likely to be a result of extensive and multiple embolizations in the pelvic vessels. Neurologic deficits affecting the lower limb have previously been reported and seem to be more commonly associated with the use of liquid embolization materials or very small particles (12,13). Other serious complications, such as perineal skin sloughing, uterovaginal and recto-vesico-vaginal fistulae, and bladder necrosis, have also been reported in series where the internal iliac arteries have been embolized with cryanoacylate as the embolizing agent (12–14). The relative paucity of side effects in our series is therefore likely to be related to the use of polyvinyl alcohol (particle diameter, 150–250 µm or 355–500 µm), which is now our agent of choice, and, also important, to the use of selective uterine artery embolization.

Embolization of the uterine arteries has not been associated with uterine infarction because of the presence of a rich collateral vascular network within the pelvis (15). This is emphasized by four patients in our series who managed to conceive following embolization. Several other cases have also been reported (4,5,7,16,17). These patients provide further evidence that arterial recanalization sufficient to sustain the uterus through a full-term gestation can occur after uterine artery embolization for vascular malformations associated with gestational trophoblastic tumors.

In conclusion, selective uterine artery embolization is a safe and effective treatment for hemorrhage from residual uterine vascular malformations after chemotherapy in patients with gestational trophoblastic tumors. Although repeat embolotherapy for recurrent bleeding may be required, hysterectomy can be avoided and fertility preserved, which is extremely important for this group of patients.


   ACKNOWLEDGMENTS
 
We are indebted to J. E. Boultbee, MB, BS, FRCR, and D. Patel, DMU, MSc, for their expert US and Doppler assessments of the relevant patients.


   FOOTNOTES
 
Author contributions: Guarantors of integrity of entire study, A.K.P.L., R.A., A.W.M.M.; study concepts, A.K.P.L., R.A., A.W.M.M.; study design, A.K.P.L., R.A.; literature research, A.K.P.L., R.A.; clinical studies, A.K.P.L., N.K.B., E.S.N., M.J.S.; data acquisition and analysis/interpretation, A.K.P.L., R.A.; statistical analysis, R.A.; manuscript preparation, A.K.P.L., R.A.; manuscript definition of intellectual content, editing, revision/review, and final version approval, all authors.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 

  1. Bagshawe KD, Dent J, Webb J. Hydatidiform mole in England and Wales 1973–83. Lancet 1986; 2:673-677.
  2. Bagshawe KD, Dent J, Newlands ES, Begent RH, Rustin GJ. The role of low-dose methotrexate and folinic acid in gestational trophoblastic tumours (GTT). Br J Obstet Gynaecol 1989; 96:795-802.
  3. Newlands ES, Bagshawe KD, Begent RHJ, Rustin GJS, Holden L, Dent J. Developments in chemotherapy for medium and high risk patients with gestational trophoblastic tumours. Br J Obstet Gynaecol 1986; 93:63-69.
  4. McIvor J, Cameron EW. Pregnancy after uterine embolization to control haemorrhage from gestational trophoblastic tumours. Br J Radiol 1996; 69:624-629.
  5. Long MG, Boultbee JE, Hanson ME, Regent RHJ. Doppler time velocity waveform studies of the uterine artery and uterus. Br J Obstet Gynaecol 1989; 96:588-593.
  6. Vogelzang RL, Nemcek AA, Jr, Skrtic Z, Gorrell J, Lurain J. Uterine arteriovenous malformations: primary treatment with therapeutic embolization. J Vasc Interv Radiol 1991; 2:517-522.
  7. Antebi E, Adar R, Deutsch V, Mozes M. Arteriovenous fistula complicating gynecological operations. Obstet Gynecol 1974; 44:858-861.
  8. Chapman DR, Lutz MH. Report of a successful delivery after nonsurgical management of a choriocarcinoma-related pelvic arteriovenous fistula. Am J Obstet Gynecol 1985; 153:155-157.
  9. Cockshott P, de V, Hendrickse JP. Persistent arteriovenous fistulae following chemotherapy of malignant trophoblastic disease. Radiology 1967; 88:329-333.
  10. Long MG, Boultbee JE, Langley R, Newlands ES, Regent RHJ, Bagshawe KD. Doppler assessment of the uterine circulation and the clinical behaviour of gestational trophoblastic tumours requiring chemotherapy. Br J Cancer 1992; 66:883-887.
  11. Vashisht A, Studd JW, Carey AH, et al. Fibroid embolization: a technique not without significant complications. Br J Obstet Gynaecol 2000; 107:1166-1170.
  12. Hare WSC, Holland CJ. Paresis following internal iliac artery embolization. Radiology 1983; 46:47-51.
  13. Lang EK. Management of haemorrhaging pelvic neoplasms by transcatheter embolization. J Interv Radiol 1989; 4:113-117.
  14. Lang EK. Transcatheter embolization of pelvic vessels for control of hemorrhage. Radiology 1981; 140:331-339.
  15. Belli Am, Hemingway AP, Neal FE, Millar DR. Arteriovenous malformation of the uterus related to trophoblastic disease: a case for surgery or embolization?. J Interv Radiol 1989; 4:112-118.
  16. Poppe W, Van Assche FA, Wilms G, Favril A, Baert A. Pregnancy after transcatheter embolization of a uterine arteriovenous malformation. Am J Obstet Gynecol 1987; 156:1179-1180.
  17. Tacchi D, Loose HW. Successful pregnancy after selective embolization of a post-molar vascular malformation: case report. Br J Obstet Gynaecol 1988; 95:814-817.



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