European Journal of Obstetrics & Gynecology and Reproductive Biology 181 (2014) 54–59
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Review
Uterine arteriovenous malformations following gestational trophoblastic neoplasia: a systematic review Omar Touhami a, Jean Gregoire a, Patricia Noel b, Xuan Bich Trinh a, Marie Plante a,* a b
Gynecologic Oncology Division, Centre Hospitalier Universitaire de Que´bec L’Hoˆtel-Dieu de Que´bec, Laval University, Quebec City, QC, Canada Radiology Department, Centre Hospitalier Universitaire de Que´bec L’Hoˆtel-Dieu de Que´bec, Laval University, Quebec City, QC, Canada
A R T I C L E I N F O
A B S T R A C T
Article history: Received 10 March 2014 Received in revised form 22 June 2014 Accepted 20 July 2014
Uterine arteriovenous malformation (AVM) following gestational trophoblastic neoplasia (GTN) is a rare condition. It can be associated with chronic vaginal bleeding or life-threatening heavy bleeding, even after complete resolution of the tumor following chemotherapy. This analysis aimed to perform an extensive systematic review highlighting clinical symptoms, imaging, management and prognosis of this rare complication of GTN. We also describe an additional case of uterine AVM following GTN. We conducted a literature search using Medline, Embase and Cochrane library to analyze the clinical data of 49 published cases of uterine AVM following GTN. Median age of the women diagnosed with AVM was 29 years (range 15–49). Median gravidity was 2 (range 1–8) and 50% of women were nulligravida. Complete molar pregnancy was the most common initial gestational trophoblastic diagnosis (48%). Overall, 44 patients (88%) were symptomatic and presented with chronic or acute abnormal vaginal bleeding. Only 3 patients had an undetectable HCG level at the time of uterine AVM diagnosis. Hypoechoic space in the myometrium is the most relevant finding on ultrasonography but the gold standard for the definitive diagnosis of AVMs is angiographic examination. Uterine artery embolization was the most common treatment option performed in 82% of the patients and was successful in controlling the bleeding in 85% of cases. We identified 20 pregnancies after successful embolization of uterine AVM following a GTN and 90% of them were successful. Because of the risk of life-threatening heavy bleeding, the diagnosis of uterine AVM should always be considered in patients with a history of recurrent unexplained vaginal bleeding after gestational trophoblastic neoplasia. Angiographic embolization is successful in the majority of cases and does not appear to compromise future pregnancy. ß 2014 Published by Elsevier Ireland Ltd.
Keywords: Uterine arteriovenous malformations Gestational trophoblastic neoplasia Hemorrhage Uterine artery embolization
Contents Introduction . . . . . . . . . . . . . . Case report . . . . . . . . . . . . . . . Materials and methods . . . . . Search strategy . . . . . . Eligibility criteria . . . . Data extraction . . . . . . Statistical analysis. . . . Results . . . . . . . . . . . . . . . . . . Clinical characteristics Management . . . . . . . . Obstetrical outcomes .
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* Corresponding author at: Gynecologic Oncology Division, Centre Hospitalier Universitaire de Que´bec, L’Hoˆtel-Dieu de Que´bec, 11 coˆte du Palais, Quebec City, Quebec, Canada, G1R 2J. Tel.: +1 418 691 5392; fax: +1 418 691 5720. E-mail address: [email protected] (M. Plante). http://dx.doi.org/10.1016/j.ejogrb.2014.07.023 0301-2115/ß 2014 Published by Elsevier Ireland Ltd.
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Discussion . . . . . . . . . . . . . . . Clinical characteristics Imaging . . . . . . . . . . . . Management . . . . . . . . Obstetrical outcomes . Conclusion . . . . . . . . . . . . . . . Funding . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . .
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Introduction Arteriovenous malformation (AVM) is an abnormal connection between arteries and veins, bypassing the capillary system. There is usually proliferation of vascular channels with formation of numerous small fistulae [1]. Uterine AVM are rare and can occur as a consequence of uterine curettage, cesarean section, gestational trophoblastic neoplasia (GTN), maternal diethylstilbestrol exposure or endometrial, cervical neoplasia [2,3]. Uterine AVM can be found in patients with gestational trophoblastic neoplasia and can cause chronic vaginal bleeding or life threatening hemorrhage, even after complete resolution of the tumor following chemotherapy. This relationship between GTN and uterine AVM could be explained by a disorganized trophoblastic proliferation, increased angiogenesis caused by high levels of human chorionic gonadotropin [4] and finally by the uterine curettage which is the cornerstone of gestational trophoblastic disease (GTD) treatment. Although ultrasound imaging with pulsed Doppler analysis and MRI are useful for the diagnosis and localization of uterine AVM [5], angiography is essential for precise delineation of feeding arteries and draining veins allowing treatment planning. Uterine AVM is a rare condition, but a potentially life-threatening one that can occur in young women who generally wish to preserve fertility, hence the importance of noninvasive treatment options that preserve fertility. In this article, we report a case of uterine AVM following GTN and we performed a systematic review of the literature on the subject. Case report A 28-year-old white female, gravida 1, para 0, was referred to our hospital because of gradual increase of human chorionic gonadotropin (HCG) levels and persistent bleeding 7 weeks after dilatation and evacuation of a complete molar pregnancy. The CT scan showed an endocavitary complex uterine mass vascularized measuring 7 5.8 5.6 cm without evidence of lung metastasis. She was diagnosed with a persistent non-metastatic gestational trophoblastic neoplasia with a stage I tumor (FIGO anatomic staging 2000) and a WHO prognostic score of 5. She was initially treated by five cycles of actinomycin-D (1.25 mg/m2 intravenously (IV) bolus dose every 2 weeks), with plateauing of HCG. Then seven cycles of Methotrexate (50 mg/m2 intramuscular (IM) weekly) were given before she developed resistance. Finally she responded completely to five cycles of EMA-CO (etoposide, methotrexate, actinomycin-D, cyclophosphamide, vincristine) with three cycles of consolidation. Three months after the end of chemotherapy she developed intermittent vaginal bleeding and two episodes of vaginal hemorrhage leading to unconsciousness with a hemoglobin value of 9.0 g/dL. HCG level remained undetectable. Pelvic ultrasound was performed to further evaluate the patient’s abnormal and persistent bleeding. The ultrasound showed a heterogeneous mass in the posterior myometrium with an anechoic internal focus measuring 15 10 15 mm. On color Doppler, a mosaic pattern of color signals due to aliasing associated
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with high velocity flow was demonstrated. Pulsed Doppler analysis revealed an elevation of the peak systolic velocity (PSV = 100 cm/s) with a low resistive index (RI = 0.39), illustrating a typical high flow, low resistance, blood flow pattern (Fig. 1). MRI also revealed a heterogeneous mass comprising a tubular focus of low signal intensity on T1 and T2-weighted sequences in keeping with flow void that was enhancing as intensely as normal vessels. This focus was surrounded by non-enhancing high signal intensity areas on both T1 and T2-weighted sequences in keeping with some myometrial hematoma (Fig. 2). At that point, the diagnosis of uterine AVM was seriously suspected. The patient was counseled to undergo embolization for the management of her suspected AVM. She was advised of the risks and benefits. Given her desire for fertility preservation, she accepted the procedure. Selective right uterine artery angiography performed via the left femoral artery showed a slightly enlarged uterine artery, feeding a vascular nidus with arteriovenous communication and early venous drainage. This was followed by embolization with Gelfoam (Gelfoam, Pharmacia & Upjohn Co., Kalamazoo, MI) (Fig. 3). The left uterine artery was then similarly selectively catheterized and embolized. Repeat pelvic arteriogram performed at the completion of the procedure demonstrated persistent minimal filling of the arteriovenous malformation. This required a second procedure 3 weeks later with embolization of the 2 uterine arteries. Pelvic arteriogram at the end of the procedure demonstrated the absence of flow in either uterine artery and no filling of the arteriovenous malformation. The patient developed a small femoral artery pseudoaneurysm, secondary to the femoral catheterization and was successfully treated by ultrasound-guided compression. Oral hormonal contraceptives were prescribed and no recurrence of abnormal bleeding was reported after 11 months of follow-up. Cycles were regular and HCG levels remained undetectable.
Fig. 1. Pulsed Doppler analysis illustrating a typical high flow, low resistance blood flow pattern in the posterior wall of the uterus.
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gestational trophoblastic disease (GTD). Studies with vaginal or no localized AVM were excluded from the review. We excluded studies reporting the diagnosis of uterine AVM not following a gestational trophoblastic disease. Data extraction From each eligible study, we extracted and tabulated the following information: age, gravidity and parity, the initial type of GTD (partial/complete), the HCG level at diagnosis, the type of chemotherapy, the circumstances surrounding the diagnosis of uterine AVM, the interval between the end of chemotherapy and the diagnosis of uterine AVM, the management option and the outcome of treatment and lastly the obstetrical outcome. Statistical analysis We calculated the frequencies of the extracted clinical items, median numbers, and ranges. Results Fig. 2. Coronal T2-weighted MRI showing a low signal intensity 16 9 mm tubular mass in keeping with flow void that was rapidly enhancing in the posterior wall of the uterus. Myometrial serpentine low signal intensity feeding vessels are also observed.
Initial search yielded 31 relevant articles. Finally, 14 articles were included in the review, 12 were case reports and 2 were observational studies totalizing 49 patients diagnosed with AVM following GTN. Studies were published between 1967 and 2012 [6–19]. Clinical characteristics Median age of the women diagnosed with AVM was 29 years (range 15–49). Median gravidity was 2 (range 1–8) and 50% of women were nulligravida. Table 1 summarizes the clinical characteristics of the cases. The initial gestational trophoblastic diagnosis consisted of complete molar pregnancy in 48% of cases,
Table 1 Patients’ characteristics. Number of cases Age, median (range) Gravidity, median (range) Parity, median (range) Interval GTD/AVM(months), median (range) HCG level at diagnosis (mIU/mL), median (range)
Fig. 3. Right internal iliac artery angiography showing opacification of a slightly enlarged right uterine artery and filling of the uterine AVM with early venous drainage.
Materials and methods Search strategy We searched the following electronic databases: MEDLINE (1967–2013), Embase (1980–2013), Cochrane Library (2004– 2013). Only English and French studies were selected. We conducted the search using the following algorithm: uterine AND (arteriovenous) AND (malformation OR fistula) AND (trophoblastic OR molar). The last update was performed in October 2013. Eligibility criteria The inclusion criteria were as follows: studies referring to arteriovenous malformations, fistula of uterus following
50 29 (15–49) 2.0 (1–8) 1 (0–4) 5 (0–156) 2864.9 (0–32,000)
Initial GTD diagnosis Complete mole Partial mole PSTT Unknown
24 12 1 13
HCG level at diagnosis (mIU/mL) Elevated Normal Unknown
27 (54%) 3 (6%) 20 (40%)
Clinical presentation Asymptomatic Chronic vaginal bleeding Heavy vaginal bleeding
6 (12%) 30 (60%) 28 (56%)
Chemotherapy No chemotherapy MTX EMACO ACT-D MTX + EMACO + ACT-D MTX + EMACO MTX + ACT-D Unknown
3 18 6 1 1 3 3 15
(48%) (24%) (2%) (26%)
(6%) (36%) (12%) (2%) (2%) (6%) (6%) (30%)
MTX, methotrexate; ACT-D, actinomycin-D; EMACO, etoposide, methotrexate, dactinomycin, cyclophosphamide, vincristine.
O. Touhami et al. / European Journal of Obstetrics & Gynecology and Reproductive Biology 181 (2014) 54–59
partial molar pregnancy in 24%, one uterine AVM occurred in a patient with a placental site trophoblastic tumor following a normal pregnancy [14], and one was diagnosed incidentally on pathological examination of a hysterectomy specimen in a patient operated for a large uterine mass [11]. The diagnosis of gestational trophoblastic tumor was made based on a plateauing of the HCG levels, an increase, or a persistence following a GTD in 42 patients (84%). Histological diagnosis of choriocarcinoma or invasive mole was made in 7 patients [6,11,13,19]. Methotrexate was the most commonly used chemotherapy agent in 52% of patients. One patient did not receive any chemotherapy following the diagnosis of gestational trophoblastic tumor, and showed decreasing then normalization of HCG levels after embolization of the uterine AVM [15]. Overall, 44 patients (88%) were symptomatic and presented with chronic or acute abnormal vaginal bleeding. Uterine AVM diagnosis was made in 6 asymptomatic patients with gestational trophoblastic tumor by ultrasound imaging or angiography [6,10,12,18]. The median HCG level at diagnosis of AVM was 2864.9 mIU/mL (range 0–32,000) and 3 patients had undetectable HCG level at the time of AVM diagnosis ([8,9], our case). The median time interval from the end of chemotherapy to AVM diagnosis was 5 months (range 0–156). Diagnosis of uterine AVM was made before starting chemotherapy in 7 patients [6,10,15].
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Table 3 Embolization attempts. Number of attempts
Number of patients
1 2 3 4 5 6
41 29 10 1 0 0 1
(70%) (24%) (2%) (0%) (0%) (2%)
Obstetrical outcomes We identified 20 patients with reported pregnancies following the diagnosis of uterine AVM, with or without treatment of uterine AVM. The earliest pregnancy was reported 2 months after embolization treatment [9,12]. The majority of the pregnancies were successful and only 2 ended with miscarriage [13]. A premature delivery with postpartum hemorrhage was reported by Chapman et al. [7] 4 years after embolization treatment of uterine AVM. Discussion Clinical characteristics
Management As can be seen in Table 2, uterine artery embolization was the most common treatment option performed in 41/50 cases (82%) with success in controlling bleeding in 85% of the embolization cases. Total abdominal hysterectomy was performed upfront in two patients [11,14] and due to embolization failure with uncontrolled bleeding in four patients [13,19]. Overall, embolization failure was observed in only six cases. In these patients, bleeding was controlled by hysterectomy in four cases as stated above and by uterine artery ligation in two cases [13,17]. Interestingly, Corusic et al. [18] reported successful laparoscopic resection of a uterine AVM in a 21 year-old asymptomatic woman following the 4th cycle of methotrexate chemotherapy. The mean number of embolization procedures required to control bleeding was 1.4 (range 1–6). Bleeding control was accomplished following only a single procedure in 26 patients (63%) (Table 3). Six patients did not require any additional treatment for their AVM following chemotherapy; Kawano et al. presented two cases with disappearance of the hypo-echoic uterine area on ultrasound imaging at the end of chemotherapy and 1 asymptomatic patient with persistence of the AVM [10]; Cockshott et al. [6] reported three cases with persistence of angiographic AVM at the end of chemotherapy in asymptomatic patients.
Table 2 Uterine AVM management. Number of patients N = 50 Embolization Successful Unsuccessful
41 35 (85%) 6 (15%)
Hysterectomy Successful
4 4 (100%)
Uterine artery ligation Successful
2 2 (100%)
Laparoscopic resection of uterine AVM Successful
1 1 (100%)
Approximately 10% of complete hydatidiform moles and 0.5% of partial hydatidiform moles undergo malignant transformation to become an invasive mole, a choriocarcinoma, or, rarely, a placental site tumor, and require further treatment. Chemotherapy has allowed complete remission in more than 95% of patients with gestational trophoblastic tumors, even when metastases are present [20]. The efficacy of chemotherapy reduced dramatically the mortality of these patients, however the prognosis may be compromised by other complications such as vaginal or intraperitoneal hemorrhage, which can be life threatening. Some studies suggest that uterine vascular malformations persist in 10–15% of patients even after complete resolution of gestational trophoblastic disease [13], but it appears that only 2% of uterine AVM are symptomatic and cause chronic or heavy bleeding [19]. The formation of uterine AVM is due primarily to the disorganized trophoblastic proliferation observed in molar pregnancies. Human chorionic gonadotropin (HCG) may have a key regulatory role in angiogenesis and vascular function [4]. Uterine curettage which is the corner-stone of GTD treatment is responsible for the formation of a myometrial scar. High levels of HCG and disorganized trophoblastic invasion causes destructive changes in vascular structures and may allow direct flow of arterial blood vessels to venous blood vessels in this scar site [7,21]. Up to 48% of the AVM cases reported in the literature followed a complete molar pregnancy, but it is still not clear if a specific type of gestational trophoblastic disease predisposes to post molar AVM. In 47 patients (94%) HCG levels were elevated and ranged between 9 and 32,000 mIU/mL, only three cases presented an undetectable HCG at the time of AVM diagnosis ([8,9], our case). Previously, Cockshott et al. [6] have highlighted that hypervascular changes in the uterus can be observed to persist even when HCG levels have normalized. The time interval from ending chemotherapy to AVM diagnosis is variable. In our review this interval ranged from 0 to 156 months, with several authors reporting diagnosis of uterine AVM even before the onset of chemotherapy [6,10,15]. Resulting from disorganized vascular structures and high blood flow, patients with uterine AVM are at risk of abnormal bleeding such as chronic or heavy vaginal bleeding. Pelvic pain also can be present [22]. Patients can also be asymptomatic; in our review, diagnosis of
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uterine AVM was made in 6 asymptomatic patients [6,10,12,18]. However, the diagnosis of uterine AVM should be considered in patients with a history of recurrent unexplained abnormal vaginal bleeding after gestational trophoblastic disease. Imaging Hypo echoic space in the myometrium is the most relevant finding on ultrasonography. A mosaic pattern with aliasing on color Doppler filling these spaces with high velocity and low resistance flow on pulsed Doppler is typical [3]. The gold standard for the definitive diagnosis of AVMs is angiographic examination; it shows typically an opacified vascular tangle with early venous filling. Angiography can also provide crucial information with regards to the vascular anatomy and the extent of the vascular malformation [2]. This information is of critical importance when performing the interventional radiologic embolization. MRI and CT scan can be useful for the diagnosis and in the event of suspected adjacent organ involvement [23]. On MRI, AVM typically manifests as multiple serpentine flow-related signal voids on T1 and T2-weighted sequences. Enhancement is similar to normal vessels.
In our review we identified 20 patients with reported pregnancies after embolization of uterine AVM following a GTN and 90% of them were successful. Conclusion Uterine AVM is a rare complication of gestational disease tumors. Because of the risk of life threatening heavy bleeding, the diagnosis of uterine AVM should always be considered in patients with a history of recurrent unexplained vaginal bleeding after gestational trophoblastic disease. Ultrasonography is helpful for diagnosis, but the gold standard remains angiographic examination and interventional radiologic embolization is generally performed at the same time. Pelvic pain is the main side effect of embolization and this procedure does not appear to compromise future pregnancy. Funding No source of support.
Management
References
Treatment of uterine AVM is based on the symptomatology, the location, the extent, and the desire for future fertility. Kawano et al. [10] presented 3 cases with disappearance of the hypo-echoic uterine area on ultrasound imaging at the end of chemotherapy cycles; Cockshott et al. [6] presented 3 cases with persistence of uterine AVM on angiographic examination at the end of chemotherapy in asymptomatic patients. They highlighted that pelvic vessels rapidly revert to the normal appearance of the nonpregnant state with uterine vessels of a caliber of 1 mm, after successful chemotherapy of malignant trophoblastic disease [6]. These cases supported the idea that management of uterine AVM is not necessary in asymptomatic patients. After successful remission following chemotherapy for GTN, patients are often very concerned about the possibility to carry a normal pregnancy in the future [24], hence the importance of the fertility sparing management of uterine AVM. Overall, 82% of the patients collected in this review have been successfully treated by embolization with bleeding control in 85% of cases. Failure of embolization have been managed by hysterectomy or by vascular surgery ligation [13,17]. Corusic et al. [18] reported successful laparoscopic resection of a uterine AVM. Embolization has several advantages: avoidance of major surgery and general anesthesia and short duration of recovery, ability to preserve fertility, prevention of operative morbidity such as massive bleeding and post-operative adherences of surgical procedures [16]. The main side effect of embolization was pelvic pain. Severe complications can occur such as perineal skin sloughing, uterovaginal and rectovesicovaginal fistulae, and neurological deficits in the lower extremities [25]. A case of buttock and lower-limb claudication has been reported [13], and our patient developed a femoral pseudoaneurysm.
[1] Polat P, Suma S, Kantarcy M, Alper F, Levent A. Color Doppler US in the evaluation of uterine vascular abnormalities. RadioGraphics 2002;22:47–53. [2] Ghai S, Rajan DK, Asch MR, Muradali D, Simons ME, TerBrugge KG. Efficacy of embolization in traumatic uterine vascular malformations. J Vasc Interv Radiol 2003;14:1401–8. [3] Peitsidis P, Manolakos E, Tsekoura V, Kreienberg R, Schwentner L. Uterine arteriovenous malformations induced after diagnostic curettage: a systematic review. Arch Gynecol Obstet 2011;284:1137–51. [4] Zygmunt M1, Herr F, Mu¨nstedt K, Lang U. Liang OD Angiogenesis and vasculogenesis in pregnancy. Eur J Obstet Gynecol Reprod Biol 2003;110(September (Suppl. 1)):S10–8. [5] Huang SC, Chou CY. The role of transvaginal ultrasonography in the management of gestational trophoblastic tumor. Am J Obstet Gynecol 1995;172(3): 1063–1064. [6] Cockshott WP, Hendrickse JP. Persistent arteriovenous fistulae following chemotherapy of malignant trophoblastic disease. Radiology 1967;88(2): 329–33. [7] 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(2):155–7. [8] Garner EI, Meyerovitz M, Goldstein DP, Berkowitz RS. Successful term pregnancy after selective arterial embolization of symptomatic arteriovenous malformation in the setting of gestational trophoblastic tumor. Gynecol Oncol 2003;88(1):69–72. [9] Tacchi D, Loose HW. Successful pregnancy after selective embolization of a post-molar vascular malformation. Case report. Br J Obstet Gynaecol 1988;95(8):814–7. [10] Kawano M, Masuzaki H, Ishimaru T. Transvaginal color Doppler studies in gestational trophoblastic disease. Ultrasound Obstet Gynecol 1996;7(3): 197–200. [11] Tajima T, Honda H, Kuroiwa T, et al. Radiologically identified molar invasion into pelvic arteriovenous shunts. Clin Imaging 2000;24(4):227–30. [12] Kelly FW. Forceps delivery after molar malignancy in a woman with arteriovenous malformation. A case report. J Reprod Med 2001;46(11): 1013–1016. [13] Lim AK, Agarwal R, Seckl MJ, Newlands ES, Barrett NK, Mitchell AW. Embolization of bleeding residual uterine vascular malformations in patients with treated gestational trophoblastic tumors. Radiology 2002; 222(3):640–4. [14] Ichikawa Y, Nakauchi T, Sato T, Oki A, Tsunoda H, Yoshikawa H. Ultrasound diagnosis of uterine arteriovenous fistula associated with placental site trophoblastic tumor. Ultrasound Obstet Gynecol 2003;21(6):606–8. [15] Carlini L, Villa A, Busci L, Trezzi G, Agazzi R, Frigerio L. Selective uterine artery embolization: a new therapeutic approach in a patient with low-risk gestational trophoblastic disease. Am J Obstet Gynecol 2006;195(1):314–5. [16] Tsai CC, Cheng YF, Changchien CC, Lin H. Successful term pregnancy after selective embolization of a large postmolar uterine arteriovenous malformation. Int J Gynecol Cancer 2006;16(Suppl. 1):439–41. [17] Milingos D, Doumplis D, Sieunarine K, Savage P, Lawson AD, Smith JR. Uterine arteriovenous malformation: fertility-sparing surgery using unilateral ligation of uterine artery and ovarian ligament. Int J Gynecol Cancer 2007;17(3):735–7. [18] Corusic A, Barisic D, Lovric H, Despot A, Planinic P. Successful laparoscopic bipolar coagulation of a large arteriovenous malformation due to invasive trophoblastic disease: a case report. J Minim Invasive Gynecol 2009;16(3): 368–371.
Obstetrical outcomes Studies on embolization for uterine leiomyoma, showed that uterus has a generous supply of collateral vessels, which prevent uterine infarction after selective embolization. Collateral circulation and recanalization was adequate to maintain an adequate blood supply to sustain a growing pregnancy after embolization [26]. Compared to myomectomy, uterine embolization of leiomyoma does not seem to be associated with an increase in intrauterine growth retardation or fetal distress [27].
O. Touhami et al. / European Journal of Obstetrics & Gynecology and Reproductive Biology 181 (2014) 54–59 [19] McGrath S, Harding V, Lim AK, Burfitt N, Seckl MJ, Savage P. Embolization of uterine arteriovenous malformations in patients with gestational trophoblastic tumors: a review of patients at Charing Cross Hospital, 2000– 2009. J Reprod Med 2012;57(7–8):319–24. [20] Seckl MJ, Sebire NJ, Berkowitz RS. Gestational trophoblastic disease. Lancet 2010;376:717–29. [21] Sugimori H, Nagata Y, Nishimura A, Taki I, Takahashi M. Angiography of trophoblastic tumors: analysis of pelvic angiography correlated with microangiography and histopathological examinations of uterine specimens. Gynecol Oncol 1975;3:61–76. [22] Halperin R, Schneider D, Maymon R, Peer A, Pansky M, Herman A. Arteriovenous malformation after uterine curettage: a report of 3 cases. J Reprod Med 2007;52:445–9.
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[23] Kwon JH. Kim GS Obstetric iatrogenic arterial injuries of the uterus: diagnosis with US and treatment with transcatheter arterial embolization. Radiographics 2002;22(1):35–46. [24] Garner EIO, Lipson E, Bernstein MR, Goldstein DP, Berkowitz RS. Subsequent pregnancy experience in patients with molar pregnancy and gestational trophoblastic tumor. J Reprod Med 2002;47:380–6. [25] Martin J, Bhanot K, Athreya S. Complications and reinterventions in uterine artery embolization for symptomatic uterine fibroids: a literature review and meta analysis. Cardiovasc Intervent Radiol 2013;36(April (2)):395–402. [26] Gupta JK, Sinha A, Lumsden MA, Hickey M. Uterine artery embolization for symptomatic uterine fibroids. Cochrane Database Syst Rev 2012;(May):5. [27] Mohan PP, Hamblin MH, Vogelzang RL. Uterine artery embolization and its effect on fertility. J Vasc Interv Radiol 2013;24(July (7)):925–30.
Contents lists available at ScienceDirect
European Journal of Obstetrics & Gynecology and Reproductive Biology journal homepage: www.elsevier.com/locate/ejogrb
Review
Uterine arteriovenous malformations following gestational trophoblastic neoplasia: a systematic review Omar Touhami a, Jean Gregoire a, Patricia Noel b, Xuan Bich Trinh a, Marie Plante a,* a b
Gynecologic Oncology Division, Centre Hospitalier Universitaire de Que´bec L’Hoˆtel-Dieu de Que´bec, Laval University, Quebec City, QC, Canada Radiology Department, Centre Hospitalier Universitaire de Que´bec L’Hoˆtel-Dieu de Que´bec, Laval University, Quebec City, QC, Canada
A R T I C L E I N F O
A B S T R A C T
Article history: Received 10 March 2014 Received in revised form 22 June 2014 Accepted 20 July 2014
Uterine arteriovenous malformation (AVM) following gestational trophoblastic neoplasia (GTN) is a rare condition. It can be associated with chronic vaginal bleeding or life-threatening heavy bleeding, even after complete resolution of the tumor following chemotherapy. This analysis aimed to perform an extensive systematic review highlighting clinical symptoms, imaging, management and prognosis of this rare complication of GTN. We also describe an additional case of uterine AVM following GTN. We conducted a literature search using Medline, Embase and Cochrane library to analyze the clinical data of 49 published cases of uterine AVM following GTN. Median age of the women diagnosed with AVM was 29 years (range 15–49). Median gravidity was 2 (range 1–8) and 50% of women were nulligravida. Complete molar pregnancy was the most common initial gestational trophoblastic diagnosis (48%). Overall, 44 patients (88%) were symptomatic and presented with chronic or acute abnormal vaginal bleeding. Only 3 patients had an undetectable HCG level at the time of uterine AVM diagnosis. Hypoechoic space in the myometrium is the most relevant finding on ultrasonography but the gold standard for the definitive diagnosis of AVMs is angiographic examination. Uterine artery embolization was the most common treatment option performed in 82% of the patients and was successful in controlling the bleeding in 85% of cases. We identified 20 pregnancies after successful embolization of uterine AVM following a GTN and 90% of them were successful. Because of the risk of life-threatening heavy bleeding, the diagnosis of uterine AVM should always be considered in patients with a history of recurrent unexplained vaginal bleeding after gestational trophoblastic neoplasia. Angiographic embolization is successful in the majority of cases and does not appear to compromise future pregnancy. ß 2014 Published by Elsevier Ireland Ltd.
Keywords: Uterine arteriovenous malformations Gestational trophoblastic neoplasia Hemorrhage Uterine artery embolization
Contents Introduction . . . . . . . . . . . . . . Case report . . . . . . . . . . . . . . . Materials and methods . . . . . Search strategy . . . . . . Eligibility criteria . . . . Data extraction . . . . . . Statistical analysis. . . . Results . . . . . . . . . . . . . . . . . . Clinical characteristics Management . . . . . . . . Obstetrical outcomes .
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* Corresponding author at: Gynecologic Oncology Division, Centre Hospitalier Universitaire de Que´bec, L’Hoˆtel-Dieu de Que´bec, 11 coˆte du Palais, Quebec City, Quebec, Canada, G1R 2J. Tel.: +1 418 691 5392; fax: +1 418 691 5720. E-mail address: [email protected] (M. Plante). http://dx.doi.org/10.1016/j.ejogrb.2014.07.023 0301-2115/ß 2014 Published by Elsevier Ireland Ltd.
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Discussion . . . . . . . . . . . . . . . Clinical characteristics Imaging . . . . . . . . . . . . Management . . . . . . . . Obstetrical outcomes . Conclusion . . . . . . . . . . . . . . . Funding . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . .
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Introduction Arteriovenous malformation (AVM) is an abnormal connection between arteries and veins, bypassing the capillary system. There is usually proliferation of vascular channels with formation of numerous small fistulae [1]. Uterine AVM are rare and can occur as a consequence of uterine curettage, cesarean section, gestational trophoblastic neoplasia (GTN), maternal diethylstilbestrol exposure or endometrial, cervical neoplasia [2,3]. Uterine AVM can be found in patients with gestational trophoblastic neoplasia and can cause chronic vaginal bleeding or life threatening hemorrhage, even after complete resolution of the tumor following chemotherapy. This relationship between GTN and uterine AVM could be explained by a disorganized trophoblastic proliferation, increased angiogenesis caused by high levels of human chorionic gonadotropin [4] and finally by the uterine curettage which is the cornerstone of gestational trophoblastic disease (GTD) treatment. Although ultrasound imaging with pulsed Doppler analysis and MRI are useful for the diagnosis and localization of uterine AVM [5], angiography is essential for precise delineation of feeding arteries and draining veins allowing treatment planning. Uterine AVM is a rare condition, but a potentially life-threatening one that can occur in young women who generally wish to preserve fertility, hence the importance of noninvasive treatment options that preserve fertility. In this article, we report a case of uterine AVM following GTN and we performed a systematic review of the literature on the subject. Case report A 28-year-old white female, gravida 1, para 0, was referred to our hospital because of gradual increase of human chorionic gonadotropin (HCG) levels and persistent bleeding 7 weeks after dilatation and evacuation of a complete molar pregnancy. The CT scan showed an endocavitary complex uterine mass vascularized measuring 7 5.8 5.6 cm without evidence of lung metastasis. She was diagnosed with a persistent non-metastatic gestational trophoblastic neoplasia with a stage I tumor (FIGO anatomic staging 2000) and a WHO prognostic score of 5. She was initially treated by five cycles of actinomycin-D (1.25 mg/m2 intravenously (IV) bolus dose every 2 weeks), with plateauing of HCG. Then seven cycles of Methotrexate (50 mg/m2 intramuscular (IM) weekly) were given before she developed resistance. Finally she responded completely to five cycles of EMA-CO (etoposide, methotrexate, actinomycin-D, cyclophosphamide, vincristine) with three cycles of consolidation. Three months after the end of chemotherapy she developed intermittent vaginal bleeding and two episodes of vaginal hemorrhage leading to unconsciousness with a hemoglobin value of 9.0 g/dL. HCG level remained undetectable. Pelvic ultrasound was performed to further evaluate the patient’s abnormal and persistent bleeding. The ultrasound showed a heterogeneous mass in the posterior myometrium with an anechoic internal focus measuring 15 10 15 mm. On color Doppler, a mosaic pattern of color signals due to aliasing associated
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with high velocity flow was demonstrated. Pulsed Doppler analysis revealed an elevation of the peak systolic velocity (PSV = 100 cm/s) with a low resistive index (RI = 0.39), illustrating a typical high flow, low resistance, blood flow pattern (Fig. 1). MRI also revealed a heterogeneous mass comprising a tubular focus of low signal intensity on T1 and T2-weighted sequences in keeping with flow void that was enhancing as intensely as normal vessels. This focus was surrounded by non-enhancing high signal intensity areas on both T1 and T2-weighted sequences in keeping with some myometrial hematoma (Fig. 2). At that point, the diagnosis of uterine AVM was seriously suspected. The patient was counseled to undergo embolization for the management of her suspected AVM. She was advised of the risks and benefits. Given her desire for fertility preservation, she accepted the procedure. Selective right uterine artery angiography performed via the left femoral artery showed a slightly enlarged uterine artery, feeding a vascular nidus with arteriovenous communication and early venous drainage. This was followed by embolization with Gelfoam (Gelfoam, Pharmacia & Upjohn Co., Kalamazoo, MI) (Fig. 3). The left uterine artery was then similarly selectively catheterized and embolized. Repeat pelvic arteriogram performed at the completion of the procedure demonstrated persistent minimal filling of the arteriovenous malformation. This required a second procedure 3 weeks later with embolization of the 2 uterine arteries. Pelvic arteriogram at the end of the procedure demonstrated the absence of flow in either uterine artery and no filling of the arteriovenous malformation. The patient developed a small femoral artery pseudoaneurysm, secondary to the femoral catheterization and was successfully treated by ultrasound-guided compression. Oral hormonal contraceptives were prescribed and no recurrence of abnormal bleeding was reported after 11 months of follow-up. Cycles were regular and HCG levels remained undetectable.
Fig. 1. Pulsed Doppler analysis illustrating a typical high flow, low resistance blood flow pattern in the posterior wall of the uterus.
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O. Touhami et al. / European Journal of Obstetrics & Gynecology and Reproductive Biology 181 (2014) 54–59
gestational trophoblastic disease (GTD). Studies with vaginal or no localized AVM were excluded from the review. We excluded studies reporting the diagnosis of uterine AVM not following a gestational trophoblastic disease. Data extraction From each eligible study, we extracted and tabulated the following information: age, gravidity and parity, the initial type of GTD (partial/complete), the HCG level at diagnosis, the type of chemotherapy, the circumstances surrounding the diagnosis of uterine AVM, the interval between the end of chemotherapy and the diagnosis of uterine AVM, the management option and the outcome of treatment and lastly the obstetrical outcome. Statistical analysis We calculated the frequencies of the extracted clinical items, median numbers, and ranges. Results Fig. 2. Coronal T2-weighted MRI showing a low signal intensity 16 9 mm tubular mass in keeping with flow void that was rapidly enhancing in the posterior wall of the uterus. Myometrial serpentine low signal intensity feeding vessels are also observed.
Initial search yielded 31 relevant articles. Finally, 14 articles were included in the review, 12 were case reports and 2 were observational studies totalizing 49 patients diagnosed with AVM following GTN. Studies were published between 1967 and 2012 [6–19]. Clinical characteristics Median age of the women diagnosed with AVM was 29 years (range 15–49). Median gravidity was 2 (range 1–8) and 50% of women were nulligravida. Table 1 summarizes the clinical characteristics of the cases. The initial gestational trophoblastic diagnosis consisted of complete molar pregnancy in 48% of cases,
Table 1 Patients’ characteristics. Number of cases Age, median (range) Gravidity, median (range) Parity, median (range) Interval GTD/AVM(months), median (range) HCG level at diagnosis (mIU/mL), median (range)
Fig. 3. Right internal iliac artery angiography showing opacification of a slightly enlarged right uterine artery and filling of the uterine AVM with early venous drainage.
Materials and methods Search strategy We searched the following electronic databases: MEDLINE (1967–2013), Embase (1980–2013), Cochrane Library (2004– 2013). Only English and French studies were selected. We conducted the search using the following algorithm: uterine AND (arteriovenous) AND (malformation OR fistula) AND (trophoblastic OR molar). The last update was performed in October 2013. Eligibility criteria The inclusion criteria were as follows: studies referring to arteriovenous malformations, fistula of uterus following
50 29 (15–49) 2.0 (1–8) 1 (0–4) 5 (0–156) 2864.9 (0–32,000)
Initial GTD diagnosis Complete mole Partial mole PSTT Unknown
24 12 1 13
HCG level at diagnosis (mIU/mL) Elevated Normal Unknown
27 (54%) 3 (6%) 20 (40%)
Clinical presentation Asymptomatic Chronic vaginal bleeding Heavy vaginal bleeding
6 (12%) 30 (60%) 28 (56%)
Chemotherapy No chemotherapy MTX EMACO ACT-D MTX + EMACO + ACT-D MTX + EMACO MTX + ACT-D Unknown
3 18 6 1 1 3 3 15
(48%) (24%) (2%) (26%)
(6%) (36%) (12%) (2%) (2%) (6%) (6%) (30%)
MTX, methotrexate; ACT-D, actinomycin-D; EMACO, etoposide, methotrexate, dactinomycin, cyclophosphamide, vincristine.
O. Touhami et al. / European Journal of Obstetrics & Gynecology and Reproductive Biology 181 (2014) 54–59
partial molar pregnancy in 24%, one uterine AVM occurred in a patient with a placental site trophoblastic tumor following a normal pregnancy [14], and one was diagnosed incidentally on pathological examination of a hysterectomy specimen in a patient operated for a large uterine mass [11]. The diagnosis of gestational trophoblastic tumor was made based on a plateauing of the HCG levels, an increase, or a persistence following a GTD in 42 patients (84%). Histological diagnosis of choriocarcinoma or invasive mole was made in 7 patients [6,11,13,19]. Methotrexate was the most commonly used chemotherapy agent in 52% of patients. One patient did not receive any chemotherapy following the diagnosis of gestational trophoblastic tumor, and showed decreasing then normalization of HCG levels after embolization of the uterine AVM [15]. Overall, 44 patients (88%) were symptomatic and presented with chronic or acute abnormal vaginal bleeding. Uterine AVM diagnosis was made in 6 asymptomatic patients with gestational trophoblastic tumor by ultrasound imaging or angiography [6,10,12,18]. The median HCG level at diagnosis of AVM was 2864.9 mIU/mL (range 0–32,000) and 3 patients had undetectable HCG level at the time of AVM diagnosis ([8,9], our case). The median time interval from the end of chemotherapy to AVM diagnosis was 5 months (range 0–156). Diagnosis of uterine AVM was made before starting chemotherapy in 7 patients [6,10,15].
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Table 3 Embolization attempts. Number of attempts
Number of patients
1 2 3 4 5 6
41 29 10 1 0 0 1
(70%) (24%) (2%) (0%) (0%) (2%)
Obstetrical outcomes We identified 20 patients with reported pregnancies following the diagnosis of uterine AVM, with or without treatment of uterine AVM. The earliest pregnancy was reported 2 months after embolization treatment [9,12]. The majority of the pregnancies were successful and only 2 ended with miscarriage [13]. A premature delivery with postpartum hemorrhage was reported by Chapman et al. [7] 4 years after embolization treatment of uterine AVM. Discussion Clinical characteristics
Management As can be seen in Table 2, uterine artery embolization was the most common treatment option performed in 41/50 cases (82%) with success in controlling bleeding in 85% of the embolization cases. Total abdominal hysterectomy was performed upfront in two patients [11,14] and due to embolization failure with uncontrolled bleeding in four patients [13,19]. Overall, embolization failure was observed in only six cases. In these patients, bleeding was controlled by hysterectomy in four cases as stated above and by uterine artery ligation in two cases [13,17]. Interestingly, Corusic et al. [18] reported successful laparoscopic resection of a uterine AVM in a 21 year-old asymptomatic woman following the 4th cycle of methotrexate chemotherapy. The mean number of embolization procedures required to control bleeding was 1.4 (range 1–6). Bleeding control was accomplished following only a single procedure in 26 patients (63%) (Table 3). Six patients did not require any additional treatment for their AVM following chemotherapy; Kawano et al. presented two cases with disappearance of the hypo-echoic uterine area on ultrasound imaging at the end of chemotherapy and 1 asymptomatic patient with persistence of the AVM [10]; Cockshott et al. [6] reported three cases with persistence of angiographic AVM at the end of chemotherapy in asymptomatic patients.
Table 2 Uterine AVM management. Number of patients N = 50 Embolization Successful Unsuccessful
41 35 (85%) 6 (15%)
Hysterectomy Successful
4 4 (100%)
Uterine artery ligation Successful
2 2 (100%)
Laparoscopic resection of uterine AVM Successful
1 1 (100%)
Approximately 10% of complete hydatidiform moles and 0.5% of partial hydatidiform moles undergo malignant transformation to become an invasive mole, a choriocarcinoma, or, rarely, a placental site tumor, and require further treatment. Chemotherapy has allowed complete remission in more than 95% of patients with gestational trophoblastic tumors, even when metastases are present [20]. The efficacy of chemotherapy reduced dramatically the mortality of these patients, however the prognosis may be compromised by other complications such as vaginal or intraperitoneal hemorrhage, which can be life threatening. Some studies suggest that uterine vascular malformations persist in 10–15% of patients even after complete resolution of gestational trophoblastic disease [13], but it appears that only 2% of uterine AVM are symptomatic and cause chronic or heavy bleeding [19]. The formation of uterine AVM is due primarily to the disorganized trophoblastic proliferation observed in molar pregnancies. Human chorionic gonadotropin (HCG) may have a key regulatory role in angiogenesis and vascular function [4]. Uterine curettage which is the corner-stone of GTD treatment is responsible for the formation of a myometrial scar. High levels of HCG and disorganized trophoblastic invasion causes destructive changes in vascular structures and may allow direct flow of arterial blood vessels to venous blood vessels in this scar site [7,21]. Up to 48% of the AVM cases reported in the literature followed a complete molar pregnancy, but it is still not clear if a specific type of gestational trophoblastic disease predisposes to post molar AVM. In 47 patients (94%) HCG levels were elevated and ranged between 9 and 32,000 mIU/mL, only three cases presented an undetectable HCG at the time of AVM diagnosis ([8,9], our case). Previously, Cockshott et al. [6] have highlighted that hypervascular changes in the uterus can be observed to persist even when HCG levels have normalized. The time interval from ending chemotherapy to AVM diagnosis is variable. In our review this interval ranged from 0 to 156 months, with several authors reporting diagnosis of uterine AVM even before the onset of chemotherapy [6,10,15]. Resulting from disorganized vascular structures and high blood flow, patients with uterine AVM are at risk of abnormal bleeding such as chronic or heavy vaginal bleeding. Pelvic pain also can be present [22]. Patients can also be asymptomatic; in our review, diagnosis of
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uterine AVM was made in 6 asymptomatic patients [6,10,12,18]. However, the diagnosis of uterine AVM should be considered in patients with a history of recurrent unexplained abnormal vaginal bleeding after gestational trophoblastic disease. Imaging Hypo echoic space in the myometrium is the most relevant finding on ultrasonography. A mosaic pattern with aliasing on color Doppler filling these spaces with high velocity and low resistance flow on pulsed Doppler is typical [3]. The gold standard for the definitive diagnosis of AVMs is angiographic examination; it shows typically an opacified vascular tangle with early venous filling. Angiography can also provide crucial information with regards to the vascular anatomy and the extent of the vascular malformation [2]. This information is of critical importance when performing the interventional radiologic embolization. MRI and CT scan can be useful for the diagnosis and in the event of suspected adjacent organ involvement [23]. On MRI, AVM typically manifests as multiple serpentine flow-related signal voids on T1 and T2-weighted sequences. Enhancement is similar to normal vessels.
In our review we identified 20 patients with reported pregnancies after embolization of uterine AVM following a GTN and 90% of them were successful. Conclusion Uterine AVM is a rare complication of gestational disease tumors. Because of the risk of life threatening heavy bleeding, the diagnosis of uterine AVM should always be considered in patients with a history of recurrent unexplained vaginal bleeding after gestational trophoblastic disease. Ultrasonography is helpful for diagnosis, but the gold standard remains angiographic examination and interventional radiologic embolization is generally performed at the same time. Pelvic pain is the main side effect of embolization and this procedure does not appear to compromise future pregnancy. Funding No source of support.
Management
References
Treatment of uterine AVM is based on the symptomatology, the location, the extent, and the desire for future fertility. Kawano et al. [10] presented 3 cases with disappearance of the hypo-echoic uterine area on ultrasound imaging at the end of chemotherapy cycles; Cockshott et al. [6] presented 3 cases with persistence of uterine AVM on angiographic examination at the end of chemotherapy in asymptomatic patients. They highlighted that pelvic vessels rapidly revert to the normal appearance of the nonpregnant state with uterine vessels of a caliber of 1 mm, after successful chemotherapy of malignant trophoblastic disease [6]. These cases supported the idea that management of uterine AVM is not necessary in asymptomatic patients. After successful remission following chemotherapy for GTN, patients are often very concerned about the possibility to carry a normal pregnancy in the future [24], hence the importance of the fertility sparing management of uterine AVM. Overall, 82% of the patients collected in this review have been successfully treated by embolization with bleeding control in 85% of cases. Failure of embolization have been managed by hysterectomy or by vascular surgery ligation [13,17]. Corusic et al. [18] reported successful laparoscopic resection of a uterine AVM. Embolization has several advantages: avoidance of major surgery and general anesthesia and short duration of recovery, ability to preserve fertility, prevention of operative morbidity such as massive bleeding and post-operative adherences of surgical procedures [16]. The main side effect of embolization was pelvic pain. Severe complications can occur such as perineal skin sloughing, uterovaginal and rectovesicovaginal fistulae, and neurological deficits in the lower extremities [25]. A case of buttock and lower-limb claudication has been reported [13], and our patient developed a femoral pseudoaneurysm.
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Obstetrical outcomes Studies on embolization for uterine leiomyoma, showed that uterus has a generous supply of collateral vessels, which prevent uterine infarction after selective embolization. Collateral circulation and recanalization was adequate to maintain an adequate blood supply to sustain a growing pregnancy after embolization [26]. Compared to myomectomy, uterine embolization of leiomyoma does not seem to be associated with an increase in intrauterine growth retardation or fetal distress [27].
O. Touhami et al. / European Journal of Obstetrics & Gynecology and Reproductive Biology 181 (2014) 54–59 [19] McGrath S, Harding V, Lim AK, Burfitt N, Seckl MJ, Savage P. Embolization of uterine arteriovenous malformations in patients with gestational trophoblastic tumors: a review of patients at Charing Cross Hospital, 2000– 2009. J Reprod Med 2012;57(7–8):319–24. [20] Seckl MJ, Sebire NJ, Berkowitz RS. Gestational trophoblastic disease. Lancet 2010;376:717–29. [21] Sugimori H, Nagata Y, Nishimura A, Taki I, Takahashi M. Angiography of trophoblastic tumors: analysis of pelvic angiography correlated with microangiography and histopathological examinations of uterine specimens. Gynecol Oncol 1975;3:61–76. [22] Halperin R, Schneider D, Maymon R, Peer A, Pansky M, Herman A. Arteriovenous malformation after uterine curettage: a report of 3 cases. J Reprod Med 2007;52:445–9.
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[23] Kwon JH. Kim GS Obstetric iatrogenic arterial injuries of the uterus: diagnosis with US and treatment with transcatheter arterial embolization. Radiographics 2002;22(1):35–46. [24] Garner EIO, Lipson E, Bernstein MR, Goldstein DP, Berkowitz RS. Subsequent pregnancy experience in patients with molar pregnancy and gestational trophoblastic tumor. J Reprod Med 2002;47:380–6. [25] Martin J, Bhanot K, Athreya S. Complications and reinterventions in uterine artery embolization for symptomatic uterine fibroids: a literature review and meta analysis. Cardiovasc Intervent Radiol 2013;36(April (2)):395–402. [26] Gupta JK, Sinha A, Lumsden MA, Hickey M. Uterine artery embolization for symptomatic uterine fibroids. Cochrane Database Syst Rev 2012;(May):5. [27] Mohan PP, Hamblin MH, Vogelzang RL. Uterine artery embolization and its effect on fertility. J Vasc Interv Radiol 2013;24(July (7)):925–30.
