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doi:10.1111/jog.12441
J. Obstet. Gynaecol. Res. Vol. 40, No. 7: 1894–1900, July 2014
Prenatal differential diagnosis of complete hydatidiform mole with a twin live fetus and placental mesenchymal dysplasia by magnetic resonance imaging Yuki Himoto1, Aki Kido1, Sachiko Minamiguchi2, Yusaku Moribata1, Ryosuke Okumura3, Haruta Mogami4, Tadayoshi Nagano5, Ikuo Konishi4 and Kaori Togashi1 Departments of 1Diagnostic Imaging and Nuclear Medicine, 2Diagnostic Pathology and 4Gynecology and Obstetrics, Graduate School of Medicine, Kyoto University, Kyoto, and Departments of 3Radiology and 5Obstetrics and Gynecology, Kitano Hospital, Osaka, Japan
Abstract Aim: To assess the use of magnetic resonance imaging (MRI) for prenatal differentiation between complete hydatidiform mole with a twin live fetus (CHMTF) and placental mesenchymal dysplasia (PMD). Methods: Three CHMTF cases and three PMD cases, from two institutions over a 6-year period, were retrospectively included in this study. Clinical findings including age, pregnancy history, serum hCG level, ultrasonography findings, complications of the mother, outcome of the fetus, and results of chromosomal study of fetus, amniotic fluid and lesion, if possible, were noted. MRI findings were evaluated by two radiologists with respect to the location of the disease (intra- or extra-fetal sac), the presence of multicystic component, and presence of intra- or extra-lesional hemorrhage. Results: In all six cases, the diseases were recognized as multicystic lesions by ultrasonography and MRI. In two of three CHMTF cases, patients continued with the pregnancy, which resulted in spontaneous abortion. In one case of CHMTF, the patient underwent artificial abortion, after which the mole progressed into an invasive mole with lung metastases. All three PMD patients had live births, and two of the three babies had fetal growth restriction. By MRI, CHMTF was located within an extra-fetal sac accompanied by intra- and/or extra-lesional hemorrhage, while PMD was located within the placenta in the fetal sac without hemorrhage. Conclusion: MRI could provide important information about the prenatal differential diagnosis of CHMTF and PMD, based on the pathophysiology and characteristics of the diseases. Key words: complete hydatidiform mole with a twin live fetus, magnetic resonance imaging, placental mesenchymal dysplasia.
Introduction Hydatidiform mole coexistent with a live fetus and placental mesenchymal dysplasia (PMD) are rare placental abnormalities that can occur during pregnancy. The clinical course and outcome of the pregnancy are
known to be quite different between hydatidiform mole coexistent with a live fetus and PMD, thus accurate differentiation is considered to be critically important.1–4 However, prenatal differentiation of these two diseases is difficult, because clinical findings, including ultrasonography (USG), are similar.1,5 The
Received: December 10 2013. Accepted: February 27 2014. Reprint request to: Dr Aki Kido, Department of Diagnostic Imaging and Nuclear Medicine, Graduate School of Medicine, Kyoto University, 54 Shogoinkawahara-cho, Sakyo-ku, Kyoto 606-8507, Japan. Email: [email protected]
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© 2014 The Authors Journal of Obstetrics and Gynaecology Research © 2014 Japan Society of Obstetrics and Gynecology
Differentiating between CHMTF and PMD by MRI
diagnosis can be confirmed by pathological evaluations, as the proliferation of trophoblasts can be seen in hydatidiform mole, while it is absent in PMD.1 Hydatidiform mole coexistent with a live fetus occurs in 0.005–0.01% of all pregnancies, and can form by one of two mechanisms. One is a complete hydatidiform mole with a twin live fetus (CHMTF). The complete mole has 46 chromosomes of all paternal origin, while the fetus has 46 chromosomes, 23 maternal and 23 paternal. The other is a partial mole with an abnormal triploid fetus, where both mole and triploid fetus have 69 chromosomes, 23 maternal and 46 paternal.6 Typically, an abnormal triploid fetus coexistent with a partial mole will die in the first trimester, due to fatal abnormalities.7 In contrast, the fetus of a CHMTF has a chance of survival because the fetus usually has no anomalies. However, the outcome of the fetus is severe because of the high incidence of complications such as spontaneous abortion, intrauterine death and pre-eclampsia. High incidences of persistent trophoblastic disease (PTD) have also been reported.5,8 Thus, the management of CHMTF is controversial, in particular the decision whether to terminate or to continue the pregnancy. Assisted reproductive technology is sometimes associated with CHMTF,5 and the desire to bear children in such cases could make the management more difficult. Placental mesenchymal dysplasia is a rare placental vascular anomaly, occurring in 0.02% of all pregnancies.1,4 The majority of reported cases are associated with a normal karyotype.1 A female preponderance with a 1:3.6–8 male : female ratio and an association with Beckwith–Wiedemann syndrome have been reported.1,4 High incidences of fetal growth restriction (FGR), fetal death and preterm labor have also been observed.1,9 Because PMD is often mistaken for gestational trophoblastic disease, it is important to distinguish PMD from molar pregnancy to avoid the unnecessary termination of pregnancy.2,10 An abnormal triploid fetus coexistent with a partial mole typically dies in the first trimester. Then, the differentiation of CHMTF and PMD becomes problematic clinically. By USG, both diseases show multicystic lesions, and resemble each other closely.1 Although the elevation of serum or urine hCG is the most important diagnostic marker in gestational trophoblastic diseases, including CHMTF, these findings have also been observed in some cases of PMD, as reported in 38% of 64 cases following a systematic review.1 Recently, magnetic resonance imaging (MRI) has been indicated for the diagnosis of fetal and placental
diseases in combination with USG.11 There have been several case reports of the assessment of CHMTF or PMD using MRI,2,12,13 but no reports describing the differentiation of MRI findings between CHMTF and PMD were found. The aim of this study was to retrospectively assess the possibility of using MRI for prenatal differentiation between CHMTF and PMD.
Methods Ethics approval for this retrospective study was granted by the institutional review board of two hospitals. We searched radiology reporting databases at two institutes for cases of CHMTF or PMD from August 2006 to December 2012. Three cases of CHMTF and three cases of PMD were identified. MRI studies were performed in all cases during pregnancy. The pathological diagnoses were made by experienced gynecological pathologists in each hospital. These six cases were included in the study. We pursued information about clinical findings and reviewed MRI findings, as described below.
Clinical findings The following findings were surveyed using electronic medical charts: age of patient, pregnancy history, method of conception, the gestational week of detection of the disease and of the performance of MRI study, USG findings assessed by obstetricians, the serum hCG value when the MRI study was performed, the maximum serum hCG value over the clinical course, morphological changes detected by USG over the clinical course, clinical diagnosis before delivery, complication of the mother, pathological findings, outcome of the fetus, the results of chromosomal study of the fetus and/or of amniotic fluid and/or of the lesion, and the presence or absence of PTD in CHMTF cases. MRI scanning protocol All MRI studies were performed using a 1.5-T machine (at Kitano Hospital, performed with Achieva or Intera [Philips Healthcare, Best, the Netherlands]; at Kyoto University Hospital, performed with Avanto or Symphony [Siemens, Erlangen, Germany]). The protocols of Kitano Hospital included axial and sagittal images of turbo spin echo (TSE) T2-weighted image (T2-WI) or balanced fast field echo, as T2-WI. Axial or sagittal images of TSE T1-weighted image (T1-WI) or gradient echo T1-WI were also included, as
© 2014 The Authors Journal of Obstetrics and Gynaecology Research © 2014 Japan Society of Obstetrics and Gynecology
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Results
cases, placentomegaly associated with dilatation of the vessels of the chorionic plate was macroscopically observed. Microscopically, proliferation of trophoblasts was absent. All cases of CHMTF were correctly diagnosed before delivery. In three cases of PMD, one case was correct, although CHMTF could not be ruled out clinically (PMD case 2). Two other cases were misdiagnosed as CHMTF (PMD case 1) and partial mole (PMD case 3). In two of three cases of CHMTF (mole case 2 and 3), patients continued the pregnancy with adequate informed consent about PTD and severe prognosis of the fetus. These resulted in spontaneous abortion. In one case (mole case 1), artificial abortion was performed, after which the mole progressed into an invasive mole with lung metastases. In contrast, all three PMD patients gave live birth to female babies, none with Beckwith–Wiedemann syndrome. Two of these three cases (PMD case 1 and 3) were complicated by FGR.
Clinical findings
Evaluation of MRI findings
The clinical findings are summarized in Table 1. In all three CHMTF cases, the serum hCG values at time of MRI studies and at the maximum level showed moderate to extreme elevation. In PMD case 3, the maximum serum hCG value exceeded the upper limit of normal for gestational period, while the serum hCG values at time of the MRI study was within normal range. All serum hCG values of the remaining cases of PMD were within the normal range at each gestational period. All of the USG findings below were recorded in electronic charts by obstetricians. All lesions of CHMTF and PMD had multicystic components as observed by USG. In two CHMTF cases (mole case 2 and 3), intraor extra-lesional hemorrhages were detected. In one CHMTF case (mole case 1), the separation of the involved area from the normal placenta was observed. The differentiation between CHMTF and PMD was not determined based on USG findings. Morphological changes over the course of the pregnancy varied in cases of both diseases, and no tendency was observed in the study. The final diagnosis was determined by pathological examination. In all CHMTF cases, proliferation of trophoblasts was microscopically observed. To exclude a partial mole, a chromosomal study in two cases (mole case 1, and 3), and immunostaining of p57kip214 in two cases (mole case 2 and 3), were performed, the results of which were consistent with CHMTF. In all PMD
Magnetic resonance imaging findings of each case are summarized in Table 2. The assessments of the two radiologists were in absolute agreement on all items. All involved areas in both diseases were equally depicted as multicystic lesions, similar to USG findings. In all CHMTF cases, lesions were located in the extra-fetal sac and were complicated by intra- or extralesional hemorrhage (Fig. 1). The location of the extralesional hemorrhage was also in agreement. All PMD cases were recognized as diffuse multicystic lesions in the placenta of the fetal sac, and no intra- or extralesional hemorrhages were observed (Fig. 2).
T1-WI. The protocols of Kyoto University Hospital included axial and sagittal images of TSE T2-WI or half-Fourier single-shot TSE, as T2-WI. Sagittal images of spin echo T1-WI or the volumetric interpolated breath-hold examination were also included, as T1-WI.
Evaluation of MRI findings Two radiologists specialized in gynecological imaging, with 5 and 16 years of experience, evaluated the following items independently using all sequences mentioned above. The items evaluated were as follows: the location of the disease (intra- or extra-fetal sac), the presence of the multicystic component, and the presence of intra- and extra-lesional hemorrhage. When an extra-lesional hemorrhage was observed, the location was also assessed: subchorionic, retroplacental or intervillous hemorrhage.
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Discussions In line with previous reports,1–4 the clinical course and outcome of the mother and the fetus differed greatly between CHMTF and PMD cases in the present study. Accurate prenatal differentiation between these two diseases by conventional methods including serum hCG and USG was not easy in practice. Serum hCG is the most important tumor marker for the differentiation of CHMTF and PMD. The elevations of serum hCG in CHMTF cases were greater than those observed in PMD cases (Table 1). In PMD case 3, the maximum serum hCG value slightly exceeded the upper limit of normal, but was not as high as the values observed in CHMTF cases. In PMD case 2, the serum hCG value decreased slightly between 18 and 19 weeks
© 2014 The Authors Journal of Obstetrics and Gynaecology Research © 2014 Japan Society of Obstetrics and Gynecology
© 2014 The Authors Journal of Obstetrics and Gynaecology Research © 2014 Japan Society of Obstetrics and Gynecology Normal, 46XX NA 46XY Invasive mole, lung metastasis
NA NA NA (−)
Negative SA (17W)
Normal, 46XX NA NA (−)
Negative SA (15W)
(+)
NA (+)
Genital bleeding Threatened miscarriage
CHMTF
No remarkable change
375 588 (13W)‡
Multicystic lesion Subchorionic hemorrhage 13W 375 588 (13W)‡
13W
30 1G1P IVF-ET
Mole case 3
NA Normal, 46XX NA (−)
NA Fetal growth restriction Fetal distress Emergent CS (33W)
(+)
838 g (−)
(−)
CHMTF
No remarkable change
151 370 (13W)†
27W 20 432 (27W)†
Multicystic lesion
37 1G0P1AA Natural conception 12W
PMD case 1
NA Normal, 46XX NA (−)
NA Transvaginal delivery (40W)
(+)
930 g (−)
Gestational diabetes
PMD
Decrease
98 171 (18W)‡
19W 90 820 (19W)‡
Multicystic lesion
31 0G Natural conception 15W
PMD PMD case 2
NA Normal, 46XX Normal, 46XX (−)
NA Fetal growth restriction Oligoamnion Transvaginal delivery (39W)
(+)
1 100 g (−)
(−)
Partial mole
Increase
90 436 (38W)‡
18W 41 578 (20W)‡
Multicystic lesion
10W
41 1G1P IVF-ET
PMD case 3
Total hCG was measured as serum hCG in the two hospitals, except for serum hCG max of mole case 2 measured by intact hCG§. The normal range of total hCG in first hospital† was: 1–10 weeks, 63–150 854 mIU/mL; 11–15 weeks, 11 795–151 996 mIU/mL; 16–22 weeks, 9383–61 410 mIU/mL; 23–40 weeks, 1737–98 576 mIU/mL. The normal range of total hCG in second hospital‡ was: 4–7 weeks, 590–187 000 mIU/mL; 8–11 weeks, 17 800–328 000 mIU/mL; 12–20 weeks, 5380–183 000 mIU/mL; 21–40 weeks, 3460–71 500 mIU/mL. AA, artificial abortion; AIH, artificial insemination by husband; CHMTF, complete hydatidiform mole with a twin live fetus; G, gravida, GW, gestational week; IVF-ET, in vitro fertilization and embryo transfer; MR, magnetic resonance; x NA, not available; P, para; PMD, placental mesenchymal dysplasia; PTD, persistent trophoblastic disease; SA, spontaneous abortion; W, week.
Chromosomal study Fetus Amniotic fluid Lesion PTD
Pathological findings Placental weight Proliferation of trophoblasts Hydropic stromal change p57kip2 Outcome of the fetus (GW) NA AA (10W)
Genital bleeding Choroiditis
NA for AA
(+)
CHMTF
CHMTF
(+)
Increase
NA for AA
NA (+)
923 865 (15W)§
1 370 500 (10W)†
NA (+)
Multicystic lesion Intra-lesional hemorrhage 14W 350 958 (9W)‡
Multicystic lesion Separation from normal placenta 9W 1 124 200 (9W)†
GW at MR study Serum hCG at MR study (GW), mIU/mL Serum hCG max (GW), mIU/mL Morphological change of the disease over clinical course Clinical diagnosis before delivery Complications of the mother
7W
9W
GW of detection of diseases Ultrasonography findings
40 2G0P1SA1AA AIH
34 4G3P1SA Natural conception
CHMTF Mole case 2
Age Pregnancy history Method of conception
Mole case 1
Table 1 Clinical findings of complete hydatidiform mole with a twin live fetus and placental mesenchymal dysplasia
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Table 2 Magnetic resonance imaging findings of complete hydatidiform mole with a twin live fetus and placental mesenchymal dysplasia
Location of disease Multicystic lesion Intra-lesional hemorrhage Extra-lesional hemorrhage
Mole case 1
CHMTF Mole case 2
Mole case 3
PMD case 1
PMD PMD case 2
PMD case 3
Extra fetal sac (+) (+)
Extra fetal sac (+) (+)
Extra fetal sac (+) (−)
Intra fetal sac (+) (−)
Intra fetal sac (+) (−)
Intra fetal sac (+) (−)
Subchorionic
Subchorionic
Subchorionic Retroplacental
(−)
(−)
(−)
CHMTF, complete hydatidiform mole with a twin live fetus; PMD, placental mesenchymal dysplasia.
of gestational age, which would be unlikely to occur in CHMTF. These results suggest that monitoring maternal serum hCG levels throughout duration of pregnancy may be useful for differential diagnosis. USG was not able to provide a reliable differentiation in the cases studied here, because both diseases were depicted as multicystic lesions based on the similarity of pathological findings, which is similar to previous reports.1,15 By USG, both diseases appeared as multicystic lesions, but their location in relation to the fetal sac and placenta was difficult to determine. In contrast, we found clear differences in the location of the two diseases by MRI; intra- or extra-fetal sac, and the presence of intra- or extra-lesional hemorrhage was agreed upon by both radiologists. The difference in the location of the disease, intra- or extra-fetal sac, may be the most important factor, which is based on the difference in pathophysiology between CHMTF and PMD. CHMTF is a dizygotic twin, where one fertilized egg becomes a fetus with normal placenta, while another fertilized egg develops into a complete hydatidiform mole. Thus, it is rational that the complete hydatidiform mole was depicted outside the fetal sac; in other words, the mole was surrounding the fetal sac in the uterine cavity (Fig. 1c). Separation of the involved area from the normal placenta was reported as a USG finding of CHMTF,16,17 which was also observed in one case in our study (mole case 1 in Table 1). This finding may represent the separation of the extra-sac lesion and the intra-sac normal placenta by the amniochorionic membrane. On the other hand, in the case of PMD, one fertilized egg develops into the fetus and the placenta complicated with PMD. Thus, PMD is depicted as the lesion within the placenta in the fetal sac (Fig. 2c). The wide field of view and the excellent tissue contrast of MRI enable us to obtain a whole image of the uterus and to assess the relation between the disease, fetal sac and the placenta.
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There was also a difference in complications by hemorrhage between the diseases. The difference could be explained by the tendency of the complete mole to bleed, which is often clinically recognized. Vaginal bleeding is a common symptom of complete hydatidiform mole, which might be caused by the separation of molar tissue from the decidua and the disruption of maternal vessels.18 Two papers of MRI findings of CHMTF have reported the presence of hemorrhage within the cystic component.13,19 The excellent tissue contrast of MRI is especially useful in the assessment of hemorrhages, including placental imaging. The complication of hemorrhaging may support the differential diagnosis of CHMTF from PMD. At present, we cannot conclusively say if this finding is specific for CHMTF, as PMD may be also accompanied by hemorrhage. Because both CHMTF and PMD are rare diseases, the actual frequency of hemorrhage is unknown, but this may become useful for differentiation after improved recognition of these incidences. Magnetic resonance imaging can be a good modality to assess the differences between CHMTF and PMD mentioned above, thanks to its objectivity, the wide field of view and the high tissue contrast. These advantages of MRI may cover the shortcomings of USG. Moreover, the whole view of both diseases shown by MRI may lead to an improved assessment by USG, such as recognizing the separation of CHMTF from normal placenta. Previous reports suggested that karyotype should be obtained for the exclusion of a partial mole, which is often unable to continue to full term.1,2 Amniocentesis is available from week 15 of the pregnancy. After the exclusion of a partial mole, the differential diagnosis between CHMTF and PMD is needed. Due to the possibility of improving diagnostic confidence or modifying the diagnosis and treatment, we consider MRI after the first trimester as a reasonable option in the differentiation between CHMTF and PMD.
© 2014 The Authors Journal of Obstetrics and Gynaecology Research © 2014 Japan Society of Obstetrics and Gynecology
Differentiating between CHMTF and PMD by MRI
(a)
(a)
(b)
(b)
(c)
Figure 1 A 34-year-old woman with complete hydatidiform mole with a twin live fetus (mole case 1). The multicystic lesion is depicted, surrounding the fetal sac (a: black arrow; white arrowhead indicates the normal placenta). Intra-lesional hemorrhage (a: white arrow) and subchorionic hemorrhage (b: white arrows) were also observed. (c) Scheme demonstrating the positional relation of the fetal sac and its surrounding extra-sac lesion. F, fetus; P, placenta. Sagittal turbo spin echo T2-weighted image (a) and T1-weighted image (b).
(c)
Figure 2 A 31-year-old woman with placental mesenchymal dysplasia (PMD case 2). The multicystic lesion (a: black arrow) is depicted in the placenta in the fetal sac. The lesion was homogenous and neither intra- nor extra-lesional hemorrhage was seen. (c) Scheme demonstrating the lesion within the placenta in the fetal sac. F, fetus. Sagittal half-Fourier single-shot turbo spin echo image as T2-weighted image (a) and volumetric interpolated breath-hold examination image as T1-weighted image (b).
© 2014 The Authors Journal of Obstetrics and Gynaecology Research © 2014 Japan Society of Obstetrics and Gynecology
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The indication of MRI during pregnancy, even after the first trimester, should be carefully considered because the safety has yet to be established.20 It may be prudent to exclude pregnant women during the first trimester of pregnancy, because of the potential risks to the fetus. Nevertheless, MRI was performed in the first trimester in mole case 1 and 3, as clinicians needed to determine whether or not to continue the pregnancy, and required objective and precise information about the fetal conditions. The most important limitation of this study is the lack of cases of partial mole with an abnormal triploid fetus. Like PMD, a partial mole develops from one egg, thus, the differentiation of PMD and partial molar pregnancy may be difficult using this method. Another limitation is the small number of subjects in this study, due to the rarity of these diseases. We will need to continue to collect cases of both diseases, and in particular information about the frequency of hemorrhage. However, the difference in the location of the lesion, intra- or extra-fetal sac, is based on the pathophysiology and could be a convincing finding, leading directly to an accurate differentiation. In conclusion, we have presented the possibility of differentiation between CHMTF and PMD using MRI, which is based on pathophysiology and characteristics of both diseases. MRI could provide important information about the prenatal differential diagnosis.
Acknowledgments We thank Koji Fujimoto, Fuki Shitano, Kayo Kiguchi, Department of Diagnostic Imaging and Nuclear Medicine, Graduate School of Medicine, Kyoto University, for assistance in preparing the manuscript.
Disclosure None declared.
References 1. Nayeri UA, West AB, Grossetta Nardini HK, Copel JA, Sfakianaki AK. Systematic review of sonographic findings of placental mesenchymal dysplasia and subsequent pregnancy outcomes. Ultrasound Obstet Gynecol 2013; 41: 366–374. 2. Ohira S, Ookubo N, Tanaka K et al. Placental mesenchymal dysplasia: Chronological observation of placental images during gestation and review of the literature. Gynecol Obstet Invest 2013; 75: 217–223.
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3. Ang DC, Rodriguez Urrego PA, Prasad V. Placental mesenchymal dysplasia: A potential misdiagnosed entity. Arch Gynecol Obstet 2009; 279: 937–939. 4. Woo GW, Rocha FG, Gaspar-Oishi M, Bartholomew ML, Thompson KS. Placental mesenchymal dysplasia. Am J Obstet Gynecol 2011; 205: e3–e5. 5. Massardier J, Golfier F, Journet D et al. Twin pregnancy with complete hydatidiform mole and coexistent fetus: Obstetrical and oncological outcomes in a series of 14 cases. Eur J Obstet Gynecol Reprod Biol 2009; 143: 84–87. 6. Matsui H, Sekiya S, Hando T, Wake N, Tomoda Y. Hydatidiform mole coexistent with a twin live fetus: A national collaborative study in Japan. Hum Reprod 2000; 15: 608–611. 7. Jauniaux E, Brown R, Snijders RJ, Noble P, Nicolaides KH. Early prenatal diagnosis of triploidy. Am J Obstet Gynecol 1997; 176: 550–554. 8. Sebire NJ, Foskett M, Paradinas FJ et al. Outcome of twin pregnancies with complete hydatidiform mole and healthy co-twin. Lancet 2002; 359: 2165–2166. 9. Pham T, Steele J, Stayboldt C, Chan L, Benirschke K. Placental mesenchymal dysplasia is associated with high rates of intrauterine growth restriction and fetal demise: A report of 11 new cases and a review of the literature. Am J Clin Pathol 2006; 126: 67–78. 10. Starikov R, Goldman R, Dizon DS, Kostadinov S, Carr S. Placental mesenchymal dysplasia presenting as a twin gestation with complete molar pregnancy. Obstet Gynecol 2011; 118 (2 Pt 2): 445–449. 11. Elsayes KM, Trout AT, Friedkin AM et al. Imaging of the placenta: A multimodality pictorial review. Radiographics 2009; 29: 1371–1391. 12. Wu TC, Shen SH, Chang SP, Chang CY, Guo WY. Magnetic resonance experience of a twin pregnancy with a normal fetus and hydatidiform mole: A case report. J Comput Assist Tomogr 2005; 29: 415–417. 13. Novick MK, Dillon EH, Epstein NF. AJR teaching file: Pregnant woman with vaginal spotting, nausea, and vomiting. AJR Am J Roentgenol 2010; 194 (6 Suppl): S79–S82. 14. Soma H, Osawa H, Oguro T et al. P57kip2 immunohistochemical expression and ultrastructural findings of gestational trophoblastic disease and related disorders. Med Mol Morphol 2007; 40: 95–102. 15. Vaisbuch E, Romero R, Kusanovic JP et al. Three-dimensional sonography of placental mesenchymal dysplasia and its differential diagnosis. J Ultrasound Med 2009; 28: 359–368. 16. Fong KW, Toi A, Salem S et al. Detection of fetal structural abnormalities with US during early pregnancy. Radiographics 2004; 24: 157–174. 17. Winter TC, 3rd, Brock BV, Fligner CL, Brown ZA. Coexistent surviving neonate twin and complete hydatidiform mole. AJR Am J Roentgenol 1999; 172: 451–453. 18. Berkowitz RS, Goldstein DP. Gestational trophoblastic disease. In: Berek JS (ed.). Novak’s Gynecology, 13th edn. Philadelphia, PA: Lippincott Williams & Wilkins, 2002; 1353–1373. 19. Matsui H, Iitsuka Y, Yamazawa K et al. Placental mesenchymal dysplasia initially diagnosed as partial mole. Pathol Int 2003; 53: 810–813. 20. Wang PI, Chong ST, Kielar AZ et al. Imaging of pregnant and lactating patients: Part 1, evidence-based review and recommendations. AJR Am J Roentgenol 2012; 198: 778–784.
© 2014 The Authors Journal of Obstetrics and Gynaecology Research © 2014 Japan Society of Obstetrics and Gynecology
doi:10.1111/jog.12441
J. Obstet. Gynaecol. Res. Vol. 40, No. 7: 1894–1900, July 2014
Prenatal differential diagnosis of complete hydatidiform mole with a twin live fetus and placental mesenchymal dysplasia by magnetic resonance imaging Yuki Himoto1, Aki Kido1, Sachiko Minamiguchi2, Yusaku Moribata1, Ryosuke Okumura3, Haruta Mogami4, Tadayoshi Nagano5, Ikuo Konishi4 and Kaori Togashi1 Departments of 1Diagnostic Imaging and Nuclear Medicine, 2Diagnostic Pathology and 4Gynecology and Obstetrics, Graduate School of Medicine, Kyoto University, Kyoto, and Departments of 3Radiology and 5Obstetrics and Gynecology, Kitano Hospital, Osaka, Japan
Abstract Aim: To assess the use of magnetic resonance imaging (MRI) for prenatal differentiation between complete hydatidiform mole with a twin live fetus (CHMTF) and placental mesenchymal dysplasia (PMD). Methods: Three CHMTF cases and three PMD cases, from two institutions over a 6-year period, were retrospectively included in this study. Clinical findings including age, pregnancy history, serum hCG level, ultrasonography findings, complications of the mother, outcome of the fetus, and results of chromosomal study of fetus, amniotic fluid and lesion, if possible, were noted. MRI findings were evaluated by two radiologists with respect to the location of the disease (intra- or extra-fetal sac), the presence of multicystic component, and presence of intra- or extra-lesional hemorrhage. Results: In all six cases, the diseases were recognized as multicystic lesions by ultrasonography and MRI. In two of three CHMTF cases, patients continued with the pregnancy, which resulted in spontaneous abortion. In one case of CHMTF, the patient underwent artificial abortion, after which the mole progressed into an invasive mole with lung metastases. All three PMD patients had live births, and two of the three babies had fetal growth restriction. By MRI, CHMTF was located within an extra-fetal sac accompanied by intra- and/or extra-lesional hemorrhage, while PMD was located within the placenta in the fetal sac without hemorrhage. Conclusion: MRI could provide important information about the prenatal differential diagnosis of CHMTF and PMD, based on the pathophysiology and characteristics of the diseases. Key words: complete hydatidiform mole with a twin live fetus, magnetic resonance imaging, placental mesenchymal dysplasia.
Introduction Hydatidiform mole coexistent with a live fetus and placental mesenchymal dysplasia (PMD) are rare placental abnormalities that can occur during pregnancy. The clinical course and outcome of the pregnancy are
known to be quite different between hydatidiform mole coexistent with a live fetus and PMD, thus accurate differentiation is considered to be critically important.1–4 However, prenatal differentiation of these two diseases is difficult, because clinical findings, including ultrasonography (USG), are similar.1,5 The
Received: December 10 2013. Accepted: February 27 2014. Reprint request to: Dr Aki Kido, Department of Diagnostic Imaging and Nuclear Medicine, Graduate School of Medicine, Kyoto University, 54 Shogoinkawahara-cho, Sakyo-ku, Kyoto 606-8507, Japan. Email: [email protected]
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© 2014 The Authors Journal of Obstetrics and Gynaecology Research © 2014 Japan Society of Obstetrics and Gynecology
Differentiating between CHMTF and PMD by MRI
diagnosis can be confirmed by pathological evaluations, as the proliferation of trophoblasts can be seen in hydatidiform mole, while it is absent in PMD.1 Hydatidiform mole coexistent with a live fetus occurs in 0.005–0.01% of all pregnancies, and can form by one of two mechanisms. One is a complete hydatidiform mole with a twin live fetus (CHMTF). The complete mole has 46 chromosomes of all paternal origin, while the fetus has 46 chromosomes, 23 maternal and 23 paternal. The other is a partial mole with an abnormal triploid fetus, where both mole and triploid fetus have 69 chromosomes, 23 maternal and 46 paternal.6 Typically, an abnormal triploid fetus coexistent with a partial mole will die in the first trimester, due to fatal abnormalities.7 In contrast, the fetus of a CHMTF has a chance of survival because the fetus usually has no anomalies. However, the outcome of the fetus is severe because of the high incidence of complications such as spontaneous abortion, intrauterine death and pre-eclampsia. High incidences of persistent trophoblastic disease (PTD) have also been reported.5,8 Thus, the management of CHMTF is controversial, in particular the decision whether to terminate or to continue the pregnancy. Assisted reproductive technology is sometimes associated with CHMTF,5 and the desire to bear children in such cases could make the management more difficult. Placental mesenchymal dysplasia is a rare placental vascular anomaly, occurring in 0.02% of all pregnancies.1,4 The majority of reported cases are associated with a normal karyotype.1 A female preponderance with a 1:3.6–8 male : female ratio and an association with Beckwith–Wiedemann syndrome have been reported.1,4 High incidences of fetal growth restriction (FGR), fetal death and preterm labor have also been observed.1,9 Because PMD is often mistaken for gestational trophoblastic disease, it is important to distinguish PMD from molar pregnancy to avoid the unnecessary termination of pregnancy.2,10 An abnormal triploid fetus coexistent with a partial mole typically dies in the first trimester. Then, the differentiation of CHMTF and PMD becomes problematic clinically. By USG, both diseases show multicystic lesions, and resemble each other closely.1 Although the elevation of serum or urine hCG is the most important diagnostic marker in gestational trophoblastic diseases, including CHMTF, these findings have also been observed in some cases of PMD, as reported in 38% of 64 cases following a systematic review.1 Recently, magnetic resonance imaging (MRI) has been indicated for the diagnosis of fetal and placental
diseases in combination with USG.11 There have been several case reports of the assessment of CHMTF or PMD using MRI,2,12,13 but no reports describing the differentiation of MRI findings between CHMTF and PMD were found. The aim of this study was to retrospectively assess the possibility of using MRI for prenatal differentiation between CHMTF and PMD.
Methods Ethics approval for this retrospective study was granted by the institutional review board of two hospitals. We searched radiology reporting databases at two institutes for cases of CHMTF or PMD from August 2006 to December 2012. Three cases of CHMTF and three cases of PMD were identified. MRI studies were performed in all cases during pregnancy. The pathological diagnoses were made by experienced gynecological pathologists in each hospital. These six cases were included in the study. We pursued information about clinical findings and reviewed MRI findings, as described below.
Clinical findings The following findings were surveyed using electronic medical charts: age of patient, pregnancy history, method of conception, the gestational week of detection of the disease and of the performance of MRI study, USG findings assessed by obstetricians, the serum hCG value when the MRI study was performed, the maximum serum hCG value over the clinical course, morphological changes detected by USG over the clinical course, clinical diagnosis before delivery, complication of the mother, pathological findings, outcome of the fetus, the results of chromosomal study of the fetus and/or of amniotic fluid and/or of the lesion, and the presence or absence of PTD in CHMTF cases. MRI scanning protocol All MRI studies were performed using a 1.5-T machine (at Kitano Hospital, performed with Achieva or Intera [Philips Healthcare, Best, the Netherlands]; at Kyoto University Hospital, performed with Avanto or Symphony [Siemens, Erlangen, Germany]). The protocols of Kitano Hospital included axial and sagittal images of turbo spin echo (TSE) T2-weighted image (T2-WI) or balanced fast field echo, as T2-WI. Axial or sagittal images of TSE T1-weighted image (T1-WI) or gradient echo T1-WI were also included, as
© 2014 The Authors Journal of Obstetrics and Gynaecology Research © 2014 Japan Society of Obstetrics and Gynecology
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Results
cases, placentomegaly associated with dilatation of the vessels of the chorionic plate was macroscopically observed. Microscopically, proliferation of trophoblasts was absent. All cases of CHMTF were correctly diagnosed before delivery. In three cases of PMD, one case was correct, although CHMTF could not be ruled out clinically (PMD case 2). Two other cases were misdiagnosed as CHMTF (PMD case 1) and partial mole (PMD case 3). In two of three cases of CHMTF (mole case 2 and 3), patients continued the pregnancy with adequate informed consent about PTD and severe prognosis of the fetus. These resulted in spontaneous abortion. In one case (mole case 1), artificial abortion was performed, after which the mole progressed into an invasive mole with lung metastases. In contrast, all three PMD patients gave live birth to female babies, none with Beckwith–Wiedemann syndrome. Two of these three cases (PMD case 1 and 3) were complicated by FGR.
Clinical findings
Evaluation of MRI findings
The clinical findings are summarized in Table 1. In all three CHMTF cases, the serum hCG values at time of MRI studies and at the maximum level showed moderate to extreme elevation. In PMD case 3, the maximum serum hCG value exceeded the upper limit of normal for gestational period, while the serum hCG values at time of the MRI study was within normal range. All serum hCG values of the remaining cases of PMD were within the normal range at each gestational period. All of the USG findings below were recorded in electronic charts by obstetricians. All lesions of CHMTF and PMD had multicystic components as observed by USG. In two CHMTF cases (mole case 2 and 3), intraor extra-lesional hemorrhages were detected. In one CHMTF case (mole case 1), the separation of the involved area from the normal placenta was observed. The differentiation between CHMTF and PMD was not determined based on USG findings. Morphological changes over the course of the pregnancy varied in cases of both diseases, and no tendency was observed in the study. The final diagnosis was determined by pathological examination. In all CHMTF cases, proliferation of trophoblasts was microscopically observed. To exclude a partial mole, a chromosomal study in two cases (mole case 1, and 3), and immunostaining of p57kip214 in two cases (mole case 2 and 3), were performed, the results of which were consistent with CHMTF. In all PMD
Magnetic resonance imaging findings of each case are summarized in Table 2. The assessments of the two radiologists were in absolute agreement on all items. All involved areas in both diseases were equally depicted as multicystic lesions, similar to USG findings. In all CHMTF cases, lesions were located in the extra-fetal sac and were complicated by intra- or extralesional hemorrhage (Fig. 1). The location of the extralesional hemorrhage was also in agreement. All PMD cases were recognized as diffuse multicystic lesions in the placenta of the fetal sac, and no intra- or extralesional hemorrhages were observed (Fig. 2).
T1-WI. The protocols of Kyoto University Hospital included axial and sagittal images of TSE T2-WI or half-Fourier single-shot TSE, as T2-WI. Sagittal images of spin echo T1-WI or the volumetric interpolated breath-hold examination were also included, as T1-WI.
Evaluation of MRI findings Two radiologists specialized in gynecological imaging, with 5 and 16 years of experience, evaluated the following items independently using all sequences mentioned above. The items evaluated were as follows: the location of the disease (intra- or extra-fetal sac), the presence of the multicystic component, and the presence of intra- and extra-lesional hemorrhage. When an extra-lesional hemorrhage was observed, the location was also assessed: subchorionic, retroplacental or intervillous hemorrhage.
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Discussions In line with previous reports,1–4 the clinical course and outcome of the mother and the fetus differed greatly between CHMTF and PMD cases in the present study. Accurate prenatal differentiation between these two diseases by conventional methods including serum hCG and USG was not easy in practice. Serum hCG is the most important tumor marker for the differentiation of CHMTF and PMD. The elevations of serum hCG in CHMTF cases were greater than those observed in PMD cases (Table 1). In PMD case 3, the maximum serum hCG value slightly exceeded the upper limit of normal, but was not as high as the values observed in CHMTF cases. In PMD case 2, the serum hCG value decreased slightly between 18 and 19 weeks
© 2014 The Authors Journal of Obstetrics and Gynaecology Research © 2014 Japan Society of Obstetrics and Gynecology
© 2014 The Authors Journal of Obstetrics and Gynaecology Research © 2014 Japan Society of Obstetrics and Gynecology Normal, 46XX NA 46XY Invasive mole, lung metastasis
NA NA NA (−)
Negative SA (17W)
Normal, 46XX NA NA (−)
Negative SA (15W)
(+)
NA (+)
Genital bleeding Threatened miscarriage
CHMTF
No remarkable change
375 588 (13W)‡
Multicystic lesion Subchorionic hemorrhage 13W 375 588 (13W)‡
13W
30 1G1P IVF-ET
Mole case 3
NA Normal, 46XX NA (−)
NA Fetal growth restriction Fetal distress Emergent CS (33W)
(+)
838 g (−)
(−)
CHMTF
No remarkable change
151 370 (13W)†
27W 20 432 (27W)†
Multicystic lesion
37 1G0P1AA Natural conception 12W
PMD case 1
NA Normal, 46XX NA (−)
NA Transvaginal delivery (40W)
(+)
930 g (−)
Gestational diabetes
PMD
Decrease
98 171 (18W)‡
19W 90 820 (19W)‡
Multicystic lesion
31 0G Natural conception 15W
PMD PMD case 2
NA Normal, 46XX Normal, 46XX (−)
NA Fetal growth restriction Oligoamnion Transvaginal delivery (39W)
(+)
1 100 g (−)
(−)
Partial mole
Increase
90 436 (38W)‡
18W 41 578 (20W)‡
Multicystic lesion
10W
41 1G1P IVF-ET
PMD case 3
Total hCG was measured as serum hCG in the two hospitals, except for serum hCG max of mole case 2 measured by intact hCG§. The normal range of total hCG in first hospital† was: 1–10 weeks, 63–150 854 mIU/mL; 11–15 weeks, 11 795–151 996 mIU/mL; 16–22 weeks, 9383–61 410 mIU/mL; 23–40 weeks, 1737–98 576 mIU/mL. The normal range of total hCG in second hospital‡ was: 4–7 weeks, 590–187 000 mIU/mL; 8–11 weeks, 17 800–328 000 mIU/mL; 12–20 weeks, 5380–183 000 mIU/mL; 21–40 weeks, 3460–71 500 mIU/mL. AA, artificial abortion; AIH, artificial insemination by husband; CHMTF, complete hydatidiform mole with a twin live fetus; G, gravida, GW, gestational week; IVF-ET, in vitro fertilization and embryo transfer; MR, magnetic resonance; x NA, not available; P, para; PMD, placental mesenchymal dysplasia; PTD, persistent trophoblastic disease; SA, spontaneous abortion; W, week.
Chromosomal study Fetus Amniotic fluid Lesion PTD
Pathological findings Placental weight Proliferation of trophoblasts Hydropic stromal change p57kip2 Outcome of the fetus (GW) NA AA (10W)
Genital bleeding Choroiditis
NA for AA
(+)
CHMTF
CHMTF
(+)
Increase
NA for AA
NA (+)
923 865 (15W)§
1 370 500 (10W)†
NA (+)
Multicystic lesion Intra-lesional hemorrhage 14W 350 958 (9W)‡
Multicystic lesion Separation from normal placenta 9W 1 124 200 (9W)†
GW at MR study Serum hCG at MR study (GW), mIU/mL Serum hCG max (GW), mIU/mL Morphological change of the disease over clinical course Clinical diagnosis before delivery Complications of the mother
7W
9W
GW of detection of diseases Ultrasonography findings
40 2G0P1SA1AA AIH
34 4G3P1SA Natural conception
CHMTF Mole case 2
Age Pregnancy history Method of conception
Mole case 1
Table 1 Clinical findings of complete hydatidiform mole with a twin live fetus and placental mesenchymal dysplasia
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Table 2 Magnetic resonance imaging findings of complete hydatidiform mole with a twin live fetus and placental mesenchymal dysplasia
Location of disease Multicystic lesion Intra-lesional hemorrhage Extra-lesional hemorrhage
Mole case 1
CHMTF Mole case 2
Mole case 3
PMD case 1
PMD PMD case 2
PMD case 3
Extra fetal sac (+) (+)
Extra fetal sac (+) (+)
Extra fetal sac (+) (−)
Intra fetal sac (+) (−)
Intra fetal sac (+) (−)
Intra fetal sac (+) (−)
Subchorionic
Subchorionic
Subchorionic Retroplacental
(−)
(−)
(−)
CHMTF, complete hydatidiform mole with a twin live fetus; PMD, placental mesenchymal dysplasia.
of gestational age, which would be unlikely to occur in CHMTF. These results suggest that monitoring maternal serum hCG levels throughout duration of pregnancy may be useful for differential diagnosis. USG was not able to provide a reliable differentiation in the cases studied here, because both diseases were depicted as multicystic lesions based on the similarity of pathological findings, which is similar to previous reports.1,15 By USG, both diseases appeared as multicystic lesions, but their location in relation to the fetal sac and placenta was difficult to determine. In contrast, we found clear differences in the location of the two diseases by MRI; intra- or extra-fetal sac, and the presence of intra- or extra-lesional hemorrhage was agreed upon by both radiologists. The difference in the location of the disease, intra- or extra-fetal sac, may be the most important factor, which is based on the difference in pathophysiology between CHMTF and PMD. CHMTF is a dizygotic twin, where one fertilized egg becomes a fetus with normal placenta, while another fertilized egg develops into a complete hydatidiform mole. Thus, it is rational that the complete hydatidiform mole was depicted outside the fetal sac; in other words, the mole was surrounding the fetal sac in the uterine cavity (Fig. 1c). Separation of the involved area from the normal placenta was reported as a USG finding of CHMTF,16,17 which was also observed in one case in our study (mole case 1 in Table 1). This finding may represent the separation of the extra-sac lesion and the intra-sac normal placenta by the amniochorionic membrane. On the other hand, in the case of PMD, one fertilized egg develops into the fetus and the placenta complicated with PMD. Thus, PMD is depicted as the lesion within the placenta in the fetal sac (Fig. 2c). The wide field of view and the excellent tissue contrast of MRI enable us to obtain a whole image of the uterus and to assess the relation between the disease, fetal sac and the placenta.
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There was also a difference in complications by hemorrhage between the diseases. The difference could be explained by the tendency of the complete mole to bleed, which is often clinically recognized. Vaginal bleeding is a common symptom of complete hydatidiform mole, which might be caused by the separation of molar tissue from the decidua and the disruption of maternal vessels.18 Two papers of MRI findings of CHMTF have reported the presence of hemorrhage within the cystic component.13,19 The excellent tissue contrast of MRI is especially useful in the assessment of hemorrhages, including placental imaging. The complication of hemorrhaging may support the differential diagnosis of CHMTF from PMD. At present, we cannot conclusively say if this finding is specific for CHMTF, as PMD may be also accompanied by hemorrhage. Because both CHMTF and PMD are rare diseases, the actual frequency of hemorrhage is unknown, but this may become useful for differentiation after improved recognition of these incidences. Magnetic resonance imaging can be a good modality to assess the differences between CHMTF and PMD mentioned above, thanks to its objectivity, the wide field of view and the high tissue contrast. These advantages of MRI may cover the shortcomings of USG. Moreover, the whole view of both diseases shown by MRI may lead to an improved assessment by USG, such as recognizing the separation of CHMTF from normal placenta. Previous reports suggested that karyotype should be obtained for the exclusion of a partial mole, which is often unable to continue to full term.1,2 Amniocentesis is available from week 15 of the pregnancy. After the exclusion of a partial mole, the differential diagnosis between CHMTF and PMD is needed. Due to the possibility of improving diagnostic confidence or modifying the diagnosis and treatment, we consider MRI after the first trimester as a reasonable option in the differentiation between CHMTF and PMD.
© 2014 The Authors Journal of Obstetrics and Gynaecology Research © 2014 Japan Society of Obstetrics and Gynecology
Differentiating between CHMTF and PMD by MRI
(a)
(a)
(b)
(b)
(c)
Figure 1 A 34-year-old woman with complete hydatidiform mole with a twin live fetus (mole case 1). The multicystic lesion is depicted, surrounding the fetal sac (a: black arrow; white arrowhead indicates the normal placenta). Intra-lesional hemorrhage (a: white arrow) and subchorionic hemorrhage (b: white arrows) were also observed. (c) Scheme demonstrating the positional relation of the fetal sac and its surrounding extra-sac lesion. F, fetus; P, placenta. Sagittal turbo spin echo T2-weighted image (a) and T1-weighted image (b).
(c)
Figure 2 A 31-year-old woman with placental mesenchymal dysplasia (PMD case 2). The multicystic lesion (a: black arrow) is depicted in the placenta in the fetal sac. The lesion was homogenous and neither intra- nor extra-lesional hemorrhage was seen. (c) Scheme demonstrating the lesion within the placenta in the fetal sac. F, fetus. Sagittal half-Fourier single-shot turbo spin echo image as T2-weighted image (a) and volumetric interpolated breath-hold examination image as T1-weighted image (b).
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The indication of MRI during pregnancy, even after the first trimester, should be carefully considered because the safety has yet to be established.20 It may be prudent to exclude pregnant women during the first trimester of pregnancy, because of the potential risks to the fetus. Nevertheless, MRI was performed in the first trimester in mole case 1 and 3, as clinicians needed to determine whether or not to continue the pregnancy, and required objective and precise information about the fetal conditions. The most important limitation of this study is the lack of cases of partial mole with an abnormal triploid fetus. Like PMD, a partial mole develops from one egg, thus, the differentiation of PMD and partial molar pregnancy may be difficult using this method. Another limitation is the small number of subjects in this study, due to the rarity of these diseases. We will need to continue to collect cases of both diseases, and in particular information about the frequency of hemorrhage. However, the difference in the location of the lesion, intra- or extra-fetal sac, is based on the pathophysiology and could be a convincing finding, leading directly to an accurate differentiation. In conclusion, we have presented the possibility of differentiation between CHMTF and PMD using MRI, which is based on pathophysiology and characteristics of both diseases. MRI could provide important information about the prenatal differential diagnosis.
Acknowledgments We thank Koji Fujimoto, Fuki Shitano, Kayo Kiguchi, Department of Diagnostic Imaging and Nuclear Medicine, Graduate School of Medicine, Kyoto University, for assistance in preparing the manuscript.
Disclosure None declared.
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