Abstract
Background:
Transvaginal Ultrasonography is a noninvasive and inexpensive medical imaging tool used for the diagnosis of various diseases.Objectives:
To identify an effective method to identify high-risk patients for developing malignancy after molar evacuation.Patients and Methods:
A prospective serial assessment of 19 patients with gestational trophoblastic disease was performed. Clinical and laboratory data, transvaginal ultrasound and Doppler findings were evaluated the day before evacuation. They were followed-up in the first week after evacuation and every two weeks during the next two months, then every month until the sixth month.Results:
Ovarian theca lutein cysts (P = 0.018) (among pre-evacuation factors) and first week ultrasound (P = 0.02) can help in detecting high-risk patients. Even though, when β-hCG titer is not available in a high-risk patient, post evacuation myometrial involvement (P = 0.005) is a useful sign for detecting persistency.Conclusions:
Some ultrasonographic features of molar pregnancy have capability to predict malignancy in the course of disease.Keywords
1. Background
Gestational trophoblastic disease (GTD) is a rare event, up to 8 per 1000 pregnancies (1). This term includes hydatidiform mole (HM) (either complete or partial) and malignant forms (persistent GTD), comprising invasive mole, choriocarcinoma and placental site trophoblastic tumor. Although HM is often treated with suction evacuation, about 15% of complete HM and 0.5% of partial HM transform into malignant forms (1-3). Serial assessment of serum human chorionic gonadotropin (hCG) titers is a standard method to identify post molar malignancy. However, in the first weeks, β-hCG test has not the capability for early detection of high-risk patients. High-risk patients need a closer follow-up. It had been shown than prophylactic chemotherapy significantly decreases the rate of persistency in this group (4, 5). Transvaginal Ultrasonography is a noninvasive and inexpensive medical imaging tool used for diagnosis of various diseases. Using other imaging modalities, like computed tomography, magnetic resonance imaging (MRI) and positron emission tomography is limited for detection of metastasis or locoregional spread (1, 6, 7). MRI is useful for detecting myometrial invasion, but not performed routinely for the assessment of persistent disease. It is only indicated in difficult cases (1). Several studies were performed to evaluate the roles of multiple prognostic factors, as ultrasound gray scale, Doppler features, patient's history (as maternal age, gestational age, previous molar pregnancy and prolonged oral contraceptive use) and lab tests (6, 8-13). These factors are signs of high-risk state, particularly when coexist. Because of early detection of molar pregnancy with ultrasound, some of these features (as theca lutein cysts, larg uterine volume) are not encountered as common as previously.
2. Objectives
In this study, we examined several predictive factors of persistency, and mainly focus on ultrasound results during follow-up courses. Some ultrasound findings were determined to be effective in prediction and diagnosis of post evacuation malignancy as well as selecting high-risk patients.
3. Patients and Methods
During the study period (September 2009 to March 2011), 19 patients were included, and 130 sonographic exams were performed. Seventy-eight examinations were relevant to patients with spontaneous remission (from the least 4 to 10 exams) and 52 exams to patients with persistent GTD (from the least 4 to 10 exams). Informed consent was taken from each patient. All patients with molar pregnancy who did not perform evacuation before starting the study were included. In addition, histopathologic examination was performed for all patients after evacuation and any pathology other than molar pregnancy was excluded. Patients who did not perform their follow-up visits were excluded as well. This prospective study was approved by our institutional review board. Before evacuation, patient's history and laboratory data such as maternal age, gestational age, new hyperthyroidism and β-hCG titer were recorded. The radiologist was blinded to patient’s β-hCG titers, and all titers were checked in one biochemistry laboratory. All patients were evaluated with transvaginal ultrasound and data about uterine volume, ovarian theca lutein cysts and uterine artery Doppler indices were collected. Sonographic examination was performed by duplex ultrasound machine (Medison Accuvix V20 Prstige) using 7.5 MHz endovaginal probe. Uterine arteries adjacent to the cervix were examined. Sample volume size was set as 2 mm, and angle between the Doppler beam and the vessel was set as low as possible. Doppler indices, including systolic to diastolic ratio (S/D), resistive index (RI) and pulsatility index (PI) were calculated for each uterine artery by ultrasound machine software. At least two waveform samples in each side were obtained and the lowest value was used, then mean of both sides was measured as well. After evacuation, serum β-hCG titers were controlled weekly and follow-up ultrasound was performed in the following manner; one week after the evacuation, then every two weeks until 9th week and once a month, thereafter until sixth month. However, sometime patients with suspicious sonographic findings (as endometrial retained tissue, indistinct junctional zone and focal increased vascularity in the uterus) or abnormal β-hCG titer were followed weekly. Patients with rising or plateauing β-hCG titers was considered persistent, and before starting chemotherapy their follow-up program was stopped. Uterine artery Doppler indices, any obvious increased vascularity or abnormal echo in the endometrium or myometrium and any new changes in the follow-up exams were evaluated carefully. Data analysis was performed using SPSS software ver. 17 (SPSS Inc., 233 South Wacker Drive, 11th Floor, Chicago, IL 60606-6412). Paired t-test, chi-square test and mann whitney U test were performed. P-value less than 0.05 were considered significant.
4. Results
In this study, 19 patients were examined. Based on β-hCG titer during the follow-up course, patients were divided into two groups; patients experienced persistent GTD (group A), including eight (42%) patients and another group (group B), including 11 (58%) patients who had spontaneous remission. Mean follow-up assessments in group A was 6.5 and in the other group was seven. The first rise or plateauing of β-hCG in patients of group A occurred at the range of 2 to 10 weeks (mean: 4.56 ± 2.8 weeks).
4.1. Pre-Evacuation Data of Patients' History, Laboratory Tests and Ultrasonography
The mean value of maternal age in patients with persistent GTD of group A was 26.3 and the other group was 25 years. None of patients was older than 40 years as a risk factor of persistency. In addition, past history of molar pregnancy was not seen in any of patients. Eight (72.7%) patients with spontaneous remission and 6 (75%) patients in the other group had histologic confirmation of complete mole and other patients in the both groups had a partial mole. Data from patient history, β-hCG, and sonographic findings are depicted in Table 1. Only existence of a theca lutein cyst was statistically significant (P = 0.018). However, there were delicate points that should be noticed:
First, three of four patients, who had theca lutein cysts, had multiple bilateral cysts, and new hyperthyroidism and uterine volume ≥ 1000 cm3 were only seen in these patients. Another patient had a few unilateral cysts with normal thyroid function test and uterine volume < 1000 cm3. Second, only two patients of group B had new hyperthyroidism, which was very faint and only one of them had uterine volume ≥ 1000 cm3. Theca lutein cysts were not seen in any of them.
| Pre-Evacuation Findings | Spontaneous Remission | Persistent GTD | P Value |
|---|---|---|---|
| Ovarian theca lutein cyst | 0 (0) | 4 (50) | 0.018 |
| Uterine volume, ≥ 1000 cm3 | 1 (9) | 3 (37.5) | 0.26 |
| Hyperthyroidismc | 2 (20) | 3 (42.9) | 0.59 |
| Gestational age, ≥ 12 weeks | 2 (18) | 4 (50) | 0.3 |
| Prolonged oral contraceptive use, > 1 year | 3 (27.3) | 3 (37.5) | 1 |
| Maternal age | 25 ± 6.2 | 26.3 ± 6.9 | 0.68 |
| Gestational age, week | 9.3 ± 2 | 10.1 ± 2.1 | 0.49 |
| β-hCG level | 137219.5 ± 177630 | 246512.8 ± 198012 | 0.15 |
| Uterine volume, cm3 | 417.9 ± 270.7 | 907 ± 638.5 | 0.25 |
4.2. Pulsed Doppler Study
Findings of pulsed Doppler ultrasound from the both groups are presented in Table 2. In the group with spontaneous remission, Doppler indices (S/D, RI and PI) of uterine arteries showed a significant increase during 9 weeks follow-up course after evacuation (P = 0.02, P = 0.04 and P = 0.01, respectively) (Figure 1). In contrast, no significant changes were seen in patients of group B (P = 1, P = 0.6 and P = 0.7, respectively) (Figure 2).
| Spontaneous | Remission | P Value | Persistent GTD | P Value | ||
|---|---|---|---|---|---|---|
| Before Evacuation | 9 Weeks After Evacuation | Before Evacuation | After β-hCG Rise or Plateauing | |||
| Uterine artery | ||||||
| S/D | 5.55 ± 2.61 | 25.8 ± 2.9 | 0.02 | 5.62 ± 2.55 | 4.8 ± 1.8 | 1 |
| RI | 0.76 ± 0.15 | 0.91 ± 0.06 | 0.04 | 0.79 ± 0.1 | 0.76 ± 0.07 | 0.6 |
| PI | 1.95 ± 0.9 | 3.12 ± 0.79 | 0.01 | 2.12 ± 0.85 | 1.91 ± 0.57 | 0.7 |
| Myometrial vessel | ||||||
| S/D | 2 ± 0.28 | 2.4 ± 0.14 | 0.18 | 1.98 ± 0.73 | 1.85 ± 0.56 | 0.49 |
| RI | 0.48 ± 0.11 | 0.58 ± 0.02 | 0.18 | 0.46 ± 0.15 | 0.42 ± 0.12 | 0.39 |
| PI | 0.72 ± 0.17 | 1 ± 0.14 | 0.18 | 0.72 ± 0.37 | 0.62 ± 0.27 | 0.24 |
The mean pi of both uterine arteries, before and after evacuation of molar pregnancy in patients with spontaneous remission
The mean pi of both uterine arteries, before and after the evacuation of molar pregnancy in patients with persistent gestational trophoblastic disease
Since the mean follow-up course in patients of group B was about 5.5 weeks, the data from another group in the 5th week was also analyzed to make a better comparison. Results indicated a significant increase in PI (P = 0.02). Besides, changes of RI and S/D were statistically significant (P = 0.06 and P = 0.09, respectively). Weekly changes in Doppler values were not significant in any of patients. Pre-evacuation Doppler indices of both groups were not significantly different (P = 0.56, P = 0.6 and P = 0.7, respectively). Hypervascularity of endometrium or myometrium, was seen in 2 (18%) patients of group B, and 7 (87.5%) of the other group. Although subtle rising in Doppler indices of patients of group B and mild decrease in the other group existed, these changes were not significant.
4.3. Post Evacuation Endometrial and Myometrial Ultrasound Findings
Eight (72.7%) patients of group B did not have any abnormality (as any retained tissue in the endometrium or any abnormal echo or focal hypervascularity in the myometrium) in the uterus on the first ultrasound exam or on other follow-up visits. In the other group, the first examination was normal in only one (12.5%) patient (P = 0.02), who had small polypoid lesions on the endometrial surface before β-hCG rise. In five (62%) patients of group A myometrial involvement, as a new nodule (in 2 patients) or a deep invasion (3 other patients) was observed in follow-up visits after evacuation; 2 patients had deep invasion in the first follow-up visit (their first β-hCG rise was detected at the second week of follow up visit in one patient and in fourth week of follow up visit in the other patient), Other three patients had new nodule or deep invasion at the same time of first rising of β-hCG titer (in two patients at seventh week and one patient at third week). In contrast, none of these myometrial findings were observed in group B. This difference was highly significant (P = 0.005). Focal indistinct junctional zone solely, without deep invasion into myometrium, was seen in two (18%) patients with spontaneous remission, and in two (25%) patients of the other group. One patient of group A had a retained tissue, which became progressively enlarged and hypervascular during the follow-up (from 15.2 × 12 mm in the first week to 45.8 × 31.9 mm in 5.5th week); Figure 3.
Transvaginal ultrasonography in a patient with persistent gestational trophoblastic disease who had retained tissue in the endometrium at the first visit, which enlarged vigorously during follow-up course
Acknowledgements
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