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Year : 2019  |  Volume : 3  |  Issue : 2  |  Page : 97-101

Analysis of clinicopathologic classification features of hydatidiform mole misdiagnosed as missed abortion preoperatively

1 Department of Family Planning, Obstetrics and Gynecology Hospital of Fudan University, Shanghai 200011, China
2 Department of Pathology, Obstetrics and Gynecology Hospital of Fudan University, Shanghai 200011, China
3 Department of Gynecology, Obstetrics and Gynecology Hospital of Fudan University, Shanghai 200011, China

Date of Submission29-May-2019
Date of Web Publication9-Jul-2019

Correspondence Address:
Prof. Jin Zhu
Department of Gynecology, Obstetrics and Gynecology Hospital of Fudan University, No. 419, Fangxie Road, Shanghai 200011
Prof. Xiao-Ying Yao
Department of Family Planning, Obstetrics and Gynecology Hospital of Fudan University, No. 419, Fangxie Road, Shanghai 200011
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/2096-2924.262393

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Objective: To analyze clinicopathologic classification features of the cases that were diagnosed as missed abortion preoperatively but turn out to be hydatidiform mole (HM) postoperatively.
Methods: A retrospective analysis was conducted on the patients who had a missed abortion in our hospital from 2017 to 2018. Clinical and pathological characteristics of different types of HMs were observed. Diagnostic value of karyotype in HM was discussed based on the karyotype analysis of villi chromosome.
Results: A total of 278 (11.2%) HM patients were misdiagnosed as missed abortion. Naked-eye detection rate of HM was 26.61%, and sensitivity of transvaginal ultrasound on HM was 7.91%. One hundred and forty-seven (52.88%) HM cases could not be genotyped via pathological hematoxylin and eosin (HE) staining. 70 HM patients underwent P57 immunohistochemistry, which had guiding significance to the classification. In addition, the karyotype diagnosis of the tissues from 15 cases basically matched their P57 classifications.
Conclusions: P57 should be listed as a routine test in hydatidiform pathological examination at the same time of HE staining, and what's more, P57 expression is consistent with genotyping, which should be recommended for the patients with HM if observed by naked eye.

Keywords: Complete Hydatidiform Mole; Missed Abortion; P57; Partial Hydatidiform Mole

How to cite this article:
Tang YH, Sun YH, Zhu J, Yao XY. Analysis of clinicopathologic classification features of hydatidiform mole misdiagnosed as missed abortion preoperatively. Reprod Dev Med 2019;3:97-101

How to cite this URL:
Tang YH, Sun YH, Zhu J, Yao XY. Analysis of clinicopathologic classification features of hydatidiform mole misdiagnosed as missed abortion preoperatively. Reprod Dev Med [serial online] 2019 [cited 2020 Jul 14];3:97-101. Available from: http://www.repdevmed.org/text.asp?2019/3/2/97/262393

Yun-Hui Tang and Yi-Hua Sun equally contributed to this article

  Introduction Top

Missed abortion refers to a condition in which a dead immature embryo or fetus is not expelled from the uterus.[1] In the past decade, the incidence of missed abortion has gradually increased. In clinics, vesicular mole is often found in the scraping from uterine after missed abortion surgery, which is identified as hydatidiform mole (HM) via pathological examination. Early HM often shows irregular vaginal bleeding in clinics, and shares similar symptoms with missed abortion, leading to misdiagnosis as missed abortion. The occurrence of pathological HM misdiagnosis as missed abortion is worth our attention.

As the most common gestational trophoblastic disease (GTD), HM is divided into complete HM (CHM) and partial HM (PHM) according to embryonic or fetal structure. The incidence of CHM is reported as 1:1,000[2] and that of PHM is relatively low. Although CHM is benign, atypia of trophocytes is more significant than that of PHM, and small part of it will develop into gestational trophoblastic neoplasia. The possibilities of local invasion and distant metastasis are 15% and 4%, respectively,[1] which need enough attention. Thus, accurate evaluation and proper treatment on CHM or PHM is of great importance in clinics.

Currently, definite diagnosis of HM mainly depends on pathological hematoxylin and eosin (HE) examination in most medical institutions. However, HE staining cannot differentiate CHM and PHM, especially at early pregnancy. CHM or PHM could not be definitely diagnosed because large amount of pathological sections have relatively small embryonic tissues, and typical bullate villi or fetus-like structure is lacking. Thus, it can only be described as bullate mole or unclassified HM (UCHM), which is a blind area in the pathological diagnosis. Some CHM not clearly classified may not get appropriate therapy.

Based on the previous experience, clinicians can identify HM by preoperative human chorionic gonadotropin (HCG) level, transvaginal ultrasound, observation of scraping intraoperatively, and pathological detection of postoperative tissue. With the rapid development of assisted detection technology, immunohistochemical analysis and PCR amplification can improve the detection of HM category and judgment of disease outcome. Thus, the classification of HM is feasible, necessary, and valuable.

To understand clinical and pathological condition of HM misdiagnosed as missed abortion, the misdiagnosed cases undergoing abortion due to missed abortion from 2017 to 2018 were retrospectively analyzed. Detection rates of preoperative ultrasound and observation and clinical and pathological features of different types of HM were investigated. According to the karyotype result of HM villus chromosome, the value of karyotype in HM genotyping was explored, and reliable HM typing method was found to avoid occurrence of misdiagnosis, missed diagnosis, and blind area.

  Materials and Methods Top

Study subjects

A total of 2,502 patients diagnosed as missed abortion undergoing induced abortion due to menstrual period within 12 weeks in the Obstetrics and Gynecology Hospital of Fudan University from 2017 to 2018 were enrolled as study subjects for retrospective analysis. Meanwhile, those who required pregnancy termination and were suggested intrauterine pregnancy by transvaginal ultrasound with menstrual period within 12 weeks in this hospital were selected as controls (a total of 6,325 women).

Inclusion criteria

  • Single-birth women with regular menstrual cycle.

Exclusion criteria

  1. Multiple birth
  2. Unexplained vaginal bleeding
  3. Genital malformation
  4. Severe comorbidities in this pregnancy.

Definition of missed abortion[3]

Uterine pregnancy with confirmed history of menopause, positive blood or urine β-hCG, associated with or without symptoms of threatened abortion. Uterus stops growing or gradually shrinks over menstrual period, but shorter than menstrual period.

Diagnostic criteria for missed abortion

Slowly increased or declined blood β-hCG or pregnancy failure diagnosed by transvaginal ultrasound: no fetal heart observed in crown-rump length ≥7 mm; no embryo observed in gestational sac with average diameter ≥25 mm; no embryo or fetal heart observed in gestational sac without yolk sac ≥2 weeks; and no embryo or fetal heart observed in gestational sac with yolk sac ≥11 days.

Definition of hydatidiform mole[1]

Postoperative pathology suggested placental villus trophoblastic proliferation and interstitial edema, and uneven-sized bubbles could be observed, which were connected by pedicels. CHM is characterized by the absence of a fetus or fetal parts (i.e., no embryonic tissues). PHM is the one with focal distribution, slower transformation, the presence of an embryo or fetus, and a triploid karyotype. Through HE staining, those without typical bullate villi or fetus-like structure and could not be clearly classified are considered to be the UCHM.


The scraping during abortion was sent for histological examination. Missed abortion cases with HM were retrospectively analyzed, detection rates of eye observation and transvaginal ultrasound were calculated, and then clinical and pathological features of HM were observed. According to the karyotype result of HM villi chromosome, diagnosis value in HM typing was explored. HM was further divided into CHM, PHM, and UCHM (reported as bubble-like mole) according to pathological diagnosis.

Statistical analysis

The data were analyzed by SPSS 22.0 (IBM SPSS Inc., Chicago, IL, USA) and expressed as mean ± standard deviation (SD). The data between the groups were analyzed by t-test and Chi-square test. A = 0.05 was used as test level.

  Results Top

Age comparison

Among 2,502 patients diagnosed as missed abortion preoperatively, 278 (11.2%) cases were misdiagnosed as HM. A total of 2,224 (88.8%) patients were pathologically confirmed as missed abortion [Figure 1]. Simultaneously, 6,325 patients undergoing induced abortion were taken as controls.
Figure 1: Patient flowchart.

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There was a statistical significance in age between HM group, missed abortion group, and induced abortion group [Table 1]. Ages in the missed abortion group and the HM group were significantly higher than that in the induced abortion group (P < 0.05), and no statistical significance between the HM group and the missed abortion group was found (P > 0.05). It was suggested that the age of patients with HM and missed abortion was relatively older, which was consistent with other reports.[4]
Table 1: Diagnostic classification of cases and age distribution of HMs, missed abortion, and induced abortion (mean ± SD)

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According to the pathological result, 278 HM cases were divided into CHM group, PHM group, and UCHM group. No significant difference in age between the groups was found. One hundred and forty-seven (52.88%) patients with HM could not be classified, becoming a large blind area in the pathological diagnosis.

Comparison of serum beta-human chorionic gonadotropin detection in missed abortion and hydatidiform mole group

Blood β-hCG level of each study subject was retrospectively compared and expressed as mean ± SD in [Table 2].
Table 2: Comparison of serum β-hCG detection in missed abortion and HM groups

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The result indicated significant difference in serum β-hCG between the missed abortion group and the HM group (P < 0.05) and that in the HM group was significantly elevated compared with the other group, which was consistent with other report.[5]

Evaluation on hydatidiform mole through naked eyes

The scraped substance from uterine cavity was observed by eyes [Table 3].
Table 3: HM observed by eyes (cases)

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Among 74 cases with bubble-like structure observed by eyes, all of them were proved to be HM by postoperative pathology. Accuracy by eyes was 100%, but the detection rate was only 26.61%.

Evaluation of transvaginal ultrasound on hydatidiform mole

HM was evaluated by preoperative transvaginal ultrasound [Table 4] and [Table 5].
Table 4: Evaluation of transvaginal ultrasound on HM

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Table 5: Evaluation of transvaginal ultrasound on HM and missed abortion (cases)

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Preoperative transvaginal ultrasound suggested 38 cases with HM possibility. Compared with the pathological results, 4 cases were PHM, 11 were CHM, and 7 were UCHM. Ultrasound examination suggested HM, and 16 cases were unidentified from the result of pathology.

Sensitivity of transvaginal ultrasound on HM was 7.91%, and positive predictive value was 57.89%. The sensitivity on missed abortion was 99.28%, and the positive predictive value was 89.61%.

Maternal P57 detected by immunohistochemistry

Among 278 HM cases, 70 cases had been confirmed by P57 immunohistochemistry. Among them, 21 had positive P57 who were diagnosed as PHM, 49 had negative P57 diagnosed as CHM, and 147 did not receive P57 detection. The result of P57 was consistent with the pathological HE staining characteristics, complying with the clinical diagnosis. Besides, P57 detection was performed on some missed abortion specimens, and maternal P57 expression was found [Figure 2].
Figure 2: Histological investigation of villi sections from CHM (a and b), PHM (c and d), and missed abortion patients (e and f). CHM villi show diffuse enlargement and edema, associated with trophocytes proliferation (a). Villous stromal cells and cytotrophoblast are negative for P57 in CHM; (b) edematous and normal-sized villi can be observed in PHM, associated with trophocytes proliferation; (c) relatively normal size of missed abortion villi, and no significant proliferation is observed in trophocytes; (e) villous stromal cells and cytotrophoblast are diffusely positive for P57 in both PHM (d) and missed abortion groups (f) Bar = 200 μm. CHM: Complete hydatidiform mole; PHM: Partial hydatidiform mole.

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Chromosome report of hydatidiform mole patients

Among the study subjects, 15 cases voluntarily received villus chromosome analysis. The result indicated that karyotype was consistent with that of P57 detection: 3 cases were triploid, of them 2 complied with the pathological diagnosis of PHM and 1 was UCHM. Besides, among 12 diploid cases, 4 complied with the pathology of CHM, 5 were UCHM, 3 were diploid diagnosed as PHM, and 2 were positive P57 [Table 6]. The karyotype was almost same as reported.[6]
Table 6: Molecular genotyping results in the HM group

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  Discussion Top

There is still no agreement on the morbidity of HM, and the difference among countries is huge.[7] The morbidity in the UK is 1:600,[8] and those in Asia and Latin America are relatively high, about 1:500. In China, the average morbidity is about 0.078% pregnancy,[1] and it is increasing recently.[9]

As a pathological diagnosis, HM has been reported in missed abortion, cesarean scar pregnancy, or even cervical pregnancy.[10],[11],[12] The most common clinical manifestations are vaginal bleeding after amenorrhea. PHM is also associated with embryonic development termination, which is similar as the manifestations of missed abortion. HM at early pregnancy is easy to be misdiagnosed as missed abortion by clinicians. In this study, we found that 224 HM cases were misdiagnosed as missed abortion, accounting for 10.07% of total simultaneous missed abortions. Thus, missed diagnosis or misdiagnosis of HM cannot be ignored.

Diagnosis of HM is based on morphology at first. Observation of the scraped substance from uterine cavity and preoperative transvaginal ultrasound are the most common discovery methods. Our study indicated that the accuracy of eye observation was very high (100.00%), but the sensitivity was not (33.03%). The features of ultrasound imaging in early pregnancy are not characteristic, and it is hard to find typical snow-like or honeycomb-like images.[13] Color ultrasonography could observe no gestational sac or fetal heart beat in the uterus, and it is easy to misdiagnose as missed abortion. Among the 2,502 patients with missed abortion at early pregnancy, ultrasound only suggested 38 cases with HM. Finally, only 22 cases had complied pathology. Among them, 18 were CHM, 4 were PHM, and 16 were misdiagnosed. Sensitivity of color Doppler ultrasound on missed abortion was up to 99.28%, but that on HM was only 7.91% and associated with misdiagnosis. Thus, we believed that color Doppler ultrasound could provide high reference value on missed abortion in early pregnancy, but definite diagnosis of HM could not be made based on it, and the advantage was much less than missed abortion. The detection rate of clinical morphology examination on HM is not high.

Postoperative pathological examination is a gold standard to confirm HM and is also a main basis for identifying CHM and PHM. Typical pathological manifestations of CHM are villous stromal edema, showing bubble-like shape and being associated with formation of center pool and hyperplasia of trophocytes. Actually, misdiagnosis of missed abortion often occurs during early pregnancy. The characteristic pathological change under microscope only accounts for 30%,[14] and most are associated with atypical morphological change. It is difficult to confirm the typing of HM by HE microscopic examination. In our retrospective study, only 47.12% HM cases were classified. The quantity of PHM was small. The possible reason of UCHM was the lack of histological features and inability to qualitative. Thus, we need more effective diagnosis methods with morphological mutation of HM.

With the development of genetics and biological molecule, wide application of molecular detection technology has changed our diagnosis method. Using immunohistochemistry to detect maternal expression, P57 imprinted gene and chromosome DNA karyotype have shown great diagnosis value, which could improve the capability of clinicians to identify early HM.[15]

P57 is a cell cycle and tumor inhibitor, located in Chromosome 11 in mother, which is also a characteristic marker to diagnose CHM.[15],[16] Due to lack of maternal gene in CHM, P57 is negative. PHM and missed abortion have both parent genes, and P57 expression may be positive, which accurately distinguishes CHM and PHM. Immunohistochemistry is the best pathological detection method to seek maternal P57. In our retrospective study, among 278 patients with missed abortion, 70 cases underwent P57 detection. The genotyping result was consistent with the characteristics of pathological HE, complying with the diagnosis. Thus, immunohistochemistry detection on P57 has been taken as a routine examination in HM pathological detection, which can basically avoid the blind area of pathology.

The cases with aberrant and discordant P57 expression can be correctly classified by genotyping. If P57 immunostaining is not ideal, or there is a difference between morphological detection and P57 result, karyotype is of great value for the identification. Genotype can correctly classify the cases with abnormal and inconsistent P57 expression. CHM is diploid (46, XX), and the complementary chromosomes are paternal origin without maternal component. More than 90% of PHM cases are triploid, including two sets of paternal chromosomes, in addition to one set of maternal chromosomes.[17],[18] The fetuses with combined chromosomes are always triploid, commonly karyotypes (69, XXY), (69, XXX), or (69, XYY). By karyotype detection, the source of sex chromosome can be identified, which helps diagnose and genotype HM.[17] In our retrospective study, a total of 15 patients underwent villus karyotype analysis, and two triploid cases complied with the conclusion of PHM P57 (+). Four diploid ones complied with the pathological result of CHM and five did not receive P57 detection and defined as UCHM. Another three karyotypes were diploid, but pathologically diagnosed as PHM. Two were positive P57. Interference of maternal chromatin could not be excluded. The result of karyotype in each group was almost the same as P57 and was almost consistent with the report.[6] Given the small sample size of chromosome, larger size will be needed in further exploration. Thus, if physicians observe bubble-like structure in surgery or suspicious HM, definite diagnosis could be made by karyotype examination.

We believe that routine pathology examination of postoperative uterine cavity tissue can help diagnose HM in missed abortion. Pathology is still a gold standard to diagnose HM. Confirmation of pathological genotyping is a critical step for timely treatment of CHM. HE staining cannot classify all the HM. Therefore, new detection method such as P57 immunohistochemical detection is needed to help accurately classify. P57 expression is highly correlated with karyotypes. Karyotype is also an effective method for HM classification. Clinicians should suggest that the patients with bubble-like tissue observed by eyes should receive chromosome examination to help genotype, which is beneficial to follow-up therapy of HM.

Financial support and sponsorship


Conflicts of interest

There are no conflicts of interest.

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  [Figure 1], [Figure 2]

  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6]


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