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Identification of causative pregnancy of gestational trophoblastic neoplasia diagnosed during pregnancy by short tandem repeat analysis.
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PMID:  24944881     Owner:  NLM     Status:  PubMed-not-MEDLINE    
Abstract/OtherAbstract:
•Gestational trophoblastic neoplasia can arise during the first trimester originating from trophoblasts of concurrent pregnancy.•Intraplacental choriocarcinoma can be developed from trophoblasts of a previous pregnancy.
Authors:
Eiko Yamamoto; Kaoru Niimi; Kanako Shinjo; Toshimichi Yamamoto; Masaharu Fukunaga; Fumitaka Kikkawa
Publication Detail:
Type:  Journal Article     Date:  2014-04-18
Journal Detail:
Title:  Gynecologic oncology case reports     Volume:  9     ISSN:  2211-338X     ISO Abbreviation:  Gynecol Oncol Case Rep     Publication Date:  2014 Aug 
Date Detail:
Created Date:  2014-06-19     Completed Date:  2014-06-19     Revised Date:  2014-06-23    
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Nlm Unique ID:  101599306     Medline TA:  Gynecol Oncol Case Rep     Country:  Netherlands    
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Languages:  eng     Pagination:  3-6     Citation Subset:  -    
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Journal ID (nlm-ta): Gynecol Oncol Case Rep
Journal ID (iso-abbrev): Gynecol Oncol Case Rep
ISSN: 2211-338X
Publisher: Elsevier
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© 2014 The Authors
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Received Day: 8 Month: 1 Year: 2014
Accepted Day: 8 Month: 4 Year: 2014
pmc-release publication date: Day: 18 Month: 4 Year: 2014
Electronic publication date: Day: 18 Month: 4 Year: 2014
collection publication date: Month: 8 Year: 2014
Volume: 9First Page: 3 Last Page: 6
PubMed Id: 24944881
ID: 4059915
Publisher Id: S2211-338X(14)00010-6
DOI: 10.1016/j.gynor.2014.04.001

Identification of causative pregnancy of gestational trophoblastic neoplasia diagnosed during pregnancy by short tandem repeat analysis
Eiko Yamamotoa Email: yamaeiko@med.nagoya-u.ac.jp
Kaoru Niimia
Kanako Shinjoa
Toshimichi Yamamotob
Masaharu Fukunagac
Fumitaka Kikkawaa
aDepartment of Obstetrics and Gynecology, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, Japan
bDepartment of Legal Medicine and Bioethics, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, Japan
cDepartment of Pathology, The Jikei University School of Medicine, 4-11-1 Izumi-honcho, Komaeshi, Tokyo 201-8601, Japan
Corresponding author. Fax: + 81 52 744 2268. yamaeiko@med.nagoya-u.ac.jp

Introduction

Gestational trophoblastic neoplasias (GTNs) are tumors that arise from trophoblasts such as invasive mole, choriocarcinoma, placental site trophoblastic tumor (PSTT) and epithelioid trophoblastic tumor (Lurain, 2011). Invasive mole is a pre-malignant disease which occurs in 10–20% cases of hydatidiform mole. Choriocarcinoma and PSTT are malignant tumors which arise from the trophoblasts of any kind of pregnancy, including hydatidiform mole. It has been shown that the causative pregnancy of GTNs is not necessarily the immediately antecedent pregnancy using DNA analysis (Fisher et al., 1995).

GTNs which are detected during pregnancy are very rare and most of them are intraplacental choriocarcinomas. Although the causative pregnancy of GTN during pregnancy may be a concurrent pregnancy or a previous pregnancy, as an extensive examination of the literature shows that there is only one study which demonstrates that the origin of intraplacental choriocarcinoma was a concurrent pregnancy (Kanehira et al., 2013). In this paper the patients presented with PSTT and intraplacental choriocarcinoma, which were diagnosed pathologically in the 11th and 38th gestational weeks, respectively. To identify the causative pregnancies, DNA analysis for 15 short tandem repeats (STRs) was performed using a commercially released kit.

Cases

Case 1 is a 37-year-old Japanese woman, gravida 8, para 6, who visited a local hospital because she found that she had become pregnant. Her last pregnancy ended in normal delivery at term and she had been having regular menstrual periods for two years. Pelvic ultrasonography detected a myoma (72 × 68 × 58 mm) and a normal sized fetus in a gestational sac. A hysterectomy was performed at the 11th week because the patient and her husband hoped for an artificial abortion and the myoma caused anemia. There was a 17 mm tumor in the myometrium next to the myoma macroscopically. Histological examination demonstrated that the tumor was composed of intermediate trophoblastic cells which invaded the myometrium in a sheet-like structure (Fig. 1B). The cells were positive for human placental lactogen (hPL) and weakly positive for hCG (Fig. 1C–D). Focal necrosis and extensive vascular invasion were seen in the myometrium. One mitotic figure per 10 high-power fields was observed. Diagnosis of PSTT was strongly considered. All villi and trophoblasts in anchoring villi were normal (Fig. 1A). Serum hCG and hPL levels were 101.4 mIU/ml and less than 0.07 μg/ml on the 14th postoperative day, and decreased with time after surgery. There has not been any clinical evidence of recurrence for over 18 months.

Case 2 concerns a 31-year-old Japanese woman, gravida 6, para 3, who became pregnant naturally. Her last pregnancy ended in spontaneous abortion and she had been having regular menstrual periods for a year. She had an ultrasound examination once or twice a month. Melena started at the 35th week which caused severe anemia. An emergency Cesarean section was performed at the 38th week and a tumor was found in the jejunum. Pathological examination showed that a small part of the placenta and the tumor of the jejunum consisted of malignant trophoblasts like syncytiotrophoblasts, cytotrophoblasts and intermediate trophoblasts. Necrosis and hemorrhage were found more in the jejunal tumor than in the placenta (Fig. 1E–F). These cells were positive for hCG strongly and the pathological diagnosis was made as choriocarcinoma. MRI, CT scans and colonoscopy showed that choriocarcinoma had spread to the brain, the lung, the liver, the ileum and the colon, as well as the myometrium. The patient had chemotherapy with MEA therapy (methotrexate, etoposide and actinomycin-D) and whole brain radiation. The patient achieved remission after seven cycles of chemotherapy, received four additional cycles for consolidation, and has been in remission for 18 months.

To identify the causative pregnancies of the two cases, STR analysis was performed. This study was approved by the ethics committee of Nagoya University Graduate School of Medicine. Informed consent was obtained from the patients and their partners. Genomic DNA was extracted from parental oral cells and microdissected tissue of villi and GTNs from paraffin sections. DNA was amplified with 15 STR markers and a gender-determination marker. The villous and PSTT allotypes showed a complete match in all 16 loci analyzed (S1). These results suggest that PSTT arose from the concurrent pregnancy. In case 2, the results of STR analysis in 14 loci were informative (Table 1). The results of the choriocarcinoma in the placenta and the jejunum were the same as the results of the villi in nine loci but different in five loci. These results suggest that choriocarcinoma originated not from the concurrent pregnancy, but from one of the previous pregnancies.


Discussion

The PSTT case in this study was detected in the uterus during the first trimester with a normal fetus. An extensive literature search including MEDLINE (1984–2013) demonstrated that only three cases of PSTT were reported to be diagnosed pathologically during normal pregnancy (Table 2) (Hopkins et al., 1992; Su et al., 1999; Liszka et al., 2009). All three cases had hysterectomy or biopsy of the myometrium when Cesarean sections were performed in the third trimester. Another case of a four-month-old boy was reported who died of PSTT with metastasis to multiple organs (Monclair et al., 2002). His mother was diagnosed as PSTT a year after the delivery when a hysterectomy was performed; however, it was strongly suspected that PSTT had arisen in the uterus during pregnancy. If the PSTT case in this study had kept her pregnancy, she would have been diagnosed after bleeding or fetal distress during pregnancy. Even if she could have had a baby at term, she would have had vaginal bleeding postpartum.

There are many case reports of intraplacental choriocarcinoma and 15–25% were found incidentally after uneventful pregnancies. There is only one reported case in the English literature whose genetic origin was examined (MEDLINE; 1946–2013; search terms: “intraplacental choriocarcinoma”, “DNA”, and “genetic”) (Kanehira et al., 2013), possibly because it has been believed that intraplacental choriocarcinoma arises naturally from trophoblasts of concurrent pregnancy. This paper is the first report to show genetically that choriocarcinoma arises during a pregnancy whose origin is a previous pregnancy. Thus, the choriocarcinoma arose in the uterus first and then metastasized to the other organs including the placenta.

Exactly which pregnancy was the origin of the intraplacental choriocarcinoma could not be confined because the DNA of the children could not be used due to ethical issues or the villous tissues of all abortions could not be used. There is also a possibility that a vanishing twin pregnancy could be the origin of the malignant trophoblasts that caused the intraplacental choriocarcinoma because other GTNs have occurred during twin pregnancies (Liszka et al., 2009). However, the patient visited an obstetrical clinic first in the fifth gestational week and this possibility may be very slight.

It is difficult to find GTNs during normal pregnancy because hCG cannot be used as a tumor marker during pregnancy. Image diagnosis, including ultrasound, CT and MRI, is not useful to diagnose GTN in the placenta. The cases in this study suggest that the possibility that GTNs arise at any time should be considered, even during pregnancy. Molecular genetic studies on the origin of GTNs can lead to a better understanding of the nature of the diseases and provide prognostic information for better management of patients.


Conflict of interest statement

The authors have no conflicts of interest to declare.


References
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Hopkins M.P.,Drescher C.W.,McQuillan A.,Keyser J.,Schmidt R.. Malignant placental site trophoblastic tumor associated with placental abruption, fetal distress, and elevated CA-125Gynecol. Oncol.47Year: 19922672711334939
Kanehira K.,Starostik P.,Kasznica J.,Khoury T.. Primary intraplacental gestational choriocarcinoma: histologic and genetic analysesInt. J. Gynecol. Pathol.32Year: 2013717523202784
Liszka L.,Wilk M.,Wodolazski A.,Palen P.,Sikora J.. Successful treatment of placental site trophoblastic tumor in twin pregnancy without hysterectomyTumori95Year: 200910811119366068
Lurain J.R.. Gestational trophoblastic disease II: classification and management of gestational trophoblastic neoplasiaAm. J. Obstet. Gynecol.204Year: 2011111820739008
Monclair T.,Abeler V.M.,Kaern J.,Walaas L.,Zeller B.,Hilstrøm C.. Placental site trophoblastic tumor (PSTT) in mother and child: first report of PSTT in infancyMed. Pediatr. Oncol.38Year: 2002187191 (discussion 92). 11836719
Su Y.N.,Cheng W.F.,Chen C.A.,Lin T.Y.,Hsieh F.J.,Cheng S.P.. Pregnancy with primary tubal placental site trophoblastic tumor—a case report and literature reviewGynecol. Oncol.73Year: 199932232510329055
Appendix A  Supplementary data

The following is the Supplementary data to this article. Supplymentary 1

STR analysis of PSTT and the normal villi.


Click here for additional data file (mmc1.docx)


Article Categories:
  • Case Report

Keywords: Keywords DNA analysis, Intra-placental choriocarcinoma, Placental site trophoblastic tumor, Pregnancy, Short tandem repeat.

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