Abstract
Backgrounds
Intraplacental choriocarcinoma (IC) is an extremely rare subtype of gestational choriocarcinoma. The long-term follow-up and reproductive outcomes of IC patients remain unclear. Here, we report a series of 14 cases and conduct a literature review to assess the fertility and recurrence results of this rare disease.
Results
Fourteen patients with pathologically confirmed IC treated in Peking Union Medical College Hospital between January 2002 and July 2022 were included in this study. Half of them had metastatic IC and were treated by chemotherapy with or without surgery. Only 1 patient had chemoresistant disease, but she achieved complete remission after immunotherapy. The median follow-up time was 45.5 months (range 4-192), and no recurrence occurred. One metastatic IC patient who achieved remission after chemotherapy had a full-term delivery. Among the 5 patients with fertility demands, 3 abandoned their pursuit of pregnancy because of “fear and worry about choriocarcinoma recurrence”. We reviewed a total of 89 cases of IC in English and Chinese literature from 1963 to 2022, and only 5 cases with subsequent pregnancy were reported, all of them were nonmetastatic IC cases.
Conclusions
IC is sensitive to chemotherapy and has good long-term remission and a low recurrence rate. Patients with metastatic or nonmetastatic IC can have good pregnancy results after treatment. Doctors should pay more attention to the psychology of these patients.
Clinical trial registration
N/A.
Similar content being viewed by others
Background
Intraplacental choriocarcinoma (IC), first reported by Driscoll [1] in 1963, is a rare subtype of gestational choriocarcinoma in which choriocarcinoma is found within the placenta. The clinical manifestations are atypical and can be asymptomatic lesions confined to the placenta [2] or metastatic choriocarcinoma with both maternal and infantile involvement [3]. It may cause fetal complications such as fetomaternal hemorrhage, stillbirth and intrauterine growth restriction in the perinatal period [4]. The reported incidence of gestational choriocarcinoma is 1 per 50,000 normal pregnancies [5]. And pathologically diagnosed IC has been reported to account for only 2.3% of gestational choriocarcinoma cases [6], making it extremely rare. Due to the rarity of IC, sometimes it’s difficult to histologically differentiate it from another equally rare disease, chorangiocarcinoma [7].
Literature review indicates that there are fewer than 100 reported IC cases until now, and the long-term follow-up and reproductive outcomes of it remain unclear. Peking Union Medical College Hospital (PUMCH) is a center for the diagnosis and treatment of gestational trophoblastic neoplasia in China. This retrospective study systematically analyzed the medical records of all IC patients treated in our center over the past 20 years (2002–2022), aiming to explore the long-term outcome and fertility results of this rare disease.
Methods
The medical records and long-term follow-up data of all patients with a pathologically confirmed diagnosis of IC at PUMCH were reviewed. Demographic data and information on the presenting symptoms, gestational week and fetal outcomes were obtained from the clinical records. In this study, IC was staged according to the revised International Federation of Gynecology and Obstetrics (FIGO) criteria for GTN and assigned FIGO scores [8]. Written informed consent was obtained from each patient, and the study was approved by the Institutional Review Board of PUMCH (K3862).
The statistical analyses were performed with SPSS version 22.0 (SPSS Inc., Chicago, IL, USA). Data are presented as the means and standard deviations (SD) or medians (ranges) for continuous variables and as frequencies (corresponding percentages) for categorical variables.
Results
Demographic and clinical characteristics of the 14 patients
A total of 2,150 women were diagnosed with gestational choriocarcinoma at PUMCH between January 2002 and July 2022. Fourteen were pathologically diagnosed with IC, including 2 previously reported cases [3, 9]. Therefore, IC accounts for 0.7% of gestational choriocarcinoma diagnoses made at our center.
The demographic and clinical characteristics of all 14 patients are presented below (Table 1). Among the 14 patients, 10 were of Han nationality, 2 were of Hui nationality, and 2 were of Manchu nationality. The median age at diagnosis was 33 years (range 26–44), with a median of 3 previous pregnancies (range 1–5). Three (21.4%) patients were diagnosed in the first trimester (pregnancy 8 to 11+ 6 weeks). The 3 patients had abnormally and significantly increased β-human chorionic gonadotropin (β-hCG) levels up to 600,000 mIU/ml, and IC was confirmed by postabortion pathology. One (7.1%) patient was diagnosed in the second trimester (pregnancy 12 to 27+ 6 weeks). The remaining 10 (71.4%) patients were diagnosed in the third trimester (pregnancy 28 to 41 weeks) or postpartum, in terms of delivery methods, 6 of them (60%) underwent cesarean section due to obstetric factors or fetal distress, the other 4 patients (including 2 with intrauterine fetal deaths) underwent vaginal delivery.
The symptoms included vaginal bleeding (6/14, 42.9%), fetomaternal hemorrhage (5/14, 35.7%), and hemoptysis (1/14, 7.1%). Among the 7 cases of nonmetastatic IC, the β-hCG level automatically dropped to normal postpartum levels within 12.9 ± 8.2 weeks. Among the 7 cases of metastatic IC, the common metastatic sites were the lung (7/7, 100%), uterus (3/7, 42.9%), intracranial region (1/7, 14.3%) and vagina (1/7, 14.3%). There was 1 case in which fetal choriocarcinoma was diagnosed first, followed by a diagnosis of maternal metastatic IC [3].
The treatment of the 7 patients with metastatic IC is shown in Table 2. All patients were treated with chemotherapy. After chemotherapy, 3 (42.9%) underwent surgical treatment. One patient (14.3%) had chemoresistant disease but achieved complete remission after programmed cell death ligand-1 (PD-L1) immunotherapy.
Perinatal outcome
Four cases were excluded because they were diagnosed in the first or second trimester, and the perinatal outcomes of the remaining 10 patients are summarized below (Table 3). There were 2 intrauterine fetal deaths. Among the other 8 patients, each with a live birth, 1 had a premature delivery (35 weeks of gestation), and 7 had full-term deliveries. One newborn baby with a jejunal mass was treated by surgical resection, and pathology confirmed that it was choriocarcinoma. Then, the baby was successfully treated with combined chemotherapy [3]. Five newborn babies were pale and had anemia, which was confirmed to be associated with FMH.
Long-term outcomes and fertility results
The median follow-up time was 45.5 months (range 4-192), and there was no recurrence among the 14 patients. Of the 5 patients with fertility demands, 2 (40.0%) became pregnant again. One patient had fetal malformation at 11 weeks of gestation and underwent therapeutically induced labor. The other patient who had metastatic IC and received actinomycin D for 4 cycles, received FAV for 1 cycle, then changed to EMA/CO for 2 cycles and underwent 3 additional cycles for consolidation after achieving remission. She had a spontaneous intrauterine pregnancy that reached term at 37 months after treatment. No abnormality was found in the placental pathology examination, and the baby was healthy. The remaining 3 (60.0%) patients abandoned their pursuit of pregnancy because of “fear and worry about choriocarcinoma recurrence”.
Literature review
We reviewed and summarized the reported cases of IC in English and Chinese Literature from 1963 to 2022, and a total of 89 cases have been reported [6, 9,10,11,12,13,14]. Of the 101 IC patients (plus the 14 cases in our center, excluding the duplicate cases), 51 (50.5%) had non-metastatic IC. Among them, 7 patients (13.7%) received prophylactic chemotherapy, 1 was lost to follow-up, and 1 (2.0%) patient relapsed with lung metastasis and was cured by multiagent chemotherapy. In particular, 1 patient had a second diagnosis of IC confirmed by histological examination of the placenta after a second pregnancy. Further investigations revealed no evidence of metastasis, and her β-hCG level spontaneously returned to normal after delivery.
Among the 50 (49.5%) patients with metastatic IC, 2 patients were lost to follow-up, 13 (26.0%) patients died during the follow-up period, and 35 (70.0%) patients achieved complete remission by chemotherapy with or without surgery/radiotherapy. We further analyzed the 13 patients who died and found that only 3 patients had received chemotherapy. The remaining 10 patients were from an era when chemotherapy was not developed, 5 patients received only surgery, 4 died prior to initiation of therapy, and there was 1 treatment-related death.
At present, only 5 cases with subsequent pregnancy have been reported, [6, 9, 15, 16] all of them were nonmetastatic IC cases, with good maternal and infant outcomes.
Discussion
The fertility and recurrence results of IC at long-term follow-up were assessed in this study. We found that IC is sensitive to chemotherapy and has good long-term remission with a low recurrence rate, and patients with metastatic or nonmetastatic IC can have good pregnancy results after treatment.
The application of chemotherapy has greatly improved the prognosis of gestational choriocarcinoma patients. As a rare subtype, the main treatment for IC is also chemotherapy. Duleba et al. [17] recommended surveillance alone in nonmetastatic IC cases and chemotherapy for metastatic IC cases. A review published in 2013 mentioned that before chemotherapy was available, the survival rate at 5 years with hysterectomy alone was 41% in nonmetastatic IC and 19% in cases of metastasis [18]. However, almost all metastatic IC patients have achieved long-term remission since the application of effective multiagent chemotherapy [6]. In our study, there was one patient with chemotherapy resistance who received PD-L1 immunotherapy and achieved long-term remission. Based on our review of the literature and the results of our study, we recommend observation for nonmetastatic IC cases and combination chemotherapy for metastatic IC.
The reproductive outcomes of IC patients have rarely been discussed. All cases with subsequent pregnancy have been reported were nonmetastatic IC patients. For patients with metastatic IC, no subsequent pregnancy has been reported ever. In our study, it is noteworthy that full-term delivery occurred in a metastatic IC patient who achieved remission after chemotherapy. A review showed that after undergoing chemotherapy for GTN, 86.7% of women desired to conceive, the term live birth rate was 75.8%, and multiagent chemotherapy did not increase the risk of adverse obstetric events or the rate of fetal malformation in pregnancy [19]. Based on the aforementioned research, we believe that both metastatic and nonmetastatic IC patients were able to have good pregnancy outcomes.
It is worth noting that 60.0% of patients in our study with fertility demands abandoned the plan for later pregnancy because of “fear and worry about choriocarcinoma recurrence”, indicating that the psychological burden of IC patients should be an important consideration. Gestational choriocarcinoma is closely related to pregnancy events, including molar pregnancies, normal pregnancies, miscarriages, and ectopic pregnancies. Patients worry about the possibility of recurrence of gestational choriocarcinoma, and psychological morbidity rates exceed community levels even among patients who do not require chemotherapy [20]. Based on the current literature and the experience of our study, there is no clear evidence that subsequent pregnancy in patients with IC leads to IC recurrence. These can be used to support subsequent pregnancy considerations in patients with IC.
Our study has some unique strengths. This is the first report of patients with metastatic IC who had successful pregnancy after undergoing treatment with chemotherapy. Moreover, this is the first study to analyze the clinical features and prognosis of more than 10 IC cases. The primary limitation of the present study is that it is a retrospective study with a long enrollment period (20 years). However, because IC is an extremely rare disease, it is difficult to report more cases in a short time span.
Conclusions
IC is a rare subtype of gestational choriocarcinoma that is sensitive to chemotherapy and has good long-term remission with a low recurrence rate. Patients with metastatic or nonmetastatic IC can have good pregnancy results after treatment. Doctors should pay more attention to the psychology of these patients.
Data availability
The datasets generated and analysed during the current study are not publicly available due the need to protect study participant privacy but are available from the corresponding author on reasonable request.
Abbreviations
- IC:
-
Intraplacental choriocarcinoma
- PUMCH:
-
Peking Union Medical College Hospital
- FIGO:
-
International Federation of Gynecology and Obstetrics
- β-hCG:
-
β-human chorionic gonadotropin
- GTN:
-
gestational trophoblastic neoplasia
- GDM:
-
gestational diabetes mellitus
- FMH:
-
fetomaternal hemorrhage
- NED:
-
no evidence of disease
- TAH:
-
total abdominal hysterectomy
- LH:
-
laparoscopic total hysterectomy
- VATS:
-
video-assisted thoracic surgery
- FAEV:
-
floxuridine, actinomycin-D, etoposide and vincristine
- FAV:
-
floxuridine, actinomycin-D and vincristine
- EMA-CO:
-
etoposide, methotrexate, actinomycin D, cyclophosphamide and vincristine
- TP/TE:
-
paclitaxel, cisplatin/paclitaxel and etoposide
- FEV:
-
floxuridine, etoposide and vincristine
- AE:
-
actinomycin-D and etoposide
- MTX:
-
methotrexate
- 5-FU:
-
5-fluorouracil
- PD-L1:
-
programmed cell death ligand 1
References
Driscoll SG. Choriocarcinoma: an incidental finding within a term placenta. Obstet Gynecol. 1963;21(1):96–101.
Jacques SM, Qureshi F. Intraplacental choriocarcinoma without associated maternal or fetal metastases. Int J Gynecol Pathol. 2011;30(4):364–5.
Liu J, Guo L. Intraplacental choriocarcinoma in a term placenta with both maternal and infantile metastases: a case report and review of the literature. Gynecol Oncol. 2006;103(3):1147–51.
Stabile G, Gentile RM, Carlucci S, et al. Maternal and fetal outcomes of intraplacental choriocarcinoma complicated by fetomaternal hemorrhage: a systematic review. J Matern Fetal Neonatal Med. 2023;36(2):2285238.
Tidy JA, Rustin GJ, Newlands ES, et al. Presentation and management of choriocarcinoma after nonmolar pregnancy. Br J Obstet Gynaecol. 1995;102(9):715–9.
Jiao L, Ghorani E, Sebire NJ, et al. Intraplacental choriocarcinoma: systematic review and management guidance. Gynecol Oncol. 2016;141(3):624–31.
Stabile G, Scalia MS, Stampalija T, et al. Placental Chorangiocarcinoma a specific histological pattern of Uncertain incidence and clinical impact: systematic review of the literature. J Clin Med. 2023;12(9):3065.
Kohorn EI, Goldstein DP, Hancock BW, et al. Workshop report: combining the staging system of the International Federation of Gynecology and Obstetrics with the scoring system of the World Heath Organization for Trophoblastic Neoplasia. Report of the Working Committee of the International Society for the Study of Trophoblastic Disease and the International Gynecologic Cancer Society. Int J Gynecol Cancer. 2000;10(1):84–8.
Song X, Li Y, Zhang H, et al. Zaoyun hebing Taipanneirongmaomoai yili [A case of early pregnancy complicated with intraplacental choriocarcinoma]. J Reprod Med. 2022;31(05):685–88. (in Chinese).
Simões M, Vale G, Lacerda C, et al. Fetomaternal hemorrhage: a clue to intraplacental choriocarcinoma and neonatal malignancy. J Matern Fetal Neonatal Med. 2022;35(25):6615–7.
He Y, Huang G. An incidental finding of intraplacental choriocarcinoma. Asian J Surg. 2022;45(5):1200–1.
Sala A, Ornaghi S, Delle Marchette M, et al. Gestational Intraplacental Choriocarcinoma in a term pregnancy: a Case Report. Cureus. 2022;14(11):e31243.
Azizi M, Akbarzade-Jahromi M, Ghaffari P, et al. Delayed diagnosis of intraplacental choriocarcinoma in a term healthy neonate-A case report and literature review. Clin Case Rep. 2022;10(11):e6640.
Huang J, Li X. A rare case report of placental choriocarcinoma during pregnancy complicated with massive fetal maternal blood transfusion. Electron J Practical Gynecol Endocrinol. 2021;8(26):87–9. (in Chinese).
Caldas RF, Oliveira P, Rodrigues C, et al. Intraplacental Choriocarcinoma: rare or underdiagnosed? Report of 2 cases diagnosed after an incomplete miscarriage and a Preterm spontaneous vaginal delivery. Case Rep Med. 2017;2017:7892980.
Monteiro S, Burling M, Doyle H. Late diagnosis of intraplacental choriocarcinoma co-existing with fetomaternal haemorrhage causing fetal demise: a case report. Case Rep Womens Health. 2021;31:e00341. Published 2021 Jul 10.
Duleba AJ, Miller D, Taylor G, et al. Expectant management of choriocarcinoma limited to placenta. Gynecol Oncol. 1992;44(3):277–80.
Black JO, Rufforny-Doudenko I, Shehata BM. Pathologic quiz case: third trimester placenta exhibiting infarction. Intraplacental choriocarcinoma. Arch Pathol Lab Med. 2003;127(8):e340–2.
Tranoulis A, Georgiou D, Sayasneh A, et al. Gestational trophoblastic neoplasia: a meta-analysis evaluating reproductive and obstetrical outcomes after administration of chemotherapy. Int J Gynecol Cancer. 2019;29(6):1021–31.
Stafford L, McNally OM, Gibson P, et al. Long-term psychological morbidity, sexual functioning, and relationship outcomes in women with gestational trophoblastic disease. Int J Gynecol Cancer. 2011;21(7):1256–63.
Acknowledgements
Not applicable.
Funding
This work was funded by National Key R&D Program of China (2023YFC2705800), the National High Level Hospital Clinical Research Funding (2022-PUMCH-A-115).
Author information
Authors and Affiliations
Contributions
Yang Liu participated in data collection, data interpretation, and statistical analyses and wrote the original draft. XCS and Yuan Li conceived the study and participated in the data interpretation and manuscript revision. HZ reviewed and confirmed the pathology slices. FZF, JZ, JJY, TR, XRW and FJ participated in patient enrollment, diagnosis and treatment, investigation, and data provision. YX provided the most cases and participated in data interpretation and manuscript revision. All authors read and approved the final manuscript.
Corresponding author
Ethics declarations
Ethics approval and consent to participate
Written informed consent was obtained from each patient, and this study was approved by the Institutional Review Board of Peking Union Medical College Hospital (K3862).
Consent for publication
Not applicable.
Competing interests
The authors declare that they have no competing interests.
Institutional review board
The study was approved by the Institutional Review Board of Peking Union Medical College Hospital.
Additional information
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.
About this article
Cite this article
Liu, Y., Song, X., Zhang, H. et al. Long-term outcome and fertility results of intraplacental choriocarcinoma: a retrospective study of 14 patients and literature review. Orphanet J Rare Dis 19, 214 (2024). https://doi.org/10.1186/s13023-024-03199-6
Received:
Accepted:
Published:
DOI: https://doi.org/10.1186/s13023-024-03199-6