†These authors contributed equally.
Academic Editor: Gloria Calagna
Background: Choriocarcinoma is a curable malignant neoplasm when
chemotherapy is properly implemented. However, when chemotherapy resistance
occurs, disease can be fatal. Misdiagnosis is common, which may lead to delaying
of the first cycle of chemotherapy and increase the possibility of
chemoresistance. Methods: We analyzed 36 choriocarcinoma cases who were
treated in our department about their clinical characteristics, and their
diagnosis and treatment processes together with the serum
Choriocarcinoma is one of the gestational trophoblastic neoplasias (GTN), a malignant neoplasm mostly generated from trophoblast, or from germ cells for minority. After the application of effective chemotherapy, the 5-year overall mortality rate of GTN reduced from over 90% to about 2% [1, 2, 3]. Nowadays, choriocarcinoma is curable even in patient with distant metastasis. However, drug resistant is always the biggest challenge for the gynecological oncologists to treat the disease, which becomes the most threatening factor for patient’s life. The specific influencing factor is unclear, it is generally accepted that tumor heterogeneity, the inherent characteristic of malignant disease, is the root of choriocarcinoma drug resistance. Delaying of the first line chemotherapy may be one of the causes of cancer cell genetic alteration accumulation, which may increase antitumor treatment tolerance of choriocarcinoma cells . However, misdiagnosis is common in gestational origin choriocarcinoma, because choriocarcinoma is a disease diagnosed mainly based on clinical manifestations, which are often lack of specificity .
The most common clinical manifestations of choriocarcinoma are amenorrhea,
vaginal bleeding and serum
In this study, we retrospectively analyzed 36 cases of choriocarcinoma patients treated in our department (all were referral from lower-level medical institutions) from March 2013 to September 2020. By the means of reviewing and analyzing the clinical characteristics, and the diagnostic and therapeutic process. Because this is a retrospective study, the informed consent of the study was not available. All the patients analyzed in this study had already completed standard treatments of choriocarcinoma, the informed consent of all the treatments were given. In this article, patient anonymity are preserved. This study was approved by our hospital Ethics Committee (Ethical Review Approval No. 251).
All the patients were staged based on FIGO (International Federation of Gynecology and Obstetrics) 2000 staging system, and the chemotherapy regiments were chosen after scoring with FIGO 2000 scoring system.
For clinically diagnosed choriocarcinoma, diseases were considered arisen from
normal pregnancy, spontaneous abortion without molar pregnancy, or from molar
pregnancy over 24 months after the last treatment. Every patients’ specified time
of disease onset were reviewed. For patient with normal pregnancy or any types of
abortion as antecedent pregnancy states, abnormal vaginal bleeding or serum
We calculated the intervals from the disease onset to the first cycle of chemotherapy. T test were carried out to analyze the influence of misdiagnosis on treatments delaying.
Two index were calculated to represent the chemotherapy sensitivity, the
percentage of serum
The intervals from onset to chemotherapy were analyzed with the percentage of
In accordance with the journal’s guidelines, we will provide our data for the reproducibility of this study in other centers if such is requested.
In these 36 cases, the age of onset ranged from 19 to 54 years old (median 32.5 years old), mean age was 34 years old. Because all patients had had sexual life, diseases were considered gestational in origin. Based on FIGO 2000 staging system, 14 cases were in stage I disease (38.9%), 3 in stage II disease (8.3%), 17 in stage III disease (47.2%), and 2 in stage IV disease (5.6%). Based on FIGO 2000 scoring system for gestational trophoblastic neoplasia, nearly half of the stage I and III patients were in low-risk group and the rest in high-risk group. All stage II patients were in low-risk group, and all stage IV patients were in high-risk group  (Table 1).
|All patients (n = 36)||FIGO score|
|Low-Risk (n = 18)||High-Risk (n = 18)|
|FIGO stage, number|
Choriocarcinoma can be developed from any type of gestational event, including molar gestation, and normal or abnormal pregnancy. In this series of patients, 22 were arisen from normal pregnancy, in which 11 from term pregnancy and 3 from spontaneous abortion. 7 patients were arisen from molar disease and 3 from invasive molar pregnancy. There was 1 patient who denial history of pregnancy, but had sexual life for more than 1 year  (Table 2).
|All (n = 36)||Misdiagnosed|
|Yes (n = 20)||No (n = 16)|
|Parauterine or Vagina||1||1||0|
|Antecedent pregnancy status|
|Invasive Molar Pregnancy||3||1||2|
|No Pregnancy History||1||1||0|
|Disease be misdiagnosed as|
|Abnormal Uterine Bleeding||1|
|Upper Respiratory Tract Infection||1|
The most common initial site of disease was uterine canal, with or without myometrial invasion shown in imaging examination, account for 77.8% of all the cases, the same as the data shown in other studies. Primary origin out of the uterine canal was rare, including 2 on ovary, 1 on fallopian arch, and 2 cases had lung metastasis lesion only. 2 stage IV cases with widespread metastasis were not able to identify the primary origins when diagnosed (Table 2).
In order to analyze the difficulties of choriocarcinoma diagnosis, we reviewed
the initial symptoms of these 36 patients. 42% of our patients referred to the
hospital due to abnormal vaginal bleeding, in which 4 with amenorrhea along with
58.3% of these 36 patients were diagnosed combined with medical history, clinical manifestations, imaging features and laboratory examinations. Notably, there were up to 9 cases diagnosed without pathology accepted vacuum extraction or uterine curettage but failed to obtain pathological samples. Among the remaining 41.7% patients who had pathological diagnosis, 7 cases accepted vacuum extraction or uterine curettage, 8 cases underwent surgical resection of the metastatic lesions.
Although pathological diagnosis is important, diagnosis based on clinical appearance is more practical and widely accepted in choriocarcinoma . Because of the lack of specific clinical manifestations to distinguish different types of malignant trophoblastic disease, the diagnosis of choriocarcinoma is a big challenge for the gynecological oncologists.
Up to 20 cases in these 36 choriocarcinoma patients were misdiagnosed at their
initial visits to the hospital. 9 patients had elevated serum
The immediate consequences of misdiagnosis were unnecessary invasive examination or even operations. In this study, only 1 in 6 patients who were misdiagnosed as ectopic gestation escaped from operation, other 5 patients suffered from laparoscopic lesion resection, including 1 extreme case who accepted laparoscopic salpingotomy twice. Patients misdiagnosed as inevitable abortion or missed abortion received 1 to 3 times of vacuum extraction or uterine curettage, including 2 cases further suffered from hysteroscopic electrocision in order to remove the intrauterine residue. All these excessive examinations or operations not only increased the suffering of patients, but also could delay the chemotherapy.
Compared to the patients who were successfully diagnosed at the initial treatment, the intervals from the disease onset to the first chemotherapy cycles of the patients misdiagnosed were inevitably extended from 5–65 days to 19–491 days (mean interval 17 days vs. 70 days, p = 0.0078) (Fig. 1).
Misdiagnosis delayed the chemotherapy of choriocarcinoma patient. The interval from choriocarcinoma disease onset to the first cycle of chemotherapy, the intervals of misdiagnosed patients were significantly longer than correctly diagnosed patients.
Whether the delaying of the treatment influenced the sensitivity of chemotherapy
or not? The prognosis of the patients and the tumors’ response to chemotherapy
are suitable for evaluation. Because of the small sample size of this study, only
4 patients relapsed until now, so that we were not able to analyze the prognosis.
We further analyzed the correlation between interval from disease onset to the
first chemotherapy cycle and the patient’s sensitivity to chemotherapy. Although
the differences were not statistical significant, data showed that the longer the
interval was, the less the rate of serum
Delaying of chemotherapy may reduce the drug sensitivity of
choriocarcinoma patient. The interval from choriocarcinoma disease onset to the
first cycle of chemotherapy were reversely correlated with the serum
Delaying of chemotherapy may increase the drug resistance of
choriocarcinoma patient. The interval from choriocarcinoma disease onset to the
first cycle of chemotherapy were correlated with the cycle number of chemotherapy
needed for serum
Retrospectively reviewed of every patients’ chemotherapy regiments, the times of regimen changing also demonstrated that misdiagnosis would make the cure much more difficult. In patients who were misdiagnosed, more patients received more than 1 regiment because of chemoresistance (10 in 20 patients vs. 6 in 16 patients), although more data were needed to carried out statistical analysis.
In our cohort, there were 5 cases of term pregnancy after the completion of choriocarcinoma treatment more than 2 years, all had healthy babies. 3 cases began with single agent Act-D (Actinomycin-D) or 5-Fu (5-Fluorouracil), in which only 1 was cured by single agent Act-D, 1 change into Act-D/5-Fu and 1 into EMA/CO regiment. Other 2 cases began with Act-D/5-Fu regiment, but adjusted to EMA/CO.
Choriocarcinoma is one of the malignant trophoblastic neoplasms, which has the potential for local invasion and distant metastasis. Choriocarcinoma can be gestational or nongestational, all the 36 patients treated in our department from March 2013 to September 2020 were diagnosed as gestational choriocarcinoma. The morbidity of gestational choriocarcinoma ranged from 1 to 9.3 in 40,000 pregnancies from data of different areas [11, 12]. One of the most important prognostic factors of choriocarcinoma patients is chemotherapy sensitivity. Up to now, studies for choriocarcinoma chemoresistance only mentioned about the predicted values of FIGO score and FIGO stage . No study showed the influence of misdiagnosis on these patients while differential diagnosis of choriocarcinoma was complicated. As the results, we will discuss this matter in our study, in order to show the relationship between misdiagnosis and chemoresistance in choriocarcinoma patients.
Retrospect analyzed of the FIGO stage of our cohort showed the same distribution as previous studies (Table 1). Utilization of lung computed tomography scan (CT) in choriocarcinoma patient results in high sensitivity of detecting pulmonary nodule, but the relatively low specificity makes it over-diagnosed of stage Ⅲ disease. Therefore, patients’ FIGO staging were not able to predict their prognosis appropriately . It is reported that approximately 50% of choriocarcinomas present after normal pregnancies, 25% after molar pregnancies. In our cohort the data was similar, 61.1% after normal pregnancies and 27.8% after molar or invasive molar pregnancies (Table 2).
Chemotherapy plays the vital role in choriocarcinoma treatment. Every patient diagnosed of gestational trophoblastic neoplasia (GTN) should be scored by FIGO scoring system and divided into low- or high- risk group, which will direct the choose of chemotherapy regiment. For low-risk group patients, single agent chemotherapy may be sufficient, while multi-agent chemotherapy is needed for high-risk group patients. Disease can be curable only with chemotherapy for most patients, but surgery should be considered when chemotherapy refractory disease occur. After appropriate regimen and sufficient cycles of chemotherapy, cure rate of low-risk group patient may approaches 100%. At the same time, with or without surgery and radiotherapy, the cure rate of high-risk group patient may over 90% .
The FIGO scoring system based on patient’s age of disease onset, antecedent pregnancy status, the interval between antecedent and onset, pre-treatment, tumor size and number of metastasis is effective in predicting the patient’s prognosis . From the FIGO scoring we can conclude that the longer the tumor progressed, the more severe the disease will be. Therefore, the interval from disease onset to the first cycle of chemotherapy is important, which may attribute to the accumulation of mutation and tumor heterogeneity.
Chemotherapy sensitivity is one deciding factor of choriocarcinoma patient’s prognosis . Although the mortality rate and recurrence rate are the best indicators of chemotherapy sensitivity, our patient cohort was too small to analyze, so that we needed to find new evidence to verify the influence of treatment delaying on chemotherapy resistance .
In this study, we analyzed the intervals from disease onset to the first cycle
of chemotherapy, data showed that when patients were misdiagnosed, their
treatment would be significantly delayed (Fig. 1). We first calculated the
percentage of serum
The pregnancy outcome of our patients showed the low reproductive toxicity of the most frequently used regiments of choriocarcinoma. Choriocarcinoma patients were mostly in their reproductive age (Table 1), and chemotherapy can be the best treatment for fertility-sparing [20, 21, 22].
There were limitations of this study. First, this is a single center study, because of the low incidence of choriocarcinoma, although we had already enrolled all the patients treated in our department from March 2013 to September 2020, only 36 cases were analyzed. Second, attribute to the high chemotherapy sensitivity of GTN and good prognosis, the sample size of this study was not enough to come to a conclusion of statistically significant. More data were needed in order to increase the value of this study.
Our study demonstrated that the interval from disease onset to first cycle of
chemotherapy influences chemotherapy sensitivity, and misdiagnosis not only lead
to unnecessary examination and operation but also lead to treatment delaying.
Because of the nonspecific symptoms, misdiagnosis of choriocarcinoma is always
the challenge of the gynecological oncologist, the misdiagnosis rate was up to
55.6% according to our data. Choriocarcinoma can be early detected following the
proper treatment process, such as serum
It is important to note that this study only reflect local practice. Because of the low incidence and high chemotherapy sensitivity, only 36 cases were enrolled. We need much more work to provide more reliable data.
LJY—Conceptualization, Methodology, Investigation, Writing - Original Draft. YYC—Conceptualization, Methodology, Investigation, Writing - Original Draft. CXZ—Formal analysis. YZW—Data curation. GFY—Conceptualization, Writing - Review & Editing, Funding acquisition.
This study was approved by The First Affiliated Hospital of Sun Yat-sen University Ethics Committee, Ethical Review Approval No. 251.
This study was supported by grants from the National Natural Science Foundation of China [grant number 81772769], the Guangzhou Science, Technology and Innovation Commission [grant number 201704020125], to Guo-Fen Yang.
The authors declare no conflict of interest.
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