Introduction/Literature Review
Choriocarcinoma belongs to a spectrum of diseases called Gestational Trophoblastic diseases, which ranges from premalignant benign diseases such as complete hydatidiform mole and partial hydatidiform mole to potentially malignant entities such as invasive mole, choriocarcinoma, and placental site trophoblastic tumor (PSTT). The latter, potentially malignant diseases are collectively called gestational trophoblastic neoplasia (GTN). [1] Gestational choriocarcinoma is the most malignant of the GTN. It is composed of malignant trophoblastic cells, which may arise from trophoblastic tissue of term pregnancies, as well as from ectopic gestation and spontaneous or induced abortions. However, 50% of cases arise from hydatidiform mole. [2] Choriocarcinoma is a highly invasive tumor, and at the time of diagnosis, it is often widespread. Lungs are the most common sites for metastasis. Other sites of metastasis include the liver, vagina, kidney, intestines, and brain. Women over the age of 40 are at increased risk for choriocarcinoma. [3] The prevalence is greatest in Asia, Africa, and Latin America and substantially lower in North America, Europe, and Australia. [4] It occurs with a frequency of only one in 40,000 pregnancies in the USA, whereas the incidence in Asia, Africa & Latin America is one in 500 to 1000 pregnancies. Women of blood group A have been shown to have a greater risk than group O women, and there is evidence of particular risk for women of group A married to men with blood group O and women of group O married to group A men, in comparison with combinations of O x O and A x A. [5] The reasons for these specific associations have remained obscure. Women with Blood group B or AB are even said to have a worse prognosis. [6] The clinical presentation of choriocarcinoma can be in the form of vaginal bleeding resulting from the local disease in the uterus or resulting from effects of distant metastasis, which can manifest in a wide variety of symptoms such as hemoptysis, severe abdominal pains, or even stroke-like symptoms. This can apparently make diagnosis difficult in such distant metastasis cases. However, the combination of obstetric history and elevated serum β-HCG usually makes the diagnosis clear. Rarely, though, the use of a CT scan or histology may be necessary for a clear diagnosis. The treatment of choriocarcinoma depends on the classification group the disease falls into according to the WHO and FIGO classifications. [7-8] The classification system is shown in Table 1.
|
Risk factor
|
|
|
Risk Score
|
|
|
|
0
|
1
|
2
|
4
|
|
Age (years)
|
<40
|
≥40
|
-
|
-
|
|
Antecedent pregnancy
|
Mole
|
Abortion
|
Term
|
-
|
|
Interval (end of antecedent Pregnancy to Chemotherapy) in months
|
<4
|
4-6
|
7-13
|
>13
|
|
Human chorionic Gonadotropin (IU/L)
|
<103
|
103-104
|
104-105
|
>105
|
|
Number of metastases
|
1
|
1-4
|
5-8
|
>8
|
|
Site of metastasis
|
Lungs
|
Spleen, Kidney
|
Gastrointestinal tract
|
Brain, Liver
|
|
Largest tumor mass
|
|
3-5cm
|
>5cm
|
-
|
|
Previous chemotherapy
|
-
|
-
|
single drug
|
≥2 drugs
|
Table 1: The classification system by the WHO and FIGO for classifying gestational trophoblastic tumors and treatment protocols
The classification places GTN, including choriocarcinoma, into the low-risk, moderate-risk, and high-risk groups. This scoring system was originally devised by Bagshawe in 1976.6 This group classification not only determines the treatment protocol, but it also suggests the prognosis of the disease. The low-risk group has a score of 0-4, the moderate-risk group has a score between 5 and 7, and the high-risk group has a score of 8 or higher. Low-risk metastatic disease is usually treated with single or multiple drug chemotherapy, while moderate-risk metastatic disease is treated with multiagent chemotherapy. High-risk metastatic disease requires aggressive multidrug chemotherapy. Generally, once a diagnosis of choriocarcinoma is made, it is regarded as a moderate-risk or high-risk metastatic disease, and multiagent chemotherapy is usually recommended. While low-risk disease has cure rates of nearly 100%, high-risk disease has cure rates of about 95%. This makes choriocarcinoma a very interesting cancer as it is one of the few advanced malignancies in medicine that can literally be cured, and hence the need for appropriate treatment.
Treatment Protocols for Gestational Trophoblastic Tumors.
Ideally, consultation with a gynecologic oncologist is required for the treatment of metastatic diseases. Low-risk Metastatic Disease (WHO score: less than 6). Women belonging to this low-risk group must receive intramuscular methotrexate. Methotrexate is administered intramuscularly, alternating daily with folinic acid for 1 week, followed by 6 rest days. Chemotherapy is changed from methotrexate to intravenous dactinomycin if the HCG level plateaus (implying resistance to methotrexate) or if toxicity to methotrexate precludes adequate chemotherapy. With the development of metastases or an elevation of β-HCG titers, combination chemotherapy should be started. Treatment is continued for one to two courses past the first normal HCG levels. Moderate-risk patients (WHO score: 5 to 7) Traditionally, moderate-risk patients are treated with multi-agent chemotherapy. The most commonly used combination chemotherapies are MAC (methotrexate, dactinomycin, cyclophosphamide, or chlorambucil) or EMA (Etoposide, methotrexate, and dactinomycin). 9 High-risk patients (WHO score: 8 or Greater). This set of patients usually requires combination chemotherapy with selective use of surgery and radiotherapy. The standard chemotherapy regimen in this high-risk group of patients is EMA/CO (Table 2), in which the drugs like etoposide, dactinomycin, and methotrexate are alternated at a weekly interval with Vincristine and cyclophosphamide. [9] Follow-up After Chemotherapy After chemotherapy treatment, HCG is measured weekly until HCG levels have become normal for 3 consecutive weeks, followed by monthly determination of HCG levels until they have become normal for 24 consecutive months (2 years). In the UK, follow-up continues indefinitely because it is unclear when it is safe to stop. However, in other countries, time varies from one center to the other.[10] Women are therefore advised not to become pregnant for 12 months following chemotherapy treatment because this may interfere with early detection of relapsed disease and also to reduce the risk of delayed teratogenicity. [11] The commonly used regimen for resistant disease is EP/EMA (Table 3).
|
Regimen 1 (EMA)
|
|
Week 1 – Day 1
|
- Actinomycin D 0.5mg IV bolus
- Etoposide 100 mg/m² IV in 500 ml N saline over 30 minutes
- Methotrexate 300 mg/m² IV in 1 liter of NS over 12 hours
|
|
Day 2
|
- Actinomycin D 0.5mg IV bolus
- Etoposide 100 mg/m² IV in 500 ml N saline over 30 minutes
- Folinic acid 15mg IM 12-hourly x 4 doses starting 24 hours after commencing methotrexate
|
|
Regimen 2 (CO)
|
|
Week 2 - Day 1
|
|
Open-label studies
|
Table 2: EMA/CO regimen for high-risk patients with gestational trophoblastic disease
|
Regimen 1 (EP)
|
|
Week 1 – Day 1
|
- Etoposide mg/m² IV in 500 ml N saline over 30 minutes
- Cisplatin mg/m² IV over 4 hours
|
|
Regimen 2 (EMA)
|
|
Week 2 – Day 1
|
- Etoposide 100 mg/m² IV over 30 minutes
- Methotrexate 300 mg/m² IV over 24 hours
- Actinomycin D 0.5mg IV bolus
|
|
Day 2
|
- Folinic acid 15mg PO 12-hourly for four doses
- (to start 24 hours after starting methotrexate)
|
Table 3: EP/EMA regimen for patients with disease resistant to EMA/CO
Choriocarcinoma Case Report
The patient was a 32-year-old para 3+1 A3 at presentation. She presented in October 2018 with a 2-month history of intermittent vaginal bleeding and a 10-day history of hemoptysis. She had her last delivery (uneventful vaginal delivery) in June 2018 associated with normal lochia flow for 4 weeks. This intermittent vaginal bleeding then started about 7 weeks after cessation of normal lochia. There was no associated cough or dyspnea, but there was associated abdominal discomfort with excessive bowel movement. Essential findings on examination were moderate pallor, vital signs were within normal range, and the chest was clinically clear. Vaginal examination revealed a darkish red suburethral vaginal nodule measuring about 3 cm in diameter. An urgent serum and urinary pregnancy test (neat & dilution) was ordered, as our laboratory did not have the facility for serum β HCG assay then, and the result came out to be positive both in neat and dilutions. A diagnosis of Choriocarcinoma was made, and further investigations were ordered. Chest x-ray revealed right basal consolidated changes. Her packed cell volume (pcv) was 34%. Serum electrolytes, urea & creatinine levels were within normal limits. Liver Function Tests (LFTs) were also within normal limits. Platelet count was normal. A prognostic scoring classification was carried out and she was scored at 5 (moderate-risk patient).
She was then counseled and commenced on chemotherapy as follows: -
a. Intramuscular methotrexate 15mg daily x 5 days
b. Intravenous Actinomycin D 600mg daily x 5 days
c. Intravenous cyclophosphamide 150mg daily x 5 days
She was made to stop breastfeeding before the commencement of chemotherapy. The above chemotherapy regimen is called the MAC regimen (although it is a modification of the original MAC III regimen). For this patient, it was repeated every 2 weeks for a total of 5 courses. At each follow-up visit for a course of chemotherapy, she was investigated, and the pcv, platelet count, serum electrolytes, urea & creatinine, and LFT were found to be normal before the commencement of each course of chemotherapy. She was also monitored at each follow-up visit with serum and urinary pregnancy test results, neat and in dilution. After the 5th course of chemotherapy, the pregnancy test was found to be negative both neat & in dilutions. The chemotherapy was then stopped, & she was given a 3-month appointment to come back with serum β hcG assay to be done in a private laboratory in Owerri, the capital city of Imo State. She was also counseled against getting pregnant again & was advised to have bilateral tubal ligation (BTL), which she objected to, and she was then placed on temporary contraception (COC Pills) to prevent pregnancyso as to allow reliable monitoring of serum β hcG due to persistent or recurrent trophoblastic disease. When she reported at the 3-month appointment, her β hcG assay done in a private lab in Owerri was 2.5miu/ml (Negative: ≤5.0 miu/ ml). No history of abnormal vaginal bleeding, and her chest was clinically clear, and a repeat chest x-ray revealed no abnormalities. She was discharged from the clinic & told to continue the COC Pills for another nine months (making a total of 12 months) & told to come back in 6 months for review. Surprisingly, this woman presented in October 2020 pregnant, at 25 weeks gestation! This was about 1 year and 3 months after she was certified cured from the choriocarcinoma. She had an uneventful pregnancy and was eventually delivered of a live female baby per vaginum on 21/1/2021. She was counseled again for bilateral tubal ligation (BTL) soon after delivery, which she consented to this time around, and on the third day postpartum, she had BTL. She has been followed up now for close to 1 year, including one serum β hcG level of 2.0 mIU/mL.
Discussion
Not surprisingly, this woman presented with abnormal vaginal bleeding many weeks following the cessation of lochia. This is probably one of the most common presentations of choriocarcinoma [11]. Choriocarcinoma should always be suspected if a woman starts bleeding abnormally per vaginum some weeks following the cessation of lochia. Although the time interval between the antecedent pregnancy and the diagnosis of choriocarcinoma is usually short, there are occasional patients with documented asymptomatic periods of 5-17 years between the last known pregnancy and the diagnosis of choriocarcinoma. Another common symptom this woman presented with was hemoptysis, which is a symptom of lung metastasis, although the chest x-ray carried out on her did not reveal the classical cannonball metastases but rather revealed right basal consolidation, which is probably a sign of early lung metastasis. The suburethral vaginal reddish nodule seen in this woman is another common presentation in choriocarcinoma, which further raised the suspicion for choriocarcinoma in her. Grossly elevated serum β hcG level is essential for the diagnosis of choriocarcinoma, as a normal serum β hcG level in this woman would have excluded choriocarcinoma. Unfortunately, when this woman presented, there was no facility for detection of serum β hcG level in our center, which led to the alternative use of pregnancy test positivity or negativity in both neat and dilutedurine samples. Persistent pregnancy test positivity in the more diluted urine samples is indicative of higher serum β hcG levels. Though this later method of assessing β hcG levels may be considered crude, it is quite reliable in making a diagnosis of choriocarcinoma in high urine dilutions combined with the clinical features of choriocarcinoma as seen in this patient. With this, we made a presumptive diagnosis of choriocarcinoma, and treatment was started, as further delay may be inimical to the patient’s life. However, for follow-up of treatment, she was referred to a private laboratory in the state capital for serum β hcG assay whose result is essential for making a diagnosis of cure. The combination chemotherapy adopted by us in the treatment of this patient is the MAC based combination chemotherapy (Methotrexate, dactinomycin, cyclophosphamide, or chlorambucil), which is one of the most commonly used chemotherapies for choriocarcinoma [10]. The original MAC therapy, “Li’s triple therapy,” was introduced by Li Mc in 1971 in which methotrexate, dactinomycin, and chlorambucil were the three cytotoxic drugs [13]. Li’s triple therapy was later modified by Berkowitz and Goldstein in 1987 who substituted chlorambucil for cyclophosphamide and called it MAC III [14]. In the MAC 111 regimen, however, the methotrexate dose was higher (1 mg/kg body weight IM), and because of this, it is given along with folinic acid (citrovorum rescue factor) to reduce the toxic effects of methotrexate. In this patient, however, we used IM methotrexate of 15mg daily, as folinic acid was not readily available to reduce the possible toxic effects of methotrexate. Gladly, this patient did very well with our regimen. Although, it is recommended that treatment is continued for one or two courses past the first normal hcG level10, we did not see any further need to do this in this case as her response to treatment was very good and we made sure we saw her 3 months after the last course that revealed normal β hcG levels and gracefully, at that visit her serum β hcG level was normal. This case further confirmed that patients successfully treated with chemotherapy for choriocarcinoma can expect normal reproduction in the future[15], although we preferred an end to her reproductive career being para 3 at the end of her successful chemotherapy, she declined bilateral tubal ligation.
Conclusion
Gestational choriocarcinoma is a potentially very fatal malignancy, but luckily, it can be diagnosed early enough with a β serum hcG assay or with a simple urine pregnancy test measurement in neat and dilutions, especially when it is combined with well-known clinical features of it. Multiple chemotherapy remains the mainstay for its cure, and even a modified form of MAC III as we used in this case, in which a lower dose of methotrexate is used, is feasible.
