MED-NERD

Gestational Trophoblastic Neoplasia (GTN): Choriocarcinoma 

Outlines:

• Introduction
• Aetiology and risk factors
• Epidemiology
• Pathophysiology
• Histopathology
• Clinical picture
• Diagnosis and evaluation
• Staging
• Differential diagnosis
• Management and Treatment
• Complications
• Prognosis
• References

 

Introduction:

Hippocrates first described gestational trophoblastic diseases (GTDs) in 400 BC. Choriocarcinoma is a rare malignant aggressive gestational trophoblastic tumour. It results from malignant transformation of a molar pregnancy mainly but can develop after all types of pregnancy including normal term pregnancy, ectopic pregnancy or spontaneous abortion. It is characterized by  biphasic malignant proliferation of cytotrophoblast and syncytiotrophoblast with absence of chorial villi. Central necrosis and haemorrhage, cytologic atypia, high mitotic counts, and aneuploidy are common. There are two types of choriocarcinoma which are gestational and non-gestational. Choriocarcinoma mainly occurs in women but may occur in men as part of a mixed germ cell tumour.
Choriocarcinoma occurs one case every 5333 tubal pregnancies, and one case every 1.6 million normal intrauterine pregnancies. Development of tumour occurs variably between 5 weeks and 15 years after gestation or even after menopause. About 0.76–4% of choriocarcinomas developed in ectopic site.
Choriocarcinomas  causes early spread to the uterine muscle layer, nearby blood vessels, and outside of the uterus to nearby organs or to distant organs producing systemic metastasis such as the lungs, brain, liver, or kidneys and chemotherapy is almost always indicated in its treatment.
Serial measurement of Human Chorionic Gonadotropin (βhCG) level considered the most useful marker for diagnosis and follow up.
 
 

Aetiology and risk factors:

Choriocarcinoma develops from abnormal malignant trophoblastic proliferation with hyperplasia and anaplasia mostly occurring after molar pregnancy. Gestational choriocarcinoma occurs following hydatidiform mole, normal pregnancy, spontaneous abortion, ectopic pregnancy, while non-gestational choriocarcinoma develops from pluripotent germ cells.
 
Some risk factors include the following:

1-Age:
GTD occurs in women of childbearing age. The age is considered an important risk factor, younger <20 year old and women >40 have higher rates. However, the risk of choriocarcinoma is lower before age 25, and increases with age until menopause.
 
2-Prior molar pregnancy:
Recurrence rate of hydatidiform mole is high. The overall risk for later pregnancies is about 1% to 2%.
 
3-Family history of molar pregnancies
 
4-Blood types:
Women with Blood types A or AB at slightly higher risk.
 
5-Birth control pills:
Administration of birth control pills increases the incidence of GTD in pregnancy, however this relation is weak and the risk is very low.
 
6-Low levels of vitamin A and carotene during pregnancy

 

Epidemiology:

-Choriocarcinoma is a rare neoplasm.  About 5% of all GTD is choriocarcinoma.
-About 1 per 40,000 pregnant women and 1 per 40 patients with hydatidiform moles will have choriocarcinoma in Europe and North America.
-Approximately  9.2 per 40,000 pregnant patients and 3.3 per 40 hydatidiform moles patients will develop choriocarcinoma.
-In the United States, about 110 to 120 per 100,000 pregnant women develop GTD, mainly  molar pregnancies.
-About 15–20% of patients, after evacuation of complete hydatidiform mole, will be treated for gestational trophoblastic neoplasia (GTN).
-About  2 to 7 pregnancies out of every 100,000  or  1 in 20,000–40,000 pregnant females will develop choriocarcinoma in the U.S.
-Choriocarcinomas nearly 50% presents after term pregnancies, 25% after molar pregnancies, and rarely presents with other  gestational events. It occurs nearly 2-3% after complete moles, and 0.1%–0.5% after partial moles
-About 1 in every 2882 pregnant patients will develop choriocarcinoma in China.
-The risk of developing choriocarcinoma is higher in Asian, African American, and American Indian female patients.
-History of prior complete hydatidiform mole is associated with 100-fold increased risk of developing choriocarcinoma.
-In primary ovarian tumours, Choriocarcinoma  represents less than 0.1%.
-Males between 20 and 30 years of age may develop choriocarcinoma, pure choriocarcinoma represents less than 1% of testicular tumours, and represents 15% of mixed germ cell tumours in testicle.
-Almost 100% cure rate with chemotherapy in low-risk GTN, and about 75% with chemotherapy in high-risk GTN.

 

Pathophysiology:

The mechanism or pathogenesis of choriocarcinoma is still unclear. Some studies showed that cytotrophoblasts act as stem cells and undergoing malignant transformation. These malignant cells differentiates into intermediate trophoblasts and syncytiotrophoblast. This is similar to the normal development of a pre-villous blastocyst occurring in other GTNs. Somatic mutation was not found, but overexpression of p53 and MDM2 was detected in choriocarcinoma.  epidermal growth factor receptor, Ras GTPase-activating protein,  NECC1, DOC-2/hDab2, TIMP3, E-cadherin, p16, and HIC-1 are other genes that may undergo  overexpression or down-regulation via hyper-methylation. HLA-G acts through inactivation of the local immune system and changing microenvironment  of the tumour and is highly detected in choriocarcinoma .
 

See: Breast Cancer

Histopathology:

Gestational choriocarcinomas mostly present with with bulky, destructive uterine masses with extensive haemorrhage and necrosis. Commonly, with deep myometrial invasion leading to perforation of uterus.
Syncytiotrophoblastic cells are characterized by large eosinophilic smudgy multinucleated appearance with large hyperchromatic nuclei, intermixed with cytotrophoblasts. Cytotrophoblastic cells are polygonal cells with distinct borders, with single irregular nuclei. It is a vary vascular tumour without chorionic villi. Choriocarcinoma invades the vessels and spreads throughout the body of uterus.
The malignant cells recapitulate chorionic villous trophoblasts of various types and are arranged in biphasic or triphasic growth patterns (sheets or cords of mononuclear tumour cells “large, intermediate trophoblastic cells with abundant amphophilic to eosinophilic cytoplasm and/or smaller cytotrophoblasts” rimmed by layers of multinuclear syncytiotrophoblastic cells). Focal haphazard arrangement of tumour cells is detected.  Nuclear enlargement, cytologic pleomorphism, and brisk mitotic activity are also detected. Tumour nests are characterized by central areas of haemorrhage and necrosis with viable tumour cells peripherally. Frequently, lympho-vascular tumour thrombi are found.
Immunohistochemically:
Malignant syncytiotrophoblasts display strong and diffuse positivity for hCG and HSD3B1. Tumour cells stain positive for cytokeratin (CK) AE1/AE3. The intermediate trophoblasts express Mel-CAM, MUC-4, and HLA-G. High Ki-67 labelling index more than 90% is also detected.
Choriocarcinoma will also have a mixture of syncytiotrophoblasts and cytotrophoblasts in mixed germ cell tumours with varying components of other germ cell tumours.
After chemotherapy, cytotrophoblasts may predominate leading to difficult diagnosis.
 
 

Clinical picture:

1-Reproductive history : molar pregnancies, spontaneous abortions
2-Due to elevated human chorionic gonadotropin (hCG) levels, patients may complain of :
-Abnormal uterine bleeding
-Hyperthyroidism
-Gynecomastia in males
 
3-Post-menopausal bleeding may be due to choriocarcinoma
4-Symptoms of other organs due to metastasis of choriocarcinoma such as:
Haemoptysis, gastrointestinal (GI) bleeding, abdominal pain or tenderness, abdominal guarding and rebound tenderness due to hemoperitoneum, jaundice as a result of biliary obstruction, haematuria, neurologic symptoms (lethargy, up to coma), vascular purple to blue-black papules or nodules in the lower genital tract due to metastasis, signs and symptoms of haemorrhagic shock due to bleeding.

 

Diagnosis and evaluation:

Assessment of choriocarcinoma include the following:

1-Reproductive history: molar pregnancies, spontaneous abortions, and other gestational events

2-Laboratory tests:
-Complete blood count (CBC)
-Coagulation studies
-Body chemistries
-Renal function panels
-Liver function panels
-Type and screen
-Quantitative hCG:
 In the United Kingdom (UK) and according to the International Federation of Obstetrics and Gynaecology (FIGO) 2000 criteria, patients with hydatidiform or molar pregnancies meeting the following criteria receive chemotherapy for GTD:
-Plateaued or elevated serum hCG after uterine evacuation
-Serum hCG more than 20,000 IU/L 4 weeks (day 1, 7, 14 and 21) following evacuation
-Greater than 10% elevation in serum hCG level over three consecutive weeks
 
-Elevated hCG for more than 6 months after evacuation even when decreasing
 
3-Histologic findings of choriocarcinoma

4-Symptoms and signs suggesting choriocarcinoma:
-Heavy vaginal bleeding
-Evidence of metastases: in lungs (signs and symptoms of pulmonary embolism, haemoptysis),  gastrointestinal or intraperitoneal bleeding, metastases in brain (symptoms of intracranial haemorrhage), or liver.

5-Radiographic evaluation:
-Chest, abdomen, brain, and pelvic computed tomography (CT)/CT scan with contrast or magnetic resonance imaging (MRI) to detect metastasis
-Lung opacities greater than 2 cm.
 
6-Karyotyping/ Genotyping:
-Gestational choriocarcinoma: has paternal chromosome complement.
-Non-gestational choriocarcinoma: has DNA matching  the patient, with occasional karyotype abnormalities.
 

Staging:

Anatomic staging system of choriocarcinoma developed by the FIGO is as the following:
-Stage I: Disease is limited to the uterus.
-Stage II: Disease extended outside the uterus but limited to the genital structures.
-Stage III: Disease extends to the lungs and may or may not involve the genital tract.
-Stage IV: Disease has extended to other distant sites (metastasis).
 
The World Health Organization (WHO) established a risk score added to the FIGO staging system for effective treatment plan.
 
-Low risk if the score is 6 or less and is associated with good prognosis even in case of tumour spread.
-High risk if the score is 7 or more which may require intense treatment even without tumour spread.
 
Patients are classified into low and high risk based on the following criteria:
 
1-Age:
0: Younger than 39 years old
1: Greater than 39 years old
 
2-Antecedent Pregnancy:
0: Mole
1: Abortion
2: Term
 
3-Pregnancy Event to Treatment Interval:
0: Less than 4 months
1: 4 to 6 months
2: 7 to 12 months
4: Greater than 1 year
 
4-Pretreatment hCG (mIU/ml):
0: Less than 1000
1: 1000 to 10,000
2: 10,000 to 100,000
4: Greater than 100,000
 
5-Tumor mass size:
0: Less than 3 cm
1: 3 to 4 cm
2: Greater than 5 cm
 
6-Site of Metastases:
0: None
1: Spleen, kidney
2: GI tract
4: Brain, liver
 
7-Number of Metastases:
0: None
1: 1 to 4
2: 5 to 8
4: Greater than 8
 
8-Previous Failed Chemotherapy:
0: None
2: Single-drug
4: Greater than 2 drugs
 
 

See: Staging of Breast Cancer (TNM system)

Differential diagnosis:

 
-In case of stable low levels of serum hCG, differential diagnosis includes a false positive or "phantom" hCG, pituitary hCG, or quiescent gestational trophoblastic disease
-Normal intrauterine pregnancy should be excluded if serum hCG levels start to rise after evacuation of a hydatidiform mole
-Mixed germ cell tumour
-Placental site trophoblastic tumour
-Solid variant of yolk sac tumour
-Embryonal carcinoma
-Biliary obstruction
-Bladder cancer
-Brain tumours
-Cerebrovascular accidents
-Haemorrhagic cystitis: Non-infectious
-Nephrolithiasis
-Urothelial tumours of the renal pelvis and ureters
-Seminoma
 

Management and Treatment:

1-Medical:

A} Antineoplastic agents:
>GTN are sensitive especially to antineoplastic agents acting in the S phase or the M phase of the cell cycle.
1) Methotrexate (MXTX) (Folex PFS, Rheumatrex): Used as a single agent or as part of multiagent regimens in treatment of GTN. Acts by blocking the conversion of uridine to thymidine.
2)Actinomycin D (Dactinomycin): Used as Methotrexate.  Inhibits DNA, RNA, and protein synthesis.
3)Cyclophosphamide (Cytoxan, Neosar): Used as part of multiagent regimens in treatment especially high-risk metastatic GTN. The active metabolites may involve cross-linking of DNA interfering with growth of both normal and neoplastic cells.
4)Etoposide (Toposar, VePesid): used as Cyclophosphamide. Acts by inhibiting topoisomerase II, breaking DNA strand, arrest of cell proliferation in late S or early G2 portion of cell cycle.
5)Vincristine (Oncovin, Vincasar PFS): Used as Cyclophosphamide. Acts by blocking mitosis.
6)Cisplatin (Platinol): Used in chemotherapy-resistant malignant GTN. Acts by DNA cross-linking formation and denaturation of double helix, inhibiting DNA synthesis and therefore inhibiting cell proliferation.
 
B} Chemotherapy modulating agent:
>Used to decrease the toxic adverse effects of MTX.
1)Folinic acid forms thymidine monophosphate by providing a methyl group to uridine monophosphate, decreasing the effect of MTX on tetra-hydro-folic acid reductase.
2)Leucovorin (Wellcovorin): Used to prevent toxicity from high doses of MTX.
 

According to the Staging:

 
-Low-risk patients (WHO score < 7) and stage I to III choriocarcinoma may be treated with single agent (methotrexate or actinomycin D especially in patients with poor liver function) chemotherapy.
>Monitoring serum hCG levels every week.
>Maintenance chemotherapy for six weeks is administrated after normal serum hCG levels.
>Serum hCG levels are observed once each month for 1 year after  3-4 normal serum hCG measurements.
>Switching from methotrexate to actinomycin D in non-metastatic or metastatic low-risk GTN  in case of developing  rising or plateauing serum hCG levels.
 
-High-risk (WHO score 7 or higher) and stage II to IV choriocarcinoma can be treated with multiple agents of chemotherapy, in addition to adjuvant radiation, and surgery. Patients may have good prognosis with intense treatment:
>The EMA-CO regimen for a 2-week cycle: Administration of combination of etoposide, methotrexate, and actinomycin D in the first week and cyclophosphamide and vincristine (Oncovin) in the second week.
>The EMA-EP regimen: Administration of cisplatin and etoposide instead of cyclophosphamide and vincristine during the second week.
>The EMA-EP regimen can be used if the EMA-CO regimen failed.
>Maintenance of these regimens for at least 6 weeks after a normal serum hCG levels.
>Administration of Corticosteroids (dexamethasone) with systemic effect to reduce brain oedema. This is commonly used in the U.S.
>Neurological intervention for solitary lesions or using stereotactic radiotherapy for multiple lesions or high risk solitary lesions for surgical morbidity is used in the UK at the Charing Cross Hospital and Duke University in North Carolina. This is followed by moderate- and high-dose intravenous methotrexate and intrathecal methotrexate. Doses of methotrexate >600 mg/m2 given intravenously to patients with brain metastases.
>If No irradiation is received, dose of methotrexate in the First day  of the EMA-CO or EMA-EP regimen is increased to 1000 mg/m2.
>15 mg every 6 hours of folinic acid are given within 24 hours after the initiation of methotrexate infusion.
 
-High risk of early death (WHO score >12, large disease burden, major bleeding): treated with low-dose induction etoposide/cisplatin (EP) on days 1 and 2 consisting of 100 mg/m2 of etoposide and 20 mg/m2 of cisplatin, repeated weekly for 1-2 cycles before starting EMA/CO.
 
-Stage IV GTN:
>Multiple agents of chemotherapy.
>After 3-4 consecutive weekly normal serum hCG levels, observation of serum hCG levels monthly for 2 years.
If hCG levels are rising during follow up, evaluation for intervening pregnancy, or persistent or recurrent disease should be done.
 
-In case of relapse after chemotherapy with EMA/CO, other protocols with or without surgery such as high-dose chemotherapy with peripheral stem cell transplant may be used.

-It was suggested to receive prophylactic dose of methotrexate in case of persistent hydatidiform mole with or without metastasis in noncompliant patients.
 

 
New therapeutic agent >Immune therapy:

- Avelumab in Chemo-resistant Gestational Trophoblastic Neoplasia (TROPHIMMUN) is a small phase II clinical trial showing that GTD resistant to chemotherapy may respond to Avelumab.

-Avelumab  acts by blocking PD-L1, which is a protein overexpressed in GTN.
- The study was done by the author Benoit You, MD, PhD, Centre Hospitalier Lyon-Sud and Lyon Investigational Center for Treatments in Oncology and Haematology, Lyon, France.
>The study included 15 women, median age 34, with GTD resistant to chemotherapy, 53% had earlier stage, and 47% had stage III of the disease.
>The participants were given Avelumab.
>If levels of hCG returned to normal after receiving Avelumab, patients were given additional 3 cycles of the drug to destroy remaining neoplastic cells.
>8 patients out of the 15 participants were considered cured after achieving normal levels of hCG.
>After follow up for 29 months, no recurrence of the disease was detected and levels of hCG were still normal.
>One woman had healthy pregnancy, the remaining 7 participants received different chemotherapeutic agent or surgery.
>Side effects of Avelumab commonly were: nausea, vomiting, fatigue, and infusion-related reactions. Side effects of Avelumab were milder than those of chemotherapy.
>The study concluded that Avelumab is promising in treatment of GTD resistant to first-line chemotherapy.
 
 

2-Surgical:

>In case of uncontrolled vaginal bleeding, hysterectomy is performed. Hysterectomy also reduces the number of chemotherapy cycles  needed for treatment.
>Embolization of the feeding vessel or uterine or hypogastric artery ligation to control hemorrhage.
>If hepatic metastases is found, hepatic artery embolization may be useful to control hemorrhage.
>Laparotomy may be required to control bleeding in organs like liver, spleen, kidney.
>If persistent tissue on pelvic ultrasonography is found, repeat D&C may reduce the number of chemotherapy cycles required for treatment.
>Neurosurgery or Craniotomy may be performed to  control bleeding and produce decompression.
>Resection of solitary metastasis such as thoracotomy may help in controlling the disease.
 

3-Radiotherapy:

>In case of metastasis to the brain, patients receive whole brain irradiation (3000 cGy) in combination with chemotherapy.
>Liver irradiation (2000 cGy) in case of liver metastasis.
 

4-Follow Up:

-Quantitative hCG levels should be measured once per week until 4 normal levels are detected.
-Then, serum hCG levels should be monitored monthly for one year with physical examination twice in the same duration.
-Serum hCG level monitoring monthly for 2 years after 3-4 consecutive weekly normal values in stage IV patients.
-Using a reliable method of contraception.
-In subsequent pregnancies: pelvic ultrasound in first trimester should be performed due to risk of recurrent choriocarcinoma.
-Histologic examination of placenta to exclude recurrence.
 
 
 

Complications:

The cure rate is usually high in patients receiving chemotherapy. Choriocarcinoma can lead to death if treatment is not initiated. Complications of chemotherapy include development of secondary malignancies, diarrhoea, nausea, vomiting, hair loss, infections, fever, and the need of Blood Transfusion.
 

 

Prognosis:

-Low risk  gestational choriocarcinoma has survival rate of nearly 100%  if patients treated with chemotherapy.
-High risk gestational choriocarcinoma has survival rate of 91% to 93% if patients treated with multiple chemotherapeutic agents with or without  radiation and surgery.
-Stage IV or cumulative score greater than 12 in females have high risk of death.
-The non-gestational choriocarcinoma has a much worse prognosis as it is  much less chemosensitive.
-A very poor prognosis in case of intra-placental choriocarcinoma with metastasis to the infant, with less than 20% survival rate.
 
 

See: Breast Cancer

See: Reye Syndrome ( Fatty Liver With Encephalopathy)

See: Antibiotic Resistance

References:

(1)Bishop BN, Edemekong PF. Choriocarcinoma. [Updated 2022 Aug 8]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2022 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK535434/ 
(2)Meddeb S, Rhim MS, Zarrouk W, Bibi M, Yacoubi MT, Khairi H. Unusual gestational choriocarcinoma arising in an interstitial pregnancy. Int J Surg Case Rep. 2014;5(11):787-8. 
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4245668/
(3)Gestational Trophoblastic Disease, American Society of Clinical Oncology (ASCO)
https://www.cancer.net/cancer-types/gestational-trophoblastic-disease/statistics#:~:text=Choriocarcinoma%20occurs%20in%20about%202,pregnancies%20in%20the%20United%20States
(4)Soper, John T. MD. Gestational Trophoblastic Disease: Current Evaluation and Management. Obstetrics & Gynecology: February 2021 - Volume 137 - Issue 2 - p 355-370.
https://journals.lww.com/greenjournal/Fulltext/2021/02000/Gestational_Trophoblastic_Disease__Current.22.aspx
(5)Enrique Hernandez, MD, FACOG, FACS, Gestational Trophoblastic Neoplasia, Medscape.
https://emedicine.medscape.com/article/279116-overview 
(6)Hui P. Gestational Trophoblastic Tumors: A Timely Review of Diagnostic Pathology. Arch Pathol Lab Med. 2019 Jan;143(1):65-74. 
https://meridian.allenpress.com/aplm/article/143/1/65/65395/Gestational-Trophoblastic-Tumors-A-Timely-Review
(7)Shohei Matsuo, Emiko Tomita, Kenjiro Fukuhara, Shogo Kasuda, Koichi Suzuki, Yoshitane Tsukamoto,Metastatic gestational choriocarcinoma in lung incidentally found by hemoptysis and confirmed by DNA genotyping, highly suggesting the index antecedent pregnancy of a girl,Human Pathology: Case Reports,
Volume 18,2019,200345,ISSN 2214-3300.
https://www.sciencedirect.com/science/article/pii/S2214330019300987 
(8)Ngan, HYS, Seckl, MJ, Berkowitz, RS, et al. Diagnosis and management of gestational trophoblastic disease: 2021 update. Int J Gynecol Obstet. 2021; 155(Suppl. 1): 86– 93. 
https://obgyn.onlinelibrary.wiley.com/doi/10.1002/ijgo.13877 
(9)ASCO20 Virtual Scientific Program: Immunotherapy for Colorectal Cancer, Maintenance Therapy for Bladder Cancer, Precision Medicine in Childhood Cancers, Treatment for Gestational Trophoblastic Disease, and Targeted Therapy for Non-Small Cell Lung Cancer, American Society of Clinical Oncology (ASCO).
https://www.cancer.net/blog/2020-05/asco20-virtual-scientific-program-immunotherapy-colorectal-cancer-maintenance-therapy-bladder-cancer