Gestational Trophoblastic Neoplasia
last authored: Dec 2010, Alison Martin
last reviewed: June 2011, Jenn Schnarr
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Introduction
Gestational trophoplastic neoplasias (GTN) fall under the larger category of gestational trophoblastic disease, which includes the tumour spectrum of hydatidiform moles (complete and partial), invasive moles, choriocarcinomas and placental-site trophoblastic tumours (PSTT). This article will review the latter two conditions in this list, choriocarcinoma and PSTT, which make up part of the GTN category. These tumours are quite unique as they arise from the trophoblastic tissue of the fetus as it develops in the maternal host. The development of this tumour is attributed to an aberrant fertilization event and may accompany or follow any type of pregnancy. Both malignancies are quite rare and unfortunately have little epidemiologic data available. Estimates for choriocarcinomas in Europe and North America say that the disease affects 1 in 40,000 pregnancies, (Lurain, 2010), while in South East Asia and Japan the number of affected pregnancies is 9.2 and 3.3 per 40,000 respectively (Goldstein & Berkowitz, 2008). PSTT is very rare with only 200 cases reported in the literature (Hernandez, 2010).
The Case of...
Jane D. is a healthy 37 year old, G2P1 African American woman. Jane was diagnosed and treated for a molar pregnancy when she was 28 years old. She became pregnant again years later and gave birth to a healthy baby girl when she was 36. The second pregnancy was uncomplicated and the baby was delivered vaginally. Eight months after she delivered her daughter she noticed some sporadic, painless vaginal bleeding but she did not seek medical attention as she’d had some irregular periods during her adolescence and ‘did not think it was a big deal’. Ten months following the birth of her daughter, Jane was admitted to hospital with fever, fatigue, shortness of breath and haemoptysis. She reported that she’d been feeling fatigued for the last 3 weeks or so and that she’d noticed she’d lost some weight despite maintaining her normal diet. She told the doctors that the sporadic vaginal bleeding she’d noticed 2 months ago had gotten worse, and that ‘maybe that has something to do with it’. Laboratory and urine tests were ordered, as well as a chest x-ray and a gynecological exam. Urine showed elevated levels of human chorionic gonadotropin (hCG), chest x-ray showed diffuse peripheral infiltrates and pelvic exam revealed blue-black nodules in the vagina. What is on your differential? What tests would you like to do next?
Causes and Risk Factors
All forms of GTN are the result of an aberrant fertilization event and are derived from the human placental trophoblast and the paternal genome with occasional maternal contribution. Risk factors include: Prior complete hydatidiform mole(Lurain, 2010) Asian, American Indian or African American ethnicity (Lurain, 2010) Advanced maternal age (Lurain, 2010) There also seems to be a correlation between increased risk of choriocarcinoma and long term oral contraceptive use and women with type A blood. (Lurain, 2010)
Pathophysiology
Choriocarcinoma is an invasive, highly vascular, anaplastic trophblastic tissue made up of cytotrophoblasts and syncitotrophoblasts that secrete human chorionic gonadotropin (hCG) in high amounts (Goldstein & Berkowitz, 2008). Choriocarcinomas have no villi and the trophoblastic cells are distributed in sheets (Hernandez, 2010). Grossly, these tumours appear red and granular with extensive focal central necrosis and hemorrhage on cut section (Hernandez, 2010)(Li, 2008). Choriocarcinomas can follow any type of pregnancy; 50% follow a molar pregnancy, 25% follow spontaneous abortion or ectopic pregnancy and 25% follow a full-term delivery (Goldstein & Berkowitz, 2008)(Hernandez, 2010). Choriocarcinomas are aneuploid (neoplastic cells have an abnormal number of chromosomes) and can be either of paternal origin or mixed maternal and paternal origin depending on the type of pregnancy from which the neoplasm arose. If a hydatidiform mole preceded the choriocarcinoma (development of choriocarcinoma occurs in 2-3% of women with previous diagnosis of hydatidiform mole), the chromosomes are of paternal origin(Hernandez, 2010). If a term pregnancy preceded the choriocarcinoma, maternal and paternal chromosomes may be present (Hernandez, 2010). It is important to note that gestational choriocarcinoma may not occur until years after the last known pregnancy(Li, 2008). Choriocarcinomas are highly malignant tumours. They rapidly invade the myometrium of the uterus as well as the uterine vessels with systemic metastases resulting from hematogenous embolization. The most common metastatic sites are the lungs, which are involved in 80% of patients(Goldstein & Berkowitz, 2008). Vaginal metastases are noted in 30% of patients(Goldstein & Berkowitz, 2008). Distant metastatic sites such as the liver, brain, kidney, GI tract and spleen are observed in about 10% of cases and constitute the highest risk of death(Goldstein & Berkowitz, 2008). At the time of diagnosis, many patients will already have metastatic lesions to the lungs (Garner, 2011). If metastatic lesions are found in the liver or brain at the time of diagnosis it is extremely likely that vaginal and pulmonary metastases will be present as well (Goldstein & Berkowitz, 2008) Placental Site Trophoblastic Tumour (PSTT) PSTTs are locally derived neoplasms from intermediate cytotrophoblast cells and are very rare (Li, 2008). These tumours show no chorionic villi and are characterized by a proliferation of cells with oval nuclei and abundant eosinophilic cytoplasm(Goldstein & Berkowitz, 2008). PSTTs are endocrinologically different from choriocarcinomas in that they secrete human placental lactogen (hPL) in higher amounts than hCG which can make them hard to detect without a large tumour burden(Hernandez, 2010). PSTTs most commonly arise months to years after a term gestation but may also occur following a spontaneous abortion or molar pregnancy. Also in contrast to choriocarcinoma, PSTTs are most often slow growing and are confined to the uterus(Goldstein & Berkowitz, 2008). However, metastases may occur via hematogenous or lymphatic routes and up to 30% of patients with PSTT present with overt metastatic disease associated with increased mortality(Garner, 2011).
Women with choriocarcinoma versus PSTT will present somewhat differently clinically, radiologically, histologically and hormonally. Because it is so rare, PSTT is most often a diagnosis of exclusion and should be considered with disease refractory to standard chemotherapy(Li, 2008). The indications for treatment/diagnosis of GTN as per the International Federation of Gynecologists and Obstetricians (FIGO) are as follows (Kohorn, 2001): Following a molar pregnancy (and evacuation): A plateau in beta-hCG levels over 3 weeks A 10% or greater rise in beat-hCG levels for three or more values over at least 2 weeks Persistence of beta-hCG levels 6 months after molar evacuation or, Histologic evidence of CCA Following a non-molar pregnancy: Patients who develop rising hCG titres following a non-molar pregnancy have CCA until proven otherwise. hCG following pregnancy is not regularly checked unless the pregnancy was ectopic or molar so women who develop GTN following a normal pregnancy usually only undergo hCG testing once they become symptomatic. It should be noted that any women in the reproductive age group that presents with abnormal bleeding or metastatic disease should undergo hCG screening to rule out CCA. At this point a thorough clinical and radiologic evaluation of the patient should be carried out to determine the extent of the disease. Rapid growth, widespread dissemination and a high propensity for hemorrhage make this a medical emergency.
Signs and Symptoms
- history
- physical exam
History
History for potential cases of GTN should include a history of all pregnancies (molar, ectopic, spontaneous abortions and full term) as well as signs and symptoms of GTN. Women with choriocarcinoma will usually present with symptoms associated with metastases (weight loss, headaches, jaundice, lethargy, fatigue, shortness of breath) while women with PSTT may present with abnormal uterine bleeding, a mass in the endometrial cavity or amenorrhea(Hernandez, 2010)(Garner, 2011) In these patients (and those with other forms of GTD), high levels of hCG may cause exaggerated pregnancy symptoms such as frequent vomiting or ‘morning sickness’(Hernandez, 2010).
Physical Exam
Pelvic examination should be performed to identify the presence of vaginal metastases, which will present as purple to blue-black papules or nodules(Goldstein & Berkowitz, 2008). Speculum examination may also be performed, but should be done with great caution, as the risk for hemorrhage with these extremely vascular tumours is high. For this reason, it is usually not necessary to obtain a biopsy of the tumour to confirm the diagnosis(Hernandez, 2010). Signs of hyperthyroidism may be present when there are high levels of hCG as this hormone may stimulate the thyroid. Abdominal tenderness and/or guarding may be present if liver, gastrointestinal metastases or hemoperitoneum have occurred(Hernandez, 2010). Jaundice may be present if liver metastases have caused biliary obstruction(Hernandez, 2010).Headaches, visual disturbance, tingling, numbness or muscle weakness may indicate brain metastases(Hernandez, 2010).
Investigations
- lab investigations
- diagnostic imaging
Lab Investigations
Human Chorionic Gonadotropin Measurement Levels and serial changes in beta-hCG are essential to diagnose and track the treatment and outcome of GTN. hCG is normally synthesized by syncytiotrophoblastic cells of the developing placenta, however, in GTN it is suspected that a hyperglycosylated hCG (hCG-h) is produced by cytotrophoblasts (Goldstein & Berkowitz, 2008). hCG is a glycoprotein and has an alpha subunit common to other glycoproteins as well as a beta subunit that is hormone specific. Measurement of hCG in patients with GTN must be performed by assays that measure the b-subunit only (Goldstein & Berkowitz, 2008) (Hernandez, 2010). After evacuation of a molar pregnancy b-hCG levels should drop in 8-10 weeks. Persistent b-hCG suggests local or metastatic disease. b-hCG can be monitored through the urine or serum. During treatment these levels should be checked weekly in the same laboratory to judge response to treatment(Li, 2008). False b-hCG results occur due to the presence of heterophile antibodies that interfere with the immunoassay. This is rare, but can be confusing. A false positive should be suspected if the clinical picture and lab results don’t coincide, if there is no identifiable antecedent pregnancy or if patients undergoing treatment with persistent low levels do not respond appropriately(Hernandez, 2010). Histology Due to the risk of hemorrhage, biopsy is not required for confirmation of diagnosis if the clinical picture fits the diagnosis of GTN(Hernandez, 2010). Other Once it is determined that a patient has an elevated and rising hCG level a thorough evaluation is required to determine the extent of the disease including blood tests to assess renal and hepatic function, peripheral blood counts and baseline serum b-hCG levels(Garner, 2011).
Diagnostic Imaging
Pelvic ultrasound and chest imaging are the most important for the diagnosis and evaluation of GTN. The pelvic ultrasound is required to exclude intrauterine pregnancy, look for evidence of retained trophoblastic tissue and to evaluate the pelvis for local spread of disease(Li, 2008). Pulmonary metastasis is quite common in women with choriocarcinomas and chest imaging is required to evaluate potential spread of the disease. Computed Tomography (CT) scans can detect pulmonary metastases in up to 40% of patients with a negative x-ray, however CT is not mandatory, especially if detected of metastases will not alter the treatment plan(Hernandez, 2010). If there is no evidence of metastases to pulmonary and vaginal sites, further imaging of the liver and brain is not mandatory as metastases to these sites are rare in cases where vaginal and pulmonary metastases have not occurred(Hernandez, 2010) CT or magnetic resonance imaging (MRI) of the brain is recommended in women with persistent disease who have vaginal or lung metastases and in all patients with a pathological diagnosis of choriocarcinoma(Li, 2008). PET scanning is sometimes indicated to identify sites of active disease(Hernandez, 2010).
Differential Diagnosis
Biliary obstruction Bladder cancer Brain tumours Cerebrovascular accidents Ovarian choriocarcinoma Pregnancy Urothelial tumours of renal pelvis and ureters Quiescent GTN hCG-secreting germ cell tumours Hemorrhagic cystitis Nephrolithiasis
Treatments
Choriocarcinoma Chemotherapy is highly effective in most patients with choriocarcinoma and represents one of the only cancers for which single agent therapy is still in use(Goldstein & Berkowitz, 2008). The choice of single vs. multi-agent therapy depends on risk category, disease stage and previous drug treatment. Single Agent Chemotherapy Patients with stage I disease have an excellent prognosis with a 5-year survival rate of 99%(Garner, 2011). Treatment in these cases is curative and choice of regimen depends on whether or not preservation of fertility is desired. In women where preservation of fertility is not the goal, a hysterectomy followed by single agent therapy is the most common treatment modality(Holstein & Raymond, 2008). In cases where preserving fertility is important to the patient, single agent chemotherapy is the primary treatment(Holstein & Raymond, 2008). The two most commonly used single agents are methotrexate (MTX) and dactinomycin (actinomycin D). If there is a poor treatment response to either of these single agents, patients can often be managed with second-line therapy of the other agent(Holstein & Raymond, 2008). The first-line treatment of choice for low-risk GTN is MTX(Garner, 2011). There are a variety of dosing regimens used clinically for MTX, however, there is little evidence supporting the superiority of one regimen over the other. MTX is commonly given with leucovorin (folinic acid) to protect against alterations in folate metabolism that can be induced by MTX toxicity(Garner, 2011). A commonly used regimen is as follows: MTX (1mg/kg IM or IV on days 1,3,5,7) and folinic acid (0.1mg/kg PO on days 2,4,6,8)(Goldstein & Berkowitz, 2008). After the first course, hCG levels are monitored weekly. If they do not drop 10 fold within 18 days or the hCG plateaus for two weeks, a second course of MTX is required (10%-30% of patients)(Goldstein & Berkowitz, 2008). Although significant MTX toxicity is rare in most dosing regimens, it is important to note that MTX is excreted entirely by the kidneys and may be hepatotoxic. Haematologic indices, renal and liver function should be monitored throughout treatment(Holstein & Raymond, 2008). Dactinomycin is generally used only in circumstances of MTX-resistant, nonmetastatic, malignant GTN or when there is evidence of abnormal liver function(Goldstein & Berkowitz, 2008). Dactinomycin is commonly delivered either in five-day regimens (12ug/kg IV) repeated every two weeks or in single higher doses (1.25mg/m2 IV) given every two weeks(Goldstein & Berkowitz, 2008). Dactinomycin is considered a highly emetogenic agent so prophylactic antiemetic regimens is indicated prior to each dose(Garner, 2011). Multi-Agent Chemotherapy Patients with high-risk metastatic disease are generally managed with multi-agent chemotherapy. Most of these regimens include EMA as their backbone. This therapy includes etoposide (100 mg/m2 IV on days 1 and 2), methotrexate (100mg/m2 IV push, followed by 200 mg/m2 over 12 hr on day 1), and dactinomycin (0.5mg days IV bolus days 1-2) and folinic acid (15 mg IM or PO every 12 hours for 4 doses starting 24 hours after MTX administration)(Holstein & Raymond, 2008). Response rates of 75% have been reported in high-risk patients(Goldstein & Berkowitz, 2008). The most common choice for management of high-risk GTN is EMA/CO, which includes EMA plus cyclophosphamide (600 mg/m2 IV on day 8) and vincristine (1mg/m2 IV on day 8)(Holstein & Raymond, 2008). The regimen is repeated every two weeks until remission and then continued for an additional 3 cycles)(Holstein & Raymond, 2008). Complete response rates with this regimen have been found to be between 71%-80% with an overall survival rate of 85%)(Holstein & Raymond, 2008). EMA/CO is a relatively well-tolerated regimen. Alopecia is generally universal with no life-threatening toxicity(Goldstein & Berkowitz, 2008). MAC is a multi-agent regimen that consists of methotrexate, dactinomycin, and chlorambucil that has been used as a front-line treatment in the past(Holstein & Raymond, 2008). The MAC regimen is considered to have a higher relapse rate than some other regimens. MAC has been used in patients with low-risk disease who are resistant to single-agent front-line therapy(Garner, 2011). A second-line regimen, EMA/EP, has been shown to have an 88% overall survival rate in a study that included patients previously treated with EMA/CO(Holstein & Raymond, 2008). This regimen includes etoposide (100 mg/m2 IV on day 1, 150mg/m2 IV day 8), methotrexate (300mg/m2 IV over 12 hours on day 1), dactinomycin (0.5 mg IV bolus day 1), folinic acid (15 mg IM or PO twice daily for 4 doses starting 24 hours after MTX administration) and cisplatin (75 mg/m2 on day 8) (Holstein & Raymond, 2008). For women resistant to both EMA/CO and EMA/EP, PVB is another second-line regimen(Garner, 2011). PVB consists of cisplatin (20mg/m2/d x 5 days every 3 weeks), vinblastine (0.15 mg/kg IV days 1-2), and bleomycin (30 units IV day 2, then weekly)(Garner, 2011). Remission rates from 20% - 57% have been reported for PVB(Holstein & Raymond, 2008). Other reported regimens include: ICE (ifofosamide, carboplatin, etoposide), BEP (bleomycin, etoposide, cisplatin), VIP (ifofosamide, etoposide, cisplatin), 5-FU and dactinomycin, single-agent paclitaxel, and paclitaxel/etoposide/cisplatin(Holstein & Raymond, 2008). In summary, low-risk, nonmetastatic disease is treated with single-agent chemotherapy. For high-risk disease multi-agent EMA/CO is the most widely used regimen. However, it should be noted that there is a lack of randomized phase III trials that aid in guiding therapy choices(Holstein & Raymond, 2008). Also, there has been significant concern regarding the risk of secondary malignancies associated with the use of eptoposide(Holstein & Raymond, 2008). Although cure rates remain high for a wide spectrum of patients with GTN, further clinical trials are required to develop optimal chemotherapy regimens(Holstein & Raymond, 2008). PSTT Primary treatment of patients with PSTT is a hysterectomy because of their relative resistance to chemotherapy(Goldstein & Berkowitz, 2008). Because the disease infiltrates deeply into the myometrium, lymph node sampling is recommended at the time of hysterectomy(Goldstein & Berkowitz, 2008). Excellent results have been achieved with EMA/EP in patients with lymphatic spread of extrauterine disease(Goldstein & Berkowitz, 2008).
Consequences and Course
Both choriocarcinoma and PSTT have the ability to locally infiltrate the myometrium as well metastasize via hematogenous and lymphatic routes. In patients with choriocarcinoma, it is very common to find metastases to the lungs, although the vagina, brain, liver, spleen and GI tract may also be involved. If left untreated, life-threatening complications such as respiratory failure or CNS hemorrhage may occur.
Resources and References
Lurain, John R. "Gestational Trophoblastic Disease I: Epidemiology, Pathology, Clinical Presentation and Diagnosis of Gestational Trophoblastic Disease, and Management of Hydatidiform Mole." American Journal of Obstetrics and Gynecology (2010). Pubmed. Web. Goldstein, Donald P., and Ross S. Berkowitz. "Gestational Trophoblastic Diseases." Cancer: Principles & Practice of Oncology. By Vincent T. DeVita, Samuel Hellman, and Steven A. Rosenberg. 8th ed. Vol. 2. Philadelphia, PA: Wolters Kluwer /Lippincott Wiliams & Wilkins, 2008. 1564-567. Print. Hernandez, Enrique. "Gestational Trophoblastic Neoplasia." Emedicine. Medscape Reference, 16 Mar. 2010. Web. <http://emedicine.medscape.com/article/279116-overview>. Li, Andrew J. "Gestational Trophoblastic Neoplasms." Danforth's Obstetrics and Gynecology. By Ronald S. Gibbs and David N. Danforth. 9th ed. Philadelphia: Lippincott Williams & Wilkins, 2008. Print. Garner, Elizabeth IO. "Malignant Gestational Trophoblastic Disease: Staging and Treatment." UpToDate Inc. Ed. Barbara Goff. 14 Feb. 2011. Web. 25 Mar. 2011. <http://www.uptodate.com/>. Kohorn, EI. “The new FIGO 2000 staging system and risk factor scoring system for gestational trophoblastic disease: description and clinical assessment.” Int J Gynecol Cancer 2001;11:73 Holstein, Sarah A., and Raymond J. Hohl. "Chemotherapy of Gynecologic Cancers." The Chemotherapy Source Book. By Michael C. Perry. Philadelphia: Wolters Kluwer Health/Lippincott Williams & Wilkins, 2008. 447-63. Print.
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