In simplest terms, gestational trophoblastic disease (GTD) represents a spectrum of diseases which arise from abnormal trophoblastic tissue. This ranges from the benign hydatidiform mole (“molar pregnancy”) through to the malignant invasive mole, choriocarcinoma and placental site tumors (PSTT). Although these diseases are relatively rare, GTD is a highly curable disease process; nonetheless, accurate diagnosis and careful follow-up is essential in order to maximize the outcome for these patients. The classification system of GTD can be confusing and has undergone many different iterations. Recently, the International Federation of Gynecology and Obstetrics (FIGO) reissued new guidelines for the staging and diagnosis of GTD in hopes of trying to standardize the diagnosis and allow for more accurate comparison across different centres.
Hydatidiform moles may be complete or partial, the former being the most common. Complete and partial hydatidiform moles are noninvasive, localized tumours that develop as a result of an aberrant fertilization event. They comprise 90% of GTD cases. The incidence of molar pregnancies ranges from 1:200-1:1000 pregnancies. There may be a higher incidence of molar pregnancies in Africa and Asia; however the varying standards in the frequency and accuracy of pathology and demographics make accurate comparisons difficult. The relative risk of molar pregnancy is highest in those pregnancies at the extremes of the reproductive age group. There is a modestly increased incidence in teenagers (1.5 fold) but a 10 fold increased risk in those aged 40 and over.
Traditionally, given the diagnosis was made at a later stage, the uterus was found to be large for gestational age and could be associated with other findings such as symptomatic theca luteal cysts, hyperemesis or hypertension. These findings are less commonly seen these days. Most patients will present with abnormal vaginal bleeding and a positive hCG, raising the suspicion of a complication of early pregnancy. Typically, a pelvic ultrasound is ordered to evaluate fetal viability and rule out the presence of an ectopic pregnancy, which often results in findings suspicious of a molar pregnancy. Partial moles are often not suspected preoperatively and are only identified following uterine curettage for a presumed non-viable pregnancy (i.e. missed abortion) and upon histological review, a partial molar pregnancy is confirmed.
The majority of women with complete and partial molar pregnancies will follow a benign course after evacuation; however, three categories of GTD are considered to represent malignant disease because of their potential for local invasion and metastatic spread. Malignant GTD is often referred to as gestational trophoblastic neoplasia (GTN) to distinguish it from the benign forms of GTD, and can develop from a molar pregnancy or can arise after any gestational event, including a spontaneous or induced abortion, ectopic pregnancy or term pregnancy. Persistent GTN is usually diagnosed in asymptomatic women undergoing routine hCG monitor following evacuation of a molar pregnancy, accounting for greater than 90 percent of malignant GTN. Rates of persistent disease range from 15-25% after a complete mole and the majority of this is localized disease. About 4% of women will have metastatic disease. In contrast, only 0.5-5% of patients develop persistent disease after a partial mole. While GTN is rare after a partial mole, both localized or metastatic disease has been reported, emphasizing the importance of appropriate follow-up.
Complete Mole (CM)
In most complete moles the genetic material is entirely male in origin and results from the fertilisation of an empty ovum lacking maternal genes. The chromosome complement is most commonly 46XX, which results from one sperm that duplicates its DNA, or less frequently 46XX or 46XY from the presence of two different sperm. On very rare occasions CM can be biparental with genetic contributions from both the mother and father. Although extremely rare, biparental molar pregnancies are associated with a high risk of further molar pregnancies and patients who have had more than 2 molar pregnancies may benefit from investigation for a hereditary predisposition to molar pregnancies.
Partial Mole (PM)
Partial moles are triploid with 2 sets of paternal and 1 set of maternal chromosomes as shown in Fig 1. Macroscopically PM may resemble the normal products of conception with initially an embryo present, which dies by week 8-9. The histology shows less swelling of the chorionic villi than in complete mole and there are usually only focal changes. As a result the diagnosis of PM can often be missed after an apparently straightforward miscarriage or termination.
The possibility of GTD should be considered in any premenopausal woman with abnormal vaginal bleeding.Investigations prior to evacuation of a presumed molar pregnancy should include: 1) a quantitative serum beta-hCG to establish a baseline titre prior to evacuation, 2) a blood group to ascertain Rhesus (Rh) factor status and 3) a chest x-ray (CXR) to exclude pulmonary metastases. Typically, an ultrasound has already been performed once an elevated hCG is identified in order to rule out a normal intrauterine pregnancy, ectopic pregnancy or spontaneous abortion. Other investigations may be necessary depending on the clinical scenario and these include a full blood count, thyroid function tests, coagulation panels, renal and liver function tests. In addition, in cases where metastatic disease is identified on CXR, we recommend CT imaging to establish the extent of metastatic disease.
Once a complete or partial mole is suspected based on hCG level and US-findings, the diagnosis must be confirmed by histologic examination. Tissue is obtained by evacuation of the uterine contents by suction curettage. Suction curettage is the preferred approach because it is less likely to result in uterine perforation than sharp curettage. The cervix should be dilated to allow the passage of a large suction catheter, preferably 12 mm. A larger catheter is sometimes required if a partial mole is identified that contains fetal tissue. Due to the real risk of bleeding and perforation, evacuation should be performed by an experienced clinician. Suction curettage should be performed under cover of peri-operative oxytocin and ergometrine to maximize uterine contraction/retraction. Serious consideration should be given to undertaking such evacuation under ultrasound guidance. If the cavity has been emptied there is little reason to perform a sharp curettage, as it is unlikely to add further to management and only increases the risk of uterine perforation. Theoretically, in a complete mole, the fetal erythrocytes necessary to sensitize the mother are lacking. However, we recommend administration of anti-Rh(D) immunoglobulin to patients that are Rh-negative as RhD antigen has been demonstrated on the trophoblast of invasive and noninvasive molar pregnancies.
Patients who are not interested in retaining fertility may opt for a hysterectomy. This eliminates the risk of local invasion, but does not prevent metastases or persistent disease and therefore careful follow-up is still required. If this option is chosen, even in the presence of enlarged theca lutein cysts, the ovaries can be preserved as these will resolve over time. Other indications for a hysterectomy include sepsis, significant bleeding or pathology confirming PSTT or choriocarcinoma.
Some studies have reported a decreased incidence of persistent GTN if perioperative chemotherapy is administered around the time of uterine evacuation. However, given that the majority of patients do not develop persistent disease following a suction curettage, we do not favour this approach and prefer to monitor patients in order to minimise the potential toxicity of chemotherapy.
Following evacuation of uterine contents, patients should be closely monitored and their care supervised by doctors with expertise in this condition, although this does not mean they must, out of necessity, be managed by a certified gynaecologic oncologist. The graph below outlines the standard regression curve of hCG following evacuation of a molar pregnancy. Approximately 50% of patients achieve normal hCG levels six to 14 weeks after molar evacuation (see diagram).
In Australia, there is no nationally coordinated program for the registration or management of GTD, but there are State-based registries in South Australia, Victoria and Queensland. We have recently established a dedicated clinic for women diagnosed with GTD or GTN at the Chris O’Brien Lifehouse. A specialist consultant and a nurse practitioner coordinate the clinic and are available to follow-up patients diagnosed with a molar pregnancy. In addition, this ensures seamless referrals for chemotherapy treatment if this becomes necessary.
We recommend quantitative hCG titres to be drawn weekly until three normal levels have been obtained. Thereafter, monthly assessment for 6 months is recommended for patients with a history of a complete hydatidiform mole. If the hCG normalizes by day 56 after uterine evacuation, surveillance continues for 6 months from the original evacuation. Otherwise, we recommend surveillance for 6 months after hCG normalization. A plateau or rise in hCG is generally indicative of the development of persistent trophoblastic disease and usually requires chemotherapeutic treatment. It is important for women to avoid a subsequent pregnancy until surveillance is complete. The use of oestrogen and progesterone-containing oral contraceptives taken during this surveillance period does not increase the risk of invasive moles or choriocarcinomas. In the absence of other contraindications, we favour the use of oral contraceptives to prevent pregnancy until follow-up has been completed and the HCG has normalized. Intrauterine contraceptive devices are not recommended because of the risk of uterine perforation.
For their part, the risk of recurrence of a partial mole after hCG has normalized is extremely low. Increasing data indicates that the risk of GTN following normalization of hCG after a partial molar pregnancy is such that surveillance of partial moles can be discontinued once the hCG has normalised. In accordance with the guidelines set forth by RANZCOG for patients diagnosed with a partial molar pregnancy, we favour surveillance with weekly hCGs until negative. After three consecutive normal levels no further testing is required and the patient can be discharged back to her GP for routine care.
Many patients with GTD are uncomfortable waiting for six months and are anxious to attempt another pregnancy. As a result, non-compliance with recommended follow-up is not uncommon. Given the potential to increase compliance, decrease patient anxiety, shorten the duration of follow-up and decrease cost of follow-up, investigators have questioned whether it would be safe to shorten the time of follow-up. Studies have demonstrated that persistent disease very rarely occurs among those women with spontaneous regression of hCG levels to undetectable levels and suggest that a significantly shorter period of follow-up may be reasonable. Until more mature outcomes-based data are available confirming the safety of shorter periods of surveillance, we continue to favour a 6 month period of surveillance for patients with complete hydatidiform moles.
It is important to counsel the patient that once the surveillance period is complete it is reasonable to attempt a pregnancy. Patients with a hydatidiform mole can anticipate normal reproduction in the future without an increased risk for obstetric complications either prenatal or intrapartum. The risk of recurrence is about 1% after one molar pregnancy and 30% after two. Therefore, an early ultrasound is recommended in any future pregnancies. In addition, an hCG level is recommended about 6 weeks following the completion of any future pregnancies regardless of the outcome of that pregnancy.
Gestational trophoblastic neoplasia (GTN) is diagnosed when there is clinical, radiologic, pathologic, and/or hormonal evidence of persistent or relapsed gestational trophoblastic disease. Although this group may be considered to have developed “malignant sequelae”, this is based on the risk of developing local complications or metastases rather than an actual change in the histology of the lesion. Often the histological diagnosis is never confirmed. Most commonly, the diagnosis is made during the period of surveillance following a molar pregnancy, but GTN can occur after any type of gestation. Patients who undergo an abnormal regression of their hCG after evacuation are deemed to have persistent GTD. This will generally manifest as either an increasing or plateauing hCG. The management of persistent GTD is similar to the management of patients diagnosed with PSTT or choriocarcinoma at initial evaluation.
The FIGO criteria for diagnosis of post-hydatidiform mole trophoblastic neoplasia (GTN) are as follows:
1. When a plateau of human chorionic gonadotropin (hCG) (+/- 10%) lasts for 4 measurements over a period of 3 weeks or longer (i.e. days 1, 7,14, 21).
2. When there is a rise of hCG (> 10%) of three consecutive weekly measurements or longer, over at least a period 2 weeks or more (i.e. days 1,7,14).
3. When the hCG level remains elevated for 6 months or more.
4. If there is a histologic diagnosis of choriocarcinoma.
Invasive mole usually arises from a complete mole and is characterised by invasion of the myometrium, which can lead to perforation of the uterus. Microscopically, invasive mole has a similarly benign histological appearance as complete mole but is characterised by the ability to invade in to the myometrium and the local structures if untreated. The usual presentation is with hCG elevations following a previous molar pregnancy, other clinical features can include abnormal bleeding, abdominal pain or swelling.
Choriocarcinoma is clinically and histologically overtly malignant. The clinical presentation of choriocarcinoma can be from the disease locally in the uterus leading to bleeding, or from distant metastases that can cause a wide variety of symptoms with the lungs, central nervous system and liver the most frequent sites of distant disease. Choriocarcinoma presenting with distant metastases can present a diagnostic challenges, however the combination of the reproductive/gynaecology history and elevated serum hCG usually makes the diagnosis apparent and a biopsy unnecessary.
Placental Site Trophoblastic Tumour (PSTT)
PSTT is diploid and arises from the non-villous trophoblast and the pathology is characterised by intermediate trophoblastic cells with vacuolated cytoplasm, the expression of PLAP rather than hCG and the absence of cytotrophoblast and villi. Placental site trophoblast tumours are the least common form of gestational trophoblast disease comprising less than 2% of all cases. PSTT most commonly follows a normal pregnancy but may occur after a non-molar abortion or a complete molar pregnancy. The most frequent presentations are abnormal bleeding or amenorrhea. The clinical presentation of PSTT can range from slow growing disease limited to the uterus to more rapidly growing metastatic disease that is similar in behaviour to choriocarcinoma. Usually the hCG levels, while they are elevated, are relatively low in PSTT compared to the other types of GTN.
Patients who have or who are suspected of having persistent GTN, choriocarcinoma, or PSTT should be referred to a centre with expertise in the management of malignant trophoblastic disease. They must undergo a thorough evaluation prior to institution of therapy. At a minimum, in preparation for treatment, blood tests are obtained to assess renal and hepatic function, peripheral blood counts, and baseline serum hCG levels. Radiographic evaluation includes pelvic ultrasound, both to look for evidence of retained trophoblastic tissue, and to evaluate the pelvis for local spread. Chest imaging is also required, as the lungs are the most common site of metastatic disease. Chest CT is more sensitive than chest x-ray and pulmonary metastases can be detected by chest CT in up to 40 percent of patients with a negative chest x-ray. Chest CT is not mandatory, however, particularly if detection of occult pulmonary metastases will not alter the treatment. As long as the clinical picture is compatible with the diagnosis of GTN, metastatic lesions should not be biopsied for confirmation because of the high vascularity of most tumors and the risk for hemorrhage. In the absence of pulmonary and vaginal involvement, brain and liver metastases are rare. Asymptomatic patients with normal chest and pelvic imaging do not require further imaging of brain or liver. CT scan 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 choriocarcinoma.
In 2002, FIGO approved a revision of the staging system for GTN that was subsequently adopted by the American Joint Committee on Cancer (AJCC). The basic FIGO stages I to IV were retained to describe the anatomic distribution of disease. However, the prior A, B, and C risk modifier subgroups were eliminated, and replaced by a modification of the World Health Organization (WHO) scoring system called the Prognostic Scoring Index (see below). Patients receive scores for a variety or risk factors and the sum of these individual risk factors provides the scoring index.
Revised FIGO classification system for GTN
Stage I Disease confined to the uterus
Stage II GTN extends outside the uterus but is limited to genital structures
Stage III GTN extends to the lungs with or without genital tract involvement
Stage IV All other metastatic sites
Modified WHO Prognostic Scoring Index
Low risk, FIGO Score < 7; High risk, FIGO Score > 7
In addition to its prognostic utility, the revised staging system is capable of predicting which patients are likely to respond poorly to single-agent chemotherapy. A prognostic score of 7 or higher is considered a high-risk score; all of these patients are more likely to be resistant to single agent therapy and require combination chemotherapy. Patients with scores under 7 are considered low-risk and can usually be managed using single-agent chemotherapy. The benefit of using the prognostic score to distinguish between clinically high-risk and low-risk disease applies primarily to FIGO stage II and III disease. The prognostic score adds little to the selection of treatment for women with FIGO stage I or stage IV disease.
In some cases, a second evacuation of the uterus is performed but studies demonstrate that even among those cases there is about a 70% chance of requiring chemotherapy and an 8% chance of uterine perforation. Repeat curettage is not recommended if the hCG is > 5000 or in the presence of metastases.
Chemotherapy is a major component of curative therapy for the majority of women diagnosed with GTN. As a group, malignant gestational trophoblastic tumors are exquisitely sensitive to chemotherapy. The choice of single agent versus combination chemotherapy depends on disease stage, risk category and response to previous drug treatment. Single agent therapy is predominately either methotrexate or Actinomcyin D, although etoposide and 5-fluorouracil (5-FU) are other active single agents.
MTX is commonly given with leucovorin (folinic acid) for “rescue”. Leucovorin calcium has no inherent antitumor activity, but is able to minimise MTX toxicity in normal cells by overcoming the defect in folate metabolism induced by MTX.
Several dosing regimens for single agent MTX with or without leucovorin are in clinical use, and there is little evidence to support the superiority of any one over another: 1) Infusional MTX, 2) An eight-day regimen of MTX and leucovorin, and 3) Weekly MTX.
Although significant toxicity with MTX is infrequent, hematologic indices should be carefully monitored during therapy. Normal renal and liver function should be demonstrated prior to each treatment, as methotrexate is entirely excreted by the kidney, and it may be hepatotoxic. Furthermore, methotrexate has also been associated with idiopathic interstitial pneumonitis.
Retrospective series suggested that single agent actinomycin D (dactinomycin) was as effective but more toxic than MTX monotherapy when used for initial treatment of patients with low-risk GTD. Over time, five-day regimens have evolved to “pulsed” regimens using single higher doses administered every two weeks. These regimens are less toxic and easier to administer.
This biweekly regimen was directly compared to single agent MTX in a trial conducted in women with low-risk GTN. The data suggest that pulsed dactinomycin may be more effective than weekly MTX. However, most women who failed initial treatment received the alternative agent, and there was only one disease recurrence in each arm. There are no randomized trials comparing dactinomycin to the more commonly used multi-day MTX regimens or higher doses of MTX. In addition, dactinomycin is associated with significantly more frequent and severe side-effects. As a result, most centers use MTX as first-line treatment and the main use of dactinomycin is for the treatment of MTX-resistant non-metastatic disease.
The data shows that the majority of low risk patients will be successfully treated with methotrexate alone. Following normalisation of the serum hCG level it is usual to continue treatment for another 3 cycles (~6 weeks) to ensure eradication of any residual disease that is below the level of serological detection.
Patients who have an inadequate response to methotrexate therapy as shown by an hCG plateau or rise have their treatment changed to second line therapy. This is either single agent dactinomycin or combination treatment if the hCG is above 300 iu/L. Overall the survival in the low risk group approaches 100% and the sequential introduction of additional chemotherapy as necessary minimises the potential long-term risks of excess treatment.
The introduction of combination chemotherapy treatments has transformed the poor prognosis of high risk trophoblastic disease. Combination chemotherapy is used for disease that is either refractory to single-agent therapy or for newly diagnosed high-risk malignant GTD (i.e. Stage II/III disease with a high prognostic risk score, Stage IV disease and/or PSTT or choriocarcinoma. Despite the absence of randomized trials to prove its superiority, the combination of etoposide, methotrexate, and dactinomycin followed by cyclophosphamide and vincristine (EMA/CO) has become the preferred regimen for initial treatment of high-risk GTD in most countries. Current data shows a cure rate for high risk patients of 80-90%. The EMA-CO regimen is repeated every two weeks until remission (i.e., normalization of beta-hCG and disappearance of all radiographically evident disease), and then generally continued for an additional three cycles (six weeks).
EMA/CO is a relatively well-tolerated regimen. Alopecia is universal, but severe haematologic toxicity is seen in less than 2 percent of chemotherapy cycles and gastrointestinal symptoms are generally mild. Of particular significance to these patients, more than one-half of patients are able to retain their fertility. This intensive regimen is associated with a small risk (~2%) of secondary malignancies.
Almost all patients with relapsed stage I or low-risk disease, and approximately 60 to 70 percent of those with relapsed high-risk disease, can be successfully salvaged with additional chemotherapy alone. Several regimens have activity in this setting. Patients with low-risk disease who are resistant to single-agent therapy are often treated with multi-agent chemotherapy.
In contrast, women who relapse after EMA/CO are usually treated with a platinum-based regimen. Taxanes are often incorporated into third-line treatment. The most commonly used regimen for patients who are refractory to EMA, EMA/CO or MAC is EMA/EP. The cumulative overall survival for these patients has been reported to be as high as 80%. Treatment-related toxicity with this intensive weekly treatment regimen can be significant. For women resistant to both EMA/CO and EMA/EP, the PVB (cisplatin, vinblastine, and bleomycin) or BEP combinations (bleomycin plus etoposide and cisplatin) are effective.
After attaining a normal hCG level, the risk of tumour relapse in women with persistent GTN is 3-9% with a mean time to recurrence is approximately 6 months regardless of initial stage of disease. We recommend that patients with stages I, II and III GTN be followed with weekly hCG levels until undetectable for three weeks and then monthly for 12 months. During that time, pregnancy should be avoided in order to be reasonably certain that the disease has been completely eradicated. Patients with stage IV disease who enter complete remission are followed for 24 months given their increased risk of late relapse. After 12 or 24 months of follow-up, some centres recommend follow-up of patients every six months for five years or indefinitely, although the risk of late relapse in the majority of patients after one year is negligible and the benefits of long-term surveillance are largely unproven. Subgroups that might fit into a high-risk category worthy of long-term surveillance include women with multi-agent resistant disease who required multiple chemotherapy regimens and those with advanced stage choriocarcinoma as well as women who developed recurrent disease.
Following either low or high risk chemotherapy treatment, fertility is usually maintained and regular menstruation restarts 2-6 months after the end of chemotherapy. We normally recommend that for 12 months after treatment that further pregnancy is avoided to minimise any teratogenic effects on developing oocytes and to minimise the possible confusion from the rising hCG between a new pregnancy and disease relapse. Despite the frequent long exposure to cytotoxic chemotherapy in the high risk group there does not appear to be any significant increase in foetal abnormalities.
Many patients after experiencing one molar pregnancy and particularly those who require chemotherapy are anxious of the problem occurring again in any subsequent pregnancy. The data suggests that the risk of a further molar pregnancy is about 10 fold higher than in the normal population, but this only equates to an approximate 1 in 70 risk. This risk appears to be independent of chemotherapy exposure, being similar for those patients who required chemotherapy and those where the molar pregnancy was cured by evacuation alone.
With the prolonged follow-up data available, it is clear that the exposure to combination chemotherapy carries some long-term health risks. Patients receiving combination chemotherapy, particularly those who receive etoposide, have increased risks of developing a second malignancy and is particularly marked for myeloid leukaemia (RR 16.6). In contrast the patients treated with single agent methotrexate do not appear to have increased risks of second malignancies.
This long-term health concern from the use of combination chemotherapy, reinforces the benefits from surveillance, allowing treatment to be commenced with single agent methotrexate whilst the patient falls within the low risk group.
Despite the very high cure rates and the low long term toxicity from chemotherapy treatment, treatment with chemotherapy can result in a number of psychological issues. During chemotherapy treatment issues regarding potential side effects, emotional problems and fertility concerns are frequent. Some studies have shown that the concerns can remain for many years. A number of surveys have demonstrated the wish of many patients to have more support through counseling and support both at diagnosis and continuing after treatment, through the appointment of a clinical nurse practitioner we hope to have enhanced the support we are routinely able to give.
Any form of GTN can metastasize. When metastases occur, the most common site is the lungs, which are involved in over 80 percent of patients. Vaginal metastases are present in up to 30 percent. Hepatic and cerebral metastases are less common, occurring in approximately 10 percent of patients and portend a worse prognosis. They are most commonly associated with choriocarcinoma following a non-molar pregnancy. The majority of patients with hepatic and cerebral metastases have concurrent pulmonary and/or vaginal metastasis.
Brain metastases are associated with a poorer prognosis than pulmonary or vaginal metastases. Nevertheless, some of these patients can be cured. There are two main therapeutic options for these patients. In the past, institution of whole brain radiotherapy was recommended concurrent with the initiation of chemotherapy. In addition to shrinking the brain metastases, concomitant cranial irradiation purportedly increases the methotrexate concentration within the CNS, reduces the risk of cerebral hemorrhage prior to eradication of tumor, and may improve survival. However, the use of concurrent methotrexate and cranial irradiation also increases the likelihood of treatment-related toxicity, especially leukoencephalopathy. An alternative to radiation therapy is with EMA/CO.
Craniotomy and resection of drug-resistant is reserved for life-threatening complications (e.g., hemorrhage and the need for acute decompression). It seems justified only for patients who do not have metastatic disease elsewhere. In such case, surgery may provide an opportunity for complete remission, even in patients with chemotherapy-resistant brain metastases.
More than 50 percent of women with isolated brain metastases may be cured using either treatment approach. As a result, concerns for long-term toxicity should be a prime consideration in choosing therapy.
The recently revised FIGO risk score recognizes the poor prognosis associated with liver metastases. About 5-20% of poor prognosis cases have liver metastases and the collected survival rate is 33%. Combination chemotherapy can induce a partial response in most women. Hepatic resection and/or selective embolization or occlusion of the hepatic arteries may be required in selected cases to control bleeding or excise resistant tumor. The role of liver irradiation is controversial.
An isolated pulmonary nodule that is resistant to chemotherapy may be treated by thoracotomy with wedge resection. Criteria that predict a favorable outcome from surgical resection include: i) Absence of other systemic metastases, ii) Unilateral solitary lung nodule, iii) No uterine involvement, iv) serum beta-hCG concentration < 1500 mIU/mL . Thus, prior to proceeding with surgical management, other sites of persistent disease must be ruled out. Non-viable fibrotic nodules, which may persist indefinitely after tumor regression, can be distinguished from viable tumor by PET scan before surgery is contemplated.
False positive or phantom hCG levels
Laboratory assays for hCG levels may yield false-positive results, which in some cases have been reported to be as high as 800mIU/mL. These false positives may be caused by antimouse heterophilic antibodies and a nonspecific protein interference. Since the management of GTD is guided by the hCG level, it is important to consider the possibility of a false-positive results, especially in discordant clinical situations. Not recognizing this possibility has led to unnecessary treatment in some cases. False positive serum hCG results can be excluded if the urine hCG is negative since heterophilic antibodies are not present in urine or by serial dilution of the serum.
Asymptomatic Low Levels of ß-hCG
For persistently elevated low levels of ß-hCG is it important to exclude phantom hCG by checking urine and serum. With real hCG the tires are positive in both while with phantom hCG the urine is usually negative. For persistently elevated real hCG, exclude uterine disease with (i)TVS and colour flow Doppler (CFD) (ii) hysteroscopy, D+C and (iii) MRI pelvis. When these are negative and the hCG persists then is necessary to exclude mediastinal lesions using CT of chest and choroid and pituitary lesions using MRI.