1-s2.0-S0140673610602802.pdf

Seminar Gestational trophoblastic disease Michael J Seckl, Neil J Sebire, Ross S Berkowitz Gestational trophoblastic disease encompasses a range of pregnancy-related disorders, consisting of the premalignant disorders of complete and partial hydatidiform mole, and the malignant disorders of invasive...

Seminar Gestational trophoblastic disease Michael J Seckl, Neil J Sebire, Ross S Berkowitz Gestational trophoblastic disease encompasses a range of pregnancy-related disorders, consisting of the premalignant disorders of complete and partial hydatidiform mole, and the malignant disorders of invasive mole, choriocarcinoma, and the rare placental-site trophoblastic tumour. These malignant forms are termed gestational trophoblastic tumours or neoplasia. Improvements in management and follow-up protocols mean that overall cure rates can exceed 98% with fertility retention, whereas most women would have died from malignant disease 60 years ago. This success can be explained by the development of effective treatments, the use of human chorionic gonadotropin as a biomarker, and centralisation of care. We summarise strategies for management of gestational trophoblastic disease and address some of the controversies and future research directions. Introduction Hippocrates was probably the first to describe gestational trophoblastic disease around 400 BC in his description of dropsy of the uterus.1 Although other observations have been made since, Marchand first associated hydatidiform mole with pregnancy in 1895.1 Healthy trophoblastic tissue aggressively invades the endometrium and develops a rich uterine vasculature, generating an intimate connection between the fetus and the mother known as the placenta. Invasion is one of the distinct features of malignant disease, and healthy trophoblast can be detected by PCR in the maternal circulation.2 Fortunately, malignant-like behaviour is tightly controlled in healthy trophoblast. However, in gestational trophoblastic disease the regulatory mechanisms fail, resulting in tumours that are highly invasive, metastatic, and very vascular. In this Seminar we discuss the epidemiology, origins, pathological changes, and clinical behaviour of the various forms of gestational trophoblastic disease. gestations, the risk of a third mole is 15–20%,11,14,15 and the risk is not decreased by change of partner.16 Some repeat molar pregnancies are due to familial or sporadic biparental molar disease (figure 1). The frequency of choriocarcinoma or placental-site trophoblastic tumour is less well known, since these diseases can arise after any type of pregnancy.17,18 Choriocarcinoma develops in around one in 50 000 deliveries,19 and placental-site trophoblastic tumour accounts for about 0·2% of cases of gestational trophoblastic disease in the UK.20 The risk of gestational trophoblastic neoplasia might also be linked to hormonal factors, since women with menarche after 12 years of age, light menstrual flow, and previous use of oral contraceptives are at increased risk.21,22 Additionally, risk of malignant disease after hydatidiform mole has been associated with oral contraceptive use (if started when human chorionic gonadotropin [hCG] concentrations are raised) in some23 but not all24 studies. Lancet 2010; 376: 717–29 Published Online July 28, 2010 DOI:10.1016/S01406736(10)60280-2 Department of Cancer Medicine (Prof M J Seckl FRCP) and Department of Histopathology (N J Sebire FRCPath), Charing Cross Gestational Trophoblastic Disease Centre, Charing Cross Hospital Campus of Imperial College London, London, UK; and New England Trophoblastic Disease Center, Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Harvard Medical School, Brigham and Women’s Hospital, Dana-Farber Cancer Institute, Boston, MA, USA (R S Berkowitz MD) Correspondence to: Prof Michael J Seckl, Department of Cancer Medicine, Charing Cross Gestational Trophoblastic Disease Centre, Charing Cross Hospital Campus of Imperial College London, London W6 8RF, UK [email protected] Causes and genetics Epidemiology Gestational trophoblastic disease arises more frequently in Asia than in North America or Europe,3,4 which could be due to differences in prevalence, discrepancies between hospital-based and population-based data, or disparity in availability of central pathology review. In the UK, all patients are included on a national register, with central pathology review; and the incidence of complete hydatidiform mole is around one per 1000 pregnancies and three per 1000 for partial hydatidiform mole.5 Other developed countries report similar data.6 The incidence of molar pregnancy has decreased in South Korea from 4·4 cases per 1000 births in the 1960s to 1·6 cases per 1000 births in the 1990s,7 possibly because of improved socioeconomic conditions and dietary changes—especially since findings from studies in animals show that diet can reset the genetic imprint.8 Additionally, an increased risk of molar pregnancy is associated with reduced consumption of dietary carotene9,10 and animal fat,9 and advanced maternal age.3,11–13 Ova from older women are more susceptible to abnormal fertilisations than are those from younger women. After a molar pregnancy, the risk of further complete and partial mole rises to 1–2%.11,14,15 After two molar In most cases, complete hydatidiform mole usually arises when an ovum without maternal chromosomes Search strategy and selection criteria We searched the Cochrane Library, Medline (via PubMed, Internet Grateful Med, OVID, and Knowledgefinder), for meta-analyses, previous systematic reviews, cohort studies (and when appropriate comparison groups), and case-control studies published in English between 1980 and 2010, with the keywords “trophoblastic disease”, “GTD”, “GTN”, “choriocarcinoma”, “molar pregnancy”, “hydatidiform mole”, “placental site trophoblastic tumor”, “genetics”, “epidemiology”, “pathology”, “treatment”, “chemotherapy”, “methotrexate”, “actinomycin D”, “dactinomycin”, “cisplatin”, “paclitaxel”, “high-dose”, “management”, “risk factors”, “hCG”, “imaging”, “ultrasound”, “PET”, “CT”, “MRI”, “prognosis”, and “staging”. We included results presented at the 15th International Society for the Study of Trophoblastic Diseases meeting in November, 2009, in Cochin, India. Reference lists from all previous publications were scanned to find any publications not already identified by our electronic search strategy. www.thelancet.com Vol 376 August 28, 2010 Descargado para Anonymous User (n/a) en Monterrey Technology de ClinicalKey.es por Elsevier en marzo 11, 2024. Para uso personal exclusivamente. No se permiten otros usos sin autorización. Copyright ©2024. Elsevier Inc. Todos los derechos reservados. 717 Seminar is fertilised by one sperm that then duplicates its DNA, resulting in a 46XX androgenetic karyotype, in which all chromosomes are paternally derived.25–27 About 10% of complete moles are 46XY,28 arising from fertilisation by two sperm (figure 1). Although nuclear DNA is entirely paternal, mitochondrial DNA remains maternal in origin.29 Findings from some studies30 show that patients Androgenetic diploid (monospermic) X XX CHM Androgenetic diploid (dispermic) Y X XY CHM with recurrent disease can have biparental molar rather than typical androgenetic disease, which might be familial or sporadic. Genetic studies in such families showed that the related genes are at chromosome 19q13.3–13.4,31 and subsequent analysis noted NLRP7 mutations in this region.32 The function of the normal protein and the mechanism by which mutations are associated with imprinting abnormalities and gestational trophoblastic disease are unknown.33 Data show clustering of mutations in the leucine-rich region of NLRP7 (figure 2), suggesting that this region is crucial for normal function.34 Some androgenetic diploid complete moles and possibly even triploid partial hydatidiform moles might also carry NLRP7 mutations,35 but confirmation from large studies is needed. Partial hydatidiform moles are almost always triploid (figure 1), and they result from fertilisation of a seemingly healthy ovum by two sperm;36–38 diploid partial moles probably do not exist, with most reported cases being misdiagnosed complete moles.39 Pathology Biparental triploid X X PHM X XXX X XX X biCHM Chromosome 19q: NLRP7 (NALP7) defect Sporadic or hereditary Autosomal recessive Figure 1: Karyotype derivation of complete and partial hydatidiform moles and rare biparental repetitive complete hydatidiform mole CHM=complete hydatidiform mole. PHM=partial hydatidiform mole. biCHM=rare biparental complete hydatidiform mole. Paternal (black) and maternal (red) derived genes are shown. R693Q R693W R693P P716A R721W L398R E113GfsX7 T61TfsX7 PYD R432X Y318CfsX7 NACHT P651S E570X C761Y N913S P716LfsX21 L6776PfsX6 Leucine-rich region Figure 2: Domain structure of NLRP7 and identified mutations noted in 17 families with biparental repetitive hydaditiform moles Predicted protein domains include PYRIN (PYD), NACHT, and a leucine-rich region. The nine missense aminoacid substitutions or mutations are shown above the protein and seven nonsense mutations are shown below the protein. There seems to be some clustering of mutations in the leucine-rich region. 718 All gestational trophoblastic disease is derived from the placenta. Hydatidiform moles and choriocarcinoma arise from villous trophoblast and placental-site trophoblastic tumours from interstitial trophoblast. Most complete and partial hydatidiform moles have distinctive morphological characteristics, although diagnostic criteria have changed because evacuation is done earlier in gestation (median 8–9 weeks in the UK). First-trimester complete moles show a characteristic abnormal budding villous structure with trophoblast hyperplasia, stromal karyorrhectic debris, and collapsed villous blood vessels. By contrast, early partial moles show patchy villous hydrops with scattered abnormally shaped irregular villi, trophoblastic pseudoinclusions, and patchy trophoblast hyperplasia (figure 3).40–42 Morphological distinction of non-molar miscarriage from partial hydatidiform mole can be difficult, since villous dysmorphism can be present but without the characteristic trophoblast hyperplasia that is noted in partial mole. Ancillary techniques are needed in some cases to differentiate non-molar miscarriage from hydatidiform mole, including immunostaining for P57kip2, the product of CDKN1C. P57kip2 is expressed by the maternal allele and is visible on histology as nuclear staining of cytotrophoblast and villous mesenchyme in placenta of all gestations apart from androgenetic complete mole.43,44 Additionally, ploidy analysis by in-situ hybridisation or flow cytometry can distinguish diploid from triploid conceptions, helping to diagnose partial mole, but is unable to distinguish complete mole from diploid non-molar miscarriage, or molar versus non-molar triploidy, which necessitate molecular investigations.18,45–47 Choriocarcinomas are malignant hCG-producing epithelial tumours with central necrosis and a characteristic biphasic architecture recapitulating cytotrophoblast-like www.thelancet.com Vol 376 August 28, 2010 Descargado para Anonymous User (n/a) en Monterrey Technology de ClinicalKey.es por Elsevier en marzo 11, 2024. Para uso personal exclusivamente. No se permiten otros usos sin autorización. Copyright ©2024. Elsevier Inc. Todos los derechos reservados. Seminar A B 1 mm 0·5 mm D C 0·1 mm 0·1 mm Figure 3: Gestational trophoblastic disease (A) Complete hydatidiform mole (magnification ×20). (B) Partial hydatidiform mole (magnification ×40). (C) Placental-site trophoblastic tumour (magnification ×200). (D) Choriocarcinoma (magnification ×100). All forms have abnormal trophoblast proliferation, which is associated with dysmorphic chorionic villi in complete and partial hydatidiform moles, but villi and abnormal trophoblast invasion are not noted in placental-site trophoblastic tumour or choriocarcinoma. cells and multinucleate, pleomorphic syncytiotrophoblastlike regions; however, mononuclear cells predominate in some cases, especially after chemotherapy.48 Intraplacental choriocarcinoma does occur and is probably the source of metastatic disease after term pregnancies. Most cases of neonatal choriocarcinoma result from metastatic spread from an intraplacental choriocarcinoma.49 Placental-site trophoblastic tumours are the malignant equivalent of extravillous, interstitial implantation site-like trophoblast and form uterine lesions with less haemorrhage and necrosis, and lower hCG concentrations than does choriocarcinoma.48,50 Epithelioid trophoblastic tumour—a variant of placental-site trophoblastic tumour with similar clinical behaviour but distinctive hyalinisation—has been reported, but data for this disease are sparse.51 Accurate measurement of hCG is key to effective management of gestational trophoblastic disease, several cancers, and pregnancy. Panel 1 summarises some of the issues related to hCG measurements. Diagnostic ultrasound for molar pregnancy Patients with complete hydatidiform mole most commonly present with vaginal bleeding in early pregnancy. Previously reported features such as anaemia, uterine enlargement, pre-eclampsia, hyperemesis, hyperthyroidism, and respiratory distress are now rare,60 probably because routine use of ultrasonography leads to diagnosis in the first rather than late-second trimester. Partial hydatidiform moles grow more slowly and present slightly later in the first or early second trimester than do complete moles, but also manifest with vaginal bleeding or missed or incomplete miscarriages.61,62 Characteristic ultrasonographic scans of complete mole show a uterine cavity filled with a heterogeneous mass (so-called snowstorm), without associated fetal development and with theca lutein ovarian cysts.63,64 However, these features are not visible in the first trimester and, although some investigators65–70 have suggested that ultrasound can be diagnostic of complete mole in early pregnancy, large studies71,72 have shown that only 40–60% of cases are detected as molar by sonography in routine clinical practice. Moreover, 10% of cases that are thought to be molar on sonography were diagnosed as nonmolar hydropic abortions on histological review.71 Findings from other reports73 are similar and emphasise www.thelancet.com Vol 376 August 28, 2010 Descargado para Anonymous User (n/a) en Monterrey Technology de ClinicalKey.es por Elsevier en marzo 11, 2024. Para uso personal exclusivamente. No se permiten otros usos sin autorización. Copyright ©2024. Elsevier Inc. Todos los derechos reservados. 719 Seminar Panel 1: hCG measurement in gestational trophoblastic disease and cancer hCG comprises an α subunit (shared with other members of the glycoprotein hormones, including thyroid-stimulating hormone and luteinising hormone) and a β subunit that confers specificity. Consequently, assays designed to specifically detect hCG have to target the β subunit. In healthy pregnancy, hCG is intact and is hyperglycosylated during the first trimester. However, in cancer, many other subtypes of β-hCG can exist, including free-βhCG, β-core, nicked free-β, or c-terminal peptide.52,53 Therefore, hCG assays used in cancer need to detect all forms of hCG and not only those found in healthy pregnancy. Moreover, the different β-hCG forms should be detected equally well. Unfortunately, most commercial assays fail to or variably detect all forms of β-hCG and therefore are prone to false-negative results in patients with cancer.52,54 Additionally, every assay is susceptible to false-positive results, usually caused by cross-reacting heterophile antibodies. These antibodies do not pass into the urine, so if hCG is present, a false-positive serum value can be excluded in most cases, although other approaches to this problem might be necessary.55 However, the false-negative issue cannot be easily resolved and is potentially clinically important, since a false-negative finding could result in delayed diagnosis or premature withdrawal of chemotherapy, or both.52,54 No commercial assay is licensed for use in cancer diagnosis or management at present, although many are used for this purpose. In the UK, we use a non-commercial rabbit polyclonal antibody that detects all forms of hCG for monitoring of patients with gestational trophoblastic disease. By comparison with other assays, our assay seems to have a low false-negative rate and, since we routinely measure hCG in serum and urine, false-positive results are rare. This assay is not available worldwide and, to our knowledge, the only commercial assay that seems comparably safe to use in gestational trophoblastic disease is the Siemens Immulite (Deerfield, IL, USA).53,54 Therefore, a new generation of cancer-specific hCG assays is urgently needed. Findings from recent studies56,57 that used a hyperglycosylated hCG assay suggest that a high ratio of this variant to total hCG can detect malignant forms of gestational trophoblastic disease. These findings correlate with some biological evidence56 suggesting that hyperglycosylated hCG induces an invasive phenotype in trophoblast and choriocarcinoma cells. Additionally, some preliminary studies58,59 suggest that free-β-hCG is a marker for placental-site trophoblastic tumour and seminomatous germ cell tumours. Prospective studies in large patient cohorts are needed to define the role of hyperglycosylated hCG and free-β-hCG in the management of gestational cancers. hCG=human chorionic gonadotropin. that false-positive and false-negative rates are high with ultrasonography—especially for partial hydatidiform mole—and histological examination is necessary to achieve a correct diagnosis.40,74 All products of conception from non-viable pregnancies should undergo histological examination irrespective of ultrasonographic findings.75 Some women who miscarry or have medical terminations will have had unsuspected molar pregnancies. Because ultrasonography cannot reliably confirm molar disease and histological examination of products might not be done after pregnancy termination, delayed diagnosis of gestational trophoblastic neoplasia, and hence substantial morbidity with the need for complex chemotherapy and surgery, can result.76 Histological examination after every termination would be impracticable, so checking of hCG concentrations at 3–4 weeks after treatment to ensure a return to a value within the normal range is recommended.77 720 Surgical evacuation Suction curettage is the preferred method of evacuation irrespective of uterine size in patients with suspected hydatidiform mole who want to preserve fertility.78,79 Intraoperative ultrasonography can reduce the risk of uterine perforation. Patients who are rhesus-negative should receive rhesus immunoglobulin at the time of evacuation because rhesus D factor is expressed on trophoblast. Women who are nulliparous should not be given prostanoids to ripen the cervix since these drugs can induce uterine contractions and might increase the risk of trophoblastic embolisation to the pulmonary vasculature.80 Hysterectomy is rarely recommended but might be considered for women who do not want further children or have life-threatening haemorrhage.81,82 Patients should be counselled that, although hysterectomy stops the risk of local invasion, it does not eliminate the possible need for chemotherapy, and monitoring of hCG concentrations should still be done.11 A healthy co-twin can develop alongside a complete or partial hydatidiform mole in one per 20 000–100 000 pregnancies (figure 4). Some investigators have suggested that such pregnancies should be terminated because of the low probability of successful outcome and the increased risk of development of malignant disease.83 However, evidence from a case series84 of 77 pregnancies suggests that about 40% of women will deliver a healthy baby without a significant increase in the risk of malignant transformation of the complete hydatidiform mole. Findings from a study76 of 2800 singleton molar pregnancies lent support to the notion that late evacuation of complete hydatidiform mole is not associated with an increased rate of malignant disease. Registration for hCG surveillance All patients with hydatidiform mole should be registered with a specialist centre for hCG surveillance, preferably one that is coordinated nationally. The UK established the first national service for gestational trophoblastic disease through a combined agreement of the Royal College of Obstetricians and Gynaecologists and the Department of Health’s National Commissioning Group. Since 1973, all women with hydatidiform mole or other forms of gestational trophoblastic disease have been registered with one of three centres for hCG monitoring and, if subsequent treatment is necessary, are treated at the Sheffield Trophoblastic Disease Centre (Sheffield, UK) or Charing Cross Hospital Trophoblast Disease Centre (London, UK). Onset of malignant change, termed persistent gestational trophoblastic disease or post-mole neoplasia, is signified by a plateaued or rising hCG concentration. Studies in the UK show that malignant change arises after 15% of complete and 0·5–1·0% of partial hydatidiform moles.11,18,85 Rates are probably higher in other countries than the UK,86 possibly because of www.thelancet.com Vol 376 August 28, 2010 Descargado para Anonymous User (n/a) en Monterrey Technology de ClinicalKey.es por Elsevier en marzo 11, 2024. Para uso personal exclusivamente. No se permiten otros usos sin autorización. Copyright ©2024. Elsevier Inc. Todos los derechos reservados. Seminar differences in hCG criteria and overdiagnosis of neoplasia, scarcity of whole-population demographics, or a difference in disease biology, although this explanation is unlikely. Precise surveillance protocols vary by country but principles are alike. In the UK, serum and urine hCG concentrations are measured every 2 weeks until the values are within the normal range, and then urine hCG concentrations are recorded monthly. Patients with normal hCG values within 56 days of uterine evacuation have a reduced risk of development of malignant disease,11,87 and are monitored for 6 months from evacuation date. When the first hCG reading within the normal range is noted after 56 days, monthly monitoring continues for 6 months.87 Some investigators suggest shortened hCG surveillance, with discontinuation after the first value within the normal range is measured, especially for women with partial mole in whom the risk of neoplasia is reduced.88,89 Shortened surveillance could enable women to attempt a subsequent pregnancy sooner, but could result in late development of neoplasia with increased morbidity and mortality. Data reported at the 2009 International Society for the Study of Trophoblastic Diseases (ISSTD) world congress from 22 000 women with complete and partial hydatidiform moles in the UK suggest that either form can occasionally develop post-mole neoplasia after the hCG has returned to normal; however, the risk of missed gestational trophoblastic neoplasia can be reduced from one in 800 women to one in 1400 by following present UK guidelines.87 Consequently, UK practice seems good for young women, but older nulliparous women should be made aware of the relative risks and benefits of an early pregnancy. During hCG follow-up, patients are encouraged to use reliable contraception, including a combination of methods, although data are conflicting about whether oral contraceptives increase the risk for gestational trophoblastic neoplasia. In the UK, practitioners avoid recommending oral contraceptives until hCG is in the normal range.23,24 After completion of hCG monitoring, serum or urine hCG concentrations should be checked 6 weeks and 10 weeks after every pregnancy to ensure no reactivation of previous molar disease.90,91 Treatment A B Complete hydatidiform mole Normal placenta Figure 4: Twin pregnancy of a complete hydatidiform mole and healthy co-twin (A) Ultrasonography and (B) MRI. Panel 2: Indications for chemotherapy for gestational trophoblastic disease in the UK Plateaued or rising hCG concentration after evacuation* Heavy vaginal bleeding or evidence of gastrointestinal or intraperitoneal haemorrhage Histological evidence of choriocarcinoma Evidence of metastases in brain, liver, or gastrointestinal tract, or radiological opacities larger than 2 cm on chest radiograph Serum hCG concentration of 20 000 IU/L or more, 4 weeks or more after evacuation, because of the risk of uterine perforation Raised hCG concentration 6 months after evacuation, even when still decreasing hCG=human chorionic gonadotropin. *A plateaued hCG concentration is defined as four or more equivalent values of hCG for at least 3 weeks (days 1, 7, 14, and 21), and rising as two consecutive increases in hCG concentration of 10% or more for at least 2 weeks (days 1, 7, and 14). associated with an increased risk of uterine perforation); or there are lung or vaginal metastases more than 2 cm in diameter (small lesions can spontaneously regress), or spread to other organs.42,92 Additionally, in the UK, chemotherapy is started to help to stop heavy bleeding that necessitates transfusion, even when the hCG concentration is falling. Indications Panel 2 shows the UK indications for treatment of gestational trophoblastic disease with chemotherapy. These recommendations are similar to those suggested by the International Federation of Gynecology and Obstetrics (FIGO)92 and include a plateaued or rising hCG (the most common reason for treatment), a persistently raised hCG at 6 months after evacuation, or histological diagnosis of choriocarcinoma. However, our experience suggests that the disease is unlikely to remit spontaneously when: the hCG concentration is more than 20 000 IU/L, 1 month after evacuation (also Staging and stratification Most patients who develop gestational trophoblastic neoplasia after hydatidiform mole are detected early by hCG monitoring so detailed investigation is rarely needed. Information on which to base therapy decisions can be obtained from clinical histories, examination, and measurement of serum hCG. Additionally, patients should have doppler pelvic ultrasonography to confirm absence of pregnancy, and to measure the uterine size and volume, spread of disease within the pelvis, and disease vascularity (figure 5). Disease vascularity can www.thelancet.com Vol 376 August 28, 2010 Descargado para Anonymous User (n/a) en Monterrey Technology de ClinicalKey.es por Elsevier en marzo 11, 2024. Para uso personal exclusivamente. No se permiten otros usos sin autorización. Copyright ©2024. Elsevier Inc. Todos los derechos reservados. 721 Seminar A Prechemotherapy B Prechemotherapy C Prechemotherapy Postchemotherapy Postchemotherapy Postchemotherapy Figure 5: Prechemotherapy and postchemotherapy imaging (A) Doppler ultrasound examination of a complete hydatidiform mole with a vascular uterine mass. (B) Chest radiograph of a patient 9 months after a term delivery with multiple pulmonary metastases. (C) Brain MRI with three obvious haemorrhagic metastases in a patient with seizures 6 months after a term delivery. suggest patients who are at risk of treatment resistance.93,94 Pulmonary metastases are most common, so chest radiography is essential.95 Chest CT is not needed when findings from chest radiography is normal, since discovery of micrometastases, which can be seen in about 40% of patients, does not affect outcome.96,97 However, if lesions are noted on chest radiograph, brain MRI and body CT are recommended to exclude more widespread disease affecting, for example, the brain or liver, which would substantially change management. FIGO report data for gestational trophoblastic neoplasia by use of prognostic scoring and anatomical staging 722 systems (table 1). Since 2002, all physicians treating gestational trophoblastic neoplasia should use this system to allow comparison of data. The combined prognostic score predicts potential for development of resistance to monochemotherapy with methotrexate or dactinomycin. A score of 0–6 suggests low risk of resistance and 7 or more indicates high risk. Such disease has almost no chance of being cured with monochemotherapy and needs multidrug treatment. Anatomical staging does not aid therapeutic choices but helps clinicians to compare results between centres. Low-risk disease About 95% of patients with hydatidiform mole who develop neoplasia are at low risk of resistance (score 0–6). In patients with stage I disease that is seemingly confined to the uterine cavity, the use of second dilatation and curettage to reduce the need for chemotherapy is controversial.98–101 Results from the UK suggest that secondary surgery is of no value when hCG concentrations are greater than 5000 IU/L, since more than 50% of such patients will need chemotherapy.101 The low effectiveness of second surgery and small risks of infection, haemorrhage, and uterine perforation should be measured against the almost 100% cure rate and comparative safety of chemotherapy. Some patients with stage I neoplasia who do not want further children request hysterectomy, which can be technically difficult with these highly vascular tumours and does not completely obviate the need for chemotherapy. For most low-risk patients with gestational trophoblastic neoplasia, monochemotherapy with methotrexate or dactinomycin is the preferred treatment. Many regimens have been used, showing a 50–90% chance of induction of remission in non-randomised, mostly retrospective, studies.102 The wide variability results from differences in dose, frequency, route of administration, and the criteria used to select patients for therapy.19,95 Some investigators suggest that intensive therapy given daily for 5–8 days every 2 weeks is better than treatments given once every 2 weeks;103 others suggest that dactinomycin is more likely to induce remission than is methotrexate.104 The few randomised studies102 that addressed some of these issues were underpowered and compared regimens that are not frequently used internationally. Patients in whom first-line therapy fails—generally because of resistance— can be easily salvaged with second-line or occasionally third-line chemotherapy, so overall survival is nearly 100%.105 Since survival is so high, patients should be given the least toxic therapy first to avoid exposure to more harmful treatments. The regimen of methotrexate (50 mg intramuscularly every 48 h for four doses) with calcium folinate (folinic acid) rescue (15 mg orally 30 h after methotrexate) regimen developed at our UK institute is effective and is well tolerated. Courses are repeated every 2 weeks. Unlike dactinomycin, this regimen does not induce hair loss; thus www.thelancet.com Vol 376 August 28, 2010 Descargado para Anonymous User (n/a) en Monterrey Technology de ClinicalKey.es por Elsevier en marzo 11, 2024. Para uso personal exclusivamente. No se permiten otros usos sin autorización. Copyright ©2024. Elsevier Inc. Todos los derechos reservados. Seminar 0 1 Age (years) 8 Brain, liver ·· Combined therapy hCG=human chorionic gonadotropin. *Patient’s score is total of individual scores for the eight prognostic factors. Low risk of resistance to monochemotherapy 0–6, high risk 7 or more. Placental-site trophoblastic tumour should not be scored but needs to be staged. Stage I disease is confined to the uterus; stage II disease extends to the genital tract; stage III disease is spread to lungs with or without extension to the genital tract; and stage IV occupies all other metastatic sites including liver, kidney, spleen, and brain. Table 1: International Federation of Gynecology and Obstetrics (2000) scoring system for gestational trophoblastic neoplasia, by prognostic factor* it has been widely used.105–107 Most patients are treated at home after a short stay in hospital to monitor any bleeding. About 2% of women have mouth ulcers, sore eyes, or rarely pleuritic or peritoneal pains from serositis.105 Patients who develop resistance to methotrexate with folinic acid rescue can be switched to dactinomycin when hCG concentrations are less than or equal to 100 IU/L or multidrug chemotherapy when concentrations are more than 100 IU/L, which will cure nearly all patients.105,106,108 The UK gestational trophoblastic disease service has increased the hCG concentration at which combination chemotherapy is started to more than 300 IU/L, to reduce the number of women being exposed to greater toxicity. Chemotherapy should be continued until hCG is within the normal range and then for a further 6 weeks (figure 6), helping to eliminate any residual tumour cells and reduce the chance of relapse. Only 30% of patients scoring 5–6 can be cured with lowrisk therapy.105,106,108,109 Therefore, revision of the FIGO scoring system would be helpful for early identification of the 70% of women in this group who develop resistance to methotrexate with folinic acid rescue and who need more intensive therapy. The amount of vascularisation as detected on doppler ultrasonography could help to provide the necessary additional information.93,94 Furthermore, data108 suggest that women in this category with an hCG concentration of more than 400 000 IU/L are unlikely to be cured by methotrexate with folinic acid rescue, so multidrug treatment should be given from the outset.108 High-risk disease Most high-risk patients with gestational trophoblastic neoplasia present with many metastases months or years after the causative pregnancy of any type. Symptoms and signs vary with disease location. Patients with brain metastases (figure 5) present with seizures, headaches, or hemiparesis,110 whereas those with lung metastasis or disease in the pulmonary vasculature might have a combination of haemoptysis, shortness of breath, or pleuritic chest pain.111 Menstrual irregularity is not universal, so unless clinicians consider gestational trophoblastic neoplasia in the differential of metastatic disease and measure the serum or urine hCG the diagnosis can be missed. If hCG concentrations are raised, the treating physician should consult the nearest gestational trophoblastic disease centre about management. Imaging investigations should include body CT, brain MRI, and pelvic MRI and Doppler ultrasonography (figure 5). If the brain scan is normal, a lumbar puncture to measure the ratio of cerebrospinal fluid to serum hCG (normal