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Treatments for Gestational Trophoblastic Disease Laura Kenny, Michael J Seckl Expert Rev of Obstet Gynecol. 2010;5(2):215-225. Abstract and Introduction Abstract Gestational trophoblastic disease (GTD) is a relatively rare but important group of benign and malignant disorders that affect women of child-bearing potential. Most cases are now diagnosed earlier than previously owing to advances in our knowledge of the disease and accuracy of ultrasonography, combined with the high analytical sensit
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  Treatments for Gestational Trophoblastic Disease Laura Kenny, Michael J SecklExpert Rev of Obstet Gynecol. 2010;5(2):215-225. Abstract and Introduction AbstractGestational trophoblastic disease (GTD) is a relatively rare but important group of benignand malignant disorders that affect women of child-bearing potential. Most cases are nowdiagnosed earlier than previously owing to advances in our knowledge of the disease andaccuracy of ultrasonography, combined with the high analytical sensitivity of humanchorionic gonadotrophin assays, although occasionally patients with metastases presentat a late stage with life-threatening complications. Early diagnosis and referral to aspecialist center for further management is vital so that patients can receive the optimalstandard of care. Patients can be grouped into high- and low-risk categories using well-established prognostic scoring systems, enabling the minimum appropriate treatment tobe recommended. Chemotherapy regimens for the disease are now well established, sothat for the vast majority, GTD is a curable condition, and patients can be reassured thatfertility is normally preserved. Regular follow-up by human chorionic gonadotrophinmeasurement following treatment is important for the detection of early relapse.Regimens for relapsed disease are usually successful, but need to be improved for theinfrequent cases that develop multiple drug resistance. In this article the subtypes of GTD,rationale for treatment, surgery and drugs used in the condition are discussed.IntroductionGestational trophoblastic disease (GTD) spans a spectrum from two premalignantconditions: partial and complete hydatidiform moles, to three malignant tumors, namely:invasive mole, gestational choriocarcinoma and placental-site trophoblastic tumor(PSTT); [1] the latter three are sometimes referred to as gestational trophoblastic neoplasia.Gestational trophoblastic tissue forms from the peripheral cells of the blastocyst a fewdays after conception. The tissue is divided into two layers: the outer syncytiotrophoblastcomposed of large mutinucelated cells and an inner layer of mononucleated cells thatmigrate out and fuse to form the cytotrophoblast. The syncytiotrophoblast subsequentlyaggressively invades the endometrium, generating an intimate connection between thefetus and the mother, known as the placenta. Normally, the growth of trophoblastic tissueis tightly regulated by as yet undefined mechanisms that prevent the development of   distant metastases. Malignant GTD occurs when these controling mechanisms fail, whichmay result in invasion of trophoblastic tissue through the myometrium, permittinghematogenous spread and tumor emboli to form.The revised International Federation of Gynecology and Obstetrics (FIGO) classification of GTD was developed in 2000 after many years of discussion between international expertsin the field, and is the most appropriate method for categorizing the disease into high- andlow-risk categories. [2] Successful management of GTD now means that for the vastmajority of patients the disease is curable. This has been largely dependent on acombination of centralized care leading to accumulated knowledge about the biology,pathology and natural history of the disease. Fertility can be preserved and normaloutcomes can be expected in subsequent pregnancies in most cases. [3] The tumors areextremely chemosensitive; the intensity of treatment is guided by the prognostic category(which comprises of human chorionic gonadotrophin [hCG] level, maternal age, length of time elapsed since previous pregnancy, size of uterine lesion, sites of metastases andnumber of previous chemotherapy regimens) at the time of referral. The high sensitivityand specificity of hCG assays allow the success of treatment to be followed accurately,enabling the early detection of treatment failure and relapse.While GTD is a relatively rare diagnosis, higher incidences (up to one in 300 pregnancies)are seen in certain populations, namely Brazil, the Philippines and in native AmericanIndians. The incidence in countries such as Japan appears to be falling, possibly owing tobetter data collection and reduced dependency on hospital-based surveys as opposed tonational population data, and possibly owing to dietary influences. This article focuses onthe Charing Cross Hospital (London, UK) experience. For a comprehensive review of thegenetic abnormalities underlying GTD, readers are referred to the paper published byFisher and Hodges. [4] The various types of hCG assays, subtypes of GTD, diagnosis,management options, and potential complications of the disease and treatment will bediscussed. HCG Assays β -subunit hCG ( β HCG) circulates in a variety of isoforms (hyperglycosylated hCG, nickedhCG, nicked hyperglycosylated hCG, hCG missing the β -subunit C-terminal extension, freea-subunit, free β -subunit, free β -subunit missing the C-terminal extension,hyperglycosylated-free β -subunit [ β hCG-H] and nicked-free β -subunit) as a result of post-translational modifications (nicked hCG occurs owing to the action of proteolytic enzymesin the placental, molar/cancer tissue or in the circulation). [5]    The detection of hCG in normal, early pregnancy is relatively straightforward, as themolecule is either intact or in the hyperglycosylated form (hCG-H). However, in cancer,the situation is more complex, as the assay needs to be sensitive enough to detect all hCGvariants equally well. The assays that are available commercially are licensed to detecthCG in pregnancy, but can result in significant differences in sensitivity when used incancer patients. Most centers use a commercial assay such as the Siemen Immulite® 1000(Siemens, IL, USA) to measure total hCG; however, no single hCG test has been approvedfor use in cancer. At Charing Cross, we use a noncommercial radioimmunoassay (RIA) thatcan detect a site on β HCG that is common to all the known forms of the hormone, andtherefore does not suffer from false negatives. Our experience in using the RIA in morethan 35,000 women with GTD has given us great confidence that we only rarely see falsepositives, and our comparative work with other assays has shown that our assay detectsall forms of hCG so far discovered equally, unlike the commercial assays examined. [6,7]  The false-positive results that can occur with hCG testing are often due to heterophileantibody production by the patient; however, these can be excluded by pairedmeasurement of hCG in the urine and serum as the antibodies are not excreted in theurine. It should be noted, however, that at low values of real hCG in the serum, there maybe no hCG detectable in the urine. This problem is overcome in our RIA by using serialdilutions of the serum; real hCG, unlike cross-reacting molecules that cause false-positiveresults, will reduce in accordance with the dilution. For commercial assays, mostmanufacturer's tests include animal serum and nonspecific animal antibodies, along withother components to prevent heterophilic antibody binding, and the incidence of false-positive hCG tests has declined. [5] There is a wide variability between different types of commercial hCG assays with regards to the sensitivity to detect all 13 dimer and subunitvariants. [6] RIAs have limited availability outside our center, and for further informationabout hCG assays, readers are referred to a comprehensive review on this subject byCole. [8]  The half-life of hCG is 24  – 36 s, and the amount of hCG produced corresponds to tumorvolume. Indeed, hCG is still the most valuable tumor marker available and is moresensitive than any commonly available imaging technique (a value of 5 U/l corresponds toa tumor volume of approximately 10 5 cells [9] ). It is important to remember that hCGproduction is not unique to pregnancy and GTD; for example, germ cell tumors and 15% of epithelial cell malignancies also produce the hormone. [10,11]   Partial & Complete Hydatidiform Moles  The incidence of partial moles (PMs) and complete moles (CMs) is 3:1000 and 1:1000 of normal pregnancies, respectively. Genetically PMs are nearly all triploid and occasionallytetraploid consisting of both maternal and paternal DNA. In PMs, the uterus is often notenlarged for gestational age and vaginal bleeding tends to occur in the second trimester,and occasionally patients present with a missed or incomplete abortion. [12] In fact, thediagnosis is rarely suspected until the histology of curettings is available. Clues to thediagnosis can occasionally be obtained by ultrasound. [13] The pre-evacuation hCG is over100,000 IU/l at diagnosis in over 90% of cases. Only 0.5% of PMs require chemotherapyfor postmolar GTD. [14]  New technologies such as gene-expression microarrays may have a role in the future forpredicting which patients require hCG follow-up postevacuation. CMs are nearly alwaysandrogenetic in srcin and result from the fertilization of an ovum lacking maternal genesby a single sperm, 23X, which then duplicates to form the homozygote 46XX. [15,16] Veryoccasionally the CM is biparental in srcin, when the maternal nuclear DNA isretained. [17] In 25% of cases, fertilization can occur by two spermatozoa, resulting in eitherthe 46XX or 46XY genotype; [18] the 46YY genotype has not yet been reported in cases of CM.The classical macroscopic 'bunch of grapes' appearance is usually seen when CMs presentin the second trimester, and is due to swelling of chorionic villi. Currently, CMs arenormally diagnosed in the first trimester when the villi contain little fluid and present witha threatened abortion or abnormal vaginal bleeding; the uterus is normally large forgestational dates. Ultrasound plays an important role in helping to raise suspicion that apregnancy is abnormal and could be molar, but in the absence of histology, this imagingmodality is not diagnostic  – as reviewed by Sebire and Seckl. [19] Occasionally, patients maypass grape-like structures or the entire mole. Those patients with rapid trophoblasticgrowth and extremely high hCG levels often present with hyperemesis and theca luteincysts (which may be palpable above the pelvic brim). Previously, patients used to presentwith preeclamptic toxemia, although this is rarely seen now owing to earlier diagnosisusing ultrasonography. Cross-reactivity between hCG and the thyroid-stimulatinghormone receptor may lead to the development of hyperthyroidism. [20]  The disease can also present at later stages with life-threatening complications frommetastases owing to a missed diagnosis; for example, when a spontaneous abortionoccurs at home, or because full histopathological examination of elective abortionmaterial is not performed routinely in abortion centers. The development of a screeningprocedure to avoid subsequent problems in such centers would avoid thiscomplication. [21] All patients who have surgery for an ectopic pregnancy should have
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