Ozalp SS, Oge T
Gestational trophoblastic diseases in Turkey.
J Reprod Med. 2013 Jan-Feb; 58(1-2):67-71 [PubMed]

OBJECTIVE: To evaluate epidemiological data, staging, prognostic scoring system and immunohistochemical reports as well as the management and outcome of hydatidiform mole (HM) in Turkey.
STUDY DESIGN: All published data in the Turkish literature from 1932-2011 were evaluated retrospectively.
RESULTS: The incidence of HM was 0.3-16 per 1,000 pregnancies and 1.0-24.5 per 1,000 deliveries. Of a total number of 929,323 pregnancies during a 68-year period, 2,227 HM cases were encountered, to give an average incidence of 2.39 per 1,000 pregnancies and 1.87 per 1,000 deliveries. Although there were big differences in reported incidences, the overall incidence is also very high, and the main reason for the differences was thought to be related to the origin of the studies: all were hospital based. An epidemiological field study of HM in the rural part of Turkey identified 4 HM cases and 6,274 pregnancies in 2,032 women aged 15-49. The frequency of HM per 1,000 live births and per 1,000 pregnancies was 0.8 and 0.6, respectively.
CONCLUSION: Multicenter, community-based studies are needed to present the real incidence, and it is vital that women with gestational trophoblastic disease be followed by a multidisciplinary team, and ideally in trophoblastic disease centers and national case registry systems for gestational trophoblastic disease.

Deng L, Zhang J, Wu T, Lawrie TA
Combination chemotherapy for primary treatment of high-risk gestational trophoblastic tumour.
Cochrane Database Syst Rev. 2013; 1:CD005196 [PubMed]

BACKGROUND: This is an update of the original review that was published in The Cochrane Database of Systematic Reviews, 2009, Issue 2. Gestational trophoblastic neoplasia (GTN) are malignant disorders of the placenta that include invasive hydatidiform mole, choriocarcinoma, placental-site trophoblastic tumour (PSTT) and epithelioid trophoblastic tumour (ETT). Choriocarcinoma and invasive hydatidiform mole respond well to chemotherapy: low-risk tumours are treated with single-agent chemotherapy (e.g. methotrexate or actinomycin D), whereas high-risk tumours are treated with combination chemotherapy (e.g. EMA/CO (etoposide, methotrexate, actinomycin D, cyclophosphamide and vincristine)). Various drug combinations may be used for high-risk tumours; however, the comparative efficacy and safety of these regimens is not clear.
OBJECTIVES: To determine the efficacy and safety of combination chemotherapy in treating high-risk GTN.
SEARCH METHODS: For the original review, we searched the Cochrane Group Specialised Register, Cochrane Central Register of Controlled Trials (CENTRAL; Issue 2, 2008), MEDLINE, EMBASE and CBM in May 2008. For the updated review, we searched Cochrane Group Specialised Register, CENTRAL, MEDLINE and EMBASE to September 2012. In addition, we searched online clinical trial registries for ongoing trials.
SELECTION CRITERIA: Randomised controlled trials (RCTs) and quasi-RCTs comparing first-line combination chemotherapy interventions in women with high-risk GTN.
DATA COLLECTION AND ANALYSIS: Two review authors independently collected data using a data extraction form. Meta-analysis could not be performed as we included only one study.
MAIN RESULTS: We included one RCT of 42 women with high-risk GTN who were randomised to MAC (methotrexate, actinomycin D and chlorambucil) or the modified CHAMOCA regimen (cyclophosphamide, hydroxyurea, actinomycin D, methotrexate, doxorubicin, melphalan and vincristine). There were no statistically significant differences in efficacy of the two regimens; however women in the MAC group experienced statistically significantly less toxicity overall and less haematological toxicity than women in the CHAMOCA group. During the study period, six women in the CHAMOCA group died compared with one in the MAC group. This study was stopped early due to unacceptable levels of toxicity in the CHAMOCA group. We identified no RCTs comparing EMA/CO with MAC or other chemotherapy regimens.
AUTHORS' CONCLUSIONS: CHAMOCA is not recommended for GTN treatment as it is more toxic and not more effective than MAC. EMA/CO is currently the most widely used first-line combination chemotherapy for high-risk GTN, although this regimen has not been rigorously compared to other combinations such as MAC or FAV in RCTs. Other regimens may be associated with less acute toxicity than EMA/CO; however, proper evaluation of these combinations in high-quality RCTs that include long-term surveillance for secondary cancers is required. We acknowledge that, given the low incidence of GTN, RCTs in this field are difficult to conduct, hence multicentre collaboration is necessary.

Huuskonen P, Myllynen P, Storvik M, Pasanen M
The effects of aflatoxin B1 on transporters and steroid metabolizing enzymes in JEG-3 cells.
Toxicol Lett. 2013; 218(3):200-6 [PubMed]

Effects of 96 h aflatoxin B1 (AFB1) exposure at concentrations from 0.2 μM to 6 μM on the mRNA and protein expression levels of the following transporters ABCB1/B4, ABCC1, ABCC2, ABCG2, OAT4 and the mRNA expression of steroid-metabolizing enzymes CYP1A1, CYP19A1, HSD3B1 and HSD17B1, and conjugating enzyme family UGT1A were evaluated in trophoblastic JEG-3 cells. Statistically significant dose-dependent five-fold increases in the expression levels with ABCC2 and OAT4 were recorded at 2 and 6μM AFB1. Protein expression of ABCG2 was decreased dose-dependently with 0.2-6 μM AFB1. With the other transporters, only a trend of increased expression was observed. Analogously, a three-fold increase in the expressions of CYP19A1, HSD3B1, HSD17B1 and UGT1A-family were observed at 0.3 μM AFB1. When an inhibitor of CYP19A1, finrozole, was dosed simultaneously with AFB1, no increases in the transcripts of transporters or steroid hydroxylases or CYP19A1 were observed. This delayed increase in the expression levels - only after 96h incubations - may indicate that the response is due to a secondary metabolite of AFB1 or other secondary controlling cascades rather than the parent compound itself. In conclusion, AFB1 affected the placental steroid synthesizing, metabolizing and conjugating enzymes as well as the expression levels of several transporter proteins in JEG-3 cells. These alterations may lead to anomalies in the foetoplacental hormonal homeostasis.

Sak ME, Soydinc HE, Evsen MS, et al.
Diploid karyotype partial mole coexisting with live term fetus--case report and review of the world literature.
Ginekol Pol. 2012; 83(10):789-91 [PubMed]

A partial molar pregnancy of diploid karyotype coexisting with live term fetus is a rare entity Most instances of partial mole are triploid and only a few eases of diploid partial moles with term delivery have been reported. Here, we report a case of partial mole concomitant with a 37-week live fetus. Postpartum karyotype of the placenta and the fetus revealed both as 46XX. Histological examination of the placenta showed a partial hydatidiform mole. We discuss the diagnosis based on presenting clinical picture and proper management of signs and symptoms of partial molar pregnancy coexisting with live term fetus and diploid karyotype, coupled with a review of the literature.

Taylor JS, Viera L, Caputo TA, et al.
Unsuccessful planned conservative resection of placental site trophoblastic tumor.
Obstet Gynecol. 2013; 121(2 Pt 2 Suppl 1):465-8 [PubMed]

BACKGROUND: Placental site trophoblastic tumor is a rare subtype of gestational trophoblastic neoplasia affecting women of reproductive age. The preferred method of treatment is surgical resection.
CASE: A 33-year-old woman, gravida 3 para 1111, was incidentally diagnosed with placental site trophoblastic tumor during an evaluation for infertility. As a result of persistent pathologic evidence of disease, she underwent a hysterectomy. The site of disease on pathologic review of the hysterectomy specimen was widely discordant from the preoperative imaging and hysteroscopic evaluations.
CONCLUSION: Wedge resection of the uterus has been suggested as an acceptable alternative to hysterectomy in women with placental site trophoblastic tumor who wish to preserve future fertility. However, this case demonstrated that preoperative imaging may not correlate with the tumor site, making wedge resection treatment ineffective.

Furtado LV, Paxton CN, Jama MA, et al.
Diagnostic utility of microsatellite genotyping for molar pregnancy testing.
Arch Pathol Lab Med. 2013; 137(1):55-63 [PubMed]

CONTEXT: Molecular genotyping by analysis of DNA microsatellites, also known as short tandem repeats (STRs), is an established method for diagnosing and classifying hydatidiform mole. Distinction of both complete hydatidiform mole and partial hydatidiform mole from nonmolar specimens is relevant for clinical management owing to differences in risk for persistent gestational trophoblastic disease.
OBJECTIVE: To determine the technical performance of microsatellite genotyping by using a commercially available multiplex assay, and to describe the application of additional methods to confirm other genetic abnormalities detected by the genotyping assay.
DESIGN: Microsatellite genotyping data on 102 cases referred for molar pregnancy testing are presented. A separate panel of mini STR markers, flow cytometry, fluorescence in situ hybridization, and p57 immunohistochemistry were used to characterize cases with other incidental genetic abnormalities.
RESULTS: Forty-eight cases were classified as hydatidiform mole (31, complete hydatidiform mole; 17, partial hydatidiform mole). Genotyping also revealed 11 cases of suspected trisomy and 1 case of androgenetic/biparental mosaicism. Trisomy for selected chromosomes (13, 16, 18, and 21) was confirmed in all cases by using a panel of mini STR markers.
CONCLUSIONS: This series illustrates the utility of microsatellite genotyping as a stand-alone method for accurate classification of hydatidiform mole. Other genetic abnormalities may be detected by genotyping; confirmation of the suspected abnormality requires additional testing.

Hyman DM, Bakios L, Gualtiere G, et al.
Placental site trophoblastic tumor: analysis of presentation, treatment, and outcome.
Gynecol Oncol. 2013; 129(1):58-62 [PubMed]

OBJECTIVE: Placental-site trophoblastic tumor (PSTT) is the rarest form of gestational trophoblastic disease (GTD). A risk-adapted treatment approach has been advocated, but controversy exists as to the most important prognostic markers for this disease. Our goal was to determine the prognostic markers for patients with PSTT seen at our center.
METHODS: We conducted a retrospective analysis of patients with PSTT seen at a single tertiary care center between 1996 and 2011. The association of FIGO stage, interval from antecedent pregnancy, antecedent pregnancy outcome, human chorionic gonadotropin (hCG) level, and age to overall survival was examined using univariate log-rank tests. Presentation, treatment, and outcome were summarized using descriptive statistics.
RESULTS: Data from 17 patients were analyzed. Eight (47%) had Stage I/II disease and 9 (53%) had Stage III/IV disease. Median overall survival for the entire cohort was 86 months (range, 2-101 months). Median duration of follow-up for surviving patients was 56 months. Increasing FIGO stage (I-III versus IV) was associated with a worse overall survival (p=0.009). Interval from antecedent pregnancy (≥12months), antecedent pregnancy outcome (full-term), hCG (≥1000 IU/L), and age (≥40) were not associated with worse survival.
CONCLUSION: FIGO stage, specifically Stage IV disease, was the most important predictor of overall survival in our cohort of PSTT patients.

Hedlund EM, Yang X, Zhang Y, et al.
Tumor cell-derived placental growth factor sensitizes antiangiogenic and antitumor effects of anti-VEGF drugs.
Proc Natl Acad Sci U S A. 2013; 110(2):654-9 [PubMed] Article available free on PMC after 08/07/2013

The role of placental growth factor (PlGF) in modulation of tumor angiogenesis and tumor growth remains an enigma. Furthermore, anti-PlGF therapy in tumor angiogenesis and tumor growth remains controversial in preclinical tumor models. Here we show that in both human and mouse tumors, PlGF induced the formation of dilated and normalized vascular networks that were hypersensitive to anti-VEGF and anti-VEGFR-2 therapy, leading to dormancy of a substantial number of avascular tumors. Loss-of-function using plgf shRNA in a human choriocarcinoma significantly accelerated tumor growth rates and acquired resistance to anti-VEGF drugs, whereas gain-of-function of PlGF in a mouse tumor increased anti-VEGF sensitivity. Further, we show that VEGFR-2 and VEGFR-1 blocking antibodies displayed opposing effects on tumor angiogenesis. VEGFR-1 blockade and genetic deletion of the tyrosine kinase domain of VEGFR-1 resulted in enhanced tumor angiogenesis. These findings demonstrate that tumor-derived PlGF negatively modulates tumor angiogenesis and tumor growth and may potentially serve as a predictive marker of anti-VEGF cancer therapy.

Alazzam M, Tidy J, Osborne R, et al.
Chemotherapy for resistant or recurrent gestational trophoblastic neoplasia.
Cochrane Database Syst Rev. 2012; 12:CD008891 [PubMed]

BACKGROUND: Gestational trophoblastic neoplasia (GTN) is a highly curable group of pregnancy-related tumours; however, approximately 25% of GTN tumours will be resistant to, or will relapse after, initial chemotherapy. These resistant and relapsed lesions will require salvage chemotherapy with or without surgery. Various salvage regimens are used worldwide. It is unclear which regimens are the most effective and the least toxic.
OBJECTIVES: To determine which chemotherapy regimen/s for the treatment of resistant or relapsed GTN is/are the most effective and the least toxic.
SEARCH METHODS: We searched the Cochrane Gynaecological Cancer Group Specialised Register, the Cochrane Central Register of Controlled Trials (CENTRAL, Issue 4), MEDLINE and EMBASE up to October 2011. In addition, we handsearched the relevant society conference proceedings and study reference lists.
SELECTION CRITERIA: Only randomised controlled trials (RCTs) were included.
DATA COLLECTION AND ANALYSIS: We designed a data extraction form and planned to use random-effects methods in Review Manager 5.1 for meta-analyses.
MAIN RESULTS: The search identified no RCTs; therefore we were unable to perform any meta-analyses.
AUTHORS' CONCLUSIONS: RCTs in GTN are scarce owing to the low prevalence of this disease and its highly chemosensitive nature. As chemotherapeutic agents may be associated with substantial side effects, the ideal treatment should achieve maximum efficacy with minimal side effects. For methotrexate-resistant or recurrent low-risk GTN, a common practice is to use sequential five-day dactinomycin, followed by MAC (methotrexate, dactinomycin, cyclophosphamide) or EMA/CO (etoposide, methotrexate, dactinomycin, cyclophosphamide, vinblastine) if further salvage therapy is required. However, five-day dactinomycin is associated with more side effects than pulsed dactinomycin, therefore an RCT comparing the relative efficacy and safety of these two regimens in the context of failed primary methotrexate treatment is desirable.For high-risk GTN, EMA/CO is the most commonly used first-line therapy, with platinum-etoposide combinations, particularly EMA/EP (etoposide, methotrexate, dactinomycin/etoposide, cisplatin), being favoured as salvage therapy. Alternatives, including TP/TE (paclitaxel, cisplatin/ paclitaxel, etoposide), BEP (bleomycin, etoposide, cisplatin), FAEV (floxuridine, dactinomycin, etoposide, vincristine) and FA (5-fluorouracil (5-FU), dactinomycin), may be as effective as EMA/EP and associated with fewer side effects; however, this is not clear from the available evidence and needs testing in well-designed RCTs. In the UK, an RCT comparing interventions for resistant/recurrent GTN will be very challenging owing to the small numbers of patients with this scenario. International multicentre collaboration is therefore needed to provide the high-quality evidence required to determine which salvage regimen/s have the best effectiveness-to-toxicity ratio in low- and high-risk disease. Future research should include economic evaluations and long-term surveillance for secondary neoplasms.

Alifrangis C, Agarwal R, Short D, et al.
EMA/CO for high-risk gestational trophoblastic neoplasia: good outcomes with induction low-dose etoposide-cisplatin and genetic analysis.
J Clin Oncol. 2013; 31(2):280-6 [PubMed]

PURPOSE: Patients with high-risk (International Federation of Gynecology and Obstetrics score ≥ 7) gestational trophoblastic neoplasia (GTN) frequently receive etoposide, methotrexate, and dactinomycin alternating weekly with cyclophosphamide and vincristine (EMA/CO). Between 1979 and 1995, overall survival (OS) with this regimen at our institute was 85.4% with a significant proportion of early deaths (< 4 weeks). Here, we determine whether survival rates have improved in a more recent patient cohort (1995 to 2010).
PATIENTS AND METHODS: Patients receiving EMA/CO were identified using the Charing Cross GTN database. Genetic analysis identified nongestational trophoblastic tumors (nGTTs). The use of induction low-dose etoposide 100 mg/m(2) and cisplatin 20 mg/m(2) (EP; days 1 and 2 every 7 days) since 1995 to reduce early deaths before commencing EMA/CO was noted.
RESULTS: Four hundred thirty-eight patients received EMA/CO between 1995 and 2010. Six patients had nGTTs, 140 had high-risk disease, and 250 had relapsed/resistant low-risk GTN. OS was 94.3% in high-risk patients (90.4% including nGTTs) and 99.6% in the low-risk group, with a median follow-up time of 4.2 years. All patients with nGTT and seven patients with high-risk GTNs died as a result of drug-resistant disease. EP induction chemotherapy was given to 23.1% of high-risk patients (33 of 140 patients) with a large disease burden, and the early death rate was only 0.7% (n = 1; 95% CI, 0.1% to 3.7%) compared with 7.2% (n = 11 of 151 patients; 95% CI, 4.1% to 12.6%) in the pre-1995 cohort.
CONCLUSION: OS after EMA/CO for high-risk GTN has increased by nearly 9%. This reflects a more accurate estimate of OS by excluding nGTTs (3.9%) in patients with atypical presentations using genetic diagnosis. Low-dose induction EP in selected individuals also allows near complete elimination of early deaths. The latter should be considered routinely in high-risk GTN.

Vereczkey I, Csernák E, Olasz J, et al.
Renal choriocarcinoma: gestational or germ cell origin?
Int J Surg Pathol. 2012; 20(6):623-8 [PubMed]

Choriocarcinoma is a rare, highly malignant trophoblastic tumor with gestational or, rarely, germ cell origin. Primary extragenital localization is extremely rare. This report describes a choriocarcinoma case clinically mimicking a primary renal cell carcinoma with multiplex pulmonary metastases. Differentiation from a sarcomatoid renal cell carcinoma with trophoblastic differentiation and identification of the exact origin, namely gestational or germ cell origin by molecular genetic methods is of great importance as it helps determine the prognosis and the most effective therapy of the disease. The Investigator Hexaplex ESS Kit was used for DNA polymorphism studies. This showed foreign alleles in the tumor DNA that confirmed the presence of paternal DNA and the gestational origin of the tumor.

Niimi K, Yamamoto E, Fujiwara S, et al.
High expression of N-acetylglucosaminyltransferase IVa promotes invasion of choriocarcinoma.
Br J Cancer. 2012; 107(12):1969-77 [PubMed] Article available free on PMC after 04/12/2013

BACKGROUND: Gestational trophoblastic diseases (GTDs) are related to trophoblasts, and human chorionic gonadotropin (hCG) is secreted by GTDs as well as normal placentas. However, the asparagine-linked sugar chains on hCG contain abnormal biantennary structures in invasive mole and choriocarcinoma, but not normal pregnancy or hydatidiform mole. N-acetylglucosaminyltransferase-IV (GnT-IV) catalyses β1,4-N-acetylglucosamine branching on asparagine-linked oligosaccharides, which are consistent with the abnormal sugar chain structures on hCG.
METHODS: We investigated GnT-IVa expression in GTDs and placentas by immunohistochemistry, western blot, and RT-PCR. We assessed the effects of GnT-IVa knockdown in choriocarcinoma cells in vitro and in vivo.
RESULTS: The GnT-IVa was highly expressed in trophoblasts of invasive mole and choriocarcinoma, and moderately in extravillous trophoblasts during the first trimester, but not in hydatidiform mole or other normal trophoblasts. The GnT-IVa knockdown in choriocarcinoma cells significantly reduced migration and invasive capacities, and suppressed cellular adhesion to extracellular matrix proteins. The extent of β1,4-N-acetylglucosamine branching on β1 integrin was greatly reduced by GnT-IVa knockdown, although the expression of β1 integrin was not changed. In vivo studies further demonstrated that GnT-IVa knockdown suppressed tumour engraftment and growth.
CONCLUSION: These findings suggest that GnT-IVa is involved in regulating invasion of choriocarcinoma through modifications of the oligosaccharide chains of β1 integrin.

Aguin E, Aguin V, Cisneros L, et al.
Does cerclage improve neonatal outcomes in a molar pregnancy and a coexistent fetus? A case report.
BMC Res Notes. 2012; 5:621 [PubMed] Article available free on PMC after 04/12/2013

BACKGROUND: Complete hydatiform mole and coexistent viable fetus is very rare. The use of a cervical cerclage for cervical indications in the presence of this condition has never been reported. Although the diagnosis was made postnatal, the objective is to present a case with good neonatal outcome.
CASE PRESENTATION: A patient presented with vaginal spotting around 23 weeks. She has a history of four preterm deliveries. Her cervix was dilated and a cerclage was placed. She presented again with PPROM around 25 weeks. She went into spontaneous preterm labor and delivered a viable fetus that is a healthy girl today. Eventually the pathology of the placenta showed a complete hydatidiform mole.
CONCLUSION: It is necessary to inform patients about the potential risks and poor outcomes of this condition. For those who desire all potential interventions, cerclage placement could be considered.

Heidar Z, Sarfjoo FS, Zademodares S, et al.
Molar ectopic pregnancy after tubectomy.
Acta Med Iran. 2012; 50(8):565-7 [PubMed]

Tubal ectopic hydatidiform mole is an uncommon but very important complication of pregnancy. The clinical manifestation is the same as ectopic pregnancy and in all of the cases management was the same as tubal ectopic pregnancy. We present a case of tubal ectopic pregnancy that after laparotomy and salpingectomy, pathologic examination reported hydatidiform mole within ectopic gestational tissue. So, a high index of suspicious is necessary for prompt diagnosis and correct fallow up of the patient.

Lybol C, Thomas CM, Blanken EA, et al.
Comparing cisplatin-based combination chemotherapy with EMA/CO chemotherapy for the treatment of high risk gestational trophoblastic neoplasia.
Eur J Cancer. 2013; 49(4):860-7 [PubMed]

BACKGROUND: Cisplatin-based chemotherapy (etoposide 100 mg/m(2) days 1-5, methotrexate 300 mg/m(2) day 1, cyclophosphamide 600 mg/m(2) day 1, actinomycin D 0.6 mg/m(2) day 2 and cisplatin 60 mg/m(2) day 4, EMACP) was compared to EMA/CO (etoposide 100 mg/m(2) days 1-2, methotrexate 300 mg/m(2) day 1 and actinomycin D 0.5 mg i.v. bolus day 1 and 0.5 mg/m(2) day 2, alternating with cyclophosphamide 600 mg/m(2) day 8 and vincristine 1 mg/m(2) day 8) for the treatment of high-risk gestational trophoblastic neoplasia (GTN).
PATIENTS AND METHODS: In the Netherlands, 83 patients were treated with EMACP and 103 patients with EMA/CO. Outcome measures were remission rate, median number of courses to achieve normal human chorionic gonadotrophin (hCG) concentrations, toxicity, recurrent disease rate and disease specific survival.
RESULTS: Remission rates were similar (EMACP 91.6%, EMA/CO 85.4%). The median number of courses of EMA/CO to reach hCG normalisation for single-agent resistant disease and primary high-risk disease was three and five courses, respectively, compared to 1.5 (p=0.001) and three (p<0.001) courses of EMACP. Patients treated with EMACP more often developed fever, renal toxicity, nausea and diarrhoea compared to patients treated with EMA/CO. Patients treated with EMA/CO more often had anaemia, neuropathy and hepatotoxicity.
CONCLUSION: EMACP combination chemotherapy is an effective treatment for high-risk GTN, with a remission rate comparable to EMA/CO. However, the difference in duration of treatment is only slightly shorter with EMACP. Cisplatin-based chemotherapy in the form of EMACP in this study was not proven more effective than EMA/CO.

Rahman RA, Ahmad S, Ismail NA, Mahdy ZA
Complete mole with a coexistent normal fetus: a case report.
J Reprod Med. 2012 Sep-Oct; 57(9-10):456-8 [PubMed]

BACKGROUND: The incidence of a coexistent normal fetus is quoted in literature as 1 in 22,000 to 100,000 pregnancies and may be associated with multiple complications including persistent trophoblastic neoplasia.
CASE: A 35-year-old woman with a complete mole and a coexistent normal fetus presented with multiple complications but was successfully managed until 30 weeks' gestation and gave birth to a healthy, normal female fetus. After delivery the mother recovered completely with no evidence of persistent trophoblastic disease.
CONCLUSION: Although termination of pregnancy is an option chosen by most patients, continuing the pregnancy while optimizing the maternal condition by appropriate management of complications can result in a successful outcome.

Diaz J, Thomas MB, Paz-Pabon C, Hernandez E
Methotrexate on a 21-day cycle for low-risk gestational trophoblastic neoplasia.
J Reprod Med. 2012 Sep-Oct; 57(9-10):411-4 [PubMed]

OBJECTIVE: To perform an outcome analysis of patients with low-risk gestational trophoblastic neoplasia (GTN) treated with a 5-day intramuscular methotrexate (MTX) regimen on a 21-day cycle.
STUDY DESIGN: A retrospective review of 31 patients with low-risk GTN treated with a 5-day MTX regimen.
RESULTS: A total of 31 patients with low-risk GTN (WHO score < 7) received single-agent MTX at a dose of 0.4 mg/kg daily for 5 days every 21 days (mean number of cycles, 3; 83% remission). The only significant toxicity encountered was grade 2 stomatitis in 8 (26%) patients.
CONCLUSION: A 5-day MTX regimen given every 21 days is convenient, well-tolerated and effective for patients with low-risk GTN.

Li M, Wu MY, Han Y, Li R
Hydatidiform mole in a perimenopausal and primary infertility patient: case report.
Eur J Gynaecol Oncol. 2012; 33(4):438-40 [PubMed]

We present a case of a 56-year-old woman with primary infertility who complained of amenorrhea for five months and vaginal bleeding for two months. Initially she was misdiagnosed with endometrial cancer due to her disease history and older age, but eventually a diagnosis of complete hydatidiform mole was confirmed and then laparoscopic total hysterectomy was performed. The patient has been followed-up as an outpatient for more than one year, and hads an excellent prognosis. To our knowledge, this is the first case of hydatidiform mole in a woman with primary infertility during the perimenopausal stage. Even though hydatidiform mole is rare in primary infertility patients during perimenopause, it should always be considered in case of misdiagnosis.

Fu J, Fang F, Xie L, et al.
Prophylactic chemotherapy for hydatidiform mole to prevent gestational trophoblastic neoplasia.
Cochrane Database Syst Rev. 2012; 10:CD007289 [PubMed]

BACKGROUND: Hydatidiform mole (HM), also called a molar pregnancy, is characterised by an overgrowth of foetal chorionic tissue within the uterus. HMs may be partial (PM) or complete (CM) depending on their gross appearance, histopathology and karyotype. PMs usually have a triploid karyotype, derived from maternal and paternal origins, whereas CMs are diploid and have paternal origins only. Most women with HM can be cured by evacuation of retained products of conception (ERPC) and their fertility preserved. However, in some women the growth persists and develops into gestational trophoblastic neoplasia (GTN), a malignant form of the disease that requires treatment with chemotherapy. CMs have a higher rate of malignant transformation than PMs. It may be possible to reduce the risk of GTN in women with HM by administering prophylactic chemotherapy (P-Chem). However, P-Chem given before or after evacuation of HM to prevent malignant sequelae remains controversial, as the risks and benefits of this practice are unclear.
OBJECTIVES: To systematically review the evidence for the effectiveness and safety of P-Chem to prevent GTN in women with a molar pregnancy.
SEARCH METHODS: We performed electronic searches in the Cochrane Gynaecological Cancer Specialised Register, the Cochrane Central Register of Controlled Trials (CENTRAL, Issue 2, 2012), MEDLINE (1946 to February week 4, 2012) and EMBASE (1980 to week 9, 2012). The search strategy was developed using free text and medical subject headings (MESH). We handsearched reference lists of relevant literature to identify additional studies.
SELECTION CRITERIA: We included randomised controlled trials (RCTs) of P-Chem for HM.
DATA COLLECTION AND ANALYSIS: Two review authors independently assessed studies for inclusion in the review and extracted data using a specifically designed data collection form. Meta-analyses were performed by pooling data from individual trials using RevMan 5.1 software.
MAIN RESULTS: We included three RCTs with a combined total of 613 participants. One study compared prophylactic dactinomycin to no prophylaxis (60 participants); the other two studies compared prophylactic methotrexate to no prophylaxis (420 and 133 participants). All participants were diagnosed with CMs. We considered the latter two studies to be of poor methodological quality.P-Chem reduced the risk of GTN occurring in women following a CM (3 studies, 550 participants; RR 0.37; 95% confidence interval (CI) 0.24 to 0.57; I(2) = 0%; P < 0.00001), However, owing to the poor quality of two of the included studies, we performed sensitivity analyses excluding these two studies. This left only one small study of high-risk women to contribute data for this primary outcome (59 participants; RR 0.28; 95% CI 0.10 to 0.73; P = 0.01), therefore we consider this evidence to be of a low quality.The time to diagnosis was longer in the P-Chem group than the control group (2 studies, 33 participants; mean difference (MD) 28.72; 95% CI 13.19 to 44.24; P = 0.0003) and the P-Chem group required more courses to cure subsequent GTN (1 poor-quality study, 14 participants; MD 1.10; 95% CI 0.52 to 1.68; P = 0.0002). We consider this evidence to be of a low to very low quality for similar reasons to those listed above.There were insufficient data to perform meta-analyses for toxicity, overall survival, drug resistance and reproductive outcomes.
AUTHORS' CONCLUSIONS: P-Chem may reduce the risk of progression to GTN in women with CMs who are at a high risk of malignant transformation; however, current evidence in favour of P-Chem is limited by the poor methodological quality and small size of the included studies. As P-Chem may increase drug resistance, delay treatment of GTN and expose women unnecessarily to toxic side effects, this practice cannot currently be recommended.

Fujiyoshi Y, Jiang S, Feng X
Intramucosal stomach adenocarcinoma metastasizing as a large intraabdominal mass with focal choriocarcinomatous differentiation.
Int J Clin Exp Pathol. 2012; 5(8):845-51 [PubMed] Article available free on PMC after 04/12/2013

We report a case of gastric intramucosal adenocarcinoma giving rise to a large metastatic intraabdominal mass with focal choriocarcinomatous differentiation. The main histological picture of the surgically resected abdominal tumor was well differentiated adenocarcinoma with focal choriocarcinomatous differentiation. Serum hCGβ level showed 710mIU/dl postoperatively, and the gastric lesion featured small foci of well differentiated adenocarcinoma in adenoma with no choriocarcinomatous differentiation. The origin of the abdominal tumor was the main point of question. HNF4α is a transcription factor of embryonic liver differentiation, whose distribution is restricted to hepatocytes and certain neoplastic tissue including gastric adenocarcinoma. Hep Par 1 is originally developed for the discrimination of hepatocellular carcinoma, but a part of gastric adenocarcinoma also shows positive staining. Immunostaining with panel of antibodies for CK7, CK20, HNF4α, and Hep-Par1 showed pattern of gastric adenocarcinoma, and a diagnosis of a very rare intramucosal gastric adenocarcinoma metastatic to the abdominal cavity was established. Diagnostic utility of the panels of above antibodies for discrimination of the tumor origin was confirmed, and the relation between the metastatic ability of the gastric adenocarcinoma and its choriocarcinomatous differentiation is discussed.

Sita-Lumsden A, Short D, Lindsay I, et al.
Treatment outcomes for 618 women with gestational trophoblastic tumours following a molar pregnancy at the Charing Cross Hospital, 2000-2009.
Br J Cancer. 2012; 107(11):1810-4 [PubMed] Article available free on PMC after 20/11/2013

BACKGROUND: Post-molar pregnancy gestational trophoblastic tumours (GTT) have been curable with chemotherapy treatment for over 50 years. Because of the rarity of the diagnosis, detailed structured information on prognosis, treatment escalations and outcome is limited.
METHODS: We have reviewed the demographics, prognostic variables, treatment course and clinical outcomes for the post-mole GTT patients treated at Charing Cross Hospital between 2000 and 2009.
RESULTS: Of the 618 women studied, 547 had a diagnosis of complete mole, 13 complete mole with a twin conception and 58 partial moles. At the commencement of treatment, 94% of patients were in the FIGO low-risk group (score 0-6). For patients treated with single-agent methotrexate, the primary cure rate ranged from 75% for a FIGO score of 0-1 through to 31% for those with a FIGO score of 6.
CONCLUSION: In the setting of a formal follow-up programme, the expected cure rate for GTT after a molar pregnancy should be 100%. Prompt treatment and diagnosis should limit the exposure of most patients to combination chemotherapy. Because of the post-treatment relapse rate of 3% post-chemotherapy, hCG monitoring should be performed routinely.

Geramizadeh B, Rad H
Cutaneous metastasis of testicular choriocarcinoma, diagnosed by fine-needle aspiration cytology: a rare case report and review of the literature.
Indian J Pathol Microbiol. 2012 Jul-Sep; 55(3):406-8 [PubMed]

Skin metastasis of testicular choriocarcinoma is very rare. Until now about nine cases have been reported in the English literature; however, only one of them has been diagnosed by fine-needle aspiration (FNA) cytology. Herein, we report our experience with FNA cytology diagnosis of a metastatic testicular choriocarcinoma to the skin of chin. The combination of highly atypical mononuclear cells (cytotrophoblasts) and multinucleated malignant cells (syncytiotrophoblasts) are characteristic of metastatic tumor in a known case of choriocarcinoma of testis.

Gupta M, Vang R, Yemelyanova AV, et al.
Diagnostic reproducibility of hydatidiform moles: ancillary techniques (p57 immunohistochemistry and molecular genotyping) improve morphologic diagnosis for both recently trained and experienced gynecologic pathologists.
Am J Surg Pathol. 2012; 36(12):1747-60 [PubMed]

Distinction of hydatidiform moles from nonmolar specimens (NMs) and subclassification of hydatidiform moles as complete hydatidiform mole (CHM) and partial hydatidiform mole (PHM) are important for clinical practice and investigational studies; however, diagnosis based solely on morphology is affected by interobserver variability. Molecular genotyping can distinguish these entities by discerning androgenetic diploidy, diandric triploidy, and biparental diploidy to diagnose CHMs, PHMs, and NMs, respectively. Eighty genotyped cases (27 CHMs, 27 PHMs, 26 NMs) were selected from a series of 200 potentially molar specimens previously diagnosed using p57 immunohistochemistry and genotyping. Cases were classified by 6 pathologists (3 faculty level gynecologic pathologists and 3 fellows) on the basis of morphology, masked to p57 immunostaining and genotyping results, into 1 of 3 categories (CHM, PHM, or NM) during 2 diagnostic rounds; a third round incorporating p57 immunostaining results was also conducted. Consensus diagnoses (those rendered by 2 of 3 pathologists in each group) were also determined. Performance of experienced gynecologic pathologists versus fellow pathologists was compared, using genotyping results as the gold standard. Correct classification of CHMs ranged from 59% to 100%; there were no statistically significant differences in performance of faculty versus fellows in any round (P-values of 0.13, 0.67, and 0.54 for rounds 1 to 3, respectively). Correct classification of PHMs ranged from 26% to 93%, with statistically significantly better performance of faculty versus fellows in each round (P-values of 0.04, <0.01, and <0.01 for rounds 1 to 3, respectively). Correct classification of NMs ranged from 31% to 92%, with statistically significantly better performance of faculty only in round 2 (P-values of 1.0, <0.01, and 0.61 for rounds 1 to 3, respectively). Correct classification of all cases combined ranged from 51% to 75% by morphology and 70% to 80% with p57, with statistically significantly better performance of faculty only in round 2 (P-values of 0.69, <0.01, and 0.15 for rounds 1 to 3, respectively). p57 immunostaining significantly improved recognition of CHMs (P<0.01) and had high reproducibility (κ=0.93 to 0.96) but had no impact on distinction of PHMs and NMs. Genotyping provides a definitive diagnosis for the ∼25% to 50% of cases that are misclassified by morphology, especially those that are also unresolved by p57 immunostaining.

Flores-Martín J, Rena V, Márquez S, et al.
StarD7 knockdown modulates ABCG2 expression, cell migration, proliferation, and differentiation of human choriocarcinoma JEG-3 cells.
PLoS One. 2012; 7(8):e44152 [PubMed] Article available free on PMC after 20/11/2013

BACKGROUND: StAR-related lipid transfer domain containing 7 (StarD7) is a member of the START-domain protein family whose function still remains unclear. Our data from an explorative microarray assay performed with mRNAs from StarD7 siRNA-transfected JEG-3 cells indicated that ABCG2 (ATP-binding cassette sub-family G member 2) was one of the most abundantly downregulated mRNAs.
METHODOLOGY/PRINCIPAL FINDINGS: Here, we have confirmed that knocking down StarD7 mRNA lead to a decrease in the xenobiotic/lipid transporter ABCG2 at both the mRNA and protein levels (-26.4% and -41%, p<0.05, at 48 h of culture, respectively). Also a concomitant reduction in phospholipid synthesis, bromodeoxyuridine (BrdU) uptake and (3)H-thymidine incorporation was detected. Wound healing and transwell assays revealed that JEG-3 cell migration was significantly diminished (p<0.05). Conversely, biochemical differentiation markers such as human chorionic gonadotrophin β-subunit (βhCG) protein synthesis and secretion as well as βhCG and syncytin-1 mRNAs were increased approximately 2-fold. In addition, desmoplakin immunostaining suggested that there was a reduction of intercellular desmosomes between adjacent JEG-3 cells after knocking down StarD7.
CONCLUSIONS/SIGNIFICANCE: Altogether these findings provide evidence for a role of StarD7 in cell physiology indicating that StarD7 modulates ABCG2 multidrug transporter level, cell migration, proliferation, and biochemical and morphological differentiation marker expression in a human trophoblast cell model.

Lybol C, Centen DW, Thomas CM, et al.
Fatal cases of gestational trophoblastic neoplasia over four decades in the Netherlands: a retrospective cohort study.
BJOG. 2012; 119(12):1465-72 [PubMed]

OBJECTIVE: To describe fatal cases of gestational trophoblastic neoplasia (GTN) over four decades and evaluate whether treatment was given according to the protocol and reveal possible implications for future management.
DESIGN: Retrospective cohort study.
SETTING: The Netherlands.
POPULATION: Women who died from GTN from 1971 to 2011.
METHODS: Records from the Dutch Central Registry for Hydatidiform Moles and the Working Party on Trophoblastic Disease were used to identify fatal cases of GTN.
MAIN OUTCOME MEASURES: Disease extent, risk classification, treatment regimens and cause of death.
RESULTS: Twenty-six women died from GTN. In five cases GTN developed after a hydatidiform mole and in 19 cases following term pregnancy. Half of the women died between 1971 and 1980, when women were not yet classified as having low-risk or high-risk disease and were therefore not yet treated accordingly. A major decline in the number of deaths was seen after the first decade, with a further decrease from 1981 to 2011. Early death occurred in nine women. In four of these women, death was treatment-related. Women who died more than 4 weeks after the start of treatment mostly died from metastatic tumour (n = 14).
CONCLUSIONS: The yearly number of women who died from GTN decreased considerably over the last four decades. Appropriate risk classification is essential to start optimal initial therapy and to prevent therapy resistance. Women with post-term choriocarcinoma represented a large proportion of the dead women and we propose that these women are considered as having high-risk disease.

Andreasen L, Bolund L, Niemann I, et al.
Mosaic moles and non-familial biparental moles are not caused by mutations in NLRP7, NLRP2 or C6orf221.
Mol Hum Reprod. 2012; 18(12):593-8 [PubMed]

Hydatidiform moles (HMs) most often occur sporadically and are either diploid androgenetic or triploid. The very rare familial recurrent HMs (FRHMs) have been related to NLRP7 and C6orf221 mutations in the mother. FRHMs are most often diploid with both maternal and paternal origin of the molar genome. We have screened a cohort of 11 women with diploid HMs with biparental contributions to the molar genome with regard to mutations in NLRP7, NLRP2, the NLRP gene most homologous to NLRP7, and C6orf221. This was done in order to reveal if mutations in the mentioned genes play a major role in development of non-recurrent biparental moles. Recently, we have shown that eight of these diploid moles consist of two different cell lines. Only one woman had a mutation in the coding DNA sequence of NLRP7, which most likely contributed to HM development. This woman had non-mosaic repeated moles, and she was the only woman in our cohort with FRHM. We found no unequivocal pathogenic mutations in NLRP2 or C6orf221. Our observations suggest that although NLRP7 and C6orf221 mutations are related to diploid biparental FRHMs, neither of these genes, nor NLRP2, are related to diploid HMs with biparental contributions to the molar genome, in general.

Unsal MA, Guven S
Complete hydatidiform mole coexisting with a live fetus.
Clin Exp Obstet Gynecol. 2012; 39(2):262-4 [PubMed]

The co-existence of a hydatidiform mole with a living fetus is a rare phenomenon. The condition is a dilemma with respect to the diagnosis and management of associated maternal (a risk of maternal complications, such as preeclampsia, hyperthyrodism, and a risk of malignancy) and fetal (elevated risk of spontaneous abortion, neonatal thyrotoxicosis) complications. A 27-year-old woman was referred to our hospital with a diagnosis of hydatidiform mole and live fetus. The pregnancy was unremarkable except for the complaints of excessive nausea and vomiting. Successive ultrasound examinations demonstrated a normally growing live fetus (14 weeks) alongside a normal placenta and an additional intrauterine echogenic mass with features of hydatidiform mole. Genetic amniocentesis at 18 weeks' of gestation showed normal diploid fetal karyotype. At 20 weeks of pregnancy, a control prenatal visit revealed intrauterine fetal death. The follow-up period for two years was unremarkable. In the case of a normal fetal karyotype and the absence of serious signs of maternal pathology, waiting until fetal viability is achieved can justifiably be proposed, however there is still a risk of prenatal complications such as intrauterine death.

Akbayir O, Alkis I, Corbacioglu A, et al.
Exaggerated placental site reaction detected during caesarean delivery: a case report.
Clin Exp Obstet Gynecol. 2012; 39(2):234-5 [PubMed]

Exaggerated placental site (EPS) reaction is an exuberant physiologic process in which intermediate trophoblasts infiltrate the underlying endometrium and myometrium at the implantation site. During a caesarean section, we noted a polypoid well shaped smooth lesion, about 3 cm in diameter on the anterior wall of the uterus apart from the placenta. The histopathologic examination revealed an exuberant proliferation of trophoblastic cells in the placental site, a low Ki-67 labelling index and the absence of mitotic activity. Distinguishing EPS reaction from the other intermediate trophoblastic tumours is critical, as the latter may likely involve surgical intervention and/or chemotherapy, although no specific treatment and follow-up is required for EPS reaction. It is necessary to be aware of this pathology and take biopsies from suspicious lesions in the placental site for pathologic examination.

Lee MJ, Vogt AP, Hsiao W, Osunkoya AO
CDX-2 expression in malignant germ cell tumors of the testes, intratubular germ cell neoplasia, and normal seminiferous tubules.
Tumour Biol. 2012; 33(6):2185-8 [PubMed]

CDX-2 is a caudal-type homeobox gene, encoding a transcription factor that plays an important role in proliferation and differentiation of intestinal epithelial cells. The utility of antibodies to CDX2 in the identification of adenocarcinomas of the gastrointestinal tract, particularly colorectal adenocarcinomas, in both primary and metastatic settings is well established. It is well-known that patients with testicular tumors may occasionally lack an obvious palpable mass. However, the expression of CDX2 in malignant germ cell tumors of the testes which have metastatic potential has not been previously studied in a large series. A tissue microarray was constructed from 52 malignant germ cell tumors of the testes including: 29 cases of classic seminoma, 8 cases of embryonal carcinoma, 8 cases of yolk sac tumor, 4 cases of malignant teratoma, 2 cases of choriocarcinoma, and 1 case of spermatocytic seminoma. Ten cases of intratubular germ cell neoplasia and seven cases of benign testicles with normal seminiferous tubules were also included in tissue microarray. Immunohistochemical stains for CDX2 was performed and analyzed. Only nuclear staining was considered positive. Positive expression of CDX2 was identified in 2/2 cases (100 %) of choriocarcinoma, 4/8 cases (50 %) of teratoma, 3/8 cases (38 %) of embryonal carcinoma, 3/8 cases (38 %) of yolk sac tumor, and 1/29 cases (3 %) of classic seminoma. CDX2 was negative in all cases of intratubular germ cell neoplasia, normal seminiferous tubules, and the only case of spermatocytic seminoma. The role of CDX-2 in the differentiation of intestinal/enteric epithelial cells may contribute to the formation of trophoblastic, glandular, villous, or cystic structures in germ cell tumors of the testes. This study suggests that the expression of CDX2 in a variety of malignant germ cell tumors of the testes may be a potential pitfall in metastatic tumors of unknown primary, which are thought to be of gastrointestinal/colorectal origin but are actually from a clinically occult testicular tumor.

Baptista AM, Belfort P
Comparison of methotrexate, actinomycin D, and etoposide for treating low-risk gestational trophoblastic neoplasia.
Int J Gynaecol Obstet. 2012; 119(1):35-8 [PubMed]

OBJECTIVE: To compare the efficacy and toxicity of 3 single agent chemotherapeutic regimens in low-risk gestational trophoblastic neoplasia (LRGTN).
METHODS: A prospective study was conducted at a referral center in Rio de Janeiro, Brazil. Patients presenting with metastatic or non-metastatic LRGTN (risk score ≤ 6) in non-probabilistic sampling were assigned to 1 of 3 treatments: methotrexate with folinic acid rescue (MTX-CF; n=20); actinomycin D (n=20); and etoposide (n=20). Women with less than 1 year of disease-free follow-up after the first normal human chorionic gonadotropin (hCG) value were excluded. Outcome measures included primary remission rate; resistance to primary and sequential chemotherapy; period between treatment initiation and remission (hCG response); and prevalence of toxic effects.
RESULTS: Primary remission was achieved by 48 patients (80.0%). The remission rate with etoposide was 100.0%, while the rates with actinomycin D and MTX-CF were 90.0% and 50.0%, respectively. Efficacy of etoposide was significantly greater than the other 2 agents (P<0.001). Alopecia was the most frequent adverse effect caused by etoposide. Common to all protocols were stomatitis, nausea, and vomiting. Mean time intervals between beginning treatment and remission were similar and all 60 participants survived.
CONCLUSION: Etoposide was the most effective regimen for treating metastatic and non-metastatic LRGTN.