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1.
Artículo en Inglés | MEDLINE | ID: mdl-37245506

RESUMEN

BACKGROUND: Gestational trophoblastic disease comprises hydatidiform moles and a rare group of malignancies that derive from trophoblasts. Although there are typical morphological features that may distinguish hydatidiform moles from non-molar products of conception, such features are not always present, especially at early stages of pregnancy. Furthermore, mosaic/chimeric pregnancies and twin pregnancies make pathological diagnosis challenging while trophoblastic tumours can also pose diagnostic problems in terms of their gestational or non-gestational origin. OBJECTIVES: To show that ancillary genetic testing can be used to aid diagnosis and clinical management of GTD. METHODS: Each author identified cases where genetic testing, including short tandem repeat (STR) genotyping, ploidy analysis, next generation sequencing and immunostaining for p57, the product of the imprinted gene CDKN1C, facilitated accurate diagnosis and improved patient management. Representative cases were chosen to illustrate the value of ancillary genetic testing in different scenarios. OUTCOME: Genetic analysis of placental tissue can aid in determining the risk of developing gestational trophoblastic neoplasia, facilitating discrimination between low risk triploid (partial) and high risk androgenetic (complete) moles, discriminating between a hydatidiform mole twinned with a normal conceptus and a triploid conception and identification of androgenetic/biparental diploid mosaicism. STR genotyping of placental tissue and targeted gene sequencing of patients can identify women with an inherited predisposition to recurrent molar pregnancies. Genotyping can distinguish gestational from non-gestational trophoblastic tumours using tissue or circulating tumour DNA, and can also identify the causative pregnancy which is the key prognostic factor for placental site and epithelioid trophoblastic tumours. CONCLUSIONS AND OUTLOOK: STR genotyping and P57 immunostaining have been invaluable to the management of gestational trophoblastic disease in many situations. The use of next generation sequencing and of liquid biopsies are opening up new pathways for GTD diagnostics. Development of these techniques has the potential to identify novel biomarkers of GTD and further refine diagnosis.

2.
Placenta ; 135: 7-15, 2023 04.
Artículo en Inglés | MEDLINE | ID: mdl-36889013

RESUMEN

INTRODUCTION: Identifying hydatidiform moles (HMs) is crucial due to the risk of gestational trophoblastic neoplasia. When a HM is suspected on clinical findings, surgical termination is recommended. However, in a substantial fraction of the cases, the conceptus is actually a non-molar miscarriage. If distinction between molar and non-molar gestations could be obtained before termination, surgical intervention could be minimized. METHODS: Circulating gestational trophoblasts (cGTs) were isolated from blood from 15 consecutive women suspected of molar pregnancies in gestational week 6-13. The trophoblasts were individually sorted using fluorescence activated cell sorting. STR analysis targeting 24 loci was performed on DNA isolated from maternal and paternal leukocytes, chorionic villi, cGTs, and cfDNA. RESULTS: With a gestational age above 10 weeks, cGTs were isolated in 87% of the cases. Two androgenetic HMs, three triploid diandric HMs, and six conceptuses with diploid biparental genome were diagnosed using cGTs. The STR profiles in cGTs were identical to the profiles in DNA from chorionic villi. Eight of the 15 women suspected to have a HM prior to termination had a conceptus with a diploid biparental genome, and thus most likely a non-molar miscarriage. DISCUSSION: Genetic analysis of cGTs is superior to identify HMs, compared to analysis of cfDNA, as it is not hampered by the presence of maternal DNA. cGTs provide information about the full genome in single cells, facilitating estimation of ploidy. This may be a step towards differentiating HMs from non-HMs before termination.


Asunto(s)
Aborto Espontáneo , Enfermedad Trofoblástica Gestacional , Mola Hidatiforme , Neoplasias Uterinas , Embarazo , Femenino , Humanos , Lactante , Neoplasias Uterinas/diagnóstico , Neoplasias Uterinas/genética , Trofoblastos , Mola Hidatiforme/diagnóstico , Mola Hidatiforme/genética
3.
Gynecol Oncol ; 165(3): 420-427, 2022 06.
Artículo en Inglés | MEDLINE | ID: mdl-35483986

RESUMEN

BACKGROUND: A combination of tumour size, differentiation grade and location may identify a group of vulvar squamous cell cancer (VSCC) patients with a very low risk of inguinal lymph node metastasis. We aim to examine these findings in a large national cohort of VSCC patients. MATERIALS AND METHODS: Population based prospective data on VSCC patients treated with vulvectomy and primary groin surgery was obtained from the Danish Gynaecological Cancer Database. Univariate chi-square and multivariate logistic regression analysis were used. Statistical tests were 2-sided. P-values of <0.05 were considered statistically significant. RESULTS: In all, 388 VSCC patients were identified. Of these 264 (63.3%) were node negative and 121 (36.7%) node positive. Increasing tumour size (diameter ≤ 2 cm vs. > 2 to 4 cm), grade (1 vs. 2-3) and location of tumour to clitoris were all associated with a significantly increased risk of inguinal lymph node metastasis OR 2.81(95% CI 1.52-5.20), OR 3.19 (95% CI 1.77-5.74) and OR 2.74 (95% CI 1.56-5.20), respectively. Previous vulvar disease was not associated with lymph node metastasis. No lymph node metastasis was demonstrated in patients with grade 1 tumours, tumour size less than 2 cm and located outside the clitoris area (n = 51). CONCLUSIONS: VSCC patients with grade 1 tumours, ≤ 2 cm and without clitoral involvement have a very low risk of inguinal lymph node metastasis. These patients may be spared inguinal lymph node staging to decrease operating time and peri- and postoperative morbidity in the future. However, studies validating our findings are needed.


Asunto(s)
Carcinoma de Células Escamosas , Neoplasias de la Vulva , Carcinoma de Células Escamosas/patología , Femenino , Ingle/cirugía , Humanos , Escisión del Ganglio Linfático/efectos adversos , Ganglios Linfáticos/patología , Ganglios Linfáticos/cirugía , Metástasis Linfática/patología , Estadificación de Neoplasias , Estudios Prospectivos , Estudios Retrospectivos , Neoplasias de la Vulva/patología
4.
Cancers (Basel) ; 14(3)2022 Feb 08.
Artículo en Inglés | MEDLINE | ID: mdl-35159119

RESUMEN

Methotrexate (MTX) is frequently used as first-line treatment for low-risk gestational trophoblastic neoplasia (GTN). Intravenous and intramuscular (im) routes of administration are the most common methods, although oral administration is used by some Scandinavian centers. The primary aim of this study was to assess the impact of form of administration (im/oral) on resistance to methotrexate (MTX-R) treatment in low-risk GTN. Secondary aims were time to hCG normalization, rates of toxicity-induced treatment switch, and rates of complete remission and recurrence. In total, 170 women treated at Karolinska University Hospital in Sweden and Aarhus University Hospital in Denmark between 1994 and 2018 were included, of whom 107 were given im and 63 oral MTX. MTX-R developed in 35% and 54% in the im and oral groups, respectively (p = 0.01). There was no difference in days to hCG normalization (42 vs. 41 days, p = 0.50) for MTX-sensitive women. Toxicity-induced treatment switch was only seen in the im group. Complete remission was obtained in 99.1% and 100% (p = 0.44), and recurrence rate within one year was 2.8% and 1.6% (p = 0.29). The form of administration of MTX had a significant impact on development of MTX-R and treatment-associated toxicity, but does not affect rates of complete remission, recurrence or survival.

5.
Mol Genet Genomic Med ; 9(1): e1565, 2021 01.
Artículo en Inglés | MEDLINE | ID: mdl-33306861

RESUMEN

BACKGROUND: In gestational trophoblastic disease, the prognosis is related to the genetic constitution. In some cases, taking a biopsy is contraindicated. METHODS: In a pregnant woman, ultrasound scanning suggested hydatidiform mole. To explore if the genetic constitution can be established without taking a biopsy (or terminating the pregnancy), cell-free DNA and circulating gestational trophoblasts were isolated from maternal blood before evacuation of the uterus. The evacuated tissue showed the morphology of a complete hydatidiform mole. Without prior whole-genome amplification, short tandem repeat analysis of 24 DNA markers was performed on the samples, and on DNA isolated from evacuated tissue, and from the blood of the patient and her partner. RESULTS: Identical genetic results were obtained in each of three circulating gestational trophoblasts and the evacuated tissue, showing that this conceptus had a diploid androgenetic nuclear genome. In contrast, analysis of cell-free DNA was less informative and less specific due to the inherent presence of cell-free DNA from the patient. CONCLUSION: Our results show that it is possible to isolate and analyze circulating gestational trophoblasts originating in a pregnancy without maternal nuclear genome. For diagnosing gestational trophoblastic diseases, genotyping circulating gestational trophoblasts appears to be superior to analysis of cell-free DNA.


Asunto(s)
Pruebas Genéticas/métodos , Mola Hidatiforme/genética , Células Neoplásicas Circulantes/metabolismo , Trofoblastos/metabolismo , Adulto , Células Cultivadas , Femenino , Humanos , Mola Hidatiforme/diagnóstico por imagen , Mola Hidatiforme/patología , Células Neoplásicas Circulantes/patología , Embarazo , Trofoblastos/patología , Ultrasonografía Prenatal
7.
Gynecol Oncol ; 156(1): 124-130, 2020 01.
Artículo en Inglés | MEDLINE | ID: mdl-31711658

RESUMEN

OBJECTIVE: The sentinel node (SN) procedure is adopted in selected patients with early-stage vulva cancer (VC) in Denmark. Due to the low incidence of VC, large population-based studies on the safety of SN outside multicenter clinical trials are lacking. The current study evaluated the risk of recurrence and survival in SN- negative VC patients. METHODS: Nationwide data was collected and registered prospectively in the Danish Gynecologic Cancer Database from January 2011 to July 2017. Patients with clinically stage IB-II unifocal vulva squamous cell carcinoma, tumor <4 cm and no clinically suspicious groin nodes or distant metastases, who underwent SN-procedure, were included. RESULTS: The SN-procedure was performed in 286 patients, of these 190 (66.4%) patients were SN-negative. Twenty-three of the 190 SN-negative patients (12.1%) had one or more recurrences during a median follow-up of 30 months (range 1-83). Four patients (2.1%) had an isolated groin recurrence identified from 5 to 17 months after primary surgery. Fourteen patients (7.4%) experienced a local recurrence in vulva, 1 patient (0.5%) had a recurrence in the vulva and the groin and 4 patients (2.1%) had distant recurrences. The 3-year overall (OS) and disease-specific survival (DSS) for SN-negative patients was 84% and 93%, respectively. The 3-year OS for patients with recurrent disease was 58%. CONCLUSIONS: This is the largest prospective nationwide study on SN-procedure in vulva cancer. The study confirms the safety of the SN-procedure in selected early-stage VC patients with a low isolated groin recurrence rate and a good DSS.


Asunto(s)
Recurrencia Local de Neoplasia/mortalidad , Recurrencia Local de Neoplasia/patología , Biopsia del Ganglio Linfático Centinela/estadística & datos numéricos , Neoplasias de la Vulva/mortalidad , Neoplasias de la Vulva/patología , Adulto , Anciano , Anciano de 80 o más Años , Carcinoma de Células Escamosas/mortalidad , Carcinoma de Células Escamosas/patología , Dinamarca/epidemiología , Femenino , Humanos , Metástasis Linfática , Persona de Mediana Edad , Estadificación de Neoplasias , Estudios Prospectivos , Sistema de Registros , Ganglio Linfático Centinela/patología , Biopsia del Ganglio Linfático Centinela/efectos adversos , Biopsia del Ganglio Linfático Centinela/métodos
8.
Ugeskr Laeger ; 181(34)2019 Aug 19.
Artículo en Danés | MEDLINE | ID: mdl-31495360

RESUMEN

This review summarises the current guidelines for vulva cancer in Denmark. Vulva cancer is a rare disease. The diagnosis is often delayed, which results in large tumours and regional spread. The most important prognostic factor is inguinal lymph node metastases. Staging and treatment is centralised to two hospitals. Primary treatment is wide local excision combined with removal of either inguinal sentinel nodes or lymphadenectomy. Treatment is associated with considerable morbidity, and supportive care is often necessary. Local curable recurrences are common. Relapses in the groin are associated with a poor prognosis. Thus, long term follow-up is essential. *) On behalf of Dansk Gynækologisk Cancer Gruppe for vulvacancer.


Asunto(s)
Neoplasias de la Vulva , Dinamarca , Femenino , Estudios de Seguimiento , Humanos , Escisión del Ganglio Linfático , Ganglios Linfáticos , Metástasis Linfática , Recurrencia Local de Neoplasia , Estadificación de Neoplasias , Pronóstico , Biopsia del Ganglio Linfático Centinela , Neoplasias de la Vulva/diagnóstico , Neoplasias de la Vulva/cirugía
9.
Medicine (Baltimore) ; 95(37): e4721, 2016 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-27631219

RESUMEN

BACKGROUND: This case report describes the use of analysis of cell-free DNA in the blood of a patient with a pregnancy with one live fetus and a choriocarcinoma diagnosed at 22 weeks of gestation. RESULTS: The result of the analysis of 16 microsatellite loci on 14 chromosomes in the cell-free DNA in plasma was consistent with the result of the analysis of a tumor biopsy indicating biparental diploid origin of the genome. The DNA markers were discordant with the markers of the placenta indicating two separate conceptions. CONCLUSION: Our results indicate that analysis of cell-free DNA in plasma allows determination of the origin of a choriocarcinoma without tissue biopsy, even in the presence of a co-existent pregnancy.


Asunto(s)
Coriocarcinoma/sangre , ADN/sangre , Adulto , Femenino , Humanos , Nacimiento Vivo , Embarazo
10.
Acta Oncol ; 55(2): 234-9, 2016.
Artículo en Inglés | MEDLINE | ID: mdl-26106854

RESUMEN

BACKGROUND: Treatment of postmolar gestational trophoblastic neoplasia (GTN) is often stratified according to FIGO score using methotrexate (MTX) for low-risk patients and first-line multi-agent chemotherapy (e.g. EMA-CO) for high-risk patients. In contrast, oral MTX may be given as first-line therapy to all GTN patients regardless of risk group. The aim was to examine the efficacy of oral MTX and a response-adapted treatment policy, which has been used for three decades at Aarhus University Hospital (AUH). MATERIAL AND METHODS: Seventy-one consecutive postmolar GTN patients treated 1981-2011 were included. Data were obtained from medical records, using histopathology and human choriogonadotropin (hCG) to verify the diagnosis. All patients received oral MTX as first-line chemotherapy. Second- and third-line chemotherapy was given according to response. RESULTS: Sixty-four (90%) patients were retrospectively categorized as FIGO low-risk disease, whereas seven patients (10%) had high-risk disease. Complete response to first-line oral MTX chemotherapy was observed in 35/71 (49%) patients, while 62/71 (87%) had complete remission on MTX (first-line) and/or MTX plus dactinomycin (second-line), without the use of multi-agent therapy. Nine patients (13%) received third-line multi-agent chemotherapy, six low-risk (67%) and three high-risk (33%) patients. There were no recurrences and no patients died as a consequence of toxicity or disease. CONCLUSION: Fifty percent of all patients can be cured on oral MTX alone. By adding dactinomycin, about 90% are cured without use of multi-agent chemotherapy. The use of oral MTX as initial treatment can minimize the number of patients receiving multi-agent chemotherapy.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Enfermedad Trofoblástica Gestacional/tratamiento farmacológico , Metotrexato/administración & dosificación , Administración Oral , Adolescente , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Gonadotropina Coriónica/sangre , Ciclofosfamida/administración & dosificación , Ciclofosfamida/uso terapéutico , Dactinomicina/administración & dosificación , Dactinomicina/uso terapéutico , Etopósido/administración & dosificación , Etopósido/uso terapéutico , Femenino , Estudios de Seguimiento , Enfermedad Trofoblástica Gestacional/patología , Humanos , Metotrexato/uso terapéutico , Persona de Mediana Edad , Embarazo , Factores de Riesgo , Resultado del Tratamiento , Vincristina/administración & dosificación , Vincristina/uso terapéutico , Adulto Joven
11.
Medicine (Baltimore) ; 94(44): e1776, 2015 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-26554776

RESUMEN

Hydatidiform mole is an abnormal human pregnancy characterized by the fetus being absent or nonviable, and the chorionic villi being vesicular and with trophoblastic hyperplasia. Most often, the mole phenotype is seen in conceptuses with an excess of paternally inherited genome set(s) relative to maternally inherited genome set(s), suggesting that the phenotype is caused by an excess of genome with a paternal imprinting pattern. However, it is unknown if correct parental origin of every imprinted gene is crucial for normal early differentiation or if abnormal parental imprinting of only one, or some, gene(s) can cause the mole phenotype.Two conceptuses included in the Danish Mole Project stood out since they presented with vesicular chorionic villi and without signs of fetal differentiation, and had apparently biparental diploid genomes, and no mutations in NLRP7 or KHDC3L were detected in the mothers. These conceptuses were subjected to a centralized histopathological revision and their genetic complements were scrutinized using fluorescence in situ hybridization, and DNA-marker and array comparative genomic hybridization analyses. Both conceptuses showed dysmorphic chorionic villi with some similarities to hydatidiform moles; however, no definite florid trophoblast hyperplasia was observed. Both conceptuses showed paternal hemizygosity of 11pter-11p15.4, most likely in nonmosaic state.Our findings suggest that the product of one (or a few) maternally expressed gene(s) on the tip of chromosome 11 is necessary for normal early embryonic differentiation. However, since the present two cases did not exhibit all features of hydatidiform moles, it is likely that abnormal parental imprinting of genes in other regions contribute to the phenotype of a hydatidiform mole.


Asunto(s)
ADN de Neoplasias/genética , Mola Hidatiforme/genética , Neoplasias Uterinas/genética , Hibridación Genómica Comparativa , Femenino , Impresión Genómica , Genotipo , Humanos , Hibridación Fluorescente in Situ , Fenotipo , Embarazo , Estudios Retrospectivos
12.
PLoS One ; 10(11): e0142545, 2015.
Artículo en Inglés | MEDLINE | ID: mdl-26562155

RESUMEN

Hydatidiform moles (HMs) are abnormal human pregnancies with vesicular chorionic villi, imposing two clinical challenges; miscarriage and a risk of gestational trophoblastic neoplasia (GTN). The parental type of most HMs are either diandric diploid (PP) or diandric triploid (PPM). We consecutively collected 154 triploid or near-triploid samples from conceptuses with vesicular chorionic villi. We used analysis of DNA markers and/or methylation sensitive-MLPA and collected data from registries and patients records. We performed whole genome SNP analysis of one case of twinning (PP+PM).In all 154 triploids or near-triploids we found two different paternal contributions to the genome (P1P2M). The ratios between the sex chromosomal constitutions XXX, XXY, and XYY were 5.7: 6.9: 1.0. No cases of GTN were observed. Our results corroborate that all triploid human conceptuses with vesicular chorionic villi have the parental type P1P2M. The sex chromosomal ratios suggest approximately equal frequencies of meiosis I and meiosis II errors with selection against the XYY conceptuses or a combination of dispermy, non-disjunction in meiosis I and meiosis II and selection against XYY conceptuses. Although single cases of GTN after a triploid HM have been reported, the results of this study combined with data from previous prospective studies estimate the risk of GTN after a triploid mole to 0% (95% CI: 0-1,4%).


Asunto(s)
Vellosidades Coriónicas/metabolismo , Mola Hidatiforme/genética , Aberraciones Cromosómicas Sexuales , Triploidía , Diploidia , Femenino , Genoma Humano/genética , Genotipo , Humanos , Cariotipo , Cariotipificación , Masculino , Modelos Genéticos , Embarazo
13.
Dan Med J ; 62(11): A5082, 2015 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-26522484

RESUMEN

Hydatidiform mole is treated with surgical uterine evacuation with suction and blunt curettage (D). Medical uterine evacuation should not be used (C). On clinical suspicion of hydatidiform mole, one representative sample of the evacuated tissue is fixed for histopathologic investigation and one is forwarded unfixed for genetic analysis (D). Serum hCG is measured on suspicion of hydatidiform mole. At the time of the uterine evacuation, the initial hCG is measured (A). After a hydatidiform mole that is both triploid and partial, serum hCG is measured weekly until there are two consecutive undetectable values (< 1 or < 2), after which the patient can be discharged from follow-up (C). After a diploid hydatidiform mole, a complete mole, or a hydatidiform mole without valid ploidy determination, serum hCG is measured weekly until the value is undetectable (< 1 or < 2). If serum hCG is undetectable within 56 days after evacuation, the patient can be discharged from follow-up after an additional four monthly measurements. If serum hCG is first normalised after 56 days, the patient is follow-up with monthly serum hCG measurement for six months. Safe contraception should be used during the follow-up period (A). If hCG stagnates (less than 10% fall over three measurements), increases, or if hCG can be demonstrated for longer than 6 months, the patient by definition has persistent trophoblastic disease (PTD). A chest X-ray should be taken and a gynaecologic ultrasound scanning performed. The patient is referred to oncologic treatment (A). Uterine re-evacuation as a treatment for PTD can, in general, not be recommended because the rate of remission is low, and there is the risk of perforation of the uterus (C). In all following pregnancies, the woman is offered an early ultrasound scan, e.g. in gestational week eight (D). Eight weeks after termination of all future pregnancies, serum hCG is measured (D). In PTD and invasive hydatidiform mole, the primary treatment is MTX, either orally every third week or IV every week (B). In MTX-resistant PTD, IV act D is added (or replaces the MTX) (B). Third line chemotherapy is BEP or EP, alternatively EMA-CO (B). Choriocarcinoma is primarily treated with chemotherapy. Hysterectomy and/or resection of metastases are possible treatments (A). Placental site trophoblastic tumour (PSTT) and epithelioid trophoblastic tumour (ETT) are primarily treated with hysterectomy. In the case of disseminated disease, chemotherapy is considered (A). The risk of reoccurrence after trophoblastic disease treated with chemotherapy is approximately 3%. Most reoccurrences are seen within 12 months, and for this reason monitoring of hCG is recommended for one year, the first third months once or twice a month, thereafter every second to third month. Patients with PSTT and ETT are monitored with measurement of hCG throughout their lifetimes (C). In genetically verified twin pregnancy with hydatidiform mole and a living foetus, the pregnancy can continue if serum hCG is monitored and ultrasound scans regularly performed, and possible obstetric complications dealt with (C). In the case of recurrent hydatidiform mole and/or familial hydatidiform mole, patients should be referred to genetic workup and counselling (C). Women with a hereditary disposition to hydatidiform mole because of a mutation in NLRP7 should be informed of the possibility of becoming pregnant via egg donation (C).


Asunto(s)
Gonadotropina Coriónica/sangre , Enfermedad Trofoblástica Gestacional/clasificación , Enfermedad Trofoblástica Gestacional/diagnóstico , Enfermedad Trofoblástica Gestacional/terapia , Complicaciones Neoplásicas del Embarazo/terapia , Neoplasias Uterinas/terapia , Consejo , Dinamarca , Femenino , Edad Gestacional , Humanos , Embarazo , Complicaciones Neoplásicas del Embarazo/diagnóstico , Factores de Riesgo , Neoplasias Uterinas/diagnóstico
14.
Eur J Cancer ; 51(13): 1725-31, 2015 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-26092638

RESUMEN

Gestational trophoblastic disease (GTD) is a spectrum of cellular proliferations arising from trophoblast. Their invasive and metastatic potential sometimes requires chemotherapy and/or surgery. Current management is generally associated with favourable prognosis. Therefore, treatments must be chosen according to the desire for further childbearing of each patient. The European Organisation for Treatment of Trophoblastic Diseases (EOTTD) is dedicated to optimise diagnosis, treatment, follow-up and research in GTD by bringing together knowledge of clinicians and researchers from 29 countries working in the field of GTD in Europe. This study assessed the level of agreement among an expert panel of the EOTTD in order to rationalise the management of patients in Europe. The RAND/UCLA Appropriateness Method was used to combine the best available scientific evidence with the collective judgment of experts to yield a statement regarding the appropriateness of performing a procedure at the level of patient-specific symptoms, medical history and test results. There was an agreement for 54 statements while the experts showed a disagreement for two statements. As there is little evidence from randomised trials on which to base recommendations about management of GTD, many of these recommendations are based on expert opinion derived from changes in management fact that have improved outcomes from nearly 100% fatality to nearly 100% cure rates. However, a large agreement among experts is invaluable to the individual clinician who is struggling to decide whether a fertility-sparing treatment of hydatidiform mole or a low-risk GTN can be chosen and how it must be conducted.


Asunto(s)
Medicina Basada en la Evidencia/normas , Enfermedad Trofoblástica Gestacional/terapia , Oncología Médica/normas , Consenso , Conducta Cooperativa , Técnica Delphi , Europa (Continente) , Femenino , Enfermedad Trofoblástica Gestacional/diagnóstico , Humanos , Cooperación Internacional , Valor Predictivo de las Pruebas , Embarazo , Pronóstico
15.
Am J Obstet Gynecol ; 211(4): 370.e1-19, 2014 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-24657790

RESUMEN

OBJECTIVE: The purpose of this study was to analyze the correlation between the genetic constitution and the phenotype in triploid pregnancies. STUDY DESIGN: One hundred fifty-eight triploid pregnancies were identified in hospitals in Western Denmark from April 1986 to April 2010. Clinical data and karyotypes were collected retrospectively, and archived samples were retrieved. The parental origin of the genome, either double paternal contribution (PPM) or double maternal contribution (MMP) was determined by an analysis of methylation levels at imprinted sites. RESULTS: There were significantly more PPM than MMP cases (P < .01). In MMP cases, the possible karyotypes had similar frequencies, whereas, in PPM cases, 43% had the karyotype 69,XXX, 51% had the karyotype 69,XXY, and 6% had the karyotype 69,XYY. Molar phenotype was seen only in PPM cases. However, PPM cases with a nonmolar phenotype were also seen. For both parental genotypes, various fetal phenotypes were seen at autopsy. Levels of human chorionic gonadotropin in maternal serum were low in MMP cases and varying in PPM cases, some being as low as in the MMP cases. CONCLUSION: In a triploid pregnancy, suspicion of hydatidiform mole at ultrasound scanning, by macroscopic inspection of the evacuated tissue, at histology, or because of a high human chorionic gonadotropin in maternal serum level each predict the parental type PPM with a very high specificity. In contrast, the sensitivity of these observations was <100%.


Asunto(s)
Cariotipo Anormal , Fenotipo , Diagnóstico Prenatal , Triploidía , Biomarcadores/sangre , Gonadotropina Coriónica/sangre , Femenino , Genotipo , Humanos , Mola Hidatiforme/sangre , Mola Hidatiforme/diagnóstico , Mola Hidatiforme/genética , Cariotipificación , Embarazo , Estudios Retrospectivos , Neoplasias Uterinas/sangre , Neoplasias Uterinas/diagnóstico , Neoplasias Uterinas/genética
16.
Hum Reprod ; 28(7): 2010-20, 2013 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-23633551

RESUMEN

STUDY QUESTION: How does tetraploidy develop in hydatidiform moles (HMs), and what is the frequency of the different origins? SUMMARY ANSWER: Most molar pregnancies with tetraploid cells appear to be produced by somatic endoreduplications, while a minority originate from a tetraploid zygote. The frequency of zygotic tetraploidy was estimated to be 0.7%. WHAT IS KNOWN ALREADY: The parental origin of the genome in tetraploid HMs has only been evaluated in a few cases, most showing three genome sets from the father (PPPM). Estimates of the proportion of HMs that are tetraploid vary between 2 and 28%. STUDY DESIGN, SIZE, DURATION: From 1986 to 2010, unfixed samples of clinically suspected molar pregnancies were forwarded to the Danish Mole Project. For this cohort study 442 samples fulfilled the following criteria for inclusion: macroscopic appearance of HM and ≥ 10 vesicular chorionic villi with a diameter of ≥ 1 mm. PARTICIPANTS/MATERIALS, SETTING, METHODS: Of 403 karyotyped samples, 21 cases disclosed ≥ 2 tetraploid metaphases. The 21 cases were scrutinized by karyotyping, flow cytometry (FC) and DNA-marker analysis. MAIN RESULTS AND THE ROLE OF CHANCE: Among 20 HMs, 3 showed the genotype PPPM: one with the sex chromosomes XXYY and two with XXXY, indicating that they originated in tetraploid zygotes. In 14 androgenetic, one likely androgenetic and two mosaics, the tetraploid cells likely developed by endoreduplications of diploid cells. One case did not fulfil the histopathological criteria for HM. LIMITATIONS, REASONS FOR CAUTION: As an inclusion criterion was the macroscopic observation of vesicular chorionic villi, some non-molar hydropic placentas may have been included and some early moles may have been excluded. WIDER IMPLICATIONS OF THE FINDINGS: In future, studies to determine that an HM is tetraploid and discriminate cases of mosaicism and to deduce the origin of the tetraploidy must use the techniques of karyotyping, DNA-marker analysis and FC in combination.


Asunto(s)
Mola Hidatiforme/genética , Tetraploidía , Femenino , Citometría de Flujo , Marcadores Genéticos , Genoma Humano , Genotipo , Humanos , Cariotipificación , Modelos Genéticos , Placenta/patología , Embarazo
17.
Eur J Hum Genet ; 19(10): 1026-31, 2011 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-21654731

RESUMEN

Hydatidiform mole (HM) is an abnormal human pregnancy, where the placenta presents with vesicular swelling of the chorionic villi. A fetus is either not present, or malformed and not viable. Most moles are diploid androgenetic as if one spermatozoon fertilized an empty oocyte, or triploid with one maternal and two paternal chromosome sets as if two spermatozoa fertilized a normal oocyte. However, diploid moles with both paternal and maternal markers of the nuclear genome have been reported. Among 162 consecutively collected diploid moles, we have earlier found indications of both maternal and paternal genomes in 11. In the present study, we have performed detailed analysis of DNA-markers in tissue and single cells from these 11 HMs. In 3/11, we identified one biparental cell population only, whereas in 8/11, we demonstrated mosaicism: one biparental cell population and one androgenetic cell population. One mosaic mole was followed by persistent trophoblastic disease (PTD). In seven of the mosaics, one spermatozoon appeared to have contributed to the genomes of both cell types. Our observations make it likely that mosaic conceptuses, encompassing an androgenetic cell population, result from various postzygotic abnormalities, including paternal pronuclear duplication, asymmetric cytokinesis, and postzygotic diploidization. This corroborates the suggestion that fertilization of an empty egg is not mandatory for the creation of an androgenetic cell population. Future studies of mosaic conceptuses may disclose details about fertilization, early cell divisions and differentiation. Apparently, only a minority of diploid moles with both paternal and maternal markers are 'genuine' diploid biparental moles (DiBiparHMs).


Asunto(s)
Diploidia , Mola Hidatiforme/genética , Mosaicismo , Femenino , Impresión Genómica , Edad Gestacional , Enfermedad Trofoblástica Gestacional/genética , Humanos , Masculino , Repeticiones de Microsatélite/genética , Embarazo , Neoplasias Trofoblásticas/genética , Neoplasias Uterinas/genética , Virilismo/genética
18.
Hum Reprod ; 23(9): 2031-5, 2008 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-18556678

RESUMEN

BACKGROUND: In twin pregnancies comprising a hydatidiform mole and a normal co-fetus, the ploidy of the mole is almost exclusively reported as diploid and very rarely as triploid. We aimed at understanding this unbalanced distribution of diploid and triploid moles in twin pregnancies by investigating the number of gametes involved. METHODS: Using polymorphic DNA markers, we compared the alleles of seven moles with those of the normal co-fetuses and deduced the number of oocytes and spermatozoa represented in each twin pregnancy. RESULTS: The genomes of all seven moles were androgenetic diploid; six moles were homozygous in all loci analyzed and one mole was heterozygous in several loci. In one homozygous mole, the paternal alleles were identical to those of the normal co-fetus in 13 non-linked informative microsatellite loci, indicating the involvement of one spermatozoon only, and thus of one oocyte only. Duplications of the paternal genome followed by abnormal cell division can explain this observation. In six moles, the paternal alleles were different from those of the normal co-fetus suggesting involvement of two (or more) spermatozoa. Overfertilization of one oocyte followed by abnormal cell division is a possibility. CONCLUSIONS: It is possible that twin pregnancies comprising a diploid mole and a normal co-fetus most often derive from one single oocyte fertilized with one or more spermatozoa. This can explain why diploid moles are far more frequent than triploid moles in twin pregnancies.


Asunto(s)
Diploidia , Enfermedades en Gemelos/genética , Mola Hidatiforme/genética , Neoplasias Uterinas/genética , Alelos , Enfermedades en Gemelos/patología , Femenino , Citometría de Flujo , Ligamiento Genético , Genoma Humano , Humanos , Mola Hidatiforme/patología , Hibridación Fluorescente in Situ , Cariotipificación , Masculino , Repeticiones de Microsatélite , Modelos Genéticos , Oocitos/crecimiento & desarrollo , Oocitos/patología , Polimorfismo Genético , Embarazo , Espermatozoides/patología , Neoplasias Uterinas/patología
19.
Am J Obstet Gynecol ; 197(1): 45.e1-5, 2007 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-17618752

RESUMEN

OBJECTIVE: This study was undertaken to evaluate the risk of persistent trophoblastic disease and obstetric complications related to a multiple pregnancy comprising a diploid hydatidiform mole and normal cofetus(es). STUDY DESIGN: From a database of 270 consecutively collected hydatidiform moles, 8 multiple and 154 singleton molar pregnancies were identified. Molar and fetal ploidy was determined, and data on clinical features and chemotherapy were collected. Differences between groups were assessed with Fisher's exact or Mann-Whitney test. RESULTS: The molar component in all 8 multiple pregnancies was diploid. Five patients with diploid mole and coexisting fetus pregnancy chose to terminate their pregnancy, 2 aborted spontaneously, and 1 patient delivered a healthy child. Two diploid mole and coexisting fetus pregnancies (25%) and 17% of the singleton molar pregnancies were followed by persistent trophoblastic disease (P = .63). CONCLUSION: The risk of persistent trophoblastic disease after a diploid mole with coexisting fetus pregnancy is similar to that after a singleton molar pregnancy, and expectant management instead of therapeutic abortion can be pursued.


Asunto(s)
Mola Hidatiforme/complicaciones , Complicaciones Neoplásicas del Embarazo , Gemelos , Neoplasias Uterinas/complicaciones , Adulto , Diploidia , Femenino , Edad Gestacional , Humanos , Embarazo , Estudios Retrospectivos , Factores de Riesgo
20.
Gynecol Oncol ; 104(2): 411-5, 2007 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-17011616

RESUMEN

OBJECTIVE: Hydatidiform mole can be classified by histopathologic characteristics and by genetic constitutions and most complete moles are diploid, whereas most partial moles are triploid. We investigated the concordance between these two classifications, characterized moles with conflicting classifications, and compared the ability of the two classifications to discriminate between patients with and without a substantial risk of persistent trophoblastic disease. METHODS: 294 cases of consecutively collected hydropic placentas clinically suspected of hydatidiform mole made the basis of this retrospective study. We determined the ploidy and reviewed the original histopathologic material in all cases. Data on possible chemotherapy were collected for each patient. RESULTS: 270 of the conceptuses were histopathologically classified as hydatidiform mole. Among the 24 conceptuses classified as non-molar miscarriage, 20 were triploids, 2 were diploid androgenetic and 2 were diploid biparental. In 23% of the conceptuses, the histopathologic and genetic classifications were conflicting. 5% of the patients with hydropic placentas classified as partial mole encountered persistent trophoblastic disease; however, the genome was diploid in all these moles. None of 131 patients with a triploid hydropic gestation encountered persistent trophoblastic disease. CONCLUSION: As full concordance between the histopathologic and the genetic classifications was not found, we believe that features beyond the genetic constitution influence the development of morphologic features in hydatidiform moles. We recommend that gestations suspected of hydatidiform mole are subjected to histopathologic examination. If hydatidiform change and trophoblastic hyperplasia are identified, the ploidy should be used to identify patients with a high risk of persistent trophoblastic disease.


Asunto(s)
Mola Hidatiforme/genética , Mola Hidatiforme/patología , Ploidias , Neoplasias Trofoblásticas/genética , Neoplasias Trofoblásticas/patología , Neoplasias Uterinas/genética , Neoplasias Uterinas/patología , Animales , Pollos , Coriocarcinoma/tratamiento farmacológico , Coriocarcinoma/genética , Coriocarcinoma/patología , Femenino , Humanos , Mola Hidatiforme/tratamiento farmacológico , Embarazo , Estudios Retrospectivos , Trucha , Neoplasias Uterinas/tratamiento farmacológico
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