Practical guidelines of the EOTTD for pathological and genetic diagnosis of hydatidiform moles.

Hydatidiform moles are rare and thus most pathologists and geneticists have little experience with their diagnosis. It is important to promptly and correctly identify hydatidiform moles given that they are premalignant disorders associated with a risk of persistent gestational trophoblastic disease and gestational trophoblastic neoplasia. Improvement in diagnosis can be achieved with uniformization of diagnostic criteria and establishment of algorithms. To this aim, the Pathology and Genetics Working Party of the European Organisation for Treatment of Trophoblastic Diseases has developed guidelines that describe the pathological criteria and ancillary techniques that can be used in the differential diagnosis of hydatidiform moles. These guidelines are based on the best available evidence in the literature, professional experience and consensus of the experts' group involved in its development.

Measurement of hCG in women with Gestational Trophoblastic Disease.

OBJECTIVES: The objective of this study was to collect information on human Chorionic Gonadotrophin (hCG) laboratory testing and reporting in women with Gestational Trophoblastic Disease (GTD), to assess the associated challenges, and to offer perspectives on hCG testing harmonisation. DESIGN: Information was collected from laboratories by electronic survey (Survey Monkey®) using a questionnaire designed by members of the European Organisation for the Treatment of Trophoblastic Disease (EOTTD) hCG Working Party. PARTICIPANTS: The questionnaire was distributed by the EOTTD board to member laboratories and their associated scientists who work within the GTD field. SETTING: The questionnaire was distributed and accessed via an online platform. METHODS: The questionnaire consisted of 5 main sections. These included methods used for hCG testing, quality procedures, reporting of results, laboratory operational aspects, and non-GTD testing capability. In addition to reporting these survey results, examples of case scenarios which illustrate the difficulties faced by laboratories providing hCG measurement for GTD patient management were described. The benefits and challenges of using centralised versus non-centralised hCG testing were discussed alongside the utilisation of regression curves for management of GTD patients. RESULTS: Information from the survey was collated and presented for each section and showed huge variability in responses across laboratories even for those using the same hCG testing platforms. An educational example was presented, highlighting the consequence of using inappropriate hCG assays on clinical patient management (Educational Example A), along with an example of biotin interference (Educational Example B) and an example of high-dose hook effect (Educational Example C), demonstrating the importance of knowing the limitations of hCG tests. The merits of centralised versus non-centralised hCG testing and use of hCG regression curves to aid patient management were discussed. LIMITATIONS: To ensure the survey was completed by laboratories providing hCG testing for GTD management, the questionnaire was distributed by the EOTTD board. It was assumed the EOTTD board held the correct laboratory contact, and that the questionnaire was completed by a scientist with in-depth knowledge of laboratory procedures. CONCLUSIONS: The hCG survey highlighted a lack of harmonisation of hCG testing across laboratories. Healthcare professionals involved in the management of women with GTD should be aware of this limitation. Further work is needed to ensure an appropriate quality assured laboratory service is available for hCG monitoring in women with GTD.

When to consult a geneticist specialising in gestational trophoblastic disease.

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.

Human chorionic gonadotrophin assays to monitor GTD.

Hydatidiform mole (HM) occurs in 1:500-1000 pregnancies and are generally characterised as a benign proliferative disorder of chorionic villous trophoblast. HM belongs to the group of disorders, collectively known as gestational trophoblastic disease (GTD), which include invasive mole, choriocarcinoma, placental site trophoblastic tumour and epitheloid trophoblastic tumour. Patients with HM are at increased risk of developing these malignant forms and hence accurate diagnosis is very important for monitoring persistent diseases and informing correct patient management. In this review, we describe the current model for HM follow-up in the UK, with special emphasis on the in-house human chorionic gonadotrophin (hCG) radioimmunoassay (RIA) currently employed for monitoring women in our programme. We briefly discuss the structure, function and significance of hCG monitoring in GTD and the limitations and benefits of the current assays used for measuring oncology hCG. In particular, we describe the preliminary work evaluating a replacement antibody for the current gold-standard UK-RIA method.