Center for the Precision Medicine of Trophoblastic Disease

Gestational trophoblastic disease (GTD) is a major disease category in diagnostic gynecological pathology. Among common clinical specimens, morphologic assessment of GTD, hydatidiform moles, continues to suffer from significant diagnostic challenges and inter- and intra-observer variability, even among experienced pathologists. However, distinction of hydatidiform moles from non-molar specimens and the sub-classification of hydatidiform moles are critical for patient care, as the risk of persistent GTD varies among subtypes of hydatidiform moles and so does the duration of clinical follow-up. Moreover, diagnostic inaccuracy compromises investigations of the epidemiology, pathogenesis, and behavior of hydatidiform moles by using inaccurately classified cases.

During the past decade, p57 immunohistochemistry and PCR-based DNA genotyping have emerged as powerful diagnostic measures to precisely classify hydatidiform moles. The modern diagnostic approach of molar gestations now requires integration of these ancillary techniques into an algorithm aiming to provide a refined diagnosis, accurate risk assessment of persistent GTD, and to guide appropriate clinical management. Endorsed by the 2020 WHO Tumor Classification of Female Genital Organs, molecular genotyping is required for accurate diagnosis of partial mole and recommended for genetic subtyping for complete moles. Once a diagnosis of hydatidiform mole is made, the patient will be followed clinically by the molar surveillance program through weekly serum beta human chorionic gonadotropin (beta-hCG) measurement to monitor the development of post-molar gestational trophoblastic tumors. In recent years, genotyping has also become an important tool in confirmation of extrauterine gestational trophoblastic tumors and their risk assessment for patient treatment options. The treatment of gestational trophoblastic neoplasia is based on the type of disease, stage, or risk group.

At Yale, experienced gynecological pathologists are pioneers in the clinical validation and applications of molecular genotyping for diagnosis of GTD and offer consultation services to pathologists throughout the United States and abroad. Yale expert consultants are authoritative writers in the field of GTD and are editorial board member/chapter contributors to the 5th edition of the WHO blue book on the classification of gestational trophoblastic disease. At Smilow Cancer Hospital, our dedicated gynecologic oncologists are passionate patient care providers in the early intervention, clinical consultation, and personalized therapy for patients diagnosed with various types of gestational trophoblastic diseases.

The first step in the diagnostic work-up of GTD is morphologic evaluation on H&E-stained sections. Based on the microscopic features, the cases are triaged for further ancillary studies using published algorithm. Correlative morphological review is crucial for correct interpretation of ancillary studies, particularly molecular genotyping in the diagnosis of molar gestations.

P57 immunostain is often used in the diagnostic work-up of hydatidiform moles, particularly in the confirmation of complete moles. A variety of other immunohistochemical stains – hCG, hPL, GATA3, p63, inhibin, etc. – may be necessary for diagnostic classification of gestational trophoblastic tumors.

DNA genotyping has become the gold standard in the diagnosis and subclassification of hydatidiform moles with superb diagnostic sensitivity and specificity. Genotyping does not require fresh tissue and can be performed on formalin fixed paraffin-embedded tissue samples. Genotyping may also play a crucial role in the diagnosis of gestational trophoblastic tumors and their risk scoring for clinical patient management.

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