Center for the Precision Medicine of Trophoblastic Disease

Gestational trophoblastic disease (GTD) encompasses a range of common pregnancy-related disorders that are either hyperplastic or neoplastic in nature and incur significant morbidity in women in the United States. The clinical and pathological assessment of patients with the most common form of GTD, hydatidiform moles, continues to face significant diagnostic challenges. However, distinguishing hydatidiform moles from non-molar gestations and sub-classifying hydatidiform moles are crucial for patient care due to their different risks of post-molar gestational trophoblastic neoplasia (GTN). Furthermore, accurate diagnosis and prognostic risk assessment are vital for patients with trophoblastic tumors, especially when the tumor presents at an extrauterine site. The modern diagnostic approach for GTD now integrates ancillary techniques, such as DNA genotyping and immunohistochemistry, into an algorithmic approach. This aims to provide precision diagnosis, accurate risk assessment, and therapeutic guidance.

Gestational choriocarcinoma displaying biphasic proliferation of highly atypical trophoblastic cells with extensive hemorrhage and necrosis.

Our expert gynecological pathologists are pioneers in the clinical validation and application of ancillary studies in the diagnosis and subclassification of GTD. They offer consultation services to pathologists both nationally and internationally. At Smilow Cancer Hospital, our dedicated gynecologic oncologists are committed to providing exceptional patient care, emphasizing early intervention, clinical consultation, and personalized therapy for those with gestational trophoblastic disease. As a beacon of clinical and academic excellence, the Yale Center for the Precision Medicine of Trophoblastic Disease is committed to advancing precision medicine by harnessing the latest molecular discoveries and novel treatment options for GTD. The center assembles a team of experts from gynecological pathology and gynecologic oncology, as well as scientific investigators, to collaborate and enhance modern diagnostic services, develop innovative therapies, and delve deep into clinical and translational investigations concerning the pathogenesis of GTD.

Between 2006 and 2023, the Center has evaluated more than 3,000 specimens for GTD diagnostic workup, including 1,200 consultation specimens. In our tertiary practice setting, hydatidiform moles are identified in 29.4% of POC specimens and among the molar gestations, 35.5% are complete moles and 64.5% are partial moles. The average turn-around-time of the diagnostic workup is 5.3 days (inclusive of the weekends). Combined with laser microdissection, STR genotyping analysis is informative in over 99.5% of the specimens (both molar gestations and trophoblastic tumors). The center is currently validating a next generation sequencing (NGS) panel for the mutation screening of several maternal effect genes that are responsible for the familial biparental complete mole, a rare inheritable form of molar gestation.

Very early complete moles demonstrating abnormal villous configuration, cellular myxoid villous stroma with frequent karyorrhexis, and trophoblastic proliferation.

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Histological Evaluation

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.

Immunohistochemistry

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.

Algorithmic approaches in the diagnostic workup of molar gestations. Products of conceptions with morphological suspicion for hydatidiform moles can be uniformly subjected to STR genotyping as a “one-stop shopping” approach (A). The second approach is to perform either STR genotyping or p57 immunohistochemistry based on the histological suspicion for either CHM or PHM, respectively (B). The third approach is to submit all suspected specimens for p57 immunohistochemistry to confirm CHM and then triage those with normal p57 expression for STR genotyping to distinguish PHM from non-molar gestations (C).

Molecular Genotyping Diagnosis

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.

STR genotyping diagnosis of tumors with trophoblastic differentiation. Comparison of the allelic patterns at STR loci between the tumor and paired normal tissue identifies the presence or absence of paternal alleles in the tumor, allowing for diagnostic separation of a gestational tumor from its non-gestational mimics. Genotyping also allows precise recognition of the index gestational event (hydatidiform mole, abortion, or term pregnancy) of gestational trophoblastic tumors.