Advances in the diagnosis and early management of gestational trophoblastic disease

Abstract

Gestational trophoblastic disease describes a group of rare pregnancy related disorders that span a spectrum of premalignant and malignant conditions. Hydatidiform mole (also termed molar pregnancy) is the most common form of this disease. Hydatidiform mole describes an abnormal conceptus containing two copies of the paternal genome, which is classified as partial when the maternal genome is present or complete when the maternal genome is absent. Hydatidiform mole typically presents in the first trimester with irregular vaginal bleeding and can be suspected on ultrasound but confirmation requires histopathological evaluation of the products of conception. Most molar pregnancies resolve without treatment after uterine evacuation, but occasionally the disease persists and develops into gestational trophoblastic neoplasia. Close monitoring of women after molar pregnancy, with regular measurement of human chorionic gonadotrophin concentrations, allows for early detection of malignancy. Given the rarity of the disease, clinical management and treatment is best provided in specialist centres where very high cure rates are achievable. This review looks at advances in the diagnosis and early management of gestational trophoblastic disease and highlights updates to disease classification and clinical guidelines. Use of molecular genotyping for improved diagnostic accuracy and risk stratification is reviewed and future biomarkers for the earlier detection of malignancy are considered.

Keywords: Biochemistry; Genetics; Medical oncology; Pathology; Pregnancy complications.

Figure 1

Gestational trophoblastic disease (GTD) classification according to the WHO 2020 Classification of Female Genital Tumours. PSN=placental site nodule; EPS=exaggerated placental site reaction; GTN=gestational trophoblastic neoplasia; ETT=epithelioid trophoblastic tumour; PSTT=placental site trophoblastic tumour

Figure 2

Genetic origin of hydatidiform moles. (A) CHMs have a diploid genome. Most CHMs (80-90%) arise from fertilisation of an empty ovum by a haploid sperm, which undergoes endoreduplication to result in diploidy (homozygous monospermy). Some CHMs (10-20%) result from fertilisation of the empty ovum by two sperm resulting in diploidy (heterozygous dispermy). (B) PHMs have a triploid genome. Most PHMs (>95%) arise from fertilisation of a single oocyte by two different sperm (heterozygous dispermic). (C) Familial recurrent hydatidiform moles due to biallelic variants in maternal effect genes (NLRP7 or KHDC3L) result in biparental recurrent CHMs. CHM=complete hydatidiform mole; PHM=partial hydatidiform mole

Figure 3

Complete hydatidiform mole. (A) In this macroscopic image of a product of conception, extensive formation of vesicles is evident giving a bunch of grapes effect. (B) The villous population is diffusely abnormal with numerous enlarged hydropic villi (16X). (C) The villi in this view are highly irregular and most show non-polar or circumferential trophoblast hyperplasia (50X). (D) In this early complete hydatidiform mole, the central villous shows the typical cauliflower-like outline with bulbous, knuckle-like projections (50X). (E) On higher magnification this early complete hydatidiform mole has abnormal, dense, myxoid stroma with prominent stromal karyorrhexis (400X). (F) p57 immunohistochemistry shows loss of staining in villous cytotrophoblast and stromal cells with preservation of staining in extravillous trophoblast (upper left) (100X)

Figure 4

Partial hydatidiform mole (PHM). (A) In this macroscopic image of a PHM, focal vesicle formation is evident with some vesicles separating from the specimen at bottom right. (B) This low power magnification shows a mixture of villous types with a group of hydropic villi seen on the right and smaller, more normal sized villi on the left (16X). (C)The villus with a star has a trophoblast pseudoinclusion (50X). (D) The PHM villi are markedly irregular with fjord-like indentations (50X). (E) Focal non-polar trophoblast hyperplasia is affecting the villus with the star while the surrounding villi show little or no hyperplasia (100X). (F) p57 immunohistochemistry is normal (100X)

Figure 5

Abnormal villous morphology. (A) This macroscopic image of a second trimester placenta has a number of clear vesicles becoming detached from the specimen. (B) On microscopy of this placenta, villous morphology was abnormal with villous enlargement, some irregularity in villous outlines, and small pseudoinclusions (50X). This case was confirmed on microarray of fresh tissue to be an example of mosaicism for monosomy X (Turner syndrome)

Figure 6

p57 discordant villi. (A)This low power magnification shows abnormal villous morphology with enlarged, hypercellular villi and a trophoblast pseudoinclusion but no trophoblast hyperplasia (50X). (B) Immunohistochemistry for p57 shows a discordant pattern with positive cytotrophoblast and negative stromal cells (100X). (C) Careful examination of the specimen identified a small focus of villi with trophoblast hyperplasia (star) (50X). (D) This focus of villi showed absence of p57 staining in stroma and cytotrophoblast in keeping with a component of CHM (50X).

Figure 7

hCG monitoring protocol for complete and partial hydatidiform moles. hCG=human chorionic gonadotrophin.*hCG monitoring is done on the same analytical platform throughout follow-up. Adapted from the Royal College of Obstetrics and Gynaecology guidelines. Reproduced with permission Joyce and colleagues