Pathology Associates Of Lexington, P.A.

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Gestational Trophoblastic Disease

Gestational Trophoblastic Disease (GTD):

The big deal for the clinician is binary: (1) non-molar POC vs. (2) molar (PHM or CHM) products of conception (POC). PHM has 2% risk of persistent GTD, CHM risk is 20%⁶. They follow partial and complete moles the same (except clinicians are braced for a higher rate of recurrence-in-the-first-year in complete moles): checking for persistent GTD which could have an invasive component or toxemia. Refraining from pregnancy for about a year...easier in younger age groups... allows time to detect signs of persistent GTD. A molar pregnancy having a subsequent molar pregnancy is about a 1% risk. Follow-up serum HCGs for 6-12 months. There is no need to follow hydropic abortions (HA).

The big deal for pathologists, therefore, is the correct distinction of all three: (1) regressively hydropic spontaneous blighted ovum or embryo abortions vs. (2) partial molar (PHM) pregnancies AND the separation of partial molar pregnancies vs. (3) complete (hydatidiform) molar pregnancies (CHM). Proper gross exam (1) in search of hydropic villi & (2) submission of adequate tissue is highly important! To settle follow-up needs in cases of HA vs. PHM (especially in older and/or infertile mothers where any delays at attempting pregnancy again are frustrating), ploidy studies may be valuable (diploidy essentially excludes PM⁶).

Unlike decades ago when molar pregnancies came to the lab in large-volume containers, routine early-gestation follow up of all pregnancies with ultrasound has us evaluating early stages of gestational POCs with no ultrasound evidence of heart motion. So the histological distinctions are less flagrant in currently modern times. Villous capillaries form normally from yolk sac elements and regress with absence of embryo (embryo absence of any etiology). So one could see villous capillaries very early in a complete mole; then such villi with capillaries become quickly "diluted out" early in complete mole which never had an embryo¹. Vessels may be "diluted" into the stem villi. Yolk-sac-derived hematopoietic cells can be seen in capillary lumens in HAs, PHMs, and CHMs.

"As always, a cautionary comment pertains to a situation of multiple gestation pregnancy with a mix of placental types in the POC specimen. Those can be very confusing, and the immunoprofile could also be confusing ¹."

The standard dictum of refraining from pregnancy for one year following diagnosis of molar pregnancy (complete or incomplete) is being liberalized by modern technology, especially in the older age group of women "whose biological clock is running out". Should the molar patient become pregnant (in months or years), a quantitative HCG can be done at the earliest chance along with an ultrasound. If HCG elevation is concordant with ultrasound dates and ultrasound detects a sac (as early as 4-5 weeks), a non-molar pregnancy is the initial working diagnosis and pregnancy allowed to continue. D&C is performed if HCG clearly high for dates and/or no evidence of sac by ultrasound ².

Is It Molar?:

	hydropic POC (HA)	partial molar (PHM)	complete molar (CHM)
clinical follow-up needed?	no	yes	yes
has grossly visible vesicular villi	almost never	+ (usually)	+ to +++
has increased villous stroma cells	not increased cellularity; maybe a little karryorrhectic⁴ nuclei.	a bit/focally cellular; maybe a some karryorrhectic⁴ nuclei.	Cellular/primitive stroma. Patches of karyorrhectic nuclei even in very early⁵.
has villi with acellular central cisterns	yes, rarely in a few villi⁴	yes	yes, widespread; but may be scant in very early gestations⁵.
character of villous population	mix of 2 types (ordinary & only microscopically⁵ hydropic/edematous)	mix of two (& non-microscopically visible hydrops leans toward molar)	Pretty much one population. Generalized villous hydrops⁵....but. don't forget the potential situation of multiple gestational POC.
shape of villous cross-sectional outlines	mostly complex	less frequently complex; but see frequent cross-sections ("inclusions")⁴ of trophoblast cords in stroma	Round & simple & few or no inclusions. Bulbous early⁵.
trophoblast features	No atypia. Not much if any circumferential hyperplasia (which, if present, is non-cytotrophoblastic). Lack of troph proliferation & trophs often attenuated⁵.	finding of even focal mild mild cyto-syncyt. troph hyperplasia & some circumferential is essential to DX of mole	atypia (especially of intermediates) & excessive⁵ cyto-syncyt. troph. hyperplasia & lots circumferential⁵
embryonic/yolk-sac-blood cells present	yes, often (somatic & other)	yes, sometimes	almost never (except early villous vessels, sometimes; some yolk-sac-derived blood cells if D&C as early as 6-10 weeks⁴)...don't forget the potential situation of multiple gestational POC.
IHC Ki-67 nuclear-positive trophs	HA is regressive; no good pattern of proliferating zones, centers, or clusters	normal/increased %	normal/increased %
IHC p57 nuclear-positive trophs³	high % +	high % +	neg./markedly reduced
DNA ploidy	Various (4-14% triploid⁶). Majority diploid. Diploidy essentially excludes PHM⁶.	always (>90%⁵) triploid; normal ovum plus two sperm⁷. [see CN06-73]	not triploid (usually diploid⁶); empty ovum plus a sperm that undergoes duplication⁷. STR by PCR can discern HA from CHM⁷.

Placental Site Nodule (PSN): can be retained for years

Exaggerated placental site reaction (EPSR): also known as syncytial endometritis; is a proliferation of intermediate trophoblasts with identical immunophenotype of normal implantation site intermediate trophoblasts. May see villi; rare or absent mitoses⁵; it may be impossible to differentiate this from PSTT⁵. May occur in association with a normal pregnancy, abortion, or molar pregnancy. No treatment or follow up needed if one can solve the nightmarishly difficult DDX between EPSR & PSTT⁵.

Placental Site trophoblastic Tumor (PSTT): may be diagnosed long after any previously known pregnancy; has extensive deposition of fibrinoid material; malignant behavior when Ki67 >50% & benign behavior when 14% or less⁵.

Epithelioid Trophoblastic Tumor: may be diagnosed long after any previously known pregnancy; HCG always elevated at time of diagnosis; discrete expansile nodule.

Choriocarcinoma: trophoblastic metastasizing malignancy.

References:

Lage JM & McEvoy R, Unknown cases: GTD cases, MUSC McKee-PT Seminar, 6 April 2005 (EBS).
discussions with OB-GYN members of our local medical staff.
Crum CC, et. al., Discrimination of Complete Hydatidiform Mole From its Mimics by Immunohistochemistry of the Paternally Imprinted Gene Product p57^KIP2.
personal e-mails or discussions from experts & "focused" practitioners.
Daya, Dean M, Professor of Pathology & Molecular Med. & OB-GYN, McMaster U., Ontario; Interpretation of Endometrial Biopsies & Curettings, 12th Annual Seminar in Pathology, 28 April-1 May 2005, Pittsburgh (EBS)
Fukunaga M, et. al., Interobserver and Intraobserver Variability in the Diagnosis of Hydatidiform Mole, AJSP 29(7):942-947.
Leonard DGB, Diagnostic Molecular Pathology, 208 pages, 2003.

(posted 2 April 2005; latest update 13 Oct 2006)