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; L11-3666 by SISH] 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:

  1. Lage JM & McEvoy R, Unknown cases: GTD cases, MUSC McKee-PT Seminar, 6 April 2005 (EBS).
  2. discussions with OB-GYN members of our local medical staff.
  3. Crum CC, et. al., Discrimination of Complete Hydatidiform Mole From its Mimics by Immunohistochemistry of the Paternally Imprinted Gene Product p57KIP2.
  4. personal e-mails or discussions from experts & "focused" practitioners.
  5. 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)
  6. Fukunaga M, et. al., Interobserver and Intraobserver Variability in the Diagnosis of Hydatidiform Mole, AJSP 29(7):942-947.
  7. Leonard DGB, Diagnostic Molecular Pathology, 208 pages, 2003.

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

 
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