This document defines and describes gestational trophoblastic disease, which includes abnormal placentas and gestational tumors. It covers topics like complete and partial hydatidiform moles, invasive and metastatic moles, gestational choriocarcinoma, placental site trophoblastic tumor, and epithelioid trophoblastic tumor. Prognostic factors, treatment approaches, and histopathological features are discussed for different conditions. The genetics, clinical presentation, imaging and spread of these gestational diseases are also summarized.

1. Gestational trophoblastic
disease
Shahin Hameed

2. Synopsis
 Introduction
 Definition
 Classification
 Epidemiology
 Etiology
 Clinical features
 Imaging
 Tumour spread & staging
 Prognostic factors

3. Synopsis
 Hydatidiform mole
 Complete mole
 Partial mole
 Invasive mole
 Metastatic mole
 Trophoblastic tumors (neoplastic)
 Gestational choriocarcinoma
 Placental site trophoblastic tumor
 Epithelioid trophoblastic tumor

4. Synopsis
 Trophoblastic tumor like lesion (benign)
 Placental site nodule
 Exaggerated placental site
 Summary
 References

5. Introduction

6. Definition ..
 Gestational trophoblastic disease constitutes a
diverse group of lesions that includes abnormally
formed placentas (hydatidiform moles), benign
nonneoplastic lesions, and gestational
trophoblastic neoplasms

8. Epidemiology
 Gestational trophoblastic disease (GTD) varies
widely among various populations
 As high as 1 in 120 pregnancies in some areas of
Asia and South America

9.  The incidence of hydatidiform moles is greater in
women older than 40 years and is also increased in
those younger than 20 years.
 Patients who have had prior GTD are more at risk of
having a second GTD after subsequent pregnancies.
 Other risk factors include: a diet low in vitamin A,
lower socioeconomic status and blood group A
women married to group 0 men

10. Aetiology
 Hydatiform moles arise from abnormal
conceptions.
 Partial moles result from diandric triploidy,
whereas complete moles result from diandry
(fertilization of an empty ovum)
 Up to 50% of choriocarcinomas and 15% of
placental site trophoblastic tumours follow
complete moles

11. Clinical features
 A complete molar pregnancy - first trimester
bleeding, a uterus larger than expected for
gestational age and the absence of fetal parts on
ultrasound in association with a markedly
elevated beta-human chorionic gonadotropin (b-
hCG) level
 Other signs include hyperemesis, toxaemia
during the first or second trimester, theca lutein
cysts and hyperthyroidism.

12.  Patients with partial molar gestations-spontaneous
abortions, sometimes with increased b-hCG levels.
 GTD should always be considered when a patient
has continued vaginal bleeding following delivery or
abortion.

13. Imaging
 A characteristic pattern of multiple vesicles
(snowstorm pattern) is commonly seen with
complete molar pregnancy.
 The diagnosis of partial molar pregnancy by
ultrasonography is more difficult.

14. Tumour spread and staging
 Choriocarcinoma spreads haematogenously and
may involve the lung (57-80%), vagina (30%),
pelvis (20%), brain (17%), and liver (10%)
 Since b-hCG titres accurately reflect the clinical
disease, histological verification is not required for
diagnosis.
 Staging should be based on history, clinical
examination and appropriate laboratory and
radiological studies.

15.  Metastatic GTD is categorized by the WHO
scoring system as low, medium and high risk
 The individual scores for each prognostic factor
are added together to obtain a total score
 A total prognostic score less than or equal to 4 is
considered low risk, a total score of 5-7 is
considered middle risk, and a total score of 8 or
greater is considered high risk

16. Somatic genetics
 Overexpression of TP53 protein more commonly
observed in complete moles and choriocarcinoma
 Overexpression of the p21 gene has also been
detected in complete moles and choriocarcinoma

17.  Both complete mole and choriocarcinoma exhibit
overexpression of several growth factors
including c-Myc, epidermal growth factors
receptor (EGFR), c-erbB-2, Rb, mdm2, and bcl-2
as compared to normal placenta and partial mole
 Strong immunostaining of c-erbB-3 and epidermal
growth factor receptor in extravillous trophoblast
of complete mole was significantly correlated with
the development of persistent gestational
trophoblastic tumour

18. Prognosis and predictive
factors
 Major adverse prognostic variables for GTD are:
(1) Age >39
(2) Prior term pregnancy
(3) Interval from antecedent pregnancy of >12
months
(4) b-hCG >105 IU/litre
(5) Tumour mass >5cm
(6) Disease in liver and brain
(7) Failure of 2 or more prior chemotherapies

19. Hydatidiform moles

20. Definition
 An abnormal placenta with villous hydrops and
variable degrees of trophoblastic proliferation.

21. Complete hydatidiform mole
 A hydatidiform mole involving most of the chorionic
villi and typically having a diploid karyotype

22. Histopathology
 The villous hydrops of a complete mole is
characterized by extensive cavitation.
 The trophoblastic proliferation has a circumferential
distribution, hyperplasia and cytological atypia .
 Intermediate trophoblast of the molar implantation site
characteristically displays marked cytologic atypia
 A gestational sac, amnion, umbilical cord and fetal
tissue are not found

24.  Recently been suggested that villous stromal nuclear
negative staining for the paternally imprinted gene
product p57 maybe diagnostically useful for
confirming the diagnosis of a complete mole

25.  Although villous cavitation may be minimal in an
"early" mole, other characteristic villous stromal
features are present, including hypercellularity and a
myxoid basophilic stroma
 In addition, unusual villous shapes with complex
bulbous protrusions ("cauliflower like" villi) and
trophoblastic atypia are present

26. Somatic genetics
 Complete moles generally have a 46,XX
karyotype, and the molar chromosomes are
completely of paternal origin
 Most complete moles appear to arise from an
anuclear empty ovum fertilized by a (23X) haploid
sperm that then replicates its own chromosomes

27.  About 10% of complete moles have a 46,XY
karyotype
 The 46,XY complete mole arises from fertilization of
an anuclear empty egg by two sperm.
 While all chromosomes in a complete mole are
entirely of paternal origin, the mitochondrial DNA is
of maternal origin

29. Partial hydatidiform mole
 A hydatidiform mole having two populations of
chorionic villi, one of normal size and the other
hydropic, with focal trophoblastic proliferation.
 The lesion typically has a triploid karyotype

30. Histopathology
 Histologically, partial moles are characterized by
the concurrence of four features
(1) Two populations of villi, one hydropic and one
"normal"
(2) Minimal trophoblastic hyperplasia involving
syncytiotrophoblast.
(3) Enlarged cavitated villi.
(4) Other villi with scalloped borders, often
containing trophoblastic inclusions.

31.  Stromal blood vessels often contain nucleated fetal
red blood cells; other evidence suggesting fetal
development including portions of the chorionic sac
wall, amnion, umbilical cord and embryonic/fetal
tissue are common

32. Differential diagnosis
(1) Complete mole.
(2) Hydropic abortus .
(3) Several rare sporadic genetic syndromes such
as the Beckwith-Weidemann syndrome and
placental angiomatous malformation which
collectively have been termed "placental
mesenchymal dysplasia"

33. Somatic genetics
 Partial moles generally have a triploid karyotype that
results from fertilization of an apparently normal
ovum by two sperm
 When fetuses are identified with partial moles, they
usually have stigmata of triploidy including multiple
congenital anomalies and growth retardation

36. Invasive hydatidiform mole
 Invasive hydatidiform mole is defined as villi of
hydatidiform mole within the myometrium or its
vascular spaces.
 A clinical diagnosis of invasive mole can be
suspected when β-hCG titers plateau or increase
following evacuation of a mole

37. Pathologic Features ..
 Grossly, invasive mole in the uterus results in an
irregular, often hemorrhagic lesion that penetrates
into the myometrium. The lesion can grow through
the myometrium, perforating the serosa or extending
into the broad ligament and adnexa
 Most invasive moles follow complete hydatidiform
mole and have the characteristic histological
appearance of that lesion.

39. Metastatic hydatidiform mole
 Metastatic hydatidiform mole is defined as
extrauterine molar villi within blood vessels or
tissues, most commonly the vagina or the lung.

40. Trophoblastic tumours
(neoplastic)

41. Gestational choriocarcinoma
A malignant neoplasm composed of large sheets of
biphasic, markedly atypical trophoblast without
chorionic villi

42.  Gestational choriocarcinoma may occur subsequent
to a molar pregnancy (50% of instances), an
abortion (25%), a normal gestation (22.5%) or an
ectopic pregnancy (2.5%)
 In rare cases an intraplacental choriocarcinoma is
diagnosed immediately following pregnancy from
placental pathological examination

43. Morphology
 The choriocarcinoma is classically a soft, fleshy,
yellow-white tumor with a marked tendency to form
large pale areas of ischemic necrosis, foci of cystic
softening, and extensive hemorrhage

44. Histopathology
 The classic pattern of choriocarcinoma has been
described as bilaminar, dimorphic, or biphasic.
 Alternating arrangement of mononucleate
trophoblastic cells and syncytiotrophoblastic cells
that characterize choriocarcinoma.

45.  The intermediate trophoblast in choriocarcinoma
may show marked variation in the degree of
cytologic atypia . Nuclear pleomorphism and
hyperchromasia often are striking, and nucleoli
can be prominent.

46.  Vascular invasion often is prominent.
 Chorionic villi are not a component of
choriocarcinoma
 Choriocarcinoma lacks the intrinsic endothelium-
lined vascular channels in the center of a tumor,
making it a unique malignant solid tumor.

48. Immunoprofile
 All trophoblastic cell types are strongly
immunoreactive for cytokeratins
 Inaddition, the syncytiotrophoblast is strongly
immunoreactive for b-hCG and weakly
immunoreactive for human placental lactogen
(hPL)
 Intermediate trophoblast shows the opposite
immunoprofile

49. Treatment
 Includes evacuation of the contents of the uterus,
surgery, and chemotherapy.
 Chemotherapy consists of the administration of
one or more of a group of drugs including
methotrexate, actinomycin D, and etoposide.
 The results of chemotherapy for gestational
choriocarcinoma are spectacular and have
resulted in up to 100% cure or remission in all
patients except some who had high-risk
metastatic trophoblastic disease.

50. Differential diagnosis
 The differential diagnosis of choriocarcinoma in
endometrial curettings includes
 previllous trophoblast from an early gestation
 persistent molar tissue following hydatidiform mole
 placental site trophoblastic tumour
 epithelioid trophoblastic tumour
 undifferentiated carcinoma.

51. Somatic genetics
 Recent studies using cDNA microarray analysis have
demonstrated decreased expression of heat shock
protein-27 in choriocarcinoma, a finding which has
been associated with chemotherapy responsiveness
in other cancers

52. Placental site trophoblastic
tumour
 A monophasic neoplasm composed of intermediate
trophoblast and cytotrophoblast without a significant
component of syncytiotrophoblast

53.  PSTTs comprise less than 2% of gestational
trophoblastic neoplasms and present as
neoplastic polygonal cells infiltrating the
endomyometrium.
 PSTTs may be preceded by a normal pregnancy
(one-half), spontaneous abortion (one-sixth), or
hydatidiform mole (one-fifth)

54. Histopathology
 The tumour cells are medium to large sized and
mononuclear or multinucleated with mild to
marked nuclear atypia, prominent nucleoli,
eosinophilic to clear cytoplasm, scattered mitoses
and occasional intranuclear inclusions
 They permeate the myometrium and vessels in a
manner reminiscent of the implantation site
trophoblast.

56. Differential diagnosis
 The differential diagnosis of placental site
trophoblastic tumour includes
 Placental site nodule
 Exaggerated implantation site
 Epithelioid leiomyosarcoma
 Epithelioid trophoblastic tumour
 Poorly differentiated carcinoma .
 Extensive sampling and immunohistochemistry
for keratin, b-hCG and hPL are helpful in
distinguishing among the above lesions

57. Somatic genetics
 A Y- chromosomal locus and/or new (paternal)
alleles not present in adjacent normal uterine
tissue was demonstrated in all cases of placental
site trophoblastic tumour studied confirming the
placental origin of these neoplasms

58. Prognosis and predictive
factors
 Patients with localized (Stage I or II) disease or a less
than 2-year interval from the prior pregnancy to
diagnosis have an excellent prognosis.
 Tumors diagnosed 4 or more years following
pregnancy, with lung involvement or with advanced
stage have a poor prognosis.
 An elevated mitotic index predicts a poor outcome

59. Epithelioid trophoblastic
tumour
 A tumour composed of a monomorphic population of
intermediate trophoblastic cells closely resembling
those of the membranous chorion

60. Histopathology
 Tumour cells of the epithelioid trophoblastic tumour
are smaller and less pleomorphic and grow in a
nodular pattern

62.  Because they are frequently found in the cervix,
they may be confused with hyalinizing squamous
cell carcinomas .
 Epithelioid trophoblastic tumours are focally
immunoreactive for placental-like alkaline
phosphatase (PLAP) and hPL but strongly and
diffusely immunoreactive for E-cadherin and
epidermal growth factor receptor

63. Somatic genetics
 A Y-chromosomal locus and/or new (paternal) alleles
not present in adjacent normal uterine tissue was
demonstrated in all cases of epithelioid trophoblastic
tumour studied

64. Prognosis and predictive
factors
 Based on available data, the behaviour of epithelioid
trophoblastic tumour resembles that of placental site
trophoblastic tumour.

65. Trophoblastic tumours like lesions
(benign)

66. Placental site nodule or plaque
 The placental site nodule or plaque is a well
circumscribed lesion with abundant hyalinized
stroma infiltrated by scattered, degenerated-
appearing intermediate trophoblastic cells that are
normally located on the fetal membrane
 These cells show no significant cytological atypia,
but rare mitoses may be present

67. Pathologic Features
 Microscopically, the placental site nodule has a
discrete, well-circumscribed, lobulated border
sometimes showing small irregular nests of cells
projecting into the surrounding tissue.
 Cluster of hyperchromatic and vacuolated
chorionic type intermediate trophoblast cells
embedded in hyaline matrix

68. Immunohistochemistry
 Strongly and diffusely positive for low-molecular-
weight cytokeratin (CK; such as CK8/18)
 Only focally positive for human placental lactogen
(hPL) and CD146 (Mel-CAM)
 Negative for mucin-4

69.  The chorionic-type intermediate trophoblastic cells in
placental site nodules are positive for p63
 There is a low level of proliferation in the cells of
placental site nodules as indicated by a few
scattered Ki-67 labeled nuclei

70. Differential Diagnosis
 Small size, circumscription, extensive eosinophilic
extracellular matrix, and paucity of mitotic figures
distinguish this lesion from PSTT, ETT, and
cervical squamous carcinoma
 The Ki-67 index in ETTs is significantly higher
(>10%) than in placental site nodules (<10%).

71. Exaggerated placental site
 Exaggerated placental site is a benign, nonneoplastic
lesion characterized by an increased number of
implantation site intermediate trophoblastic cells that
extensively infiltrate the endometrium and underlying
myometrium.
 No specific treatment or follow-up is necessary

72. Differential Diagnosis
 Exaggerated placental site may be difficult to
distinguish from PSTT, particularly in curetting
 The presence of chorionic villi (and/or fetal parts)
and abundant multinucleated intermediate
trophoblastic cells and the absence of confluence
of intermediate trophoblastic cells in the
endomyometrium suggest the diagnosis of an
exaggerated placental site rather than a PSTT.

73.  The Ki-67 nuclear labeling index using a Ki-67-
specific (MIB-1) antibody is superior to the mitotic
index as a diagnostic aid in the differential diagnosis
of exaggerated placental site versus PSTT .
 Specifically, the Ki-67 index of the trophoblastic cells
in an exaggerated placental site is near zero in
contrast to 14% ± 6.9% in a PSTT

75. Summary
 Various forms of gestational trophoblastic disease
can be defined and related to discrete pathologic
aberrations occurring at different trophoblastic
subpopulations and stages of trophoblastic
differentiation during placentation
 The recognition and separation of the individual
categories of gestational trophoblastic disease are
important because each disease entity has
distinctive clinical manifestations and each requires
different therapeutic approaches

76. References
 Lora Hedrick Ellenson, Edyat C Pirog. Female
genital tract. Robbins & Cotran’s Pathologic Basis
of Disease 2010;8;1057-1061
 D.R Genest, R.S Berkpwitz. Gestational
trophoblastic disease. Pathology & Genetics of
breast & female genital organ WHO;2008;250-
254
 Le Ming Shih, Micheal T Mazur. Female
reproductive system and peritoneum. Gestational
trophoblastic disease. Sternberg’s Diagnostic
Surgical Patholgy;2;5;2049-2068
 Rosai & Ackerman’s Surgical Pathology.
Gestational trophoblastic disease;2;9;1740-1749

77. Thank you ..