Gestational Trophoblastic Disease
Moderator: Dr. le-Ming Shih
Section 5 -
Diagnostic Pitfalls of Molar Lesions
Academic Unit of Pathology, University of Sheffield Medical School
Sheffield , S10 2RX , UNITED KINDOM
An excellent review of the pathology of molar disease has recently been published . This
handout will focus on recent developments over the last 5 years.
Hydatidiform mole is characterized by:
- hydropic change
- cistern formation
- excessive trophoblast
- abnormal distribution of trophoblast
- trophoblastic inclusions
Partial mole :
- 46XX, paternal
- haploid sperm fertilizes empty ovum & undergoes
- diploid sperm fertilizes empty ovum
- all chorionic villi affected
- pleomorphism of trophoblast
- absence of fibrosis
Pathological mimics of partial mole :
- triploid; 69,XXY 69,XXX or 69,XYY
- defective zona pellucidum
- dispermic fertilization of haploid ovum
- fetal parts may be present
- two populations of villi
- enlarged villi (>or= 3-4mm) with central
- irregular (angulated) profile of villi with
- excess trophoblast may be subtle
- abnormal (angioectatic) vasculature in second
Discordance in histopathological diagnosis is frequently seen in partial mole versus hydropic
miscarriage and results from difficulty in evaluating trophoblastic hyperplasia. Ploidy analysis can
improve concordance (see below).
- Beckwith-Wiedemann syndrome
- Placental angiomatous malformation
- Twin gestation with complete mole and existing fetus (see below)
- Early complete mole (see below)
- Hydropic spontaneous miscarriage
Early complete mole
In the 1960s the mean age at evacuation of hydatidiform mole was 17 weeks. Nowadays, with the
introduction of ultrasound examination as part of the routine clinical management of early pregnancy
complications, it is 9.4 weeks and before the classical clinical or pathological features have developed.
Thus, the histological features of complete hydatidiform mole are more subtle . A common
error made by histopathologists in molar disease is the erroneous diagnosis of early complete
hydatidiform mole as partial mole. Non-triploid partial moles probably do not exist .
Certain typical features are seen only in early complete mole:
We have recently shown (unpublished data) that the stromal debris which is a feature of early complete
mole is the result of increased stromal proliferation and apoptosis, a finding also recently demonstrated
by Kim et al .
- abnormally shaped villi –branching or polypoid
- stromal mucin
- stromal vessels may be present
- STROMAL NUCLEAR DEBRIS
Ki-67 index & p53 of villous stroma (unpublished data)
|DIAGNOSIS ||MEAN ||N ||Std deviation|
|Early complete mole ||22.31|
|Partial mole ||8.33|
|Hydropic miscarriage ||5.19|
There is a statistically significant strong positive correlation between Ki67 proliferation index and
p53 expression (rho=0.840; p<0.05). Ki67 proliferation index and p53 expression of villous stromal
cells are strongly correlated with the amount of stromal karyorrhetic debris (rho=0.791; p<0.05).
Kim et al suggest that complete vasculogenic differentiation is
significantly retarded in early complete mole, due to increased apoptosis in the precursor components of
blood vessels .
Ploidy analysis and p57kip2
Ploidy analysis is of great value in making the distinction between a diploid complete mole and a
triploid partial mole. It may also aid the distinction between a diploid hydropic miscarriage and a
triploid partial mole . This may be achieved by flow cytometry or digital image analysis. In
my own laboratory we have moved exclusively to digital image analysis. However, the greatest recent
advance in the histopathology of molar pregnancy has been the introduction of immunohistochemistry for
An interesting finding is that the non-villous (extravillous or intermediate) trophoblast is
positive even in complete mole . As yet, there is no satisfactory
biological explanation for this interesting phenomenon.
- paternally imprinted gene, 11p15.5
- maternally expressed
- villous cytotrophoblast p57kip2 -ve in
- villous cytotrophoblast p57kip2 +ve in
- syncytiotrophoblast always p57kip2 –ve
Combined digital image ploidy analysis and p57kip2 can now be used in a complementary way
to facilitate the diagnosis of complete and partial mole .
|Suspected diagnosis ||Flow cytometry ||Image cytometry ||p57kip2 status ||Revised diagnosis|
|Partial mole ||Diploid* ||Triploid* ||+ve ||Partial mole|
|Complete mole ||Triploid ||Triploid ||+ve ||Partial mole|
|Partial mole ||Diploid ||Diploid ||-ve ||Complete mole|
|Partial mole ||Diploid ||Diploid ||+ve ||Hydropic miscarriage|
Note greater reliability of digital image analysis compared with flow
Twin molar pregnancy
Cases of twin molar gestations comprising a complete mole with coexisting fetus are often
misinterpreted as partial molar singleton pregnancies .
- twin molar pregnancies are dizygotic
- Normal fetus and mole or two moles together
- One case report published as "twin molar
gestation" actually comprised 2 x normal fetuses and 2 x complete moles i.e. quads
- Incidence of 1:22 000 to 1:100 000
- Association with infertility treatments and
- Increased risks of obstetric complications in
twin molar pregnancies
- Persistent gestational trophoblastic disease
in 20-55%(14 – 20% in non-twin mole)
- Metastatic disease (27.7%) (16% in non-twin
- Poor survival rate of the normal twin (24 -
- Spontaneous abortion (43%)
- Severe pre-eclampsia (6%)
- Others (antepartum haemorrhage,
Ectopic molar pregnancy
Normal early placentation shows:
- Rare, mostly tubal
- 40 cases of tubal mole in world literature
- Over diagnosed because histopathologists do
not appreciate the exuberance of normal trophoblast in the early first trimester
- Tertiary histopathological review is
- Absent/mild circumferential trophoblast
- Absent/mild hydrops
- Inconspicuous stromal apoptosis
- Mild/moderate scalloping of villi
Persistent trophoblastic disease (PTD)
PTD is not a histopathological diagnosis. It includes:
PTD occurs in
- invasive mole
- 15-20% of patients with complete mole
- rare following partial mole – many early
complete moles are misdiagnosed as partial moles
- the majority are invasive moles
- Paradinas FJ, Elston CW. Gestational Trophoblastic Diseases In: Haines & Taylor Obstetrical and Gynaecological Pathology, Fifth edition Editors H Fox, M Wells, Churchill Livingstone 2003: 1359-1430.
- Genest DR. Partial hydatidiform mole; clinicopathological features, differential diagnosis, ploidy and molecular studies, and gold standards for diagnosis. Int J Gynecol Pathol 2001; 20: 315-322.
- Fukunaga M, Katabuchi H, Nagasaka T, Mikami Y, Minamiguchi S, Lage JM. Interobserver and intraobserver variability in the diagnosis of hydatidiform mole. Am J Surg Pathol 2005; 29: 942-947.
- Sebire NJ, Makrydimas G, Agnantis NJ, Zagorianakou N, Rees H, Fisher RA. Updated diagnostic criteria for partial and complete hydatidiform moles in early pregnancy. Anticancer Res 2003; 23: 1723-1728.
- Genest Dr, Ruiz RE, Weremowicz S, Berkowitz RS, Goldstein DP, Dorfman DM. Do nontriploid partial hydatidiform moles exist? A histologic and flow cytometric reevaluation of nontriploid specimens. J Reprod Med 2002; 47; 363-368.
- Kim MJ, Kim KR, Ro JY, Lage JM, Lee HI. Diagnostic and pathogenetic significance of increased stromal apoptosis and incomplete vasculogenesis in complete hydatidiform moles in very early pregnancy periods. Am J Surg Pathol 2006; 30: 362-369.
- Jun SY, Ro JY, Kim KR. p57kip2 is useful in the classification and differential diagnosis of complete and partial hydatidiform moles. Histopathology 2003; 43; 17-25.
- Crisp H, Burton JL, Stewart R, Wells M. Refining the diagnosis of hydatidiform mole: image ploidy analysis and p57KIP2 immunohistochemistry. Histopathology 2003; 43: 363-373.
- Merchant SH, Amin MB, Viswanatha DS, Malhotra RK, Moehlenkamp C, Joste NE. p57KIP2 immunohistochemistry in early molar pregnancies: emphasis on its complementary role in the differential diagnosis of hydropic abortuses. Hum Pathol 2005; 36; 180-186.
- Sebire NJ, Lindsay I. p57KIP2immunostaining in the diagnosis of complete versus partial hydatidiform moles. Histopathology 2006; 48: 873-874.
- Hancock BW, Martin K, Evans C, Everard JE, Wells M. Twin mole and viable fetus: the case for misdiagnosis. J Reprod Med (in press).
- Burton JL, Lidbury EA Gillespie AM, Tidy JA, Smoth O, Lawry J, Hancock BW, Wells M. Over-diagnosis of hydatidiform mole in early tubal ectopic pregnancy. Histopathology 2001; 38: 409-417.
- Sebire NJ, Lindsay I, Fisher RA, Savage P, Seckl MJ. Overdiagnosis of complete and partial hydatidiform mole in tubal ectopic pregnancies. Int J Gynecol Pathol 2005; 24; 260-264.