Case Presentation
Brigitte M. Ronnett, MD
Department of Pathology
The Johns Hopkins University School of Medicine
Baltimore, MD USA
Case Presentation
• The patient is a 39 year-old woman, G2P1,
who presented with a missed abortion at 8-10
weeks and ultrasound findings suggesting a
molar pregnancy (serum beta-HCG level not
available). The material for review is from the
curettage specimen.
Diagnosis?
Original diagnosis: Partial hydatidiform mole
• In follow-up, the beta-HCG level became
undetectable by 6 months and remained so
during an additional 6 months of follow-up,
without requiring chemotherapy.
Case Presentation
• Follow-up: 2 years later, 8 month history of
dysfunctional uterine bleeding (menorrhagia), serum
beta-HCG level 750,000 mIU/mL (patient reported that
she had not been sexually active since the prior molar
pregnancy)
• Imaging studies & hysteroscopy: 6.0-7.8 cm uterine
mass; no evidence of metastatic GTD
• Curettage: markedly atypical trophoblast without villi
Algorithmic Approach to Diagnosis of Hydatidiform Moles
Possible Hydatidiform Mole
p57 Immunohistochemistry
p57 negative
(villous stroma, cytotrophoblast)
p57 positive
(villous stroma, cytotrophoblast)
Molecular Genotyping
Androgenetic Diploidy
Diandric Triploidy
Biparental Diploidy
Complete
Hydatidiform Mole
Partial
Hydatidiform Mole
Non-molar
p57
p57
Non-molar Specimen: Biparental Diploidy
p57
p57
CH3
CH3
CH3
Maternal Chr 11
Paternal Chr 11
RNA
p57 protein
p57: paternally imprinted,
maternally expressed
IHC
Positive in nuclei of villous stromal
cells, cytotrophoblast, and
intermediate trophoblast
Partial Hydatidiform Mole: Diandric Triploidy
p57
p57
CH3
CH3
CH3
p57
Maternal Chr 11
Paternal Chr 11 (2 copies)
CH3
CH3
CH3
RNA
p57 protein
p57: paternally imprinted,
maternally expressed
IHC
Positive in nuclei of villous
stromal cells, cytotrophoblast,
and intermediate trophoblast
Complete Hydatidiform Mole: Androgenetic Diploidy
p57
X CH
3
CH3
CH3
p57
CH3
CH3
CH3
RNA
X
p57 protein
p57: paternally imprinted,
maternally expressed
IHC
Negative in villous stromal
cells and cytotrophoblast
No maternal DNA
Paternal Chr 11 (2 copies)
(intermediate trophoblastic cells +)
Diagnosis?
Original diagnosis: Partial hydatidiform mole
Consultation diagnosis:
• Androgenetic/biparental mosaic/chimeric
conception with a molar component
(complete hydatidiform mole)
Characterization of
Androgenetic/Biparental Mosaic/Chimeric
Conceptions, Including Those with a
Molar Component
Brigitte M. Ronnett, MD
Department of Pathology
The Johns Hopkins University School of Medicine
Baltimore, MD USA
533 POC specimens analyzed by p57 IHC +/- genotyping
168
CHMs
126
PHMs
222
NMs
17 complex specimens
per genotyping
11 specimens with distinct
p57 and genotyping patterns
5 without foci
of trophoblastic
hyperplasia
6 with foci of
trophoblastic
hyperplasia
p57
FISH: diploid XX stromal cells &
diploid XX cytotrophoblast
Non-molar mosaic specimen
p57+ biparental diploid
XX cytotrophoblast
p57- androgenetic diploid
XX villous stromal cells
p57+ biparental diploid
cytotrophoblast &
p57- androgenetic diploid
villous stromal cells
P:M = 2.5:1
Molecular Genotyping:
Androgenetic/Biparental Diploid Mosaic
Decidua
VWA
THO1
D13S317
179
183
P
Villi
186
217
221
P
183 171
P
209
M
M
179
P:M allele ratio
M
186
2.7
3.1
221
3.1
p57
p57
FISH: diploid XX stromal cells &
diploid XX cytotrophoblast
(both p57-discordant mosaic villi
and p57-negative molar villi with
trophoblastic hyperplasia)
Non-molar mosaic component
p57+ biparental diploid
XX cytotrophoblast
p57- androgenetic diploid
XX villous stromal cells
p57+ biparental diploid
cytotrophoblast &
p57- androgenetic diploid
villous stromal cells
P:M = 2.5:1
Molar component: features of CHM
p57- androgenetic
diploid cytotrophoblast
p57- androgenetic diploid
villous stromal cells
p57- androgenetic diploid
cytotrophoblast &
p57- androgenetic diploid
villous stromal cells
P:M = 2:0
p57
Non-molar mosaic
component
p57+ biparental diploid XX cytotrophoblast
p57- androgenetic diploid XX villous stromal cells
Molar component: CHM
p57- androgenetic diploid XX cytotrophoblast
p57- androgenetic diploid XX villous stromal cells
Mixture of p57+ & p57biparental & androgenetic
diploid cytotrophoblast &
p57- androgenetic diploid
villous stromal cells
P:M ~ 5:1
Mosaic
component
Molar
component
P:M = 2.5:1
P:M = 2:0
Molecular Genotyping:
Androgenetic/Biparental Diploid Mosaic with Molar Component
Decidua
Amelogenin
103
Villi
THO1
170
223
175
M
P:M allele ratio
(with
trophoblastic
hyperplasia)
103
P:M allele ratio
P
239
M
304
P
296
223
170
Villi
300
P
103
(no
trophoblastic
hyperplasia)
CSF1PO
TPOX
M
304
5:1
3:1
P
175
2:0
4:1
P
239
2:0
P
296
2:0
p57
FISH: diploid XX stromal cells &
mixed diploid XX, triploid XXX, and
tetraploid XXXX cytotrophoblast
(p57-discordant mosaic villi)
Non-molar mosaic component
p57+ biparental diploid XX,
triploid XXX, & tetraploid
XXXX cytotrophoblast
p57- androgenetic diploid
XX villous stromal cells
p57+ biparental diploid,
triploid, and tetraploid
cytotrophoblast &
p57- androgenetic diploid
villous stromal cells
P:M >2:1*
*depends on number of paternal sets in aneuploid cells
p57
FISH: diploid XX stromal cells
& diploid XX cytotrophoblast
(p57-negative molar villi with
trophoblastic hyperplasia)
Molar component: features of CHM
p57- androgenetic
diploid cytotrophoblast
p57- androgenetic diploid
villous stromal cells
p57- androgenetic diploid
cytotrophoblast &
p57- androgenetic diploid
villous stromal cells
P:M = 2:0
Molecular Genotyping:
Androgenetic/Biparental Mosaic with Molar Component (CHM)
Decidua
THO1
171
P
Villi
(no
trophoblastic
hyperplasia)
P:M allele ratio
Villi
(with
trophoblastic
hyperplasia)
P:M allele ratio
183
175
D5S818
131
153
148
D3S1358
135
157
P
M
123
P
M
M
171
135
157
2.7:1
P
175
4.3:1
148
P
Biparental
(P:M > 2:1)
3.9:1
123
P
Androgenetic
2:0
2:0
2:0
Molecular Genotyping:
Androgenetic/Biparental Mosaic with Molar Component (CHM)
Decidua
103
Villi
(with
trophoblastic
hyperplasia)
THO1
Amelogenin
103
171
175
P:M allele ratio
Trophoblast
(recurrent GTD)
103
183
P
148
135
157
P
123
2:0
P
P
P
2:0
123
P
M,M*
M*
171
P:M allele ratio
D3S1358
131
153
148
2:0
175
D5S818
M,M*
153, 157
131,135
M*
183
2:0
2:0
2:0
*maternal DNA
contamination
Case Presentation
• Therapy: multi-agent chemotherapy (+high-risk factors); over 2
months, the beta-HCG levels declined significantly but plateaued
(29 mIU/mL).
• Hysterectomy: 5.0 cm firm yellow well-circumscribed mass in
myometrium
• Pathology: complete microscopic evaluation disclosed
extensively necrotic tumor with surrounding inflammatory cells
and only occasional multinucleated cells; immunohistochemical
analysis demonstrated extensive expression of beta-HCG and
focal expression of cytokeratins in the necrotic tumor
• Follow-up: 4 weeks post-operatively, the serum beta-HCG level
had declined to 3 mIU/mL; resumption of chemotherapy was
planned for the post-operative period
Summary
• Androgenetic/biparental mosaic/chimeric
conceptions can be recognized by their unusual p57
expression patterns
– Characterized by a mixture of p57-positive
biparental and p57-negative androgenetic cells
• Genotyping results are complicated, with variable
paternal:maternal allele ratios and an excess of
paternal alleles
• Often misclassified as PHM by morphology
• Those with a p57-negative androgenetic component
with features of CHM have some risk of persistent
GTD and warrant management as a molar pregnancy
Acknowledgements
Johns Hopkins Molecular Diagnostics Laboratory:
Cheryl DeScipio, PhD
Lisa Haley, MS
Katie Beierl, BS
Stacey Mosier, BS
ProPath, Dallas, TX:
Kathleen M. Murphy, PhD
Sharon Tandy, BS
Debra S. Cohen, MS