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Case Presentation
- The patient is a 39 year-old woman, G2P1,
Case Presentation Brigitte M. Ronnett, MD Department of Pathology - - PowerPoint PPT Presentation
Case Presentation Brigitte M. Ronnett, MD Department of Pathology - - PowerPoint PPT Presentation
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
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Diagnosis?
- 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. Original diagnosis: Partial hydatidiform mole
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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
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Possible Hydatidiform Mole p57 negative
(villous stroma, cytotrophoblast)
p57 Immunohistochemistry p57 positive
(villous stroma, cytotrophoblast)
Diandric Triploidy Biparental Diploidy Molecular Genotyping Androgenetic Diploidy Partial Hydatidiform Mole Non-molar Complete Hydatidiform Mole
Algorithmic Approach to Diagnosis of Hydatidiform Moles
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p57
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p57
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Non-molar Specimen: Biparental Diploidy p57 protein RNA
Maternal Chr 11 Paternal Chr 11
CH3 CH3 CH3
p57 p57
IHC
Positive in nuclei of villous stromal cells, cytotrophoblast, and intermediate trophoblast
p57: paternally imprinted, maternally expressed
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Partial Hydatidiform Mole: Diandric Triploidy p57 protein RNA
Paternal Chr 11 (2 copies)
CH3 CH3 CH3
p57 p57
IHC
CH3 CH3 CH3
p57 Maternal Chr 11
Positive in nuclei of villous stromal cells, cytotrophoblast, and intermediate trophoblast
p57: paternally imprinted, maternally expressed
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Complete Hydatidiform Mole: Androgenetic Diploidy
p57: paternally imprinted, maternally expressed
p57 protein RNA
Paternal Chr 11 (2 copies)
CH3 CH3 CH3
p57
IHC
CH3 CH3 CH3
p57
X
No maternal DNA
Negative in villous stromal cells and cytotrophoblast
(intermediate trophoblastic cells +)
X
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Diagnosis?
Consultation diagnosis:
- Androgenetic/biparental mosaic/chimeric
conception with a molar component (complete hydatidiform mole) Original diagnosis: Partial hydatidiform mole
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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
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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
- f trophoblastic
hyperplasia 6 with foci of trophoblastic hyperplasia
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p57
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FISH: diploid XX stromal cells & diploid XX cytotrophoblast
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Non-molar mosaic specimen
p57+ biparental diploid XX cytotrophoblast p57- androgenetic diploid XX villous stromal cells
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p57+ biparental diploid cytotrophoblast & p57- androgenetic diploid villous stromal cells
P:M = 2.5:1
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THO1 D13S317
183
Decidua Villi
VWA
179 183 179 221 209 217 171 186 P:M allele ratio 2.7 3.1 3.1 186 221
M P M P M P
Molecular Genotyping:
Androgenetic/Biparental Diploid Mosaic
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p57
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p57
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FISH: diploid XX stromal cells & diploid XX cytotrophoblast (both p57-discordant mosaic villi and p57-negative molar villi with trophoblastic hyperplasia)
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Non-molar mosaic component
p57+ biparental diploid XX cytotrophoblast p57- androgenetic diploid XX villous stromal cells
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p57+ biparental diploid cytotrophoblast & p57- androgenetic diploid villous stromal cells
P:M = 2.5:1
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p57- androgenetic diploid villous stromal cells
Molar component: features of CHM
p57- androgenetic diploid cytotrophoblast
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p57- androgenetic diploid cytotrophoblast & p57- androgenetic diploid villous stromal cells
P:M = 2:0
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p57
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Non-molar mosaic component Molar component: CHM
p57+ biparental diploid XX cytotrophoblast p57- androgenetic diploid XX villous stromal cells p57- androgenetic diploid XX cytotrophoblast p57- androgenetic diploid XX villous stromal cells
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P:M ~ 5:1
Mixture of p57+ & p57- biparental & androgenetic diploid cytotrophoblast & p57- androgenetic diploid villous stromal cells
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P:M = 2.5:1 P:M = 2:0 Mosaic component Molar component
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Amelogenin 103 THO1 TPOX 170 Decidua 223 CSF1PO 300 304 Villi
(with trophoblastic hyperplasia)
296 239 175 103 P:M allele ratio 2:0 2:0 2:0
P P P
Villi
(no trophoblastic hyperplasia)
P:M allele ratio 103 170 223 175 239 4:1 3:1 5:1
M M P P
296 304
M P
Molecular Genotyping: Androgenetic/Biparental Diploid Mosaic with Molar Component
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p57
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FISH: diploid XX stromal cells & mixed diploid XX, triploid XXX, and tetraploid XXXX cytotrophoblast (p57-discordant mosaic villi)
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Non-molar mosaic component
p57- androgenetic diploid XX villous stromal cells p57+ biparental diploid XX, triploid XXX, & tetraploid XXXX cytotrophoblast
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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
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p57
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FISH: diploid XX stromal cells & diploid XX cytotrophoblast (p57-negative molar villi with trophoblastic hyperplasia)
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p57- androgenetic diploid villous stromal cells
Molar component: features of CHM
p57- androgenetic diploid cytotrophoblast
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p57- androgenetic diploid cytotrophoblast & p57- androgenetic diploid villous stromal cells
P:M = 2:0
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Molecular Genotyping: Androgenetic/Biparental Mosaic with Molar Component (CHM)
THO1 D5S818 171 Decidua 123 148 153 175 D3S1358 P:M allele ratio 2:0 2:0 2:0 135 131 183 157 Villi
(with trophoblastic hyperplasia)
Villi
(no trophoblastic hyperplasia)
P:M allele ratio 3.9:1 4.3:1 2.7:1 171 123 148 175 135 157
P P P P P P M M M Androgenetic Biparental (P:M > 2:1)
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Amelogenin 103 THO1 D5S818 171 Decidua 123 148 153 175 D3S1358 103 103 175 148 123 P:M allele ratio 2:0 2:0 2:0 P:M allele ratio 2:0 2:0 2:0 135 131 183 157 171 153, 157 131,135 183 Villi
(with trophoblastic hyperplasia)
Trophoblast
(recurrent GTD)
P P P P P P M* M* M,M* M,M*
*maternal DNA contamination
Molecular Genotyping: Androgenetic/Biparental Mosaic with Molar Component (CHM)
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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
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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
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