problematic pathologies of neoplastic placentationhandouts.uscap.org/2016_gyne_cesar_1.pdfint j...
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Problematic Pathologies of Neoplastic Placentation
Matthew Cesari, MD, CM, FRCPC Gynecologic Pathologist, Sunnybrook Health Sciences Centre
Assistant Professor, University of Toronto
March 13, 2016
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OBJECTIVES
• To describe key concepts in placentation;
• To relate these concepts to the classification of non-molar gestational trophoblastic disease;
• To develop an approach to the diagnosis of non-molar gestational trophoblastic disease.
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Basic Concepts in Placentation
Fertilization
Robboy, 2nd Ed.
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Basic Concepts in Placentation
Fertilization
IMPLANTATION (DAYS 6-11)
Robboy, 2nd Ed.
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Basic Concepts in Placentation
Fertilization
IMPLANTATION (DAYS 6-11) and NIDATION
Proliferation of pre-villous trophoblast: Cytotrophoblast (trophoblastic stem cell)
Syncytiotrophoblast (terminally differentiated)
(Villous) Intermediate trophoblast
Robboy, 2nd Ed.
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Basic Concepts in Placentation
Fertilization
IMPLANTATION NIDATION (pre-villous trophoblast)
MESENCHYMAL VILLOUS FORMATION
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Courtesy: Dr. K. Grondin
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Basic Concepts in Placentation FERTILIZATION IMPLANTATION NIDATION (pre-villous trophoblast)
MESENCHYMAL VILLOUS FORMATION
PRIMARY VILLI
CHORION FRONDOSOM (“placental disk”)
CHORION LAEVE (“membranes”)
IMPLANTATION (“anchoring”)
OXYGENATION
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Basic Concepts in Placentation FERTILIZATION IMPLANTATION NIDATION
(pre-villous trophoblast)
MESENCHYMAL VILLOUS FORMATION
PRIMARY VILLI
Villous Intermediate Trophoblast
Implantation-type intermediate trophoblast
Chorionic-type Intermediate trophoblast
Primary villi
Chorion frondosum
Chorion laeve
P L A C E N T A
VIT
S
C
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Implantation
Anchoring cell columns of villous intermediate trophoblast
Implantation-type intermediate trophoblast
Loss of E-cadherin Loss of Ki-67 Gain of hPL Gain of Mel-CAM (CD146) Gain of p57
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Anchoring cell columns of villous intermediate trophoblast
Implantation-type intermediate trophoblast
Loss of E-cadherin Loss of Ki-67 Gain of hPL Gain of Mel-CAM (CD146) Gain of p57
Myometrial Invasion
Vascular Invasion
Gain of E-cadherin Gain of VEGFR
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Chorion Laeve (“membranes”)
PRIMARY VILLI
FUSION OF PRIMARY VILLI
ATROPHY OF VILLOUS STROMA WITH RETENTION OF TROPHOBLAST
FUSION OF ATROPHIED VILLI/RETAINED TROPHOBLAST WITH DECIDUA OF OPPOSITE SIDE OF ENDOMETRIAL CAVITY
Blaustein, 6th Ed.
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Chorion Laeve
Fusion of primary villi with villous intermediate trophoblast
Chorionic type intermediate trophoblast of membranes
Gain of PlAP Gain of p63
Atrophic villus Decidua
EPITHELIAL FUNCTION
Blaustein, 6th Ed.
Blaustein, 6th Ed.
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Basic Concepts in Placentation FERTILIZATION IMPLANTATION NIDATION (pre-villous trophoblast)
MESENCHYMAL VILLOUS FORMATION
PRIMARY VILLI
CHORION FRONDOSOM (“placental disk”)
CHORION LAEVE
IMPLANTATION (“anchoring”)
OXYGENATION
DIAGNOSING TROPHOBLASTIC NEOPLASIA:
1) LINEAGE OF TROPHOBLAST (DIFFERENTIATION); 2) PROLIFERATIVE ACTIVITY.
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CYTOTROPHOBLAST
SYNCYTIOTROPHOBLAST
(Extravillous) Implantation site intermediate trophoblast - Exaggerated placental site
(Extravillous) Chorionic intermediate trophoblast - Placental site nodule
NEOPLASTIC CYTOTROPHOBLAST STEM CELL
CHORIOCARCINOMA (arrest at nidation/pre-villous stage)
PLACENTAL SITE TROPHOBLASTIC TUMOUR (maturation to implantation)
EPITHELIOID TROPHOBLASTIC TUMOUR (maturation to chorion)
MIXED TUMOURS
VILLOUS INTERMEDIATE TROPHOBLAST
Lancet Oncol 2007;8:642-50 Am J Surg Pathol 2007;31:1726-1732
GESTATIONAL TROPHOBLASTIC NEOPLASIA
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CASE 1
28 F G1P0A1(spontaneous abortion) Spotting 3 months following evacuation hCG: 170 000 mIU/mL
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Gestational Choriocarcinoma
Am J Surg Pathol 2007;31:1726-32
Definition:
Malignant epithelial tumour of predominantly intermediate and syncytial trophoblast – with a minor component of cytotrophoblast – showing morphological arrest of differentiation at the pre-villous stage of placental development (“nidation”).
Robboy, 2nd Ed.
NIDATION
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Gestational Choriocarcinoma
Antecedent gestation:
- 50% complete hydatidiform mole - 25% spontaneous abortion (probably undiagnosed early complete moles) - 22.5% term delivery (occult “in situ”?) and ectopic - <2.5% partial hydatidiform moles
Clinically: - Bleeding - HCG > 10 000 - Thyrotoxicosis - Hyperreactio luteinalis (bilateral theca-lutein cysts) - Hemorrhage (brain, lung, liver, GI, etc) - Lower risk of pelvic LN mets (vs. germ cell vs. PSTT/ETT)
Pre-chemo era:
- 50% term pregnancy - 25% complete hydatidiform mole
Modern day:
Br Med J 1969;3:733-37
Obstet Gynecol 2006;108:176-87
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Genetics: - 75% show amplification of 7q21-q31 - 75% loss of 8p12-p21 - Usually 46XX
- 2 cases gynogenetic (Cancer Res 1990;50:488-91)
Time to presentation: - Soon post gestation; up to 10-14 years post gestation
Gestational Choriocarcinoma
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LOW RISK DISEASE: (WHO SCORE < 7)
Gestational Choriocarcinoma Therapy
SINGLE-AGENT CHEMOTHERAPY (methotrexate or actinomycin-D)
Cure rate >90% 20% develop resistance to initial drug; 90% salvage rate with alternate single-agent
Am J Obstet Gynecol 2011;204:11-18
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HIGH RISK DISEASE: (WHO SCORE >/= 7)
Gestational Choriocarcinoma Therapy
MULTI-AGENT CHEMOTHERAPY (EMA-CO or EMA-EP)
Cure rate approaches 80-90%
30% recurrence overall
Salvage rates for metastasis to: Brain: 75% Liver: 73% GI: 50%
Am J Obstet Gynecol 2011;204:11-18
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Courtesy: Dr. R. Soslow
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B-hCG
Courtesy: Dr. R. Soslow
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Courtesy: Dr. R. Soslow
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B-hCG Courtesy: Dr. R. Soslow
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Ki-67 Courtesy: Dr. R. Soslow
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Intraplacental (“in situ”) Choriocarcinoma
- Mimics infarct grossly and microscopically (abundant fibrin)
- Villous morphology preserved - Villi surrounded by choriocarcinoma
Risk of disseminated maternal and fetal choriocarcinoma!!
Robboy, 2nd Ed. Gynecol Oncol 2006;103:1147-51 Int J Gynecol Pathol 2012;32:71-5
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Chorangiocarcinoma ONLY CASE REPORTS: Possibly neoplastic proliferation of trophoblast in association with vascular placental proliferation
Trophoblastic proliferation
+
Chorangiosis / Chorangioma
?Chorangioma + trophoblastic hyperplasia ?Trophoblastic neoplasia + reactive chorangiosis ?Reactive trophoblast and reactive chorangiosis ?Collision tumour
No clinically malignant outcome to date.
Robboy, 2nd Ed.
Placenta 2012;33:658-61 Int J Gynecol Pathol 2009;28:267-71 Virchows Arch 2000;436:167-71 Placenta 1988;9:607-13
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Basic Concepts in Placentation FERTILIZATION IMPLANTATION NIDATION (pre-villous trophoblast)
MESENCHYMAL VILLOUS FORMATION
PRIMARY VILLI
CHORION FRONDOSOM (“placental disk”)
CHORION LAEVE
IMPLANTATION (“anchoring”)
OXYGENATION
Exaggerated Placental Site
Placental site nodule
Legend: Non-neoplastic anatomic rests Malignant
Choriocarcinoma: - Classical - “Monomorphic”/Atypical - Intraplacental (‘in situ’)
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Basic Concepts in Placentation FERTILIZATION IMPLANTATION NIDATION (pre-villous trophoblast)
MESENCHYMAL VILLOUS FORMATION
PRIMARY VILLI
CHORION FRONDOSOM (“placental disk”)
CHORION LAEVE
IMPLANTATION (“anchoring”)
OXYGENATION
Exaggerated Placental Site
Placental site nodule
“Chorangiocarcinoma”
Legend: Non-neoplastic anatomic rests Malignant Misunderstood kid
Choriocarcinoma: - Classical - “Monomorphic”/Atypical - Intraplacental (‘in situ’)
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CASE 2
28F G1P1 (normal baby girl) Baby and mother well 2 years post delivery: spotting and microscopic hematuria hCG: 104 mIU/mL; ultrasound normal
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Ki-67
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Placental Site Trophoblastic Tumour Definition: Trophoblastic neoplasm showing differentiation toward implantation-
type intermediate trophoblast.
Clinical: - Women of reproductive age (20 to 63 years; mean 30 years) - Amenorrhea or abnormal bleeding - Mean of 34 months post pregnancy - Low level B-hCG (less than 1000 mIU/mL) - Nephrotic syndrome (Gynecol Oncol 1995;59:300-3)
Macroscopic: - Mean size 5 cm - Fairly well-circumscribed; Infiltrative deep myometrial border - Sometimes polypoid - Sometimes hemorrhagic
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Placental Site Trophoblastic Tumour Genetics: >85% have antecedent female gestation ROLE FOR PATERNAL X
Exaggerated Placental Site
55% XY
45% XX
Paternal contribution
Vs.
Behaviour:
85% self limited; even with deep myometrial invasion
Predictors of poor outcome: - Extrauterine disease - Time from last pregnancy (>48 months) - Age > 35 years - Mitotic count > 5/10 hpf - Sheets of cells with clear cytoplasm - B-hCG > 1000 - Diffuse p53 expression
Int J Gynecol Pathol 2008;27:562-67 Mod Pathol 2007;20:1055-60 Lab Invest 2000;80:965-72
Lancet 2009;374:48-55 Gynecol Oncol 2006;100:511-20 Gynecol Oncol 2001;82:415-19 Gynecol Oncol 1999;73:216-22
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Why Not Choriocarcinoma?
PSTT: CHORIOCARCINOMA: B-hCG < 1000 B-hCG > 2500 p63 negative p63 positive Ki-67 up to 30% Ki-67 > 90% No syncytiotrophoblast Syncytiotrophoblast Distinct vascular colonization
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Basic Concepts in Placentation FERTILIZATION IMPLANTATION NIDATION (pre-villous trophoblast)
MESENCHYMAL VILLOUS FORMATION
PRIMARY VILLI
CHORION FRONDOSOM (“placental disk”)
CHORION LAEVE
IMPLANTATION (“anchoring”)
OXYGENATION
Exaggerated Placental Site Placental site trophoblastic tumour
Placental site nodule
Legend: Non-neoplastic anatomic rests Low grade malignant Malignant Misunderstood kid
Choriocarcinoma: - Classical - “Monomorphic”/Atypical - Intraplacental (‘in situ’)
“Chorangiocarcinoma”
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CASE 3
37F G1P1 (2 year old baby girl) Vaginal bleeding and bulky uterus on ultrasound Hysterectomy for “fibroids” Pre-op hCG = 27 000
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IHC
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INHIBIN
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HPL
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P63
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Ki-67
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What is your diagnosis?
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Macroscopic: - Discrete solitary nodule: - 50% Lower uterine segment/endocervix - 30% Fundus - 20% Extrauterine (ectopic, mets, etc)
Epithelioid Trophoblastic Tumour
Courtesy: Dr. R. Soslow
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ETT mimics: - HSIL - Invasive squamous cell carcinoma
Courtesy: Dr. R. Soslow
Mod Pathol 2006;19:75-82
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Epithelioid Trophoblastic Tumour Definition: Trophoblastic neoplasm showing differentiation toward chorionic-type
intermediate trophoblast.
Clinical: - Women of reproductive age (mean 38 years) - Abnormal bleeding - Mean of 76 months post pregnancy - Low levels of B-hCG (less than 2500 mIU/mL)
Antecedent gestation: - Term gestation: 67% - Spontaneous abortion: 16% - Hydatidiform mole: 16%
Behaviour: - 75-85% are clinically benign - 15-25% metastasis - 13% death
Unfavourable histology: Mitotic count > 6 per 10 hpf
Gynecol Oncol 2015; 137:456-61 Int J Gynecol Cancer 2013;23:1334-38 J Obstet Gynecol 2011;204:11-18
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Why Not Choriocarcinoma or PSTT?
PSTT: CHORIOCARCINOMA: ETT: B-hCG < 1000 B-hCG > 2500 B-hCG < 2500 p63 negative p63 positive p63 positive Ki-67 up to 30% Ki-67 > 90% Ki-67 > 10% No syncytiotrophoblast Syncytiotrophoblast No syncytiotrophoblast Distinct vascular Distinct squamoid colonization appearance and calcifications
CHEMOTHERAPY
SURGERY
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Epithelioid Trophoblastic Tumour
How do you explain a beta-hCG of 27 000?
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But on the edge of one slide…
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Ki-67
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Mixed Epithelioid Trophoblastic Tumour and Choriocarcinoma
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Why Not Choriocarcinoma or PSTT?
PSTT: CHORIOCARCINOMA: ETT: B-hCG < 1000 B-hCG > 2500 B-hCG < 2500 p63 negative p63 positive p63 positive Ki-67 up to 30% Ki-67 > 90% Ki-67 > 10% No syncytiotrophoblast Syncytiotrophoblast No syncytiotrophoblast Distinct vascular Distinct squamoid colonization appearance and calcifications
CHEMOTHERAPY
SURGERY
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CHORIOCARCINOMA METASTATIC TO BRAIN
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INVASIVE CANDIASIS AT AUTOPSY
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CYTOTROPHOBLAST
SYNCYTIOTROPHOBLAST
(Extravillous) Implantation site intermediate trophoblast - Exaggerated placental site
(Extravillous) Chorionic intermediate trophoblast - Placental site nodule
NEOPLASTIC CYTOTROPHOBLAST STEM CELL
CHORIOCARCINOMA (arrest at nidation/pre-villous stage)
PLACENTAL SITE TROPHOBLASTIC TUMOUR (maturation to implantation)
EPITHELIOID TROPHOBLASTIC TUMOUR (maturation to chorion)
MIXED TUMOURS
VILLOUS INTERMEDIATE TROPHOBLAST
Lancet Oncol 2007;8:642-50 Am J Surg Pathol 2007;31:1726-1732
Take Home Message – No. 1
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Take Home Message – No.2 (“Trophogram”)
TROPHOBLASTIC?
INHIBIN + LMWCK (CAM 5.2) +
CONFIRMED TROPHOBLASTIC
B-hCG > 2500 B-hCG + syncytiotrophoblast
CHORIOCARCINOMA
IMPLANTATION TYPE CHORIONIC TYPE
p63 - hPL +++ CD146 +
p63 + hPL +/- CD146 -
Ki-67 < 1% Ki-67 > 10%
EPS PSTT PSN ETT
Ki-67 < 8% CYCLIN E -
Ki-67 > 12% CYCLIN E +
Ann Diagn Pathol 2007;11:228-34
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Developmental classification of GTD FERTILIZATION IMPLANTATION NIDATION (pre-villous trophoblast)
MESENCHYMAL VILLOUS FORMATION
PRIMARY VILLI
CHORION FRONDOSOM (“placental disk”)
CHORION LAEVE
IMPLANTATION (“anchoring”)
OXYGENATION
Exaggerated Placental Site Placental site trophoblastic tumour
Placental site nodule Epithelioid trophoblastic tumour
“Chorangiocarcinoma”
Hydatidiform mole - Complete - Partial - Invasive / Metastatic
Legend: Non-neoplastic anatomic rests Low grade malignant Malignant Misunderstood kid Placental malformations
Choriocarcinoma: - Classical - “Monomorphic”/Atypical - Intraplacental (‘in situ’)
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JACOB AT 3½ MONTHS
Early Complete Mole