problematic pathologies of neoplastic placentationhandouts.uscap.org/2016_gyne_cesar_1.pdfint j...

Problematic Pathologies of Neoplastic Placentation

Matthew Cesari, MD, CM, FRCPC Gynecologic Pathologist, Sunnybrook Health Sciences Centre

Assistant Professor, University of Toronto

March 13, 2016

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.

Basic Concepts in Placentation

Fertilization

Robboy, 2nd Ed.


Fertilization

IMPLANTATION (DAYS 6-11)

Robboy, 2nd Ed.


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.


Fertilization

IMPLANTATION NIDATION (pre-villous trophoblast)

MESENCHYMAL VILLOUS FORMATION

Courtesy: Dr. K. Grondin

Basic Concepts in Placentation FERTILIZATION IMPLANTATION NIDATION (pre-villous trophoblast)


PRIMARY VILLI

CHORION FRONDOSOM (“placental disk”)

CHORION LAEVE (“membranes”)

IMPLANTATION (“anchoring”)

OXYGENATION

Basic Concepts in Placentation FERTILIZATION IMPLANTATION NIDATION

(pre-villous trophoblast)


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

Implantation

Anchoring cell columns of villous intermediate trophoblast


Loss of E-cadherin Loss of Ki-67 Gain of hPL Gain of Mel-CAM (CD146) Gain of p57

Anchoring cell columns of villous 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

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.

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.



PRIMARY VILLI


CHORION LAEVE


OXYGENATION

DIAGNOSING TROPHOBLASTIC NEOPLASIA:

1) LINEAGE OF TROPHOBLAST (DIFFERENTIATION); 2) PROLIFERATIVE ACTIVITY.

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

CASE 1

28 F G1P0A1(spontaneous abortion) Spotting 3 months following evacuation hCG: 170 000 mIU/mL

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


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

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


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

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

Courtesy: Dr. R. Soslow

B-hCG


B-hCG Courtesy: Dr. R. Soslow

Ki-67 Courtesy: Dr. R. Soslow

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

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



PRIMARY VILLI


CHORION LAEVE


OXYGENATION

Exaggerated Placental Site

Placental site nodule

Legend: Non-neoplastic anatomic rests Malignant

Choriocarcinoma: - Classical - “Monomorphic”/Atypical - Intraplacental (‘in situ’)



PRIMARY VILLI


CHORION LAEVE


OXYGENATION



“Chorangiocarcinoma”

Legend: Non-neoplastic anatomic rests Malignant Misunderstood kid


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

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

Placental Site Trophoblastic Tumour Genetics: >85% have antecedent female gestation ROLE FOR PATERNAL X


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

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



PRIMARY VILLI


CHORION LAEVE


OXYGENATION

Exaggerated Placental Site Placental site trophoblastic tumour


Legend: Non-neoplastic anatomic rests Low grade malignant Malignant Misunderstood kid



CASE 3

37F G1P1 (2 year old baby girl) Vaginal bleeding and bulky uterus on ultrasound Hysterectomy for “fibroids” Pre-op hCG = 27 000

INHIBIN

What is your diagnosis?

Macroscopic: - Discrete solitary nodule: - 50% Lower uterine segment/endocervix - 30% Fundus - 20% Extrauterine (ectopic, mets, etc)

Epithelioid Trophoblastic Tumour


ETT mimics: - HSIL - Invasive squamous cell carcinoma


Mod Pathol 2006;19:75-82

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

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

Epithelioid Trophoblastic Tumour

How do you explain a beta-hCG of 27 000?

But on the edge of one slide…

Mixed Epithelioid Trophoblastic Tumour and Choriocarcinoma

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

CHORIOCARCINOMA METASTATIC TO BRAIN

INVASIVE CANDIASIS AT AUTOPSY

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

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

Developmental classification of GTD FERTILIZATION IMPLANTATION NIDATION (pre-villous trophoblast)


PRIMARY VILLI


CHORION LAEVE


OXYGENATION

Exaggerated Placental Site Placental site trophoblastic tumour

Placental site nodule Epithelioid trophoblastic tumour


Hydatidiform mole - Complete - Partial - Invasive / Metastatic

Legend: Non-neoplastic anatomic rests Low grade malignant Malignant Misunderstood kid Placental malformations


JACOB AT 3½ MONTHS

Early Complete Mole

problematic pathologies of neoplastic placentationhandouts.uscap.org/2016_gyne_cesar_1.pdfint j...

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