Tumors of Extravascular Trophoblasts

Slide 1 · Tumors of extravascular trophoblasts

Placental site trophoblastic tumor (PSTT) • Epithelioid trophoblastic tumor (ETT)

Dr Abu Suraih Sakhri

MBBS, MD (Pathology)

www.abusuraihsakhri.com

Slide 2 · What this lecture will enable

Identify the two malignant extravillous trophoblastic tumors

Recognize their contrasting growth patterns and immunophenotypes

Distinguish them from choriocarcinoma and epithelial mimics

Apply the updated FIGO 2026 framework

Slide 3 · Where PSTT and ETT fit in GTD

Gestational trophoblastic disease

Gestational trophoblastic neoplasia

PSTT / ETT

Gestational trophoblastic disease spans non-neoplastic, premalignant, and malignant proliferations • PSTT and ETT are uncommon malignant gestational trophoblastic neoplasms • Their cell of origin differs from the dual trophoblastic pattern of choriocarcinoma

Slide 4 · Extravillous trophoblast: The parent lineage

Normal implantation

Extravillous trophoblast

Maternal tissue / vessels

Intermediate/extravillous trophoblast normally infiltrates the maternal implantation site • It participates in remodeling and interacting with maternal vessels • Neoplastic variants retain recognizable features of this invasive phenotype

Slide 5 · Two differentiation patterns

PSTT

ETT

Implantation-site type

Chorionic-type intermediate trophoblast

Infiltrative sheets / cells

Nodules / cohesive nests

HPL, CD146: Often diffuse

P63: Often positive

Slide 6 · Why these are not typical choriocarcinomas

PSTT / ETT

Choriocarcinoma

Intermediate trophoblast

Two trophoblast populations

Often modest hCG

Often markedly raised hCG

Surgery central

Usually chemotherapy-responsive

Slide 7 · Clinical recognition begins with pregnancy history

Both entities typically arise after a gestational event

Presentation may follow term pregnancy, loss, or molar gestation

Absence of a recent pregnancy does not exclude these tumors

Slide 8 · Think beyond the serum hCG result

Low hCG ≠ no trophoblastic malignancy

A uterine neoplasm after pregnancy may be trophoblastic despite only moderate hCG elevation

Tumor histology should not be overruled by an unimpressive biochemical result

Symptoms, imaging and pathology must be interpreted together

Slide 9 · Diagnostic problems that matter

Recognizing infiltrating trophoblast among myometrial fibers

Separating PSTT from ETT on morphology and targeted stains

Excluding choriocarcinoma and cervical squamous carcinoma

Assessing local extent and metastatic disease

Slide 10 · PSTT: Core pathologic identity

Infiltrative implantation-type tumor

A malignant tumor of implantation-type extravillous trophoblast

Typically presents as a mass involving the uterus

Locally infiltrative, particularly at the myometrial interface

Slide 11 · PSTT: Antecedent gestation

That about half follow a normal pregnancy

Spontaneous abortion and hydatidiform mole are other antecedents

The type and timing of pregnancy inform the clinical history

Slide 12 · PSTT: Presenting symptoms

Abnormal uterine bleeding is a major presentation

Amenorrhea can replace or accompany bleeding

A uterine mass may be discovered during evaluation

Slide 13 · PSTT: Serum hCG profile

Moderate hCG • significant tumor

Moderately elevated hCG

The hCG level may under-represent the size or seriousness of tumor

Do not use the high hCG profile of choriocarcinoma as the diagnostic template

Slide 14 · PSTT: Microscopic cellular composition

Schematic — not a histologic specimen

Polygonal mononuclear trophoblasts predominate

Binucleated cells may be admixed

Neoplastic cells characteristically have abundant cytoplasm

Slide 15 · PSTT: Growth through myometrium

Schematic — not a histologic specimen

Tumor cells insinuate between individual smooth-muscle fibers

This splaying pattern reflects infiltrative growth

The pattern is particularly helpful at the tumor–myometrium boundary

Slide 16 · PSTT: Tropism for maternal vessels

Maternal vessel

Schematic — not a histologic specimen

Malignant extravillous trophoblast often engages maternal vessel walls

The vascular relationship recalls physiologic extravillous trophoblast

Vascular involvement helps prioritize PSTT in the differential

Slide 17 · PSTT: Invasion need not be hemorrhagic

PSTT

Choriocarcinoma

Infiltrative interstitial growth

Destructive hemorrhagic growth

Maternal vessel-wall affinity

Marked vascular destruction

Hemorrhage not required

Hemorrhage often extensive

Slide 18 · PSTT: Cytologic clues

Intermediate trophoblast may show cytologic atypia

Abundant eosinophilic or clear cytoplasm supports trophoblastic differentiation

Variable pleomorphism requires architectural and immunophenotypic correlation

Slide 19 · PSTT: Architectural clues

Diffuse or sheet-like growth is more typical than compact nodules

Individual infiltrating cells can be prominent

Vessel-wall involvement and myometrial infiltration are highly informative

Slide 20 · PSTT: HPL staining

HPL: Typically diffuse

Human placental lactogen is commonly strong and widespread

A diffuse hPL pattern supports implantation-type differentiation

Interpret staining with morphology and controls, not as an isolated diagnosis

Slide 21 · PSTT: CD146 staining

CD146: Often widespread

CD146 (Mel-CAM) is commonly expressed by implantation-site trophoblast

Diffuse expression supports PSTT in an appropriate context

No single marker is infallible across all tumors

Slide 22 · PSTT: P63 is a discriminator

PSTT

ETT

P63 usually negative

P63 usually positive

HPL commonly diffuse

HPL commonly focal

Vessel affinity

Hyaline matrix / nodules

Slide 23 · PSTT: Coherent diagnostic pattern

History + location

Infiltrative architecture

Concordant IHC

PSTT favored

Postgestational uterine tumor • Mononuclear/polygonal trophoblast with abundant cytoplasm • Myometrial splaying and maternal-vessel affinity • Diffuse hPL / CD146 with absent or limited p63

Slide 24 · PSTT: Major pathological mimics

Exaggerated placental site can show implantation-site trophoblast

Choriocarcinoma differs in cellular composition and hemorrhage

ETT is more nodular and often p63 positive

Poorly differentiated uterine malignancy requires a considered panel

Slide 25 · PSTT: Localized disease

The extent of uterine invasion determines local surgical assessment

Favorable outcomes with surgery for localized tumors

Complete anatomic assessment remains essential because metastasis is possible

Slide 26 · PSTT: Metastatic potential

Potentially lethal after dissemination

Malignancy is real despite relatively indolent-appearing invasion

Death from disseminated disease in about 10%–15%

A localized pathologic appearance cannot substitute for staging

Slide 27 · PSTT: Why surgery dominates treatment

Assess disease extent

Localized PSTT

Primary surgery

Risk-adapted follow-up

PSTT is less sensitive to chemotherapy than typical choriocarcinoma • Hysterectomy is the central treatment for most localized disease • Metastatic or high-risk cases need specialized multidisciplinary assessment

Slide 28 · PSTT: Pathologist’s report priorities

Establish trophoblastic tumor type using morphology and an IHC panel

Document depth/extent of myometrial and vascular involvement

Describe necrosis and mitotic activity without unsupported cutoffs

Communicate uncertainty or mixed morphology explicitly

Slide 29 · ETT: Core pathologic identity

Nodular chorionic-type tumor

Malignant tumor of chorionic-type intermediate trophoblast

Usually composed of cohesive mononuclear epithelioid cells

Often forms a relatively circumscribed/nodular mass

Slide 30 · ETT: Relationship to preceding pregnancy

Usually detected after a prior pregnancy

An interval of years may occur before clinical presentation

Record the index pregnancy and its timing for prognostic assessment

Slide 31 · ETT: Principal anatomic sites

Most occur within the uterus or cervix

The lower uterine segment/cervix is an important diagnostic setting

Extrauterine presentations also occur

Slide 32 · ETT: Presenting symptoms

Amenorrhea is commonly

Some patients have a clinically palpable mass

Symptoms do not reliably indicate tumor location or stage

Slide 33 · ETT: Cohesive tumor architecture

Schematic — not a histologic specimen

Cohesive nests, sheets and nodules predominate

Growth is often more expansile than the dispersed PSTT pattern

This distinction is relative—not proof of benign behavior

Slide 34 · ETT: Cells and cytoplasm

Schematic — not a histologic specimen

Predominantly mononuclear epithelioid trophoblast

Cytoplasm may be clear or eosinophilic

Relatively uniform cells can mimic an epithelial carcinoma

Slide 35 · ETT: Extracellular hyaline material

Hyalinized extracellular matrix

Schematic — not a histologic specimen

Characteristic eosinophilic/pink hyaline material can surround tumor nests

Hyalinization is a valuable histologic architectural clue

This material may resemble keratin and complicate differential diagnosis

Slide 36 · ETT: Geographic necrosis

Schematic — not a histologic specimen

Geographic necrosis is frequently associated with ETT nodules

A necrotic core bordered by viable epithelial-like cells is a useful pattern

Necrosis must not be mistaken for keratinization alone

Slide 37 · ETT: Invasion versus metastasis

Local appearance

Biologic behavior

Nodules can be relatively discrete

May metastasize

Limited obvious vessel infiltration

Hematogenous spread possible

Epithelial-like architecture

Trophoblastic malignancy

Slide 38 · ETT: P63 supports chorionic-type lineage

P63 positive is not specific for ETT

Nuclear p63 expression is typically a feature of ETT

P63 supports distinction from implantation-type PSTT

P63 cannot by itself exclude a cervical squamous neoplasm

Slide 39 · ETT: HPL and CD146 are less diffuse

HPL may be absent or focal rather than broadly expressed

CD146 expression is typically less extensive than in PSTT

A combined panel is more robust than any single stain

Slide 40 · ETT: Potential squamous carcinoma mimic

Cervical mass

P63 positive lesion

Trophoblastic panel + morphology

ETT vs SCC

Cervical site, epithelioid morphology, hyaline material and p63 cause overlap • Use gestational history and trophoblastic markers together • Interpret the relationship to native cervical epithelium in the tissue section

Slide 41 · ETT: Placental site nodule mimic

Placental site nodules represent a different, generally benign lesion

Atypical placental site nodules require careful separation from ETT

Cellularity, destructive features and proliferation should be integrated

Slide 42 · ETT: Metastatic pattern

Lung and bone as important metastatic sites

Metastatic potential justifies full staging despite nodular architecture

New symptoms in distant organs merit clinical evaluation

Slide 43 · ETT: Prognosis in the source

Denominator matters in outcome claims

Deaths among patients with metastatic ETT

The cited 10%–15% mortality wording refers to females with metastatic disease

Do not generalize that percentage to every ETT patient

Slide 44 · ETT: Coherent diagnostic pattern

History + site

Nodules / hyaline matrix

Concordant IHC

ETT favored

Postgestational tumor in uterus/cervix or other site • Cohesive epithelioid trophoblast with clear/eosinophilic cytoplasm • Hyaline matrix ± geographic necrosis • Often p63 positive with hPL/CD146 less diffuse

Slide 45 · PSTT and ETT: Dominant phenotype

PSTT

ETT

Single infiltrating cells / sheets

Nests / nodules

Maternal vessel-wall affinity

Hyaline material / necrosis

Implantation type

Chorionic type

Slide 46 · PSTT and ETT: Clinical comparison

PSTT

ETT

Uterine mass common

Uterine/cervical mass common

Bleeding or amenorrhea

Amenorrhea ± mass

Moderate hCG often

HCG often relatively low

Slide 47 · PSTT and ETT: IHC comparison

PSTT

ETT

HPL: Often diffuse

HPL: Focal/variable

CD146: Often diffuse

CD146: Less extensive

P63: Usually absent

P63: Commonly nuclear-positive

Slide 48 · Choriocarcinoma: A critical contrast

PSTT / ETT

Choriocarcinoma

Intermediate trophoblast dominant

Bi-/multicellular trophoblast

More limited hCG in many cases

Often very high hCG

Surgery typically central

Chemotherapy is central

Slide 49 · Exaggerated placental site: Clinical pitfall

Benign implantation-site proliferation can resemble PSTT

Clinical gestational context and the extent of atypical proliferation matter

Use the overall tissue architecture and proliferation, not hPL alone

Slide 50 · Squamous carcinoma: Clinical pitfall

An ETT in the cervix can resemble squamous carcinoma

P63 positivity alone is not a distinguishing marker

A tailored epithelial + trophoblastic IHC panel is required

Slide 51 · Diagnostic workflow from biopsy to diagnosis

Architecture

Trophoblastic panel

Exclude mimics

Integrated diagnosis

Confirm lesion is a true neoplastic trophoblastic proliferation • Describe infiltrative vs nodular architecture • Use p63, hPL, CD146 and relevant exclusion markers • Correlate with pregnancy and imaging history

Slide 52 · What hCG can and cannot tell you

HCG is valuable for assessment and serial follow-up

A modest hCG value does not exclude PSTT or ETT

Definitive classification still rests on histopathology and context

Slide 53 · Diagnostic uncertainty: When to refer

Tiny curettage fragments may not capture diagnostic tumor borders

Atypical placental site lesions may be difficult to subtype

Expert gestational trophoblastic pathology review is appropriate in equivocal cases

Slide 54 · Contemporary update: FIGO 2026

2026 FIGO: Stage + pregnancy interval

A specific FIGO staging scheme now addresses PSTT and ETT

Histologic PSTT/ETT can establish gestational trophoblastic neoplasia

The ordinary GTN modified WHO risk score is NOT used for PSTT/ETT

Slide 55 · FIGO 2026: Stages I and II

Stage I

Stage II

Uterine corpus / cervix only

Extension beyond uterus/cervix

No extrauterine spread

Still limited to genital structures

Slide 56 · FIGO 2026: Stages III and IV

Stage III

Stage IV

Lung metastases

Other distant organs

Nodes below diaphragm

Nodes above diaphragm

Slide 57 · FIGO 2026: 48-month prognostic divider

Document pregnancy

Measure interval

<48 m: GP / ≥48 m: PP

For stages I–III, interval <48 months is a good prognostic factor • Interval ≥48 months is a poor prognostic factor • All stage IV disease carries poor prognosis in this system

Slide 58 · FIGO 2026: Stage annotation

Stage I–III : GP / PP

Represent stages I–III with GP or PP for pregnancy interval

Example: Stage I:GP versus stage I:PP

Do not attach the modified WHO GTN numeric score to PSTT/ETT

Slide 59 · FIGO 2026: Nodal interpretation

Nodes below diaphragm contribute to stage III; Above to stage IV

FIGO suggests ≥10 mm short-axis as an imaging threshold

Use LN r for radiologic or LN p for pathologic evidence

Slide 60 · FIGO 2026: Imaging for local extent

Contrast-enhanced pelvic MRI is recommended for PSTT/ETT local staging

Assess depth of myometrial and parametrial involvement

Ultrasound/CT alone is inadequate for detailed local staging

Slide 61 · FIGO 2026: Why staging affects care

Anatomic stage

Pregnancy interval

Multidisciplinary plan

Local stage informs operative planning • Metastatic extent changes the need for combined modalities • Prior-pregnancy interval is part of prognostic stratification

Slide 62 · Contemporary management: Localized disease

Hysterectomy is primary therapy for most PSTT/ETT

Fertility-sparing resection is considered only in carefully selected localized cases

Management should occur with experienced trophoblastic-disease teams

Slide 63 · Contemporary management: Advanced disease

PSTT and ETT are relatively chemoresistant

Selected metastatic lesions may merit surgical resection

Combination chemotherapy can be considered by specialist teams

Outcomes depend on disease distribution and pregnancy interval

Slide 64 · After treatment: Surveillance logic

Serial hCG remains useful when measurable

Imaging and symptom assessment may be needed when hCG is not strongly informative

The oncology team should specify individualized longitudinal follow-up

Slide 65 · Case 1: Infiltrative uterine tumor

A patient presents months after pregnancy with abnormal bleeding

The uterus contains a myometrial mass; HCG is moderately elevated

Biopsy: Polygonal trophoblasts separating muscle fibers; HPL diffuse

Which tumor is most likely, and what feature is decisive?

Slide 66 · Case 1: Interpretation

PSTT is favored

Interstitial myometrial infiltration and abundant intermediate-trophoblast cytoplasm are pivotal

Diffuse hPL supports implantation-site differentiation

Stage determination and specialist treatment planning are next

Slide 67 · Case 2: Cervical epithelioid lesion

A cervical mass appears years after a pregnancy

Histology: Cohesive nests of mononuclear cells and hyaline matrix

P63 is positive; HPL is only focal

Which trophoblastic neoplasm is favored? What mimic must be excluded?

Slide 68 · Case 2: Interpretation

ETT is favored by the nodular/hyaline architecture and p63 profile

Cervical squamous carcinoma remains a major mimic

Use an integrated trophoblastic/epithelial panel and history

Prognostic staging requires pregnancy interval and metastatic workup

Slide 69 · Case 3: Stage and pregnancy interval

Histologic ETT is confined to the uterus

Treatment begins 5 years after the preceding pregnancy

No distant lesions are detected

What FIGO 2026 notation best describes the case?

Slide 70 · Case 3: Interpretation

FIGO 2026 stage I:PP

Stage I = uterine corpus/cervix only

Interval ≥48 months creates the poor-prognostic-factor suffix

Do not calculate the standard GTN modified WHO score

Slide 71 · Integrated diagnostic summary

PSTT: Infiltrative implantation-site morphology, often hPL/CD146 diffuse

ETT: Nodular epithelial-like morphology, hyaline matrix, often p63 positive

Both are malignant despite sometimes limited hCG elevation

Stage anatomically and apply the FIGO 2026 pregnancy-interval factor

Slide 72 · Selected scientific sources

Robbins, Cotran & Kumar. Pathologic Basis of Disease. 11th ed.; Ch. 22.

Öz Atalay et al. Turk J Obstet Gynecol. 2023; morphologic/IHC study.

Horowitz et al. Gynecol Oncol. 2017; PSTT/ETT review.

Ngan et al. Int J Gynaecol Obstet. 2025 and 2026 FIGO reports.