Placental site trophoblastic lesions

Gestational trophoblastic diseases

Hydatidiform mole - complete mole - partial mole Invasive mole Choriocarcinoma Placental trophoblastic disease Persistent trophoblastic disease

History
John Beard and the Trophoblast John Beard (1858-1924), was a Scottish embryologist who used the light microscope to study developmental embryology as well as cancer pathology. In 1905, Beard was the first to report that trophoblast cells act and behave in a manner identical to cancer cells, acting invasively, and inducing their own blood supply.

Glossary
Amnion- the inner layer of the external membranes in direct contact with the amnionic fluid. Chorion- the outer layer of the external membranes composed of trophoblasts and extracellular matrix in direct contact with the uterus. Chorionic plate- the connective tissue that separates the amnionic fluid from the maternal blood on the fetal surface of the placenta. Chorionic villous- the final ramification of the fetal circulation within the placenta. Intervillous space- the space in between the chorionic villi where the maternal blood circulates within the placenta Decidua- the transformed endometrium of pregnancy

Glossary
Cytotrophoblast- a mononuclear cell which is the precursor cell of all other trophoblasts. Invasive trophoblast - the population of trophoblasts that leave the placenta, infiltrates the endo and myometrium and penetrates the maternal spiral arteries, transforming them into low capacitance blood channels. Junctional trophoblast - the specialized trophoblast that keep the placenta and external membranes attached to the uterus. Syncytiotrophoblast - the multinucleated trophoblast that forms the outer layer of the chorionic villi responsible for nutrient exchange and hormone product Spiral arteries - the maternal arteries that travel through the myo and endometrium which deliver blood to the placenta.

What are Trophoblasts?

In the pregnant mammal, trophoblasts are the infiltrative components of the developing embryo which forms the placenta. This invasive, infiltrative behavior is very similar to the way cancer cells infiltrate and invade surrounding tissues. The trophoblast cells combine with the maternal endometrium to form the placenta. These trophoblast cells are known to produce human chorionic gonadotropin (HCG).

Trophoblasts
Following implantation of the blastocyst trophoblast cells begin to differentiate.

Cytotrophoblast cells differentiate, migrate and invade into the uterine stroma in early pregnancy.

The cytotrophoblast stem cells either fuse to form syncytiotrophoblasts or aggregate to form anchoring villous trophoblasts.

 The anchoring villous trophoblast give rise to a sub-population known as extravillous trophoblasts or the Intermediate trophoblasts which invade the uterine wall and its blood vessels, particularly the spiral arteries. The extravillous trophoblast cells remodel the maternal spiral arteries, displacing smooth muscle and endothelial cells, in order to produce a blood vessel with a larger diameter, increased blood flow and reduced resistance. This is an essential step in establishing and maintaining a normal pregnancy and is necessary for the higher blood requirement of the fetus later in pregnancy.

Differentiating between all the 3

Cyto
Mononuclear cells with clear cytoplasm Keratin positivity

Sycytio
MNG cells with abundant eosino cyto hCG,keratin,PLAP ,Preg related B1 GP,Inhibin positivity. EMA,HNK1,CD146 negativity.

Intermediate
Similar to syncytio

hPL(v.strong), keratin,CD146,HN K1(villi),EMA(chor ion),HLA-G positivity.

Trophoblast differentiation pathways

Concomitant with the overall development of placental architecture is the differentiation of three distinct trophoblast types. Depending on their subsequent function in vivo, undifferentiated cytotrophoblasts can develop into 1) hormonally active villous syncytiotrophoblasts 2) extravillous anchoring trophoblastic cell columns 3) invasive intermediate trophoblasts
Within the villi of the human placentaat all gestational agesthere always exists a population of cytotrophoblasts which remain undifferentiated and available for differentiation as necessary.

Cytotrophoblast The stem cell of the placenta

Gives rise to the differentiated forms of trophoblasts. Within the chorionic villi, cytotrophoblasts fuse to form the overlying syncytiotrophoblast. The villous syncytiotrophoblast makes the majority of the placental hormones, the most studied being hCG, Cyclic AMP and its analogs. More recently hCG itself, have been shown to direct cytotrophoblast differentiation towards a hormonally active syncytiotrophoblast phenotype.

 At the point where chorionic villi make contact with external extracellular matrix (decidual stromal ECM in the case of intrauterine pregnancies), a population of trophoblasts proliferates from the cytotrophoblast layer to form the second type of trophoblast the junctional trophoblast.

They make a unique fibronectintrophouteronectin (TUN)that appears to mediate the attachment of the placenta to the uterus. TGF, and more recently, leukemia inhibitory factor (LIF), have been shown to downregulate hCG synthesis and upregulate TUN secretion.

 Finally, a third type of trophoblast differentiates towards an invasive phenotype and leaves the placenta entirely the invasive intermediate trophoblast. In addition to making human placental lactogen, these cells also make urokinasetype plasminogen activator (u-PA) and type 1 plasminogen activator inhibitor (PAI-1). Phorbol esters have been shown to increase trophoblast invasiveness in in vitro model systems and to upregulate PAI-1 in cultured trophoblasts.

In brief.

Complications of pregnancy related to trophoblasts and the placenta

Diseases of trophoblast invasion: 1)Preeclampsia

decreased invasiveness of the trophoblast

2)Gestational trophoblastic neoplasia

increased invasiveness of the trophoblast

Placental site trophoblastic lesions

Tumors Placental site trophoblastic tumor Epitheloid trophoblastic tumor Tumorlike conditions Exaggerated placental site reaction Placental site nodules Placental plaques

Expanded trophoblast invasion : exaggerated placental site reaction with increased numbers of benign intermediate trophoblasts

placental site trophoblastic tumors

invasive moles frank choriocarcinoma

Placental site trophoblastic tumors

Rare form of trophoblastic disease. Also called as Atypical choriocarcinoma and trophoblastic pseudotumor Tumor represents neoplastic transformation of the intermediate trophoblast which normally plays a critical role in the implantation. 75% - normal pregnancies 5% - ectopic/molar pregnancies. 20% - spontaneous/induced abortions

 Though considered a disease of reproductive age, reports have shown detection of PSTT even up to age of 66 years. It can occur as early as 1 week or as late as 17 years after abortion, normal delivery or molar pregnancy.

Pathogenesis
Unknown???? A paternally derived X chromosome is may be required for its development.

Clinical features
Irregular bleeding PV Amenorrhoea Abdominal pain Ruptured uterus Post menopausal bleed. Enlarged neck node

Gross Pathology
Myometrial mass May be - well localized or ill defined Hemorrhage not as conspicuous as in invasive mole or choriocarcinoma Deep uterine penetration.
A solid hemorrhagic nodule is seen distending the myometrium and protruding into the endometrial cavity.

Histopathology
Trophoblastic cells: large cytoplasm: abundant eosinophilic nuclear pleomorphism Invade myometrium and vessel lumina

Medium-sized cells of intermediate trophoblastic type are seen growing in a diffuse fashion into the myometrium. The biphasic pattern resulting from the admixture of cytotrophoblast and syncytiotrophoblast, which is typical of choriocarcinoma, is absent.

Special Stains and Immunohistochemistry

Immunohistochemical features correspond to those of intermediate trophoblast immunoreactivity for: hPL strong and widespread hCG tends to be focal positivity for: keratin CD66a (CEACAM1) CD146 (Mel-CAM) pregnancy-associated major basic protein HLA-G High expression of: p53 gene product epidermal growth factor receptor

Differential Diagnosis
Other gestational trophoblastic diseases Non-neoplastic placental proliferations of intermediate trophoblast Distinguished from choriocarcinoma by: lack of dimorphic population of cytotrophoblast and syncytiotrophoblast: though may be scattered multinucleated cells lack or paucity of hemorrhage - interdigitating pattern of muscle invasion

Genetics
DNA pattern usually diploid MIB-1 (Ki-67) labeling index:
-higher than in exaggerated placental site reaction -lower than in choriocarcinoma

Management
Generally poor response to chemotherapy All cases ultimately undergo hysterectomy. But now complete long term remission is reported with multiagent chemotherapy in cases of PSTT. Chemotherapy is usually reserved for postoperative recurrence and those with high mitotic index. The possibility of PSTT should be kept in mind in cases with GTD who fail to show a fall in ?hCG after chemotherapy. Since disease has an unpredictable course and poor response to chemotherapy simple hysterectomy remains the mainstay of treatment.

Prognosis
1020% mortality rate if not treated properly Poor prognostic factors are -an internal of >2 years from known antecedent pregnancy -mitotic count >5/10 HPF -extensive necrosis -extension outside the uterus

Tumour size, depth of myometrial involvement and vascular involvement do not seem to be predictors of outcome.
Risk of death is reported 14 times greater if mitotic figures were greater than 5/10 HPF. Sometimes widespread metastases: generally associated with: high mitotic count in primary tumor extensive necrosis preponderance of cells with clear cytoplasm High mitotic index is associated with not only metastatic disease but appears to be an indicator of recurrence too.

Newer entity in GTD Epitheloid trophoblastic tumor

Denovo Change in the metastatic foci of choriocarcinoma. Occurs in reproductive age group Presents with abd pain and vaginal bleeding. S.hCG levels high not as high as choriocarcinoma. Malignant tumor with metastasis.

 Gross similar to chorioca. Microscopy solid sheets of intermediate tropho.,extensive necrosis IHC keratin,EMA,E-cadherin(strong +) hPL(focal)

Placental site reaction

Also called syncitial endometritis Misnomer no inflammation,syncytio Exaggerated reaction of the intermediate trophoblast. Distinction from the PSTT is difficult. PSR size is microscopic lacks mitotic activity presence of decidua and villi

Placental site nodule and plaque

Single/multiple nodules/plaques Extensively hylinized Can also occur in cervix,fallopian tubes etc Features to differentiate: smaller size better circumscription extensively hylinization paucity of mitosis degenerative appearance. Diffusely positive for PLAP,focal positive for hPL,CD 146.

Summary
Placental site trophoblastic tumour (PSTT) is an uncommon form of gestational trophoblastic disease (GTD).

PSTT is so rare that even those centres treating large numbers of patients with GTD will infrequently manage patients with this condition.
PSTT presents a challenge to clinicians managing GTD due to its rarity and varied biological behaviour there is noconsensus on optimal treatment strategies.

It is critical to make the distinction between this and other more common forms of GTD, as the PSTT is less chemo-sensitive and adverse outcomes are more common.

References
Robbins -8th edition Ackerman textbook of surgical pathology 9th edition. Symmers text book of female reproductive pathology volume 6

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