Gestational Trophoblastic Disease

Encompasses tumours & tumour-like conditions derived from placental trophoblast.
Common denominator → abnormal proliferation of either chorionic villi or trophoblastic epithelium.
Entities (in increasing order of aggressiveness):
• Hydatidiform mole (benign, non-invasive)
• Invasive mole
• Choriocarcinoma
• Placental-site trophoblastic tumour (PSTT)
Incidence differences:
• USA: ≈ 1/ $1000–2000$ pregnancies
• Indonesia: ≈ 1/ $100$ pregnancies
• Choriocarcinoma: 1/ $20{,}000–30{,}000$ pregnancies in USA; higher in South-East Asia & Africa.

First-trimester villus: delicate mesenchymal core → covered by 2 epithelial layers:
• Inner cytotrophoblast (mononuclear).
• Outer syncytiotrophoblast (multinucleated).
Third-trimester villus: dense capillary network, markedly thinned trophoblastic layers.

Pathology: cystic (hydropic) swelling of chorionic villi ± trophoblastic hyperplasia.
Diagnosis now occurs earlier (mean 8.5 wk vs 17 wk) due to routine ultrasound.
Two cytogenetically distinct benign forms:
• Complete mole
• Partial mole
Age risk peaks: teenagers & $40–50$ yr group.
↑ Risk of subsequent GTD: invasive mole &/or choriocarcinoma.

Genetics / pathogenesis:
• Fertilisation of an "empty" (anucleate) ovum.
• $90\%$ : single sperm duplicates → $46,XX$ androgenetic diploid.
• $10\%$ : dispermy → $46,XX$ or $46,XY$ .
Morphology (gross):
• "Snow-storm"/"grape-like" translucent vesicles filling and expanding uterus.
• Fetal tissues absent (very rare to see).
Histology:
• Almost all villi enlarged, hydropic with central cisternae.
• Diffuse, circumferential trophoblastic hyperplasia.
• Villi lack fetal vessels.
• Immunostain: p57 negative (no maternal genome → no p57KIP2 expression in cytotrophoblast & villous stroma).
Clinical / complications:
• Serum $\beta$ -hCG massively elevated & rises faster than normal gestation.
• $\approx 20\%$ persist/invade; $2.5\%$ progress to choriocarcinoma.
• Follow $\beta$ -hCG to zero & maintain 0 for 6–12 mo.

Genetics / pathogenesis:
• Dispermy fertilises normal ovum → triploid $69,XXY$ (common) or $69,XXX$ , rarely tetraploid $92,XXXY$ .
Morphology (gross):
• Uterus less distended; mixture of normal placenta & swollen villi; fetal parts often present.
Histology:
• Only a fraction of villi hydropic; others near-normal.
• Trophoblastic proliferation focal, mild.
• Villi may show scalloping, irregular outlines.
Clinical / complications:
• Serum $\beta$ -hCG mildly/moderately ↑.
• ↑ risk of persistent molar disease (< $5\%$ ) but NOT significant risk for choriocarcinoma.
Immunostain: p57 positive (maternal genome present).

Typical presentation:
• Vaginal bleeding / spontaneous miscarriage.
• U/S: diffuse villous enlargement → "snow-storm" pattern.
• Uterus often larger than gestational date in complete mole.
Labs:
• Serial quantitative $\beta$ -hCG mandatory (weekly until negative, then monthly).
• Endpoint: undetectable levels maintained ≥ $6–12$ months.

Karyotype:
• Complete: diploid $46,XX$ (paternal)
• Partial: triploid $69,XXX/XXY$
Villi involved:
• Complete: all villi hydropic
• Partial: mixture hydropic & normal
Fetal tissue:
• Complete: none
• Partial: usually present
Trophoblast:
• Complete: diffuse, circumferential hyperplasia
• Partial: focal, mild hyperplasia
Persistent GTN risk:
• Complete: $\approx20\%$
• Partial: < $5\%$

Definition: mole (usually complete) that invades myometrium ± perforates uterine wall.
Pathology: hydropic villi + proliferating cyto- & syncytiotrophoblast infiltrate myometrium & vessels.
Clinical:
• Vaginal bleeding, enlarged uterus, persistently high $\beta$ -hCG.
• Villi can embolise to lungs/brain but do not establish metastases; regress spontaneously.
Complications: uterine rupture → haemoperitoneum; may require hysterectomy.
Therapy: highly chemo-sensitive (methotrexate/actinomycin-D regimens).

Malignant neoplasm of trophoblast derived from gestational tissue (50 % mole, 25 % abortion, 22 % normal pregnancy, remainder ectopic).
Pathology:
• NO chorionic villi.
• Sheets/nests of cyto- and syncytiotrophoblast with haemorrhage & necrosis.
Behavior: rapidly invasive, widespread haematogenous mets ☞ lungs (≈ $50\%$ ), vagina (30–40 %), brain, liver, kidney.
Clinical:
• Scant uterine mass; irregular brown/bloody discharge; elevated $\beta$ -hCG (can be extremely high; occasionally low if tumour necrotic).
• Mets may precede detection of uterine lesion.
Treatment & prognosis:
• Evacuation + multi-agent chemotherapy (methotrexate/EMA-CO).
• Nearly $100\%$ remission for gestational CC; non-gestational (germ-cell) CC more resistant (lack paternal antigens → weaker immune response).

Rarest GTD (< $2\%$ ).
Origin: malignant transformation of extravillous (intermediate) trophoblast → polygonal cells producing human placental lactogen (hPL).
Antecedent pregnancy: normal (≈ $50\%$ ), miscarriage, or molar gestation.
Clinical: uterine mass ± abnormal bleeding/amenorrhoea; moderate $\beta$ -hCG (lower than CC) + elevated hPL.
Prognosis factors:
• Localised & ≤ $2$ yr from pregnancy → excellent.
• Advanced stage or > $2$ yr interval → poor; 10–15 % mortality from disseminated disease.
Morphology: fleshy, tan haemorrhagic mass infiltrating myometrium; histology shows discohesive intermediate trophoblast with hyperchromatic nuclei, eosinophilic cytoplasm.

Complete mole → choriocarcinoma risk: $\approx\frac{1}{40}$ (≈2.5 %).
Normal pregnancy → choriocarcinoma risk: $\approx\frac{1}{150{,}000}$ .
Serum $\beta$ -hCG follow-up rule: continue until $\beta$ -hCG = 0$ & remains 0 for 6\text{–}12\,\text{months}$.
Triploidy formula (partial mole): n{maternal}=23,\;n{paternal}=46 \;\Rightarrow 69\text{ chromosomes}.

Early detection via routine ultrasound has shifted presentation to first trimester, reducing morbidity.
Continuous \beta$$-hCG surveillance is critical ⟶ ensures early capture of persistent GTD & minimises mortality.
Fertility preservation: majority of treated GTD patients subsequently achieve normal pregnancies.
Non-gestational choriocarcinoma highlights importance of recognising germ-cell tumours; prognosis & therapy differ.
Immunohistochemical use of p57 is a paradigm of molecular imprinting aiding routine diagnostics.