• Prevalence: ~1.5 per 1,000 pregnancies in the UK, but much higher in Asian and Southeast Asian populations ^[1]
• In Hong Kong and Southeast Asia, the incidence of hydatidiform mole is approximately 2–3 per 1,000 pregnancies — roughly double the Western rate ^[1][2]
• Complete moles are more common than partial moles in Asian populations
• Gestational trophoblastic neoplasia (GTN) develops in:
  • ~15–20% of complete moles
  • ~0.5–5% of partial moles
  • Much rarer after non-molar pregnancies (but choriocarcinoma can follow any pregnancy including term delivery, miscarriage, or ectopic pregnancy)

• Bimodal age distribution: extremes of maternal age are a risk factor ^[1]
  • Adolescents ( < 20 years)
  • Older mothers ( > 35–40 years, risk increases sharply > 45 years)
• Why? At the extremes of reproductive age, there is a higher rate of abnormal fertilisation events (aging oocytes are more prone to chromosomal errors)

• Higher incidence in Asia (Japan, China, Southeast Asia, India) compared to Europe/North America
• Partly genetic, partly nutritional (low carotene / vitamin A intake has been implicated), partly related to surveillance differences

After fertilisation, the morula develops into a blastocyst by day 5–6, consisting of:

1. Inner cell mass (embryoblast) → forms the embryo
2. Outer cell layer (trophoblast) → forms the placenta

The trophoblast differentiates into:

• Cytotrophoblast (CTB): inner layer of mononuclear stem cells — the "progenitor" cells
• Syncytiotrophoblast (STB): outer multinucleated layer formed by fusion of CTBs — this is the layer in direct contact with maternal blood; it produces hCG, human placental lactogen (hPL), and other hormones
• Extravillous trophoblast (EVT): invades the decidua and myometrium, remodels spiral arteries to establish uteroplacental circulation

• hCG is a glycoprotein hormone with an α-subunit (shared with TSH, LH, FSH) and a β-subunit (unique to hCG)
• Produced primarily by the syncytiotrophoblast
• Functions: maintains the corpus luteum in early pregnancy (progesterone production), promotes angiogenesis, immunomodulation
• The β-subunit of hCG shares homology with the β-subunit of TSH — this is why very high hCG levels (as seen in GTD) can stimulate the TSH receptor and cause gestational thyrotoxicosis ^[3][4]

• The trophoblast forms finger-like projections called chorionic villi, which are bathed in maternal blood within the intervillous space
• In a hydatidiform mole, these villi become hydropic (swollen with fluid) → the characteristic "grape-like" vesicles seen macroscopically
• Why hydropic? Absent or defective fetal vasculature within the villi → fluid accumulates in the villous stroma (no fetal circulation to drain it)

This is the bread-and-butter obstetric emergency differential. The key differentials are:

When you encounter a very high β-hCG, the differential is not just GTD. Other causes of elevated β-hCG include:

This is the scenario where GTN is diagnosed biochemically rather than histologically ^[9]:

In non-molar pregnancy, choriocarcinoma usually presents with abnormal uterine bleeding or amenorrhoea ^[1]. The differential here is broad:

The fundamental distinction rests on cytogenetics and histology:

• Complete mole = entirely paternal genome → unchecked trophoblastic growth, no embryo, very high hCG
• Partial mole = extra paternal haploid set (triploid) → some embryonic development but abnormal, lower hCG, focal changes
• Normal pregnancy = balanced biparental contribution → normal embryonic and placental development

Why does this matter clinically? Because the GTN risk is vastly different: ~15–20% for CM vs ~0.5–5% for PM ^[1]. This determines the intensity of post-evacuation hCG surveillance.

Partial moles are frequently misdiagnosed as missed or incomplete miscarriages because the presentation overlaps. The lesson: all products of conception from any miscarriage should be sent for histological examination ^[1][9]. Without histology, a partial mole will be missed, and the patient will not receive appropriate hCG surveillance — potentially allowing a GTN to develop undetected.

After evacuation of a mole, persistent hCG could represent either retained molar tissue or malignant transformation (GTN). The distinction is made by:

• hCG kinetics (plateau/rise = GTN; slow fall = retained tissue)
• Imaging (myometrial invasion / metastases = GTN)
• GTN is diagnosed biochemically — tissue diagnosis not required ^[9]

In a woman of reproductive age presenting with haemoptysis and multiple pulmonary nodules on CXR, the differential includes:

• Pulmonary metastases from choriocarcinoma
• Pulmonary embolism (especially postpartum)
• Pulmonary tuberculosis (important in Hong Kong!)
• Primary lung cancer (rare in young women)
• Vasculitis (e.g., granulomatosis with polyangiitis)

The key test: check β-hCG. If markedly elevated → choriocarcinoma until proven otherwise. This is a life-saving diagnosis.

Risk factors for gestational thyrotoxicosis include markedly elevated hCG: twin pregnancy, hyperemesis gravidarum, molar pregnancy ^[3].

The differential for thyrotoxicosis in early pregnancy:

• Gestational thyrotoxicosis (hCG-mediated — no goitre, no autoantibodies, resolves as hCG falls) ^[3]
• Graves' disease (autoimmune — goitre, TSH receptor antibodies positive, persists/worsens) ^[3]
• Subacute thyroiditis (tender goitre, recent viral illness)
• Factitious thyrotoxicosis (exogenous thyroid hormone intake)

Gestational thyrotoxicosis is biochemically indistinguishable from Graves'; distinguished by: past history of thyroid disease, thyrotoxic symptoms pre-conception, presence of goitre, autoantibody profile. Anti-thyroid drugs are NOT indicated for gestational thyrotoxicosis ^[3].

To diagnose GTD, requires a tissue pathological diagnosis ^[9]. You cannot definitively call something a hydatidiform mole on clinical or biochemical grounds alone — you need histology of the evacuated products of conception. This is because:

• Clinical features (bleeding, high hCG, USS findings) are suggestive but not pathognomonic
• A "snowstorm" on USS strongly suggests a complete mole, but the definitive distinction between complete and partial mole (and between molar and non-molar pregnancy) requires histopathological examination ± immunohistochemistry ± cytogenetic/molecular analysis of the tissue

What the histopathologist looks for:

To diagnose GTN, requires a prior diagnosis of GTD that was treated, but the hCG remains persistently high → tissue diagnosis is thus not required ^[9].

The FIGO 2021 criteria for diagnosing GTN after evacuation of a hydatidiform mole are based on hCG kinetics:

FIGO Criteria for Post-Molar GTN:

Any ONE of the following after evacuation of a hydatidiform mole:

1. Plateau of hCG for 4 measurements over a period of ≥3 weeks (i.e., day 1, 7, 14, 21) ^[1]
2. Rise of hCG for 3 consecutive weekly measurements or longer, over ≥2 weeks (i.e., day 1, 7, 14) ^[1]
3. Histological diagnosis of choriocarcinoma (if tissue is obtained)
4. hCG still elevated ≥6 months after mole evacuation (even if still declining)

Persistently high hCG after molar pregnancy: most common presentation of GTN ^[1].

Why is tissue diagnosis not required for GTN? Because:

• Re-curettage is risky (risk of uterine perforation, haemorrhage, dissemination)
• hCG is a highly reliable surrogate marker — its behaviour (plateau/rise) after complete evacuation is virtually diagnostic of persistent/malignant trophoblastic disease
• Treatment decisions (chemotherapy) can be safely made on the basis of hCG kinetics + imaging alone

When GTN (usually choriocarcinoma) occurs after a non-molar pregnancy (miscarriage, ectopic, term delivery), there is no prior GTD diagnosis to anchor to. Diagnosis is made by:

• Markedly elevated β-hCG in a woman with recent pregnancy + symptoms (AUB, haemoptysis, neurological signs)
• Imaging showing characteristic metastatic pattern (lung nodules, vascular uterine mass)
• Biopsy of accessible metastatic site if needed (but often avoided due to bleeding risk)
• Abnormal uterine bleeding or amenorrhoea: usually the presenting symptom in non-molar pregnancy ^[1]

Why β-hCG and not total hCG?

• The α-subunit of hCG is shared with TSH, LH, and FSH → measuring total hCG or α-subunit alone lacks specificity
• The β-subunit is unique to hCG → β-hCG is specific for trophoblastic tissue (or certain germ cell tumours)
• β-hCG is used since the α-subunit is common to several pituitary hormones ^[10]

Key hCG findings and interpretation:

Practical points:

• hCG should be measured by a quantitative immunoassay (not urine dipstick)
• Must use the same laboratory for serial measurements (different assays have different calibrations)
• The hCG discriminatory zone for ultrasound: at hCG > ~1,500–2,000 mIU/mL (transvaginal), an IUP should be visible — if not, consider ectopic or GTD

The first-line imaging modality. What you're looking for depends on the scenario:

Complete Mole:

• "Snowstorm" appearance — the classic description: the uterine cavity is filled with diffuse, heterogeneous, echogenic material containing numerous small anechoic (cystic) spaces
• This represents the hydropic villi — the cystic spaces are the fluid-filled villous cisterns
• No fetus or gestational sac is seen
• In early first trimester, the classic snowstorm may not be fully developed — may appear as an echogenic endometrial mass with small cystic spaces
• Bilateral theca-lutein cysts may be seen — large, multiloculated, bilateral ovarian cysts

Partial Mole:

• Focal cystic changes in the placenta (Swiss-cheese pattern) with an abnormal fetus (often growth-restricted)
• Less dramatic than complete mole — often indistinguishable from missed miscarriage on initial USS
• May show increased placental thickness with scattered small cystic spaces

GTN (post-molar or choriocarcinoma):

• Heterogeneous vascular mass in the myometrium — Doppler shows markedly increased vascularity (low-resistance, high-velocity flow)
• May see myometrial invasion
• Must distinguish from uterine arteriovenous malformation (AVM) — both are highly vascular; clinical context (hCG level) differentiates

• Indicated for ALL patients with confirmed or suspected molar pregnancy — this is part of the standard pre-evacuation workup
• Why? To detect pulmonary metastases (the lung is the most common site of metastasis in GTN, ~80%) ^[1]
• Symptoms of pulmonary metastases: dyspnoea, chest pain, cough, haemoptysis ^[1]

Findings in pulmonary GTN:

• CT thorax: More sensitive than CXR for detecting small pulmonary metastases. FIGO recommends CT chest when CXR is negative but GTN is suspected, as CT may detect lesions missed on plain film (and the number of metastases affects the FIGO/WHO risk score)
• CT abdomen + pelvis: For staging — to detect hepatic metastases, pelvic disease extent, lymphadenopathy
• CT/MRI brain: Indicated if:
  • β-hCG > 100,000 mIU/mL with metastatic disease
  • Lung metastases present (brain is the next most common site after lungs)
  • Any neurological symptoms
  • High-risk GTN (WHO score ≥ 7)

• MRI pelvis: Superior soft-tissue resolution for assessing myometrial invasion depth and local extent of disease (useful for invasive mole and PSTT)
• MRI brain: Preferred over CT for detecting brain metastases (higher sensitivity for small parenchymal lesions, no radiation)
• Not routine for all GTD — reserved for staging confirmed GTN

• Colour and pulsed Doppler of the uterus in GTN shows characteristic high-velocity, low-resistance flow within the tumour
• Uterine artery pulsatility index (PI) is often markedly reduced
• Useful for:
  • Monitoring response to chemotherapy (normalisation of flow = response)
  • Distinguishing GTN from retained POC (which has less dramatic vascularity)
  • Distinguishing from uterine AVM

Before suction evacuation of a suspected mole, a comprehensive workup is essential:

The definitive diagnostic investigation for GTD:

Diagnostic algorithm for pathology:

Once GTN is diagnosed, it must be staged and risk-scored to guide treatment:

FIGO Anatomical Staging:

WHO Prognostic Risk Score:

• Total score ≤ 6 → Low risk → single-agent chemotherapy (methotrexate or actinomycin D)
• Total score ≥ 7 → High risk → multi-agent chemotherapy (EMA-CO)

Before evacuation, the patient must be assessed and stabilised:

Suction evacuation of the uterus is the standard initial treatment for hydatidiform mole regardless of uterine size and whether the mole is complete or partial.

Why suction evacuation?

• It is the safest method of evacuation — suction curettage provides controlled, efficient removal of molar tissue while minimising the risk of uterine perforation
• The molar tissue is soft and friable → suction is more effective and safer than sharp curettage
• Oxytocin infusion is started after the cervix is dilated and suction has begun (not before) — why? Because oxytocin-induced uterine contractions before evacuation can force trophoblastic tissue into the venous sinuses → trophoblastic embolisation
• Anti-D immunoglobulin should be administered to Rh-negative women after evacuation

Technical considerations:

• Large-bore suction cannula (10–14 mm) for larger uteri
• Simultaneous oxytocin infusion once evacuation is underway to reduce blood loss
• Intraoperative ultrasound guidance is recommended to ensure completeness and reduce perforation risk
• ALL products of conception MUST be sent for histopathological examination ^[9]

• A second evacuation may be considered if:
  • There is significant retained molar tissue on USS after the first evacuation
  • hCG is plateauing (not rising — if rising, it is GTN and needs chemotherapy, not re-evacuation)
• However, repeat evacuation carries risks: uterine perforation, Asherman syndrome (intrauterine adhesions), and importantly, if the tissue has already invaded the myometrium (invasive mole), re-evacuation may perforate
• Maximum of two evacuations — beyond that, persistent hCG should be treated as GTN

• Hysterectomy is the recommended standard treatment for women who have completed their family and desire sterilisation ^[12]
• Particularly appropriate for:
  • Older women with complete mole (higher GTN risk)
  • Patients with uterine haemorrhage unresponsive to evacuation
  • PSTT/ETT (relatively chemoresistant — hysterectomy is the primary treatment)
• Hysterectomy does NOT eliminate the need for hCG surveillance — GTN can still develop from microscopic metastatic disease even after hysterectomy (though the risk is reduced)
• It removes the primary site of disease but cannot address distant metastases

Why the difference? Complete moles have a much higher GTN risk (15–20%) compared to partial moles (0.5–5%) ^[1], so they require longer surveillance.

• Reliable contraception is ESSENTIAL during the entire surveillance period
• Why? A new pregnancy would cause hCG to rise → impossible to distinguish from GTN
• Combined oral contraceptive pill (COCP) or barrier methods are recommended
• COCP is safe to start after hCG has normalised (there was historical concern that COCP might stimulate trophoblast, but current evidence shows it is safe after hCG normalisation)
• Intrauterine device (IUD) should be avoided until hCG normalises (risk of uterine perforation through residual molar tissue, risk of infection)

As established in the diagnostic criteria section ^[1][9]:

Plateau of hCG for ≥4 measurements over ≥3 weeks (day 1, 7, 14, 21) Rise of hCG for ≥3 consecutive weekly measurements over ≥2 weeks (day 1, 7, 14) hCG still elevated ≥6 months post-evacuation Histological diagnosis of choriocarcinoma

First-line: Methotrexate (MTX) with folinic acid rescue

• How it works: Methotrexate is a folate antagonist — it inhibits dihydrofolate reductase (DHFR), blocking the conversion of dihydrofolate → tetrahydrofolate → thymidylate and purine synthesis → DNA synthesis is impaired → rapidly dividing trophoblastic cells die
• Why folinic acid rescue? Folinic acid (leucovorin) is reduced folate that bypasses the DHFR block → rescues normal cells (which cycle more slowly than trophoblast) from MTX toxicity without protecting the tumour
• Regimen: MTX 50 mg IM on days 1, 3, 5, 7 + folinic acid 15 mg PO on days 2, 4, 6, 8 (alternating days), repeated every 2 weeks
• Continue treatment: until hCG normalises, then give 2–3 consolidation cycles after normalisation (to eradicate microscopic residual disease)
• Cure rate: ~90–95% as first-line for low-risk GTN

Side effects of MTX:

Contraindications to MTX:

• Significant renal impairment (MTX is renally excreted — accumulation → severe toxicity)
• Hepatic impairment (pre-existing)
• Significant myelosuppression (WCC < 1.5 × 10⁹/L, platelets < 100 × 10⁹/L)
• Active infection
• Third-space fluid collections (pleural effusion, ascites) — MTX accumulates in these → prolonged exposure → toxicity

Second-line single-agent: Actinomycin D (Act-D)

• Used when MTX fails (hCG plateau/rise during MTX) or MTX is contraindicated
• How it works: Intercalates into DNA → inhibits RNA synthesis → blocks transcription
• Regimen: Actinomycin D 1.25 mg/m² IV, repeated every 2 weeks; or pulsed 5-day regimen
• Can achieve remission in ~70% of MTX-resistant low-risk GTN
• If Act-D also fails → escalate to multi-agent chemotherapy

First-line: EMA-CO

EMA-CO stands for:

• E = Etoposide (topoisomerase II inhibitor → DNA strand breaks)
• M = Methotrexate (+ folinic acid rescue)
• A = Actinomycin D
• CO = Cyclophosphamide + Vincristine (Oncovin)

Regimen structure (alternating weekly):

• Week 1 (EMA): Etoposide + MTX + Act-D (days 1–2)
• Week 2 (CO): Cyclophosphamide + Vincristine (day 8)
• Alternating every week

Continue: until hCG normalises → then 6–8 consolidation cycles after normalisation (more than low-risk because of higher disease burden)

Cure rate: ~85–95% for high-risk GTN

Side effects of EMA-CO:

Indications for EMA-CO:

• WHO risk score ≥ 7
• FIGO stage IV (any score)
• Failed single-agent chemotherapy

• WHO score ≥ 12, or widespread liver/brain metastases, or massive tumour burden
• Problem: Starting full-dose EMA-CO immediately in ultra-high-risk patients can cause tumour lysis → massive haemorrhage from highly vascular metastases → death
• Solution: Low-dose induction chemotherapy first
  • EP (Etoposide + Cisplatin) × 1–3 cycles — reduces tumour bulk slowly and safely
  • Then escalate to full-dose EMA-CO
• This "gentle start" approach significantly reduces early treatment-related mortality

For patients who fail EMA-CO:

• High risk of intracranial haemorrhage (choriocarcinoma is extremely vascular)
• Whole-brain radiotherapy (WBRT) is given concurrently with EMA-CO
• Intrathecal MTX may be added to ensure CNS drug penetration (MTX poorly crosses the blood-brain barrier at standard doses)
• Some centres increase the MTX dose in EMA-CO to 1 g/m² to achieve therapeutic CNS levels
• Dexamethasone for cerebral oedema
• Emergency neurosurgery if large haemorrhagic lesion

• Also high risk of haemorrhage with treatment
• Treat with EMA-CO (high-risk by definition — liver metastases score 4 on WHO scoring)
• Hepatic artery embolisation may be considered for uncontrolled haemorrhage

• Most common metastatic site (~80%) ^[1]
• Usually respond well to chemotherapy alone
• Thoracotomy/pulmonary resection reserved for isolated chemoresistant lesions

• Fertility is generally preserved after chemotherapy for GTD (even multi-agent)
• No increased risk of congenital anomalies in subsequent pregnancies
• Advise USS in early pregnancy in subsequent pregnancies to confirm normal IUP and exclude recurrent mole
• Risk of recurrent molar pregnancy: ~1–2% after one mole, ~15–20% after two moles

• Registration with a GTD registry (e.g., in the UK, all patients are registered with the Charing Cross Hospital registry)
• In Hong Kong, patients are followed at specialist GTD centres (e.g., Queen Mary Hospital)
• Lifelong awareness: any abnormal bleeding in future should prompt hCG testing

• The most immediate and common complication
• Pathophysiology: Hydropic villi distend the uterine cavity and disrupt the decidual vasculature → bleeding from the trophoblast-decidua interface. The molar tissue is highly vascular but lacks normal placental architecture → poorly controlled bleeding
• Can be acute (massive vaginal haemorrhage requiring emergency evacuation) or chronic (iron deficiency anaemia from persistent bleeding)
• Abnormal vaginal bleeding is the most common presenting symptom of GTD ^[1][13]

• Pathophysiology: Beta-subunit of hCG shares homology with beta-subunit of TSH ^[3][4]. When hCG exceeds ~100,000–200,000 mIU/mL (common in complete moles), it cross-activates the TSH receptor on thyroid follicular cells → unregulated T4/T3 production → clinical thyrotoxicosis
• Complications of unrecognised thyrotoxicosis include:
  • Thyroid storm — a life-threatening emergency characterised by hyperthermia, tachycardia, delirium, cardiac failure. Risk is particularly high during anaesthesia for evacuation if thyrotoxicosis is undiagnosed
  • Atrial fibrillation / high-output cardiac failure — especially in older patients or those with pre-existing cardiac disease
• Anti-thyroid drugs are NOT indicated for gestational thyrotoxicosis — it is self-limiting once hCG falls after evacuation ^[3]
• Management: β-blockers (propranolol) for rate control; if thyroid storm develops → propranolol + hydrocortisone + cooling + supportive care

• Pathophysiology: The markedly abnormal trophoblast in a complete mole produces excessive anti-angiogenic factors (soluble fms-like tyrosine kinase-1 / sFlt-1, soluble endoglin) → endothelial dysfunction → hypertension, proteinuria, oedema
• Normal pre-eclampsia occurs after 20 weeks — pre-eclampsia before 20 weeks is virtually pathognomonic of molar pregnancy
• Complications: seizures (eclampsia), HELLP syndrome, cerebrovascular haemorrhage, placental abruption (though no normal placenta exists in a complete mole)
• Resolves after evacuation of the mole

• Pathophysiology: Extremely high hCG stimulates the area postrema (chemoreceptor trigger zone) in the medulla, which lies outside the blood-brain barrier → severe nausea and vomiting
• Complications of hyperemesis:
  • Dehydration and electrolyte imbalance (hypokalaemia, hyponatraemia, metabolic alkalosis from vomiting → or metabolic acidosis from starvation ketosis)
  • Wernicke encephalopathy — thiamine (vitamin B1) depletion from persistent vomiting → triad of confusion, ophthalmoplegia, ataxia. This is a medical emergency. Always give IV thiamine BEFORE IV glucose (glucose without thiamine → accelerates thiamine consumption → precipitates Wernicke)
  • Mallory-Weiss tear from forceful vomiting → upper GI bleeding
  • Aspiration pneumonia — especially under anaesthesia for evacuation

• Pathophysiology: Extremely high hCG causes excessive stimulation of the ovarian follicles ^[1] → bilateral, multiloculated ovarian cysts (theca-lutein cysts)
• Found in ~30% of complete moles
• Complications:
  • Ovarian torsion — the enlarged ovaries are at risk of twisting on their vascular pedicle → acute pelvic pain, nausea/vomiting, ischaemia → ovarian infarction if not detorsed
  • Cyst rupture → haemoperitoneum, acute abdomen
  • Ovarian hyperstimulation syndrome (OHSS)-like picture — third-space fluid shifts, ascites, pleural effusions, haemoconcentration, thromboembolic risk
• Usually resolve spontaneously after evacuation and normalisation of hCG — do NOT remove the ovaries surgically unless torsion or rupture requires intervention

• Pathophysiology: Fragments of proliferating trophoblast can enter the uterine venous sinuses → travel to the pulmonary vasculature → trophoblastic pulmonary embolism
• This is different from metastasis — it is mechanical deportation of benign trophoblast (though the distinction from early metastatic spread can be blurred)
• Presentation: acute dyspnoea, tachycardia, hypoxia — can mimic pulmonary thromboembolism
• More common with large complete moles and during evacuation (uterine manipulation forces tissue into veins)
• Usually self-limiting as the deported trophoblast is cleared by the immune system, but can cause transient respiratory compromise
• In severe cases: respiratory failure, ARDS

• Rare but can occur with large, advanced complete moles
• Pathophysiology: Release of thromboplastic substances from disrupted trophoblastic tissue → activation of the coagulation cascade → consumption of clotting factors and platelets → paradoxical bleeding
• Presents with uncontrollable haemorrhage, petechiae, abnormal coagulation screen (prolonged PT/APTT, low fibrinogen, elevated D-dimer, thrombocytopenia)
• Management: treat the underlying cause (evacuate the mole), replace clotting factors (FFP, cryoprecipitate, platelets), supportive care

• ~15% of complete moles and ~0.5–5% of partial moles develop GTN ^[1]
• 50% of GTN arises from molar pregnancy; 50% from non-molar pregnancy ^[1]
• The malignant trophoblast invades the myometrium (invasive mole) or metastasises haematogenously (choriocarcinoma)

Choriocarcinoma: very aggressive with early vascular invasion and widespread metastasis ^[1]

• The single most dangerous acute complication of GTN
• Intracerebral haemorrhage from brain metastases → can be fatal
• Haemoptysis / pulmonary haemorrhage from lung metastases
• Intraperitoneal haemorrhage from hepatic metastasis rupture
• Vaginal haemorrhage from vaginal metastases (do NOT biopsy)
• Why so haemorrhagic? Trophoblastic tissue is inherently highly vascular and lacks normal vessel wall architecture → fragile vessels → spontaneous or treatment-induced haemorrhage