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HYDATIDIFORM MOLE, MOLAR PREGNANCY & ANENCEPHALY

Complete MBBS Exam-Ready Notes (Dutta's Standard)

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PART 1: HYDATIDIFORM MOLE (MOLAR PREGNANCY)

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DEFINITION

1. Hydatidiform Mole (Benign GTD)
   • Complete Hydatidiform Mole (CHM)
   • Partial Hydatidiform Mole (PHM)
2. Gestational Trophoblastic Neoplasia (GTN)
   • Invasive mole
   • Choriocarcinoma
   • Placental-site trophoblastic tumor (PSTT)
   • Epithelioid trophoblastic tumor (ETT)

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INCIDENCE / EPIDEMIOLOGY

• USA/Europe: ~1 in 1,000-1,200 pregnancies
• Asia (Southeast): Higher rates - up to 1 in 100-200 pregnancies (Japan, Philippines, Korea)
• Decreasing incidence in South Korea attributed to westernized diet and improved living standards

• Maternal age: Extremes of reproductive life
  • Women >40 years: 2-10 fold increased risk
  • Women >50 years: 1 in 3 pregnancies results in molar gestation
  • Adolescents: 7-fold increased risk (ovum more susceptible to abnormal fertilization)
• Nutritional factors: Low dietary carotene (vitamin A precursor) and low animal fat intake
• Prior molar pregnancy

• Use of oral contraceptives
• History of irregular menstruation
• NOT strongly associated with maternal age or dietary factors

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PATHOLOGY AND CYTOGENETICS

Complete Hydatidiform Mole (CHM)

• Mass of translucent, thin-walled, fluid-filled vesicles resembling a "bunch of grapes"
• No fetal or embryonic tissue
• No umbilical cord, no amniotic membrane

• Diffuse hydatidiform swelling and cavitation of chorionic villi
• Diffuse trophoblastic hyperplasia (both cytotrophoblast and syncytiotrophoblast)
• Absence of fetal/embryonic tissue
• Central cistern formation
• Avascular stroma

• 46,XX in ~90% of cases
• 46,XY in ~10%
• ALL chromosomes are ANDROGENETIC (paternal origin)
• Mechanism: An empty/anucleate ovum is fertilized by a single sperm (23,X) which then duplicates → 46,XX (Homozygous) OR by two separate sperms → 46,XY or 46,XX (Heterozygous)
• No maternal chromosomes are present → explains absence of fetal tissue

• p57 is a paternally imprinted, maternally expressed gene product
• In CHM: p57 is ABSENT (no maternal chromosomes) - villous stroma and cytotrophoblast cells do not stain
• In all other gestations including partial moles: p57 is POSITIVE
• This is used to distinguish CHM from hydropic abortion and partial mole

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Partial Hydatidiform Mole (PHM)

• Fetal or embryonic tissue present (often abnormal/malformed fetus)
• Admixture of normal and swollen villi

1. Focal hydatidiform swelling, cavitation, and trophoblastic hyperplasia
2. Marked villous scalloping (festooning) - diagnostic
3. Prominent stromal trophoblastic inclusions
4. Identifiable embryonic or fetal tissue

• Triploid: 69 chromosomes (69,XXX or 69,XXY or 69,XYY)
• Extra haploid set is of paternal origin
• Results from fertilization of a normal ovum by TWO sperms (dispermy) OR by a single sperm that duplicates → 69,XXY most common
• Fetus (when present) shows stigmata of triploidy: growth retardation, syndactyly, hydrocephaly, multiple congenital malformations

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TABLE: FEATURES OF COMPLETE vs PARTIAL MOLE

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ADVANCES IN PATHOLOGIC DIAGNOSIS

• Smaller villi
• Less trophoblastic hyperplasia
• More primitive villous stroma
• Less global necrosis

1. Flow cytometry - to determine ploidy (diploid vs triploid)
2. p57 immunostaining - negative in CHM, positive in PHM and hydropic abortions

• Summary: CHM = diploid + p57 negative; Hydropic abortion = diploid + p57 positive; PHM = triploid + p57 positive

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FAMILIAL RECURRENT MOLAR PREGNANCY

• Rare condition characterized by recurrent complete moles of biparental origin (not the usual androgenetic type)
• Mutations in NLRP7 (most common) and KHDC3L genes - involved in normal maternal imprinting
• Loss of maternally transcribed genes → dysregulation of parental imprinting → molar pregnancy

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CLINICAL FEATURES

Complete Hydatidiform Mole - Classic vs. Current

• Most common symptom (previously 97%, now ~46%)
• May be dark brown ("prune-juice") or bright red
• Trophoblast separates from decidua, disrupts maternal vessels
• Large volumes of blood may distend uterine cavity
• Anaemia was present in 50% previously, now only ~5%

• Classic sign, present in ~28% currently (was >50% previously)
• Due to chorionic tissue overgrowth + retained blood
• Associated with markedly elevated hCG

• Due to very high hCG levels (hCG has TSH-like activity)
• May be severe enough to require hospitalization

• Pathognomonic of molar pregnancy (preeclampsia normally does not occur before 20 weeks)
• Present in ~1% currently (was 27% previously)

• Bilateral, multiloculated ovarian cysts
• Due to massive overstimulation by very high hCG
• Present in ~50% when uterus is large for dates
• Generally regress spontaneously after mole evacuation
• May undergo torsion, hemorrhage, or infection
• Do NOT need surgical removal unless these complications occur

• Due to thyroid stimulation by hCG (hCG has weak TSH-like activity due to structural similarity)
• Signs: tremor, tachycardia, warm moist skin
• Resolves after mole evacuation

• Pathognomonic - patient may pass grape-like vesicles
• Confirms diagnosis

Partial Hydatidiform Mole

• Usually presents like a missed abortion
• Vaginal bleeding is common
• Uterus is usually equal to or smaller than dates (unlike complete mole)
• hCG levels are lower than complete mole
• Patient may not have classic features
• Fetus may be present but abnormal

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DIAGNOSIS

1. Ultrasonography (Investigation of Choice)

• Complete mole: "Snowstorm" appearance - intrauterine echogenic mass with multiple small cystic spaces (representing swollen villi), no fetal parts, no gestational sac
• Partial mole: Swiss cheese appearance with focal cystic spaces, may have fetal parts
• Theca lutein cysts may be seen bilaterally
• Diagnose earlier now with transvaginal USG in first trimester

2. Serum β-hCG

• Markedly elevated in complete mole (>100,000 mIU/mL, often >500,000 mIU/mL)
• Moderately elevated in partial mole
• Used for diagnosis, monitoring, and follow-up

3. Histopathology

• Definitive diagnosis after evacuation
• p57 staining and flow cytometry as discussed above

4. Chest X-Ray

• To rule out pulmonary metastases before treatment

5. Other Blood Tests

• CBC (anaemia), LFT, RFT, TFT (thyroid function if clinical hyperthyroidism)
• Blood group and Rh type

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NATURAL HISTORY (Risk of GTN Progression)

• hCG >100,000 mIU/mL
• Uterus large for dates
• Theca lutein cysts >6 cm
• Maternal age >40 years
• Prior molar pregnancy

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TREATMENT

1. Suction Curettage (Treatment of Choice)

• Preferred method regardless of uterine size
• Technique:
  • IV access, blood ready
  • Cervical dilatation
  • Suction curettage (10-12 mm cannula)
  • After most molar tissue is removed, gentle sharp curettage of uterine wall
  • Oxytocin infusion during/after procedure to minimize blood loss
  • Do NOT give oxytocin BEFORE evacuation - risk of tumor embolization
• Fresh tissue sent for histopathology

2. Hysterectomy

• If patient desires sterilization - hysterectomy may be performed with mole in situ
• Ovaries can be preserved (even if theca lutein cysts present; aspirate cysts if very large)
• Does NOT eliminate the need for hCG follow-up (does not prevent metastasis)

3. Prophylactic Chemotherapy

• Controversial
• May be useful in high-risk patients when hCG monitoring is not reliably available
• Single course of Actinomycin D at time of evacuation
• Two RCTs showed significant decrease in persistent tumor in high-risk moles with prophylaxis (47-50% vs 14%)
• NOT routine practice in most centers

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FOLLOW-UP AFTER MOLAR EVACUATION

hCG Monitoring Protocol

• Weekly serum β-hCG until normal for 3 consecutive weeks
• Then monthly until normal for 6 consecutive months
• Average time to first normal hCG: ~9 weeks post-evacuation
• Once hCG is undetectable, risk of developing GTN approaches zero

Contraception During Follow-Up

• Effective contraception is mandatory during entire follow-up period (pregnancy would confuse hCG monitoring)
• OCP or barrier methods - oral contraceptives are safe and do not increase GTN risk
• IUD contraindicated until normal hCG (risk of perforation, bleeding, infection)

Criteria for GTN (Persistent Trophoblastic Disease) - FIGO 2000

1. hCG plateau (±10%) for 3 consecutive measurements over 2 weeks
2. hCG rise (>10%) for 2 consecutive measurements over 1 week
3. hCG remains elevated for 6 months
4. Histologic diagnosis of choriocarcinoma

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SUBSEQUENT PREGNANCY

• After uncomplicated mole with hCG remission - pregnancy outcomes are excellent
• No increased risk of congenital anomalies or pregnancy complications in subsequent pregnancies
• Patients should wait until hCG is normal before attempting conception (usually advised to wait 6-12 months)
• After GTN treated with chemotherapy - also good outcomes, but wait till remission

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GESTATIONAL TROPHOBLASTIC NEOPLASIA (GTN) - BRIEF OVERVIEW

Invasive Mole

• Molar villi invade myometrium
• Most common form of GTN after CHM
• Presents with vaginal bleeding, uterine subinvolution after mole evacuation
• Responds well to chemotherapy (Methotrexate or ActD)

Choriocarcinoma

• Malignant tumor of trophoblast (cytotrophoblast + syncytiotrophoblast), NO villi
• Can follow molar pregnancy (50%), normal pregnancy (25%), abortion (25%), ectopic pregnancy
• Highly vascular, early hematogenous spread
• Most chemosensitive solid tumor known

Metastatic Sites (in order of frequency)

1. Lungs (80%) - "snowstorm" pattern, embolic pattern, pleural effusion
2. Vagina (30%) - highly vascular lesions, may bleed vigorously if biopsied
3. Pelvis (20%)
4. Liver (10%) - may rupture, cause right upper quadrant pain
5. Brain (10%)

PSTT and ETT

• Uncommon variants - consist predominantly of intermediate trophoblast
• Produce small amounts of hCG and hPL
• Relatively insensitive to chemotherapy
• Treatment: Surgery (hysterectomy)

FIGO Staging of GTN

• Stage I: Confined to uterus
• Stage II: Extends to genital structures (vagina, ovary, broad ligament, fallopian tube)
• Stage III: Pulmonary metastases (with or without genital tract involvement)
• Stage IV: Other metastatic sites (liver, brain, kidney)

WHO Prognostic Scoring System

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PART 2: ANENCEPHALY

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DEFINITION

• Absence of the cranial vault (calvarium)
• Absence of the cerebral hemispheres (forebrain/telencephalon missing)
• Exposed, necrotic brain tissue (angiomatous stroma replaces the brain - "area cerebrovasculosa")
• Brainstem remains intact (hence the misnomer "anencephaly" = no brain; brainstem survives)

• Exencephaly (Acrania) = Predecessor stage: brain is exposed due to absence of calvaria, skin, and meninges but brain tissue is present
• Anencephaly = Later stage: brain degenerates → only necrotic vascular tissue remains
• This is the exencephaly-anencephaly sequence

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INCIDENCE

• Most common neural tube defect
• 1:1000 live births (approximately)
• Henry's: anencephaly comprises ~50% of all NTDs
• More common in females than males (3:1 ratio)
• Geographic variation: Higher in Ireland, UK, Egypt, lower in Far East
• Recurrence risk: ~4-5% (increases to 10% after two affected pregnancies)

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EMBRYOLOGY AND PATHOGENESIS

• Three phases of anencephaly development:
  1. Dysraphia - Failure of neural groove to close in the rostral region between days 18-20 post-ovulation
  2. Exencephaly - During embryonic period: a well-differentiated brain is exposed outside the skull (no protective calvaria)
  3. Anencephaly - During fetal period: the exposed brain undergoes degeneration/necrosis due to amniotic fluid exposure → replaced by area cerebrovasculosa

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ETIOLOGY / RISK FACTORS

1. Folic acid deficiency (most important preventable cause)
   • Neural tube closure requires folate for DNA synthesis and methylation
   • Supplementation with 400 μg folic acid daily before conception and in first trimester prevents majority of NTDs
2. Genetic factors - mutations in genes involved in folate metabolism (MTHFR C677T polymorphism)
3. Maternal diabetes mellitus
4. Valproate and other antiepileptics
5. Maternal hyperthermia in early pregnancy
6. Chromosomal abnormality - 2% of cases
7. Meckel-Gruber syndrome (autosomal recessive) - anencephaly + polydactyly + cystic kidneys

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PATHOLOGICAL FEATURES

• Complete absence of calvarium above the orbits (base of skull is preserved)
• Prominent, bulging eyes (frog-like facies)
• Facial features preserved (mouth, nose, ears intact)
• Short, thick neck
• Brain replaced by area cerebrovasculosa (vascular fibrous tissue with degenerated neural elements)
• Spinal defects may coexist (craniorachischisis)

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CLINICAL FEATURES IN MOTHER AND FETUS

Antenatal Presentation

• Polyhydramnios in ~50% of cases - because anencephalic fetus lacks a swallowing reflex (last 2 months of pregnancy)
• Fundal height may be larger than dates (due to polyhydramnios)
• Fetal parts palpable but head shape abnormal
• Frog-like position on palpation

At Delivery

• Characteristic frog-like facies
• Head shape: absence of skull vault, prominent orbits
• Exposed brain mass at vertex (area cerebrovasculosa)
• May be stillborn or survive a few hours

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DIAGNOSIS

Prenatal Screening

• Nuchal translucency (NT) scan - can reliably diagnose anencephaly
• Early exencephaly: irregular head shape with exposed brain tissue
• Absence of BPD (biparietal diameter) on USG

• Maternal Serum Alpha-Fetoprotein (MSAFP) - markedly elevated (neural tissue exposed to amniotic fluid → AFP leaks into amniotic fluid → maternal blood)
• AFP from fetal serum leaks through open neural tissue
• Elevated MSAFP used to screen for open NTDs
• Anomaly scan (18-20 weeks): Absence of cranial vault, "frog eye" appearance

• Also elevated (almost always >95th percentile in anencephaly)
• Done if MSAFP elevated on amniocentesis

• Absent calvarium (no bony echo above orbits)
• Absence of cerebral cortex
• Prominent orbits - "frog eyes" / "Mickey Mouse sign"
• Polyhydramnios
• Echogenic amniotic fluid (from leaking fetal brain tissue)
• Can diagnose as early as 11 weeks (first trimester scan)

• Positive in open NTDs including anencephaly

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DIFFERENTIAL DIAGNOSIS

1. Amniotic band syndrome resulting in anencephaly-like appearance
2. Severe microcephaly
3. Large encephalocele

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ASSOCIATED ANOMALIES

• Open spina bifida / craniorachischisis
• Cephalocele
• Congenital heart defects
• Cleft lip and palate
• Renal anomalies
• Skeletal anomalies
• Polyhydramnios in 50% of cases
• Chromosomal abnormality in ~2%
• Adrenal hypoplasia (due to absent hypothalamic-pituitary axis)

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MANAGEMENT

During Pregnancy

1. Confirm diagnosis with detailed USG at anomaly scan
2. Counselling - inform parents that condition is uniformly lethal
3. Option of termination of pregnancy (TOP) offered at any gestational age (lethal anomaly)
4. If pregnancy continuing: serial USG to monitor amniotic fluid volume
5. No need for antenatal testing (NST, BPP) due to uniformly fatal prognosis
6. Polyhydramnios management: amnioreduction if symptomatic maternal respiratory compromise

At Delivery

• Vaginal delivery preferred - do NOT perform cesarean section for fetal indication (futile, exposes mother to risk)
• Cephalic position: may deliver vaginally despite absent skull (head collapses/compresses easily)
• Breech: if labor does not progress, destructive operation or C-section only for maternal indication
• Pitressin (oxytocin) to induce labor if awaiting spontaneous delivery

Neonatal Management

• Supportive care only - condition is incompatible with prolonged survival
• Most die within hours to days of birth
• Do NOT initiate intensive resuscitative measures
• Organ donation possible (kidneys, heart) as brainstem function may be intact temporarily

Recurrence Prevention

• Folic acid 5 mg/day in all women planning next pregnancy (high-dose for previous NTD)
• Normal population: 400 μg/day preconceptionally

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PROGNOSIS

• 100% fatal - incompatible with sustained life
• Most are stillborn or die within hours of birth
• A small number may survive a few days with only brainstem function

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PART 3: QUICK COMPARISON TABLE FOR EXAM

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PART 4: HIGH-YIELD EXAM POINTS

Hydatidiform Mole - Musts to Remember

1. Complete mole = 46,XX, all paternal chromosomes, p57 NEGATIVE, uterus > dates, very high hCG
2. Partial mole = 69 chromosomes (triploid), fetal tissue present, focal changes, p57 POSITIVE
3. "Snowstorm" on USG = complete mole; "Swiss cheese" = partial mole
4. Preeclampsia before 20 weeks = think molar pregnancy
5. Theca lutein cysts = result of high hCG stimulation; do NOT remove operatively
6. Suction curettage = treatment of choice; give oxytocin AFTER (not before) evacuation
7. hCG follow-up: weekly till normal for 3 weeks, then monthly till normal for 6 months
8. IUD contraindicated during follow-up; OCP is safe
9. Choriocarcinoma = most chemosensitive solid tumor
10. Metastatic sites: Lungs (80%) > Vagina (30%) > Pelvis (20%) > Liver/Brain (10% each)
11. GTN treatment: Low risk = single agent (MTX or ActD); High risk = EMA-CO regimen

Anencephaly - Musts to Remember

1. Most common NTD; failure of rostral neural tube to close by day 20-26
2. Exencephaly → Anencephaly sequence (brain degenerates after exposure)
3. More common in females; 1:1000 live births
4. Pathognomonic triad: absent calvarium, absent cerebral cortex, area cerebrovasculosa
5. Polyhydramnios in 50% (no swallowing reflex)
6. Markedly elevated MSAFP and amniotic fluid AFP
7. USG: "frog eyes" / absent biparietal diameter
8. Uniformly fatal - do NOT do C-section for fetal indication
9. Prevention: Folic acid 400 μg/day pre-conceptionally; 5 mg/day if prior NTD
10. Brainstem intact - hence misnomer; swallowing absent because forebrain controls it
11. Craniorachischisis = anencephaly + open spinal defect (severest NTD)

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Molar Pregnancy = Hydatidiform Mole

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Why the Confusion?

• "The patient was diagnosed with a molar pregnancy" = "The patient was diagnosed with a hydatidiform mole"
• Berek & Novak's Gynecology chapter heading literally reads: "Hydatidiform Moles" and uses "molar pregnancy" throughout the same paragraph

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The Only Real Distinction Worth Knowing

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Bottom Line for Exams

Do not write them as different conditions in any exam. They are the same. If a question says "molar pregnancy" it means hydatidiform mole. Write everything you know about complete mole, partial mole, GTD, hCG, suction curettage, and follow-up - the term used in the question does not change the answer.