Molar Pregnancy (Hydatidiform Mole)

1. Clinical Overview

Summary

A molar pregnancy (hydatidiform mole) is a form of gestational trophoblastic disease (GTD) characterised by abnormal proliferation of trophoblastic tissue following aberrant fertilisation. [1,2] Molar pregnancies are classified into two main subtypes: complete hydatidiform mole (CHM) and partial hydatidiform mole (PHM). [3,4]

Complete moles are entirely paternally derived (androgenetic diploid, typically 46,XX), with no fetal tissue present. They result from fertilisation of an empty ovum by either one sperm that duplicates or two sperm. [5] Partial moles are triploid (typically 69,XXY), containing one maternal and two paternal haploid chromosome sets, and may have some fetal tissue. [6]

Molar pregnancies typically present in the first trimester with vaginal bleeding, excessively elevated hCG levels (often > 100,000 mIU/mL), and the classic "snowstorm" or "bunch of grapes" ultrasound appearance. [7,8] The standard treatment is suction curettage (evacuation of retained products of conception). [9]

The critical clinical concern is the 15-20% risk of persistent gestational trophoblastic disease (GTD) or choriocarcinoma following complete mole, necessitating strict hCG surveillance and registration with a specialist GTD centre. [10,11] With appropriate follow-up and chemotherapy when indicated, cure rates exceed 95% even in metastatic disease. [12]

Key Facts

• Complete Mole: 46,XX (androgenetic diploid); no fetus; higher malignancy risk (15-20%)
• Partial Mole: 69,XXY (diandric triploid); may have some fetal tissue; lower risk (1-5%)
• Ultrasound: "Snowstorm" or "Bunch of grapes" appearance
• hCG: Excessively high (can cause hyperemesis, thyrotoxicosis)
• Treatment: Suction curettage (evacuate uterus)
• Follow-up: hCG monitoring; mandatory registration with specialist GTD centre
• Contraception: Avoid pregnancy during hCG surveillance (6-12 months)
• Prognosis: Cure rate > 95% even with persistent GTD/metastatic disease

Clinical Pearls

"Snowstorm on Ultrasound": The classic appearance of complete mole — multiple echogenic vesicles filling the uterus with characteristic hydropic villi.

"Excessively High hCG": hCG levels are much higher than expected for gestational age (often > 100,000 mIU/mL). This can cause hyperemesis and even thyrotoxicosis (hCG shares α-subunit homology with TSH and can cross-stimulate TSH receptors).

"Must Follow Up hCG": After evacuation, hCG must be monitored until normalised and for months afterwards to detect persistent GTD or choriocarcinoma. Registration with a specialist GTD centre is MANDATORY in the UK.

"No Oxytocin Before Evacuation": Avoid uterotonics before suction curettage as they may increase risk of trophoblastic embolisation and haemorrhage.

"p57 Immunostaining Differentiates": Complete moles are p57-negative (absent maternal genome), whereas partial moles and hydropic abortus are p57-positive.

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2. Epidemiology

Incidence

• Complete mole accounts for approximately 80% of molar pregnancies
• Partial mole accounts for approximately 20% of molar pregnancies

Risk Factors

Exam Detail: High-Yield for MRCOG:

• The strongest risk factors are maternal age > 40 years and previous molar pregnancy.
• After two prior molar pregnancies, the recurrence risk increases to 15-20%, and patients should be counselled about genetic testing for familial recurrent hydatidiform mole (biparental complete mole due to NLRP7 or KHDC3L mutations).
• Partial moles do NOT have the same recurrence risk pattern as complete moles.

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3. Aetiology & Pathophysiology

Molecular Pathogenesis

Molar pregnancies arise from aberrant fertilisation events resulting in genomic imbalance — specifically an excess of paternally derived chromosomes. [5,17]

Complete Hydatidiform Mole (CHM)

Partial Hydatidiform Mole (PHM)

Genomic Imprinting

Genomic imprinting is central to the pathophysiology of molar pregnancies. [5]

• Paternal genome drives trophoblastic/placental proliferation
• Maternal genome drives embryonic development

In complete moles, the absence of the maternal genome results in:

• Excessive trophoblastic proliferation (no maternal restraint)
• No embryonic development
• Markedly elevated hCG production

In partial moles, the presence of one maternal genome allows:

• Some embryonic development (usually non-viable)
• Less pronounced trophoblastic hyperplasia
• Moderately elevated hCG

Exam Detail: Viva Question: Why is p57 immunohistochemistry useful in distinguishing complete mole from partial mole?

Model Answer: p57KIP2 is a cyclin-dependent kinase inhibitor encoded by the CDKN1C gene on chromosome 11p15.5, which is paternally imprinted and maternally expressed. In complete moles, there is no maternal genome, so p57 expression is absent in cytotrophoblast and villous stromal cells. In partial moles and hydropic abortus, the maternal genome is present, so p57 is positive. This allows reliable differentiation when histomorphology alone is ambiguous. [18]

Why High hCG?

hCG-Mediated Complications

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4. Clinical Presentation

Symptoms

Less Common Presentations

Clinical Pearl: Early Diagnosis Reduces Complications: In the modern era with routine first-trimester ultrasound, classic presentations (passage of vesicles, early pre-eclampsia, very large uterus) are now rare. Most molar pregnancies are diagnosed at 8-12 weeks before severe complications develop. [7]

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5. Clinical Examination

General Examination

Abdominal Examination

Speculum Examination

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6. Investigations

Laboratory Investigations

Exam Detail: hCG Levels:

• Normal pregnancy at 8-10 weeks: 20,000-200,000 mIU/mL
• Molar pregnancy: often > 100,000 mIU/mL and rising inappropriately
• Levels > 100,000 mIU/mL are associated with higher risk of persistent GTD and complications (thyrotoxicosis, respiratory distress)

Note: hCG levels alone cannot definitively diagnose molar pregnancy; ultrasound and histology are required.

Imaging

Transvaginal Ultrasound (First-Line)

Chest X-Ray

Histopathology (Definitive Diagnosis)

Diagnosis of molar pregnancy is confirmed histologically after evacuation of products of conception. [3,4]

Exam Detail: MRCOG Oral Exam Pearls:

• Histopathology is the gold standard for diagnosis and classification
• p57 immunohistochemistry is now routinely used to distinguish complete moles (p57-negative) from partial moles/hydropic abortus (p57-positive) [18]
• Molecular genotyping (STR analysis) can be used in equivocal cases to determine parental origin of chromosomes

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7. Differential Diagnosis

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8. Management

Initial Management

┌──────────────────────────────────────────────────────────┐
│   MOLAR PREGNANCY: INITIAL MANAGEMENT                     │
├──────────────────────────────────────────────────────────┤
│                                                          │
│  1. CONFIRM DIAGNOSIS:                                    │
│     • Transvaginal ultrasound (snowstorm appearance)     │
│     • Serum β-hCG (markedly elevated)                    │
│     • Counsel patient on diagnosis and plan             │
│                                                          │
│  2. PRE-EVACUATION WORKUP:                                │
│     • FBC, Group & Save, TFTs, U&E                       │
│     • Chest X-ray (baseline for surveillance)           │
│     • Consent for suction curettage and registration    │
│       with GTD centre                                    │
│     • Discuss contraception for follow-up period        │
│                                                          │
│  3. STABILISE IF REQUIRED:                                │
│     • IV access, fluid resuscitation if bleeding        │
│     • Crossmatch blood if severe anaemia/haemorrhage    │
│     • Consider anti-thyroid therapy if severe           │
│       thyrotoxicosis (usually not required)             │
│                                                          │
└──────────────────────────────────────────────────────────┘

Evacuation of Molar Pregnancy

Suction curettage (ERPC) is the treatment of choice. [9,11]

Clinical Pearl: Why Avoid Oxytocin Before Evacuation?

Administering oxytocin before evacuating the mole causes the uterus to contract, potentially forcing trophoblastic tissue into the venous circulation and increasing the risk of:

• Pulmonary trophoblastic embolisation
• Dissemination of disease

Oxytocin should be given only after complete evacuation. [9]

Alternative: Hysterectomy

Important: Even after hysterectomy, hCG surveillance is still required as metastatic disease can still develop. [11]

Post-Evacuation Management

┌──────────────────────────────────────────────────────────┐
│   POST-EVACUATION FOLLOW-UP (CRITICAL)                   │
├──────────────────────────────────────────────────────────┤
│                                                          │
│  REGISTRATION:                                            │
│  • MANDATORY registration with specialist GTD centre     │
│    (UK: Charing Cross, Sheffield, Dundee)               │
│  • Centre coordinates all follow-up hCG monitoring      │
│                                                          │
│  hCG SURVEILLANCE PROTOCOL:                               │
│                                                          │
│  Complete Mole:                                           │
│  • Weekly hCG until normalised (less than 5 IU/L) for 3 weeks    │
│  • Then monthly hCG for 6 months after normalisation    │
│  • Total follow-up: typically 6-12 months [10,11]       │
│                                                          │
│  Partial Mole:                                            │
│  • Weekly hCG until normalised (less than 5 IU/L)                │
│  • Then monthly hCG until 3 consecutive normal values   │
│  • Total follow-up: typically 3-6 months                │
│                                                          │
│  CONTRACEPTION:                                           │
│  • AVOID pregnancy until hCG surveillance complete      │
│  • Pregnancy would interfere with hCG monitoring        │
│  • Preferred: Combined oral contraceptive pill          │
│  • Avoid IUCD until hCG normalised (perforation risk)   │
│                                                          │
│  INDICATIONS FOR CHEMOTHERAPY (Persistent GTD):           │
│  • hCG plateau (3 values over ≥3 weeks)                 │
│  • hCG rise (10% increase over 3 values in ≥2 weeks)    │
│  • Persistently elevated hCG > 6 months                  │
│  • Histological choriocarcinoma                         │
│  • Evidence of metastases                               │
│                                                          │
└──────────────────────────────────────────────────────────┘

Exam Detail: MRCOG Key Point — GTD Centre Registration:

In the UK, registration with a GTD centre is MANDATORY by law under the UK Cancer Registry. This is a unique legal requirement for cancer surveillance in the UK. The three UK centres are:

• Charing Cross Hospital, London (England)
• Weston Park Hospital, Sheffield (Northern England)
• Ninewells Hospital, Dundee (Scotland)

The UK has the best outcomes worldwide for GTD due to centralised follow-up and treatment. [11,12]

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9. Persistent Gestational Trophoblastic Disease (GTD)

Definition

Persistent GTD (also termed gestational trophoblastic neoplasia, GTN) is defined by: [10,11]

1. hCG plateau: 3 consecutive hCG values (±10%) over ≥3 weeks
2. hCG rise: 10% increase in hCG over 3 consecutive values spanning ≥2 weeks
3. Persistent elevation: hCG remains elevated > 6 months post-evacuation
4. Histological evidence of choriocarcinoma or invasive mole

Incidence

Histological Types of GTN

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10. Staging & Risk Stratification (FIGO 2000)

FIGO Anatomic Staging

FIGO Prognostic Scoring System (Modified WHO)

Risk stratification determines low-risk vs. high-risk GTN, guiding chemotherapy choice. [11,12]

Risk Classification:

• Low risk: Total score ≤6
• High risk: Total score ≥7

Exam Detail: Viva Question: A 28-year-old woman had a complete mole evacuated 3 months ago. Her hCG was 50,000 IU/L initially, fell to 500 IU/L at 6 weeks, but has now risen to 2,000 IU/L. Chest X-ray shows two lung nodules. What is her FIGO score and how would you manage her?

Model Answer:

• Age less than 40: 0 points
• Antecedent pregnancy (mole): 0 points
• Interval 3 months (4-6 months): 1 point
• Pre-treatment hCG 2,000 IU/L (1,000-10,000): 1 point
• Site of metastases (lung): 0 points
• Number of metastases (2): 1 point

Total FIGO score: 3 → Low-risk GTN

Management: Single-agent chemotherapy (methotrexate or actinomycin D), referred to specialist GTD centre for coordination of treatment. Cure rate > 95%. [11,12]

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11. Treatment of Persistent GTD / GTN

Low-Risk GTN (FIGO Score ≤6)

Single-agent chemotherapy is first-line. [12]

• First-line: Methotrexate (less toxic, easier to administer)
• Second-line: Actinomycin D (if methotrexate-resistant)
• Overall cure rate: > 95% for low-risk GTN [12]

High-Risk GTN (FIGO Score ≥7)

Multi-agent chemotherapy is required. [12]

• Overall cure rate: 80-90% for high-risk GTN [12]
• CNS metastases: Require intrathecal methotrexate + cranial irradiation
• Liver metastases: Associated with poorer prognosis

Role of Surgery in GTN

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12. Complications

Complications of Molar Pregnancy Itself

Persistent GTD / Malignant Transformation

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13. Prognosis & Outcomes

After Evacuation

After Chemotherapy for GTN

Future Reproductive Outcomes

Clinical Pearl: Reassurance for Patients:

• The cure rate is > 95% even for metastatic disease
• Fertility is preserved in the vast majority
• Future pregnancies are usually normal
• The key is strict adherence to hCG surveillance to detect persistent GTD early

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14. Evidence & Guidelines

Key Guidelines

1. RCOG Green-top Guideline No. 38: The Management of Gestational Trophoblastic Disease (2020) [11]

   • Comprehensive UK guideline covering diagnosis, evacuation, follow-up, and treatment
   • Emphasises mandatory registration with GTD centres

2. FIGO Oncology Committee Opinion: Staging and Risk Factor Scoring System for GTN (2000) [12]

   • International standardised staging and scoring

3. ESMO Clinical Practice Guidelines: Gestational Trophoblastic Disease (2020) [12]

   • European guidelines aligning with FIGO staging

4. Society of Gynecologic Oncology of Canada (GOC) Guideline No. 408 (2021) [11]

   • Canadian guideline emphasising centralised care

Key Evidence

Diagnosis:

• p57 immunohistochemistry is highly sensitive and specific for distinguishing complete moles (p57-negative) from partial moles/hydropic abortus (p57-positive). [18]
• Molecular genotyping (STR analysis) can clarify equivocal cases. [3]

Treatment:

• Suction curettage is superior to medical management (misoprostol) for molar pregnancy due to lower bleeding risk and more complete evacuation. [9]
• Centralised follow-up in specialist GTD centres significantly improves outcomes. [11,12]

Chemotherapy:

• Methotrexate and actinomycin D have equivalent efficacy for low-risk GTN (~90% cure rate). [12]
• EMA-CO is the gold standard multi-agent regimen for high-risk GTN (85-90% cure rate). [12]

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15. Examination Focus

Viva Questions & Model Answers

Q1: What is the genetic basis of complete vs partial mole?

A: Complete moles are diploid (46,XX or 46,XY) and entirely paternally derived (androgenetic). They arise from fertilisation of an empty ovum by either one sperm that duplicates (90%, homozygous 46,XX) or two sperm (10%, heterozygous 46,XX or 46,XY). There is no maternal genomic contribution.

Partial moles are triploid (69,XXY or 69,XXX) with one maternal and two paternal haploid sets (diandric). They arise from fertilisation of a normal ovum by two sperm (dispermy).

The absence of maternal genome in complete moles removes restraint on trophoblastic proliferation, leading to excessive placental growth and no embryonic development. [5,6]

Q2: How would you manage a 35-year-old woman diagnosed with a complete mole at 10 weeks gestation?

A:

1. Confirm diagnosis: TVS (snowstorm appearance), serum hCG (markedly elevated)
2. Pre-evacuation workup: FBC, Group & Save, TFTs, CXR (baseline)
3. Counsel patient: Explain diagnosis, evacuation, follow-up, contraception
4. Suction curettage: Under GA, avoid oxytocin before evacuation, send tissue for histology
5. Anti-D: If Rh-negative
6. Post-evacuation:
   • Mandatory registration with GTD centre (e.g., Charing Cross)
   • Weekly hCG until normalised (less than 5 IU/L) for 3 consecutive weeks
   • Monthly hCG for 6 months after normalisation
   • Reliable contraception (COCP preferred) until surveillance complete
   • Educate: Avoid pregnancy; report any symptoms (bleeding, respiratory, neurological)

Q3: A woman has persistent GTD with FIGO score 5. What chemotherapy would you use and what is the prognosis?

A: FIGO score 5 is low-risk GTN (score ≤6). First-line treatment is single-agent chemotherapy with methotrexate. If methotrexate-resistant, second-line is actinomycin D. The cure rate is > 95%. Treatment is coordinated by a specialist GTD centre. [12]

Q4: Why is hCG surveillance mandatory after molar pregnancy?

A: hCG surveillance is mandatory because:

• 15-20% of complete moles develop persistent GTD or choriocarcinoma [10]
• 1-5% of partial moles develop persistent GTD [10]
• Early detection (via rising/plateauing hCG) allows timely chemotherapy before metastases develop
• Cure rate is > 95% if detected and treated early [12]
• Centralised surveillance in GTD centres has made the UK a world leader in GTD outcomes [11]

Q5: What are the indications for chemotherapy after molar pregnancy evacuation?

A:

1. hCG plateau: 3 consecutive hCG values (±10%) over ≥3 weeks
2. hCG rise: 10% increase over 3 consecutive values spanning ≥2 weeks
3. Persistent elevation: hCG remains elevated > 6 months post-evacuation
4. Histological choriocarcinoma
5. Evidence of metastases (clinical or radiological)

These criteria define persistent GTD (GTN) requiring chemotherapy. [10,11]

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16. Patient/Layperson Explanation

What is a Molar Pregnancy?

A molar pregnancy (also called a hydatidiform mole) is an abnormal pregnancy where the placenta grows in an unusual way and a baby doesn't develop normally — or at all. It happens because of a problem at the time of fertilisation (when the sperm meets the egg).

What Are the Types?

• Complete mole: No baby develops at all. The placenta forms abnormal grape-like tissue.
• Partial mole: Some fetal tissue may develop, but it is never viable (cannot survive).

What Causes It?

Molar pregnancy is caused by an imbalance in genetic material at fertilisation:

• In a complete mole, the egg has no genetic material from the mother, and the sperm duplicates itself.
• In a partial mole, the egg is fertilised by two sperm, leading to too much genetic material.

It is not caused by anything you did or didn't do. It is a random event.

What Are the Symptoms?

• Vaginal bleeding in early pregnancy (most common)
• Severe morning sickness (nausea and vomiting)
• Uterus larger than expected for how far along you are
• Very high levels of pregnancy hormone (hCG)

How is It Diagnosed?

• Ultrasound scan: Shows a characteristic "snowstorm" or "bunch of grapes" appearance instead of a normal pregnancy
• Blood test: Very high hCG (pregnancy hormone) levels

How is It Treated?

The abnormal tissue is removed by a small operation called suction curettage (similar to a D&C or ERPC). This is done under general anaesthetic (you are asleep). The tissue is sent to the laboratory to confirm the diagnosis.

Why is Follow-Up Important?

In a small number of cases (15-20% for complete mole, 1-5% for partial mole), some abnormal tissue can remain or start growing back. In rare cases, it can become cancerous (choriocarcinoma).

The good news is: If caught early through regular blood tests (checking hCG levels), this is highly curable (> 95% cure rate) with chemotherapy.

You will be registered with a specialist centre (in the UK: Charing Cross, Sheffield, or Dundee) who will coordinate your follow-up.

What Does Follow-Up Involve?

• Regular blood or urine tests to check your hCG levels go back to normal
• Complete mole: Weekly tests until normal, then monthly for 6 months
• Partial mole: Weekly tests until normal, then monthly for a shorter period

Can I Get Pregnant Again?

Yes, most women can have normal pregnancies after a molar pregnancy. However, you should:

• Wait until your hCG levels are normal and your follow-up is complete (usually 6-12 months)
• Use reliable contraception during follow-up (the contraceptive pill is recommended)
• The risk of it happening again is low (1-2%)

When Should I Seek Urgent Help?

Contact your doctor or specialist centre immediately if you have:

• Heavy vaginal bleeding
• Severe abdominal pain
• Difficulty breathing or chest pain
• Severe headaches or neurological symptoms

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17. References

Primary Guidelines & Reviews

1. Soper JT. Gestational Trophoblastic Disease: Current Evaluation and Management. Obstet Gynecol. 2021;137(2):355-370. doi:10.1097/AOG.0000000000004240. PMID: 33416290

2. Joyce CM, Fitzgerald B, McCarthy TV, Coulter J, O'Donoghue K. Advances in the diagnosis and early management of gestational trophoblastic disease. BMJ Med. 2022;1(1):e000321. doi:10.1136/bmjmed-2022-000321. PMID: 36936581

3. Tsakiridis I, Giouleka S, Kalogiannidis I, et al. Diagnosis and Management of Gestational Trophoblastic Disease: A Comparative Review of National and International Guidelines. Obstet Gynecol Surv. 2020;75(12):747-756. doi:10.1097/OGX.0000000000000848. PMID: 33369685

Molecular & Genetic Studies

4. Roberts DJ, Mutter GL. Advances in the molecular biology of gestational trophoblastic disease. J Reprod Med. 1994;39(3):201-8. PMID: 8035375

5. Fulop V, Mok SC, Berkowitz RS. Molecular biology of gestational trophoblastic neoplasia: a review. J Reprod Med. 2004;49(6):415-22. PMID: 15283047

6. Doshi N, Surti U, Szulman AE. Morphologic anomalies in triploid liveborn fetuses. Hum Pathol. 1983;14(8):716-23. doi:10.1016/s0046-8177(83)80145-2. PMID: 6683705

Diagnostic Studies

7. Soper JT. Gestational trophoblastic disease. Obstet Gynecol. 2006;108(1):176-87. doi:10.1097/01.AOG.0000224697.31138.a1. PMID: 16816073

8. Lewis GH, DeScipio C, Murphy KM, et al. Characterization of androgenetic/biparental mosaic/chimeric conceptions, including those with a molar component: morphology, p57 immunohistochemistry, molecular genotyping, and risk of persistent gestational trophoblastic disease. Int J Gynecol Pathol. 2013;32(2):199-214. doi:10.1097/PGP.0b013e3182630d8c. PMID: 23370656

9. Samadder A, Kar R. Utility of p57 immunohistochemistry in differentiating between complete mole, partial mole & non-molar or hydropic abortus. Indian J Med Res. 2017;145(1):133-137. doi:10.4103/ijmr.IJMR_982_15. PMID: 28574027

Management Guidelines

10. Eiriksson L, Dean E, Grenier C, et al. Guideline No. 408: Management of Gestational Trophoblastic Diseases. J Obstet Gynaecol Can. 2021;43(1):91-105.e1. doi:10.1016/j.jogc.2020.03.001. PMID: 33384141

11. Royal College of Obstetricians and Gynaecologists. Green-top Guideline No. 38: The Management of Gestational Trophoblastic Disease. London: RCOG; 2020. Available at: https://www.rcog.org.uk/guidance/browse-all-guidance/green-top-guidelines/management-of-gestational-trophoblastic-disease-green-top-guideline-no-38/

12. Ngan HYS, Seckl MJ, Berkowitz RS, et al. Update on the diagnosis and management of gestational trophoblastic disease. Int J Gynaecol Obstet. 2018;143 Suppl 2:79-85. doi:10.1002/ijgo.12615. PMID: 30306586

Epidemiology & Risk Factors

13. Savage P, Seckl M. Gestational trophoblastic disease. Obstet Gynaecol Reprod Med. 2018;28(7):196-201. doi:10.1016/j.ogrm.2018.05.003

14. Smith HO. Gestational trophoblastic disease epidemiology and trends. Clin Obstet Gynecol. 2003;46(3):541-556. doi:10.1097/00003081-200309000-00006. PMID: 12972738

15. Altieri A, Franceschi S, Ferlay J, Smith J, La Vecchia C. Epidemiology and aetiology of gestational trophoblastic diseases. Lancet Oncol. 2003;4(11):670-678. doi:10.1016/s1470-2045(03)01245-2. PMID: 14602247

16. Sebire NJ, Fisher RA, Foskett M, et al. Risk of recurrent hydatidiform mole and subsequent pregnancy outcome following complete or partial hydatidiform molar pregnancy. BJOG. 2003;110(1):22-26. PMID: 12504932

Pathophysiology

17. Berkowitz RS, Goldstein DP. Current advances in the management of gestational trophoblastic disease. Gynecol Oncol. 2013;128(1):3-5. doi:10.1016/j.ygyno.2012.07.116. PMID: 22846466

18. Buza N, Hui P. Immunohistochemistry and other ancillary techniques in the diagnosis of gestational trophoblastic diseases. Semin Diagn Pathol. 2014;31(3):223-232. doi:10.1053/j.semdp.2014.02.008. PMID: 24815941

19. Walkington L, Webster J, Hancock BW, Everard J, Coleman RE. Hyperthyroidism and human chorionic gonadotrophin production in gestational trophoblastic disease. Br J Cancer. 2011;104(11):1665-1669. doi:10.1038/bjc.2011.139. PMID: 21559015

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