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Gestational trophoblastic neoplasia 

Gestational trophoblastic neoplasia
Gestational trophoblastic neoplasia

Philip Savage

and Michael J. Seckl

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Arising from the cells of conception, gestational trophoblastic disease (GTD) forms a spectrum of disorders from the premalignant complete and partial hydatidiform moles through to the malignant invasive mole, choriocarcinoma and very rare placental site trophoblastic tumours (PSTT). The latter three conditions are also collectively known as gestational trophoblastic neoplasia (GTN) and, although uncommon, are important to recognize as this enables life-saving therapy to be commenced. About 10% of molar pregnancies fail to die out after uterine evacuation and transform into malignant GTN that require additional chemotherapy (1). These cases are usually recognized early and therefore rarely prove difficult to treat, with cure rates approaching 100% reported in most modern series (2). However, GTN can also develop after any type of pregnancy including miscarriages, term deliveries, and medical abortions. Such patients are often not suspected of having GTN and may present late with widespread disease associated with a wide variety of medical, surgical, and gynaecological problems (3). The prompt diagnosis and early effective treatment of these women is aided by an awareness and understanding of these rare, but highly curable malignancies and good team-working between physicians, gynaecologists, pathologists, and oncologists

Classification and genetic origins of GTN

Premalignant forms of GTN

Partial and complete molar pregnancies

Molar pregnancies (MPs) arise from trophoblast cells from abnormal fertilizations that have unbalanced genetic inputs from the ovum and the sperm. As shown in Fig., partial molar pregnancies (PHM) have three sets of chromosomes, two paternal in origin and one maternal occurring as a result of the oocyte being fertilized by two sperm (4). Complete molar pregnancies (CHM) have 46 chromosomes all are derived from the father with the maternal genetic material lost either at conception or earlier in oocyte development (5). The result of these genetic errors at fertilization produces rapidly dividing trophoblast cells that make human chorionic gonadotropin (hCG), are unable to produce a viable fetus, but have a malignant potential.

Fig. The origin and genetic structures of normal conceptions and partial and complete molar pregnancies.

The origin and genetic structures of normal conceptions and partial and complete molar pregnancies.

The differing genetic structure of complete moles and partial moles leads to different degrees of risk of a malignant phenotype. Following uterine evacuation 8–20% of women with a complete mole will develop persistent disease, whilst approximately 0.5% or fewer of those with PHM will require additional treatment (6).

Malignant forms of GTN (termed gestational trophoblast tumours GTT)

Invasive mole

Pathologically invasive mole (chorioadenoma destruens) appears benign having a similar microscopic appearance to a complete molar pregnancy. However, the clinical phenotype of invasive mole is malignant, with invasion of the trophoblast tissue through the myometrium and spread into the pelvis. If left untreated, invasive mole can result in heavy vaginal bleeding, uterine rupture, and pain and haematuria from bladder invasion.

Fortunately, in areas with routine ultrasound assessment in pregnancy, the rare cases of invasive mole are usually promptly diagnosed and treated before these serious complications can arise.

Choriocarcinoma and placental site trophoblastic tumours

In contrast to MPs, choriocarcinoma, and PSTT mainly arise from the malignant transformation of trophoblast cells that have the standard complement of 46 chromosomes with 23 from each parent (7). However, occasionally histologically identical cases of choriocarcinoma and PSTT may also arise from both types of molar pregnancy (6, 8). The large majority of cases of choriocarcinoma, irrespective of their genetic route, share a marked sensitivity to chemotherapy, although choriocarinoma cases arising with a long interval from the antecedent pregnancy are more difficult to treat (9).

Placental site trophoblastic tumours are the rarest form of GTN, but frequently PSTT remains localized within the uterus and these cases can be cured with surgery alone (10). In contrast, cases of PSTT with distant metastases have a variable response to chemotherapy, with successful treatment closely linked to length of the interval from the causative pregnancy (11).

Epidemiology of GTN

Incidence and risk factors for molar pregnancies

Historical series with high incidence rates for MPs have previously been reported from Korea, the Philippines, and Japan. However, most modern series suggest that the incidence of molar pregnancies is now relatively uniform at 1–3 cases per 1000 livebirths in most racial and geographical groupings (12). Whilst it is likely that some cases, particularly of partial molar pregnancy, go undiagnosed it is likely that the overall incidence of CHM and PHM are similar.

A number of environmental risk factors have been suggested for molar pregnancies, but the only clear risk factors appear to be conceptions at the extremes of maternal age and a previous occurrence of a molar pregnancy. For girls under the age of 15 there is a 10–20-fold increased molar pregnancy incidence, whilst women aged 45–50 have a 20-fold increase and those over 50 years a 200-fold increased risk compared with women aged 20–40 years (13). This age-related increased risk is more marked for complete molar pregnancies where the risk for women conceiving in early 50s is more than 500-fold increased. The risks for partial molar pregnancies and also for non-molar hydropic abortions are also increased but at significantly lower rates.

The other important risk factor for a MP is a previous occurrence. In this situation the risk of a further molar pregnancy is approximately 1 in 75 as shown in Fig where the subsequent pregnancy outcome for women with one previous molar pregnancy is shown.

Fig. The subsequent pregnancy outcome for 1911 women with a previous diagnosis of a molar pregnancy. The incidence of a further mole in this group of women is approximately 1:50, compared to a 1:500 risk for the normal population.

The subsequent pregnancy outcome for 1911 women with a previous diagnosis of a molar pregnancy. The incidence of a further mole in this group of women is approximately 1:50, compared to a 1:500 risk for the normal population.

For women who have had two prior molar pregnancies the risk increases further to 1 in 5–10.


The incidence of gestational choriocarcinoma is approximately 1 per 50 000 pregnancies and no epidemiological variables have been consistently linked with choriocarcinoma, perhaps owing to the rarity of the disease.

Placental site trophoblastic tumours

Placental site trophoblastic tumours are extremely rare, with an estimated incidence of 2–5 cases per million livebirths and prevalence of 0.2% of all GTD cases (10, 11) There are no documented risk factors with the diagnosis occurring evenly across the childbearing age range. A recent publication suggests that cases of PSTT occur predominantly or potentially only after a pregnancy with a female conception (14), but our UK experience does not support this observation (11).

Human chorionic gonadotropin (hCG) and GTN

All forms of GTN constitutively make hCG, enabling most cases of malignant GTN to be diagnosed clinically from the history, clinical tests, and tumour marker results without the need for an additional potentially hazardous biopsy. In addition to the role of hCG measurement in diagnosis, the measurement of hCG levels are also central to the optimal treatment via prognostic scoring, treatment monitoring and post chemotherapy follow-up.

Human chorionic gonadotropin (hCG)

In health, hCG is produced by the cytotrophoblast cells of the placenta and plays a key role in placental steroidigenesis, and the control of trophoblast cell migration and invasion into the uterine endometrium. Human chorionic gonadotropin (hCG) is a glycosylated 36.7 kDA heterodimer consisting of alpha and beta chains. The 92 amino acid 14 kDa alpha unit has a common structure shared with α‎-subunits of luteinizing hormone, follicle-stimulating hormone (FSH) and thyroid-stimulating hormone (TSH), whilst the 145 amino acid 22 Da beta core fragment is specific to hCG. As a result of the shared structural determinants between hCG and TSH, the high levels of hCG production in pregnancy and GTN can occasionally lead to thyroid hyperstimulation and thyrotoxicosis (15).

In pregnancy the levels of hCG in blood and urine rise quickly through the first trimester, usually peaking at levels of 12 000–200 000 IU/l at 12 weeks and then declining in the later stages to levels of 5 000–40 000 IU/l at delivery. After delivery the serum and urine hCG values should fall promptly and reach normal levels by the third week postpartum (16). The excretion of hCG is predominantly via the kidneys and, as a result, in renal failure, there can be modest elevation of baseline levels, in the absence of any disease activity.

GTN is the most common malignancy making hCG in women, but hCG can also be produced in malignant ovarian germ cell tumours and occasionally in lung cancer, bladder cancer, cervical cancer, and very rarely in others malignancies (17).

With the exception of rare patients with cross-reacting antibodies that can lead to false positives in some assays the finding, of an elevated hCG level is generally diagnostic of either pregnancy or malignancy. However, in some women there can also be physiological pituitary production of low levels of hCG that can lead to confusion regarding the diagnosis, recurrence or on-going presence of active tumour cells in trophoblast disease. This situation is best characterized in postmenopausal women, where detectable levels of pituitary hCG are produced in parallel with the characteristic high levels of luteinizing hormone and FSH (18). A similar situation can occur in patients treated with chemotherapy for GTN. Here, the combination of ovarian suppression initially by high hCG levels and then by chemotherapy allows oestrogen levels to drop sufficiently to produce a postmenopausal endocrine picture with resultant luteinizing hormone, FSH and on occasion hCG elevation. Recent reports suggest that determining the relative amounts of full size hCG from hCG fragments may be helpful in pointing towards this diagnosis and the use of oestrogen replacement may suppress the pituitary production, so clarifying this difficult clinical situation.

Clinical presentation and diagnosis of GTN

Molar pregnancies

The use of routine first-trimester ultrasound has dramatically altered the presentation and natural history of molar pregnancies across the world (19). The classical textbook molar pregnancy findings of excessive uterine enlargement, hyperemesis, and pre-eclampsia, are now very unusual when routine ultrasound is employed. The actual accuracy and limitations of ultrasound to diagnose molar pregnancies prior to evacuation are summarized in Fig., showing that ultrasound performed at an average of 10–14 weeks of gestation results in the pre-evacuation diagnosis of approximately 80% of the cases of CHM, but only 30% of PHM.

Fig. The diagnostic accuracy of pre-evacuation ultrasound at varying time points in complete and partial molar pregnancies. Complete molar pregnancies are generally correctly diagnosed on ultrasound, however partial moles are more difficult to diagnose on imaging alone even at the more advanced gestational ages.

The diagnostic accuracy of pre-evacuation ultrasound at varying time points in complete and partial molar pregnancies. Complete molar pregnancies are generally correctly diagnosed on ultrasound, however partial moles are more difficult to diagnose on imaging alone even at the more advanced gestational ages.

These results support the value of routine ultrasound as a screening procedure for MPs, but also reinforce the importance of histological review of other failed pregnancies to detect the missed cases. Ultrasound examination of women with MP frequently indicates the presence of enlarged theca-lutein ovarian cysts that can lead to abdominal and pelvic pain, which are assumed to be linked to the high hCG levels seen in MP.

Potentially, hCG measurements in the early stages of pregnancy could support the pre-evacuation diagnosis of a molar pregnancy. A number of studies have shown that hCG levels are frequently higher in complete molar pregnancies than in normal singleton pregnancies, but there is a considerable overlap and hCG levels can often low in partial molar pregnancies.

More recently, research has indicated that the level of β‎hCG and the ratio of β‎hCG to total hCG can help distinguish between molar and normal conceptions with near 100% specificity and high sensitivity. However, despite this accuracy, the logistics of performing and financing this relatively complex testing as a screening procedure when molar pregnancies are so rare and already have such high cure rates is likely to present an obstacle to routine application. Overall, these hCG findings are not of high specificity and also require accurate knowledge of the gestational age. As the earliest evacuation of molar pregnancies brings only a small reduction in the risk of developing malignancy, it is important to wait until the diagnosis becomes clear on ultrasound of either a molar pregnancy or a failed non-molar pregnancy to avoid the risk of evacuating a healthy pregnancy.

As a result of the earlier diagnosis by ultrasound, the classical clinical findings of molar pregnancy (excessive uterine enlargement, hyperemesis and hCG values greater than 100 000 IU/l) are rarely observed, and hyperthyroidism and pre-eclampsia are extremely rare. Pre-eclampsia when it occurs can be life-threatening, but is extremely rare if the molar pregnancy is diagnosed before 10–12 weeks. Clinical hyperthyroidism resulting from the cross-reaction between hCG and thyroid-stimulating hormone (TSH) can also be a feature of untreated advanced molar pregnancy in a small number of women. The presenting symptoms include thyroid enlargement, tachycardia, fever and tremor, and very occasionally, women can present with a thyroid storm (20). The other medical conditions associated with untreated advanced molar pregnancy can also include respiratory distress, high-output congestive heart failure secondary to pre-eclampsia, anaemia, or hyperthyroidism.

Persistent disease following a molar pregnancy

After evacuation, approximately 10–15% of women with a complete mole and 1% of those with a partial mole will develop persistent disease and require further treatment generally with chemotherapy. Predicting which patients will require chemotherapy and those in whom the disease will remit spontaneously would be a valuable procedure, but at present there are no clinically accurate prognostic parameters in this situation. The patterns of hCG fall after evacuation and the ratios of various hCG components have been reported to be useful in predicting the need for additional therapy, but these approaches remain insufficiently accurate to make pre-emptive treatment decisions.

In the absence of a clinically effective method to accurately predict the need for additional treatment, ideally all molar pregnancy patients should take part in a structured follow-up programme, such as the centralized system pioneered in the UK. This programme allows all women with molar pregnancies to be closely monitored via their hCG levels and called for treatment before any serious problems from the growing trophoblast tissue can occur.

Where adequate follow-up is not available the use of adjuvant chemotherapy postevacuation for all patients has been explored. However, the results of treatment with brief courses of methotrexate or dactinomycin resulted in unacceptable relapse rates between 5–10%. In addition to the failure rates, the use of uniform adjuvant treatment has the disadvantage of delivering excess treatment to the large majority of women who would have already been cured by their evacuation alone.


Choriocarcinoma is rare, can occur with a wide time range after the causative pregnancy, and may present with a wide variety of symptoms and signs dependent on the sites of metastatic disease. The most frequent presentation is with vaginal bleeding and in the cases that follow shortly after delivery, the bleeding is often initially ascribed to ‘normal’ postpartum blood loss. However, women with choriocarcinoma often bleed heavily, usually have a vascular mass in the uterus visible on ultrasound, and will have significantly elevated hCG levels, whilst in comparison, after a normal delivery the hCG level should fall to normal after 3 weeks (16).

Characteristically choriocarcinoma is a rapidly growing malignancy with cases of metastatic spread reported to almost all anatomical sites. The most commonly involved sites are the lungs, vagina, central nervous system (CNS), liver, kidneys, and gastrointestinal tract. Lung metastases are present at diagnosis in over 80% of women with choriocarcinoma and may lead to cough, dyspnoea, haemoptysis, and pleuritic chest pain. Fortunately, respiratory failure is rare, as mechanical ventilation for these women with highly vascular pulmonary lesions is associated with poor survival. Intra-abdominal sites of metastatic disease can produce intraperitoneal bleeding, melaena, and severe pain, while the neurological manifestations include headaches, fits, loss of consciousness and hemiplegia. With such a broad range of presentations, clinicians of all specialities should consider the possibility of choriocarcinoma in any woman with CNS symptoms, postpartum cerebrovascular accidents or evidence of metastatic cancer of unknown origin. In these cases, hCG measurement may be life-saving, as even for advanced cases of choriocarcinoma with cerebral metastases the expectation is cure with prompt treatment.

Placental site trophoblastic tumours

The majority of women with PSTT present with either vaginal bleeding or with amenorrhoea with an interval from the end of the antecedent pregnancy to the time of diagnosis reported as ranging between 1 week to 25 years. At present the diagnosis can not confidently be made with hCG measurements alone, but the combination of a relatively low hCG level for the volume of the disease can be a pointer for PSTT, as can an elevated ratio of β‎hCG to total hCG (21). In suspected cases a biopsy confirming the diagnosis of PSTT can allow the optimal treatment to be delivered.

Management of GTN

Pre-treatment investigations in women with GTN

For most women needing treatment following a recent molar pregnancy, the investigations can be limited to a Doppler ultrasound of the pelvis and a chest X-ray. These allow the formal exclusion of a new pregnancy as the cause of the hCG elevation, measurement of the size of uterine tumour, and demonstrate any obvious pulmonary metastases. The results are used in the FIGO prognostic scoring system as shown in Table that determines the intensity of the initial chemotherapy treatment (22).

Table The FIGO prognostic scoring system for patients with gestational trophoblast tumours. Patients with a total scoring of 0-6 are in the low risk treatment group and those of 7 and above are in the high risk treatment group.









Antecedent pregnancy




Months from index pregnancy





Pretreatment hCG IU/l


1,000–10 000

10 000–100 000

>100 000

Largest tumour size

<3 cm

3–5 cm

>5 cm

Site of mets


Spleen, kidney


Brain, liver

Number of mets




Previous chemotherapy

Single agent

Two or more drugs

Women presenting with suspected choriocarcinoma or PSTT should be fully staged with computed tomography (CT) scans of the thorax and abdomen, and magnetic resonance imaging (MRI) scans of the brain and pelvis. These women frequently have nonpulmonary metastases and the presence of CNS or hepatic disease may alter the choice of initial chemotherapy treatment.

Postmolar pregnancy—indications for chemotherapy treatment

Retrospective analysis of patients from the UK and other follow-up programmes has produced the treatment indications as shown in Box, which shows the FIGO criteria and a wider set employed at Charing Cross Hospital.

A minority of the women with disease limited to the uterus after a molar pregnancy can be cured by a second uterine evacuation, but most will need chemotherapy. Analysis of recent UK data and Dutch data has indicated that a second evacuation is rarely of benefit if the hCG level is above 5000 IU/l and most recommendations are for primary chemotherapy in these women (23).

Staging classification and prognostic classification

The intensity of the initial chemotherapy treatment is determined by the FIGO prognostic scoring system as shown in Table In this, the prognostic factors, including the woman’s age, prior pregnancy, hCG level, and number and sites of metastases, are scored and the total value places women into either low-risk (score 0–6) or high-risk (score greater than or equal to 7) prognostic and treatment groups.

Chemotherapy treatment

Low-risk disease management

In the UK women who fall into the low-risk prognostic group receive relatively gentle chemotherapy with intramuscular methotrexate combined with oral folinic acid rescue. At Charing Cross Hospital, the first course of treatment is usually given as an inpatient due to the risks of bleeding worsening with the commencement of treatment. The subsequent courses are usually administered closer to home. For low-risk patients with lung metastases visible on the chest X-ray, CNS prophylaxis with intrathecal methotrexate is administered on three occasions each 2 weeks apart.

The side effects of low-risk methotrexate treatment are modest without routine major toxicity. This treatment does not cause hair loss or significant nausea, and myelosuppression is rare. The most frequent adverse effects are pleural inflammation, mucositis, and hepatic toxicity, but each of these occurs only rarely (2).

During treatment, women have their hCG levels monitored closely and following hCG normalization, chemotherapy is continued for another three cycles (6 weeks) to ensure eradication of any serologically undetectable disease. The typical total length of treatment for patients presenting in the low risk group is in the order of 3–4 months. Overall, 70% of the low-risk group patients will be successfully treated with methotrexate and folinic acid alone, but for those with an inadequate response to methotrexate shown by an hCG plateau or rise second-line chemotherapy is used. For this, single-agent dactinomycin given at 0.5 mg for days 1–5 every 2 weeks is used if the hCG is below 300 IU/l at the time of change, or the EMA/CO combination chemotherapy if the hCG level is above 300 IU/l.

Figure shows the hCG and treatment graphs of two low-risk patients who required chemotherapy following complete molar pregnancies. The first patient was cured with methotrexate treatment alone, while the other, after an initial response to methotrexate, needed to intensify to EMA/CO chemotherapy to successfully complete treatment. Overall, the survival for patients presenting in the low-risk treatment group approaches 100% and the stepwise introduction of the more intensive chemotherapy regimens minimizes the risks of long-term toxicity in the majority of women.

Fig. Treatment graphs of 2 patients with low risk trophoblast disease. Both patients started initial treatment with methotrexate. In patient (a) this was sufficient for curative treatment. Patient (b) had to change to more intensive treatment with the EMA-CO regimen and has also been cured.

Treatment graphs of 2 patients with low risk trophoblast disease. Both patients started initial treatment with methotrexate. In patient (a) this was sufficient for curative treatment. Patient (b) had to change to more intensive treatment with the EMA-CO regimen and has also been cured.

High-risk disease management

Historical data predating the availability of the modern multi-agent chemotherapy regimens indicates that only 10% of the high-risk prognostic group of patients would be cured with single-agent therapy alone (24). The development of combination chemotherapy treatments in the 1970s transformed this situation and most modern series give cure rates for high-risk patients above 85% using EMA/CO chemotherapy or other related combinations (25).

The EMA/CO regimen is myelosuppressive and patients frequently need support with granulocyte colony-stimulating factor (G-CSF) injections to keep treatment on time. Fortunately, life-threatening toxicity is rare with EMA/CO and the majority of women tolerate treatment well. As with the low-risk treatment patients, chemotherapy is continued for 6 weeks after the normalization of the hCG and relapse after this is rare. Figure shows the treatment graph of a high-risk patient who was successfully treated for choriocarcinoma, whilst Fig. shows the radiological response of the lung metastases in a patient with high risk choriocarcinoma presenting with respiratory failure.

Fig. A treatment graph for a high risk patient with choriocarcinoma successfully treated with the EMA-CO regimen demonstrating the fall and normalisation of hCG level in response to chemotherapy treatment.

A treatment graph for a high risk patient with choriocarcinoma successfully treated with the EMA-CO regimen demonstrating the fall and normalisation of hCG level in response to chemotherapy treatment.

Fig. CT scan of the thorax before and after chemotherapy treatment in a patient with choriocarcinoma who presented with respiratory failure 3 months after the birth of a healthy child.

CT scan of the thorax before and after chemotherapy treatment in a patient with choriocarcinoma who presented with respiratory failure 3 months after the birth of a healthy child.

Management of placental site trophoblast tumours

PSTTs are very rare, but the optimal care for patients with this malignancy has important differences from that of choriocarcinoma. In PSTT, the management is dependent on the disease stage and, when the disease is radiologically limited to the uterus, surgical management with hysterectomy is usually curative. In metastatic disease, treatment is with chemotherapy using the intensive EP/EMA regimen. In this diagnosis chemotherapy is continued for 8 weeks after the normalization of the hCG level and following this, a hysterectomy is recommended as viable tumour cells can persist in the uterine wall despite the serum hCG falling to normal. The key prognostic factor in the management of PSTT appears to be the interval between presentation and the antecedent pregnancy. The current data for PSTT patients treated in the UK show a 98% cure rate for those presenting within 4 years of the antecendent pregnancy, but a 100% mortality rate beyond this time point (11). This was not a consequence of differences in disease stage or hCG levels at presentation and possibly reflects a biological switch in the tumour behaviour after 4 years.

Postchemotherapy follow-up

Risk of relapse

After the successful completion of chemotherapy the outlook is generally excellent for most GTN patients. The risk of relapse is less than 3% for low-risk patients and 8% for high-risk patients treated with the EMA/CO regimen (26). The majority of these recurrences happen within the first 12 months following treatment and during this period patients are advised to defer a subsequent pregnancy.

Fortunately, even at relapse, most women with a trophoblast tumour remain highly curable and a recent analysis has indicated that 100% of women who were originally in the low-risk category can be cured on relapse, with a cure rate of 85% for those relapsing after initially presenting with high-risk disease (26).

Subsequent fertility and health

For the majority of patients receiving chemotherapy treatment, fertility is maintained and regular periods restart within 6 months of completion. However, chemotherapy treatment does lead to some gonadal toxicity, and brings the menopause forwards by approximately 1 year for low-risk methotrexate patients and 5 years for those women receiving EMA/CO chemotherapy (27). After completion of chemotherapy, the standard recommendations are to postpone a future pregnancy for 12 months to minimize any damaging effects on any developing oocytes. Despite the exposure to cytotoxic chemotherapy, particularly in the high-risk group, there does not appear to be any significant increase in subsequent fetal abnormalities and most women wishing to conceive are able to do so (28).

With the long-term follow-up of large numbers of survivors, it has become clear that intensive chemotherapy treatment with the EMA/CO and EP/EMA regimens can result in an increased risk of a later malignancy. An analysis in the 1990s of the Charing Cross Hospital GTN database of 1377 patients treated with indicated that there was a 1.5-fold increased risk of further malignancy, with the largest increase being for myeloid leukaemia (29).


Gestational trophoblastic neoplasia is a group of rare, but highly curable conditions. The optimal management of molar pregnancies with routine first-trimester ultrasound combined with effective follow-up programmes has produced near 100% cure rates for women generally achieved using treatments of low toxicity.

Patients with choriocarcinoma and PSTT, the more complicated forms of the disease, can present with a variety of symptoms from distant disease with or without out any gynaecological symptoms. In these cases measuring the hCG level can be life-saving as this will prompt the diagnosis to be made and even in the most advanced cases treatment usually leads to cure

In keeping with a number of other trophoblast centres around the world, Charing Cross Hospital operates a 24-h/day emergency treatment and advice service, and potential new cases or difficult diagnoses can always be discussed by phone or email urgently.


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