Submission for Glasgow Obstetrical and Gynaecological Society Medical Student Prize

Gestational Trophoblastic Disease

Submission for Glasgow Obstetrical and Gynaecological Society Medical Student Prize

Clinical case taken from a patient met during SSC in Ninewells Hospital, Dundee

MBChB IV

Emma Lauren Scahill

Registration Number: 0906306s

Clinical Case:

Miss X, a forty two year old para 2+0 woman was admitted to the Gynaecological Ward at Ninewells Hospital, Dundee,on 4/11/12 withsignificant vaginal bleeding in the context of several positive home pregnancy tests. Her last menstrual period (LMP) was at the beginning of August 2012, prior to this her menstrual cycle was reported as regular with 3 days bleeding every 21 days. In the five week period before admission Miss X had increasingly worse vaginal bleeding with the appearance of clots. She was admitted for observation and conservative management of a suspected incomplete miscarriage.At the time of admission she also reported mild left iliac fossa pain. She denied systemic symptoms other than ‘feeling tired recently’. There were no gastrointestinal symptoms but she described being aware of ‘pressure’ when passing urine. Her last cervical smear in 2011 was ‘normal’.

Miss X gave birth to a 4167gram male infant at term in October 1989 by Caesarean section because of failure to progress. In February 2011 she gave birth to a 3884gram male infant by elective Caesarean section at term. In the post natal period of her second pregnancy she required evacuation of retained products of conception. Both pregnancies were otherwise uncomplicated.

She has a past medical history of post-natal depression following the birth of her second son in 2011. There was no other medical history of note. Miss X is currently taking 20mg sertraline once daily for depression and 5mg diazepam as required for anxiety. She has no drug allergies.

There is no relevant family history. She lives with her partner and two sons and is currently not working as she is supporting her mother who is awaiting a liver transplant. Miss X smokes 15 cigarettes a day and her alcohol intake is minimal. Systemic enquiry was unremarkable.

On examination the patient was haemodynamically stable and general observations were satisfactory. Cardiovascular, respiratory and gastrointestinal examinations were unremarkable. PV speculum examination revealed the presence of blood in the vault but no clots or tissue products present. The cervical os was closed although leakage of blood was observed. There was no cervical excitation and no adnexal masses palpated.

On the first day of Miss X’s admission her PV bleeding continued although she remained apyrexial and haemodynamically stable. She had no further abdominal or pelvic discomfort. Blood results revealed an elevated βhCG (25918 IU/L),whilst full blood count, U+Es, LFTs and inflammatory markers were normal. An ultrasound scan revealed no obvious pregnancy but noted a mass consistent in appearance with invasive mole.

In view of the results of the ultrasound scan, histopathology was carried out on tissue passed PV by the patient. Unfortunately this did not aid diagnosis so a pipelle biopsy was carried out on her second day of admission which was also unremarkable.

An MRI scan on her third day of admission was strongly suggestive of an invasive mole confined to the uterus. This scan was also interpreted as excluding the possibility of a Caesarean scar ectopic pregnancy. The patient was transferred to Charing Cross Hospital in London for further management of invasive mole in view of the imaging results and persistently elevated βhCG levels.

Discussion

Gestational trophoblastic disease (GTD) is a term used to describe a spectrum of disease processes that originate from the placenta. These interrelated disorders occur when trophoblastic cells from the outside of the blastocyst, which normally invade the endometrium to form the placenta, proliferate in an uncontrolled manner. GTDcan be premalignant, where the proliferation is localised and non-invasive, or malignant1,2. A pre-malignant tumour is called a hydatidiform mole, which is subcategorized based on its genetic composition and histopathological features into either a complete or partial mole. There are three types of malignant GTD which are collectively referred to as gestational trophoblastic neoplasia (GTN); an invasive molewhich arises from a complete or partial hydatidiform mole that invades locally into the myometrium, a choriocarcinomawhere there are metastases and a very rare placental site trophoblastic tumour1,2. The patient in this case was found to have an invasive mole.

GTD is not common in the United Kingdom with an incidence of 1/714 live births. The risk of development of gestational trophoblastic neoplasia is 1/50 000 after a live birth3. The incidence of GTD is increased two fold in the Asian population and is also increased in the reproductive age extremes2. The Royal College of Obstetricians and Gynaecologists estimates that a Consultant in O&G may only have one new patient with a molar pregnancy every two years. A registration and treatment process has been developed for GTD patients in the UK and this has been associated with high cure rates (98-100%) and low chemotherapy rates (5-8%)3. Treatment centres in the UK are located in Sheffield and London and there is a Hydatidiform mole follow-up centre in Ninewells Hospital, Dundee. Following the diagnosis of an invasive mole, Miss X was transferred from Dundee to Charing Cross Hospital in London for treatment.

Patients withcomplete hydatidiform moles often present with heavy vaginal bleeding at 6-12 weeks gestation. Other clinical features include excessive uterine enlargement, hyperemesis, early failed pregnancy, pregnancy induced hypertension and abnormally high beta hCG levels for gestational date2,3. Partial hydatidiform moles also present with vaginal bleeding but rarely have any of the accompanying clinical features mentioned above. Presentation of gestational trophoblastic neoplasia depends on the extent of disease and the histopathology. Typically an invasive mole or choriocarcinoma presents with irregular bleeding, as in this case, orbleeding following the evacuation of a hydatidiform mole. It may also present with enlargement of the uterus. Rare metastatic spread can present with abdominal pain, melaena, respiratory failure or neurological symptoms such as seizures1,2. Fortunately this patient had no evidence of metastatic spread.

Definitive diagnosis of gestational trophoblastic disease is through histological examination of the tissue obtained following curettage. In this case attempts were made to obtain a tissue diagnosis, however, these were all unsuccessful. Surgical curettage was deemed too high risk as the tumour was visualised as being highly vascular with a concomitant risk of significant haemorrhage. Furthermore, Miss X was keen to avoid hysterectomy which may have been the only effective way of controlling such a haemorrhage.

Serum βhCG level is measured as βhCG is released from the trophoblastic cells and is present in both the patient’s blood and urine. The level of βhCG can aid in distinguishing between the types of GTD, a complete mole is associated with a βhCG level >100,000 mIU/ml. whereas, a partial mole or placental site trophoblastic tumour have βhCG levelswithin the normal range for pregnancy. βhCG concentrationis also useful in management of GTD as it gives an insight into the effectiveness of treatment and possiblerecurrence of the disease1.

Ultrasound scanning is the most common imaging modality used in the diagnosis of GTD. Hydatidiform moles are often described as an area of mixed echogenicity replacing the placentawhen there is no foetus present. It can also be used to determine if the mole is invading the surrounding tissue. Pelvic and vaginal metastases may be excluded by a pelvic examination1. Other imaging modalities such as chest x-ray, magnetic resonance imaging and computerised tomography scanning prove useful in the investigation of possible metastatic disease. In this case diagnosis was entirely based on imaging as ultrasound and MRI proved invaluable in the detection of the invasive mole.Although the location of the mass and the timing of the pregnancy would fit well with a Caesarean Scar ectopic, the features on the MRI were more in keeping with an invasive mole.

The optimum treatment for both complete and partial hydatidiform moles is surgical evacuation. This is carried out irrespective of uterine size and has the desirable ability of persevering the patient’s fertility. Intramuscular Anti-D is given to rhesus negative patients prior to the procedure as the trophoblastic tissue expresses rhesus D factor. Hysterectomy is not commonly indicated unless the patient does not want to preserve her fertility or has a life-threatening haemorrhage2,3. The patient’s βhCG levels are monitored following removal of the mole and in some cases additional chemotherapy is required. It is important that patients are followed up at a trophoblastic screening centre. If the serum hCG level has returned to normal within 56 days of the pregnancy, follow up is for 6 months from the date of evacuation. If hCG has not returned to normal within 56 days of the pregnancy, then follow up is for 6 months from the normalisation of the hCG level3.

Gestational trophoblastic neoplasia can be treated with either single or multi-agent chemotherapy. Treatment decisions are based on the FIGO Scoring System3 shown in the table below. The scoring system predicts the risk of development of drug resistance to single agent chemotherapy and, therefore, indicates the most suitable therapeutic agent(s).

FIGO Scoring System3

FIGO Scoring / 0 / 1 / 2 / 4
Age (years) / <40 / 40, >40 / - / -
Antecedent pregnancy / Mole / Abortion / Term
Interval months from end of index pregnancy to treatment / <4 / 4-<7 / 7-<13 / 13,>13
Pretreatment serum hCG (IU/L) / <103 / 103-<104 / 104-<105 / 105, >105
Largest tumour size, inc. uterus (cm) / <3 / 3-<5 / 5,>5 / -
Site of metastases / Lung / Spleen, kidney / Gastro-intestinal / Liver, brain
No. of metastases / - / 1-4 / 5-8 / >8
Previous failed chemotherapy / - / - / Single drug / 2 or more drugs

The components of the patient’s FIGO score are highlighted in yellow and combine to give a score of five.

Patients with a score of less than six are considered to be ‘low risk’ and are treated with monochemotherapy using either methotrexate or dactinomycin. The methotrexate regimen is as follows, 50mg intramuscular methotrexate every 48 hours for four doses with rescue folinic acid 15mg orally 30 hours after the methotrexate. Typically the patient receives methotrexate on alternating days with the folinic acid for one week, this is followed by six treatment free or ‘rest’ days. As dactinomycin is associated with hair loss, the methotrexate regimen is the most widely used within the UK. Patients can be treated at home after a short hospital stay to monitor any bleeding2,3. In patients who develop resistance to methotrexate with folinic acid rescue, their serum hCG concentration determines further management. If a patients hCG is 100IU/L or less they can be given dactinomycin. However, if the hCG is above 100IU/L they are offered multi-agent chemotherapy, a curative treatment in the majority of patients. Cure rates for patients with a FIGO score of less than six is almost 100%.Treatment is continued until six weeks after hCG levels have returned to within normal rangewhich helps to target any residual tumour cells and reduce the risk of relapse2,3. As the patient’s FIGO score was five she was considered low risk and she is currently being treated with the methotrexate regimen.

Patients with a FIGO score of seven or more are at high risk of developing drug resistance and require multi-agent chemotherapy. Although the majority of high risk patients present late with many metastases the cure rate is 95% for women with a FIGO score of seven or above3. Several different multidrug chemotherapy regimens have been developed. The EMA-CO regimen is used in the UK and worldwide, it is effective and has manageable short term toxic effects. The treatment causes reversible hair loss and is myelosuppressive but this effect can be reduced with filgrastim which boosts the patient’s neutrophil count2. The EMA-CO regimen constists of etoposide, methotrexate and dactinomycin (EMA) which alternates every week with vincristine and cyclophosamide (CO)2. Treatment is continued until six weeks after the normalisation of hCG levels, as in low risk disease3.

Words: 1922

References

1. Lurain J. Gestational trophoblastic disease I: epidemiology, pathology, clinical presentation and diagnosis of gestational trophoblastic disease and management of hydatidiform mole. The American Journal of Obstetrics and Gynaecology. 2010;203(6): 531-9

1. Seckl MJ, Sebire NJ, Berkowitz RS.Gestational trophoblastic disease. Lancet. 2010; 376: 717-29

1. Green Top Guideline No. 38. The Management of gestational trophoblastic disease. The Royal College of Obstetricians and Gynaecologists. February 2010.

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