The Controversy of Hydatidiform Mole Treatment In Women age ≥ 40 year-old

Background: Hydatidiform mole or commonly known as molar pregnancy is one of the gestational trophoblastic disease (GTD) caused by an abnormal trophoblast proliferation. About 50% of gestational trophoblast neoplasm (GTN) arises from molar pregnancy. Higher risk of GTN was found in older patient, especially women age ≥40 years old. Management of hydatidiform mole is often faced come challenges, especially in developing country like Indonesia. Although, suction curettage is the most recommended treatment for the evacuation of molar pregnancy, hysterectomy is considerable for women who have completed childbirth and do not wish to preserve their fertility. Case: Here we present case of 48 years old women with hydatidiform mole. Considering the age of the patient and the completion of her childbearing, we decided to do a laparotomy total abdominal hysterectomy for the evacuation of the mole instead of suction curettage. Turned out that this patient had an invasive mole, one of the types of gestational trophoblastic neoplasia. Conclusion: Although suction curettage is the most frequent technique for molar evacuation, hysterectomy is a reasonable option as primary treatment to be performed in older patients and for those who do not wish to preserve their fertility. The other important points such as socio-economic status, education level, and geographical issues should be considered also on managing older patients with hydatidiform mole in developing countries.


Background
Hydatidiform Mole or commonly known as molar pregnancy is one of the gestational trophoblastic disease caused by an abnormal trophoblast proliferation. 1 It is a rare but important pregnancy-related disease with an incidence of 1,1 to 1,57 in 1000 pregnancies in United States, Australia, New Zealand, and Europe, whereas in South East Asia reached 2 cases per 1000 pregnancies. 2The highest incidence of molar pregnancy was found in women with a previous history of molar pregnancy and those at extreme age. 2,3There is 1.3 fold increase of incidence in teenager (<21 years old) and 10 fold increase in women age ≥40 years old. 3 About 50% of gestational trophoblast neoplasm (GTN) arises from molar pregnancy.Gestational trophoblast neoplasm occurs in 1 per 40.000 pregnancies in Europe and America, and 9,2 per 40.000 pregnancies in South East Asia. 4The treatment option is important in order to evacuate the molar tissue, also to determine the patient's fertility.Suction curettage is the recommended treatment for the evacuation of molar pregnancy. 5--------------------------------------------------------------------------- Another author suggests hysterectomy as treatment for women who have completed childbirth and do not wish to preserve their fertility. 6Management of hydatidiform mole is often faced come challenges, especially in developing country like Indonesia.We present a case of 48 years old woman, G6P2A3, with hydatidiform mole associated with thyrotoxicosis which was treated with total abdominal hysterectomy.

Case Report
A 48 years old woman G6P2A3 on her 11 th week age of gestation presented with a chief complaint of vaginal bleeding accompanied with blood clots since few hours prior to consult.She had a history of abdominal pain, nausea, vomiting, and loss of appetite.She also felt sweaty and palpitations without any provocation.
This patient has a history of chronic uncontrolled hypertension.She only had two times prenatal check-up at a midwife and no ultrasound had done.On physical examination she had tachycardia (112 BPM), high blood pressure (180/110 mmHg), the respiration rate was 18 breaths per minute, and the temperature was 36,5°C.There were no exophthalmos and enlargement of thyroid gland.Cardiovascular examination revealed sinus tachycardia without murmurs or gallop.The abdomen was soft, no tenderness with palpated enlarged uterus as 16 weeks size.
Obstetrics and gynecology examination revealed a normal vulva and vagina.On speculum examination, the vaginal canal seemed smooth, the cervix was also smooth and there was minimal blood from the ostium of cervix, there was no mass seen.From bimanual examination, the uterus was palpated enlarged in size equals to 16 th week of pregnancy and no tenderness or adnexal mass was palpated.
The ultrasonography examination of the uterus showed an enlarged uterus filled with 11x10x6 cm echogenic and anechoic mass with a snow storm appearance; there was no mass on the adnexa or free fluid on the cul de sac (rectouterine pouch); and the bilateral ovarium were normal.
The laboratory examination showed a microcytic hypochromic anemia (Hb 10,8 and normal level of MCV, MCH, MCHC), decreased level of tyrothrophin/TSH (0,007 mIU/mL), also increased level of free T4 (2,51 ng/dL) and beta-human chorionic gonadotropin level (1.534.319mIU/mL).The chest x-ray examination was normal.The echocardiography showed sinus tachycardia.She was diagnosed with hydatidiform mole with thyrotoxicosis.The patient was referred to internal medicine to manage the thyrotoxicosis condition.Considering the age of the patient and the completion of her childbearing as well as the socioeconomic status of this patient, we decided to do a laparotomy total abdominal hysterectomy for the evacuation of the mole instead of doing suction curettage.We noted a mass at the fundal area of the uterus measured 1,5 x 1 cm during the surgery, that changed our initial diagnosis of hydatidiform mole into an invasive mole.Histopathology examination confirmed the diagnosis of invasive mole.The postoperative course was uneventful, patient was discharged on the second day post surgery in good condition and planned to refer to the oncologist for further evaluation and management.

Discussion
Hydatidiform Mole or commonly known as molar pregnancy is one of the gestational trophoblastic disease caused by an abnormal trophoblast proliferation. 1 Gestational trophoblastic disease (GTD) consist of hydatidiform mole (partial, complete) and nonmolar trophoblast neoplasm (invasive mole, choriocarcinoma, placental site trophoblastic tumor, epitheloid trophoblastic tumor). 7ydatidiform mole usually arises from chromosomal abnormalities during fertilization.Complete mole has a diploid chromosome (46,XX), caused by an absent or inactivated maternal chromosome when it was fertilized by paternal chromosome. 7Partial mole have triploid karyotype (69,XXX; 69,XXY; or 69,XYY) which consists of two paternal haploid chromosomes and one maternal haploid chromosome. 7Invasive mole (chorioadenoma destruens) mostly arise from a complete mole, characterized by molar tissue invasion of myometrium. 3tient with hydatidiform mole commonly presents with vaginal bleeding or passing blot clot (molar tissue), hyperemesis, signs of anemia, enlargement of uterus more than the actual gestational age. 8datidiform mole may be associated with thyrotoxicosis caused by an excessive hCG levels. 7Thus, the patient may also experience thyrotoxicosis symptoms such as palpitation, easily sweaty, increased heart rate and blood pressure. 7In molar pregnancy, ß-hCG level can increase beyond the level appropriate to the gestational age. 8ß-hCG level in normal pregnancy does not exceed 60,000 mIU/mL, but in molar pregnancy it exceed 100,000 mIU/ mL or even millions in complete mole. 9om ultrasound examination, complete mole can be seen on second trimester as intrauterine heterogeneous mass ("snowstorm" appearance) without fetal development, and with thecaluthein ovarian cyst. 10Partial mole appear as a placenta that has a thickened multi-cystic lesion and contain fetus. 2,7Whereas invasive mole appear as heterogenous, hyperechoic, solid mass with cystic vascular spaces, located within the myometrium.Another modalities to assess suspected invasive mole are colour Doppler (to asses prominent blood flow signals as angiogenesis and neovascularization) and Doppler velocimetric (low-impedance arterial flow and high velocity). 11The pathological anatomy examination is to confirm the diagnosis of GTD. 7  In this case report, the patient experienced most of hydatidiform mole's symptoms and her ultrasonography examination showed a "snowstorm" appearance, there were no features of invasive mole.She was not examined by colour Doppler or Doppler velocimetry due to limited resources.
There are several options available for the treatment of GTD includes suction curettage, hysterectomy, and chemotherapy. 14According to the Society of Obstetricians and Gynaecologists of Canada (SOGC) Guidelines, suction curettage is the preferred method of mola hydatidosa evacuation regardless of uterine size, especially in patients who desire to preserve fertility. 15,16On the other hand, curettage can increase the risk of uterine perforation (especially when sharp curettage is being used), hemorrhage, and pulmonary emboli.These complications rarely occur in cases where the uterine size is below a 16 week pregnancy. 17A routine repeated evacuation of hydatidiform mole is not warranted, because there were no clear indications and it does not eliminate the risk of gestational trophoblast neoplasm. 16,18][20] Hysterectomy can also be performed in cases which the repair of uterine rupture is not possible or when the hemorrhage threatens the life of the patient.In case of massive hemorrhage, performing hysterectomy may be a lifesaving intervention to the patient. 17,19It is also advisable in older patient especially ≥40 years old women whose risk of developing GTN is increased. 15Because malignant A sequelae are mostly occur in older age groups after molar evacuation (37.5% of patients aged ≥50 years; 27.5% of patients aged 40-49 years; 13.9% of patients aged ≤15 years). 6ysterectomy plays an important role in the management of older patients and lowers risk for malignant sequelae than with suction curettage.Hysterectomy decreases the risk for postmolar GTN to 3.5% compared to 20% risk following suction curettage. 6However, this procedure does not eliminate the possibility of the metastasis to the other organs in case of GTN. 18,19Bahar et al concluded that primary hysterectomy does not worsen the prognosis of GTD and it does not eliminate the need for follow-up. 21The patients still require follow-up with assessment of hCG levels.A careful ß-hCG level monitoring is important to detect persistence of trophoblastic disease as a specific marker secreted by trophoblast cell. 5he measurement can be perform at 48 hours after molar evacuation, then the results were compared with another examination every 1 to 2 weeks until the ß-hCG levels cannot be detected anymore, followed by examination every month for 6 consecutive months.Once the levels of ß-hCG result is confirmed to be in normal level, the patient is allowed to get pregnant. 7,15Pregnancy during this monitoring can be a complicating factor in the interpretation of ß-hCG levels.Therefore, patient should be recommend to use contraception (hormonal or barrier). 14Approximately 50% of gestational trophoblast neoplasm arise from hydatidiform mole.About 15-20% of complete hydatidiform mole cases develops into gestational trophoblastic neoplasms (GTN).Whereas partial hydatidiform moles have a risk of 1-5% to develop into GTN.Risk factors for neoplasm includes ß-hCG levels >100,000 mIU/mL, uterine size larger than gestational age; theca-lutein cysts > 6cm, and older age (≥40 years old). 7,14he treatment for this patient was decided based on some considerations, such as her age (48 years old which increase her risk of malignancy) and her completion of childbearing (hysterectomy considered as surgical sterilization, because she already has two children).The monitoring follow up of ß-hCG levels also can be challenging, because it was cost and time consuming process, especially in developing country where the decision making were influenced by some factors.The contributing factors due to poor follow up in developing countries are low socio-economic status, geographical problems (patient came from remote area with a lack of proper facilities to reach the hospital), and poor literacy level (patient's inability to understand the importance of follow up). 22These acknowledgements lead us to do hysterectomy because it can reduce the risk of malignancy higher than suction curettage.Therefore, we decided to do a laparotomy total abdominal hysterectomy with an incidental finding of mass at fundal of the uterine, which suspected as invasive mole.

Conclusion
Hydatidiform mole is a rare but important pregnancy related condition which can develop into gestational trophoblast neoplasm.An early diagnosis is needed to determine the management plan.The primary management is surgical evacuation followed by ß-hCG levels monitoring.Although suction curettage is the most frequent technique for molar evacuation, hysterectomy is a reasonable option as primary treatment to be performed in older patients and for those who do not wish to preserve their fertility.The other important points such as socio-economic status, education level, and geographical issues should be considered also on managing older patients with hydatidiform mole in developing countries.

Figure 3 :
Figure 3 : A. Transvaginal ultrasound of Invasive mole : ill-defined heterogenous hyerechoic solid lesion with cystic areas seen in myometrium, right fundal region of the uterus, away from myometrium; 12 B. Pelvic ultrasound of complete hydatidiform mole : vesicle pattern of multiple echoes, hypoechoic lesion within placenta (snowstorm appearance)13

Figure 4 :
Figure 4 : A. Colour Doppler showed prominent blood flor within lesion suggestive of neovascularization.B. Pulsed Doppler showed low vascular impedance arterial blood flow 12