Life-threatening rupture of interstitial ectopic pregnancy: a rare presentation of metastatic invasive mole

Abstract

An invasive mole is an uncommon type of gestational trophoblastic disease, and if considering its implantation in an interstitial extrauterine location, we are facing a rarer condition.

There are 14 cases described of interstitial ectopic gestational trophoblastic disease. As far as we know, we present the third case of invasive mole within interstitial location, in this case with pulmonary metastases.

The diagnosis of an interstitial implantation is challenging. Our patient was initially diagnosed with an intrauterine hydatidiform molar pregnancy, and a uterine aspiration was performed. Two weeks later, she presented with haemodynamical instability due to a severe haemoperitoneum. A laparotomy was immediately performed and revealed a ruptured interstitial pregnancy with molar vesicle extrusion. Besides its rarity, we highlight the clinical presentation with hypovolaemic shock due to rupture of ectopic pregnancy in a young nulliparous woman, which required an emergent surgical approach with lifesaving purpose while preserving future fertility.

Background

Interstitial ectopic pregnancy corresponds to an implantation of trophoblast in the interstitial portion of the fallopian tube, a tortuous segment with 0.7 mm in diameter and 1–2 cm in length covered by a thin continuous layer of myometrium. This location accounts for 2%–3% of all ectopic pregnancies.¹

Gestational trophoblastic disease (GTD) comprises benign and malignant conditions that develop from abnormal proliferation of trophoblast of the placental tissue. This heterogeneous group encompasses hydatidiform moles and gestational trophoblastic neoplasia (GTN).²

Invasive molar disease and choriocarcinoma are forms of GTN, and their presentation as an interstitial ectopic pregnancy is a very rare occurrence, with an estimated incidence lower than 0.01%.³

In the literature, there are few cases of GTD associated with interstitial ectopic pregnancies. Until October 2022, about 14 cases of interstitial ectopic GTD have been described.^2–14

As far as we know, we present the third case of invasive hydatidiform mole within interstitial location.^{2 3} We highlight in our case the clinical presentation with hypovolaemic shock due to rupture of interstitial ectopic pregnancy and a more advanced stage of GTN, with pulmonary metastases.

In this type of ectopic pregnancies, the surrounding myometrial tissue allows progression of the gestation, and the presentation is often later than in tubal implantation.¹ Therefore, their rupture may result in catastrophic haemorrhage. Although more conservative surgical alternatives are increasingly being used, in case of haemodynamic instability, the cornual resection by laparotomy is lifesaving.¹⁴

An early diagnosis of an interstitial ectopic pregnancy is extremely important to timely management, but the differential diagnosis in these cases is very difficult, which is what we discuss here.

The patient’s consent was obtained. Confidentiality was ensured and no ethical issues were raised.

Case presentation and investigations

A woman in her 20s, gravida 1 para 0, without relevant medical history, no use of contraception and uncertain last menstrual period, presented with nausea, vomiting and mild vaginal bleeding. Her last pregnancy was 2 months ago, an apparently early pregnancy loss with spontaneous resolution.

Speculum examination was without alterations, and no active vaginal bleeding was observed. The uterus had a normal size and transvaginal sonography (TVS) showed an irregular poorly defined endometrium, with a thickness of 34 mm and a uterine cavity filled by blood clots. Her serum β-HCG was 49.728 IU/L and hydatidiform molar pregnancy was suspected. She returned the next day with a negative SARS-CoV-2 PCR test to perform uterine vacuum aspiration. Twenty-four hours later, the β-HCG raised to 58.028 IU/L with normal blood count, coagulation, liver and kidney function tests. A thorax X-ray was performed, without significant alterations. During uterine evacuation, a considerable volume of content was aspirated, with appearance of blood, and no apparent vesicular structures were noted.

The patient was discharged and underwent serial β-HCG follow-up protocol: 48 hours later (51.418 IU/L) and 1 week later (64.296 IU/L). At this last evaluation, the TVS revealed a thin and regular endometrium with a vascularised heterogeneous formation in Doppler colour near the left uterine horn, without adnexal masses. Histopathological result of uterine evacuation revealed hydatidiform mole in scant quantity despite the considerable volume of aspirated material. Because of the extremely rare occurrence, an interstitial ectopic implantation was not assumed at that time, and the patient was discharged with an urgent referral to a gynaecological-oncology appointment for additional investigation and treatment, due to GTD persistence.

Two days later, our patient was admitted with an acute abdomen and haemodynamic instability, with transabdominal ultrasound revealing a severe haemoperitoneum that progressed to hypovolaemic shock. The patient was immediately transferred to the operating room, where concomitant resuscitative measures (crystalloid, tranexamic acid, fibrinogen and red cell concentrate transfusion) and a laparotomy were performed. An ectopic pregnancy with implantation in the interstitial portion of the fallopian tube and molar vesicle extrusion was observed (figure 1).

Figure 1.

Clinical photograph showing rupture of an ectopic pregnancy with implantation in interstitial portion of the fallopian tube and molar vesicle extrusion.

Differential diagnosis

Interstitial pregnancy diagnosis is challenging because of unspecific symptoms and challenging ultrasound appearance, as the implantation in the intrauterine portion of the fallopian tube with invasion of uterine wall may look like an intrauterine pregnancy.

In this case, the clinical course with elevated β-HCG levels raised the hypothesis of GTD, but an ectopic pregnancy in this context is uncommon and an interstitial location is even more unexpected. Based on this, the first hypothesis was an intrauterine hydatidiform mole and only intraoperatively was the interstitial ectopic location revealed. Then, attending to pulmonary metastases, one would need to differentiate between invasive mole and choriocarcinoma. The definitive diagnosis is histopathological, conditioning treatment and prognosis.

Treatment

For the imperative lifesaving purpose of this surgery, with an estimated amount of blood of 1300 mL in abdominal cavity and a potential GTN, a conservative surgical approach was accomplished with successful haemostasis. Based on preserving future fertility, a cornual resection with ipsilateral salpingectomy was performed (figure 2), with possible entry into the uterine cavity (and assumed communication during previous vacuum aspiration).

Figure 2.

Status after left cornual resection with ipsilateral salpingectomy.

Outcome and follow-up

Postoperatively, the patient remained haemodynamically stable, without complications besides a 79 g/L level of haemoglobin that was properly managed. She underwent further investigation, with CT of the chest, abdomen and pelvis, which revealed pulmonary nodules consistent with metastases, but no evidence of intra-abdominal disease. Brain MRI was normal.

Two days after surgery, the β-HCG was 9. 272 IU/L and at day 4, the patient was discharged and maintained a weekly protocol of β-HCG follow-up, with progressive decrease of values (figure 3).

Figure 3.

Time evolution of serum β-HCG levels (IU/L). MTX, methotrexate.

The case was referred to multidisciplinary team management, including gynaecological-oncology, medical oncology and radiology.

Grossly, the cornual resection specimen consisted of two irregular and elastic brown fragments with friable areas, with 1.2 and 3 cm of greatest dimensions, the larger fragment presenting partial serosa lining. The ipsilateral salpingectomy specimen measured 7×0.5 cm and had a normal appearance. Microscopically, the cornual resection specimen revealed the presence of chorionic villi with irregular contours and marked atypical trophoblastic proliferation, non-polar and occasionally radiary, and lymphovascular and uterine wall invasion were observed (figure 4). The proximal part of the fallopian tube, which was in continuity with the intrauterine portion, revealed the same histological findings. The isthmus, ampulla and infundibulum portions did not show alterations. The ectopic implantation in the intrauterine portion of the fallopian tube was confirmed.

Figure 4.

(A) H&E showing extravillous trophoblastic atypical proliferation invading myometrium (+) and blood vessels (*). (B) Smooth muscle actin IHC (immunohistochemistry) marks vessel walls and myometrium brown, highlighting trophoblastic vascular invasion. (C) HCG IHC stains brown the extravillous trophoblastic atypical proliferation.

The final histopathological report revealed a diagnosis of an invasive mole with origin in a complete hydatidiform mole.

According to WHO risk factor scoring with International Federation of Gynecology and Obstetrics (FIGO) staging, this case was classified as low-risk GTN (FIGO stage III: score <7) and the patient started chemotherapy with methotrexate monotherapy. She underwent five cycles of chemotherapy. At the beginning of the fourth cycle, the β-HCG was 4.7 IU/L and in the fifth cycle, it was 1.2 IU/L. One month after completing chemotherapy, β-HCG was negative.

Despite being correctly advised about her clinical condition, the patient adopted irregular intake of a combined contraceptive pill.

Currently, 12 months after the last cycle, the patient maintains β-HCG follow-up and contraception, with no evidence of disease recurrence.

Discussion

Interstitial pregnancy refers to an implantation of a gestational sac in the intramural portion of the fallopian tube. This is considered an extrauterine or ectopic pregnancy, which is defined as an implantation outside the endometrial cavity.¹⁵

GTD associated with interstitial ectopic pregnancy is a rarer situation with an estimated incidence lower than 0.01%.^{3 4}

GTN includes choriocarcinoma, placental site trophoblastic tumour, epithelioid trophoblastic tumour (ETT) and invasive mole. They are entities from the heterogeneous group of GTD with malignant behaviour and capacity for local invasion and metastases.^{16 17}

In our case, we were facing an invasive mole, which is histologically defined by the presence of myometrial and/or lymphovascular invasion by trophoblast cells, always encompassing molar villi or by the presence of metastases containing molar villi, even without myometrial invasion. Although its definition is histological, the diagnosis is often clinical with high levels of β-HCG.^{17 18}

Regarding the suspicion of intrauterine GTD, our patient was initially submitted to a uterine vacuum aspiration with the histological report revealing hydatidiform mole in scant quantity. The molar invasion from initial interstitial location, communicating with the endometrial cavity, is the probable explanation, and that conclusion was supported by the histological result.

Although the ultrasound revealed an empty uterine cavity with a heterogeneous formation at left uterine horn, the interstitial ectopic location was only confirmed intraoperatively. The differential diagnosis from an intrauterine pregnancy and the distinction from an ultrasound image of interstitial implantation with invasion of uterine wall can be difficult. The ultrasound criteria to diagnose an interstitial ectopic pregnancy are the presence of an empty uterine cavity and the visualisation of the gestational sac separated from the lateral edge of the uterine cavity, with a surrounding myometrial layer.¹⁵

In a MEDLINE search, we found a few similar published cases of interstitial ectopic GTD, using the following keywords: “interstitial ectopic”, “molar ectopic”, “ectopic choriocarcinoma” and “cornual ectopic”. This last term is incorrectly used in this case, because cornual ectopic pregnancies are implantations that occur in the horn of uteri with Mullerian abnormalities. However, the designation ‘cornual ectopic pregnancy’ is often inadequately used to describe an interstitial ectopic pregnancy.¹

In the accessible literature, there are 14 cases described (table 1): 6 were molar pregnancies (2 partial moles,^{4 5} 2 invasive moles^{2 3} and 2 unspecified^{6 7}), 6 were choriocarcinoma,^{2 8–12} 1 was ETT¹³ and 1 was unspecified GTN.¹⁴

Table 1.

Prior cases of gestational trophoblastic disease (GTD) associated with interstitial ectopic pregnancy

Type of GTD	Medical history	Clinical presentation β-HCG (IU/L)	Ultrasound	Surgical treatment	Author
Partial mole	LMP: 12 weeks of amenorrhoea	Nausea, vomiting, abdominal pain β-HCG 97.000	Multicystic mass near fundus	Cornual resection by laparotomy	Zite et al4
	G1P0 (nulliparous)	Vaginal bleeding β-HCG 57.739	Multicystic echogenic mass in the lateral wall of the uterus	Laparoscopic cornuostomy	Hwang et al5
Invasive mole	G4P2012 uncertain LMP	Abdominal mild tenderness, vaginal bleeding Haemodynamically stable β-HCG 103.724	Mass arising from the cornua (echogenic internal debris and significant peripheral vascular flow)	Laparoscopic cornual resection and ipsilateral salpingectomy	Toal et al2
	G2P1001 LMP: 7 weeks of amenorrhoea	Abdominal pain Haemodynamically stable β-HCG 27.624	Heterogeneous latero-uterine mass, vascularised	Cornual resection and ipsilateral salpingectomy by laparotomy	Khlifi et al3
Unspecified hydatidiform mole	G6P2002	Nausea, vomiting, abdominal pain β-HCG n/a	n/a	Laparotomy, supracervical hysterectomy	Siegal and Rudolph 6
	G4P3003	Abdominal pain, vaginal bleeding Haemodynamically stable β-HCG 2.905 (postoperative)	Hyperechoic mass in posterolateral uterine wall	Laparotomy, total abdominal hysterectomy	Chauhan et al 7
Choriocarcinoma	G4P2012	Vomiting, abdominal pain Haemodynamically stable β-HCG 23.397	No IUP, large amount of free fluid in peritoneal cavity	Cornual resection by laparotomy	Toal et al2
	LMP: 12 weeks of amenorrhoea	Abdominal pain, vaginal bleeding Haemodynamically stable β-HCG 13.380	No IUP, subserous echogenic mass on left fundus	Cornual resection by laparotomy	Venturini et al8
	G8P2052 (2 ectopic pregnancies)	Failure of medical treatment for a suspected ectopic pregnancy Haemodynamically stable β-HCG 1.900	No IUP, thin endometrium	Laparoscopic cornual resection	Rotas et al9
	G4P3003 LMP: 7 weeks of amenorrhoea	Abdominal pain β-HCG 6.320	No IUP, intramural echogenic mass on the left side of the fundus	Laparoscopic cornual resection Emergency hysterectomy (acute abdomen, persistent GTD)	Meddeb et al10
	G5P2022 LMP: 21 days	Abdominal pain Haemodynamically stable β-HCG 78.465	No IUP, cornual mass with peripheral hypervascularity and subserosal haemorrhage	Total abdominal hysterectomy with bilateral salpingectomy by laparotomy	Han and Kaye11
	G2P0010	Haemodynamically stable β-HCG 2.989	Echogenic hypervascular mass in right fundus	Cornual resection and ipsilateral salpingectomy by laparotomy	Chau et al12
Epithelioid trophoblastic tumour	G2P1001 LMP: 12 weeks of amenorrhoea	Abdominal pain, vaginal bleeding β-HCG 2.764	No IUP, right adnexal mass	Cornual resection by laparotomy	Fang et al13
Unspecified GTN	G2P0010	Abdominal pain Haemodynamically stable β-HCG 58.769	Heterogeneous mass in the cornua, vascularised	Laparoscopic cornuostomy	Chen et al14

GP, gesta para; GTN, gestational trophoblastic neoplasia; IUP, intrauterine pregnancy; LMP, last menstrual period; n/a, not available.

Analysing the two previously described cases of invasive mole with interstitial implantation, the patient’s ages were between 30 and 40 years, both had at least one successful delivery and presented haemodynamically stable, with maximum β-HCG values ranging from 32 685 to 103 724 IU/L.^{2 3} The TVS revealed an empty uterine cavity with a lateral vascularised mass. Laparoscopic surgery, based on suspicion of an ectopic pregnancy, was performed.

Intraoperatively, an unruptured interstitial ectopic pregnancy was found. In one case, a mini-laparotomy conversion was performed to minimise the risk of bleeding.³ In both cases, a cornual resection with unilateral ipsilateral salpingectomy was performed. The disclosure of a GTD, and particularly the diagnosis of invasive mole, were only revealed in histological definitive result.^{2 3} No evidence of metastatic disease was observed in these cases, and this is another distinctive feature of our case, besides the catastrophic clinical presentation in a very young nulliparous patient.

In 3 of the 14 cases of interstitial ectopic GTD described, lung metastases involvement was present, and all these cases corresponded to choriocarcinoma. Although less common, metastatic disease occurs in approximately 15% of invasive moles, mainly to the lungs or vagina.¹⁷ Our case is the first described with pulmonary metastases arising from an invasive mole with interstitial ectopic implantation.

According to WHO risk factor scoring and FIGO staging, our case was classified as low-risk GTN (FIGO stage III: score <7) with an estimated survival of approximately 100% with appropriate treatment. The protocol of follow-up in these cases is monthly measure of β-HCG until 12 months after its normalisation.¹⁸

Regarding future fertility, patients should be reassured that they can have normal future pregnancies. About 1% of subsequent pregnancies will result in a molar pregnancy and this risk increases to 20% after two molar pregnancies have occurred.¹⁸

In subsequent pregnancies, the placenta should be sent for pathology, and the β-HCG should be evaluated at 6 weeks post partum, at which time it should be undetectable.

Patients should be advised to wait at least 1 year after the end of chemotherapy to become pregnant, with hormonal contraception being the contraceptive method of choice.¹⁸

Learning points.

• Gestational trophoblastic disease pregnancy with implantation in an interstitial ectopic location is a very rare situation with an estimated incidence lower than 0.01%.

• An early diagnosis of an interstitial pregnancy diagnosis is extremely important for timely management but challenging because of difficult ultrasound aspects. In particular, implantation in the intrauterine portion of the fallopian tube with invasion of uterine wall makes the ultrasound differentiation from an intrauterine pregnancy very difficult.

• In this type of ectopic pregnancy, the surrounding myometrial tissue allows progression of the gestation, and the presentation is often later than in tubal implantation. Therefore, their rupture may result in catastrophic haemorrhage.

• These situations require an emergent surgical treatment with a lifesaving purpose and besides the potential invasive gestational trophoblastic neoplasia, a conservative approach with preservation of the uterus and contralateral uterine tube must be preferred, regarding future fertility.

• According to WHO risk factor scoring with International Federation of Gynecology and Obstetrics staging, the low-risk gestational trophoblastic neoplasia has an estimated survival of approximately 100% with appropriate treatment based on chemotherapy with methotrexate monotherapy.

Ethics statements

Patient consent for publication

Obtained.