Non-gestational uterine choriocarcinoma inside a leiomyoma: importance of early suspicion in prognosis

Abstract

Uterine choriocarcinoma is a trophoblastic neoplasm most commonly related to pregnancy. However, there are already cases of non-gestational uterine choriocarcinoma (NGC) described in literature. The difficult diagnosis may delay treatment and threaten patient survival. We report the case of a 37-year-old patient presenting with abnormal haemorrhage and moderate levels of beta-human chorionic gonadotropin (β-hCG). As imaging exams did not show any suspicious site for the origin, choriocarcinoma was not considered so the treatment was delayed. Anatomopathological diagnosis was given both from the surgical sample of hysterectomy and from a skin lesion. The lesion was discovered inside a myoma. At this point, β-hCG levels were substantially high and she presented with respiratory distress due to pulmonary metastasis. The patient was transferred to an intensive care unit and underwent mechanical ventilation as well as life-saving chemotherapy. At 10 months after diagnosis, she is well and in remission. The delay from not suspecting the diagnosis was almost fatal for the patient.

Background

Choriocarcinoma is a rare and highly malignant neoplasm composed of biphasic cellular components with mononuclear cytotrophoblasts and multinucleated syncytiotrophoblasts.¹ Choriocarcinoma can be classified as gestational or non-gestational according to its pathogenic origin.² Gestational choriocarcinoma occurs in association with any type of gestational event as pregnancy, miscarriage, ectopic pregnancy or hydatidiform moles.² In contrast, non-gestational uterine choriocarcinoma (NGC) usually develops from germ cells or due to dedifferentiation of somatic carcinomas.³ These two subtypes have different aetiologies, biological activities and, probably the most relevant, prognosis.³ It is known that NGC accounts for approximately 0.6% of all ovarian tumours; NGC of the uterus is even rarer.⁴ Due to its rarity, symptoms are often non-specific and can range from abnormal uterine bleeding, abdominal pain or endocrine disorders.⁵

Case presentation

A 37-year-old woman presented at the emergency room (ER) complaining of abnormal uterine bleeding. She had a history of amenorrhoea for 2.5 months and had her last full-term uneventful pregnancy 3 years earlier.

As prior pathological background, she reported T-cell lymphoma 10 years earlier treated with chemotherapy and radiation (thoracic). Her urine pregnancy test was positive, but there was no sign of obvious intrautering or extrauterine pregnancy during the ultrasound exam. The only abnormal finding was a small intramural leiomyoma measuring 18 mm. Beta-human chorionic gonadotropin (β-hCG) levels were obtained, with a result of 370 IU/L. In intrauterine pregnancies, serum β-hCG levels tend to duplicate every 48 hours. Elevations lower than that are suggestive of ectopic pregnancy. She was discharged and instructed to return 1 week later for re-evaluation. The ultrasound remained with no signs of gestational sac, and the β-hCG level was at 536 IU/L. After 7 days, the β-hCG level was still rising (700 IU/L). The elevation was not suggestive of intrauterine pregnancy, and the team suspected it could be an ectopic pregnancy, so methotrexate was administered. Initially, she showed a favourable progression of values with a reduction to 531 IU/L but a rapid rise to 672 IU/L, so she was given another dose of methotrexate, which is protocol in extrauterine pregnancies. There was no evidence of trophoblastic tissue on scan. She again showed an initial decrease in β-hCG values with a new rise to 970 IU/L, so the team decided to do an endometrial biopsy along with dilation and curettage, as well as a diagnostic laparoscopy to detect any gestational tissue that could not be seen on ultrasound. The histology results did not reveal any evidence of trophoblastic tissue, and the laparoscopy was negative for ectopic pregnancy.

Investigations

Due to the sustained progression of ever-increasing β-hCG levels (970 IU/L→4100 IU/L→10 000 IU/L) without evidence of any trophoblastic tissue, she underwent additional diagnostic tests: (1) CT of the brain that showed no signs of lesions; (2) thoracic CT that showed three small lesions in the superior right lobe of 8 mm; (3) MRI of the brain, negative for lesions; (4) pelvic and abdominal MRI that showed an intramural lesion in relation with leiomyoma with a size of 30 mm; and a (5) positron emission tomography (PET)–CT that showed the same pulmonary lesions stated in the thoracic CT, in probable relation with radiation sequels. Serum carbohydrate antigen 125 and α-fetoprotein levels were within normal range. The patient did not report any more episodes of abnormal uterine bleeding after the first event.

At this point, she is referred to our institution (oncological centre), 3 months after her first ER evaluation, presenting a β-hCG level of 31 000 IU/L and a pelvic ultrasound that still showed no signs of gestational sac and a larger leiomyoma than previously reported (40 mm), but with no abnormal vascularisation or other suspected characteristics (figure 1).

Figure 1.

Sonographic image of the leiomyoma.

Differential diagnosis

There are a few other conditions, besides pregnancy-related disorders as well as NGC, that can present with elevation of β-hCG levels. Differential diagnoses could be as follows: lung tumour; urinary tract malignancies (transitional cell carcinoma of the bladder, hypernephroma, and renal cell cancer); sarcomas (in particular osteosarcoma); pancreatic carcinoma; or squamous cell carcinoma of the bone.⁶ As it was a young patient who wished to preserve fertility and there was no histological diagnosis that could confirm our suspicion that it was a choriocarcinoma, she preferred to wait to see if there were any other findings in exams that could make her more certain of the decision to accept the hysterectomy. The PET–CT did not show any suspicious lesions besides the small lung nodes, but they were not accessible by bronchoscopy, and it did not seem reasonable to submit the patient to a thoracotomy based on a low-rate probability. This delay was almost fatal.

Treatment

The gynaecological team was of the opinion that a hysterectomy should be performed after oocyte collection to preserve fertility. The patient required time to think about the proposed intervention. She returned 5 days later and presented β-hCG levels of 110 000 IU/L. We reinforced the necessity of short-term surgery due to rapidly rising β-hCG levels. The case was presented in a multidisciplinary team meeting, and oncologists, radiologists and gynaecologists agreed that surgery should be advised in order to obtain a histological diagnosis. She underwent total abdominal hysterectomy with concomitant bilateral salpingectomy. As the ovaries did not show macroscopic alterations suspected of malignant involvement, oophorectomy was not performed. The uterus was slightly enlarged in dimensions but had no macroscopical abnormalities.

On the ninth day after the surgery, she presented at our department reporting the appearance of skin lesions on the trunk, thighs and back. On physical examination, the lesions were suspicious and were biopsied immediately. β-hCG levels were 414 586 IU/L, so we requested a thoracoabdominopelvic CT. While waiting for the scheduling of the exam, the patient presented at the ER (14th day after surgery) complaining of fatigue, fever, anorexia and breathing difficulty. On physical examination, she presented with general malaise with ambient air saturation of 88% and an enlarged liver. Thoracic X-ray showed bilateral extensive infiltration that occupied practically the entire lung parenchyma, suggestive of diffuse pulmonary metastasis (figure 2). Abdominal ultrasound showed evidence of liver lesions, also suspected of metastasis, that did not appear in the previous abdominal MRI.

Figure 2.

Chest X-ray after five cycles of chemotherapy (left) and at the beginning of life-saving chemotherapy (right).

Histopathology of the uterus revealed an enlarged uterus with 10 cm of longitudinal diameter. The uterine body was deformed by an expanse of myomatous-looking nodular formation with 4×3.9×3.5 cm. In its antrum, in the most peripheral portion, two vaguely nodular, infiltrative and extensively haemorrhagic areas were observed. Microscopic description revealed that the myometrium was the site of a voluminous interstitial leiomyomatous lesion, of moderate cellularity, with characteristics of a usual leiomyoma, with areas of dystrophic calcification. In its sinus, in the most peripheral portion, two vaguely nodular, discontinuous, infiltrative areas were observed, the largest extensively haemorrhagic with 3 mm in diameter. Scattered cells with atypical epithelioid morphology, with moderate atypia and mitotic activity, were observed in the smaller nodule, with frequent large multinucleated eosinophilic cytoplasmic cells with marked atypia. Immunohistochemical analysis of these cells revealed positive immunostaining for human placental lactogen (HPL), α-inibin, β-hCG, CAM5.2 and GATA3. The proliferation activity evaluated through Ki-67 was above 90%. The final diagnosis was choriocarcinoma.

Histological examination of the skin lesion revealed, in the dermis thickness, a tumorous lesion, nodular and infiltrative, not larger than 3 mm, and extensively necrotised and haemorrhagic, and within it, they observed epithelioid morphology cells with marked atypia. Immunohistochemical analysis of these cells also revealed positive immunostaining for HPL, α-inibin, β-hCG, CAM5.2 and GATA3. Proliferation index (Ki67) was higher than 90%.

She was admitted and started life-saving chemotherapy with an alternate scheme of etoposide, methotrexate and actynomicin D–cyclophosphamide and vincristine (EMA-CO)). Chemotherapy was commenced on receipt of histological results of both the hysterectomy specimen and the skin lesion. Day 3 after commencing chemotherapy, she developed an Acute Respiratory Distress Syndrome (ARDS) presenting with haemoptysis, tachypnoea (70 cpm) and oxygen saturations of 70%. She was transferred to the intensive care unit and underwent mechanical ventilation, multimodal support and intensive antibiotic regime. As life-saving chemotherapy was the only treatment option, she completed the alternate cycle of CO chemotherapy. She developed stage IV neutropenia, so the third cycle was administered in a lower dose combined with recombinant granulocyte colony-stimulating factor. The patient responded well to all treatments and, after 17 days of in situ intubation, she met conditions to be extubated, returning 3 days later to the oncology board.

Outcome and follow-up

The levels of β-hCG responded favourably to the administered chemotherapy with decreasing values (82 000 IU/L→50 414 IU/L→40 439 IU/L) and partial regression of the pulmonary lesions (figure 3). She was discharged and continued treatments as an outpatient. She underwent a staging CT scan after three cycles of EMA and three cycles of CO that showed partial regression of the pulmonary lesions and maintenance of the liver metastasis, but with smaller dimensions than previously reported. At the time this clinical case was prepared, the patient was undergoing the 11th cycle of chemotherapy and was asymptomatic, with β-hCG values of 8.2 IU/L. Pulmonary lesions at this point were undetected and liver metastasis was smaller than previously reported.

Figure 3.

Graphical evolution of β-hCG levels throughout treatment and surveillance. β-hCG, beta-human chorionic gonadotropin. MTX, methotrexate

Discussion

Gestational choriocarcinoma arises from chorionic cells from a previous pregnancy, either intrauterine, ectopic or molar, and mostly occurs in women of reproductive age, usually over 12 months following a preceding pregnancy.² NGC, however, comes from pluripotent germ cells or from poorly differentiated somatic carcinomas, especially from the central axis of the body, such as pineal gland, mediastinum, oesophagus, jejunum, colon, pancreas, kidney, bladder, breast and others.^{1 2} The most frequent gynaecological spot of NGC is in the ovary, corresponding to 0.6% of all ovarian tumours. The uterine location is even rarer.⁴ It is most often reported in children, men and postmenopausal women, as it is easy to present this diagnosis in a non-fertile woman.³ Although there currently exists a method that allows doctors to distinguish between GC and NGC, DNA testing by short tandem repeat (STR) analysis, this method is expensive and not available in all centres.^7–9 Saito et al in the 1960s described clinical criteria to make the distinction among choriocarcinoma types: (1) absence of disease in the uterine cavity, (2) pathological confirmation of disease, (3) exclusion of molar pregnancy and (4) exclusion of coexistence intrauterine pregnancy suggesting the presence of NGC.¹⁰ In our case, we present a 37-year-old woman, of childbearing age, with a previous term pregnancy 3 years earlier, who had a diagnosis of choriocarcinoma and met all the Saito et al’s criteria for NGC. She underwent both a curettage and evacuation and a diagnosis laparoscopy that did not show any signs of intrauterine or extrauterine pregnancy. She also did not have any other findings in the uterine cavity in the histological examination of the hysterectomy sample that excluded molar pregnancy as well.

Commonly reported symptoms of NGC are lower abdominal pain, atypical genital bleeding, amenorrhoea, nausea and vomiting, symptoms that mimic early pregnancy as they are symptoms, depending on β-hCG levels.⁴ Our patient presented at the ER complaining of amenorrhoea and abnormal genital bleeding, so it fits the most frequent clinical condition, but again, it could easily be mistaken for an intrauterine pregnancy.

Serum β-hCG levels are the most used parameter for both diagnosis and monitoring therapeutic response.¹¹ Although both Gestational Choriocarcinoma (GC) and Non-Gestational Choriocarcinoma (NGC) secrete excess β-hCG, the levels are relatively lower in NGC, especially in the initial stages of the disease, with an exponentially rise associated with metastisation.¹² In our case, the patient initially started with low levels of β-hCG (<1000 IU/L) and remained low until she presented with lung and skin lesions (>100 000 IU/L). The National Comprehensive Cancer Network (NCCN) guidelines, in the case of a choriocarcinoma, recommends imaging staging with chest, abdominal and pelvic CTs, reserving MRI/PET for further evaluation, especially with ovarian masses.⁴ Staging of NGC remains unclear, but the author usually tends to follow the International Federation of Gynaecology and Obstetrics (FIGO) staging classifications for gestational trophoblastic disease.¹³ Initially, our patient did not show any signs of distance lesions, so she could be classified as a stage I on the FIGO classification—disease only in the uterus. The disease rapidly evolved and on admission in the ICU she was classified as stage IV—Gestational Trophoblastic Disease extended to other distance sites. Regarding the FIGO 2000 risk factor scoring system,¹³ she was classified as high risk due to a previous term pregnancy more than 12 months before, having metastatic lesions in the lung and skin, with liver lesions not confirmed, and having more than eight metastatic lesions.

Not only the rapid spread and, consequently, the high staging of NGC is in line with previous literature, but they are especially aggressive as most are classified as FIGO’s high risk. Wang et al reports a series of 19 cases of which only 52.9% were classified as FIGO stage IV, but the majority (78.9%) were high-risk patients.² Shao et al, in the largest report NGC retrospective cohort to data studied 37 NGC patients.³ His work showed metastatic lesions in more than half (56.8%) of the studied population, with the lungs being the most common metastatic location, followed by the brain and liver, which we can also describe in our patient. He did not report any case with cutaneous lesions. In this series, 16/37 patients were in stage IV at the moment of diagnosis, also supporting the highly aggressive nature of this disease.³

Regarding β-hCG levels, as was previously mentioned, the values are usually lower than the ones reported in gestational choriocarcinoma.¹¹ Shao et al refers to an interval between 89 and 386 000 IU/L with median highest level of 77.278 IU/L.³ Others report serum highest levels of 92 202, 76 600, 207 300 and 300 000 IU/L.1 2 4 9 In our case, although initially low and with a tendency to plateau, the values rapidly increased with the highest serum concentration being 414 586 iU/L, slightly higher than previously reported, but in probable relation with the delay in starting the treatments.

GC is the most curable gynaecological neoplasia with an overall survival rate between 82% and 100% even in advanced stage diseases.¹² It is often treated with methotrexate-based chemotherapy, such as the EMA-CO regimen.^{3 4} However, NGCs are extremely rare, and there is a lack of information on therapeutic options. Most authors follow the same guidelines as GC and report a combination of surgery and chemotherapy for majority of patients, and usually two to three cycles of chemotherapy prior to surgery.^1–4 Multidisciplinary team advice was to obtain a histological diagnosis first rather than neoadjuvant chemotherapy.

As aforementioned, according to FIGO, GC can be divided in two groups: low and high risk.¹³ For low-risk patients, single-agent lines of chemotherapy can be administered, but for the high-risk group, they recommend multidrug therapy as gold standard first line, namely, EMA-CO and fluorouracil-based combination regimes.² We started multidrug chemo with EMA-CO and, after an initial myelosuppression, the patient responded well with partial regression of the pulmonary lesions and decreased in the β-hCG levels. She continued chemotherapy cycles until low β-hCG values (8 IU/L) were obtained and the patient was asymptomatic.

Although GC is the most curable gynaecological neoplasia, NGC presents with a lower remission rate. Wang et al in his literature review reported a ‘death of disease’ rate of 23.5% and a recurrence rate of 17.6%.² Only about half of the studied sample (52.9%) was without evidence of disease at 12 months’ follow-up period.² Shao et al, on the other hand, found complete remission rates of about 80%.³ The disparity in these numbers is probably related to the low number of the sample and not to the established therapies, as these were similar in both reviews. The latest, however, are reports of NGC predominantly from the ovaries. When we focus our research on NGC of the uterus, the previous reports showed a mortality rate of 80%.¹ All these patients underwent surgery followed by chemotherapy. The women who died were diagnosed in stage III–IV, and the death of disease occurred in the first 12 months after diagnosis. More frequently, there are reports of choriocarcinoma diagnosis concomitant with another neoplasia such as endometrioid carcinoma, serous carcinoma of the endometrium or malignant mixed mesodermal tumour of the uterus.^14–17 The prognosis of these cases was heavily influenced by the β-hCG levels at time of diagnosis. β-hCG levels of <100 IU/L or undetectable did not present with distant lesions and all patients survived.^14–17 Also, to date, there is only one reported case of an NGC of the uterus in a premenopausal woman.¹ Sano et al described a case of a 46-year-old woman, nulligravida, who presented to the clinic complaining of hypermenorrhoea. β-hCG levels were not measured at this point. She underwent gynaecological examination and was diagnosed with myoma delivery. As she proceeded with vaginal bleeding postmyoma delivery, she underwent abdominal myomectomy and was diagnosed with choriocarcinoma through postoperative pathological examination. As she had no history of previous pregnancies and was abstinent from sexual intercourse for 1 year, the authors suspected that she had NGC. The diagnosis was confirmed by microsatellite DNA polymorphic analysis. β-hCG levels at this point were 207.00 IU/L; CT scans additionally revealed lung metastasis, but head MRI did not reveal brain lesions—FIGO stage III. She underwent total abdominal hysterectomy and bilateral salpingo-oophoretomy, followed by six courses of EMA-CO chemotherapy and had total remission of the disease. The lowest β-hCG level obtained was 492 IU/L. However, new lesions appeared in the lung and the liver, and the therapeutical scheme was switched to etoposide and cisplatin followed by EMA. This second-line therapy neither shrunk the lesions nor decreased β-hCG levels. The patient died 1 year after starting treatments.¹ In fact, the location of the tumour was probably what delayed the procedure the most. As is known, uterine fibroids are quite common. It is the most common tumour in women of reproductive age and most are benign. When they tend towards malignancy, they usually degenerate into sarcomas and are accompanied by suggestive sonographic features such as Doppler hypervascularisation and large growth in short periods of time.¹ Our patient presented with a small intramural myoma but it did not show any signs of malignancy neither in the ultrasound nor at PET–CT. Moreover, although there was a growth in a short period of time, the growth was negligible when we consider that there is an interobserver subjectivity regarding ultrasound examinations. In hindsight, it was a mistake to not consider the fibroid as a potential malignancy site and not have immediately progressed to surgery or chemotherapy, but there was not a high degree of suspicion of the medical team, hence the importance of this case for the community.

Considering our patient, we already have a 10-month follow-up period after the first manifestation and the patient seems to be responding well to all established treatments and, although she was in critical condition, the EMA-CO chemotherapy was life-saving.

The good response to the chemotherapy as well as the patient’s age and the previous pregnancy were the only three factors that could lead the authors to consider GC as the prime diagnosis instead of NGC. However, there are many lines of evidence that there was no gestational tissue in the uterus prior to diagnosis (dilatation and evacuation, diagnostic laparoscopy and histological examination of the uterus). Also, as previously said, the case met all Saito et al’s criteria for NGC. The authors assumed that the lack of confirmation of the diagnosis by DNA testing is a weakness but considerd that there was no room for much doubt.

Regarding histological examination, the cells revealed immunostaining for HPL, α-inibin, β-hCG, CAM5.2 and GATA3 with a high proliferation activity (Ki67) above 90%, consistent with previous reports of high mitogenic rate and presence of HPL and β-hCG.¹ In our case, only malignant cells were found inside the leiomyoma. Sano et al, in his report of a NGC mimicking leiomyoma, also reports normal endometrium and no tumour cells in either ovary.¹

In summary, we experienced a very rare case of a premenopausal woman who was diagnosed with NGC inside a myoma. The importance of the case we report is related to the lack of diagnostic suspicion in both imaging (CT and MRI) and nuclear medicine exams (PET), which did not show any suspicious alteration. In fact, there was a small increase in the size of the intramural myoma, but it did not show lesions on PET-CT, so to hysterectomise a patient with a desire for conception was difficult but, retrospectively, essential. It shows the importance of giving due consideration to a small growth of a myomatous structure when there are no other suspicious lesions and to always consider NGC when a patient presents elevated β-hCG levels.

Patient’s perspective.

As a woman with a desire for a new pregnancy, it was very difficult to accept, without a definitive diagnosis but only a presumption, that the uterus should be removed. That’s why I asked the medical team to delay the surgery until there was more certainty. It was my desire to give a brother to my daughter, and I felt less of a woman and a failure as a mother at the thought of never bleeding again. Also, when I was admitted to the hysterectomy, the doctor told me that it might not be enough to solve my problem. I cried as I’ve never cried before, of fear and sadness. The question mark was still present, but also the fear of death. I remember some things about being in a coma. I remember someone talking to me, saying ‘Stay with us’. The truth is that, in retrospect, both the doctors and I waited too long, to the point of having to fight for my life. As I woke up from the coma, I realised I had to think first for myself, and not to feel guilty about not having a uterus anymore. I know I still have a long way to go and that the question mark still lives within me. Serum hCG levels now command my life, I have no control whatsoever. As I cannot regret, the only thing I have left is to accept it. I’m going to be cured and I’ll be, once again, the mother my daughter needs. I hope that this clinical report can be helpful, so that others in the future don't wait as much as I did, to the point of saying goodbye to my daughter thinking I would never see her again.

Learning points.

• Non-gestational choriocarcinoma is a rare condition but should always be in mind when a patient presents with elevated beta-human chorionic gonadotropin (β-hCG) levels and no sign of pregnancy.

• Leiomyoma may be a rare site for non-gestational uterine choriocarcinoma (NGC).

• Persistent β-hCG values should be treated consequently and immediately in cases of clinically occult primaries of choriocarcinoma, as waiting for a histological diagnosis may be fatal.

• If there is a high index of suspicion, chemotherapy should be administered.

• Although it has a different pathogenesis and prognosis, NGC responds well to the same line of chemotherapy.

Ethics statements

Patient consent for publication

Consent obtained directly from patient(s).