Academic Editor: Michael H. Dahan
Background: The most common clinical types of gestational trophoblastic neoplasia are invasive hydatidiform mole and choriocarcinoma, which can be diagnosed without pathology, and be cured by chemotherapy. Epithelial trophoblastic tumor, a rare type of gestational trophoblastic neoplasia, does not exhibit precise clinical manifestations upon auxiliary examinations. Therefore, since epithelial trophoblastic tumors are prone to misdiagnoses and missed diagnoses, their diagnosis have to be confirmed through pathology and immunohistochemistry. Case: We describe a case of a 37-year-old woman that had been misdiagnosed at a local hospital after she had presented with irregular vaginal bleeding and elevated human chorionic gonadotropin. The initial diagnosis was ectopic pregnancy and she was subjected to left salpingectomy, however, after treatment, there was no significant drop in human chorionic gonadotropin. Later, she was diagnosed with gestational trophoblastic neoplasia and was treated with multiple chemotherapy and hysterectomy. However, after treatment, her human chorionic gonadotropin was found to repeatedly fluctuate. Eventually, pathological examination of a resected lung lesion confirmed the presence of epithelial trophoblastic tumors. Conclusions: Epithelial trophoblastic tumor is an intermediate trophoblastic tumor that is not sensitive to conventional chemotherapy. Surgical resection is the recommended therapeutic option. Gestational trophoblastic neoplasia patients presenting with persistently low levels of human chorionic gonadotropin and resistance to conventional chemotherapy should, therefore, be considered for early surgical resection, or tissue biopsy to pathologically confirm the diagnosis and inform treatment options.
Gestational trophoblastic neoplasia (GTN) is a type of gestational trophoblastic disease that consists of diseases such as invasive hydatidiform mole (IHM), choriocarcinoma (CC), placental site trophoblastic tumor (PSTT) and epithelioid trophoblastic tumor (ETT). Clinically, it is manifested through human chorionic gonadotropin (hCG) elevation. The most common are IHM and CC, which do not require pathology for diagnosis, and are sensitive to chemotherapy, which is the preferred therapeutic option. Rare diseases, such as PSTT and ETT are pathologically diagnosed and respond poorly to chemotherapy, therefore, surgical resection is the preferred therapeutic option. ETT, the most rare form of GTN, was first described in 1998 as originating from chorionic intermediate trophoblasts [1]. It is distinct from PSTT, which originates from placental intermediate trophoblasts. Due to this distinction, ETT became an independently classified pathological type that was subsequently accepted by the World Health Organization in 2003, and entered into the classification system of gynecological tumors. Approximately 1.39–2.00% of all gestational trophoblastic diseases are ETT [2]. Due to its low incidence rates, the clinical features of ETT have not been clearly elucidated, making its diagnosis to be pathology dependent. This enhances the probability of either missing or misdiagnosing ETT as ectopic pregnancy, cervical cancer, etc. In this study, we describe a case of a 37-year-old woman who was initially misdiagnosed with ectopic pregnancy, and later diagnosed with multi-drug resistant GTN. After pathological lung lesion resection, she was eventually diagnosed with ETT.
We describe a case of a 37-year-old woman (gravida 5, para 3)
whose last delivery was a normal vaginal delivery, that occurred in October 2013.
On 10 July 2018, she sought medical intervention from a local hospital,
presenting with irregular vaginal bleeding for half a month as the main
complaint. Her
Even though her
Between 29 September and 23 October, 2018, two courses of chemotherapy
(methotrexate/tetrahydrofolate (MTX/CF)) were administered to
the patient, yielding a significant reduction in
Chest CT scan was performed on 27 November 2012. The area indicated by the arrow was the thick-walled cavity-like lesion of the right lower lobe.
Hysteroscopic biopsy was performed on 30 November 2018, and it did not reveal
any abnormal lesions in the uterine cavity. Even though postoperative pathology
revealed a small piece of decidual tissue, no clear villi and trophoblast
components were found. The
On 9 April 2019 chest CT revealed a nodular and patchy density increase in the
right lower lobe, with unclear borders; and localized thickening of the
surrounding pleura, suggesting that the cavity in the right lower lobe was not
visible, and less lesion than before. On 7 May 2019, the
After multiple chemotherapy, chest CT was re-examined on 24 June 2019. The area indicated by the arrow shows that the lesion of the right lower lobe was significantly reduced and the thick wall disappeared.
On 1 July 2019 she was subjected to thoracic surgery, and right lower lobe
dorsal segment resection was performed under video-assisted thoracoscopic surgery
(VATS). Postoperative pathology revealed a metastatic trophoblastic tumor, which
was considered ETT based on the patient’s history and immunohistochemistry.
Immunohistochemical findings were CK(pan) (+), CK5/6 (individual +), CK7 (+), P63
(+), hCG (partial +), human placental lactogen (hPL) (small amount +), Ki-67
(60%), TTF-1 (-), and Napsin A (-) (Fig. 3).
Hematoxylin and eosin (HE) staining and
immunohistochemistry of the tumor cells. (A) Hematoxylin and eosin (HE) staining
showed that the tumor cells were relatively single in shape and arranged in a
nested arrangement (40
Main treatment and
We used the available information in literature and the characteristics of this patient to describe. Clinical manifestations, auxiliary examinations, pathological diagnosis, and treatment were used to understand the course of the disease.
There is no obvious specificity in the clinical manifestations of ETT. Even though vaginal bleeding and lower abdominal pain are the most common ETT symptoms, cough, hemoptysis, chest pain and other discomforts can also be experienced when lung metastases occur. ETT is prevalent among women of child-bearing age (15–48 years), with a pregnancy history. Its development occurs between 1 and 18 years, from the last pregnancy [3]. Approximately 40% of these lesions occur in the uterine corpus while 31% occur in the uterine cervix [4]. The most common lesions outside of the uterus occur in the lungs, accounting for about 19% [4, 5]. This patient was 37 years old and had had her last pregnancy when she was 33 years old. Her initial symptoms were vaginal bleeding and she later developed symptoms of metastatic sites such as cough, consistent with previous reports in literature.
In urine and serum of both pregnant women and tumors patients a fifteen various
forms of hCG were identified. Upon auxiliary examination, hCG levels in ETT
patients is usually slightly elevated (
Through ultrasound imaging, a retrospective study reported that ETT lesions exhibited clearly bordered hypoechogenic halo, and that there were more doppler blood flow signals around the tumor than within the tumor [8]. Space-occupying lesions, and some calcified lesions that had been previously observed in CT images, are ETT symptoms [9]. Calcifications are usually small, and they are often not typical in CT images. In this case, a thick-walled cavity-like mass was seen on chest CT, without any visible calcifications. The radiology department considered them as infections, since calcifications are usually small in size and are not typical in CT images. Through Magnetic Resonance Imaging (MRI), ETT lesions exhibit a high signal on the T2 weighted image (T2WI) [10], while tumors show a low vascular mass on enhanced MRI [9]. These imaging characteristics have not been systematically evaluated, and therefore, they cannot be used as a reference in clinical practice.
Due to the low prevalence of ETT cases, clinical manifestations and auxiliary examinations of the disease are not clear, therefore, ETT is prone to missed diagnoses and misdiagnoses. For instance, elevated hCG levels, abnormal vaginal bleeding and lung metastatic tumors are also common clinical CC manifestations, and usually before surgery, tubal thickening can be misdiagnosed as ectopic pregnancy [6, 11]. Besides, this patient’s condition had been initially misdiagnosed as an ectopic pregnancy in a local hospital. In addition, since ETT often occurs in the cervix and lower uterus, it is often misdiagnosed as cervical cancer [12]. Therefore, due to the importance of pathology and immunohistochemistry in the diagnosis of ETT, it is necessary to conduct a pathological examination for an accurate diagnosis [13].
Pathologically, ETT lesions are cystic solid or solid nodular masses with a soft texture, clear boundaries, and swollen growth; but less invasive in growth. Moreover, they are dark brown or gray brown and are occasionally accompanied by hemorrhagic and necrotic lesions. Microscopically, the tumors comprise relatively single mononuclear trophoblasts, with eosinophilic or transparent cytoplasms and a mitotic image of about 0–9/10 HPF. Microscopic examinations revealed that tumor cell islands are surrounded by necrotic areas, which appear as map-like or island-like features [5, 14, 15]. Immunohistochemical analyses of epithelial-derived markers such as cytokeratin (CK), epidermal growth factor receptor (EGFR), epithelial membrane antigen (EMA), and epithelial cadherin (E-cadherin), are also helpful in the diagnosis and differential diagnosis of ETT. Furthermore, placental alkaline phosphatase (PLAP) and P63 become positive in the presence of ETT, while hCG and hPL are usually focally positive. The expression of Ki-67, a marker of cell proliferation activity, in ETT is usually higher than 10% [14, 16]. Levels above 50% are correlated with a higher risk of recurrence [17]. Despite PSTT and ETT being intermediate trophoblastic tumors, they can be differentiated on the basis of P63 and hPL expression levels. P63 is negative in PSTT and positive in ETT [16], while hPL is diffusely positive in PSTT and focally positive in ETT [16, 18]. In addition, hCG expression in CC is usually positive, while hPL and P63 are usually negative [16], which are distinguishing features for CC from ETT. Currently, for tumors located in the cervix or lower uterus, P16 is used to differentiate between ETT and cervical cancer. Unlike cervical cancer, P16 is negative in ETT [19] while hCG is negative in cervical cancer. In our case, immunohistochemistry showed that P63 was positive; hCG as well as hPL were both focal positive; while Ki-67 was 60% positive, consistent with ETT characteristics. In addition, a lesion in the lung had to be confirmed to being different from a primary lung tumor. We used thyroid transcription factor (TTF)-1 and Napsin A, which are highly sensitive and specific in the positive expression of primary lung adenocarcinoma, to differentiate the two [20]. However, expressions of TTF-1 and Napsin A in this case were both negative.
Typically, ETT follow normal term pregnancies but can occur after any pregnancy event including molar pregnancy and typically present from months to many years after the antecedent pregnancy. In this case, there was no histological confirmation of either gestation or trophoblastic disease at the fallopian tube or uterus, so we speculate that ETT lesions in the lungs presumably originated from the normal term pregnancy in 2013.
ETT was previously called “multiple nodules of intermediate trophoblasts” and
“atypical CC” because they occurred after intensive chemotherapy for pulmonary
CC metastasis [21]. So it was previously suggested to be associated with
chemotherapy-resistant CC [21]. And Lu et al. [22] reported on 4
patients with CC who underwent surgery after chemotherapy and found that these
tumor cells showed immunohistochemical results similar to ETT. In this case, the
patient also received multiple courses of chemotherapy before lung surgery, so it
should be differentiated from CC. The serum hCG is significantly elevated in CC
patients, usually
Based on the GTN clinical staging issued by the International Federation of
Gynecology and Obstetrics (FIGO) in 2002 [15], the ETT tumor in this case was at
FIGO stage III and is recommended for surgery [23, 24]. However, for patients
with FIGO stage I, hysterectomy is recommended. Since ovarian metastases from ETT
are rare, premenopausal women can retain bilateral ovaries, while for patients
with FIGO II-IV stage, hysterectomy, coupled with extensive removal of metastatic
lesions, is recommended [25]. For postoperative treatment, the National
Comprehensive Cancer Network (NCCN) guideline 2019 [25] recommends classification
based on tumor stage and potential high-risk factors including; tumor cell
mitosis
Since ETT is an intermediate trophoblast tumor, hCG is a less reliable marker for its detection. Therefore, hCG is used as a marker for follow-up monitoring, while imaging is more important for ETT diagnosis [28]. This case is still being followed up, her hCG levels have always been normal, and no recurrent lesions have since been detected on chest CT.
Low incidence rates, lack of clear and specific clinical manifestations as well as very low routine auxiliary examinations of ETT, enhances its clinical misdiagnosis and missed diagnosis. For a more accurate diagnosis, the diagnosis of ETT should be based on a combination of clinical data, pathology, and immunohistochemistry. Therefore, for patients with persistently low hCG levels and who are resistant to conventional chemotherapy, early surgery or tissue biopsy should be considered to confirm the diagnosis by pathological examination and to guide treatment.
GTN, gestational trophoblastic neoplasia; IHM, invasive hydatidiform mole; CC,
choriocarcinoma; PSTT, placental site trophoblastic tumor; ETT, epithelioid
trophoblastic tumor; hCG, human chorionic gonadotropin;
TZ collected the clinical data and drafted the manuscript. JHQ, JY and PY participated in the surgical treatment. WQW completed the pathological examination. JWF and JS reviewed the manuscript. TZ and QHW consulted the relevant literature. All authors contributed to editorial changes in the manuscript. All authors read and approved the final manuscript.
The study participant gave a written informed consent, and this study was ethically approved by the Ethics Committee of the First Affiliated Hospital, ZheJiang University School of Medicine (approval number: 201800536).
Thanks to all the peer reviewers for their opinions and suggestions.
This manuscript was supported by a grant from the Key Program of the Department of Science and Technology of Zhejiang Province, China (No. 2020C03116).
The authors declare no conflict of interest.
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