Our study encompassed 13 patients treated at the Peking Union Medical College Hospital (PUMCH) as well as 27 who were reported in the literature as having been diagnosed with primary cervical GTN. The uterine cervix is evidently an extremely rare location for the development of GTNs, the clinical presentations of which are nonspecific. Unlike most patients with GTN that can be diagnosed clinically and achieved CR by chemotherapy alone, the definitive diagnoses of primary cervical GTN were primarily made based on pathological examinations, while most patients underwent hysterectomy for uncontrolled bleeding or chemoresistant lesions. These findings highlight the importance of surgery both in the diagnosis of primary cervical GTN as well as in the treatment approach.
The pathogenesis of cervical GTN remains unclear. It may develop from a cervical metastasis arising from a primary tumor in the corpus that later spontaneously regresses; alternatively, it may constitute the malignant transformation of a cervically implanted fetus or else arise from chorionic cells from a preceding pregnancy that migrate to the site and undergo malignant transformation after a period of dormancy [4].
GTNs are solid tumors that can be diagnosed without histological evidence if patients present with typical clinical, laboratory, and radiographic features [24]; however, our retrospective study and literature review showed that patients with GTNs located in the uterine cervix had no specific clinical features. The majority of patients with this condition seek advice from physicians because of irregular vaginal bleeding, the rates of which among our patients and those identified in our literature review were 92.3% and 92.6%, respectively; these rates are higher than that associated with post-term choriocarcinoma (74%) [25]. Moreover, the incidence of uncontrolled massive vaginal bleeding was markedly high owing to the anatomical position of the lesion. Although cervical carcinoma, cervical myoma, and pregnancy-associated disorders may be more common manifestations of cervical masses associated with vaginal bleeding, significantly elevated serum β-HCG levels should alert clinicians to the possibility of a cervical GTN. Hence, given its importance as a marker, β-hCG should be monitored stringently.
Transvaginal color Doppler ultrasonography is essential for the early diagnosis of cervical GTN because it allows for the detection of hypervascularity (with diastolic blood flow) in tumoral vessels that arise owing to angiogenesis and neovascularization [12]. The typical vasculature has a turbulent appearance with color distortion, high velocity, and a low resistance index [26]; in comparison, a typical cervical pregnancy consists of a gestational sac in the mass. However, some advanced cervical cancers with hypervascularity are difficult to differentiate from GTN on ultrasonographic images, necessitating magnetic resonance imaging (MRI) to derive essential information regarding location, parametrial extension, and blood supply. On both T1-and T2-weighted images, abundant GTN vascularization exhibiting tortuous flow can be observed in various spaces. Hemorrhagic lesions appearing as areas of slightly higher signal intensity than the adjacent myometrium on T1-weighted images can best be observed using dynamic contrast-enhanced MRI (Fig. 2). Moreover, chest radiography and computed tomography may provide evidence of any pulmonary metastases.
While profuse bleeding may occur after biopsy, a histological diagnosis is important and may be lifesaving for patients with any of the aforementioned conditions. For those with cervical lesions that do not exhibit the typical manifestations described above, pathological examination should be considered for a definitive diagnosis. Notably, four patients in our literature review were misdiagnosed with cervical squamous cell carcinoma based on the original pathology, resulting in inappropriate treatment [3, 10, 17, 20]. Two of them were definitively diagnosed following cervical conization; the third after undergoing radical hysterectomy, bilateral salpingo-oophorectomy, and bilateral pelvic-paraaortic lymph node dissection; and the fourth following hysterectomy. The difficulty experienced by pathologists in distinguishing cervical squamous cell carcinoma (particularly the poorly differentiated type) from choriocarcinoma has been well described [3, 10, 17, 20]. Measuring serum β-hCG levels and reviewing pathologic slides subjected to immunocytochemistry are helpful for achieving the correct diagnosis, as evident in our findings.
Surgery for GTN excision can be very dangerous if bleeding is not controlled, especially considering the extremely high vascularization of these lesions. Uterine artery embolization is safe and effective for stopping excessive vaginal bleeding; this reduces the risk of hemorrhage before surgery and allows for successful conservative management using chemotherapy alone, thereby preserving fertility [11, 13]. Since successful pregnancies have been reported after uterine artery embolization in patients with GTN, such a procedure may be a safe and highly effective alternative in patients with cervical GTN, and ought to be the treatment of choice for women who wish to preserve their fertility. Hysterectomy may be considered in patients with uncontrolled uterine bleeding and in those who have no plans to become pregnant in the future [24].
Chemotherapy is considered as the primary treatment for GTNs, including in patients with distant metastases, and most patients could achieve CR by chemotherapy alone. A high risk FIGO score (> 6) and a clinicopathological diagnosis of choriocarcinoma are both associated with an increased risk of resistance to single-agent chemotherapy [24]; hence, multi-agent chemotherapy regimens are recommended for these patients. Only three patients in our literature review did not receive chemotherapy; their initial serum β-hCG levels were only 13–20 mlU/mL, and pathological examination revealed PSTT and ETT in two of them, respectively. Although surgery is considered less critical for the management of GTN, certain invasive procedures may be necessary to remove chemoresistant lesions in the uterus and metastatic sites as well as to control associated complications, especially for patients with PSTT and ETT. Hysterectomy was the initial treatment in 15.4% and 29.6% of patients in our retrospective study and among those we reviewed in the literature, respectively, and as many as 81.8% and 65%, respectively, underwent this surgical procedure during chemotherapy owing to the presence of chemoresistant lesions in the remaining patient. The high rate of surgery may be attributable to the large tumor size, which makes it difficult for the necrotic tissue to be absorbed; consequently, healing in this area may be relatively slow.
All patients in our retrospective study and literature review achieved CR following treatment. In all, 23 patients with cervical GTN underwent a prognostic analysis, among whom three relapsed 4–6 months after their last chemotherapy session. The recurrence rate was 13%, which was higher than that in a review of 1827 patients with GTN who achieved CR at our center, 118 (6.5%) of whom experienced recurrence during follow-up [27]. Notably, two of the three patients who relapsed in the study had not undergone hysterectomy, with the site of recurrence being the cervix. Thus, oncological safety should be considered when preserving fertility, especially in patients with a large tumor size.
One of the limitations of our study was its retrospective and observational nature; as such, the data were not randomized. Another limitation was that the sample sizes in both our study and in the literature were small; several patients were not included because they were reported in Japanese and other languages. Although a wider search was conducted for the years before 1980, chemotherapy was not widely used at that time and some patients died because they did not receive appropriate treatment. Longer-term follow-up periods are required to confirm our results.