Clinical significance of circulating tumor cells in predicting disease progression and chemotherapy resistance in patients with gestational choriocarcinoma.

Gestational choriocarcinoma (GC) is a highly aggressive tumor. In our study, we systematically investigated EpCAM/CD147 expression characteristics in patients with GC and assessed the role of circulating tumor cells (CTCs) in predicting chemotherapy response and disease progression. GC tissues were positive for either epithelial cellular adhesion molecule (EpCAM) or CD147, and all samples exhibited strong human chorionic gonadotropin (HCG) expression. Among all the recruited patients (n = 115), 103 had at least 1 CTC in a 7.5-mL peripheral blood sample, and the percentage of patients with ≥4 CTCs in a particular FIGO stage group increased with a higher FIGO stage (p < 0.001). Furthermore, the pretreatment CTC count was related to tumor size (r = 0.225, p = 0.015) and the number of metastases (r = 0.603, p < 0.001). A progression analysis showed that among the 115 included patients who qualified for further examination, 52 of the 64 patients defined as progressive had ≥4 pretreatment CTCs, while only 7 of the 51 non-progressive patients had ≥4 pretreatment CTCs (p < 0.001). In multivariate analysis, CTCs (≥4) remained the strongest predictor of PFS when other prognostic markers, FIGO score and FIGO stage were included. Moreover, based on the chemotherapy response, patients with ≥4 CTCs were more likely to be resistant to chemotherapy than those with <4 CTCs (P < 0.001). These findings demonstrates the feasibility of CTC detection in cases of GC by adopting EpCAM/CD147 antibodies together as capturing antibodies. The CTC count is a promising indicator in the evaluation of biological activities and the chemotherapy response in GC patients.

[Primary mediastinal choriocarcinoma: A case report and literature review].

Primary mediastinal choriocarcinoma in male is not a very common disease, with nonspecific clinical manifestations. Gynecomastia and testicular atrophy are present in some cases. The levels of serum human chorionic gonadotropin are often significantly increased. Giant lump in the mediastinum and bilateral lungs multiple metastases can be seen on the computed tomography for lung. The diagnosis for it depends on pathological biopsy. Current treatment method is a comprehensive, consisting of chemotherapy, radiotherapy and surgery. This paper reported a case of primary mediastinal choriocarcinoma in male, who were diagnosed and treated in the Second Xiangya Hospital of Central South University. He was admitted for cough and hemoptysis, and finally diagnosed by biopsy. The prognosis is very poor. Therefore, it is important to take physical examination regularly because it can be detected and diagnosed early.

Clinical Characteristics of Gestational Trophoblastic Neoplasia: A 15-Year Hospital-Based Study.

OBJECTIVE: To analyze the clinical profile of invasive mole (IM) and choriocarcinoma (CCA) in the past 15 years in Western China. MATERIALS AND METHODS: A retrospective study was performed on 221 patients with IM and 70 patients with CCA treated in the First Affiliated Hospital of Xi'an Jiaotong University from 1994 to 2009. Patients were assigned into 3 groups by 5 years, and the clinical characteristics were compared among these groups. RESULTS: The incidence was not significantly changed in the past 15 years, whereas the mean age of gestational trophoblastic neoplasia (GTN) was increased significantly, especially for the patients 40 years or older. The symptoms of the patients with GTN did not show significant variation, but the number of patients with CCA without clinical symptoms was increased significantly. The mean values of beta human chorionic gonadotropin in the patients with IM and those with CCA were 459.43 and 661.70 mIu/L, respectively, and the size of uterine lesion was concentrated at 4 cm or less in both the patients with IM and those with CCA, without significant differences. CONCLUSIONS: In the past 15 years, the incidence of GTN was still higher than in other countries from 1994 to 2009, and the mean age of patients with GTN was increased significantly, especially for the patients older than 40 years. Furthermore, patients with no clinical manifestations increased significantly, which should be paid more attention in the future works. Serum level of beta human chorionic gonadotropin and pelvic ultrasonography are still 2 important indexes for diagnosing and monitoring condition of GTN.

A retrospective study to evaluate single agent methotrexate treatment in low risk gestational choriocarcinoma in the United Kingdom.

OBJECTIVE: To determine whether single agent chemotherapy with intramuscular methotrexate 50mg administered on days 1, 3, 5, and 7 and oral folinic acid 15mg administered on days 2, 4, 6, and 8 in 2 weekly cycles (IM MTX/FA) is an effective treatment regimen for patients with low risk gestational choriocarcinoma. METHOD: Electronic databases were searched to identify patients with gestational choriocarcinoma at the Sheffield and Charing Cross supra-regional trophoblastic disease centres from January 2000 to December 2011. Clinical notes of low risk patients with FIGO score 0-6 were retrospectively reviewed to assess treatment outcomes and subsequent relapse. RESULTS: 65 patients were identified with low risk choriocarcinoma. Serum hCG levels normalised in 24 patients without the requirement of chemotherapy (19 with histological confirmation, 4 highly suspicious histology and 1 clinical diagnosis). Of 23 patients with histologically confirmed choriocarcinoma, 8 (35%) had a sustained complete response to IM MTX/FA and did not relapse. Both patients with FIGO score 6, and 1 patient with FIGO stage III metastatic disease developed resistance to IM MTX/FA and required further treatment. Despite the development of drug resistance or relapse all patients were successfully salvaged by subsequent treatments. CONCLUSIONS: Not all patients with low risk choriocarcinoma that have had primary intervention prior to staging, such as surgical resection or uterine evacuation will require chemotherapy, providing hCG levels continue to decline to normal. Low risk (FIGO 0-5) patients should initially receive IM MTX/FA due to its low toxicity, outpatient administration and reasonable efficacy. Patients with FIGO score 6 or FIGO stage III disease should make an informed choice between IM MTX/FA and combination chemotherapy.

Pure Choriocarcinoma of the Ovary in Silver-Russell Syndrome.

Pure ovarian choriocarcinoma is an extremely rare malignancy that can be gestational or non-gestational in origin. Silver-Russell syndrome (SRS) is a rare congenital developmental disorder characterized by pre- and postnatal growth failure, relative macrocephaly, a triangular face, hemihypotrophy, and fifth-finger clinodactyly. We report a rare case of pure ovarian choriocarcinoma occurring in a 19-year-old woman with SRS. Following surgery, multiple chemotherapy courses were effective and she was free of disease at the 10-month follow-up.

Changes in clinical presentation of postterm choriocarcinoma at the New England Trophoblastic Disease Center in recent years.

OBJECTIVE: To review the last 15 year experience of choriocarcinoma following a term gestation at the New England Trophoblastic Disease Center (NETDC) and compare these results to earlier data to determine any changes in the clinical presentation and outcome of this disease. METHODS: Women with postterm choriocarcinoma from 1996 through 2011 followed by the NETDC were identified by diagnosis codes. Twenty charts were identified and reviewed. These data were then compared to published results from the NETDC of 44 women from 1964 to 1996. RESULTS: Time from antecedent pregnancy to diagnosis of choriocarcinoma was significantly longer in the current series, 46.1 vs. 19.7 weeks (p = 0.03). Despite this change, patient outcomes remained comparable, with similar overall mortality rates (13% vs. 10%, p = NS). However, patient presentation was notably different. In the early series, five (11%) infants suffered hydrops or stillbirth, while in the recent series there were no adverse infant outcomes (p = 0.08). Six women in the current series presented in the absence of symptoms suspicious for choriocarcinoma (either by an incidental positive pregnancy test without other symptoms or by placental pathology), compared to one woman in the prior series (30% vs. 2%, p = 0.001). CONCLUSIONS: In recent years postterm choriocarcinoma is being diagnosed or referred later after the antecedent pregnancy at our regional referral center. Recent patients more commonly have no other symptoms than a question of pregnancy and are less likely diagnosed due to the presence of fetal hydrops or stillbirth. Despite later diagnoses, survival with postterm choriocarcinoma continues to be high.

First confirmation by genotyping of transplacental choriocarcinoma transmission.

A mother developed multimetastatic gestational choriocarcinoma 13 months after delivery, and her infant died aged 11 months from the same tumor. The transplacental choriocarcinoma transmission was confirmed by genotyping. Henceforth, we recommend a 2-year maternal human chorionic gonadotropin follow-up after neonatal choriocarcinoma and extensive imaging if the human chorionic gonadotropin rises.

Nonadipose tissue production of leptin: leptin as a novel placenta-derived hormone in humans.

Leptin is a circulating hormone that is expressed abundantly and specifically in the adipose tissue. It is involved in the regulation of energy homeostasis, as well as the neuroendocrine and reproductive systems. Here, we demonstrate production of leptin by nonadipose tissue, namely, placental trophoblasts and amnion cells from uteri of pregnant women. We show that pregnant women secrete a considerable amount of leptin from the placenta into the maternal circulation as compared with nonpregnant obese women. Leptin production was also detected in a cultured human choriocarcinoma cell line, BeWo cells, and was augmented during the course of forskolin-induced differentiation of cytotrophoblasts into syncytiotrophoblasts. Plasma leptin levels were markedly elevated in patients with hydatidiform mole or choriocarcinoma and were reduced after surgical treatment or chemotherapy. Leptin is also produced by primary cultured human amnion cells and is secreted into the amniotic fluid. The present study provides evidence for leptin as a novel placenta-derived hormone in humans and suggests the physiologic and pathophysiologic significance of leptin in normal pregnancy and gestational trophoblastic neoplasms.

Correlation levels of serum placental growth factor and human chorionic gonadotropin in gestational trophoblastic disease patients.

OBJECTIVE: To determine the correlation between serum placental growth factor (PlGF) and human chorionic gonadotropin (hCG) in patients with gestational trophoblastic disease (GTD) and to compare serum levels of PlGF in patients with gestational trophoblastic neoplasia to those of patients with hydatidiform mole. STUDY DESIGN: Blood and urine samples were collected from GTD patients. Blood and urine levels for PlGF were processed and quantitated by enzyme-linked immunosorbent assay in parallel with serum levels for hCG. Correlation levels of serum PlGF and hCG were analyzed. Serum levels of PlGF and hCG were correlated with the clinical manifestations of GTD. RESULTS: The correlation between serum levels of PlGF and hCG was not linear (r = 0.274, p = 0.229). The median PlGF levels in benign and malignant groups were 24.0 and 38.3 pg/mL, respectively (p = 0.014). The median serum hCG levels in benign and malignant groups were 7,335.0 and 9,974.5 mlU/mL, respectively (p = 0.942). The linear correlation between urine and serum levels for PlGF was not detected (r = 0.064). CONCLUSION: Levels of correlation for serum PlGF and hCG in GTD patients were not linear. Median serum levels of PlGF between benign and malignant groups were significantly different. This suggests that there is a higher production of PlGF levels in patients with choriocarcinoma or malignant GTD.

Spontaneous uterine perforation of choriocarcinoma with negative beta-human chorionic gonadotropin after chemotherapy.

OBJECTIVE: To report an extremely rare case of spontaneous uterine perforation of choriocarcinoma with negative beta-human chorionic gonadotropin (ß-hCG) post-chemotherapy. CLINICAL PRESENTATION AND INTERVENTION: We present a 35-year-old choriocarcinoma patient whose serial serum ß-hCG levels following a fifth course of chemotherapy had been within the normal range, but who developed spontaneous uterine perforation with intra-abdominal hemorrhage after eight courses of combined chemotherapy. The patient then underwent an emergency hysterectomy and survived. CONCLUSION: Patients with persistent focus of disease in the uterus might experience uterine perforation even after adequate chemotherapy, and therefore, the follow-up for patients after chemotherapy is very important.

Testicular choriocarcinoma metastatic to skin and multiple organs. Two case reports and review of literature.

Two cases of males with subcutaneous masses as the first clinical sign of testicular choriocarcinoma are reported. The urine and serum human chorionic gonadotropin (hCG) test confirmed high level hCG from male choriocarcinoma. These cases, although very rare, can be a great diagnostic and therapeutic challenge and should be considered in the differential diagnosis of subcutaneous masses occurring in young males.

Severe spontaneous acute tumor lysis syndrome and hypoglycemia in patient with germ cell tumor.

Tumor lysis syndrome has been observed in patients with bulky, treatment-sensitive tumors, in particular hematological malignancies, especially after medical treatment (chemotherapy, corticosteroids, radiation, hormonal agents, and biological response modifiers). Tumor lysis syndrome has been observed also in solid malignancies and it very rarely occurs spontaneously. Tumor lysis syndrome-associated metabolic abnormalities include hyperuricemia, hyperphosphatemia, hyperkalemia, hypocalcemia and uremia. Severe hypoglycemia is another rare metabolic disorder, uncommonly associated with solid malignancies. The case described here is peculiar for the abrupt onset of these two rare conditions in a patient with a metastatic germ cell tumor.

Differences in total human chorionic gonadotropin immunoassay analytical specificity and ability to measure human chorionic gonadotropin in gestational trophoblastic disease and germ cell tumors.

OBJECTIVE: To determine the ability of several radioimmunoassays and commercial two-site immunoassays to detect the first World Health Organization International Reference Reagents (IRRs) for 6 defined human chorionic gonadotropin (hCG) variants and to compare their performance in measuring hCG in sera from patients with gestational trophoblastic disease (GTD) and germ cell tumors (GCTs) of the testis or ovary. STUDY DESIGN: The reactivity of the different assays with the 6 IRRs together with the current fourth International Standard (IS, 75/589) was tested using 5 commercial two-site assays as well as 2 competitive polyclonal radioimmunoassays (RIAs) and a competitive monoclonal immunoassay. Individual samples from 41 patients (19 GCT and 22 GTD) with high circulating levels of hCG (range, 718-6,055,000 IU/L) were diluted and measured using the various immunoassays. RESULTS: The results of 4 GCT patient samples varied markedly among the assays, including 1 sample that was grossly underestimated by 3 of the commercial assays. CONCLUSION: Comparison of each assay's reactivity to the variant isoforms revealed that recognition of the isoforms was highly variable, particularly for hCGbeta and hCGbeta core fragment (hCGbetacf).

Salvage chemotherapy with methotrexate, etoposide and actinomycin D in men with metastatic nonseminomatous germ cell tumors with a choriocarcinoma component: a preliminary report.

The objective of the present study was to assess the use of salvage chemotherapy using methotrexate, etoposide and actinomycin D (MEA) in men with nonseminomatous germ cell tumor (NSGCT) with a choriocarcinoma component. Nine patients were included. They had initially received bleomycin, etoposide and cisplatin, and high-dose ifosfamide, carboplatin and etoposide as induction chemotherapies. However, they failed to achieve the normalization of ß-human chorionic gonadotropin (ß-HCG). Therefore, MEA therapy (methotrexate: 450 mg/body on day 1, actinomycin D: 0.5 mg/body on days 1­5, etoposide: 100 mg/body on days 1­5) was subsequently administered. After MEA therapy (median: 3 cycles), serum ß-HCG was normalized in five of the nine patients. Of these five, three achieved long-term disease-free survival and one died of disease unrelated to NSGCT, whereas the remaining patient developed disease recurrence and died of disease progression. All four patients who failed to achieve the normalization of ß-HCG died of disease progression. Although several severe toxicities greater than grade 3, which were mainly associated with bone marrow suppression, occurred in all patients, there was no treatment-related death. Considering the current outcomes, MEA regimen could be an attractive option as a salvage chemotherapy for metastatic NSGCT patients with a choriocarcinoma component showing resistance to intensive conventional chemotherapies.

[A case of metastatic choriocarcinoma responding to combination chemotherapy with paclitaxel and carboplatin].

A 53-year-old woman with choriocarcinoma (high-risk gestational trophoblastic disease: FIGO score 17) was treated with paclitaxel (175 mg/m(2)) and carboplatin (AUC=5). The patient was treated with an EMA/CO regimen as initial chemotherapy, but she developed EMA/CO-induced interstitial lung disease after the 3rd course of treatment. After high-dose steroid therapy, she received combination chemotherapy with paclitaxel and carboplatin. Her hCG-/b dropped to <0.1 ng/mL after 11 courses of the chemotherapy. A paclitaxel+carboplatin regimen is potentially effective for high-risk GTD, but a more effective combination or schedule with a platinum-taxane regimen should be explored.

Prenatal findings in a case of massive fetomaternal hemorrhage associated with intraplacental choriocarcinoma.

We describe biochemical assessment of maternal circulation in a case of massive fetomaternal hemorrhage at term associated with intraplacental choriocarcinoma. Markedly elevated maternal serum hCG level at 37 weeks of gestation suggested choriocarcinoma as a cause of fetomaternal hemorrhage in this case. Measurement of maternal hCG may be a useful parameter when intraplacental choriocarcinoma is in the differential diagnosis. In addition, the placenta should be examined in all cases of fetomaternal hemorrhage.

A rare case of cutaneous metastasis of postpartum choriocarcinoma.

Gestational trophoblastic disease has been reported to be responsive to chemotherapy, with a 90% cure rate. Several factors place patients at high risk of experiencing treatment failure with single agent chemotherapy. Choriocarcinoma following term pregnancy is very rare and associated with a poor prognosis and a mortality rate of 33-40%. We present a rare case of cutaneous metastasis of choriocarcinoma to the left third digit.

[Choriocarcinoma with pulmonary metastasis: diagnosis and treatment]. / Choriocarcinome avec atteinte pulmonaire: stratégie diagnostique et thérapeutique.

INTRODUCTION: Choriocarcinoma is a rare tumour which results from the anarchic proliferation of a gonadic or extra gonadic germinal cell. CASE REPORT: A 45 year old pre menopausal woman of African origin presented with a persistent cough and deterioration of general status. The chest X-ray revealed a cavitated mass of the right upper lobe. Other lesions were associated (liver, kidney and scalp). Choriocarcinoma, suspected in the presence of an elevated ssHCG without a gravid uterus, was confirmed by biopsy excision of a haemorrhagic cutaneous lesion of the scalp. Despite the poor prognosis methotrexate based chemotherapy resulted in control of the disease and a good remission.

Delayed effects of whole brain radiotherapy in germ cell tumor patients with central nervous system metastases.

PURPOSE: Central nervous system (CNS) metastases are uncommon in patients with germ cell tumors, with an incidence of 2-3%. CNS metastases have been managed with whole brain radiotherapy (WBRT) and concomitant cisplatin-based combination chemotherapy. Our previous study did not observe serious CNS toxicity (Int J Radiat Oncol Biol Phys 1991;22:17-22). We now report on 5 patients who developed delayed significant CNS toxicity. PATIENTS AND METHODS: We observed 5 patients with delayed CNS toxicity. The initial diagnosis was between 1981 and 2003. All patients had poor-risk disease according to the International Germ Cell Consensus Collaborative Group criteria. Of the 5 patients, 3 had CNS metastases at diagnosis and 2 developed relapses with CNS metastases. These 5 patients underwent WBRT to 4,000-5,000 cGy in 18-28 fractions concurrently with cisplatin-based chemotherapy. RESULTS: All 5 patients developed delayed symptoms consistent with progressive multifocal leukoencephalopathy. The symptoms included seizures, hemiparesis, cranial neuropathy, headaches, blindness, dementia, and ataxia. The median time from WBRT to CNS symptoms was 72 months (range, 9-228). Head imaging revealed multiple abnormalities consistent with gliosis and diffuse cerebral atrophy. Of the 5 patients, 3 had progressive and 2 stable symptoms. Treatment with surgery and/or steroids had modest benefit. The progressive multifocal leukoencephalopathy resulted in significant debility in all 5 patients, resulting in death (3 patients), loss of work, steroid-induced morbidity, and recurrent hospitalizations. CONCLUSION: Whole brain radiotherapy is not innocuous in young patients with germ cell tumors and can cause late CNS toxicity.

Intraplacental choriocarcinoma arising in a second trimester placenta with partial hydatidiform mole.

We report a well-documented case of a 28-year-old woman, gravida 3, para 1, undergoing termination at 22 weeks for fetal congenital malformations with concurrent partial hydatidiform mole and choriocarcinoma. A fetal ultrasound showed spina bifida, and an elective termination was performed. One month later, the patient presented with vaginal bleeding, cough, and shortness of breath. A chest computed tomographic scan revealed multiple lung nodules. A pelvic ultrasound was consistent with retained products of conception, and endometrial sampling showed an atypical trophoblastic proliferation consistent with choriocarcinoma. The serum beta-human chorionic gonadotropin level was greater than 100,000 IU/mL. The placental pathology reviewed at our institution showed microscopic foci of choriocarcinoma arising in a partial hydatidiform mole. Flow cytometry performed on paraffin-embedded tissue showed a triploid peak, which confirmed the partial molar nature of this gestation. Immunohistochemistry showed nuclear p57 expression in the partial molar villous trophoblastic and stromal cells, but not in the severely atypical trophoblasts, further supporting the diagnosis of intraplacental choriocarcinoma distinct from the partial mole. Although the molecular pathogenesis remains to be elucidated, this report provides additional evidence that choriocarcinoma may arise directly from partial molar gestations. Moreover, it emphasizes the importance of thorough sampling of placentas with partial hydatidiform mole in search of minute foci of choriocarcinoma because they might represent a potential source of metastatic gestational trophoblastic disease.