Reduction of pl-CSA through ChSy-2 knockout inhibits tumorigenesis and metastasis of choriocarcinoma in JEG3 cells.

Background: Placental-like chondroitin sulfate A (pl-CSA) is exclusively expressed in cancerous and placental tissues and is highly correlated with the degree of malignancy. However, the mechanism through which pl-CSA regulates tumorigenesis and metastasis in choriocarcinoma remains unclear. Methods: Stable transfectants of the JEG3 choriocarcinoma cell line, including a negative control (NC) line and a cell line with knockout of the biosynthetic enzyme CS synthase-2 (ChSy-2) (ChSy-2-/-), were obtained using CRISPR/Cas9 systems and identified by immunofluorescence, flow cytometry, western blots and enzyme-linked immunosorbent assays (ELISAs). The proliferation, migration, invasion and colony formation of the cells were determined by a cell counting kit, scratch-wound assays, transwell assays and soft agar colony formation assays in vitro, respectively. The tumorigenesis and metastasis of choriocarcinoma were also investigated through two xenograft models in vivo. Results: The ChSy-2 protein in the ChSy-2-/-group was below the detection threshold, which was accompanied a significant reduction in the pl-CSA level. Reducing pl-CSA through ChSy-2 knockout significantly inhibited cell proliferation, migration, invasion and colony formation in vitro and tumorigenesis and metastasis of choriocarcinoma, with deceases in tumor volume and metastatic foci and a high percent survival compared to the NC in vivo. Conclusion: pl-CSA, as a necessary component of JEG-3 cells, was efficiently reduced through ChSy-2 knockout, which significantly inhibited the tumorigenesis and metastasis of choriocarcinoma. ChSy-2/pl-CSA could be alternative targets for tumor therapy.

Demographics, natural history and treatment outcomes of non-molar gestational choriocarcinoma: a UK population study.

OBJECTIVE: To investigate the demographics, natural history and treatment outcomes of non-molar gestational choriocarcinoma. DESIGN: A retrospective national population-based study. SETTING: UK 1995-2015. POPULATION: A total of 234 women with a diagnosis of gestational choriocarcinoma, in the absence of a prior molar pregnancy, managed at the UKs two gestational trophoblast centres in London and Sheffield. METHODS: Retrospective review of the patient's demographic and clinical data. Comparison with contemporary UK birth and pregnancy statistics. MAIN OUTCOMES: Incidence statistics for non-molar choriocarcinoma across the maternal age groups. Cure rates for patients by FIGO prognostic score group. RESULTS: Over the 21-year study period, there were 234 cases of non-molar gestational choriocarcinoma, giving an incidence of 1:66 775 relative to live births and 1:84 226 to viable pregnancies. For women aged under 20, the incidence relative to viable pregnancies was 1:223 494, for ages 30-34, 1:80 227, and for ages 40-45, 1:41 718. Treatment outcomes indicated an overall 94.4% cure rate. Divided by FIGO prognostic groups, the cure rates were low-risk group 100%, high-risk group 96% and ultra-high-risk group 80.5%. CONCLUSIONS: Non-molar gestational choriocarcinoma is a very rare diagnosis with little prior detailed information on the demographics and natural history. The data in this study give age-related incidence data based on a large national population study. The results also demonstrated the widely varying natural history of this rare malignancy and the marked correlation of disease incidence with rising maternal age. TWEETABLE ABSTRACT: National gestational choriocarcinoma database indicates a close association between increasing maternal age and incidence.

Precision genotyping diagnosis of lung tumors with trophoblastic morphology in young women.

Trophoblastic differentiation has been previously described in somatic carcinomas at different primary sites, including the lung. Lung carcinomas with trophoblastic morphology presenting in women during the reproductive years pose a unique diagnostic challenge due to their overlapping microscopical and immunophenotypical features with metastatic choriocarcinoma of gestational origin. Distinction between the two entities is paramount as they require different chemotherapeutic regimens and have a markedly different prognostic outlook. Here we report a series of three female patients (ages 37-48 years) presenting with lung masses. Two of the three patients were noted to have elevated serum beta-hCG levels at the time of their presentation, while serum beta-hCG was not evaluated preoperatively in the third patient. None of them had a clinical history of molar pregnancy or gestational trophoblastic neoplasia. Core biopsies of the lung masses were performed in two patients and one patient underwent a wedge resection, showing poorly differentiated carcinoma in all cases with scattered multinucleated giant cells, hemorrhage, and necrosis. Beta-hCG immunostain was performed in two cases and showed diffuse immunoreactivity. Clinical history and imaging studies were not conclusive in any of the cases to rule out a gestational origin. Short tandem repeat genotyping analysis was performed to compare the allelic patterns between tumor and normal tissues and revealed identical profiles in one case, consistent with somatic origin, and unique paternal alleles in two cases, confirming metastatic gestational choriocarcinoma. The patient with primary somatic lung carcinoma died of disease within 15 months despite chemotherapy, while both patients with gestational choriocarcinoma responded well to chemotherapy and are alive without evidence of disease. Our cases illustrate the diagnostic pitfalls of lung tumors with trophoblastic differentiation in young women. Genotyping analysis offers precise diagnostic distinction between primary lung carcinoma and gestational choriocarcinoma with major therapeutic and prognostic implications for the patients.

Unusual Imaging Findings Associated with Germ Cell Tumors.

Germ cell tumors, because they contain immature and mature elements, can differentiate into different tissue types. They can exhibit unusual imaging features or manifest in a syndromic fashion. The authors describe these features and assign them to one of the following categories: (a) unusual manifestations of metastatic disease (growing teratoma syndrome, choriocarcinoma syndrome, ossified metastases, and gliomatosis peritonei); (b) autoimmune manifestations (sarcoidlike reaction and paraneoplastic syndromes); (c) endocrine syndromes (sex hormone production, struma ovarii, and struma carcinoid); or (d) miscellaneous conditions (ruptured dermoid cyst, squamous cell carcinoma arising from a mature teratoma, Currarino triad, fetus in fetu, pseudo-Meigs syndrome, and pancreatitis). Rare conditions associated with germ cell tumors demonstrate characteristic imaging findings that can help lead to the appropriate diagnosis and management recommendations. When evaluating for potential metastatic disease, alternative benign diagnoses should be considered (eg, growing teratoma syndrome, ossified metastases, ruptured dermoid cyst, gliomatosis peritonei, and sarcoidlike reaction), which may impact management. Germ cell tumors may also lead to life-threatening complications such as extensive hemorrhage from choriocarcinoma metastases or the rupture of mature teratomas, cases in which timely diagnosis is crucial. Autoimmune and endocrine manifestations such as paraneoplastic encephalitis, autoimmune hemolytic anemia, and hyperthyroidism may occur owing to the presence of germ cell tumors and can create a diagnostic dilemma for clinicians. Knowledge of the syndromic and unusual imaging findings associated with germ cell tumors helps guide appropriate management. ©RSNA, 2019.

Metastatic Choriocarcinoma Masquerading as a Congenital Glabellar Hemangioma.

Infantile choriocarcinoma (ICC) is a rare, highly malignant form of gestational trophoblastic neoplasia. Rapid diagnosis and initiation of treatment are paramount in reaching a successful outcome. Patients with these tumors typically present with a triad of anemia, hepatomegaly, and precocious puberty. Cutaneous manifestations of ICC are extraordinarily rare with few documented cases. Here, we describe a male neonate who presented to our Dermatology clinic with a rapidly growing, markedly vascular glabellar mass associated with abnormal laboratory values suggestive of Kasabach-Merritt phenomenon. The initial clinical impression of infantile hemangioma led to an initial treatment with propranolol. However, the mass continued to enlarge and a biopsy was obtained. Histology revealed a high-grade, poorly differentiated carcinoma. A robust immunohistochemical battery demonstrated tumor reactivity with Glut-1, GATA3, Glypican-3, CAM5.2, and ß-hCG establishing the diagnosis of metastatic choriocarcinoma. The diagnosis was further supported by the elevated serum ß-hCG. In addition to the glabellar mass, imaging demonstrated tumor foci in the liver and lung. Clinical investigation of the mother revealed no evidence of disease.

A Rare Case of Gestational Choriocarcinoma Presenting as Cornual Ectopic Pregnancy.

BACKGROUND: Choriocarcinoma associated with cornual pregnancy is extremely rare. To our knowledge, only three other cases have been reported in the literature. CASE: A 38-year-old woman was found to have a left cornual ectopic pregnancy on ultrasound after presenting with abdominal pain, irregular vaginal bleeding, and a positive pregnancy test. Laparoscopy confirmed the diagnosis and she underwent total abdominal hysterectomy. Three weeks later, she presented with vaginal bleeding. A solid ulcerating lesion was found arising from the vaginal wall and biopsy revealed metastatic gestational choriocarcinoma. CONCLUSION: Careful histopathological examination of the surgical specimen and diligent monitoring of ß-human chorionic gonadotropin to zero is crucial to prevent potentially missing this very malignant, but highly curable disease. Early systemic metastases are common and presentation can include bleeding from vaginal metastases.

[A Case of Choriocarcinoma of the Small Intestine with Multiple Lung and Liver Metastases].

A 73-year-old male presented with melena and severe anemia. An esophagogastroduodenoscopy(EGD)and colonoscopy( CS)revealed no source of hemorrhage. Multiple small intestinal tumors were observed on abdominal ultrasound(US). CT also showed mesenteric lymph node metastases and multiple lung and liver metastases. Since active bleeding was suspected, we performed an emergency surgery. The small intestine including 2 tumors and 2 mesenteric lymph node metastases were resected. On histopathological examination, choriocarcinoma was diagnosed. The blood hCG level was remarkably elevated. The primary lesion could not be detected. Chemotherapy containing cisplatin(CDDP)and irinotecan(CPT-11)was initiated; although the blood hCG level was temporally lowered, the patient died of liver failure 8 months after the surgery.

p40 in metastatic pulmonary trophoblastic tumour: potential diagnostic pitfall on histopathology.

p40, one of the two isomers of p63, is nowadays widely used for diagnosis of squamous cell carcinoma, especially in subtyping non-small cell carcinoma on lung biopsies. We describe a case in which lung tumour was misdiagnosed as squamous cell carcinoma due to p40 immunopositivity. A 36-year-old lady presented with cough and left sided chest pain of 2 months duration. Chest imaging revealed a lesion in left lower lobe of the lung and biopsy was suggestive of squamous cell carcinoma. However, past history revealed amputation of great toe for non-healing discharging ulcer which on histopathology was diagnosed as choriocarcinoma. She also had a history of hysterectomy five years ago, details of which were not available. Post-amputation ß-hCG levels were high and she had been treated with multimodality chemotherapy for choriocarcinoma. She had good response to chemotherapy initially, however became resistant later on. Review of the lung biopsy in the light of the past history along with extensive literature review led to the final diagnosis of metastatic trophoblastic tumour to lung. Hence, awareness that p40 immunopositivity can be seen in trophoblastic tumours is essential to avoid misdiagnosis, especially in sites like the lung where squamous cell carcinoma is common.

Clinical characteristics and prognosis of 272 postterm choriocarcinoma patients at Peking Union Medical College Hospital: a retrospective cohort study.

BACKGROUND: The objective of our study was to investigate the clinical characteristics and prognosis of postterm choriocarcinoma patients at Peking Union Medical College Hospital within the past 30 years. METHODS: The clinical characteristics and pertinent follow-up data of 272 patients with postterm choriocarcinoma diagnosed from December 1985 through December 2014 in our hospital were reviewed. The clinical characteristics of two cohorts cut off at 2006 were compared using χ (2) tests. Risk factors of prognosis were estimated by multivariate Cox proportional regression analysis. RESULTS: The most common initial symptom was abnormal uterine bleeding. After individualized treatment 239 patients (87.9 %) achieved complete remission, including 140 patients received initial treatment of 5-fluorouracil-based multidrug chemotherapy. There were almost no statistically significant differences in the clinical characteristics and survival rates between the two cohorts. The results of the multivariate analysis showed that history of resistance to multidrug chemotherapy, liver metastasis and FIGO score greater than 12 were independent risk factors of prognosis. CONCLUSIONS: Postterm choriocarcinoma patients were usually accompanied by several high-risk factors that should received combined chemotherapy to prevent delay in adequate treatment. 5-fluorouracil-based multidrug chemotherapy, which has been applied at PUMCH for several decades, can be an effective initial treatment for postterm choriocarcinoma patients. More emphasis should be placed on those who have history of resistance to multidrug chemotherapy, liver metastasis or a FIGO score greater than 12.

Pegylated Liposomal Doxorubicin Is an Active Agent for Chemotherapy-Resistant Choriocarcinoma: A Report of Two Cases.

BACKGROUND: Despite advances in chemotherapy, radiation, surgery, and supportive treatments, a significant proportion of high-risk metastatic gestational trophoblastic disease patients develop resistant disease and die. Of those cured, protracted treatments can lead to long-term morbidity or later toxicity and death. Here we describe 2 patients with brain metastases who failed multiple lines of standard chemotherapy and radiation but had complete response to pegylated liposomal doxorubicin (PLD). CASE 1: A 35-year-old woman presented with choriocarcinoma in the brain, lungs, and subcutaneous tissues 11 months after full-term delivery. Her FIGO risk score was 14. Over 3 years she was treated with EMA-CO, EMA-CE, Taxol, gemcitabine, brain radiation, and excisional craniotomy for recurrent choriocarcinoma. She showed complete response of choriocarcinoma brain metastases following 2 cycles of PLD. She was choriocarcinoma free until her death 9 months later from acute myelogenous leukemia. CASE 2: A 52-year-old multigravid woman presented with choriocarcinoma 3 years following miscarriage. Her FIGO score was 16. Over 18 months she was treated with EMA-CO, TP/TE and IT MTX, and radiation. Her disease proved resistant and midbrain tumor unresectable. She showed complete response to PLD following 3 cycles but ultimately died from neurologic complications. CONCLUSION: PLD is an active agent in the treatment of high-risk choriocarcinoma.

Testicular choriocarcinoma: a rare variant that requires a unique treatment approach.

Testicular germ cell tumors represent the most common malignancy among young men. While 5-year overall survival and cure for this population is greater than 95%, choriocarcinoma is an aggressive subtype of this disease with far worse prognosis--5-year survival for choriocarcinoma is less than 80%. In order to be able to treat these patients appropriately, a provider must recognize characteristic features of choriocarcinoma including elevated human chorionic gonadotropin in a young man with testicular mass; the astute clinician should also know the signs and symptoms of choriocarcinoma syndrome, characterized by bleeding from metastatic sites, which represents a medical emergency and is associated with high morbidity and mortality. Treatment should be directed towards a goal of tumor marker normalization, and patients with refractory disease should be considered for advanced therapies and clinical trials. Choriocarcinoma is a unique and aggressive germ cell malignancy, and these patients require early aggressive treatment to improve their chance of survival.

Gestational Trophoblastic Neoplasia Metastasis to the Pituitary: A Case Report.

BACKGROUND: Pituitary metastasis secondary to gestational trophoblastic neoplasia (GTN) is an extremely rare condition that has not been previously reported in the literature. CASE: A 23-year-old female presented with symptoms of amenorrhea for 6 months. She was diagnosed with choriocarcinoma, and chemotherapy was scheduled. Three months after drug withdrawal she complained of headache and visualfield defects. Brain magnetic resonance images showed suprasellar and intrasellar space-occupying lesions. Pituitary metastasis of choriocarcinoma was considered. She received etoposide, methotrexate, actinomycin, etoposide, and cisplatinum multiagent chemotherapy combined with intrathecal methotrexate administration. Complete radiological remission was obtained after cessation of chemotherapy. During the 13-month follow-up period no disease progression or recurrence was noted. CONCLUSION: Pituitary metastasis of GTN is possible and is a curable disease that should be considered in young women with a history of choriocarcinoma who have neurologic symptoms. This metastasis responds well to chemotherapy.

Secondary brain choriocarcinoma: a case report.

Choriocarcinoma metastasizes widely. One in every ten choriocarcinoma that leaves its primary site, metastasizes to the brain. This 27 years old patient presented with symptoms of space occupying lesion that was confirmed by CT-SCAN. There was no history of vaginal bleeding and amenorrhoea was concealed by unmarried patient. Chest X-ray was normal. Tumor was excised after craniotomy. Histology of tumor was that of secondary choriocarcinoma. Patient responded excellently to chemotherapy and was well one year after. We strongly recommend a high index of suspicion of choriocarcinoma in management of brain tumors. ß-HCG assay should be included in investigation of all patients with intracranial tumors irrespective of sex.

Histology of a cerebral hemorrhage: AVM as a seat of a metastatic choriocarcinoma.

INTRODUCTION: There are published cases of cerebral hemorrhage secondary to vascular alterations caused by choriocarcinoma metastases. However, it is extremely rare to find this type of bleeding secondary to an association of such a metastasis with a brain arteriovenous malformation (AVM). CLINICAL CASE: We present the case of a 19-year-old male who came to the Emergency Department complaining of intense headache of abrupt onset. His physical examination revealed a striking increase in size of the right testicle of tumoral origin. Chest X-ray evidenced metastasis to the lungs and a brain CT showed a frontal hemorrhage of probably metastatic origin. The latter eventually progressed to cause the death of the patient. Pathology of the brain hematoma disclosed a choriocarcinoma within the brain AVM nidus. CONCLUSIONS: The case presented is an extremely rare confluence of choriocarcinoma brain metastasis within an AVM. The hemorrhagic onset could have been secondary to bleeding from either of the two histological components of the subjacent mixed pathological lesion.

[Long-term survival and effective treatment of synchronous liver metastases in a case of primary gastric choriocarcinoma by using hepatic arterial infusion chemotherapy, irinotecan, and cisplatin].

A 62-year-old man was admitted to our hospital because of appetite loss. Computed tomography(CT)revealed thickness of the gastric wall, multiple liver tumors, and lung nodes. Upper gastrointestinal endoscopy revealed an easy bleeding type 2 tumor at the gastric antrum. We performed distal gastrectomy to control bleeding from the gastric tumor. Histological findings from the gastric lesion indicated primary gastric choriocarcinoma(PCG). Combination chemotherapy using hepatic arterial infusion chemotherapy for synchronous liver metastases and S-1 was administered for 5 months after the operation. CT revealed that the liver metastases decreased remarkably. On the other hand, lung metastases increased. Irinotecan and cisplatin were administered. Liver metastases did not increase, as observed using imaging studies. The patient died 17 months after the operation for cachexia. PCG is a highly aggressive tumor that is often associated with liver metastasis. It is important to control liver metastasis from PCG.

Hepatic metastasis in gestational trophoblastic neoplasia: patient characteristics, prognostic factors, and outcomes.

OBJECTIVE: To identify patient characteristics, determine prognostic factors, and evaluate outcomes for women with hepatic metastases in gestational trophoblastic neoplasia (GTN). STUDY DESIGN: Seventeen GTN patients with hepatic metastases were treated at our institution between 1962 and 2010. Demographic data, disease characteristics, and survival were all analyzed retrospectively. Fisher's exact test was used to determine significance. RESULTS: The median age was 29 years (range, 16-48), and the antecedent pregnancy was nonmolar in 12 patients (75%) and a hydatidiform mole in 4 patients (25%). Fifteen patients (88%) had metastatic disease outside the liver, including lung (13), brain (5), and other intraabdominal organs (8). Median FIGO score was 14 (range, 12-19). Chemotherapy consisted of single-agent methotrexate or actinomycin D in 2 patients; methotrexate, actinomycin D, cyclophosphamide (MAC) in 4 patients; and etoposide, methotrexate, actinomycin D, cyclophosphamide and vincristine (EMACO) in 11 patients. Complete response rate to chemotherapy was 82% for EMA-CO versus 17% for other types of chemotherapy (p = 0.035). Overall survival was 41% (7/17). CONCLUSION: Survival of patients with GTN and hepatic metastases increased from 17% (1/6) to 55% (6/11) after 1986 when EMA-CO chemotherapy was introduced. Survival was significantly decreased for patients with concomitant intraabdominal or brain metastases (11% vs. 75%, p = 0.015).

Gestational choriocarcinoma metastasis to the extraocular muscle: a case report.

This case report describes a biopsy-proven metastasis of gestational choriocarcinoma to the medial rectus muscle. Patient evaluation and follow up included comprehensive ophthalmologic history and examination, external and fundus photography, immunohistochemistry preparations of the medial rectus muscle specimen, MRI, ultrasound of the abdomen and pelvis, comprehensive blood tests, and CT scans of the chest, abdomen, and pelvis. The tissue specimen was obtained via a medial perilimbal conjunctival peritomy. MRI revealed a mass intrinsic to the right medial rectus muscle. Immunohistochemical staining confirmed gestational choriocarcinoma metastasis in medial rectus muscle biopsy. The patient showed general and orbital improvement following 7 subsequent cycles of chemotherapy. In conclusion, gestational choriocarcinoma may metastasize to the orbit in addition to the previously reported ocular site, the choroid. A chemotherapy regimen of etoposide, methotrexate, actinomycin-D, cyclophosphamide, and vincristine can effectively treat the intraorbital component of the disease.

Pulmonary metastatic gestational choriocarcinoma following an uncomplicated term pregnancy: a case report.

BACKGROUND: Choriocarcinoma is a highly malignant pregnancy-related trophoblastic neoplasm, characterized by early metastasis to the lungs. Therefore, patients may manifest nongynecological symptoms owing to distant metastases. The incidence of choriocarcinoma after a term pregnancy is really rare (1/160,000 pregnancies). CASE PRESENTATION: We report a case of a 20-year-old Iranian woman, gravida 2 para 1 live 1 abortion 1, who was referred to our gynecology department with sudden onset dyspnea and pain in the left hemithorax the day after her labor. The index pregnancy was without any complications. After the initial workup, the elevation of ß-human chorionic gonadotropin (HCG) levels (> 1,000,000) along with the identification of clinical (vaginal lesions) and radiological evidence of distant metastases (bilateral pulmonary nodes) directed us toward pulmonary metastatic choriocarcinoma diagnosis. After the oncology consult, the etoposide, methotrexate, actinomycin D, cyclophosphamide, and vincristine chemotherapy regimen was started for the patient. She responded well to the treatment and is currently continuing her chemotherapy process. CONCLUSION: The prognosis of choriocarcinoma is very good if the treatment is started on time. We suggest that clinicians should consider gestational trophoblastic neoplasia in their differential diagnosis of the post-natal period complications, especially after a term and nonmolar pregnancy.