Establishment and characterization of a non-gestational choriocarcinoma patient-derived xenograft model.

BACKGROUND: Non-gestational choriocarcinoma (NGC) is a rare subtype of malignant germ cell tumour and there is no consensus on its treatment. The lack of suitable preclinical models for NGC is a challenge in drug discovery research. Patient-derived xenograft (PDX) models recapitulate the tumour microenvironment of the original cancer tissue. Therefore, they have received considerable attention for studies on rare cancer. Here, we aimed to establish a PDX model from a patient with recurrent NGC. METHODS: Fresh NGC tumour tissue was immediately transplanted into a severely immune-deficient mouse (NOD.Cg-Prkdcscid1l2rgtm1Wjl/SzJ) and maintained for more than three in vivo passages. Subsequently, we evaluated the molecular characteristics of the PDX model using immunohistochemistry, polymerase chain reaction, and RNA sequencing. Moreover, the PDX tumours were transplanted into BALB/c nude mice, and we evaluated their sensitivity for cisplatin and methotrexate. RESULTS: The PDX tumour maintained the morphological features of NGC. Moreover, Immunohistochemistry revealed that the human chorionic gonadotropin, cytokeratin 7, and EpCAM expression levels were similar to those in the primary tumour. Furthermore, serum human chorionic gonadotropin levels were elevated in both the primary tumour and the PDX models. Additionally, using PCR analysis with species-specific primers, we confirmed that the PDX tumour contained human genes and was derived from human tissue. Moreover, the gene expression profile of the NGC was compared with that of epithelial ovarian cancer samples and cell lines, and 568 dysregulated genes in the NGC were extracted. The expression of the dysregulated genes in PDX was significantly correlated with that in the primary tumour (R2 = 0.873, P < 0.001). Finally, we demonstrated that the PDX tumour was sensitive to cisplatin and methotrexate; therefore, its clinical response to the agents was similar to that of the primary tumour. CONCLUSIONS: We successfully established a PDX model of NGC, to the best of our knowledge, for the first time. The established PDX retained the molecular and transcriptome characteristics of the primary tumour and can be used to predict drug effects. It may facilitate further research and the development of novel therapeutic agents for NGC.

Coriocarcinoma Ovariano Não Gestacional Misto: Relevância do Diagnóstico Precoce em um Relato de Caso / Mixed Non-Gestational Ovarian Choriocarcinoma: Relevance of Early Diagnosis in a Case Repor / Coriocarcinoma Mixto de Ovario no Gestacional: Relevancia del Diagnóstico Precoz en un Informe de Caso

O coriocarcinoma ovariano não gestacional é uma apresentação rara de câncer de ovário, acometendo principalmente mulheres pré-púberes. É considerada uma neoplasia agressiva, sendo comum a ocorrência de expansão para o pulmão em cerca de 80% dos pacientes, como no caso a seguir. Relato do caso: Sexo feminino, 12 anos de idade, com sangramento vaginal e distensão abdominal prolongados. A tomografia computadorizada mostrou volumosa massa heterogênea predominantemente cística e múltiplos septos grosseiros de permeio. Dosagem do beta-HCG de 49.929,81 mUI/ml. Foi submetida à laparotomia mediana para estadiamento, com anexectomia esquerda mais ressecção do tumor retroperitoneal e do omento, identificando-se estádio IV. O exame histopatológico concluiu ser um tumor de células germinativas do ovário constituído por coriocarcinoma não gestacional. Após alta hospitalar, foi submetida a sessões de quimioterapia. Posteriormente, apresentou em exames de imagem nódulos em ambos os pulmões, além de formações expansivas distribuídas no parênquima hepático. Nesse contexto, foi realizada metastectomia pulmonar meses depois. Após isso, novos exames de imagem foram realizados para o reestadiamento da doença. Foram encontrados alguns nódulos pulmonares residuais e, na ressonância magnética de crânio, sinais de hemorragia crônica. A evolução da paciente não foi favorável, havendo agravamento do estado geral e óbito um ano após o diagnóstico. Conclusão: Compreende-se, desse modo, a agressividade dessa doença, em especial na faixa pediátrica feminina, uma vez que a metástase precoce ocorre em uma porcentagem significativa dos casos, levando a um prognóstico desfavorável

Non-gestational ovarian choriocarcinoma is a rare form of ovarian cancer, mainly affecting prepubertal women. It is considered an aggressive neoplasm and expansion to the lung is common in around 80% of patients, as in the following case. Case report: Female, 12 years old, with prolonged vaginal bleeding and abdominal distension. Computed tomography showed a large heterogeneous mass, predominantly cystic, with multiple coarse septa. The beta HCG level was 49,929.81 mUI/ml. She underwent median laparotomy for staging, with left adnexectomy plus resection of the retroperitoneal tumor and omentum, identifying stage IV. The histopathological examination concluded that it was a germ cell tumor of the ovary consisting of non-gestational choriocarcinoma. After being discharged from hospital, she underwent chemotherapy sessions. Subsequently, imaging showed nodules in both lungs, as well as expansive formations distributed in the liver parenchyma. In this context, pulmonary metastasectomy was performed months later. After this, new imaging tests were carried out to restage the disease and the following findings were seen: some residual pulmonary nodules and on the MRI of the skull, a sign of chronic hemorrhage. The patient's evolution was not favorable, her general condition worsened and she died one year after diagnosis. Conclusion: The aggressiveness of this disease is clear, especially in female pediatric patients, since early metastasis occurs in a significant percentage of cases, leading to an unfavorable prognosis.

El coriocarcinoma ovárico no gestacional es una presentación poco frecuente del cáncer de ovario, que afecta principalmente a mujeres prepúberes. Se considera una neoplasia agresiva y la expansión al pulmón es frecuente en alrededor del 80% de las pacientes, como en el caso siguiente. Informe del caso: Mujer de 12 años con hemorragia vaginal prolongada y distensión abdominal. La tomografía computarizada mostró una gran masa heterogénea, predominantemente quística, con múltiples septos gruesos. El nivel de beta HCG era de 49 929,81 mUI/ml. Se le practicó una laparotomía media para la estadificación, con anexectomía izquierda más resección del tumor retroperitoneal y del epiplón, identificándose un estadio IV. El examen histopatológico concluyó que se trataba de un tumor germinal de ovario consistente en un coriocarcinoma no gestacional. Tras el alta hospitalaria, se sometió a sesiones de quimioterapia. Posteriormente, el diagnóstico por imagen mostró nódulos en ambos pulmones, así como formaciones expansivas distribuidas en el parénquima hepático. En este contexto, meses más tarde se le practicó una metastasectomía pulmonar. Tras ésta, se realizaron nuevas pruebas de imagen para reestadificar la enfermedad y se observaron los siguientes hallazgos: algunos nódulos pulmonares residuales y, en la resonancia magnética del cráneo, una señal de hemorragia crónica. La evolución de la paciente no fue favorable, su estado general empeoró y falleció un año después del diagnóstico.Conclusión: Por lo tanto, es comprensible la agresividad de esta enfermedad, especialmente en las mujeres pediátricas, ya que en un porcentaje significativo de casos se producen metástasis tempranas, lo que conlleva un pronóstico desfavorable

A rare case of gestational ovarian choriocarcinoma coexistent with intrauterine pregnancy.

OBJECTIVE: To report the rare case of gestational primary ovarian choriocarcinoma coexistent with intrauterine pregnancy, successfully treated with surgery and systemic chemotherapy. We also describe the utility of short tandem repeat (STR) genotyping in the diagnosis of choriocarcinoma. CASE REPORT: A 38-year-old woman at 17 gestational weeks presented with an ovarian tumor rupture in the left ovary. Left salpingo-oophorectomy was performed and the patient was diagnosed with gestational ovarian choriocarcinoma via histopathology and STR genotyping. After artificial abortion, the patient underwent 8 cycles of chemotherapy. Abdominal hysterectomy was performed because of the presence of low levels of human chorionic gonadotropin and the tumor that developed behind the uterus. However, no viable choriocarcinoma cells were found in the residual tumor, suggesting that the patient achieved full remission. CONCLUSIONS: Early detection is crucial in treating choriocarcinomas; thus, clinicians should consider the possibility of choriocarcinoma at the presence of an ovarian tumor during pregnancy. Gestational and non-gestational choriocarcinomas differ in prognosis and sensitivity to chemotherapy due to their different etiologies. Therefore, STR genotyping may be beneficial in predicting the patient's prognosis or selecting the appropriate regimen.

Primary non-gestational mediastinal choriocarcinoma metastatic to the brainstem.

Choriocarcinoma is a highly malignant tumour emerging from the syncytiotrophoblast divided into gestational and non-gestational presentations. Primary choriocarcinoma of the mediastinum is rare. Metastases to the brain often occur; however, brainstem involvement has not been reported for non-gestational choriocarcinoma. We described a middle-aged man who developed a complete left oculomotor nerve paralysis secondary to a brainstem tumour at the midbrain. The workup for the primary source of the brainstem tumour included a chest CT scan, which revealed a mediastinal mass. A mediastinal mass needle biopsy confirmed the diagnosis of primary mediastinal choriocarcinoma. Despite aggressive chemotherapy, the patient died 6 months after the initial presentation from neurological complications and multiorgan failure.

Clinical Experience of Male Primary Choriocarcinoma at the Samsung Medical Center.

PURPOSE: The objective of this study was to describe and analyze the clinicopathological features of primary choriocarcinoma (PCC) observed in male patients treated at the Samsung Medical Center between 1996 and 2020. MATERIALS AND METHODS: We reviewed the clinical records of 14 male patients with PCC retrospectively to assess their demographic, histological, and clinical characteristics at the time of diagnosis as well as identify the treatment outcomes. RESULTS: The median age of the patients was 33 years. The primary tumor site was the testicles in seven cases (50%), the mediastinum in six cases (43%), and the brain in one case (7%). The most common metastatic site was the lungs (79%), followed by the brain (43%). All patients with PCC received cytotoxic chemotherapy. Twelve patients had records of their response to cytotoxic chemotherapy; of these 12 patients, eight (8/12, 67%) achieved an objective response, and four (4/12, 33%) achieved stable disease response as the best response during chemotherapy. CONCLUSION: It is known that most male PCC patients eventually develop resistance to cytotoxic chemotherapy and die. Factors such as poor response to chemotherapy, high disease burden, brain metastasis, and hemoptysis at the time of diagnosis are associated with shorter survival time in male PCC patients. Programmed death-1/programmed death-ligand 1 blockade therapy can be a salvage treatment for chemotherapy-resistant male PCC patients.

Primary mediastinal choriocarcinoma presenting as cutaneous metastasis with resistance to chemotherapy: case report and literature review.

Cutaneous metastases of choriocarcinoma are rare. They may indicate poor prognosis and resistance to chemotherapy. In this report, we present a case of a 25-year-old man who presented with central pleuritic chest pain and right upper arm mass for about a week. The patient also had significant weight loss during the last 5 months along with an episode of generalized seizure. Chest computed tomography scan revealed an 8 cm anterior mediastinal mass. A skin punch biopsy from the right upper arm mass revealed a malignant neoplasm with morphology consistent with metastatic choriocarcinoma. Further work-up revealed multiple lung and brain lesions. Ultrasound of the testes revealed no abnormalities. Several chemotherapy regimens were tried; however, there was no response and the disease showed progression. The patient died 6 months after initial presentation.

Successful Treatment of Nongestational Choriocarcinoma in a 15-Year-Old Girl: A Case Report.

BACKGROUND: Nongestational choriocarcinoma is a rare ovarian malignancy with a prognosis worse than that of gestational choriocarcinoma. Debulking surgery is the primary treatment for ovarian carcinoma. However, fertility preservation is important in young women. CASE: A 15-year-old girl with no sexual experience was admitted for abnormal uterine bleeding. Ultrasonography showed a solid mass in the right ovary and her serum ß-human chorionic gonadotrophin levels were markedly elevated. We performed right oophorectomy, omentectomy, and peritoneal washing cytology. The uterus and left adnexa were preserved. She was diagnosed with nongestational choriocarcinoma, stage IIA. She received adjuvant chemotherapy (etoposide, methotrexate, actinomycin, cyclophosphamide, and oncovin regimen) and has been disease-free for more than 5 years. SUMMARY AND CONCLUSION: Fertility-sparing surgery combined with chemotherapy is an acceptable treatment option for young patients with locally advanced nongestational choriocarcinoma.

Extragonadal Non-gestational Choriocarcinoma with Tonsillar Presentation.

Extragonadal non-gestational choriocarcinoma is a rare but well-described phenomenon occurring in patients with midline germ cell tumors. Choriocarcinoma (ChC) is an aggressive neoplasm usually developing in women as a rare complication of pregnancy. In male patients ChC occurs in the testes, usually as a component of mixed germ cell tumors. Very few patients develop extragonadal choriocarcinoma with the tumor occurring in midline locations, such as the mediastinum, retroperitoneum, and central nervous system (mostly pineal gland). Non-midline choriocarcinoma can occur in the lung, gastrointestinal tract, and breast, sometimes blended with another primary malignancy. A midline choriocarcinoma manifesting as a head and neck malignancy is exceptional. During an evaluation of multiple enlarged cervical lymph nodes suspected to be lymphoma in a 72-year-old man, a core biopsy was taken from one of the left neck lymph nodes which histologically showed a necrotic malignancy with strong diffuse pancytokeratin staining. After an initial interpretation of metastatic carcinoma, further samples were taken from both tonsils and from a right level 5 neck lymph node. Histologically, all samples contained the same tumor, showing profound pleomorphism and multinucleated syncytial-type giant cells. A panel of immunohistochemistry studies were performed, including ß-human chorionic gonadotropin, with positive findings leading to a diagnosis of extragonadal non-gestational choriocarcinoma.

Imaging in gynecological disease (22): clinical and ultrasound characteristics of ovarian embryonal carcinomas, non-gestational choriocarcinomas and malignant mixed germ cell tumors.

OBJECTIVE: To describe the clinical and ultrasound characteristics of three types of rare malignant ovarian germ cell tumor: embryonal carcinoma, non-gestational choriocarcinoma and malignant mixed germ cell tumor. METHODS: This was a retrospective multicenter study. From the International Ovarian Tumor Analysis (IOTA) database, we identified patients with a histological diagnosis of ovarian embryonal carcinoma, non-gestational choriocarcinoma or malignant mixed germ cell tumor, who had undergone preoperative ultrasound examination by an experienced ultrasound examiner between 2000 and 2020. Additional patients with the same histology were identified from the databases of the departments of gynecological oncology in the participating centers. All tumors were described using IOTA terminology. Three examiners reviewed all available ultrasound images and described them using pattern recognition. RESULTS: One patient with embryonal carcinoma, five patients with non-gestational ovarian choriocarcinoma and seven patients with ovarian malignant mixed germ cell tumor (six primary tumors and one recurrence) were identified. Seven patients were included in the IOTA studies and six patients were examined outside of the IOTA studies. The median age at diagnosis was 26 (range, 14-77) years. Beta-human chorionic gonadotropin levels were highest in non-gestational choriocarcinomas and alpha-fetoprotein levels were highest in malignant mixed germ cell tumors. Most tumors were International Federation of Gynecology and Obstetrics (FIGO) Stage I (9/12 (75.0%)). All tumors were unilateral, and the median largest diameter was 129 (range, 38-216) mm. Of the tumors, 11/13 (84.6%) were solid and 2/13 (15.4%) were multilocular-solid; 9/13 (69.2%) manifested abundant vascularization on color Doppler examination. Using pattern recognition, the typical ultrasound appearance was a large solid tumor with inhomogeneous echogenicity of the solid tissue and often dispersed cysts which, in most cases, were small and irregular. Some tumors had smooth contours while others had irregular contours. CONCLUSIONS: A unilateral, large solid tumor with inhomogeneous echogenicity of the solid tissue and with dispersed small cystic areas in a young woman should raise the suspicion of a rare malignant germ cell tumor. This suspicion can guide the clinician to test tumor markers specific for malignant germ cell tumors. © 2020 International Society of Ultrasound in Obstetrics and Gynecology.

Vómitos / Vomiting

Los vómitos son un motivo frecuente de consulta. La mayoría de las veces se deben a enfermedades benignas; sin embargo, pueden ser el síntoma inicial de patologías graves y complejas, como procesos neoplásicos con afectación del sistema nervioso central, donde son el resultado del aumento de la presión intracraneal. El cáncer de testículo representa aproximadamente el 1 % de todas las neoplasias y constituye la neoplasia maligna más frecuente en hombres de entre 15 y 34 años. El coriocarcinoma supone entre el 0,3 y el 1 % de las neoplasias testiculares; es considerado como el más raro y con peor pronóstico de todas debido a su rápida diseminación. La mayoría de los casos debutan con síntomas en relación con las metástasis. Presentamos el caso de un paciente de 16 años que acude a consulta por mareos y vómitos. Presentaba una auscultación pulmonar patológica, por la que se solicitó una radiografía torácica que mostró neumotórax derecho e imagen en suelta de globos. Al ampliar estudio, se objetiva una B-HCG elevada y lesión nodular en la ecografía testicular. En el TAC cerebral se objetivaron lesiones metastásicas responsable de los vómitos. Se realizó biopsia de una lesión ulcerada del cuero cabelludo que informó metástasis de coriocarcinoma testicular

Vomiting is a frequent complaint. Most times it is caused by benign conditions. However, it can also be the initial symptom of serious and complex illnesses, such as neoplastic processes with central nervous system involvement, where vomiting is the result of increased intracranial pressure. Testicular cancer accounts for 1% of all neoplasms, and is the most frequent malignancy in men between 15 and 34 years. Choriocarcinoma accounts for 0.3-1% of testicular neoplasms, and it is considered the rarest of all and the one with the worst prognosis due to rapid spread. Most cases begin with symptoms related to the metastases. We present the case of a 16-year-old patient with dizziness and vomiting. His pulmonary auscultation was pathological, so a chest x-ray was performed, showing right pneumothorax and multiple pulmonary nodules. Further study showed elevated B-HCG and a nodular lesion in testicular ultrasound. Metastatic lesions responsible for the vomiting were found in the brain CT. A biopsy of an ulcerated lesion of the scalp showed metastasis of testicular choriocarcinoma

Urothelial Carcinomas With Trophoblastic Differentiation, Including Choriocarcinoma: Clinicopathologic Series of 16 Cases.

Trophoblastic differentiation (including choriocarcinoma) arising in urothelial carcinoma has been described in numerous case reports, but never in a single series. We present a series of these tumors, describing the morphologic spectrum, applying traditional and novel immunohistochemical stains, and characterizing clinical follow-up. We identified 16 cases, arising predominantly in the bladder (N=14), but also the ureter (N=1) and prostatic urethra (N=1). Six of our cases (38%) contained invasive urothelial carcinoma with admixed syncytiotrophoblasts, 8 cases (50%) consisted of invasive urothelial carcinoma with choriocarcinoma, 1 case (6%) showed urothelial carcinoma in situ with associated choriocarcinoma, and 1 case (6%) consisted of pure choriocarcinoma. Other subtypes of variant morphology were seen in 5 of our cases (31%) and included squamous, glandular, lipoid, chordoid/myxoid, and sarcomatoid features. Given the limited specificity of human chorionic gonadotropin immunohistochemistry, we also studied the expression of a novel specific trophoblastic marker, hydroxyl-δ-5-steroid dehydrogenase, as well as Sal-like protein 4. Human chorionic gonadotropin expression was seen in nearly all cases (93%) but was often not limited to the trophoblastic component, staining the urothelial component also in 85% of the cases. Expression of hydroxyl-δ-5-steroid dehydrogenase was more sensitive and more specific, staining 100% of the cases and limited to trophoblasts in all but 1 case. Sal-like protein 4 expression was variable, staining trophoblast in only 50% of cases and staining the urothelial carcinoma component in 43% of those positive cases. Most of our tumors presented at a high stage and were associated with poor clinical outcomes, with at least muscle-invasive disease (pT2) in 10 of the 14 bladder tumors (71%), periureteric fat invasion in the ureter tumor (pT3), distant metastases in 7 of 16 cases (44%) and death of disease in 3 of the 15 patients with follow-up (20%). Our study describes a series of urothelial carcinomas with trophoblastic differentiation, demonstrating the morphologic spectrum of this entity, its frequent association with other subtypes of variant morphology, its characteristic immunoprofile, and its aggressive clinical behavior.

Frequent EGFR expression/EGFR amplification and lack of activating mutation in testicular choriocarcinoma.

Choriocarcinoma (CC) is the rarest but most aggressive histological component of adult testicular germ cell tumor (TGCT). Although we previously reported a putative role of epidermal growth factor receptor (EGFR) alterations in the progression of CC, little is known about the kinase-activating mutation status of EGFR, which predicts the response to EGFR-tyrosine kinase inhibitors. In this study, we clinicopathologically reviewed a total of 12 cases of mixed TGCTs with CC components. Immunohistochemistry, fluorescence in situ hybridization, and direct sequencing was performed to investigate EGFR expression, EGFR copy number alterations, and functional mutation of EGFR in these CC components, respectively. Four (33%) of 12 cases exhibited predominant CC components (>50%), and all these patients died due to disease within 62 months. Overexpression of EGFR, higher copy number of EGFR, and amplification of EGFR was observed in 12 (100%), 10 (83%), and 9 (75%) of 12 CC components, respectively. None of the cases showed any mutational events in exons 18 to 24, which encode the tyrosine kinase domain of EGFR. These results confirm an important role of EGFR in the tumor aggressiveness of testicular CCs and may suggest its possible innate resistance against conventional anti-EGFR therapies.