Hepatoid adenocarcinoma of the stomach with neuroendocrine differentiation:A case report and review of literature

BACKGROUND Both hepatoid adenocarcinoma of the stomach(HAS)and neuroendocrine differentiation(NED)are rare histological subtypes of gastric cancer with unique clinicopathological features and unfavorable outcomes.HAS with NED is even rarer.CASE SUMMARY Here,we report a 61-year-old man with HAS with NED,as detected by gastric wall thickening by positron emission tomography/computed tomography for a pulmonary nodule.Distal gastrectomy was performed,and pathological examination led to the diagnosis of HAS with NED.However,liver metastases occurred 6 mo later despite adjuvant chemotherapy,and the patient died 27 mo postoperatively.CONCLUSION We treated a patient with HAS with NED who underwent adjuvant chemotherapy after radical surgery and still developed liver metastases.We first report the detailed processes of the treatment and development of HAS with NED,providing an important reference for the clinical diagnosis and treatment of this condition.

Comprehensive treatment for metastatic castration-resistant prostate cancer with neuroendocrine differentiation:a case report

Retrospective analysis of the progression of a case of metastatic castration-resistant prostate cancer with neuroendocrine differentiation:the patient was a 65 year old man with prostate adenocarcinoma on prostate biopsy,Gleason 4+4 score=8,70%,ISUP4 group,localized invasion of nerves.Progressed to metastatic castration-resistant prostate cancer after 8 months of novel endocrine therapy,persistent elevated PSA after endocrine therapy,chemotherapy,and radiation,abdominal metastasis,brain metastasis,gastric metastasis,and staging as neuroendocrine differentiation after second prostate biopsy,which is a highly malignant subtype and has been concerned as a mechanism of resistance to targeted therapies.We discuss how to choose a more optimal treatment plan and outline the patient's diagnostic and therapeutic course.We provide a reflection for the clinical study of metastatic castration-resistant prostate cancer with neuroendocrine type.

Prostate tumor neuroendocrine differentiation via EMT: The road less traveled

The long-standing challenge in the treatment of prostate cancer is to overcome therapeutic resistance during progression to lethal disease.Aberrant transforming-growth factor-b(TGF-b)signaling accelerates prostate tumor progression in a transgenic mouse model via effects on epithelial-mesenchymal transition(EMT),and neuroendocrine differentiation driving tumor progression to castration-resistant prostate cancer(CRPC).Neuroendocrine prostate cancer(NEPC)is highly aggressive exhibiting reactivation of developmental programs associated with EMT induction and stem cell-like characteristics.The androgen receptor(AR)is a critical driver of tumor progression as well as therapeutic response in patients with metastatic CRPC.The signaling interactions between the TGF-β mechanistic network and AR axis impact the EMT phenotypic conversions,and perturbation of epithelial homeostasis via EMT renders a critical venue for epithelial derived tumors to become invasive,acquire the neuroendocrine phenotype,and rapidly metastasize.Combinations of microtubule targeting taxane chemotherapy and androgen/AR targeting therapies have survival benefits in CRPC patients,but therapeutic resistance invariability develops,leading to mortality.Compelling evidence from our group recently demonstrated that chemotherapy(cabazitaxel,second line taxane chemotherapy),or TGF-β receptor signaling targeted therapy,caused reversion of EMT to mesenchymal-epithelial transition and tumor re-differentiation,in in vitro and in vivo prostate cancer models.In this review,we discuss the functional contribution of EMT dynamic changes to the development of the neuroendocrine phenotypedthe newly characterized pathological feature of prostate tumors in the context of the tumor microenvironment-navigated cell lineage changes and the role of this neuroendocrine phenotype in metastatic progression and therapeutic resistance.

Molecular aspects of prostate cancer with neuroendocrine differentiation

Neuroendocrine differentiation （NED）, which is not uncommon in prostate cancer, is increases in prostate cancer after androgen-deprivation therapy （ADT） and generally appears in castration- resistant prostate cancer （CRPC）. Neuroendocrine ceils, which are found in normal prostate tissue, are a small subset of cells and have unique function in regulating the growth of prostate ceils. Prostate cancer with NED includes different types of tumor, including focal NED, pure neuroendocrine tumor or mixed neuroendocrine-adenocarcinoma. Although more and more studies are carried out on NED in prostate cancer, the molecular components that are involved in NED are still poorly elucidated. We review neuroendocrine cells in normal prostate tissue, NED in prostate cancer, terminology of NED and biomarkers used for detecting NED in routine pathological practice. Some recently reported molecular components which drive NED in prostate cancer are listed in the review.

Syndrome of inappropriate antidiuresis in prostate adenocarcinoma with neuroendocrine differentiation: a case report and literature review

Syndrome of inappropriate antidiuresis (SIAD) is a common paraneoplastic syndrome commonly associated with thoracic malignancies, gastrointestinal cancers and kidney tumors. It is defined as hyponatremia in euvolemic patients, often due to abnormal secretion of antidiuretic hormone by tumor cells. Tolvaptan, a vasopressin-2-receptor antagonist, is currently recommended for patients affected by SIAD with mild or moderate symptoms. Among patients with prostatic cancer, SIAD represents a rare condition but it is frequently associated with poorly differentiated adenocarcinoma or pure small-cell carcinoma histotype. We report a case of SIAD appeared at disease progression in a 60-year-old male patient with acinar adenocarcinoma with neuroendocrine differentiation together with a literature review.

ONECUT2 as a key mediator of androgen receptorindependent cell growth and neuroendocrine differentiation in castration-resistant prostate cancer

Despite androgen dependence in a majority of castration-resistant prostate cancers,some cancer cells are independent of androgen receptor(AR)function,a feature of heterogeneity in prostate cancer.One of the aggressive variants of prostate cancer that are AR independent is neuroendocrine prostate cancer(NEPC).This manuscript will focus on the new finding of human one cut domain family member 2(ONECUT2)transcription factor and its role in castration resistance,especially in NEPC.

MicroRNAs in treatment-induced neuroendocrine differentiation in prostate cancer

Prostate cancer is a condition commonly associated with men worldwide.Androgen deprivation therapy remains one of the targeted therapies.However,after some years,there is biochemical recurrence and metastatic progression into castration-resistant prostate cancer(CRPC).CRPC cases are treated with second-line androgen deprivation therapy,after which,these CRPCs transdifferentiate to form neuroendocrine prostate cancer(NEPC),a highly aggressive variant of CRPC.NEPC arises via a reversible transdifferentiation process,known as neuroendocrine differentiation(NED),which is associated with altered expression of lineage markers such as decreased expression of androgen receptor and increased expression of neuroendocrine lineage markers including enolase 2,chromogranin A and synaptophysin.The etiological factors and molecular basis for NED are poorly understood,contributing to a lack of adequate molecular biomarkers for its diagnosis and therapy.Therefore,there is a need to fully understand the underlying molecular basis for this cancer.Recent studies have shown that microRNAs(miRNAs)play a key epigenetic role in driving therapy-induced NED in prostate cancer.In this review,we briefly describe the role of miRNAs in prostate cancer and CRPCs,discuss some key players in NEPCs and elaborate on miRNA dysregulation as a key epigenetic process that accompanies therapy-induced NED in metastatic CRPC.This understanding will contribute to better clinical management of the disease.

Clinicopathological characteristics and prognosis of 232 patients with poorly differentiated gastric neuroendocrine neoplasms

BACKGROUND Poorly differentiated gastric neuroendocrine neoplasms(PDGNENs)include gastric neuroendocrine carcinoma(NEC)and mixed adenoneuroendocrine carcinoma,which are highly malignant and rare tumors,and their incidence has increased over the past few decades.However,the clinicopathological features and outcomes of patients with PDGNENs have not been completely elucidated.AIM To investigate the clinicopathological characteristics and prognostic factors of patients with PDGNENs.METHODS The data from seven centers in China from March 2007 to November 2019 were analyzed retrospectively.RESULTS Among the 232 patients with PDGNENs,191(82.3%)were male,with an average age of 62.83±9.11 years.One hundred and thirteen(49.34%)of 229 patients had a stage III disease and 86(37.55%)had stage IV disease.Three(1.58%)of 190 patients had no clinical symptoms,while 187(98.42%)patients presented clinical symptoms.The tumors were mainly(89.17%)solitary and located in the upper third of the stomach(cardia and fundus of stomach:115/215,53.49%).Most lesions were ulcers(157/232,67.67%),with an average diameter of 4.66±2.77 cm.In terms of tumor invasion,the majority of tumors invaded the serosa(116/198,58.58%).The median survival time of the 232 patients was 13.50 mo(7,31 mo),and the overall 1-year,3-year,and 5-year survival rates were 49%,19%,and 5%,respectively.According to univariate analysis,tumor number,tumor diameter,gastric invasion status,American Joint Committee on Cancer(AJCC)stage,and distant metastasis status were prognostic factors for patients with PDGNENs.Multivariate analysis showed that tumor number,tumor diameter,AJCC stage,and distant metastasis status were independent prognostic factors for patients with PDGNENs.CONCLUSION The overall prognosis of patients with PDGNENs is poor.The outcomes of patients with a tumor diameter>5 cm,multiple tumors,and stage IV tumors are worse than those of other patients.

Clinicopathological Features of Extraskeletal Myxoid Chondrosarcoma:An Analysis of 9 Cases

Objective： To investigate the Clinicopathological （EMC）. Methods： Nine cases of extraskeletal characteristics of extraskeletal myxoid chondrosarcoma myxoid chondrosarcoma were studied. Extensive immunohistochemical analysis was performed in all the cases and ultrastructural studies were done in 2 extraskeletal myxoid chondrosarcomas. Follow-up information was available for seven patients. Results： There were 7 males and 2 females whose ages ranged from 31 to 69 years （median 52.78 years）. Local pain or tenderness and the presence of a palpable mass were the main complaints of the patients. The tumors were located mainly in the lower extremities （66.7%）. Most tumors were deep-seated. They usually had a distinct multinodular configuration delineated by fibrous connective tissue. The tumor cells were arranged in delicate intersecting strands, rings, and garlands for the most part. The myxoid matrix was abundant in most cases. Immunohistochemical analysis was performed in all the cases and ultrastructural studies were done in 2 extraskeletal myxoid chondrosarcomas. EMC expressed vimentin （100%, 9/9）, neuron-specific enolase （77.8%, 7/9）, S-100 protein （66.7%, 6/9）, synaptophysin and chromogranin A （22.2%, 2/9）. None of the tumors expressed EMA and desmin. Ultrastructurally： EMC was characterized by distinct cords of cells immersed in a glycosaminoglycan rich matrix. The cells were rich in mitochondria, had well-developed Golgi apparatus and there were numerous smooth vesicles. In many cells, there were also prominent glycogen deposits and lipid droplets. Some tumor cells had intracisternal microtubules. In one of the 2 extraskeletal myxoid chondrosarcomas there were 140-180 nm diameter membrane-bound dense-core secretory granules in cell bodies. Conclusion： Extraskeletal myxoid chondrosarcoma （EMC） is a rare soft tissue sarcoma characterized by distinctive morphological and cytogenetical features. However, the chondroid nature has been a subject of controversy, and its line of differentiation remains to be determined. A substantial proportion of EMC shows immunophenotypic and/or ultrastructural evidence of neuroendocrine differentiation. EMC has high potential of local recurrence and metastasis, and a high disease-associated death rate.