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1.
Virchows Arch ; 478(1): 5-19, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33474631

RESUMO

Neuroendocrine neoplasms (NENs) of the lung encompass neuroendocrine tumors (NETs) composed of typical (TC) and atypical (AC) carcinoids and full-fledged carcinomas (NECs) inclusive of large cell neuroendocrine carcinoma (LCNEC) and small cell carcinoma (SCLC). NETs and NECs are thought to represent distinct and separate lesions with neither molecular overlap nor common developmental continuum. Two perspectives were addressed regarding the morphologic and molecular classification of lung NENs: (i) a supervised approach by browsing the traditional classification, the relevant gene alterations, and their clinical implications; and (ii) an unsupervised approach, by reappraising neoplasms according to risk factors and natural history of disease to construct an interpretation model relied on biological data. We herein emphasize lights and shadows of the current classification of lung NENs and provide an alternative outlook on these tumors focused on what we currently know about the biological determinants and the natural history of disease.


Assuntos
Carcinoma Neuroendócrino/patologia , Neoplasias Pulmonares/patologia , Pulmão/patologia , Tumores Neuroendócrinos/patologia , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Carcinoma Neuroendócrino/genética , Carcinoma Neuroendócrino/metabolismo , Humanos , Pulmão/metabolismo , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Tumores Neuroendócrinos/genética , Tumores Neuroendócrinos/metabolismo
2.
Nat Commun ; 11(1): 1884, 2020 04 20.
Artigo em Inglês | MEDLINE | ID: mdl-32313004

RESUMO

Transformation of castration-resistant prostate cancer (CRPC) into an aggressive neuroendocrine disease (CRPC-NE) represents a major clinical challenge and experimental models are lacking. A CTC-derived eXplant (CDX) and a CDX-derived cell line are established using circulating tumor cells (CTCs) obtained by diagnostic leukapheresis from a CRPC patient resistant to enzalutamide. The CDX and the derived-cell line conserve 16% of primary tumor (PT) and 56% of CTC mutations, as well as 83% of PT copy-number aberrations including clonal TMPRSS2-ERG fusion and NKX3.1 loss. Both harbor an androgen receptor-null neuroendocrine phenotype, TP53, PTEN and RB1 loss. While PTEN and RB1 loss are acquired in CTCs, evolutionary analysis suggest that a PT subclone harboring TP53 loss is the driver of the metastatic event leading to the CDX. This CDX model provides insights on the sequential acquisition of key drivers of neuroendocrine transdifferentiation and offers a unique tool for effective drug screening in CRPC-NE management.


Assuntos
Carcinoma Neuroendócrino/genética , Carcinoma Neuroendócrino/metabolismo , Transdiferenciação Celular/genética , Células Neoplásicas Circulantes/metabolismo , Próstata/metabolismo , Neoplasias da Próstata/genética , Neoplasias da Próstata/metabolismo , Animais , Linhagem Celular Tumoral , Modelos Animais de Doenças , Resistencia a Medicamentos Antineoplásicos , Regulação Neoplásica da Expressão Gênica , Proteínas de Homeodomínio/metabolismo , Humanos , Masculino , Camundongos , Camundongos Endogâmicos NOD , Células Neoplásicas Circulantes/efeitos dos fármacos , Feniltioidantoína/análogos & derivados , Feniltioidantoína/farmacologia , Filogenia , Próstata/patologia , Receptores Androgênicos/genética , Alinhamento de Sequência , Serina Endopeptidases/metabolismo , Fatores de Transcrição/metabolismo , Transcriptoma , Proteína Supressora de Tumor p53/genética
3.
J Surg Oncol ; 122(2): 243-253, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32346887

RESUMO

BACKGROUNDS AND OBJECTIVES: Recent studies have suggested that insulinoma-associated protein 1 (INSM1) is a useful marker for pathological diagnosis of pulmonary neuroendocrine tumors. In the present study, we investigated the association between INSM1 expression and prognosis in patients with pulmonary high-grade neuroendocrine carcinomas (HGNEC) and assessed the usefulness of INSM1 as a prognostic biomarker in these patients. METHODS: Seventy-five consecutive patients with HGNEC who underwent complete surgical resections from January 2000 to December 2018 were enrolled in this study. We classified these patients into two groups: the INSM1-positive group (n = 59) and INSM1-negative group (n = 16). We compared the clinicopathological characteristics, overall survival (OS), and recurrence-free survival (RFS) between the groups. In addition, we performed univariate and multivariate analyses to identify the prognostic factors associated with postoperative survival. RESULTS: Significant differences in tumor diameter and vascular invasion between the groups were found. OS and RFS were significantly poorer in the INSM1-positive group than in the INSM1-negative group. Univariate and multivariate analyses revealed that INSM1 expression was the strongest predictor of poor prognosis for OS and RFS. CONCLUSIONS: INSM1 expression had the greatest influence on the prognosis in patients with HGNEC and may be a prognostic biomarker in these patients.


Assuntos
Carcinoma Neuroendócrino/metabolismo , Carcinoma Neuroendócrino/patologia , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Proteínas Repressoras/biossíntese , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/biossíntese , Feminino , Humanos , Imuno-Histoquímica , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Gradação de Tumores , Prognóstico , Taxa de Sobrevida
4.
J Clin Ultrasound ; 48(4): 227-230, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32045024

RESUMO

Metastases to the submandibular gland are extremely rare; a literature search retuned only three previously reported cases from a thyroid gland primary site. Herein, we report two cases of metastatic thyroid carcinoma to the submandibular gland in a 64-year-old woman with PTC and a 70-year-old-woman with medullary thyroid carcinoma (MTC). The metastases were identified on CT and PET/CT in one case and on CT in the other case, but both were diagnosed with ultrasound-guided fine-needle aspiration. Our cases highlight that while rare, both PTC and MTC can metastasize to the submandibular gland.


Assuntos
Carcinoma Neuroendócrino/secundário , Neoplasias da Glândula Submandibular/secundário , Câncer Papilífero da Tireoide/secundário , Neoplasias da Glândula Tireoide/patologia , Idoso , Biópsia por Agulha Fina , Calcitonina/metabolismo , Carcinoma Neuroendócrino/diagnóstico por imagem , Carcinoma Neuroendócrino/metabolismo , Feminino , Humanos , Pessoa de Meia-Idade , Tomografia Computadorizada com Tomografia por Emissão de Pósitrons , Neoplasias da Glândula Submandibular/diagnóstico por imagem , Câncer Papilífero da Tireoide/diagnóstico por imagem , Câncer Papilífero da Tireoide/metabolismo , Neoplasias da Glândula Tireoide/diagnóstico por imagem , Neoplasias da Glândula Tireoide/metabolismo , Neoplasias da Glândula Tireoide/secundário , Tireoidectomia , Tomografia Computadorizada por Raios X , Ultrassonografia
5.
Cancer Cytopathol ; 128(4): 269-277, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-31977134

RESUMO

BACKGROUND: Pancreatic neuroendocrine tumor (PNET) is a diagnostic challenge with limited samples in not only identification but grading. Prior studies have shown insulinoma-associated protein 1 (INSM1) to be a robust marker in identifying PNETs from other solid pancreatic tumors on resection specimens. In this study, we investigated the utility of INSM1 not only for identifying PNETs but also for grading in cell blocks (CBs) and surgical resections (SRs). METHODS: A search for PNET cases between 2000 and 2019 identified 55 samples (26 CBs and 29 SRs) that were further separated into high (2 CBs, 3 SRs), intermediate (4 CBs, 7 SRs), and low (20 CBs, 19 SRs) grades based on their final pathology report and Ki-67 level. Immunohistochemical (IHC) staining for INSM1 (C-8, Santa Cruz Biotechnology [1:100]) was performed and quantified using an H score of 0 to 300. Non-PNET solid pancreatic tumors were compared and included acinar cell carcinoma, solid pseudopapillary neoplasm, and ductal adenocarcinoma. RESULTS: All 55 cases of PNET demonstrated nuclear INSM1 staining. The average H scores for INSM1 staining of PNET were 254 and 252 in CB and SR, respectively. The H scores decreased with increasing tumor grade, with low-grade (G1), intermediate-grade (G2), and high-grade (G3) tumors showing average INSM1 H scores of 229 and 253, 266 and 253, and 30 and 33 in both CB and SR, respectively. CONCLUSION: IHC with INSM1 plays a role in identifying and potentially grading PNETs.


Assuntos
Biomarcadores Tumorais/metabolismo , Carcinoma Neuroendócrino/diagnóstico , Tumores Neuroendócrinos/diagnóstico , Neoplasias Pancreáticas/diagnóstico , Proteínas Repressoras/metabolismo , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma Neuroendócrino/metabolismo , Carcinoma Neuroendócrino/patologia , Humanos , Imuno-Histoquímica/métodos , Antígeno Ki-67/metabolismo , Masculino , Pessoa de Meia-Idade , Gradação de Tumores , Tumores Neuroendócrinos/metabolismo , Tumores Neuroendócrinos/patologia , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/patologia , Reprodutibilidade dos Testes , Sensibilidade e Especificidade , Adulto Jovem
6.
Anticancer Res ; 40(1): 121-132, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31892560

RESUMO

BACKGROUND/AIM: Pancreatic neuroendocrine tumors (pNETs) are rare pancreatic neoplasms, and therapeutic options for pNETs are limited. Metformin is an anti-hypoglycemic drug that appears to have anticancer effects. However, little is known about the effect of metformin on pNETs. In this study, we investigated the anti-proliferative effect of metformin on a human pNET cell line. MATERIALS AND METHODS: The anti-proliferative properties of metformin were evaluated in QGP-1 and NCI-H727 cells using a cell counting kit-8 assay. Xenograft mouse models were used to assess the tumor effect in vivo. RESULTS: Metformin inhibited the proliferation and anti-tumor growth of QGP-1 cells, accompanied by their arrest during the cell cycle at the G0/G1 phase. Immunohistochemical analysis of tumor tissues revealed down-regulation of cyclin D1 and proliferating cell nuclear antigen in the metformin-treated group. Additionally, metformin induced apoptosis, and the expression of survivin and claspin were decreased in metformin-treated QGP-1 cells according to the apoptosis array. Furthermore, the angiogenic related protein TIMP-1 was down-regulated, and its miRNA expression was altered by metformin in QGP-1 cells. CONCLUSION: Taken together, our study demonstrated the therapeutic potential of metformin and provides molecular mechanistic insights into its anti-tumoral effect on pNETs. This study is the first one describing anti-tumoral effects in pNETs.


Assuntos
Apoptose/efeitos dos fármacos , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Metformina/farmacologia , Biomarcadores , Carcinoma Neuroendócrino/tratamento farmacológico , Carcinoma Neuroendócrino/metabolismo , Carcinoma Neuroendócrino/patologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Humanos , MicroRNAs/genética , Neovascularização Patológica/tratamento farmacológico , Neovascularização Patológica/metabolismo , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/patologia , Transdução de Sinais/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto
7.
BMC Cancer ; 20(1): 27, 2020 Jan 10.
Artigo em Inglês | MEDLINE | ID: mdl-31924180

RESUMO

BACKGROUND: High grade gastroenteropancreatic (GEP) neuroendocrine neoplasms (NEN) with a Ki67 proliferation index > 20%, include well-differentiated tumours grade 3 (NET G3) and poorly differentiated (PD) neuroendocrine carcinomas (NEC). Abnormal p53-expression is a feature of PD tumours, while expression of chromogranin A (CgA) and somatostatin-receptor 2a (SSTR-2a) may be a feature of well-differentiated tumours. The aim of this study was to elucidate the expression and prognostic value of these three markers in 163 GEP-NEN patients with a Ki67-index > 20%. METHOD: Clinical data, histopathology and overall survival were analysed according to Kaplan-Meier's method and Cox regression. The expression of SSTR-2a, CgA and synaptophysin was analysed in tumour specimens by immunohistochemistry, and semi-quantitatively scored as negative (< 5%), heterogeneously positive (5-30%) or strongly positive (> 30%). P53 was defined as normal when scored as heterogeneously positive (1-30%), and abnormal when negative (0%) or strongly positive (> 30%). RESULTS: In multivariate analysis, better survival was observed among patients with heterogeneously positive p53 compared to strongly positive (p < 0.001). When dichotomised, tumours with a heterogeneously positive p53 vs. negative and strongly positive p53 also showed a significantly better survival (p = 0.002). Survival was significantly worse for negative CgA compared to heterogeneously positive CgA (p = 0.02). Strongly positive SSTR-2a expression was found in 26% of the 163 included patients. Well-differentiated morphology correlated with strong expression of SSTR-2a and CgA, and heterogeneously positive p53-staining, and was more frequent in pancreatic primaries. In pancreatic primaries, strongly positive SSTR-2a was associated with longer survival (univariate analysis, p = 0.02). A significantly lower Ki67 proliferation index was found in patients with a heterogeneously positive p53, a positive SSTR-2a and CgA expression. CONCLUSION: Our results suggest that abnormal p53-expression is an independent negative prognostic marker in GEP-NEN with a Ki67-index > 20%. Patients with heterogeneously positive p53 had the best prognosis. SSTR-2a was a positive prognostic marker in pancreatic NEN. Negative CgA was associated with a significantly worse OS compared to heterogeneously positive CgA-expression in a multivariate sub-analysis. Lower Ki67 index correlated significantly with heterogeneously positive p53, positive SSTR-2a and CgA expression.


Assuntos
Carcinoma Neuroendócrino/diagnóstico , Carcinoma Neuroendócrino/metabolismo , Cromogranina A/metabolismo , Neoplasias Gastrointestinais/diagnóstico , Neoplasias Gastrointestinais/metabolismo , Neoplasias Pancreáticas/diagnóstico , Neoplasias Pancreáticas/metabolismo , Receptores de Somatostatina/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais , Carcinoma Neuroendócrino/etiologia , Carcinoma Neuroendócrino/mortalidade , Linhagem Celular Tumoral , Feminino , Seguimentos , Neoplasias Gastrointestinais/etiologia , Neoplasias Gastrointestinais/mortalidade , Humanos , Imuno-Histoquímica , Masculino , Pessoa de Meia-Idade , Gradação de Tumores , Neoplasias Pancreáticas/etiologia , Neoplasias Pancreáticas/mortalidade , Prognóstico , Modelos de Riscos Proporcionais , Proteína Supressora de Tumor p53/metabolismo , Adulto Jovem
8.
Proc Natl Acad Sci U S A ; 117(4): 2032-2042, 2020 01 28.
Artigo em Inglês | MEDLINE | ID: mdl-31932422

RESUMO

Resistance to androgen deprivation therapy, or castration-resistant prostate cancer (CRPC), is often accompanied by metastasis and is currently the ultimate cause of prostate cancer-associated deaths in men. Recently, secondary hormonal therapies have led to an increase of neuroendocrine prostate cancer (NEPC), a highly aggressive variant of CRPC. Here, we identify that high levels of cell surface receptor Trop2 are predictive of recurrence of localized prostate cancer. Moreover, Trop2 is significantly elevated in CRPC and NEPC, drives prostate cancer growth, and induces neuroendocrine phenotype. Overexpression of Trop2 induces tumor growth and metastasis while loss of Trop2 suppresses these abilities in vivo. Trop2-driven NEPC displays a significant up-regulation of PARP1, and PARP inhibitors significantly delay tumor growth and metastatic colonization and reverse neuroendocrine features in Trop2-driven NEPC. Our findings establish Trop2 as a driver and therapeutic target for metastatic prostate cancer with neuroendocrine phenotype and suggest that high Trop2 levels could identify cancers that are sensitive to Trop2-targeting therapies and PARP1 inhibition.


Assuntos
Antígenos de Neoplasias/metabolismo , Biomarcadores Tumorais/metabolismo , Neoplasias Ósseas/secundário , Carcinoma Neuroendócrino/patologia , Moléculas de Adesão Celular/metabolismo , Regulação Neoplásica da Expressão Gênica , Poli(ADP-Ribose) Polimerase-1/metabolismo , Neoplasias de Próstata Resistentes à Castração/patologia , Animais , Antígenos de Neoplasias/genética , Apoptose , Biomarcadores Tumorais/genética , Neoplasias Ósseas/tratamento farmacológico , Neoplasias Ósseas/metabolismo , Carcinoma Neuroendócrino/tratamento farmacológico , Carcinoma Neuroendócrino/metabolismo , Moléculas de Adesão Celular/genética , Movimento Celular , Proliferação de Células , Seguimentos , Humanos , Masculino , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Invasividade Neoplásica , Fenótipo , Poli(ADP-Ribose) Polimerase-1/antagonistas & inibidores , Poli(ADP-Ribose) Polimerase-1/genética , Inibidores de Poli(ADP-Ribose) Polimerases/farmacologia , Prognóstico , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Neoplasias de Próstata Resistentes à Castração/metabolismo , Taxa de Sobrevida , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto
9.
Nat Commun ; 11(1): 338, 2020 01 17.
Artigo em Inglês | MEDLINE | ID: mdl-31953400

RESUMO

Neuroendocrine prostate cancer (NEPC) is an aggressive malignancy with no effective targeted therapies. The oncogenic MUC1-C protein is overexpressed in castration-resistant prostate cancer (CRPC) and NEPC, but its specific role is unknown. Here, we demonstrate that upregulation of MUC1-C in androgen-dependent PC cells suppresses androgen receptor (AR) axis signaling and induces the neural BRN2 transcription factor. MUC1-C activates a MYC→BRN2 pathway in association with induction of MYCN, EZH2 and NE differentiation markers (ASCL1, AURKA and SYP) linked to NEPC progression. Moreover, MUC1-C suppresses the p53 pathway, induces the Yamanaka pluripotency factors (OCT4, SOX2, KLF4 and MYC) and drives stemness. Targeting MUC1-C decreases PC self-renewal capacity and tumorigenicity, suggesting a potential therapeutic approach for CRPC and NEPC. In PC tissues, MUC1 expression associates with suppression of AR signaling and increases in BRN2 expression and NEPC score. These results highlight MUC1-C as a master effector of lineage plasticity driving progression to NEPC.


Assuntos
Carcinoma Neuroendócrino/metabolismo , Progressão da Doença , Mucina-1/metabolismo , Plasticidade Neuronal/fisiologia , Neoplasias da Próstata/metabolismo , Animais , Aurora Quinase A/metabolismo , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Carcinogênese/genética , Carcinoma Neuroendócrino/genética , Linhagem Celular Tumoral , Proteína Potenciadora do Homólogo 2 de Zeste/metabolismo , Regulação Neoplásica da Expressão Gênica , Proteínas de Homeodomínio/metabolismo , Humanos , Fatores de Transcrição Kruppel-Like/metabolismo , Masculino , Camundongos , Camundongos Nus , Mucina-1/genética , Proteína Proto-Oncogênica N-Myc/metabolismo , Células-Tronco Neoplásicas/metabolismo , Fator 3 de Transcrição de Octâmero/metabolismo , Fatores do Domínio POU/metabolismo , Próstata/patologia , Neoplasias da Próstata/genética , Neoplasias de Próstata Resistentes à Castração/genética , Neoplasias de Próstata Resistentes à Castração/metabolismo , Proteínas Proto-Oncogênicas c-myc , Fatores de Transcrição SOXB1/metabolismo , Transdução de Sinais , Sinaptofisina/metabolismo , Proteína Supressora de Tumor p53/metabolismo
10.
Cancer Sci ; 111(2): 610-620, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31845438

RESUMO

High-grade neuroendocrine lung cancer (HGNEC), which includes small cell lung cancer (SCLC) and large cell neuroendocrine carcinoma (LCNEC) of the lung is a rapidly proliferating, aggressive form of lung cancer. The initial standard chemotherapeutic regimens of platinum doublets are recommended for SCLC and have been frequently used for LCNEC. However, there are currently no molecularly targeted agents with proven clinical benefit for this disease. The deubiquitinating enzyme ubiquitin C-terminal hydrolase-L1 (UCHL1) is a neuroendocrine cell-specific product that is known as a potential oncogene in several types of cancer, but little is known about the biological function of UCHL1 and its therapeutic potential in HGNEC. In this study, we found that preclinical efficacy evoked by targeting UCHL1 was relevant to prognosis in HGNEC. UCHL1 was found to be expressed in HGNEC, particularly in cell lines and patient samples of SCLC, and the combined use of platinum doublets with selective UCHL1 inhibitors improved its therapeutic response in vitro. Immunohistochemical expression of UCHL1 was significantly associated with postoperative survival in patients with HGNEC and contributed towards distinguishing SCLC from LCNEC. Circulating extracellular vesicles (EV), including exosomes isolated from lung cancer cell lines and serum from early-stage HGNEC, were verified by electron microscopy and nanoparticle tracking analysis. Higher levels of UCHL1 mRNA in EV were found in the samples of patients with early-stage HGNEC than those with early-stage NSCLC and healthy donors' EV. Taken together, UCHL1 may be a potential prognostic marker and a promising druggable target for HGNEC.


Assuntos
Carcinoma Neuroendócrino/patologia , Vesículas Extracelulares/genética , Neoplasias Pulmonares/patologia , Carcinoma de Pequenas Células do Pulmão/patologia , Ubiquitina Tiolesterase/genética , Ubiquitina Tiolesterase/metabolismo , Células A549 , Idoso , Idoso de 80 Anos ou mais , Carcinoma Neuroendócrino/tratamento farmacológico , Carcinoma Neuroendócrino/genética , Carcinoma Neuroendócrino/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Inibidores Enzimáticos/farmacologia , Inibidores Enzimáticos/uso terapêutico , Vesículas Extracelulares/metabolismo , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Masculino , Pessoa de Meia-Idade , Gradação de Tumores , Platina/farmacologia , Platina/uso terapêutico , Prognóstico , Carcinoma de Pequenas Células do Pulmão/tratamento farmacológico , Carcinoma de Pequenas Células do Pulmão/genética , Carcinoma de Pequenas Células do Pulmão/metabolismo , Ubiquitina Tiolesterase/antagonistas & inibidores , Regulação para Cima
11.
Diagn Cytopathol ; 48(4): 386-389, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31883317

RESUMO

Fine-needle aspiration cytology (FNAC) is a preliminary test for the diagnosis of thyroid lesions. We hereby report a rare case of medullary thyroid carcinoma (MTC) co-existing with Hashimoto's thyroiditis (HT). This case was substantiated with ancillary tests on cytology material to give a novel insight. A 60-year-old female presented clinically with diffuse enlargement of the thyroid, and right-side nodule on ultrasonography. FNAC of the isthmic area showed features of HT, while cytology of right-side nodule displayed sheets of plasmacytoid cells and frequent scattered large bizarre and pleomorphic cells, lymphoglandular bodies and pale eosinophilic material. The differential diagnosis of MTC with co-existent HT or high-grade lymphoma was considered. To establish the diagnosis, serum calcitonin and ancillary studies on aspirated material were carried out. High serum calcitonin (7251 pg/mL), Congophilia on smears, and CD 45-ve; CD56+ve expression of tumor cells on flowcytometric analysis established the diagnosis of MTC over lymphoma. This diagnosis was further confirmed upon histopathology. Ancillary studies on aspirated material established the diagnosis of MTC and excluded the diagnosis of lymphoma. Establishing the correct diagnosis was cardinal in such a scenario as these diseases have extremely diverse management.


Assuntos
Carcinoma Neuroendócrino , Doença de Hashimoto , Neoplasias da Glândula Tireoide , Biópsia por Agulha Fina , Carcinoma Neuroendócrino/diagnóstico , Carcinoma Neuroendócrino/metabolismo , Carcinoma Neuroendócrino/patologia , Feminino , Doença de Hashimoto/diagnóstico , Doença de Hashimoto/metabolismo , Doença de Hashimoto/patologia , Humanos , Pessoa de Meia-Idade , Neoplasias da Glândula Tireoide/diagnóstico , Neoplasias da Glândula Tireoide/metabolismo , Neoplasias da Glândula Tireoide/patologia
12.
Int J Oncol ; 56(1): 348-358, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31746350

RESUMO

Rearranged during transfection kinase (RET) is a validated molecular target in medullary thyroid cancer (MTC), as activating mutations in RET are often associated with the development of MTC. The present study reports the first preclinical characterization of salinomycin and selected analogs as potent RET transcriptional inhibitors. Reverse transcription­PCR and immunoblotting revealed that salinomycin profoundly decreased RET expression in the TT human MTC cell line by inhibiting RET transcription. Moreover, salinomycin resulted in remarkable anti­proliferative activity against MTC that is driven by RET (gain of function mutation) by selectively inhibiting the intracellular PI3K/Akt/mTOR signaling pathway. Also, flow cytometry and fluorescence­activated cell sorting showed that salinomycin induces G1 phase arrest and apoptosis by reducing the expression of retinoblastoma protein, E2F1, cyclin D and CDK4. The structure­activity relationship of salinomycin was investigated in this study. Some of the salinomycin derivatives showed the ability to reduce RET expression where others fail to alter RET expression. These results suggest that the RET­suppressing effect of salinomycin may be largely attributed to disruption of the Wnt pathway, presumably through interference with the ternary LRP6­Frizzled­Wnt complex. Furthermore, these findings support the further preclinical evaluation of salinomycin and its analogs as a promising new class of therapeutic agents for the improved treatment of MTC.


Assuntos
Antibacterianos/farmacologia , Biomarcadores Tumorais/antagonistas & inibidores , Carcinoma Neuroendócrino/tratamento farmacológico , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-ret/antagonistas & inibidores , Piranos/farmacologia , Neoplasias da Glândula Tireoide/tratamento farmacológico , Apoptose , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Carcinoma Neuroendócrino/metabolismo , Carcinoma Neuroendócrino/patologia , Ciclo Celular , Proliferação de Células , Humanos , Proteínas Proto-Oncogênicas c-ret/genética , Proteínas Proto-Oncogênicas c-ret/metabolismo , Neoplasias da Glândula Tireoide/metabolismo , Neoplasias da Glândula Tireoide/patologia , Células Tumorais Cultivadas
13.
J Nucl Med ; 61(4): 520-526, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-31519804

RESUMO

Treatment of patients with advanced medullary thyroid carcinoma (MTC) is still a challenge. For more than 2 decades, it has been known that the cholecystokinin 2 receptor is a promising target for the treatment of MTC with radiolabeled minigastrin analogs. Unfortunately, kidney toxicity has precluded their therapeutic application so far. In 6 consecutive patients, we evaluated with advanced 3-dimensional dosimetry whether improved minigastrin analog 177Lu-DOTA-(d-Glu)6-Ala-Tyr-Gly-Trp-Nle-Asp-PheNH2 (177Lu-PP-F11N) is a suitable agent for the treatment of MTC. Methods: Patients received 2 injections of about 1 GBq (∼80 µg) of 177Lu-PP-F11N with and without a solution of succinylated gelatin (SG, a plasma expander used for nephroprotection) in a random crossover sequence to evaluate biodistribution, pharmacokinetics, and tumor and organ dosimetry. An electrocardiogram was obtained and blood count and blood chemistry were measured up to 12 wk after the administration of 177Lu-PP-F11N to assess safety. Results: In all patients, 177Lu-PP-F11N accumulation was visible in tumor tissue, stomach, and kidneys. Altogether, 13 tumors were eligible for dosimetry. The median absorbed doses for tumors, stomach, kidneys, and bone marrow were 0.88 (interquartile range [IQR]: 0.85-1.04), 0.42 (IQR: 0.25-1.01), 0.11 (IQR: 0.07-0.13), and 0.028 (IQR: 0.026-0.034) Gy/GBq, respectively. These doses resulted in median tumor-to-kidney dose ratios of 11.6 (IQR: 8.11-14.4) without SG and 13.0 (IQR: 10.2-18.6) with SG; these values were not significantly different (P = 1.0). The median tumor-to-stomach dose ratio was 3.34 (IQR: 1.14-4.70). Adverse reactions (mainly hypotension, flushing, and hypokalemia) were self-limiting and not higher than grade 1. Conclusion: 177Lu-PP-F11N accumulates specifically in MTC at a dose that is sufficient for a therapeutic approach. With a low kidney and bone marrow radiation dose, 177Lu-PP-F11N shows a promising biodistribution. The dose-limiting organ is most likely the stomach. Further clinical studies are necessary to evaluate the maximum tolerated dose and the efficacy of 177Lu-PP-F11N.


Assuntos
Carcinoma Neuroendócrino/radioterapia , Compostos Heterocíclicos com 1 Anel/química , Lutécio/uso terapêutico , Oligopeptídeos/química , Oligopeptídeos/uso terapêutico , Radioisótopos/uso terapêutico , Receptor de Colecistocinina B/agonistas , Neoplasias da Glândula Tireoide/radioterapia , Carcinoma Neuroendócrino/metabolismo , Feminino , Humanos , Masculino , Oligopeptídeos/farmacocinética , Oligopeptídeos/farmacologia , Tomografia Computadorizada com Tomografia Computadorizada de Emissão de Fóton Único , Neoplasias da Glândula Tireoide/metabolismo , Distribuição Tecidual
14.
Histopathology ; 76(2): 251-264, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31233624

RESUMO

AIMS: Special AT-rich sequence-binding protein 2 (SATB2) is a transcriptional regulator with critical roles in brain, craniofacial and skeletal development. It has emerged as a key marker of lower gastrointestinal (GI) tract columnar epithelial and osteoblastic differentiation. Transcription factor immunohistochemistry is useful in assigning site of origin in well-differentiated neuroendocrine tumours (NETs), and has had a limited role in poorly differentiated neuroendocrine carcinomas (NECs). This study sought to evaluate the role of SATB2 in assigning site of origin in neuroendocrine epithelial neoplasms. METHODS AND RESULTS: Tissue microarrays were constructed from the following: 317 NETs (37 thyroid, 46 lung, 16 stomach, 12 duodenum, 70 pancreas, 106 jejunoileum, 24 appendix, and six rectosigmoid), 44 phaeochromocytomas/paragangliomas, and 79 NECs (29 Merkel cell, 30 lung, and 20 extrapulmonary visceral); nine appendiceal and 19 rectal NETs were examined in whole sections. SATB2 immunohistochemistry was scored for extent (%) and intensity (0-3+), with an H-score being calculated. SATB2 was expressed by 96% of rectosigmoid NETs, 79% of appendiceal NETs, and only 7% of other well-differentiated neoplasms (P < 0.0001). Expression in lower GI tract NETs (median H-score of 255) was stronger than in other positive tumours (median H-score of 7) (P < 0.0001). Any SATB2 expression was 86% sensitive/93% specific for lower GI tract origin. SATB2 was expressed by 79% of Merkel cell carcinomas (median H-score of 300), 33% of lung NECs (median H-score of 23), and 60% of extrapulmonary visceral NECs (median H-score of 110), with stronger expression in Merkel cell carcinoma (P < 0.001). At an H-score cutoff of ≥150, SATB2 was 69% sensitive/90% specific for Merkel cell carcinoma. CONCLUSIONS: SATB2 is frequently and strongly expressed by lower GI tract NETs; we have adopted it as our rectal NET marker. Relatively frequent and strong expression in Merkel cell carcinoma may have value in assigning NEC site of origin.


Assuntos
Biomarcadores Tumorais/metabolismo , Carcinoma de Célula de Merkel/metabolismo , Proteínas de Ligação à Região de Interação com a Matriz/metabolismo , Neoplasias Epiteliais e Glandulares/metabolismo , Tumores Neuroendócrinos/metabolismo , Neoplasias Retais/metabolismo , Fatores de Transcrição/metabolismo , Carcinoma de Célula de Merkel/diagnóstico , Carcinoma de Célula de Merkel/patologia , Carcinoma Neuroendócrino/diagnóstico , Carcinoma Neuroendócrino/metabolismo , Carcinoma Neuroendócrino/patologia , Diferenciação Celular , Estudos de Coortes , Diagnóstico Diferencial , Humanos , Imuno-Histoquímica , Iowa , Trato Gastrointestinal Inferior/metabolismo , Trato Gastrointestinal Inferior/patologia , Neoplasias Epiteliais e Glandulares/diagnóstico , Neoplasias Epiteliais e Glandulares/patologia , Tumores Neuroendócrinos/diagnóstico , Tumores Neuroendócrinos/patologia , Neoplasias Retais/diagnóstico , Neoplasias Retais/patologia , Análise Serial de Tecidos
15.
Clin J Gastroenterol ; 13(1): 110-115, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31264080

RESUMO

We present an extremely rare case of carcinosarcoma with 4 different tumor components in an 88-year-old female. After a diagnosis of acute cholecystitis, we performed percutaneous transhepatic gallbladder drainage in the patient without success, followed by a cholecystectomy and choledocholithotomy. The mass was a 60 × 25 mm polypoid lesion of the gallbladder identified histologically as a carcinosarcoma with adenocarcinoma, neuroendocrine carcinoma, undifferentiated carcinoma and chondrosarcoma components. The biliary-type adenocarcinoma portion exhibited acinar growth patterns with columnar cells having large and markedly hyperchromatic nuclei. These tumor cells were immunohistochemically positive for MUC1 and CDX2. The neuroendocrine carcinoma, small cell type, cells were densely packed and small, with scant cytoplasm, finely granular nuclear chromatin and absence of nucleoli. The mitotic index was high. These tumor cells were immunohistochemically positive for synaptophysin, Ki-67 (index 40%), MUC1, CDX2 and c-Kit. The undifferentiated carcinoma consisted exclusively of spindle cells containing large, markedly hyperchromatic nuclei with a high mitotic index. These tumor cells were immunohistochemically positive for AE1/AE3. The chondrosarcoma was composed of blue-gray chondroid matrix and atypical chondrocytes containing large, hyperchromatic nuclei. These tumor cells were immunohistochemically positive for S100. Its attributes might be suggestive of a greater malignant potential and pathogenesis of carcinosarcoma.


Assuntos
Adenocarcinoma/patologia , Carcinoma Neuroendócrino/patologia , Carcinossarcoma/patologia , Condrossarcoma/patologia , Neoplasias da Vesícula Biliar/patologia , Tumor Misto Maligno/patologia , Adenocarcinoma/complicações , Adenocarcinoma/diagnóstico por imagem , Adenocarcinoma/metabolismo , Idoso , Fator de Transcrição CDX2/metabolismo , Carcinoma/complicações , Carcinoma/diagnóstico por imagem , Carcinoma/metabolismo , Carcinoma/patologia , Carcinoma Neuroendócrino/complicações , Carcinoma Neuroendócrino/diagnóstico por imagem , Carcinoma Neuroendócrino/metabolismo , Carcinossarcoma/complicações , Carcinossarcoma/diagnóstico por imagem , Carcinossarcoma/metabolismo , Colecistectomia , Colecistite Aguda/complicações , Colecistite Aguda/diagnóstico por imagem , Colecistite Aguda/cirurgia , Colecistolitíase/complicações , Colecistolitíase/diagnóstico por imagem , Colecistolitíase/cirurgia , Coledocolitíase/complicações , Coledocolitíase/diagnóstico por imagem , Coledocolitíase/cirurgia , Condrossarcoma/complicações , Condrossarcoma/diagnóstico por imagem , Condrossarcoma/metabolismo , Feminino , Neoplasias da Vesícula Biliar/complicações , Neoplasias da Vesícula Biliar/diagnóstico por imagem , Neoplasias da Vesícula Biliar/metabolismo , Humanos , Antígeno Ki-67/metabolismo , Tumor Misto Maligno/complicações , Tumor Misto Maligno/diagnóstico por imagem , Tumor Misto Maligno/metabolismo , Mucina-1/metabolismo , Proteínas Proto-Oncogênicas c-kit/metabolismo , Proteínas S100/metabolismo , Tomografia Computadorizada por Raios X
17.
PLoS One ; 14(11): e0225260, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31725814

RESUMO

Patients with medullary thyroid cancer (MTC) are often diagnosed with spread tumour disease and the development of better systemic treatment options for these patients is important. Treatment with the radiolabelled somatostatin analogue 177Lu-octreotate is already a promising option but can be optimised. For example, combination treatment with another substance could increase the effect on tumour tissue. Gemcitabine is a nucleoside analogue that has been shown to sensitise tumour cells to radiation. The aim of this study was to investigate potentially additive or synergistic effects of combining radiation with gemcitabine for treatment of MTC. Nude mice transplanted with patient-derived MTC tumours (GOT2) were divided into groups and treated with radiation and/or gemcitabine. Radiation treatment was given as 177Lu-octreotate or external beam radiotherapy (EBRT). The volume of treated and untreated tumours was followed. The absorbed dose and amount of gemcitabine were chosen to give moderate tumour volume reduction when given as monotherapy to enable detection of increased effects from combination treatment. After follow-up, the mice were killed and tumours were immunohistochemically (IHC) analysed. Overall, the animals that received a combination of EBRT and gemcitabine showed the largest reduction in tumour volume. Monotherapy with EBRT or gemcitabine also resulted in a clear detrimental effect on tumour volume, while the animals that received 177Lu-octreotate monotherapy showed similar response as the untreated animals. The GOT2 tumour was confirmed in the IHC analyses by markers for MTC. The IHC analyses also revealed that the proliferative activity of tumour cells was similar in all tumours, but indicated that fibrotic tissue was more common after EBRT and/or gemcitabine treatment. The results indicate that an additive, or even synergistic, effect may be achieved by combining radiation with gemcitabine for treatment of MTC. Future studies should be performed to evaluate the full potential of combining 177Lu-octreotate with gemcitabine in patients.


Assuntos
Carcinoma Neuroendócrino/terapia , Desoxicitidina/análogos & derivados , Radiossensibilizantes/uso terapêutico , Neoplasias da Glândula Tireoide/terapia , Animais , Carcinoma Neuroendócrino/diagnóstico , Carcinoma Neuroendócrino/metabolismo , Desoxicitidina/farmacologia , Desoxicitidina/uso terapêutico , Humanos , Imuno-Histoquímica , Camundongos , Octreotida/análogos & derivados , Octreotida/farmacologia , Octreotida/uso terapêutico , Radiossensibilizantes/farmacologia , Radiometria , Radioterapia , Neoplasias da Glândula Tireoide/diagnóstico , Neoplasias da Glândula Tireoide/metabolismo
19.
Orphanet J Rare Dis ; 14(1): 266, 2019 11 21.
Artigo em Inglês | MEDLINE | ID: mdl-31752927

RESUMO

BACKGROUND: Primary neuroendocrine carcinomas of the gallbladder and biliary tract are rare, with pure large cell neuroendocrine carcinomas (LCNEC) being exceedingly rare and with a particularly poor prognosis. METHODS: We performed a review of published data on biliary tract large cell neuroendocrine carcinomas in PubMed. RESULTS: Preliminary search revealed over 2000 results but we found only 12 cases of pure large cell neuroendocrine carcinomas of biliary tract noted in literature to date. Because it commonly presents with non-specific symptoms of abdominal pain and jaundice, diagnosis is made after resection with histo-pathological and immunohistochemical analysis. These cancers are particularly aggressive with high recurrence rates, most often presenting with metastasis to regional lymph nodes and/or the liver resulting in a poor prognosis. Overall, complete surgical excision with systemic chemotherapy is the treatment mainstay. If the cancer is unresectable due to multiple metastases, medical management with systemic chemotherapy is the primary treatment modality. CONCLUSION: The prognosis of hepatobiliary LCNEC remains poor with median survival of only 11 months from initial diagnosis. Studies focusing on high grade neuroendocrine carcinoma are needed to enhance our understanding of biology and therapeutics in this rare but aggressive cancer.


Assuntos
Carcinoma de Células Grandes/patologia , Carcinoma Neuroendócrino/patologia , Idoso , Sistema Biliar/metabolismo , Sistema Biliar/patologia , Carcinoma de Células Grandes/metabolismo , Carcinoma Neuroendócrino/metabolismo , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico
20.
Lung Cancer ; 138: 102-108, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31678831

RESUMO

OBJECTIVES: For stage IV pulmonary large cell neuroendocrine carcinoma (LCNEC), the only therapeutic option is palliative chemotherapy. DLL3 is a new therapeutic target, which seems to be often expressed in SCLC and LCNEC. It has recently been reported that DLL3 mRNA expression is particularly upregulated in the LCNEC subgroup with STK11/KEAP1 and TP53 co-mutations, in contrast to lower expression levels in RB1 and TP53 co-mutated LCNEC. Our aim was to investigate DLL3 protein expression in stage IV LCNEC and correlate data with mutational profiles (i.e.STK11/KEAP1/RB1), immunostaining results (pRb, NE markers) and clinical characteristics. MATERIALS AND METHODS: Immunohistochemical analysis for DLL3 (SC16.65) and ASCL1 (SC72.201) was performed on 94 and 51 FFPE tissue sections, respectively, of pathologically reviewed stage IV LCNEC. DLL3 and ASCL1 were scored positive if ≥1% of the tumor cells showed cytoplasmic/membranous or dotlike (DLL3) or nuclear (ASCL1) immunostaining. Data were correlated with available sequencing (TP53, RB1, STK11, KEAP1), immunostaining (pRb, NE markers) and clinical data. RESULTS: DLL3 was expressed in 70/94 (74%) LCNEC, 56 (80%) of which showed cytoplasmic/membranous staining. Median H-score was 55 (interquartile range 0-160). DLL3 staining was not different in pRb immunohistochemistry negative and positive patients (DLL3+ in 53/70 (76%) vs. 14/21 (67%), p = 0.409) or RB1 mutated and wildtype patients (DLL3+ in 27/34 (79%) vs. 23/33 (70%), p = 0.361). Nevertheless, 6/6 (100%) STK11 mutated, 10/11 (91%) KEAP1 mutated and 9/9 (100%) TP53 wildtype tumors were DLL3+ . Furthermore, DLL3 expression was associated with expression of ASCL1 and at least 2 out of 3 neuroendocrine markers. CONCLUSION: The high percentage (74%) of DLL3 expression in stage IV LCNEC denotes the potential of DLL3 targeted therapy in this patient group.


Assuntos
Carcinoma de Células Grandes/metabolismo , Carcinoma de Células Grandes/patologia , Carcinoma Neuroendócrino/metabolismo , Carcinoma Neuroendócrino/patologia , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Proteínas de Membrana/metabolismo , Idoso , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Carcinoma de Células Grandes/genética , Carcinoma Neuroendócrino/genética , Feminino , Humanos , Imuno-Histoquímica , Peptídeos e Proteínas de Sinalização Intracelular/biossíntese , Peptídeos e Proteínas de Sinalização Intracelular/genética , Neoplasias Pulmonares/genética , Masculino , Proteínas de Membrana/biossíntese , Proteínas de Membrana/genética , Pessoa de Meia-Idade , Mutação , Estadiamento de Neoplasias , Prognóstico , Estudos Retrospectivos
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