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2.
Virchows Arch ; 478(1): 129-135, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33555458

RESUMO

Neuroendocrine tumors of the thymus (TNET) are exceedingly rare neoplasms. Their histomorphology is identical to neuroendocrine tumors elsewhere in the body (in particular the lungs) and bears no similarity with thymomas and thymic carcinomas. Recent molecular findings have profoundly changed our perception of these tumors and may impact future histological classification systems.


Assuntos
Carcinoma Neuroendócrino/classificação , Tumores Neuroendócrinos/classificação , Neoplasias do Timo/classificação , Carcinoma Neuroendócrino/patologia , Humanos , Tumores Neuroendócrinos/patologia , Timoma/classificação , Timoma/patologia , Neoplasias do Timo/patologia
3.
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
4.
Medicine (Baltimore) ; 100(1): e23835, 2021 Jan 08.
Artigo em Inglês | MEDLINE | ID: mdl-33429744

RESUMO

ABSTRACT: Immune check-point inhibitors (ICIs) have changed our view on how to treat cancer. Despite their approval in treatment of many different cancers, efficacy of immune check-point inhibitors (ICI) in neuroendocrine neoplasia is limited and poorly understood. Established treatment options of neuroendocrine tumors (NET) and neuroendocrine carcinomas (NECs) are based on surgery, tumor-targeted medical treatments, Peptide Receptor Radionuclide Therapy (PRRT), and locoregional therapies. However, in many patients these treatments lose efficacy over time, and novel therapies are urgently needed. We report on 8 patients diagnosed with neuroendocrine neoplasms (NEN) that were treated with ICI (pembrolizumab, avelumab, nivolumab plus ipilimumab) as salvage therapy. In this cohort, we observed tumor response with partial remission in 3 patients and stable disease in 1 patient. Four patients showed progressive disease. Of note, responses were observed both in PD-L1 positive and PD-L1 negative patients. Here, we discuss clinical courses of these patients in the context of available literature to highlight limitations and drawbacks currently preventing the use of ICI in routine management of patients with NEN.


Assuntos
Carcinoma Neuroendócrino/tratamento farmacológico , /farmacologia , Adulto , Anticorpos Monoclonais Humanizados/farmacologia , Anticorpos Monoclonais Humanizados/uso terapêutico , Carcinoma Neuroendócrino/patologia , Feminino , Humanos , Ipilimumab/farmacologia , Ipilimumab/uso terapêutico , Masculino , Pessoa de Meia-Idade , Nivolumabe/farmacologia , Nivolumabe/uso terapêutico , Centros de Atenção Terciária/organização & administração , Centros de Atenção Terciária/tendências
5.
Am J Surg Pathol ; 45(1): 25-34, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33177340

RESUMO

Assessment of the Ki67 index is critical for grading well-differentiated neuroendocrine tumors (WD-NETs), which can show a broad range of labeling that defines the WHO grade (G1-G3). Poorly differentiated neuroendocrine carcinomas (PD-NECs) have a relatively high Ki67 index, >20% in all cases and commonly exceeding 50%. After anecdotally observing PD-NECs with an unexpectedly low and heterogeneous Ki67 index following chemotherapy in 5 cases, we identified 15 additional cases of treated high-grade neuroendocrine neoplasms (HG-NENs). The study cohort comprised 20 cases; 11 PD-NECs, 8 mixed adenoneuroendocrine carcinomas, and 1 WD-NET, G3 from various anatomic sites (gastrointestinal tract, pancreas, larynx, lung, and breast). The Ki67 index was evaluated on pretreatment (when available) and posttreatment samples. Topographic heterogeneity in the Ki67 index was expressed using a semi-quantitative score of 0 (no heterogeneity) to 5 (>80% difference between maximal Ki67 and minimal Ki67 indices). Relative to the pretreatment group (n=9, mean Ki67 of 86.3%, range 80% to 100%), the neoplasms in the posttreatment group (n=20, mean Ki67 of 47.7%, range 1% to 90%) showed a significantly lower Ki67 index (18/20 cases). Of the 18 cases with a relatively low Ki67 index, 15 showed heterogeneous labeling (mean heterogeneity score of 2.3, range 1 to 5) and in 3 cases it was a homogeneously low. This phenomenon was observed in all subtypes of HG-NENs. In 6 cases, the alterations in Ki67 index following treatment were sufficient to place these HG-NENs in the WHO G1 or G2 grade, erroneously suggesting a diagnosis of WD-NET, and in 9 cases there was sufficient heterogeneity in the Ki67 index to suggest that a limited biopsy may sample an area of low Ki67, even though hotspot regions with a Ki67 index of >20% persisted. In 7 cases, the alterations in the Ki67 index were accompanied by morphologic features resembling a WD-NET. These observations suggest that there is a potential for misinterpretation of previously treated PD-NECs as WD-NETs, or for assigning a lower grade in G3 WD-NETs. While the prognostic significance of treatment-associated alterations in Ki67 index is unknown, awareness of this phenomenon is important to avoid this diagnostic pitfall when evaluating treated NENs.


Assuntos
Carcinoma Neuroendócrino/patologia , Antígeno Ki-67/análise , Gradação de Tumores/métodos , Antineoplásicos/uso terapêutico , Biomarcadores Tumorais/análise , Carcinoma Neuroendócrino/tratamento farmacológico , Humanos , Índice Mitótico
6.
Int J Mol Sci ; 21(24)2020 Dec 19.
Artigo em Inglês | MEDLINE | ID: mdl-33352665

RESUMO

Evolution of tumor-immune microenviroments (TIMEs) occurs during tumor growth and dissemination. Understanding inter-site tumor-immune heterogeneity is essential to harness the immune system for cancer therapy. While the development of immunotherapy against lung cancer with driver mutations and neuroendocrine tumors is ongoing, little is known about the TIME of large cell neuroendocrine carcinoma (LCNEC) or anaplastic lymphoma kinase (ALK) rearrangement-positive lung cancer. We present a case study of a 32-year-old female patient with ALK-rearrangement-positive LCNEC, who had multiple distant metastases including mediastinal lymph-node, bilateral breasts, multiple bones, liver and brain. Multiple biopsy samples obtained from primary lung and three metastatic tumors were analyzed by fluorescent multiplex immunohistochemistry. Tissue localizations of tumor-infiltrating lymphocytes in the tumor nest and surrounding stroma were evaluated. T cell and B cell infiltrations were decreased with distance from primary lung lesion. Although each tumor displayed a unique TIME, all tumors exhibited concomitant regression after treatment with an ALK-inhibitor. This study provides the first evidence of the coexistence of distinct TIME within a single individual with ALK-rearrangement-positive LCNEC. The present study contributes to our understanding of heterogeneous TIMEs between primary and metastatic lesions and provides new insights into the complex interplay between host-immunity and cancer cells in primary and metastatic lesions.


Assuntos
Quinase do Linfoma Anaplásico/genética , Carcinoma Neuroendócrino/patologia , Rearranjo Gênico , Neoplasias Pulmonares/patologia , Linfócitos do Interstício Tumoral , Microambiente Tumoral , Adulto , Carcinoma Neuroendócrino/tratamento farmacológico , Carcinoma Neuroendócrino/genética , Feminino , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Prognóstico , Inibidores de Proteínas Quinases/uso terapêutico
7.
Medicine (Baltimore) ; 99(50): e23271, 2020 Dec 11.
Artigo em Inglês | MEDLINE | ID: mdl-33327249

RESUMO

BACKGROUND: Mixed neuroendocrine nonneuroendocrine neoplasms (MiNENs) originating from the biliary system (gallbladder, biliary tract, or ampulla of Vater) are extremely rare and have not been discussed in detail or systematically. We aimed to present the demographics, clinicopathological characteristics, management, and prognostic factors of biliary MiNENs. METHODS: A systematic search of electronic biomedical databases (Web of Science, PUBMED, and Embase) was performed to identify eligible studies. Survival was analyzed with the Kaplan-Meier method. Log-rank tests were used to evaluate the differences between groups, and the effects of various clinical and histopathological features on prognosis were analyzed by univariate and multivariate Cox regression. RESULTS: Fifty-three publications (patients, n = 67) were included. The median overall survival time was 21.0 months. Fifty-one patients (76.1%) underwent radical surgery and median survival for 41 months (P < .001). Twenty-two patients who received adjuvant radiochemotherapy treatment after radical surgery had a median survival for 43 months (P = .076). Radical resection (P < .001), Ki-67 index (P = .011), tumor stage (P < .001), neuroendocrine (NEC) grade (P = .011), and non-NEC grade (P = .017) were independent statistically significant prognostic factors according to univariate analysis; radical resection (P = .010) and small morphological subtype (P = .036) were independent statistically significant prognostic factors associated with higher overall survival according to multivariate analysis, and radical resection (P = .005) and age < 65 years (P = .026) were associated with higher recurrence free survival time. CONCLUSION: Radical resection is essential for long-term survival. Aggressive multimodality therapy with adjuvant radiochemotherapy and biotherapy may improve survival of biliary MiNENs. Further randomized controlled trials are needed to determine the standard treatment.


Assuntos
Neoplasias do Sistema Biliar/patologia , Carcinoma Neuroendócrino/patologia , Tumor Misto Maligno/patologia , Tumores Neuroendócrinos/patologia , Sistema Biliar/patologia , Neoplasias do Sistema Biliar/diagnóstico , Neoplasias do Sistema Biliar/terapia , Carcinoma Neuroendócrino/diagnóstico , Carcinoma Neuroendócrino/terapia , Humanos , Tumor Misto Maligno/diagnóstico , Tumor Misto Maligno/terapia , Tumores Neuroendócrinos/diagnóstico , Tumores Neuroendócrinos/terapia , Prognóstico , Análise de Sobrevida
8.
J Card Surg ; 35(10): 2802-2803, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-33043656

RESUMO

We present the clinical case of a 60-year-old woman complained of dyspnea on exertion. Echocardiogram showed a giant mass in the right ventricle (RV) with obstruction to the outflow tract. Thorax computed tomography confirmed a mass of greater than 60 mm infiltrating RV and causing severe stenosis in the pulmonary artery, with severe pericardial effusion. Cardiac surgery was performed for tumor resection and pulmonary root replacement with a biological valved conduit. Histological analysis diagnosed a poorly differentiated large-cell neuroendocrine carcinoma. The patient had no immediate postoperative complications and has completed radiotherapy at a 9-month follow-up.


Assuntos
Carcinoma Neuroendócrino/diagnóstico por imagem , Carcinoma Neuroendócrino/cirurgia , Procedimentos Cirúrgicos Cardíacos/métodos , Ecocardiografia , Neoplasias Cardíacas/diagnóstico por imagem , Neoplasias Cardíacas/cirurgia , Ventrículos do Coração/diagnóstico por imagem , Ventrículos do Coração/cirurgia , Artéria Pulmonar/diagnóstico por imagem , Artéria Pulmonar/cirurgia , Tomografia Computadorizada por Raios X , Implante de Prótese Vascular/métodos , Carcinoma Neuroendócrino/complicações , Carcinoma Neuroendócrino/patologia , Constrição Patológica/diagnóstico por imagem , Constrição Patológica/etiologia , Constrição Patológica/cirurgia , Feminino , Neoplasias Cardíacas/complicações , Neoplasias Cardíacas/patologia , Ventrículos do Coração/patologia , Humanos , Pessoa de Meia-Idade , Derrame Pericárdico/diagnóstico por imagem , Derrame Pericárdico/etiologia , Artéria Pulmonar/patologia , Índice de Gravidade de Doença , Resultado do Tratamento
9.
Medicine (Baltimore) ; 99(43): e22652, 2020 Oct 23.
Artigo em Inglês | MEDLINE | ID: mdl-33120755

RESUMO

RATIONALE: Poorly differentiated neuroendocrine carcinoma of the breast is a rare cancer with poor prognosis. There is no standard treatment for the disease. Neoadjuvant therapies and surgery are considered to be the main treatment when the tumor diameter is greater than 5.0 cm. Neoadjuvant therapies include chemotherapy and endocrine therapy. However, the effect of neoadjuvant endocrine therapy is not clear in the disease. PATIENT CONCERNS: In August 2014, a 28-year-old premenopausal woman noted a mass that was approximately 3.0 cm*2.0 cm in size on her right breast with pain. Subsequently, the mass has been always increasing significantly. In August 2015, the mass was approximately 7.0 cm*5.0 cm in size, accompanied by pain, no nipple retraction and discharge, no orange peel-like skin changes, and no dimples. In addition, she had no salient past history. DIAGNOSES: Histopathological examinations by a biopsy with a thick needle (hollow needle) and surgical resection confirmed poorly differentiated neuroendocrine carcinoma of the right breast. INTERVENTIONS: First and remarkably, she underwent 3 months of neoadjuvant endocrine therapy (goserelin once every 28 days, and letrozole 10 mg every day). Then, she underwent surgery - stage I breast reconstruction by using prosthesis. Adjuvant endocrine therapy has been used since the operation. OUTCOMES: According to response evaluation criteria in solid tumors 1.1, the tumor was shrunk by 78.87% after neoadjuvant endocrine therapy. No salient complications were observed. We have followed her for 48 months, and there are no signs of recurrence and metastasis. LESSONS: Poorly differentiated neuroendocrine carcinoma of the breast is rare and has a poor prognosis. Currently, there is no standard treatment for this disease. Studies show estrogen receptor and progesterone receptor of neuroendocrine carcinoma of the breast are often highly expressed. In the case, it can be observed that estrogen receptor and progesterone receptor are highly expressed. Therefore, neoadjuvant endocrine therapy may be considered in neuroendocrine carcinoma of the breast when the mass is large and the patient refuses neoadjuvant chemotherapy. We hope to provide an attractive evidence for neoadjuvant endocrine therapy of neuroendocrine carcinoma of the breast. However, more cases are still being needed for research.


Assuntos
Antineoplásicos Hormonais/administração & dosagem , Inibidores da Aromatase/administração & dosagem , Neoplasias da Mama/tratamento farmacológico , Carcinoma Neuroendócrino/tratamento farmacológico , Gosserrelina/administração & dosagem , Letrozol/administração & dosagem , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/diagnóstico , Neoplasias da Mama/patologia , Carcinoma Neuroendócrino/diagnóstico , Carcinoma Neuroendócrino/patologia , Feminino , Humanos , Terapia Neoadjuvante/métodos
10.
Medicine (Baltimore) ; 99(36): e21912, 2020 Sep 04.
Artigo em Inglês | MEDLINE | ID: mdl-32899024

RESUMO

Gallbladder neuroendocrine carcinoma (GB-NEC) is a group of rare and heterogeneous neoplasms and there are few reports at present.We analyzed the clinical and pathological features of 7 patients with GB-NEC who were admitted to Zhejiang Provincial People's Hospital from January 2011 to October 2019.The median age of 7 patients was 58 years with male to female ratio of 1:2.5. Right upper quadrant discomfort was the main complaint and no patients presented carcinoid syndrome-related symptoms. In contrast-enhanced computed tomography (CT) examination, 5 of 6 patients showed well-defined margin and continuous thin line-like contrast enhancement on the mucosa. Among the patients with liver metastases before surgery, 66.7% of patients were cancer antigen 125 (CA-125) positive, and among the patients presented with liver metastases during follow-up period, all patients were CA-125 positive. All patients with elevated CA-125 did not have ascites, ovarian carcinoma, peritoneal carcinoma, and endometrial carcinoma. According to postoperative pathological report, 1 patient was stage IIIA, and the other 6 patients were stage IVB. Six patients underwent surgery, and 1 patient just underwent liver biopsy. Two patients underwent laparoscopic radical cholecystectomy, and neither of them encountered serious complications after surgery with the overall survival time of 4.6 and 16.8 months, respectively. Compared with the patients without chemotherapy, 3 patients postoperatively treated with chemotherapy lived longer. The median survival of all 7 patients was 4.6 months and the 1-, 2-year survival rates were 14.29%, 0%.Surgical resection, including laparoscopic radical cholecystectomy, is feasible for the treatment of advanced GB-NEC in selected patients and has the advantages of prolonging survival in combination with chemotherapy. The elevation of CA-125 can be utilized as an important predictor of poor prognosis, while more investigations are necessary to confirm it.


Assuntos
Carcinoma Neuroendócrino/patologia , Neoplasias da Vesícula Biliar/patologia , Biomarcadores/sangue , Antígeno Ca-125/sangue , Carcinoma Neuroendócrino/diagnóstico por imagem , Carcinoma Neuroendócrino/mortalidade , Carcinoma Neuroendócrino/terapia , Feminino , Neoplasias da Vesícula Biliar/diagnóstico por imagem , Neoplasias da Vesícula Biliar/mortalidade , Neoplasias da Vesícula Biliar/terapia , Humanos , Masculino , Pessoa de Meia-Idade , Tomografia Computadorizada por Raios X
11.
Medicine (Baltimore) ; 99(38): e22306, 2020 Sep 18.
Artigo em Inglês | MEDLINE | ID: mdl-32957392

RESUMO

RATIONALE: Gastric mixed adenoneuroendocrine carcinoma (gMANEC) is a rare malignant tumor. Most gMANECs are diagnosed at an advanced stage and have a worse prognosis than gastric adenocarcinoma. In order to improve the prognosis, it is necessary to diagnose gMANEC at an early stage. However, the endoscopic features of early gMANECs are unclear. We, herein, report a case of early gMANEC that showed characteristic magnifying endoscopic findings. PATIENT CONCERNS: A 78-year-old man was referred to our institution for endoscopic resection of a gastric lesion. He had a medical history of distal gastrectomy due to early gastric cancer with negative surgical margins 9 years previously. DIAGNOSIS: Esophagogastroduodenoscopy showed a reddish depressed lesion on the suture line of the gastric remnant, which was classified as type 0-IIc according to the Paris classification. ME-NBI at the oral side of the lesion revealed the absence of the microsurface pattern (MSP) and scattered microvessels with dilation and caliber variation, while ME-NBI at the anal side showed an irregularly tubular MSP. An endoscopic forceps biopsy showed a well- to moderately differentiated adenocarcinoma. INTERVENTIONS: We performed endoscopic submucosal dissection, and en bloc resection of the tumor was successfully achieved. OUTCOMES: The histological findings showed two distinct components: neuroendocrine carcinoma (NEC) and well-differentiated adenocarcinoma, which comprised ∼60% and 40% of the tumor, respectively. The NEC component corresponded to the site with the absence of an MSP and scattered microvessels on ME-NBI, while the well-differentiated adenocarcinoma component corresponded to the site with an irregularly tubular MSP. The pathological diagnosis was mixed adenoneuroendocrine carcinoma, infiltrating into the deep submucosal layer. LESSONS: We propose that the absence of an MSP plus an irregular MSP is characteristics of gMANEC, which was useful for the diagnosis of gMANEC before treatment.


Assuntos
Carcinoma Neuroendócrino/patologia , Neoplasias Gástricas/patologia , Idoso , Carcinoma Neuroendócrino/diagnóstico , Carcinoma Neuroendócrino/cirurgia , Endoscopia do Sistema Digestório , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Invasividade Neoplásica , Neoplasias Gástricas/diagnóstico , Neoplasias Gástricas/cirurgia
12.
Medicine (Baltimore) ; 99(33): e21628, 2020 Aug 14.
Artigo em Inglês | MEDLINE | ID: mdl-32872023

RESUMO

RATIONABLE: Large cell neuroendocrine carcinoma of the lung is rare, especially in the area of the foramen magnum. No previous studies have reported metastatic large cell neuroendocrine lung cancer to the foramen magnum. This paper will be the first time to report this special case. PATIENT CONCERNS: A case of a 37-year-old woman presented with headache that had developed 20 days previously. Imaging examination revealed a circular abnormal signal at the posterior margin of the foramen magnum. DIAGNOSES: The patient we report was diagnosed with a metastatic intracranial tumor. INTERVENTIONS: The patient underwent occipital craniotomy. Pathological results showed metastatic neuroendocrine carcinoma of the brain. Whole body PET-CT examination showed that fusiform soft tissue shadows could be seen near the hilum of the lower lobe of the left lung. OUTCOMES: The final bronchoscopy pathological results showed the large cell neuroendocrine carcinoma of the lung. The patient underwent further chemotherapy and radiotherapy in the oncology department. LESSONS: Diagnosis and treatment of large cell neuroendocrine carcinoma of the lung are difficult. The prognosis is poorer, and effective treatment is urgently needed.


Assuntos
Neoplasias Encefálicas/secundário , Carcinoma Neuroendócrino/patologia , Forame Magno/patologia , Neoplasias Pulmonares/patologia , Adulto , Neoplasias Encefálicas/diagnóstico por imagem , Neoplasias Encefálicas/cirurgia , Carcinoma Neuroendócrino/diagnóstico por imagem , Carcinoma Neuroendócrino/terapia , Feminino , Humanos , Neoplasias Pulmonares/diagnóstico por imagem , Neoplasias Pulmonares/terapia , Tomografia Computadorizada com Tomografia por Emissão de Pósitrons , Tomografia Computadorizada por Raios X
13.
Am J Surg Pathol ; 44(10): 1308-1321, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32739935

RESUMO

Neuroendocrine carcinoma (NEC) is an aggressive malignant tumor that rarely arises from the gallbladder. Here, we investigated the clinicopathologic and immunohistochemical characteristics of 34 NECs of the gallbladder. The patients were predominantly women (68%) with a median age of 63 years (range, 37 to 82 y). NECs frequently occurred in the fundus (44%) as mass-forming lesions (66%). Histologically, 17 tumors were of small cell type, and another 17 were of large cell type. Twenty-three cases (68%) were associated with biliary intraepithelial neoplasia (38%) and intracholecystic papillary neoplasm (29%). The majority of tumors exhibited a diffuse growth pattern (74%), followed by organoid (24%) or scirrhous (2%) growth patterns. Histologic features related to neuroendocrine differentiation, such as nuclear molding (56%), perilobular pseudopalisading (18%), and rosette formation (15%), were identified. Immunohistochemically, cytokeratin 7 and 20 were expressed in 19 (56%) and 8 (24%) cases, respectively. Loss of Rb1 expression and concomitant overexpression of p16 were observed in 25 (74%) cases. No BRAF mutations were identified in any of the 34 NECs. For survival analysis, the 1-, 3-, and 5-year overall survival rates were 64%, 35%, and 19%, respectively. In a multivariate analysis, the receipt of adjuvant chemoradiation therapy was identified as the only independent prognostic factor associated with the overall survival rate. The 1- and 3-year overall survival rates of patients with NECs were poorer for patients with poorly differentiated adenocarcinoma of the gallbladder (P<0.001). The complete resection and application of postoperative adjuvant therapy may influence a better clinical outcome in patients with NEC of the gallbladder.


Assuntos
Biomarcadores Tumorais/análise , Carcinoma Neuroendócrino/patologia , Neoplasias da Vesícula Biliar/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma Neuroendócrino/genética , Carcinoma Neuroendócrino/mortalidade , Inibidor p16 de Quinase Dependente de Ciclina/genética , Feminino , Neoplasias da Vesícula Biliar/genética , Neoplasias da Vesícula Biliar/mortalidade , Humanos , Imuno-Histoquímica , Masculino , Pessoa de Meia-Idade , Proteínas Proto-Oncogênicas B-raf/genética
14.
APMIS ; 128(11): 563-572, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32794589

RESUMO

Neuroendocrine tumors (NETs) are often diagnosed from the metastases of an unknown primary tumor. Specific immunohistochemical (IHC) markers indicating the location of a primary tumor are needed. The proprotein convertase subtilisin/kexin type 2 (PCSK2) is found in normal neural and neuroendocrine cells, and known to express in NETs. We investigated the tissue microarray (TMA) of 86 primary tumors from 13 different organs and 9 metastatic NETs, including primary tumor-metastasis pairs, for PCSK2 expression with polymer-based IHC. PCSK2 was strongly positive in all small intestine and appendiceal NETs, the so-called midgut NETs, in most pheochromocytomas and paragangliomas, and in some of the typical and atypical pulmonary carcinoid tumors. NETs showing strong positivity were re-evaluated in larger tumor cohorts confirming the primary observation. In the metastases, the expression of PCSK2 mirrored that of the corresponding primary tumors. We found negative or weak staining in NETs from the thymus, gastric mucosa, pancreas, rectum, thyroid, and parathyroid. PCSK2 expression did not correlate with Ki-67 in well-differentiated NETs. Our data suggest that PCSK2 positivity can indicate the location of the primary tumor. Thus, PCSK2 could function in the IHC panel determined from screening metastatic NET biopsies of unknown primary origins.


Assuntos
Neoplasias das Glândulas Suprarrenais/genética , Carcinoma Neuroendócrino/genética , Neoplasias Gastrointestinais/genética , Neoplasias Pulmonares/genética , Tumores Neuroendócrinos/genética , Paraganglioma/genética , Feocromocitoma/genética , Pró-Proteína Convertase 2/genética , Adenocarcinoma/diagnóstico , Adenocarcinoma/genética , Adenocarcinoma/patologia , Adenocarcinoma/cirurgia , Neoplasias das Glândulas Suprarrenais/diagnóstico , Neoplasias das Glândulas Suprarrenais/patologia , Neoplasias das Glândulas Suprarrenais/cirurgia , Biomarcadores Tumorais/genética , Carcinoma Neuroendócrino/diagnóstico , Carcinoma Neuroendócrino/patologia , Carcinoma Neuroendócrino/cirurgia , Cromogranina A/genética , Feminino , Neoplasias Gastrointestinais/diagnóstico , Neoplasias Gastrointestinais/patologia , Neoplasias Gastrointestinais/cirurgia , Expressão Gênica , Humanos , Imuno-Histoquímica , Antígeno Ki-67/genética , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/cirurgia , Metástase Linfática , Masculino , Estadiamento de Neoplasias , Tumores Neuroendócrinos/diagnóstico , Tumores Neuroendócrinos/patologia , Tumores Neuroendócrinos/cirurgia , Paraganglioma/diagnóstico , Paraganglioma/patologia , Paraganglioma/cirurgia , Feocromocitoma/diagnóstico , Feocromocitoma/patologia , Feocromocitoma/cirurgia , Neoplasias da Glândula Tireoide/diagnóstico , Neoplasias da Glândula Tireoide/genética , Neoplasias da Glândula Tireoide/patologia , Neoplasias da Glândula Tireoide/cirurgia
15.
Anticancer Res ; 40(8): 4741-4748, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32727800

RESUMO

BACKGROUND/AIM: We aimed to investigate the efficacy of immune-cell therapy in terms of the survival of patients with neuroendocrine carcinoma of the uterine cervix (NECC), which lacks standardized therapeutic approaches. PATIENTS AND METHODS: We identified 17 patients who were diagnosed as having NECC and treated with immune-cell therapy. The clinical characteristics of these patients were extracted from their records and their overall survival was measured. RESULTS: Of the 17 patients, two patients with early-stage NECC without recurrence and three patients with less than four treatments were excluded. The median survival times from the time of diagnosis and from the initial administration of immune-cell therapy were 49.7 and 24.4 months, respectively. The overall survival rates at 1, 2, and 5 years were 63.6%, 38.2%, and 25.5%, respectively. Long-term survival was observed in the patients with distant metastases. CONCLUSION: The preliminary results of this retrospective study suggested the potential efficacy of immune-cell therapy for NECC.


Assuntos
Carcinoma Neuroendócrino/imunologia , Carcinoma Neuroendócrino/terapia , Colo do Útero/patologia , Neoplasias do Colo do Útero/imunologia , Neoplasias do Colo do Útero/terapia , Adulto , Carcinoma Neuroendócrino/patologia , Terapia Baseada em Transplante de Células e Tecidos/métodos , Feminino , Humanos , Imunoterapia Adotiva/métodos , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/imunologia , Recidiva Local de Neoplasia/patologia , Recidiva Local de Neoplasia/terapia , Estadiamento de Neoplasias/métodos , Prognóstico , Neoplasias do Colo do Útero/patologia
16.
PLoS One ; 15(6): e0234505, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32544169

RESUMO

In order to improve treatment selection for high grade neuroendocrine carcinomas of the cervix (NECC), we performed a comparative genomic analysis between this rare tumor type and other cervical cancer types, as well as extra-cervical neuroendocrine small cell carcinomas of the lung and bladder. We performed whole exome sequencing on fresh-frozen tissue from 15 NECCs and matched normal tissue. We then identified mutations and copy number variants using standard analysis pipelines. Published mutation tables from cervical cancers and extra-cervical small cell carcinomas were used for comparative analysis. Descriptive statistical methods were used and a two-sided threshold of P < .05 was used for significance. In the NECC cohort, we detected a median of 1.7 somatic mutations per megabase (range 1.0-20.9). PIK3CA p.E545K mutations were the most frequency observed oncogenic mutation (4/15 tumors, 27%). Activating MAPK pathway mutations in KRAS (p.G12D) and GNAS (p.R201C) co-occurred in two tumors (13%). In total we identified PI3-kinase or MAPK pathway activating mutations in 67% of NECC. When compared to NECC, lung and bladder small cell carcinomas exhibited a statistically significant higher rate of coding mutations (P < .001 for lung; P = .001 for bladder). Mutation of TP53 was uncommon in NECC (13%) and was more frequent in both lung (103 of 110 tumors [94%], P < .001) and bladder (18 of 19 tumors [95%], P < .001) small cell carcinoma. These comparative genomics data suggest that NECC may be genetically more similar to common cervical cancer subtypes than to extra-cervical small cell neuroendocrine carcinomas of the lung and bladder. These results may have implications for the selection of cytotoxic and targeted therapy regimens for this rare disease.


Assuntos
Carcinoma Neuroendócrino/genética , Variações do Número de Cópias de DNA/genética , Genômica , Neoplasias do Colo do Útero/genética , Adulto , Carcinoma Neuroendócrino/patologia , Colo do Útero/metabolismo , Colo do Útero/patologia , Cromograninas/genética , Classe I de Fosfatidilinositol 3-Quinases/genética , Estudos de Coortes , Feminino , Subunidades alfa Gs de Proteínas de Ligação ao GTP/genética , Humanos , Pessoa de Meia-Idade , Mutação/genética , Proteínas Proto-Oncogênicas p21(ras)/genética , Proteína Supressora de Tumor p53 , Neoplasias do Colo do Útero/patologia , Sequenciamento Completo do Exoma
17.
Medicine (Baltimore) ; 99(26): e20854, 2020 Jun 26.
Artigo em Inglês | MEDLINE | ID: mdl-32590784

RESUMO

INTRODUCTION: Although primary hepatic neuroendocrine carcinomas, whose prognostic mechanisms remain unclear, are rare, coexistence of neuroendocrine carcinomas and other tumors is rarer. In this report, we describe a unique case of coexistence between primary hepatic neuroendocrine carcinoma and a distal cholangiocarcinoma in the pancreas. PATIENT CONCERNS: A 64-year-old woman with a history of diabetes, but none of hepatitis, was admitted to hospital because of intermittent epigastric distension and pain discomfort for more than 1 month aggravated 1 day. A contrast-enhanced computed tomography (CT) scan of the upper abdomen and abdominal magnetic resonance imaging (MRI) revealed a thickening of the bile duct wall in the middle and lower segment of common bile duct and the corresponding lumen is narrow and low-density tumors with ring enhancement (1.83 cm × 1.9 cm) in lobi hepatis dexte. DIAGNOSIS: Primary neuroendocrine carcinoma of the liver was diagnosed to be coexisting with a distal cholangiocarcinoma, which had invaded the pancreas. Immunohistochemical examination revealed that the neoplastic cells strongly expressed chromogranin A, synaptophysin, and CD56 proteins. The tumor cells did not express HepPar-1, glypican-3, S-100, CK7, and CK19 in the liver tumor. A distal bile duct in pancreatic tissues shows the characteristics of typical bile duct carcinoma, as an invasion of carcinoma is also seen in the pancreatic tissues. Gastrointestinal endoscopy, chest and abdominal CT, abdominal MRI, and positron emission tomography (PET)-CT were used to exclude metastatic neuroendocrine tumors of the liver. INTERVENTIONS: Resection of the pancreas-duodenum, the right anterior lobe of the liver, and regional lymph nodes was performed in patients. OUTCOMES: The patient had survived for 5 months after the operation. CONCLUSION: A unique case of a coexistence of primary hepatic neuroendocrine carcinoma and a distal cholangiocarcinoma, which had invaded the pancreas. No treatment guidelines are established for the treatment of the unique case.


Assuntos
Carcinoma Neuroendócrino/diagnóstico , Colangiocarcinoma/diagnóstico , Fígado/anormalidades , Antígeno CD56/análise , Antígeno CD56/sangue , Carcinoma Neuroendócrino/patologia , Colangiocarcinoma/patologia , Cromogranina A/análise , Cromogranina A/sangue , Feminino , Humanos , Imuno-Histoquímica/métodos , Fígado/patologia , Fígado/fisiopatologia , Pessoa de Meia-Idade , Prognóstico , Sinaptofisina/análise , Sinaptofisina/sangue , Tomografia Computadorizada por Raios X/métodos
18.
Am J Clin Pathol ; 154(3): 369-380, 2020 08 05.
Artigo em Inglês | MEDLINE | ID: mdl-32445471

RESUMO

OBJECTIVES: The possibility of a so-called primary lymph node neuroendocrine carcinoma has been described in the literature. Here we evaluate cases fitting such a diagnosis and find that the cases demonstrate a convincing and pervasive pattern consistent with metastatic Merkel cell carcinoma. METHODS: Six cases of primary lymph node Merkel cell carcinoma and one case of metastatic neuroendocrine carcinoma at a bony site, all with unknown primary, were sequenced using a combination of whole-exome and targeted panel methods. Sequencing results were analyzed for the presence of an ultraviolet (UV) mutational signature or off-target detection of Merkel cell polyomavirus (MCPyV). RESULTS: Four of six primary lymph node cases were positive for a UV mutational signature, with the remaining two cases positive for off-target alignment of MCPyV. One case of neuroendocrine carcinoma occurring at a bony site was also positive for a UV mutational signature. CONCLUSIONS: We find no evidence to corroborate the existence of so-called primary Merkel cell carcinoma of lymph node.


Assuntos
Carcinoma de Célula de Merkel/patologia , Carcinoma Neuroendócrino/patologia , Linfonodos/patologia , Metástase Linfática/patologia , Neoplasias Cutâneas/patologia , Carcinoma de Célula de Merkel/virologia , Carcinoma Neuroendócrino/virologia , Humanos , Linfonodos/virologia , Poliomavírus das Células de Merkel , Neoplasias Cutâneas/virologia , Infecções Tumorais por Vírus/patologia , Infecções Tumorais por Vírus/virologia
19.
Am J Surg Pathol ; 44(10): 1419-1428, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32452872

RESUMO

We investigated the prognostic value of a range of histologic parameters in medullary thyroid carcinoma (MTC) to design a grading system to predict overall survival. We assessed 76 patients with MTCs undergoing primary tumor resection for age, sex, tumor size, vascular space invasion, lymph node metastasis, multiple endocrine neoplasia type 2 (MEN2) status, mitotic count, Ki-67 proliferative index, spindled morphology, sheet-like growth pattern, coagulative necrosis, incipient necrosis, nuclear grade, multinucleation, prominent nucleoli, fibrosis, and amyloid deposition. In addition to the clinical features of age and the diagnosis of MEN2, the only histologic features that significantly predicted reduced overall survival were Ki-67 proliferative index, mitotic count, and the presence of coagulative necrosis. Using a combination of these 3 variables, we propose a 3-tiered grading system based solely on proliferative activity (Ki-67 proliferative index and mitotic count) and necrosis. There were 62 (82%) low-grade MTCs (low proliferative activity, no necrosis), 9 (12%) intermediate grade (low proliferative activity and necrosis present, or intermediate proliferative activity and no necrosis), and 5 (7%) high grade (intermediate proliferative activity and necrosis present, or high proliferative activity with or without necrosis). The mean overall survival was 193, 146, and 45 months, respectively (P=0.0001) for the 3 grades. The grading system remained prognostic when controlled for other factors associated with survival including age and known MEN2 syndrome. We conclude that this proposed grading system, which uses only a combination of proliferative activity (Ki-67 index, mitotic count) and coagulative necrosis, is a strong predictor of overall survival in MTC.


Assuntos
Carcinoma Neuroendócrino/patologia , Gradação de Tumores/métodos , Neoplasias da Glândula Tireoide/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma Neuroendócrino/mortalidade , Feminino , Humanos , Antígeno Ki-67/análise , Masculino , Pessoa de Meia-Idade , Índice Mitótico , Necrose/patologia , Prognóstico , Análise de Sobrevida , Neoplasias da Glândula Tireoide/mortalidade , Adulto Jovem
20.
PLoS One ; 15(5): e0233720, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32459817

RESUMO

Since patients with medullary thyroid cancer (MTC) often have metastatic disease at the time of diagnosis, the development of efficient systemic treatment options for MTC is important. Vandetanib and cabozantinib are two tyrosine kinase inhibitors (TKIs) that were recently approved by FDA and EMA for systemic treatment of metastatic MTC. Additionally, since MTC is of a neuroendocrine tumour type, treatment with radiolabelled somatostatin analogues (e.g. 177Lu-octreotate) is a valid option for patients with MTC. The aim of this study was to investigate the potentially increased therapeutic effect of combining radiation therapy with these TKIs for treatment of MTC in a mouse model. Nude mice carrying patient-derived MTC tumours (GOT2) were treated with external beam radiotherapy (EBRT) and/or one of the two TKIs vandetanib or cabozantinib. The tumour volume was determined and compared with that of mock-treated controls. The treatment doses were chosen to give a moderate effect as monotherapy to be able to detect any increased therapeutic effect from the combination therapy. At the end of follow-up, tumours were processed for immunohistochemical (IHC) analyses. The animals in the combination therapy groups showed the largest reduction in tumour volume and the longest time to tumour progression. Two weeks after start of treatment, the tumour volume for these mice was reduced by about 70-75% compared with controls. Furthermore, also EBRT and TKI monotherapy resulted in a clear anti-tumour effect with a reduced tumour growth compared with controls. The results show that an increased therapeutic effect could be achieved when irradiation is combined with TKIs for treatment of MTC. Future studies should evaluate the potential of using 177Lu-octreotate therapy in combination with TKIs in patients.


Assuntos
Anilidas/farmacologia , Carcinoma Neuroendócrino/terapia , Quimiorradioterapia , Proteínas de Neoplasias/antagonistas & inibidores , Piperidinas/farmacologia , Proteínas Tirosina Quinases/antagonistas & inibidores , Piridinas/farmacologia , Quinazolinas/farmacologia , Neoplasias da Glândula Tireoide/terapia , Animais , Carcinoma Neuroendócrino/enzimologia , Carcinoma Neuroendócrino/patologia , Feminino , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Proteínas de Neoplasias/metabolismo , Proteínas Tirosina Quinases/metabolismo , Neoplasias da Glândula Tireoide/enzimologia , Neoplasias da Glândula Tireoide/patologia , Ensaios Antitumorais Modelo de Xenoenxerto
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