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OBJECTIVE: Epidemiological studies highlight an association between pancreatic ductal adenocarcinoma (PDAC) and oral carriage of the anaerobic bacterium Porphyromonas gingivalis, a species highly linked to periodontal disease. We analysed the potential for P. gingivalis to promote pancreatic cancer development in an animal model and probed underlying mechanisms. DESIGN: We tracked P. gingivalis bacterial translocation from the oral cavity to the pancreas following administration to mice. To dissect the role of P. gingivalis in PDAC development, we administered bacteria to a genetically engineered mouse PDAC model consisting of inducible acinar cell expression of mutant Kras (Kras +/LSL-G12D; Ptf1a-CreER, iKC mice). These mice were used to study the cooperative effects of Kras mutation and P. gingivalis on the progression of pancreatic intraepithelial neoplasia (PanIN) to PDAC. The direct effects of P. gingivalis on acinar cells and PDAC cell lines were studied in vitro. RESULTS: P. gingivalis migrated from the oral cavity to the pancreas in mice and can be detected in human PanIN lesions. Repetitive P. gingivalis administration to wild-type mice induced pancreatic acinar-to-ductal metaplasia (ADM), and altered the composition of the intrapancreatic microbiome. In iKC mice, P. gingivalis accelerated PanIN to PDAC progression. In vitro, P. gingivalis infection induced acinar cell ADM markers SOX9 and CK19, and intracellular bacteria protected PDAC cells from reactive oxygen species-mediated cell death resulting from nutrient stress. CONCLUSION: Taken together, our findings demonstrate a causal role for P. gingivalis in pancreatic cancer development in mice.
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Carcinoma in Situ , Carcinoma Ductal Pancreático , Microbiota , Neoplasias Pancreáticas , Lesões Pré-Cancerosas , Camundongos , Humanos , Animais , Proteínas Proto-Oncogênicas p21(ras)/genética , Proteínas Proto-Oncogênicas p21(ras)/metabolismo , Composição de Bases , Lesões Pré-Cancerosas/patologia , Filogenia , RNA Ribossômico 16S/metabolismo , Análise de Sequência de DNA , Neoplasias Pancreáticas/patologia , Carcinoma Ductal Pancreático/patologia , Carcinoma in Situ/genética , Células Acinares/patologia , Bactérias/genéticaRESUMO
OBJECTIVE: Cellular senescence limits tumourigenesis by blocking the proliferation of premalignant cells. Additionally, however, senescent cells can exert paracrine effects influencing tumour growth. Senescent cells are present in premalignant pancreatic intraepithelial neoplasia (PanIN) lesions, yet their effects on the disease are poorly characterised. It is currently unknown whether senolytic drugs, aimed at eliminating senescent cells from lesions, could be beneficial in blocking tumour development. DESIGN: To uncover the functions of senescent cells and their potential contribution to early pancreatic tumourigenesis, we isolated and characterised senescent cells from PanINs formed in a Kras-driven mouse model, and tested the consequences of their targeted elimination through senolytic treatment. RESULTS: We found that senescent PanIN cells exert a tumour-promoting effect through expression of a proinflammatory signature that includes high Cox2 levels. Senolytic treatment with the Bcl2-family inhibitor ABT-737 eliminated Cox2-expressing senescent cells, and an intermittent short-duration treatment course dramatically reduced PanIN development and progression to pancreatic ductal adenocarcinoma. CONCLUSIONS: These findings reveal that senescent PanIN cells support tumour growth and progression, and provide a first indication that elimination of senescent cells may be effective as preventive therapy for the progression of precancerous lesions.
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Adenocarcinoma/patologia , Senescência Celular/efeitos dos fármacos , Ciclo-Oxigenase 2/metabolismo , Neoplasias Pancreáticas/patologia , Lesões Pré-Cancerosas/patologia , Senoterapia/uso terapêutico , Adenocarcinoma/metabolismo , Animais , Modelos Animais de Doenças , Camundongos , Neoplasias Pancreáticas/metabolismo , Lesões Pré-Cancerosas/metabolismoRESUMO
BACKGROUND: Lymphoma of the nervous system is rare and usually involves the brain, spinal cord, or peripheral nerves. Hence, it has varied clinical presentations, and correct diagnosis is often challenging. Incorrect diagnosis delays the appropriate treatment and affects prognosis. We report 5 patients with delayed diagnosis of lymphoma involving the central and/or peripheral nervous system, initially evaluated for other neurological diagnoses. We also discuss the challenge of diagnosis and appropriate testing. METHODS: Retrospective review of 2011-2019 records of patients with confirmed nervous system lymphoma diagnosed in a tertiary care medical center. RESULTS: We present 5 adult patients initially evaluated for inflammatory myelopathy, inflammatory lumbosacral plexopathy, atypical parkinsonism, and demyelinating disease of the CNS. Final diagnosis of the nervous system lymphoma was delayed by 4 to 18 months and was based on tissue biopsy in 4, and on CSF and bone marrow examination in 1 patient. CONCLUSIONS: Lymphoma may imitate various central and peripheral nervous system disorders. We suggest several red flags that indicate the need to consider lymphoma, including subacute but progressive symptomatic evolution, painful neurological deficit, unclear clinical diagnosis, and transient steroid responsiveness. Correct diagnosis often requires a combination of diagnostic tests, while pathology testing is crucial for early diagnosis and is strongly recommended in the appropriate clinical setting.
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Linfoma , Adulto , Encéfalo , Erros de Diagnóstico , Humanos , Linfoma/diagnóstico , Estudos Retrospectivos , Medula EspinalRESUMO
OBJECTIVE: Von Hippel-Lindau (VHL) syndrome is a rare and complex disease. In 1996, we described a 3 generation VHL 2A kindred with 11 mutation carriers. We aim to share our experience regarding the long-term follow-up of this family and the management of all our other VHL patients focusing on frequently encountered neuroendocrine neoplasms: pheochromocytoma/paraganglioma and pancreatic neuroendocrine neoplasms (PNEN). METHODS: All VHL patients in follow-up at our tertiary center from 1980 to 2019 were identified. Clinical, laboratory, imaging, and therapeutic characteristics were retrospectively analyzed. RESULTS: We identified 32 VHL patients in 16 different families, 7/16 were classified as VHL 2 subtype. In the previously described family, the 4 initially asymptomatic carriers developed a neuroendocrine tumor; 7 new children were born, 3 of them being mutation carriers; 2 patients died, 1 due to metastatic PNEN-related liver failure. Pheochromocytoma was frequent (22/32), bilateral (13/22;59%), often diagnosed in early childhood when active screening was timely performed, associated with paraganglioma in 5/22, rarely malignant (1/22), and recurred after surgery in some cases after more than 20 years. PNEN occurred in 8/32 patients (25%), and was metastatic in 3 patients. Surgery and palliative therapy allowed relatively satisfactory outcomes. Severe disabling morbidities due to central-nervous system and ophthalmologic hemangiomas, and other rare tumors as chondrosarcoma in 2 patients and polycythemia in 1 patient were observed. CONCLUSION: A multidisciplinary approach and long-term follow-up is mandatory in VHL patients to manage the multiple debilitating morbidities and delay mortality in these complex patients.
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Neoplasias das Glândulas Suprarrenais , Tumores Neuroendócrinos , Neoplasias Pancreáticas , Doença de von Hippel-Lindau , Neoplasias das Glândulas Suprarrenais/epidemiologia , Neoplasias das Glândulas Suprarrenais/terapia , Criança , Pré-Escolar , Humanos , Recidiva Local de Neoplasia , Tumores Neuroendócrinos/epidemiologia , Tumores Neuroendócrinos/terapia , Neoplasias Pancreáticas/epidemiologia , Neoplasias Pancreáticas/terapia , Estudos Retrospectivos , Proteína Supressora de Tumor Von Hippel-Lindau , Doença de von Hippel-Lindau/epidemiologia , Doença de von Hippel-Lindau/genéticaRESUMO
BACKGROUND AND AIM OF THE STUDY: The prosthetic valve of choice in patients with carcinoid valve disease (CVD) remains controversial due to the limited life expectancy of patients with advanced-stage neuroendocrine tumors (NETs) on the one hand, and concerns regarding structural valve deterioration (SVD) on the other hand. METHODS: The records of 17 patients (11 females, seven males; mean age 65 ± 11 years; undergoing 18 operations) with primarily right heart failure due to CVD were reviewed. All patients received somatostatin analogs perioperatively. Hospital and follow up data (acquired via direct patient contact and echocardiography) collected included baseline characteristics, procedural details, and clinical outcomes. RESULTS: The primary NET site was the ileum (n = 11), lungs (n = 2) and stomach, colon and appendix (n = 1 each). In one patient the primary tumor location could not be identified. Preoperative urinary levels of 5-hydroxyindole acetic acid (5-HIAA; 61 ± 36 mg/24 h) and serum levels of chromogranin A (2926 ± 4057 ng/ml) were 10- and 50-fold greater than normal, respectively. A total of 23 valves was implanted: five tricuspid valve replacements (TVR; four tissue and one mechanical), TVR and pulmonary valve replacements (PVR; three tissue and one mechanical), and TVR and mitral valve replacements (MVR; one tissue and two mechanical). The 30-day mortality was 11% (n = 2). No patient experienced a carcinoid crisis. The mean follow up was 24 ± 21 months (range: 4-85 months). Four patients (receiving seven valves) developed SVD at 12, 14, 15, and 20 months after surgery, and all of these patients died. The actuarial four-year survival and freedom from SVD were 23 ± 14% and 43 ± 15%, respectively. CONCLUSIONS: The data acquired suggested that the main advantage of tissue valve prostheses, namely to avoid lifelong, intense anticoagulation, might be offset by accelerated SVD. The use of mechanical valves should be considered in CVD patients with a large primary tumor mass and persistent high urinary levels of 5-HIAA, and who are unresponsive to therapy.
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Doença Cardíaca Carcinoide/cirurgia , Doenças das Valvas Cardíacas/cirurgia , Implante de Prótese de Valva Cardíaca/instrumentação , Próteses Valvulares Cardíacas , Valvas Cardíacas/cirurgia , Tempo para o Tratamento , Idoso , Anticoagulantes/uso terapêutico , Doença Cardíaca Carcinoide/diagnóstico por imagem , Doença Cardíaca Carcinoide/mortalidade , Doença Cardíaca Carcinoide/fisiopatologia , Feminino , Doenças das Valvas Cardíacas/diagnóstico por imagem , Doenças das Valvas Cardíacas/mortalidade , Doenças das Valvas Cardíacas/fisiopatologia , Implante de Prótese de Valva Cardíaca/efeitos adversos , Implante de Prótese de Valva Cardíaca/mortalidade , Valvas Cardíacas/diagnóstico por imagem , Valvas Cardíacas/fisiopatologia , Humanos , Israel , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Seleção de Pacientes , Desenho de Prótese , Estudos Retrospectivos , Fatores de Risco , Texas , Fatores de Tempo , Resultado do TratamentoRESUMO
Objective and Impact Statement: Human epidermal growth factor receptor 2 (HER2) is a critical protein in cancer cell growth that signifies the aggressiveness of breast cancer (BC) and helps predict its prognosis. Here, we introduce a deep learning-based approach utilizing pyramid sampling for the automated classification of HER2 status in immunohistochemically (IHC) stained BC tissue images. Introduction: Accurate assessment of IHC-stained tissue slides for HER2 expression levels is essential for both treatment guidance and understanding of cancer mechanisms. Nevertheless, the traditional workflow of manual examination by board-certified pathologists encounters challenges, including inter- and intra-observer inconsistency and extended turnaround times. Methods: Our deep learning-based method analyzes morphological features at various spatial scales, efficiently managing the computational load and facilitating a detailed examination of cellular and larger-scale tissue-level details. Results: This approach addresses the tissue heterogeneity of HER2 expression by providing a comprehensive view, leading to a blind testing classification accuracy of 84.70%, on a dataset of 523 core images from tissue microarrays. Conclusion: This automated system, proving reliable as an adjunct pathology tool, has the potential to enhance diagnostic precision and evaluation speed, and might substantially impact cancer treatment planning.
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Senescent cells within tumors and their stroma exert complex pro- and anti-tumorigenic functions. However, the identities and traits of these cells, and the potential for improving cancer therapy through their targeting, remain poorly characterized. Here, we identify a senescent subset within previously-defined cancer-associated fibroblasts (CAFs) in pancreatic ductal adenocarcinomas (PDAC) and in premalignant lesions in mice and humans. Senescent CAFs isolated from mouse and humans expressed elevated levels of immune-regulatory genes. Depletion of senescent CAFs, either genetically or using the Bcl-2 inhibitor ABT-199 (venetoclax), increased the proportion of activated CD8+ T cells in mouse pancreatic carcinomas, whereas induction of CAF senescence had the opposite effect. Combining ABT-199 with an immune checkpoint therapy regimen significantly reduced mouse tumor burden. These results indicate that senescent CAFs in PDAC stroma limit the numbers of activated cytotoxic CD8+ T cells, and suggest that their targeted elimination through senolytic treatment may enhance immunotherapy.
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Linfócitos T CD8-Positivos , Fibroblastos Associados a Câncer , Carcinoma Ductal Pancreático , Senescência Celular , Imunoterapia , Neoplasias Pancreáticas , Sulfonamidas , Animais , Fibroblastos Associados a Câncer/imunologia , Fibroblastos Associados a Câncer/metabolismo , Fibroblastos Associados a Câncer/patologia , Neoplasias Pancreáticas/imunologia , Neoplasias Pancreáticas/terapia , Neoplasias Pancreáticas/patologia , Neoplasias Pancreáticas/genética , Linfócitos T CD8-Positivos/imunologia , Camundongos , Humanos , Carcinoma Ductal Pancreático/imunologia , Carcinoma Ductal Pancreático/terapia , Carcinoma Ductal Pancreático/patologia , Carcinoma Ductal Pancreático/genética , Senescência Celular/imunologia , Imunoterapia/métodos , Sulfonamidas/farmacologia , Sulfonamidas/uso terapêutico , Camundongos Endogâmicos C57BL , Linhagem Celular Tumoral , Ativação Linfocitária/imunologia , Feminino , Inibidores de Checkpoint Imunológico/farmacologia , Inibidores de Checkpoint Imunológico/uso terapêutico , Adenocarcinoma/imunologia , Adenocarcinoma/terapia , Adenocarcinoma/genética , Adenocarcinoma/patologia , Masculino , Compostos Bicíclicos Heterocíclicos com PontesRESUMO
INTRODUCTION: The use of chromogranin A (CGA) as a circulating biomarker in lung carcinoids (LCs) is limited by low specificity and sensitivity. This study aimed to evaluate plasma progastrin-releasing peptide (ProGRPp) as an alternative to plasma CGA (CGAp), for the diagnosis and follow-up of LC. METHODS: ProGRPp and CGAp concentrations were measured in 107 patients with LC and 105 patients with benign lung disease (BLD). RESULTS: ProGRPp distinguished patients with LC with active disease in the pretreatment (n = 43) and post-treatment (n = 43) groups from those with BLD: area under the curve for both 0.864 (p < 0.0001); sensitivity 67.4% and 58.1%, respectively; specificity 96.2%; at 64 pg/mL cutoff. CGAp failed to differentiate both LC groups from those with BLD: area under the curve 0.579 and 0.526 (for both p > 0.1); sensitivity 34.9% and 25.6%, respectively; specificity 73.3%; at 104 ng/mL cutoff. Only ProGRPp correlated with the Ki67 proliferation index (r = 0.40, p < 0.001) and was associated with mitotic count (p = 0.025), stage (p = 0.018), grade (p = 0.019), and the expression of thyroid transcription factor-1 (p = 0.005). ProGRPp had a high sensitivity (92.3%) in LC with diffuse idiopathic pulmonary neuroendocrine cell hyperplasia. Abnormal postoperative ProGRPp level was associated with residual disease (p = 0.029). The changes in ProGRPp level during treatment, a decrease greater than 30% and an increase greater than 8%, were associated with image-based outcomes, partial response and disease progression, respectively (p < 0.0001). CGAp did not reflect the disease course. CONCLUSIONS: ProGRPp was superior to CGAp in diagnosing LC with correlations concerning proliferation, grading, staging, diffuse idiopathic pulmonary neuroendocrine cell hyperplasia co-occurrence, and response to treatment. ProGRPp is an optimal emerging biomarker to be further evaluated.
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Carcinoma Neuroendócrino , Neoplasias Pulmonares , Tumores Neuroendócrinos , Humanos , Neoplasias Pulmonares/diagnóstico , Cromogranina A , Hiperplasia , Peptídeos , Progressão da Doença , Pulmão , Biomarcadores TumoraisAssuntos
Calcinose/diagnóstico , Cesárea , Achados Incidentais , Neoplasias Intestinais/diagnóstico , Neoplasias de Tecido Fibroso/diagnóstico , Complicações Neoplásicas na Gravidez/diagnóstico , Calcinose/patologia , Calcinose/cirurgia , Feminino , Humanos , Neoplasias Intestinais/patologia , Neoplasias Intestinais/cirurgia , Intestino Delgado/cirurgia , Neoplasias de Tecido Fibroso/patologia , Neoplasias de Tecido Fibroso/cirurgia , Gravidez , Complicações Neoplásicas na Gravidez/patologia , Complicações Neoplásicas na Gravidez/cirurgia , Adulto JovemRESUMO
Pancreatic cancer is one of the most lethal cancers, owing to its late diagnosis and resistance to chemotherapy. The tumor suppressor WW domain-containing oxidoreductase (WWOX), one of the most active fragile sites in the human genome (FRA16D), is commonly altered in pancreatic cancer. However, the direct contribution of WWOX loss to pancreatic cancer development and progression remains largely unknown. Here, we report that combined conditional deletion of Wwox and activation of KRasG12D in Ptf1a-CreER-expressing mice results in accelerated formation of precursor lesions and pancreatic carcinoma. At the molecular level, we found that WWOX physically interacts with SMAD3 and BMP2, which are known activators of the TGF-ß signaling pathway. In the absence of WWOX, TGFß/BMPs signaling was enhanced, leading to increased macrophage infiltration and enhanced cancer stemness. Finally, overexpression of WWOX in patient-derived xenografts led to diminished aggressiveness both in vitro and in vivo. Overall, our findings reveal an essential role of WWOX in pancreatic cancer development and progression and underscore its role as a bona fide tumor suppressor.
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Genes Supressores de Tumor , Neoplasias Pancreáticas , Oxidorredutase com Domínios WW , Animais , Humanos , Camundongos , Proteína Morfogenética Óssea 2/genética , Neoplasias Pancreáticas/genética , Fator de Crescimento Transformador beta/genética , Proteínas Supressoras de Tumor/genética , Oxidorredutase com Domínios WW/genética , Neoplasias PancreáticasRESUMO
PURPOSE: Neuroendocrine neoplasms (NENs) differ in their biological behavior and growth potential in a way that can be predicted using histological classification and grading systems. A subset of pancreatic NENs (pNENs) may develop a more aggressive phenotype during the course of the disease, associated with an increase in the Ki-67 proliferation index (PI). The purpose of the study was to present the clinical characteristics of these patients. METHODS: Using re-biopsy of growing lesions, we investigated the increase in Ki-67 PI sufficient to change initial grading (G). RESULTS: Of 264 patients with well differentiated (WD) pNENs who showed progressive disease during follow-up, 15 (6%) exhibited an increase in Ki-67 PI at a median time 36.8 (9.3-255.8) months. All neoplasms had WD-morphology: five had G1 (Ki-67 median value 1%), nine G2 (median value 5%), one G3 (25%) grades. Upon change of Ki-67 PI, 3 patients had G2 (8%) and 12 G3 (57.5%) NENs, while all retained their WD-morphology. At last follow-up, eight patients were alive with a median overall survival (OS) of 52.5 (9.5-264.3) months. Μedian OS was shorter in patients who had a change in Ki-67 PI before 36 months compared to those who had a change of Ki-67 PI at a later stage (27.5 95%CI: 11.88-43.06 vs. 120.87 95%CI: 96.05-145.69; log-rank p = 0.018). CONCLUSIONS: During the course of their disease, 6% patients with progressive pNENs develop an increase in Ki-67 PI resulting in an increase in grading status while maintaining their morphology. This process is associated with worse OS when it occurs at an early stage.
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Tumores Neuroendócrinos , Neoplasias Pancreáticas , Testes Diagnósticos de Rotina , Humanos , Antígeno Ki-67 , Gradação de Tumores , Estadiamento de Neoplasias , Tumores Neuroendócrinos/patologia , Neoplasias Pancreáticas/patologia , PrognósticoAssuntos
Neoplasias Cardíacas/diagnóstico , Hemangiossarcoma/diagnóstico , Linfoma Difuso de Grandes Células B/diagnóstico , Idoso de 80 Anos ou mais , Feminino , Átrios do Coração/patologia , Neoplasias Cardíacas/patologia , Ventrículos do Coração/patologia , Hemangiossarcoma/patologia , Humanos , Linfoma Difuso de Grandes Células B/patologiaRESUMO
Acinar metaplasia is an initial step in a series of events that can lead to pancreatic cancer. Here we perform single-cell RNA-sequencing of mouse pancreas during the progression from preinvasive stages to tumor formation. Using a reporter gene, we identify metaplastic cells that originated from acinar cells and express two transcription factors, Onecut2 and Foxq1. Further analyses of metaplastic acinar cell heterogeneity define six acinar metaplastic cell types and states, including stomach-specific cell types. Localization of metaplastic cell types and mixture of different metaplastic cell types in the same pre-malignant lesion is shown. Finally, single-cell transcriptome analyses of tumor-associated stromal, immune, endothelial and fibroblast cells identify signals that may support tumor development, as well as the recruitment and education of immune cells. Our findings are consistent with the early, premalignant formation of an immunosuppressive environment mediated by interactions between acinar metaplastic cells and other cells in the microenvironment.
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Células Acinares/patologia , Carcinoma Ductal Pancreático/genética , Regulação Neoplásica da Expressão Gênica , Pâncreas/patologia , Neoplasias Pancreáticas/genética , Lesões Pré-Cancerosas/genética , Animais , Animais Geneticamente Modificados , Biópsia , Carcinoma Ductal Pancreático/mortalidade , Carcinoma Ductal Pancreático/patologia , Carcinoma Ductal Pancreático/cirurgia , Diferenciação Celular , Modelos Animais de Doenças , Feminino , Fatores de Transcrição Forkhead/genética , Fatores de Transcrição Forkhead/metabolismo , Heterogeneidade Genética , Proteínas de Homeodomínio/genética , Proteínas de Homeodomínio/metabolismo , Humanos , Estimativa de Kaplan-Meier , Masculino , Metaplasia/genética , Camundongos , Mutação , Pâncreas/citologia , Pâncreas/cirurgia , Pancreatectomia , Neoplasias Pancreáticas/mortalidade , Neoplasias Pancreáticas/patologia , Neoplasias Pancreáticas/cirurgia , Lesões Pré-Cancerosas/patologia , Proteínas Proto-Oncogênicas p21(ras)/genética , RNA-Seq , Análise de Célula Única , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Microambiente Tumoral/genéticaRESUMO
Fusobacterium nucleatum is a common oral bacterium that is enriched in colorectal adenomas and adenocarcinomas (CRC). In humans, high fusobacterial CRC abundance is associated with chemoresistance and poor prognosis. In animal models, fusobacteria accelerate CRC progression. Targeting F. nucleatum may reduce fusobacteria cancer progression and therefore determining the origin of CRC F. nucleatum and the route by which it reaches colon tumors is of biologic and therapeutic importance. Arbitrarily primed PCR performed previously on matched same-patients CRC and saliva F. nucleatum isolates, suggested that CRC F. nucleatum may originate from the oral cavity. However, the origin of CRC fusobacteria as well as the route of their arrival to the tumor have not been well-established. Herein, we performed and analyzed whole genome sequencing of paired, same-patient oral, and CRC F. nucleatum isolates and confirmed that CRC-fusobacteria originate from the oral microbial reservoir. Oral fusobacteria may translocate to CRC by descending via the digestive tract or using the hematogenous route during frequent transient bacteremia caused by chewing, daily hygiene activities, or dental procedures. Using the orthotropic CT26 mouse model we previously showed that IV injected F. nucleatum colonize CRC. Here, we compared CRC colonization by gavage vs. intravenous inoculated F. nucleatum in the MC38 and CT26 mouse orthotropic CRC models. Under the tested conditions, hematogenous fusobacteria were more successful in CRC colonization than gavaged ones. Our results therefore provide evidence that the hematogenous route may be the preferred way by which oral fusobacteria reach colon tumors.
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Sistema Cardiovascular , Neoplasias do Colo , Infecções por Fusobacterium , Animais , Fusobacterium nucleatum , Humanos , BocaRESUMO
PURPOSE: The decreased life expectancy of MEN-1 patients is mainly related to pancreatic neuroendocrine tumors (pNETs). At best, limited data is available on the natural history of MEN-1-associated pNETs, as these tumors are rare and have a wide range of biologic behavior. Our study aims to explore the clinical course of patients with MEN-1-associated pNETs and the long-term outcomes. METHODS: This longitudinal study was conducted on the MEN-1 cohort treated at our referral center over a 22-year period (1996-2018). Relevant clinical data were retrospectively analysed. RESULTS: Among the 33 MEN-1 patients included in our study, pNETs were identified in 21 subjects with a penetrance of 48% by the age of 50. Non-functioning and functioning pNETs were diagnosed in sixteen (76%) and five (24%) patients, respectively. Two-thirds of the patients had multifocal tumors. The median number of pancreatic macroscopic lesions per individual was 4.0 ± 3.9 (range 1-8) with a mean size of 1.3 ± 2.1 cm (range 0.5-10). The metastatic rate according to the dominant pNET lesion reached 100%, 62% and 6% for tumors sized > 4 cm, 2.1-4 cm, and 1-2 cm, respectively. Over the study period, one or more therapeutic interventions for pNETs were required in 20 out of the 21 patients. pNET-related metastatic complication was the main cause of death within this MEN-1 cohort. The overall survival rate for the pNETs patients was 86% during a mean follow-up period of 8.0 ± 4.6 years. CONCLUSIONS: In our MEN-1 cohort, non-functioning pNETs were the most frequent type of pancreaticoduodenal tumor, and the tumor size correlated with the risks of metastasis and death. Increased awareness, early diagnosis, and a multidisciplinary approach may improve the associated morbidity and mortality in these patients.
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Neoplasia Endócrina Múltipla Tipo 1 , Tumores Neuroendócrinos , Neoplasias Pancreáticas , Humanos , Estudos Longitudinais , Neoplasia Endócrina Múltipla Tipo 1/terapia , Tumores Neuroendócrinos/epidemiologia , Tumores Neuroendócrinos/terapia , Neoplasias Pancreáticas/epidemiologia , Neoplasias Pancreáticas/terapia , Estudos RetrospectivosRESUMO
OBJECTIVE: The differential diagnosis of retroperito-neal tumors includes lymphoid, germ cell, and neurogenic tumors such as paraganglioma. Paragangliomas are rare neuroendocrine tumors of the autonomic nervous system, which may secrete catecholamines and their metabolites. Clinical features include sustained or paroxysmal hypertension, headaches, sweating, and palpitations. Here we present an unusual case of a retroperitoneal tumor entrapping a sympathetic nerve ganglion and mimicking paraganglioma. METHODS: A 57-year-old man with a history of controlled hypertension presented with paroxysms of tachycardia, flushing, high blood pressure, and headache. Ambulatory blood pressure monitoring showed uncontrolled labile hypertension with a normal nocturnal dip. Abdominal computed tomography (CT) demonstrated a 6.1 cm mass in the right retroperitoneum with adjacent lymphadenopathy. Paraganglioma was suspected and 24-hour urine demonstrated elevated normetanephrines (575 mcg/24 hours; normal, 5 to 290 mcg/24 hours) and vanillylmandelic acid (8.3 mg/24 hours; normal, 0.5 to 6.6 mg/24 hours). 68-Gallium DOTATATE positron emission tomography/CT showed weak uptake in the retroperitoneal mass and no other mass lesions. RESULTS: Following preparation with alpha-adrenergic blockers, surgical excision was performed with diagnostic and curative intent. Postoperatively, hypertension and paroxysmal symptoms resolved completely. The histopathology report described seminoma with an entrapped large ganglion within the tumor. CONCLUSION: We describe a retroperitoneal seminoma with an entrapped ganglion causing hypertension and paroxysmal symptoms, with laboratory and imaging features compatible with paraganglioma. Awareness of the rare possibility of mechanical pressure on a ganglion, within the differential diagnosis of retroperitoneal mass and sympathetic symptoms may aid in clinical decision making in atypical cases.
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Convex endobronchial ultrasound transbronchial needle aspiration (C-EBUS-TBNA) has become an essential modality for diagnosis and staging of hilar, mediastinal, and central pulmonary lesions. A Trans-thoracic pleural biopsy is the accepted practice for diagnosing pleural nodules. However, the diagnostic yield of a pleural biopsy is limited and surgical procedures pose a greater risk. We report a unique case of using a C- EBUS scope for the diagnosis of pleural nodules and mediastinal lymph node metastasis in a man with metastatic renal cell carcinoma.
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BACKGROUND: Chronic lymphocytic lymphoma (CLL) can be associated with several malignancies, but rarely with myelofibrosis. Only isolated case reports in the literature described the association between CLL and primary myelofibrosis (PMF) in the same patient. OBJECTIVES: We describe a case of CLL characterized by the development of PMF and a review of literature. METHODS: We describe an 86-year-old female diagnosed as having CLL and followed by the development of splenomegaly and progressively rising LDH levels 27 months later. A bone marrow biopsy was consistent with the diagnosis of PMF, with positive JAK-2 V617F mutation. We also review the clinical and molecular characteristics of patients with CLL and PMF. RESULTS: Patients with CLL and PMF are usually older. A lead diagnosis of CLL harbored by PMF is the most common clinical course, although concomitant diseases may occur in 31.7% of patients. JAK-2 V617F mutation can be found in 48.7% of patients. CONCLUSION: This case reported here constitutes an unusual situation of CLL characterized by the development of PMF. Etiologic and pathogenic associations-the role of t (1; 6) and JAK-2 V617F mutation-are discussed.
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BACKGROUND: Multiple endocrine neoplasia (MEN) 2A is an autosomal dominant disorder that results from a mutation in the RET proto-oncogene on chromosome 10. Almost all of the affected patients develop medullary thyroid carcinoma (MTC). The American Thyroid Association recommends prophylactic thyroidectomy in MEN 2A pediatric patients, with the age of the recommended thyroidectomy varying according to the codon mutation present. OBJECTIVES: This report questions the reliability of the currently placed guidelines and whether the age threshold for prophylactic thyroidectomy in patients with known codon 634 mutations should be lowered, in parallel with an earlier evaluation of calcitonin levels in the serum. METHODS: We report the preoperative diagnosis as well as operative and postoperative course of a 3-year-old female patient with MEN 2A (codon 634 mutation) who underwent prophylactic thyroidectomy. The postoperative histopathologic findings are presented and discussed. RESULTS: Despite the prophylactic nature of the operation, in parallel with a borderline calcitonin increase in the serum, bilateral MTC was discovered on pathology. CONCLUSION: It is likely that the current guidelines should be revised to recommend calcitonin screening and prophylactic thyroidectomy at an earlier age for MEN 2A patients with known codon 634 mutations.