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1.
Ann Surg ; 275(6): 1165-1174, 2022 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-33214420

RESUMO

OBJECTIVE: This study aimed to identify risk factors for recurrence after pancreatic resection for intraductal papillary mucinous neoplasm (IPMN). SUMMARY BACKGROUND DATA: Long-term follow-up data on recurrence after surgical resection for IPMN are currently lacking. Previous studies have presented mixed results on the role of margin status in risk of recurrence after surgical resection. METHODS: A total of 126 patients that underwent resection for noninvasive IPMN were followed for a median of 9.5 years. Dedicated pathological and radiological reviews were performed to correlate clinical and pathological features (including detailed pathological features of the parenchymal margin) with recurrence after surgical resection. In addition, in a subset of 32 patients with positive margins, we determined the relationship between the margin and original IPMN using driver gene mutations identified by next-generation sequencing. RESULTS: Family history of pancreatic cancer and high-grade IPMN was identified as risk factors for recurrence in both uni- and multivariate analysis (adjusted hazard ratio 3.05 and 1.88, respectively). Although positive margin was not significantly associated with recurrence in our cohort, the size and grade of the dysplastic focus at the margin were significantly correlated with recurrence in margin-positive patients. Genetic analyses showed that the neoplastic epithelium at the margin was independent from the original IPMN in at least 9 of 32 cases (28%). The majority of recurrences (74%) occurred after 3 years, and a significant minority (32%) occurred after 5 years. CONCLUSION: Sustained postoperative surveillance for all patients is indicated, particularly those with risk factors such has family history and high-grade dysplasia.


Assuntos
Adenocarcinoma Mucinoso , Carcinoma Ductal Pancreático , Carcinoma Papilar , Neoplasias Intraductais Pancreáticas , Neoplasias Pancreáticas , Adenocarcinoma Mucinoso/genética , Adenocarcinoma Mucinoso/patologia , Adenocarcinoma Mucinoso/cirurgia , Carcinoma Ductal Pancreático/genética , Carcinoma Ductal Pancreático/patologia , Carcinoma Ductal Pancreático/cirurgia , Carcinoma Papilar/patologia , Carcinoma Papilar/cirurgia , Seguimentos , Humanos , Margens de Excisão , Recidiva Local de Neoplasia/patologia , Pancreatectomia/métodos , Neoplasias Intraductais Pancreáticas/genética , Neoplasias Intraductais Pancreáticas/cirurgia , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/patologia , Neoplasias Pancreáticas/cirurgia , Estudos Retrospectivos
2.
Mod Pathol ; 33(4): 639-647, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-31700162

RESUMO

Venous invasion is three times more common in pancreatic cancer than it is in other major cancers of the gastrointestinal tract, and venous invasion may explain why pancreatic cancer is so deadly. To characterize the patterns of venous invasion in pancreatic cancer, 52 thick slabs (up to 5 mm) of tissue were harvested from 52 surgically resected human ductal adenocarcinomas, cleared with a modified iDISCO method, and labeled with fluorescent-conjugated antibodies to cytokeratin 19, desmin, CD31, p53 and/or e-cadherin. Labeled three-dimensional (3D) pancreas cancer tissues were visualized with confocal laser scanning or light sheet microscopy. Multiple foci of venous and even arterial invasion were visualized. Venous invasion was detected more often in 3D (88%, 30/34 cases) than in conventional 2D slide evaluation (75%, 25/34 cases, P < 0.001). 3D visualization revealed pancreatic cancer cells crossing the walls of veins at multiple points, often at points where preexisting capillary structures bridge the blood vessels. The neoplastic cells often retained a ductal morphology (cohesive cells forming tubes) as they progressed from a stromal to intravenous location. Although immunolabeling with antibodies to e-cadherin revealed focal loss of expression at the leading edges of the cancers, the neoplastic cells within veins expressed e-cadherin and formed well-oriented glands. We conclude that venous invasion is almost universal in pancreatic cancer, suggesting that even surgically resectable PDAC has access to the venous spaces and thus the ability to disseminate widely. Furthermore, we observe that sustained epithelial-mesenchymal transition is not required for venous invasion in pancreatic cancer.


Assuntos
Carcinoma Ductal Pancreático/patologia , Transição Epitelial-Mesenquimal , Imageamento Tridimensional , Microscopia Confocal , Neoplasias Pancreáticas/patologia , Veias/patologia , Idoso , Idoso de 80 Anos ou mais , Antígenos CD/análise , Baltimore , Biomarcadores Tumorais/análise , Caderinas/análise , Carcinoma Ductal Pancreático/química , Carcinoma Ductal Pancreático/cirurgia , Desmina/análise , Feminino , Técnica Indireta de Fluorescência para Anticorpo , Alemanha , Humanos , Queratina-19/análise , Masculino , Pessoa de Meia-Idade , Invasividade Neoplásica , Neoplasias Pancreáticas/química , Neoplasias Pancreáticas/cirurgia , Molécula-1 de Adesão Celular Endotelial a Plaquetas/análise , Proteína Supressora de Tumor p53/análise , Veias/química
3.
Gut ; 67(9): 1652-1662, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-29500184

RESUMO

OBJECTIVE: Intraductal papillary mucinous neoplasms (IPMNs) are precursor lesions that can give rise to invasive pancreatic carcinoma. Although approximately 8% of patients with resected pancreatic ductal adenocarcinoma have a co-occurring IPMN, the precise genetic relationship between these two lesions has not been systematically investigated. DESIGN: We analysed all available patients with co-occurring IPMN and invasive intrapancreatic carcinoma over a 10-year period at a single institution. For each patient, we separately isolated DNA from the carcinoma, adjacent IPMN and distant IPMN and performed targeted next generation sequencing of a panel of pancreatic cancer driver genes. We then used the identified mutations to infer the relatedness of the IPMN and co-occurring invasive carcinoma in each patient. RESULTS: We analysed co-occurring IPMN and invasive carcinoma from 61 patients with IPMN/ductal adenocarcinoma as well as 13 patients with IPMN/colloid carcinoma and 7 patients with IPMN/carcinoma of the ampullary region. Of the patients with co-occurring IPMN and ductal adenocarcinoma, 51% were likely related. Surprisingly, 18% of co-occurring IPMN and ductal adenocarcinomas were likely independent, suggesting that the carcinoma arose from an independent precursor. By contrast, all colloid carcinomas were likely related to their associated IPMNs. In addition, these analyses showed striking genetic heterogeneity in IPMNs, even with respect to well-characterised driver genes. CONCLUSION: This study demonstrates a higher prevalence of likely independent co-occurring IPMN and ductal adenocarcinoma than previously appreciated. These findings have important implications for molecular risk stratification of patients with IPMN.


Assuntos
Biomarcadores Tumorais/genética , Carcinoma Ductal Pancreático/genética , Mutação/genética , Neoplasias Pancreáticas/genética , Adenocarcinoma Mucinoso/genética , Idoso , Carcinoma Ductal Pancreático/diagnóstico , Carcinoma Ductal Pancreático/mortalidade , Carcinoma Papilar/genética , Cromograninas/genética , Proteínas de Ligação a DNA/genética , Feminino , Seguimentos , Subunidades alfa Gs de Proteínas de Ligação ao GTP/genética , Genes p16 , Humanos , Masculino , Pessoa de Meia-Idade , Mutação de Sentido Incorreto/genética , Invasividade Neoplásica , Proteínas Oncogênicas/genética , Neoplasias Pancreáticas/diagnóstico , Neoplasias Pancreáticas/mortalidade , Valor Preditivo dos Testes , Prevalência , Estudos Retrospectivos , Sensibilidade e Especificidade , Índice de Gravidade de Doença , Proteína Smad4/genética , Análise de Sobrevida , Ubiquitina-Proteína Ligases , Estados Unidos
4.
J Pathol ; 243(2): 148-154, 2017 10.
Artigo em Inglês | MEDLINE | ID: mdl-28722124

RESUMO

Undifferentiated carcinoma of the pancreas with osteoclast-like giant cells (UCOGC) is currently considered a morphologically and clinically distinct variant of pancreatic ductal adenocarcinoma (PDAC). In this study, we report clinical and pathological features of a series of 22 UCOGCs, including the whole exome sequencing of eight UCOGCs. We observed that 60% of the UCOGCs contained a well-defined epithelial component and that patients with pure UCOGC had a significantly better prognosis than did those with an UCOGC with an associated epithelial neoplasm. The genetic alterations in UCOGC are strikingly similar to those known to drive conventional PDAC, including activating mutations in the oncogene KRAS and inactivating mutations in the tumor suppressor genes CDKN2A, TP53, and SMAD4. These results further support the classification of UCOGC as a PDAC variant and suggest that somatic mutations are not the determinants of the unique phenotype of UCOGC. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.


Assuntos
Carcinoma Ductal Pancreático/patologia , Neoplasias Pancreáticas/patologia , Idoso , Idoso de 80 Anos ou mais , Carcinoma Ductal Pancreático/genética , Carcinoma Ductal Pancreático/mortalidade , Exoma/genética , Feminino , Humanos , Imuno-Histoquímica , Masculino , Pessoa de Meia-Idade , Mutação/genética , Proteínas de Neoplasias/genética , Osteoclastos/patologia , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/mortalidade , Neoplasias Pancreáticas
5.
Cancer Res ; 80(13): 2804-2817, 2020 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-32376602

RESUMO

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignancy characterized by extensive local invasion and systemic spread. In this study, we employed a three-dimensional organoid model of human pancreatic cancer to characterize the molecular alterations critical for invasion. Time-lapse microscopy was used to observe invasion in organoids from 25 surgically resected human PDAC samples in collagen I. Subsequent lentiviral modification and small-molecule inhibitors were used to investigate the molecular programs underlying invasion in PDAC organoids. When cultured in collagen I, PDAC organoids exhibited two distinct, morphologically defined invasive phenotypes, mesenchymal and collective. Each individual PDAC gave rise to organoids with a predominant phenotype, and PDAC that generated organoids with predominantly mesenchymal invasion showed a worse prognosis. Collective invasion predominated in organoids from cancers with somatic mutations in the driver gene SMAD4 (or its signaling partner TGFBR2). Reexpression of SMAD4 abrogated the collective invasion phenotype in SMAD4-mutant PDAC organoids, indicating that SMAD4 loss is required for collective invasion in PDAC organoids. Surprisingly, invasion in passaged SMAD4-mutant PDAC organoids required exogenous TGFß, suggesting that invasion in SMAD4-mutant organoids is mediated through noncanonical TGFß signaling. The Rho-like GTPases RAC1 and CDC42 acted as potential mediators of TGFß-stimulated invasion in SMAD4-mutant PDAC organoids, as inhibition of these GTPases suppressed collective invasion in our model. These data suggest that PDAC utilizes different invasion programs depending on SMAD4 status, with collective invasion uniquely present in PDAC with SMAD4 loss. SIGNIFICANCE: Organoid models of PDAC highlight the importance of SMAD4 loss in invasion, demonstrating that invasion programs in SMAD4-mutant and SMAD4 wild-type tumors are different in both morphology and molecular mechanism.


Assuntos
Adenocarcinoma/mortalidade , Biomarcadores Tumorais/metabolismo , Carcinoma Ductal Pancreático/mortalidade , Regulação Neoplásica da Expressão Gênica , Organoides/patologia , Neoplasias Pancreáticas/mortalidade , Proteína Smad4/metabolismo , Adenocarcinoma/metabolismo , Adenocarcinoma/patologia , Adenocarcinoma/cirurgia , Biomarcadores Tumorais/genética , Carcinoma Ductal Pancreático/metabolismo , Carcinoma Ductal Pancreático/patologia , Carcinoma Ductal Pancreático/cirurgia , Movimento Celular , Proliferação de Células , Humanos , Invasividade Neoplásica , Organoides/metabolismo , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/patologia , Neoplasias Pancreáticas/cirurgia , Prognóstico , Transdução de Sinais , Proteína Smad4/genética , Taxa de Sobrevida , Células Tumorais Cultivadas
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