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1.
Gut ; 71(5): 961-973, 2022 May.
Artigo em Inglês | MEDLINE | ID: mdl-33849943

RESUMO

OBJECTIVE: Recent studies have found aristaless-related homeobox gene (ARX)/pancreatic and duodenal homeobox 1 (PDX1), alpha-thalassemia/mental retardation X-linked (ATRX)/death domain-associated protein (DAXX) and alternative lengthening of telomeres (ALT) to be promising prognostic biomarkers for non-functional pancreatic neuroendocrine tumours (NF-PanNETs). However, they have not been comprehensively evaluated, especially among small NF-PanNETs (≤2.0 cm). Moreover, their status in neuroendocrine tumours (NETs) from other sites remains unknown. DESIGN: An international cohort of 1322 NETs was evaluated by immunolabelling for ARX/PDX1 and ATRX/DAXX, and telomere-specific fluorescence in situ hybridisation for ALT. This cohort included 561 primary NF-PanNETs, 107 NF-PanNET metastases and 654 primary, non-pancreatic non-functional NETs and NET metastases. The results were correlated with numerous clinicopathological features including relapse-free survival (RFS). RESULTS: ATRX/DAXX loss and ALT were associated with several adverse prognostic findings and distant metastasis/recurrence (p<0.001). The 5-year RFS rates for patients with ATRX/DAXX-negative and ALT-positive NF-PanNETs were 40% and 42% as compared with 85% and 86% for wild-type NF-PanNETs (p<0.001 and p<0.001). Shorter 5-year RFS rates for ≤2.0 cm NF-PanNETs patients were also seen with ATRX/DAXX loss (65% vs 92%, p=0.003) and ALT (60% vs 93%, p<0.001). By multivariate analysis, ATRX/DAXX and ALT status were independent prognostic factors for RFS. Conversely, classifying NF-PanNETs by ARX/PDX1 expression did not independently correlate with RFS. Except for 4% of pulmonary carcinoids, ATRX/DAXX loss and ALT were only identified in primary (25% and 29%) and NF-PanNET metastases (62% and 71%). CONCLUSIONS: ATRX/DAXX and ALT should be considered in the prognostic evaluation of NF-PanNETs including ≤2.0 cm tumours, and are highly specific for pancreatic origin among NET metastases of unknown primary.


Assuntos
Deficiência Intelectual , Tumores Neuroendócrinos , Neoplasias Pancreáticas , Talassemia alfa , Proteínas Correpressoras/genética , Genes Homeobox , Proteínas de Homeodomínio , Humanos , Deficiência Intelectual/genética , Chaperonas Moleculares/genética , Recidiva Local de Neoplasia/genética , Tumores Neuroendócrinos/genética , Proteínas Nucleares/genética , Neoplasias Pancreáticas/patologia , Telômero/genética , Telômero/patologia , Fatores de Transcrição/genética , Proteína Nuclear Ligada ao X/genética , Talassemia alfa/genética
2.
Pathobiology ; 89(1): 49-55, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-34515187

RESUMO

BACKGROUND: Endoscopic ultrasound-guided ablation (EUS-A) therapy is a minimally invasive procedure for pancreatic-cystic tumors in patients with preoperative comorbidities or in patients who are not indicated for surgical resection. However, histopathologic characteristics of pancreatic cysts after ablation have not been well-elucidated. METHODS: Here, we analyzed pathological findings of 12 surgically resected pancreatic cysts after EUS-A with ethanol and/or paclitaxel injection. RESULTS: Mean patient age was 49.8 ± 13.6 years with a 0.3 male/female ratio. Clinical impression before EUS-A was predominantly mucinous cystic neoplasms. Mean cyst size before and after ablation therapy was similar (3.7 ± 1.0 cm vs. 3.4 ± 1.6 cm; p = 0.139). Median duration from EUS-A to surgical resection was 18 (range, 1-59) months. Mean percentage of the residual neoplastic lining epithelial cells were 23.1 ± 37.0%. Of the resected cysts, 8 cases (67%) showed no/minimal (<5%) residual lining epithelia, while the remaining 4 cases (33%) showed a wide range of residual mucinous epithelia (20-90%). Ovarian-type stroma was noted in 5 cases (42%). Other histologic features included histiocytic aggregation (67%), stromal hyalinization (67%), diffuse egg shell-like calcification along the cystic wall (58%), and fat necrosis (8%). CONCLUSION: Above all, diffuse egg shell-like calcification along the pancreatic cystic walls with residual lining epithelia and/or ovarian-type stroma were characteristics of pancreatic cysts after EUS-A. Therefore, understanding these histologic features will be helpful for precise pathological diagnosis of pancreatic cystic tumor after EUS-A, even without knowing the patient's history of EUS-A.


Assuntos
Cisto Pancreático , Neoplasias Pancreáticas , Pseudocisto Pancreático , Adulto , Endossonografia , Etanol , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Paclitaxel , Cisto Pancreático/diagnóstico por imagem , Cisto Pancreático/cirurgia , Neoplasias Pancreáticas/diagnóstico por imagem , Neoplasias Pancreáticas/tratamento farmacológico
3.
APMIS ; 129(12): 729-742, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34779030

RESUMO

Yes-associated protein (YAP) and TEA domain-containing sequence-specific transcription factors 4 (TEAD4) are essential components of the Hippo pathway. Abnormal regulation of the Hippo pathway contributes to the progression and metastasis of many cancer types. However, their clinicopathologic and prognostic significances have not been studied in gallbladder cancers. Here, we systematically evaluated the YAP and TEAD4 immunolabelings and their association with clinicopathologic characteristics and survival outcomes using 212 specimens of surgically resected gallbladder cancers. High YAP and TEAD4 immunolabelings were identified in 70 (33%) cases and were associated with infiltrative growth pattern, poor differentiation, perineural invasion, and advanced pT classification and AJCC stage. High YAP immunolabeling was significantly associated with high TEAD4 immunolabeling (p < 0.001). High immunolabeling levels of YAP or TEAD4 alone and the combined YAPhigh TEAD4high group were significantly associated with poor survival in both univariate (p < 0.001) and multivariate analyses (HR = 2.358; 95% CI, 1.369-4.061; p = 0.002). Therefore, the YAP and TEAD4 immunolabelings are associated with aggressive behavior of gallbladder cancers and may be useful as a prognostic indicator in patients with surgically resected gallbladder cancer.


Assuntos
Proteínas de Ciclo Celular/análise , Proteínas de Ligação a DNA/análise , Neoplasias da Vesícula Biliar/mortalidade , Proteínas Musculares/análise , Fatores de Transcrição/análise , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Neoplasias da Vesícula Biliar/química , Neoplasias da Vesícula Biliar/patologia , Humanos , Imuno-Histoquímica , Masculino , Pessoa de Meia-Idade , Prognóstico
4.
Front Oncol ; 11: 658564, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34367955

RESUMO

BACKGROUND: Gallbladder cancer (GBC) has a poor prognosis. Although complete surgical resection is the only successful approach for improving survival, additional therapeutic modalities are required for recurrent or surgically unresectable GBCs. MATERIALS AND METHODS: To determine the expression status of HER2 and the mismatch repair (MMR) proteins MLH1, MSH2, MSH6, and PMS2, immunohistochemical staining of MMR proteins and HER2 was carried out in 216 surgically resected GBCs. HER2 labeling was scored by adopting a scoring system for gastric carcinomas. Tissues scoring 0 to 2+ were defined as HER2 negative, whereas those scoring 3+ were regarded as HER2-positive. In addition, silver in situ hybridization and microsatellite instability (MSI) analysis were conducted to confirm HER2 amplification and MSI, respectively. RESULTS: Three of 216 GBCs (1.3%) showed MMR protein deficiency. All three observed MSI cases exhibited dual loss of MSH2 and MSH6 protein expression. However, no cases showed loss of either MLH1 or PMS2 expression. No association was observed between MMR protein deficiency and other clinicopathological factors. HER2 amplification was noted in 30 (13.9%) GBCs and associated with Crohn-like lymphoid reaction (P = 0.023). No survival difference was observed based on HER2 overexpression or HER2 amplification status. CONCLUSION: MMR protein deficiency and HER2 overexpression were observed in a small subset (1.3% and 13.9%, respectively) of GBCs without simultaneous occurrence of deficient MMR protein expression and HER2 overexpression. The presence of Crohn-like lymphoid reaction may help identify cases with HER2 amplification, by using hematoxylin-stained slides. Although the proportion of MMR protein-deficient- and HER2-overexpressing GBCs was small, applying immunotherapy to MMR protein-deficient GBCs and herceptin to HER2-overexpressing GBCs may provide alternative treatment options for patients with GBC.

5.
HPB (Oxford) ; 23(2): 220-230, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-32654914

RESUMO

BACKGROUND: Solid pseudopapillary neoplasms (SPNs) of the pancreas have low malignant potential. However, malignant SPNs are not fully understood. METHODS: To evaluate risk factors affecting malignant potential, the clinicopathologic features of 375 surgically resected SPNs were compared. RESULTS: Fifty (13.3%) had malignant histologic features. Twenty-seven and 22 had perineural and lymphovascular invasions, respectively. Adjacent organ invasion was noted in 9 cases. Recurrence occurred in 8 cases. The median recurrence time after surgical resection was 67 months and was associated with a higher pT category (P = 0.001), lymphovascular invasion (P < 0.001), and synchronous metastasis (P < 0.001). SPN patients with malignant histologic features had worse recurrence-free survival (RFS; 10-year survival rate, 73.2%) than those without malignant histologic features (96.3%; P = 0.01). Patients with a higher pT category (P = 0.04), synchronous metastasis (P < 0.01), and lymphovascular invasion (P < 0.01) had worse RFS. Lymphovascular invasion (P = 0.042) and a higher T category (P = 0.002) were poor prognostic factors for recurrence. CONCLUSION: Lymphovascular invasion and a higher T category were worse prognostic factors for recurrence in SPN patients with malignant histologic features. For SPN patients with malignant histologic features, a longer follow-up may be required.


Assuntos
Carcinoma Papilar , Neoplasias Pancreáticas , Carcinoma Papilar/cirurgia , Humanos , Recidiva Local de Neoplasia , Pâncreas , Pancreatectomia/efeitos adversos , Neoplasias Pancreáticas/cirurgia , Prognóstico , Estudos Retrospectivos
6.
J Pathol Transl Med ; 55(5): 349-354, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32580538

RESUMO

Appendiceal actinomycosis is very rare and its diagnosis is often difficult even in surgically resected specimens. Here we report two cases of appendiceal actinomycosis confirmed by pathologic examination of surgically resected specimens. Characteristic histologic features included transmural chronic inflammation with Crohn-like lymphoid aggregates and polypoid mucosal protrusion into cecal lumen through fibrous expansion of the submucosa. Chronic active inflammation involved the mucosa of the appendix and cecum around the appendiceal orifice. Crohn's disease with predominant cecal involvement and inflammatory pseudotumor were considered as differential diagnoses. Careful examination revealed a few actinomycotic colonies in the mucosa, confirming the diagnosis. A high index of suspicion with awareness of the characteristic histologic features might prompt careful inspection for the actinomycotic colonies, leading to the appropriate diagnosis of this rare disease.

7.
Pancreatology ; 20(7): 1486-1494, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32948429

RESUMO

OBJECTIVES: Venous invasion is a poor prognostic factor for pancreatic ductal adenocarcinoma (PDAC). However, our understanding of various features of venous invasion is limited. Our aim is to comprehensively evaluate various histopathologic features of venous invasion, including status, type (lymphatic or venous), number of invasion foci, and histologic pattern (pancreatic intraepithelial neoplasia [PanIN]-like, conventional) in PDACs. METHODS: Various features of venous invasion, including status, number of invasion foci, histologic patterns [pancreatic intraepithelial neoplasia (PanIN)-like, conventional], and size of involved vessels in 471 surgically resected PDACs were evaluated with all available hematoxylin and eosin (H&E)-stained slides. RESULTS: Venous invasion was observed in 319 cases (67.7%) and was more frequently associated with increased tumor size, extrapancreatic extension, resection margin involvement, diffuse tumor distribution, lymph node metastasis, and perineural invasion (all Ps < .05). High frequency (≥3 foci) of venous invasion was associated with shorter overall survival both in the entire group and in the early stage subgroup (stage I; all Ps < .05). Multivariate analysis indicated that a high frequency (≥3 foci) of venous invasion, large tumor size (>4 cm), higher histologic grade, and lymph node metastasis, were independent prognostic factors of worse overall survival (all Ps < .05). CONCLUSION: Precise evaluation of venous invasion status, including foci number of invasion, can provide additional prognostic information for patients undergoing surgical resection of PDAC, especially for those with early disease stage.


Assuntos
Carcinoma Ductal Pancreático/irrigação sanguínea , Carcinoma Ductal Pancreático/patologia , Neoplasias Pancreáticas/irrigação sanguínea , Neoplasias Pancreáticas/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma Ductal Pancreático/cirurgia , Feminino , Humanos , Estimativa de Kaplan-Meier , Metástase Linfática/patologia , Masculino , Margens de Excisão , Pessoa de Meia-Idade , Invasividade Neoplásica/patologia , Metástase Neoplásica , Estadiamento de Neoplasias , Neoplasias Pancreáticas/cirurgia , Prognóstico , Fluxo Sanguíneo Regional , Análise de Sobrevida , Veias/patologia
8.
Histopathology ; 76(7): 1005-1012, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32181510

RESUMO

AIMS: Biliary intraductal tubular neoplasms that are non-mucinous and negative for mucin 5AC (MUC5AC) are called intraductal tubulopapillary neoplasms (ITPNs). Intraductal tubular neoplasms with mucinous cytoplasm and MUC5AC positivity also occur and their nature remains unclear, although some pathologists may classify these as 'intraductal papillary neoplasms of the bile duct (IPNBs) of gastric type'. This study aimed to elucidate genetic features of biliary intraductal tubular neoplasms. METHODS AND RESULTS: Six resected cases of biliary intraductal neoplasm with >70% tubular configuration were characterised by clinicopathological examination and whole exome sequencing, and the findings obtained were compared between MUC5AC-negative (n = 2) and -positive cases (n = 4). The intraductal tumours consisted of the pancreatobiliary-type epithelium with high-grade dysplasia arranged in back-to-back tubules. Both of the two MUC5AC-negative cases were non-invasive neoplasms and developed in the liver, whereas all MUC5AC-positive cases had invasive carcinoma and were present in the intrahepatic (n = 2), perihilar (n = 1) and distal bile ducts (n = 1). In an exome-sequencing study, MUC5AC-negative cases harboured mutations in CTNNB1, SF3B1, BAP1 and BRCA1 (one case each). KRAS mutations were observed in three of four MUC5AC-positive cases (75%) but none of the MUC5AC-negative neoplasms. Compared to published data, known driver genes of other intraductal neoplasms of the pancreatobiliary system (e.g. APC, CTNNB1, STK11, GNAS and PIK3CA) were wild-type in all but one MUC5AC-negative case with CTNNB1 mutation. Chromatin modifiers (ARID1A, BAP1 and KMT2C) were also altered in MUC5AC-positive cases, similar to usual cholangiocarcinomas. CONCLUSIONS: This exome-sequencing study suggested that MUC5AC-negative biliary ITPNs are genetically distinct from pancreatic ITPNs and IPNBs. They may also biologically differ from MUC5AC-positive tubular neoplasms despite morphological resemblance.


Assuntos
Neoplasias dos Ductos Biliares/patologia , Carcinoma Ductal/patologia , Carcinoma Papilar/patologia , Idoso , Neoplasias dos Ductos Biliares/genética , Carcinoma Ductal/genética , Carcinoma Papilar/genética , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Mucina-5AC/metabolismo , Sequenciamento Completo do Exoma
9.
Arch Pathol Lab Med ; 144(6): 755-763, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-31755778

RESUMO

CONTEXT.­: The roles of the gallbladder and cystic duct (CD) invasions in distal bile duct carcinoma (DBDC) have not been well elucidated. OBJECTIVE.­: To define the characteristics and prognostic significance of gallbladder or CD invasions in patients with DBDC. DESIGN.­: Organ invasion patterns with clinicopathologic features were assessed in 258 resected DBDCs. RESULTS.­: CD invasions (N = 31) were associated with frequent concomitant pancreatic and/or duodenal invasions (23 of 31, 74%) and showed stromal infiltration (16 of 31, 52%) and intraductal cancerization (15 of 31, 48%) patterns. In only 2 cases, invasions with intraductal cancerization were observed in the gallbladder neck. Conversely, all pancreatic (N = 175) and duodenal (83) invasions developed through stromal infiltration. CD invasions were associated with larger tumor size (P = .001), bile duct margin positivity (P = .001), perineural invasions (P = .04), and higher N categories (P = .007). Patients with pancreatic or duodenal invasions had significantly lower survival rates than those without pancreatic (median, 31.0 versus 93.9 months) or duodenal (27.5 versus 56.8 months, P < .001, both) invasions. However, those with gallbladder or CD invasions did not have different survival times (P = .13). Patients with concomitant gallbladder/CD and pancreatic/duodenal invasions demonstrated significantly lower survival rates than those without organ invasions (P < .001). CONCLUSIONS.­: Gallbladder invasions were rare in DBDCs as neck invasions with intraductal cancerization. CD invasions occurred by stromal infiltrations and intraductal cancerization, whereas all pancreatic and duodenal invasions had stromal infiltration patterns. Gallbladder and/or CD invasions did not affect survival rates of patients with DBDC, while pancreatic and duodenal invasions affected survival rates. Therefore, these differences in survival rates may originate from the different invasive patterns of DBDCs.


Assuntos
Neoplasias dos Ductos Biliares/patologia , Colangiocarcinoma/patologia , Ducto Cístico/patologia , Vesícula Biliar/patologia , Invasividade Neoplásica/patologia , Idoso , Neoplasias dos Ductos Biliares/mortalidade , Colangiocarcinoma/mortalidade , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Taxa de Sobrevida
10.
Cancer Res Treat ; 52(2): 455-468, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31623417

RESUMO

PURPOSE: The 8th edition of gallbladder cancer staging in the American Joint Committee on Cancer (AJCC) staging system changed the T and N categories. MATERIALS AND METHODS: In order to validate the new staging system, a total of 348 surgically resected gallbladder cancers were grouped based on the 8th edition of the T and N categories and compared with patients' survival. RESULTS: Significant differences were noted between T1b-T2a (p=0.003) and T2b-T3 (p < 0.001) tumors, but not between Tis-T1a, T1a-T1b, and T2a-T2b tumors. However, significant survival differences were observed both by the overall and pair-wise (T1-T2, T2-T3) comparisons (all, p < 0.001) without dividing T1/T2 subcategories. When cases with ≥ 6 examined lymph nodes were evaluated, significant survival differences were observed among the entire comparison (p < 0.001) and pair-wise comparisons of N0-N1 (p=0.001) and N1-N2 (p=0.039) lesions. When cases without nodal dissection (NX) were additionally compared, significant survival differences were observed between patients with N0-NX (p=0.001) and NX-N1 (p < 0.001) lesions. CONCLUSION: The T category in the 8th edition of the AJCC staging system did not completely stratify the prognosis of patients with gallbladder cancer. Modification by eliminating T subcategories can better stratify the prognosis. In contrast, the N category clearly determines patients' survival with ≥ 6 examined lymph nodes. The survival time in patients of gallbladder cancers without nodal dissection is between N0 and N1 cases. Therefore, close postoperative followed up is recommended for those patients.


Assuntos
Neoplasias da Vesícula Biliar/cirurgia , Linfonodos/cirurgia , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Prognóstico , Estados Unidos
12.
Adv Sci (Weinh) ; 6(11): 1802115, 2019 Jun 05.
Artigo em Inglês | MEDLINE | ID: mdl-31179210

RESUMO

Colorectal cancer (CRC) is the second-leading cause of cancer-related mortality worldwide, which may be effectively reduced by early screening. Colon cancer secreted protein-2 (CCSP-2) is a promising blood marker for CRC. An electric-field effect colorectal sensor (E-FECS), an ion-sensitive field-effect transistor under dual gate operation with nanostructure is developed, to quantify CCSP-2 directly from patient blood samples. The sensing performance of the E-FECS is verified in 7 controls and 7 CRC samples, and it is clinically validated on 30 controls, 30 advanced adenomas, and 81 CRC cases. The concentration of CCSP-2 is significantly higher in plasma samples from CRC and advanced adenoma compared with controls (both P < 0.001). Sensitivity and specificity for CRC versus controls are 44.4% and 86.7%, respectively (AUC of 0.67), and 43.3% and 86.7%, respectively, for advanced adenomas (AUC of 0.67). CCSP-2 detects a greater number of CRC cases than carcinoembryonic antigen does (45.6% vs 24.1%), and the combination of the two markers detects an even greater number of cases (53.2%). The E-FECS system successfully detects CCSP-2 in a wide range of samples including early stage cancers and advanced adenoma. CCSP-2 has potential for use as a blood-based biomarker for CRC.

13.
Histopathology ; 75(4): 559-567, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31077597

RESUMO

AIMS: Mucinous cystic neoplasms (MCNs) of the pancreas are cystic neoplasms lined by mucinous lining epithelium (MLE) with associated ovarian-type stroma. Although a non-MLE (NMLE) can be observed in some MCNs, whether cystic neoplasms with ovarian-type stroma and NMLE should be classified as MCNs or separately designated is debated. METHODS AND RESULTS: To test this, NMLEs were defined as flat or cuboidal epithelial cells without intracytoplasmic mucin. A total of 112 MCNs were reviewed, and the epithelium was classified as NMLE or MLE. A total of 110 females and two males with a mean age of 46.5 ± 12.3 years were included in this study. At least focal NMLE was noted in 76.8% (86/112) of MCNs. The mean percentage of the neoplastic epithelium that was NMLE in these 86 cases was 46%. NMLE was predominant (>50%) in 38.4% (43/112) of cases. MCNs with NMLE were smaller (42 ± 21 mm) than those with MLE (60 ± 36 mm, P < 0.001), and all NMLEs had low-grade dysplasia. Twelve MCNs with NMLE or MLE were selected for KRAS mutation analysis with droplet digital polymerase chain reaction after laser capture microdissection. All 12 MCNs showed multiple types of KRAS mutation, which were detected in 92% (11/12) of NMLE foci and 89% (8/9) of MLE foci. Predominant NMLE was common in small MCNs with low-grade dysplasia. CONCLUSIONS: Clonal KRAS mutations were observed in both NMLE and MLE, supporting the hypothesis that MCNs with NMLE should be classified as MCNs.


Assuntos
Cistadenocarcinoma Mucinoso/patologia , Neoplasias Pancreáticas/patologia , Proteínas Proto-Oncogênicas p21(ras)/genética , Adulto , Cistadenocarcinoma Mucinoso/genética , Epitélio/patologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Neoplasias Pancreáticas/genética
14.
Histopathology ; 75(3): 365-375, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30882917

RESUMO

AIMS: To investigate whether genetic or inflammatory pro-oncogenic factors are relevant to the increased risk of gallbladder cancers in patients with pancreaticobiliary maljunction (PBM). METHODS AND RESULTS: Mutations in KRAS exon 2 were examined by a highly sensitive, droplet digital PCR platform using surgically resected specimens of PBM-associated (n = 31) and non-associated gallbladder cancers (n = 49). The tissue expression of IL-6 and IL-33, which are suspected to promote biliary carcinogenesis, was analysed by quantitative real-time PCR and in-situ hybridisation. The incidence of KRAS mutations was similarly low in PBM-associated (five of 32 cases; 16%) and non-associated cancers (four of 49 cases; 8%) (P = 0.272). The tissue expression of IL-33 mRNA, but not IL-6 mRNA, was significantly higher in PBM-associated gallbladder cancers than in gallbladder cancers without PBM (P = 0.004). A similar degree of IL-33 overexpression was also observed in the background non-cancerous mucosa in cases of PBM-associated gallbladder cancers, and was significantly greater than that in PBM cases with cholecystitis alone (P < 0.001). The results of in-situ hybridisation indicated that the source of IL-33 production in PBM-associated carcinomas was the endothelium, cancer cells and non-neoplastic biliary epithelium. In a combined PBM-associated and non-associated cohort, IL-33 overexpression in gallbladder cancers correlated with less aggressive features (e.g. a lower pT stage and longer overall survival), similar to recently reported findings on large-duct cholangiocarcinomas. CONCLUSIONS: KRAS mutations do not appear to be associated with a high risk of malignancy in PBM, while IL-33 overexpression may provide a pro-oncogenic microenvironment in the gallbladder mucosa of patients with PBM.


Assuntos
Ducto Colédoco/anormalidades , Neoplasias da Vesícula Biliar/patologia , Interleucina-33/biossíntese , Ductos Pancreáticos/anormalidades , Idoso , Feminino , Neoplasias da Vesícula Biliar/genética , Neoplasias da Vesícula Biliar/metabolismo , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Proteínas Proto-Oncogênicas p21(ras)/genética , Regulação para Cima
15.
Pancreas ; 48(3): 400-411, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30747828

RESUMO

OBJECTIVE: Although complete surgical resection is the only curative method for pancreatic cancer, the radial resection margins of pylorus-preserving pancreaticoduodenectomy specimens might be underevaluated. METHODS: KRAS mutation was assessed with droplet digital polymerase chain reaction on cells collected from the radial resection margins of 81 patients, and the results were compared with those of conventional pathologic resection margin (pRM) evaluation. RESULTS: KRAS mutation was detected in 76 patients (94%), and molecular resection margin (mRM) positivity defined by a KRAS mutation rate of 4.19% or greater was observed in 18 patients (22%). Patients with mRM-positive had significantly worse recurrence-free survival (RFS) than those with mRM-negative in entire groups (P = 0.008) and in subgroups without chemotherapy or radiation therapy (all, P < 0.001). When combined pRMs-mRMs were evaluated, patients with combined pRM-mRM-positive (either pRM- or mRM-positive) had significantly worse RFS than those with combined resection margin-negative (both pRM and mRM negative) by univariate (P = 0.002) and multivariate (P = 0.03) analyses. CONCLUSIONS: KRAS mutational analysis with ultrasensitive droplet digital polymerase chain reaction of the radial resection margin in pancreatic cancer patients who underwent pylorus-preserving pancreaticoduodenectomy can provide more accurate information on RFS by using alone or in combination with conventional pRM evaluation, especially in patients without chemotherapy or radiation therapy.


Assuntos
Carcinoma Ductal Pancreático/cirurgia , Margens de Excisão , Mutação , Neoplasias Pancreáticas/cirurgia , Reação em Cadeia da Polimerase/métodos , Proteínas Proto-Oncogênicas p21(ras)/genética , Carcinoma Ductal Pancreático/genética , Carcinoma Ductal Pancreático/terapia , Quimiorradioterapia , Feminino , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/terapia , Pancreaticoduodenectomia/métodos , Estudos Retrospectivos
16.
Hum Pathol ; 84: 92-104, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30261192

RESUMO

Identifying the accurate origin of periampullary cancers is important because different origins may trigger different clinicopathological behaviors. The presence of intraepithelial precursor lesions, including high-grade pancreatic intraepithelial neoplasias (PanINs) and/or high-grade biliary intraepithelial neoplasias (BilINs), may be suggestive of the origin of the periampullary carcinoma in challenging cases. To prove the usefulness of high-grade intraepithelial precursor lesions in identifying the origin of ambiguous periampullary cancers, the status and grades of PanINs and BilINs were evaluated in 256 periampullary carcinomas with a well-defined cancer origin as a test set, including 114 pancreatic cancers, 82 distal bile duct cancers, 54 ampullary cancers, and 6 duodenal cancers. One hundred twelve periampullary carcinomas with clinically equivocal epicenter either by radiologic imaging or by endoscopic finding used as a validation set. High-grade PanINs were found more commonly in pancreatic cancers than in distal bile duct, ampullary, and duodenal cancers both in test (P = .002) and validation sets (P < .001). Similarly, high-grade BilINs were identified more frequently in distal bile duct cancers than in ampullary, pancreatic, and duodenal cancers both in test (P < .001) and validation sets (P = .039). High-grade PanINs were found most commonly in pancreatic cancers, whereas high-grade BilINs were seen most frequently in distal bile duct cancers. In addition, both high-grade PanINs and high-grade BilINs are uncommonly noted in ampullary or duodenal cancers. The recognition of high-grade intraepithelial lesions can help identify the primary origin of periampullary cancers, especially when the epicenter of the periampullary cancer is ambiguous.


Assuntos
Ampola Hepatopancreática/patologia , Carcinoma in Situ/patologia , Carcinoma Ductal Pancreático/patologia , Neoplasias do Ducto Colédoco/patologia , Neoplasias Duodenais/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade
17.
Cancer Res Treat ; 51(1): 98-111, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-29510611

RESUMO

PURPOSE: T category of the eighth edition of the American Joint Committee on Cancer (AJCC) staging system for distal bile duct carcinoma (DBDC) was changed to include tumor invasion depth measurement, while the N category adopted a 3-tier classification system based on the number of metastatic nodes. Materials and Methods: To validate cancer staging, a total of 200 surgically resected DBDCs were staged and compared according to the seventh and eighth editions. RESULTS: T categories included T1 (n=37, 18.5%), T2 (n=114, 57.0%), and T3 (n=49, 24.5%). N categories included N0 (n=133, 66.5%), N1 (n=50, 25.0%), and N2 (n=17, 8.5%). Stage groupings included I (n=33, 16.5%), II (n=150, 75.0%), and III (n=17, 8.5%). The overall 5-year survival rates (5-YSRs) of T1, T2, and T3 were 59.3%, 42.4%, and 12.2%, respectively. T category could discriminate patient survival by both pairwise (T1 and T2, p=0.011; T2 and T3, p < 0.001) and overall (p < 0.001) comparisons. The overall 5-YSRs of N0, N1, and N2 were 47.3%, 17.0%, and 14.7%, respectively. N category could partly discriminate patient survival by both pairwise (N0 and N1, p < 0.001; N1 and N2, p=0.579) and overall (p < 0.001) comparisons. The overall 5-YSRs of stages I, II, and III were 59.0%, 35.4%, and 14.7%, respectively. Stages could distinguish patient survival by both pairwise (I and II, p=0.002; II and III, p=0.015) and overall (p < 0.001) comparisons. On multivariate analyses, T and N categories (p=0.014 and p=0.029) and pancreatic invasion (p=0.006) remained significant prognostic factors. CONCLUSION: The T andNcategories of the eighth edition AJCC staging system for DBDC accurately predict patient prognosis.


Assuntos
Neoplasias dos Ductos Biliares/patologia , Neoplasias dos Ductos Biliares/cirurgia , Colangiocarcinoma/patologia , Colangiocarcinoma/cirurgia , Idoso , Procedimentos Cirúrgicos do Sistema Biliar , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Invasividade Neoplásica , Estadiamento de Neoplasias , Prognóstico , Análise de Sobrevida , Resultado do Tratamento , Estados Unidos
18.
J Transl Med ; 16(1): 374, 2018 12 28.
Artigo em Inglês | MEDLINE | ID: mdl-30593273

RESUMO

BACKGROUND: The clinical significance of fibroblast growth factor receptor 1 (FGFR1) protein expression in pancreatic cancer is largely unknown. In this study, we aimed investigate the clinical significance of FGFR1 expression in pancreatic cancer. METHODS: First, we investigated the relationship between FGFR pathway gene expression and clinicopathological data in three pancreatic cancer cohorts containing 313 cases. Subsequently, to confirm the findings from the discovery cohorts, we performed immunohistochemistry (IHC) of FGFR1 protein in a validation cohort of 205 pancreatic cancer cases. RESULTS: In discovery cohort 1, FGFR1 and Klotho beta (KLB) overexpression was associated with low tumor stage (P < 0.05), low tumor grade (P < 0.05), and better overall survival. Multivariate analysis predicted FGFR1 (P < 0.05) as a prognostic factor for better overall survival. In discovery cohorts 2 and 3, only FGFR1 overexpression was associated with better overall survival (P < 0.05). In the validation cohort, there were 15.7% and 61% strong and weak/moderate FGFR1-positive cases, respectively. FGFR1-positive cases showed better overall survival than FGFR1-negative cases (P < 0.05). Furthermore, multivariate analysis revealed FGFR1 positivity as an independent prognostic factor for better overall survival in pancreatic cancer patients (hazard ratio 0.677, 95% confidence interval 0.471-0.972, P = 0.035). CONCLUSIONS: FGFR1 expression, as estimated by IHC, may be used to define clinically distinct subtypes in pancreatic cancer. Moreover, FGFR1-based subclassification of pancreatic cancer may lead to new therapeutic approaches for the FGFR1-positive subtype.


Assuntos
Regulação Neoplásica da Expressão Gênica , Neoplasias Pancreáticas/genética , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/genética , Estudos de Coortes , Estudos de Associação Genética , Humanos , Estimativa de Kaplan-Meier , Análise Multivariada , Modelos de Riscos Proporcionais , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/metabolismo , Reprodutibilidade dos Testes
19.
J Cutan Pathol ; 45(12): 886-890, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30178542

RESUMO

BACKGROUND: Primary cutaneous mucinous carcinoma (PCMC) is a rare epithelial tumor with unclear histogenesis. METHODS: We evaluated the immunohistochemical expression of the estrogen receptor (ER), progesterone receptor (PR), and androgen receptor (AR) in six cases of PCMC. The immunoreactivity of adipophilin and gross cystic disease fluid protein (GCDFP)-15 was investigated to determine the origin of the tumor. RESULTS: The study included five males and one female aged 50 to 69 years who presented with a cutaneous mass in the face. Immunoreactivity for ER, PR, and AR was observed in all cases, and all cases were negative for adipophilin but positive for GCDFP-15. CONCLUSIONS: This report is the first to show AR expression in PCMC. All of followed cases manifested indolent clinical course, and the prognostic significance of hormone receptors in PCMC remains unclear. The negative immunoreactivity of PCMC for adipophilin and positivity for GCDFP-15 suggests a more likely relationship to apocrine than to sebaceous glands.


Assuntos
Adenocarcinoma Mucinoso/metabolismo , Proteínas de Transporte/biossíntese , Neoplasias Faciais/metabolismo , Regulação Neoplásica da Expressão Gênica , Glicoproteínas/biossíntese , Proteínas de Neoplasias/biossíntese , Perilipina-2/biossíntese , Receptores de Esteroides/biossíntese , Neoplasias Cutâneas/metabolismo , Adenocarcinoma Mucinoso/patologia , Idoso , Neoplasias Faciais/patologia , Feminino , Humanos , Masculino , Proteínas de Membrana Transportadoras , Pessoa de Meia-Idade , Neoplasias Cutâneas/patologia
20.
Virchows Arch ; 472(5): 739-748, 2018 May.
Artigo em Inglês | MEDLINE | ID: mdl-29666945

RESUMO

Well-differentiated pancreatic neuroendocrine neoplasms/tumors (PanNETs) are rare neoplasms with diverse clinical behavior. Biomarker discovery is important for predicting clinical course and prognosis of PanNET patients. Carbonic anhydrase 9 (CA9) and vimentin are hypoxia and epithelial-mesenchymal transition-related proteins of which expression in many carcinomas has been associated with poor prognosis, but their significance in PanNET has yet to be determined. We assessed CA9 and vimentin expression in 164 PanNETs and compared this with clinicopathologic characteristics. CA9 expression was observed in normal islets, while neuroendocrine microadenomas and small (< 1 cm) PanNETs showed loss of CA9 expression. CA9 and vimentin expression was observed in 38 (23%) and 36 (22%) of PanNETs, respectively. CA9 expression was associated with larger size (p = 0.001), higher grade (p < 0.001), higher pT category (p < 0.001), lymph node (p = 0.003) and distant (p = 0.047) metastases, higher AJCC stage (p < 0.001), and lymphovascular (p < 0.001) and perineural (p = 0.002) invasion. PanNET patients with CA9 expression had a shorter recurrence-free survival (5-year survival rate 47%) than those without CA9 expression (76%) by univariate (p = 0.001) but not multivariate analysis. Vimentin expression correlated with CA9 expression (p < 0.001) but not with other clinicopathologic factors. In conclusion, CA9 expression was observed in normal islets, while neuroendocrine microadenomas and small (< 1 cm) PanNETs showed CA9 expression loss. CA9 expression gradually reappeared in larger PanNETs, and this was associated with clinical progression and decreased patient survival by univariate but not multivariate analysis.


Assuntos
Antígenos de Neoplasias/biossíntese , Biomarcadores Tumorais/análise , Anidrase Carbônica IX/biossíntese , Tumores Neuroendócrinos/enzimologia , Neoplasias Pancreáticas/enzimologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Antígenos de Neoplasias/análise , Anidrase Carbônica IX/análise , Intervalo Livre de Doença , Feminino , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Tumores Neuroendócrinos/mortalidade , Neoplasias Pancreáticas/mortalidade , Modelos de Riscos Proporcionais , Adulto Jovem
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