Publications by authors named "Jia-Huei Tsai"

52 Publications

Lymphadenopathy Associated With Neutralizing Anti-interferon-gamma Autoantibodies Could Have Monoclonal T-cell Proliferation Indistinguishable From Malignant Lymphoma and Treatable by Antibiotics: A Clinicopathologic Study.

Am J Surg Pathol 2021 May 20. Epub 2021 May 20.

Graduate Institute of Clinical Medicine Graduate Institute of Pathology, National Taiwan University Departments of Pathology Internal Medicine, National Taiwan University Hospital and National Taiwan University College of Medicine Departments of Pathology Medicine, National Taiwan University Cancer Center Department of Laboratory Medicine Center of Infection Control, National Taiwan University Hospital, Taipei, Taiwan.

Early recognition of adult-onset immunodeficiency associated with neutralizing anti-interferon gamma autoantibodies (anti-IFNγ Abs) remains difficult, and misdiagnoses have been reported. Although febrile lymphadenopathy is among the most common initial manifestations of this disorder, no comprehensive clinicopathologic analysis of lymphadenopathy in patients with anti-IFNγ Abs has been reported. Here, we describe 26 lymph node biopsy specimens from 16 patients. All patients exhibited concurrent disseminated nontuberculous mycobacterial infections, and 31% received a tentative diagnosis of lymphoma at initial presentation. We found 3 distinct histomorphologic patterns: well-formed granuloma (46%), suppurative inflammation or loose histiocytic aggregates (31%), and lymphoproliferative disorder (LPD, 23%). The latter shared some of the features of malignant T-cell lymphoma, IgG4-related disease, and multicentric Castleman disease. Half of the specimens with LPD had monoclonal T cells, and 33.3% were indistinguishable from angioimmunoblastic T-cell lymphoma as per current diagnostic criteria. All lymphadenopathy with LPD features regressed with antibiotics without administration of cytotoxic chemotherapy or immunotherapy. The median follow-up time was 4.3 years. Our study highlights the substantial challenge of distinguishing between lymphoma and other benign lymphadenopathy in the setting of neutralizing anti-IFNγ Abs. Increased vigilance and multidisciplinary discussion among clinicians and pathologists are required to achieve the most appropriate diagnosis and management.
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http://dx.doi.org/10.1097/PAS.0000000000001731DOI Listing
May 2021

Chemotherapy agents stimulate dendritic cells against human colon cancer cells through upregulation of the transporter associated with antigen processing.

Sci Rep 2021 Apr 27;11(1):9080. Epub 2021 Apr 27.

Graduate Institute of Oncology, National Taiwan University, Taipei, Taiwan, R.O.C..

Single immunotherapy fails to demonstrate efficacy in patients with microsatellite stable (MSS) metastatic colorectal cancer (mCRC). Research on immune reactions before and after systemic agents for mCRC is warranted. Our study examined cell line models to compare the expression of immune surface markers on colon cancer cells before and after chemotherapy agents. We also elucidated mechanisms underlying the effects of chemotherapy agents on immune surface markers. We used real-world clinical samples with NanoString analysis and the Perkin-Elmer Opal multiplex system. We established that chemotherapy agents, particularly 7-ethyl-10-hydroxycamptothecin (SN-38), the active metabolite of irinotecan, stimulated the expression of stimulatory MHC class I alleles through stimulation the pathway of transporters associated with antigen processing 1 and 2 (TAP1 and TAP2) in cell line models. Application of infected cell protein 47 (ICP-47), a specific inhibitor of the TAP1/TAP2, significantly inhibited expression of TAP1/TAP2 and also inhibited the expression of the downstream MHC class I. In the functional assay, SN-38 significantly promoted the phagocytosis of colon cancer cells by monocyte-derived dendritic cells (MoDCs). We confirmed that the expression of major histocompatibility complex (MHC) class I, significantly increased after first-line chemotherapy and targeted therapy in the samples of real-world patients with de novo mCRC. Our study provides new insights for novel immunotherapy combinations.
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http://dx.doi.org/10.1038/s41598-021-88648-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8079421PMC
April 2021

Lymphoepithelioma-like Intrahepatic Cholangiocarcinoma Is a Distinct Entity With Frequent pTERT/TP53 Mutations and Comprises 2 Subgroups Based on Epstein-Barr Virus Infection.

Am J Surg Pathol 2021 Apr 12. Epub 2021 Apr 12.

Department of Pathology, National Taiwan University Hospital Graduate Institute of Pathology, College of Medicine, National Taiwan University, Taipei, Taiwan.

The molecular characteristics of lymphoepithelioma-like intrahepatic cholangiocarcinoma (LELCC) remain elusive. We examined 27 LELCC cases through next-generation sequencing using a panel of genes commonly mutated in primary liver cancers. Alterations in BAP1, ARID1A, ARID2, and PBRM1 were detected through immunohistochemistry. Fluorescence in situ hybridization was performed to analyze FGFR2 fusions and CCND1 amplification. LELCC is histologically classified as predominantly undifferentiated or glandular. Epstein-Barr virus-encoded small RNA (EBER) expression was found in 16 LELCCs. Approximately 50% of LELCCs expressed programmed death-ligand 1 strongly. Notably, recurrent pTERT and TP53 mutations were detected in 9 (38%) and 8 (33%) tumors, respectively. Only 2 LELCCs exhibited loss of expression for PBRM1. Alterations in genes typically involved in intrahepatic cholangiocarcinoma, including IDH1, IDH2, ARID1A, ARID2, and BAP1, and FGFR2 fusions, were not identified. The 2-step clustering analysis showed 2 distinct subgroups in LELCC, which were separated by EBER expression. A meta-analysis of all reported cases (n=85) has shown that EBER+ LELCC is strongly associated with the female sex, younger age, and exhibited predominantly glandular differentiation (P=0.001, 0.012, and <0.001, respectively). Patients with EBER- LELCC were more likely to have viral hepatitis and cirrhosis (P=0.003 and 0.005, respectively). Genetic analysis demonstrated that EBER- LELCC was significantly associated with pTERT and TP53 mutations (P=0.033 and 0.008, respectively). In conclusion, LELCC is genetically distinct from intrahepatic cholangiocarcinoma. EBER- LELCC may exhibit a different pathogenesis from EBER+ LELCC. High programmed death-ligand 1 expression in LELCC has implications for potential immunotherapeutic strategies.
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http://dx.doi.org/10.1097/PAS.0000000000001716DOI Listing
April 2021

Fatal acute-on-chronic liver failure in amiodarone-related steatohepatitis: a case report.

BMC Gastroenterol 2021 Feb 2;21(1):50. Epub 2021 Feb 2.

Department of Surgery, National Taiwan University Hospital, 100, Taipei, Taiwan.

Background: Amiodarone is an antiarrhythmic drug that has been recognized to induce hepatotoxicity. We report a case of acute-on-chronic liver failure (ACLF) in a patient who was receiving amiodarone for more than 2 years. The patient developed cirrhosis and suppurative microabscesses of the liver and died of progressive liver failure.

Case Presentation: A 69-year-old woman with risk factors for nonalcoholic fatty liver disease (NAFLD) was treated with oral amiodarone at a daily dose of 400 mg for more than 2 years, until she developed epigastralgia and vomiting. Initial laboratory findings included leukocytosis and elevated liver enzymes. Images of abdominal computed tomography scan revealed diffusely increased hepatic attenuation density (in contrast to decreased density in NAFLD), hepatomegaly, periportal edema, and ascites. Liver biopsy targeting the hotspot identified through positron emission tomography confirmed the diagnosis of amiodarone-associated chronic steatohepatitis and superimposed microabscesses. The patient died of progressive ACLF despite intensive supportive care.

Conclusion: Accumulation of amiodarone can result in chronic liver disease and pose an additional risk of ACLF following infection.
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http://dx.doi.org/10.1186/s12876-021-01632-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7856745PMC
February 2021

An Integrative Morphomolecular Classification System of Gastric Carcinoma With Distinct Clinical Outcomes.

Am J Surg Pathol 2020 08;44(8):1017-1030

Departments of Pathology.

A robust morphomolecular classification system for gastric carcinoma is required. A 4-tier morphologic classification is proposed, including diffuse, intestinal, tubular, and lymphoid types. A tissue microarray for mismatch repair immunohistochemistry and Epstein-Barr virus (EBV) in situ hybridization were performed in 329 gastric carcinomas. DNA flow cytometry was used to detect aneuploidy in formalin-fixed paraffin-embedded samples. Lymphoid histology was the third most common histologic pattern at our institute and strongly associated with EBV infection and PMS2/MLH1-deficiency (both P<0.001). HER2 overexpression and SATB2 expression more frequently occurred in intestinal histology (both P<0.001). Loss of ARID1A expression was strikingly associated with lymphoid histology (P<0.001) and negative E-cadherin expression was correlated with diffuse histology (P=0.001). Programmed death-ligand 1 expression was most frequently present in lymphoid-type gastric carcinoma than other histologic subtypes and correlated with the molecular features of PMS2/MLH1-deficiency and EBV infection (all P<0.001). Aneuploidy was detected in 53% of gastric carcinomas and was highly correlated with intestinal type and the least with the lymphoid type (P<0.001). Notably, lymphoid-type gastric carcinoma showed the best outcome, whereas tubular type showed the worst survival rate (P<0.001). We integrated aneuploidy with morphologic patterns to propose a morphomolecular classification scheme, which served as a successful and independent prognostic factor in multivariate 5-year disease-free survival analysis (P<0.001). Overall, we describe an integrated morphomolecular classification system for gastric carcinomas to effectively predict patient outcomes. This system is cost-effective and reliable and can help select target therapeutics and facilitate clinical management.
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http://dx.doi.org/10.1097/PAS.0000000000001521DOI Listing
August 2020

A Mysterious Case of Jaundice After Development of Skin Vesicles.

Gastroenterology 2020 11 19;159(5):1669-1671. Epub 2020 Apr 19.

Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan; Division of Gastroenterology and Hepatology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan; Hepatitis Research Center, National Taiwan University Hospital, Taipei, Taiwan. Electronic address:

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http://dx.doi.org/10.1053/j.gastro.2020.04.031DOI Listing
November 2020

GNA11 joins GNAQ and GNA14 as a recurrently mutated gene in anastomosing hemangioma.

Virchows Arch 2020 Mar 9;476(3):475-481. Epub 2019 Nov 9.

Department of Anatomic Pathology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, No. 123, Ta Pei Rd., Niao Sung District, Kaohsiung, Taiwan.

Anastomosing hemangioma (AH) is a distinct benign vascular tumor that may be histologically confused with an angiosarcoma. Recently, recurrent GNAQ and GNA14 mutations were identified in AH. GNA11, another paralogue of GNAQ and the one that shows the highest degree of homology to GNAQ, has not yet been found to be mutated in AH. In this study, we investigated the clinicopathological and molecular features of 26 AHs. By Sanger sequencing and MassARRAY analysis, mutually exclusive mutations in exon 5 of GNAQ, GNA11, and GNA14 were identified in 10, 5, and 5 tumors, respectively, of the 22 investigated tumors, with an overall mutation rate of 91%. No notable differences in the clinicopathological features were observed between GNAQ-, GNA11-, or GNA14-mutated tumors. Our results implicated GNA11 mutations, as well as previously known mutations of its paralogues GNAQ and GNA14, as essential drivers in the pathogenesis of AH.
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http://dx.doi.org/10.1007/s00428-019-02673-yDOI Listing
March 2020

Hepatocellular adenoma in Taiwan: Distinct ensemble of male predominance, overweight/obesity, and inflammatory subtype.

J Gastroenterol Hepatol 2020 Apr 7;35(4):680-688. Epub 2019 Nov 7.

Department of Pathology, National Taiwan University Hospital, Taipei, Taiwan.

Background And Aim: The clinicopathologic features of hepatocellular adenoma in Asian populations have been poorly defined. The study aimed to characterize this rare entity in a single institution in Taiwan.

Methods: In total, 45 hepatocellular adenomas from 1995 to 2018 were included and sent for pathologic review and molecular subtyping.

Results: The numbers of patients with hepatocellular adenoma has doubled in the recent decade. Surprisingly, men outnumbered women in our cohort (n = 26, 58% vs N = 19, 42%). A collection of clinical information revealed that overweight/obesity accounts for most of the associated conditions of hepatocellular adenoma. Only three women took oral contraceptives. There were 34 inflammatory (75%), three LFABP-negative (7%), four β-catenin activated (9%), and four unclassified (9%) hepatocellular adenomas. Ten inflammatory hepatocellular adenomas demonstrated strong and homogeneous glutamine synthetase staining and were thus also β-catenin activated. Notably, overweight and obesity were significantly associated with inflammatory hepatocellular adenoma than other subtypes (P = .029 and .056, respectively) and were strongly correlated with steatosis in background liver (P = .028 and.007, respectively). Malignant transformation (four borderline tumors and two hepatocellular carcinomas) was identified in six adenomas (two women and four men). All six hepatocellular adenomas with malignancy were β-catenin activated; β-catenin activation could serve as a biomarker for malignant progression.

Conclusions: The clinicopathologic features of hepatocellular adenoma in Taiwan are distinct from those reported in Western countries. Rare oral contraceptive usage and an emerging epidemic of overweight/obesity in Taiwan provides new insights into the pathogenesis of hepatocellular adenoma.
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http://dx.doi.org/10.1111/jgh.14903DOI Listing
April 2020

Thrombotic Hemangioma With Organizing/Anastomosing Features: Expanding the Spectrum of GNA-mutated Hemangiomas With a Predilection for the Skin of the Lower Abdominal Regions.

Am J Surg Pathol 2020 02;44(2):255-262

Graduate Institute of Pathology, National Taiwan University College of Medicine, Taipei, Taiwan.

In this study, we aimed to present the clinicopathologic and molecular features of a distinct group of hemangioma with GNA mutations that exhibited prominent thrombosis and organization changes with florid intravascular endothelial cell proliferation that we provisionally termed "thrombotic hemangioma with organizing/anastomosing features." Twenty-six cases were included. No sex predilection was seen (male:female=13:13). Patients' age ranged from 17 to 89 years (median: 51 y). All but 1 occurred in the skin whereas the remaining tumor involved the neck soft tissue. Remarkably, the majority (18) occurred in the lower abdominal/inguinal regions. Histologically, thrombotic hemangioma with organizing/anastomosing features were circumscribed tumors composed of variably sized and congested thin-walled vessels. The most striking features were prominent thrombosis and organization with florid intravascular endothelial cell proliferation. The proliferating endothelial cells exhibit a streaming pattern with focal anastomosing-like feature resembling anastomosing hemangioma. The stroma was sclerotic or hyalinized but could also be myxoid/edematous. Other features included vessels with nuclear hobnailing and perivascular hyalinization, cherry hemangioma-like component, cavernous-like or sinusoidal hemangioma-like areas, Masson hemangioma-like feature, and spindle cell fascicular pattern. Mitotic activity was usually low and nuclei were bland but 2 tumors exhibited moderate nuclear atypia and higher mitotic activity. Extramedullary hematopoiesis and hyaline globules were not identified. Genetically, by Sanger sequencing and MassARRAY analysis, mutually exclusive GNAQ, GNA11, and GNA14 exon 5 mutations were identified in 15, 5, and 2 tumors, respectively, with a combined mutation rate of 85% (22/26). In conclusion, we described a distinct group of hemangioma and expanded the clinicopathologic features of GNA-mutated hemangiomas.
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http://dx.doi.org/10.1097/PAS.0000000000001392DOI Listing
February 2020

Targeted next-generation sequencing identifies distinct clinicopathologic and molecular entities of intraductal papillary neoplasms of the bile duct.

Mod Pathol 2019 11 23;32(11):1637-1645. Epub 2019 Jun 23.

Department of Pathology, National Taiwan University Hospital, Taipei, Taiwan.

Intraductal papillary neoplasm of the bile duct (IPNB) is a mass-forming neoplasm in the bile duct considered to be the biliary counterpart of pancreatic intraductal papillary mucinous neoplasm (IPMN). By its cell lineage, IPNB can be classified into gastric, intestinal, pancreatobiliary, and oncocytic types. Recently, a group of Japanese and Korean pathologists proposed that IPNB be classified into two types, with type 1, being the histological counterpart of IPMN and type 2, having a more complex histological architecture. We used targeted next-generation sequencing to study the molecular change of 37 IPNBs and identified frequent mutations of KRAS (49%), GNAS (32%), RNF43 (24%), APC (24%), TP53 (24%), and CTNNB1 (11%) in IPNBs. Intestinal-type IPNB was associated with KRAS, GNAS, and RNF43 mutations. Japan-Korea consensus type 1 was associated with KRAS and GNAS mutations. All four IPNBs with CTNNB1 mutations were of pancreatobiliary type and located in the extrahepatic bile duct. A hierarchical analysis identified three distinct groups within IPNB: group 1 was Japan-Korea consensus type 1 tumors with macroscopic mucin, old age, and frequent KRAS, GNAS, and RNF43 mutations. Group 2 was Japan-Korea consensus type 2 with intestinal differentiation and frequent KRAS mutation but rare GNAS mutation, MUC2 expression, and macroscopic mucin. Group 3 was characterized by CTNNB1 mutation, extrahepatic location, lack of expression of intestinal markers, Japan-Korea consensus type 2, and lack of mutations in KRAS, APC, RNF43, and GNAS. Our results indicated that IPNB is a heterogeneous disease and that the activation of Ras-mitogen-activated protein kinase (MAPK), Wnt/β-catenin, and G-protein-coupled receptor (GPCR)-cAMP signaling is the main oncogenic mechanism of IPNB.
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http://dx.doi.org/10.1038/s41379-019-0306-9DOI Listing
November 2019

High frequency of GNA14, GNAQ, and GNA11 mutations in cherry hemangioma: a histopathological and molecular study of 85 cases indicating GNA14 as the most commonly mutated gene in vascular neoplasms.

Mod Pathol 2019 11 12;32(11):1657-1665. Epub 2019 Jun 12.

Graduate Institute of Pathology, National Taiwan University College of Medicine, Taipei, Taiwan.

Cherry hemangioma is the most common hemangioma in adult life. Neoplastic and non-neoplastic theories had both been proposed for its pathogenesis, but its nature is still poorly understood. We noted a significant subset of anastomosing hemangiomas and congenital hemangiomas harbored a population of small capillaries surrounded by a perivascular hyaline layer, reminiscent of the vessels seen in cherry hemangioma. Both anastomosing hemangioma and congenital hemangioma harbor recurrent mutations in exon 5 of GNAQ and its paralogues. In this study, we analyzed 68 cherry hemangiomas and 17 cherry hemangioma-like hemangiomas exhibiting additional non-classical features including markedly dilated, cavernous vessels, and/or a deep component extending to the deep dermis. By Sanger sequencing, GNAQ, GNA11, and GNA14 exon 5 mutations were identified in 12, 4, and 32 cherry hemangiomas, respectively, and 5, 3, and 3 cherry hemangioma-like hemangiomas, respectively. MassARRAY analysis detected mutations (including exon 2 GNAQ mutations) in additional 8 cherry hemangiomas and 3 cherry hemangioma-like hemangiomas. Overall, the cherry hemangiomas and cherry hemangioma-like hemangiomas had equal GNA mutation rates (82%), and GNA14 and GNAQ mutations were present in approximately half of cherry hemangiomas and cherry hemangioma-like hemangiomas, respectively. All mutations were mutually exclusive. KRAS mutation was also detected in one cherry hemangioma-like hemangioma without GNA mutations. In summary, our study demonstrated recurrent GNA14/GNAQ/GNA11 mutations were present in the majority of this very common hemangioma and established its neoplastic nature. Our results also expanded the morphological spectrum of GNA-mutated hemangiomas to include tumors composed of cavernous-like vessels and indicated GNA14 was the most commonly mutated gene in vascular tumors.
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http://dx.doi.org/10.1038/s41379-019-0284-yDOI Listing
November 2019

Traditional Serrated Pathway-associated Colorectal Carcinoma: Morphologic Reappraisal of Serrated Morphology, Tumor Budding, and Identification of Frequent PTEN Alterations.

Am J Surg Pathol 2019 08;43(8):1042-1051

Departments of Pathology.

The phenotypic characteristics of traditional serrated adenoma (TSA)-associated malignancies remain obscure. This study was a morphologic reappraisal of 27 colorectal carcinomas arising from TSA (TSA-CRCs) and 53 BRAF-mutated/microsatellite-stable colorectal carcinomas (BRAF-mut/MSS CRCs). Makinen's criteria for serrated adenocarcinoma were applied to assess the morphologic similarity of the 2 entities. Tumor budding, another histologic feature of serrated adenocarcinoma, was also evaluated. Phosphatase and tensin homologue deleted on chromosome 10 (PTEN), a commonly mutated gene in the serrated pathway, was assessed with immunohistochemistry. Tumors with aberrant PTEN expression were subjected to molecular analysis using quantitative methylation assay, exon sequencing, and fluorescence in situ hybridization. Most cases (>90%) of TSA-CRCs and BRAF-mut/MSS CRCs exhibited a constellation of serrated morphology, including epithelial serrations, abundant eosinophilic cytoplasm, and discernible/vesicular nuclei. A majority (65%) of them qualified for the diagnosis of serrated adenocarcinoma. High-grade tumor budding was closely associated with serrated morphology and was a significant independent factor for poor patient survival in multivariate analysis (P=0.008). Aberrant PTEN expression was detected in nearly half of the cases of both entities (P=0.501). Among the 44 samples with aberrant PTEN expression, 8 harbored PTEN somatic mutations, which were characterized by random distribution without hotspot clustering, 12 had promoter hypermethylation, and 14 had deleted alleles. These findings support a unique model of colorectal carcinogenesis that is similar between TSA-CRCs and BRAF-mut/MSS CRCs. Both entities exhibited common histologic patterns and similar molecular alterations and may well constitute the TSA pathway.
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http://dx.doi.org/10.1097/PAS.0000000000001274DOI Listing
August 2019

CpG Island Methylator Phenotype May Predict Poor Overall Survival of Patients with Stage IV Colorectal Cancer.

Oncology 2019 12;96(3):156-163. Epub 2018 Dec 12.

Department of Oncology, National Taiwan University Hospital, Taipei City, Taiwan,

Objective: We aimed to study the prognostic role of CpG island methylator phenotype (CIMP) in patients with different stages of colorectal cancer (CRC).

Material And Methods: We analyzed CIMP in stage I-IV CRC specimens from patients who were diagnosed between 2005 and 2013. CIMP status was determined using a 5-gene MethyLight-based assay. The clinicopathologic characteristics were reviewed and the overall survival (OS) was compared between patients with CIMP-high CRC and those with CIMP-low/negative CRC.

Results: Among 450 CRC specimens with successfully determined CIMP statuses, 74 (16.4%) were CIMP-high CRC. Although there was no difference in OS between patients with CIMP-high and CIMP-low/negative CRC across all stages (p = 0.4526), intriguingly, patients with stage IV CIMP-high CRC had significantly worse OS than those with stage IV CIMP-low/negative CRC (p = 0.0047). In a multivariate analysis, CIMP status remained an independent prognostic factor for overall mortality (HR = 5.60, 95% CI: 2.12-14.79, p = 0.0005) in metastatic CRC after adjusting for clinicopathologic variables and anti-cancer therapies.

Conclusion: Our results revealed that the presence of CIMP independently predicts poor OS in patients with stage IV CRC.
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http://dx.doi.org/10.1159/000493387DOI Listing
March 2019

BRAF and KRAS mutations in tubular apocrine adenoma and papillary eccrine adenoma of the skin.

Hum Pathol 2018 03 12;73:59-65. Epub 2017 Dec 12.

Department of Pathology, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei 10051, Taiwan.

Tubular apocrine adenoma (TAA) and papillary eccrine adenoma (PEA) are benign sweat gland tumors. Their names imply that they exhibit apocrine and eccrine differentiation, respectively. However, morphologically they are very similar and are often indistinguishable. The molecular pathogenesis of either tumor is poorly understood at present. On the basis of an index case of nipple adenoma that was morphologically reminiscent of cutaneous TAA/PEA and harbored a BRAF mutation, we investigated whether a similar genetic change is also present in TAA/PEA. BRAF, RAS, and PIK3CA mutation analyses, and BRAF-specific immunohistochemistry were performed for 24 TAAs/PEAs, 10 eccrine poromas, 7 apocrine cystadenomas, 2 TAA-like adenomas associated with nevus sebaceus, and one apocrine adenoma probably arising in anogenital mammary-like glands (AGMLGs). The results demonstrated that BRAF mutations were present in TAAs (9/15, 60%) and PEAs (7/9, 78%), but not in other neoplasms. Two additional TAAs harbored KRAS mutations. In addition, a KRAS mutation was identified in one nevus sebaceus-associated TAA-like adenoma. The speculated AGMLG-related apocrine adenoma had a PIK3CA mutation. We concluded that activating BRAF and KRAS mutations were commonly present in TAAs/PEAs, indicating that in addition to a morphological resemblance, they are closely related genetically. Therefore, they could be considered to be united as a single entity. By contrast, the apocrine adenoma probably arising in AGMLG harbored a PIK3CA mutation, which is also commonly present in hidradenoma papilliferum. Further studies are necessary to determine whether the pathogenesis of AGMLG-related tumors is similar to breast tumors.
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http://dx.doi.org/10.1016/j.humpath.2017.12.002DOI Listing
March 2018

Association of Aneuploidy and Flat Dysplasia With Development of High-Grade Dysplasia or Colorectal Cancer in Patients With Inflammatory Bowel Disease.

Gastroenterology 2017 12 24;153(6):1492-1495.e4. Epub 2017 Aug 24.

Department of Pathology, University of California at San Francisco, San Francisco, California. Electronic address:

There is controversy over how to best manage patients with inflammatory bowel disease and flat low-grade dysplasia (fLGD) in the colon. We performed a retrospective analysis of formalin-fixed paraffin-embedded colon tissues with fLGD from 37 patients undergoing surveillance colonoscopy for inflammatory bowel disease from 1990 to 2015 at the University of California at San Francisco Medical Center, to determine whether detection of aneuploidy is associated with later development of high-grade dysplasia (HGD) or colorectal cancer. Medical data were collected from the patients for a mean follow-up time of 37 months. Using flow cytometry analysis of paraffin-embedded colon tissue, we detected aneuploidy in 15 of 37 samples with fLGD (40.5%). By comparison, aneuploidy was detected in 14 of 15 samples with flat HGD (93.3%) and 2 of 45 samples that were negative for dysplasia (4.4%). The univariate hazard ratio for subsequent detection of HGD or colorectal cancer in patients with fLGD and aneuploidy was 5.3 (95% CI, 1.542-24.121) within a mean follow-up time of 37 months. The presence of aneuploidy therefore identifies patients with fLGD in colon tissue who have an increased risk for HGD or colorectal cancer and may provide supportive evidence to a morphologic impression or suspicion of flat HGD.
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http://dx.doi.org/10.1053/j.gastro.2017.08.031DOI Listing
December 2017

Diagnosis and risk stratification of Barrett's dysplasia by flow cytometric DNA analysis of paraffin-embedded tissue.

Gut 2018 07 22;67(7):1229-1238. Epub 2017 Jun 22.

Department of Pathology, University of California at San Francisco, San Francisco, California, USA.

Objective: The diagnosis of dysplasia in Barrett's oesophagus (BO) can be challenging, and reliable ancillary techniques are not available. This study examines if DNA content abnormality detected by flow cytometry can serve as a diagnostic marker of dysplasia and facilitate risk stratification of low-grade dysplasia (LGD) and indefinite for dysplasia (IND) patients using formalin-fixed paraffin-embedded (FFPE) BO samples with varying degrees of dysplasia.

Design: DNA flow cytometry was performed on 80 FFPE BO samples with high-grade dysplasia (HGD), 38 LGD, 21 IND and 14 negative for dysplasia (ND). Three to four 60-micron thick sections were cut from each tissue block, and the area of interest was manually dissected.

Results: DNA content abnormality was identified in 76 HGD (95%), 8 LGD (21.1%), 2 IND (9.5%) and 0 ND samples. As a diagnostic marker of HGD, the estimated sensitivity and specificity of DNA content abnormality were 95% and 85%, respectively. For patients with DNA content abnormality detected at baseline LGD or IND, the univariate HRs for subsequent detection of HGD or oesophageal adenocarcinoma (OAC) were 7.0 and 20.0, respectively (p =<0.001).

Conclusions: This study demonstrates the promise of DNA flow cytometry using FFPE tissue in the diagnosis and risk stratification of dysplasia in BO. The presence of DNA content abnormality correlates with increasing levels of dysplasia, as 95% of HGD samples showed DNA content abnormality. DNA flow cytometry also identifies a subset of patients with LGD and IND who are at higher risk for subsequent detection of HGD or OAC.
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http://dx.doi.org/10.1136/gutjnl-2017-313815DOI Listing
July 2018

NRASQ61R immunohistochemistry detects both NRASQ61R and KRASQ61R mutations in colorectal cancer.

Pathology 2017 Jun 19;49(4):387-390. Epub 2017 Apr 19.

Department of Pathology, National Taiwan University Hospital, Taipei, Taiwan; Graduate Institute of Pathology, College of Medicine, National Taiwan University, Taipei, Taiwan. Electronic address:

The NRASQ61R monoclonal antibody (clone sp174) is a mutation-specific antibody that is increasingly being used to detect the NRAS mutation in melanomas. This antibody has been reported to be highly correlated with the NRAS mutation status in melanomas and follicular neoplasms of the thyroid gland. However, its utility in colorectal carcinoma (CRC) has remained largely unknown. In this study, we assessed the sensitivity, specificity, and diagnostic utility of NRASQ61R immunohistochemistry in a cohort consisting of tissue sections of 113 CRCs, which were molecularly profiled for the KRAS, NRAS, and BRAF mutations. Five CRCs tested positive for NRASQ61R immunohistochemistry. Four of these CRCs exhibited the NRAS mutation and one exhibited the KRAS mutation. All of the other 108 colorectal carcinomas lacking the NRAS or KRAS mutation tested negative for NRASQ61R immunohistochemistry. In the positively stained cases, we observed a diffuse staining pattern in >90% of the tumour cells with a moderate-to-strong intensity. By contrast, the staining was essentially entirely negative in cases negative for the NRAS or KRAS mutations. We concluded that although it cross-reacts with the mutant KRAS protein, the NRASQ61R antibody is a useful diagnostic tool that assists in the molecular testing of CRCs and facilitates patient management.
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http://dx.doi.org/10.1016/j.pathol.2017.01.008DOI Listing
June 2017

Complementary roles of β-catenin and glutamine synthetase immunostaining in diagnosis of chemotherapy-treated and untreated hepatoblastoma.

J Formos Med Assoc 2017 Jul 27;116(7):549-553. Epub 2016 Oct 27.

Graduate Institute of Pathology, National Taiwan University, Taipei, Taiwan; Department of Pathology, National Taiwan University Hospital, Taipei, Taiwan. Electronic address:

Background/purpose: This study aimed to evaluate the expression of β-catenin and its downstream target glutamine synthetase (GS) in hepatoblastoma (HB), and to evaluate the use of these two markers for diagnosing HB.

Methods: Eighteen untreated HBs and 22 HBs resected after neoadjuvant chemotherapy were analyzed using β-catenin and GS immunostaining.

Results: We detected nuclear β-catenin immunostaining in nearly all untreated HBs, including in fetal and embryonal epithelial components and in mesenchymal elements. We also observed diffuse GS expression in the epithelial component; however, it was frequently absent in embryonal and mesenchymal areas. In HBs resected after neoadjuvant chemotherapy, we recognized four histological patterns: fetal, hepatocellular-carcinoma-like, clear-cell, and normal-liver-like. All these patterns displayed diffuse GS expression. Fetal pattern showed diffuse nuclear β-catenin immunostaining. Nuclear β-catenin immunostaining was weak in the hepatocellular-carcinoma-like and clear-cell patterns. In normal-liver-like area, β-catenin expression was only located in the cell membrane.

Conclusion: The results suggest that nuclear β-catenin expression and diffuse GS immunostaining are the hallmarks of HB. Although epithelial and mesenchymal components of HB display nuclear β-catenin staining, this expression is attenuated following chemotherapy-induced cell maturation. GS immunostaining is especially useful for the assessment of section margins after neoadjuvant chemotherapy.
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http://dx.doi.org/10.1016/j.jfma.2016.09.013DOI Listing
July 2017

Aggressive non-alcoholic steatohepatitis following rapid weight loss and/or malnutrition.

Mod Pathol 2017 06 3;30(6):834-842. Epub 2017 Mar 3.

Department of Pathology, University of California, San Francisco, CA, USA.

While non-alcoholic steatohepatitis is a slowly progressive disease, patients may rarely present in acute liver failure. We describe six patients who developed severe hepatic dysfunction following rapid weight loss or malnutrition. Rapid weight loss (18 to 91 kg) occurred after Roux-en-Y gastric bypass in four patients and starvation-like dieting or hypoalbuminemia was noted in two patients. Four patients either died or received an urgent liver transplant. Pathologic findings were characterized by advanced alcoholic steatohepatitis-like features, including extensive/circumferential centrizonal pericellular fibrosis, central scar with perivenular sclerosis/veno-occlusion with superimposed hepatocellular dropout, abundant/prominent hepatocellular balloons, and numerous Mallory-Denk bodies, but there was no history of excess alcohol consumption. This study characterizes clinicopathologic features of aggressive non-alcoholic steatohepatitis following rapid weight loss or malnutrition, which should be included in the differential diagnosis with alcohol when a patient is considered for liver transplantation. The mechanism of liver injury in aggressive steatohepatitis is unknown, but rapid fat mobilization in obese patients may potentially cause oxidative stress to the liver and further study is needed to determine if there is a genetic predisposition to this form of injury and if antioxidants may protect the liver during rapid weight loss/malnutrition.
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http://dx.doi.org/10.1038/modpathol.2017.13DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5935795PMC
June 2017

RNF43 mutation frequently occurs with GNAS mutation and mucin hypersecretion in intraductal papillary neoplasms of the bile duct.

Histopathology 2017 Apr 10;70(5):756-765. Epub 2017 Jan 10.

Department of Pathology, National Taiwan University Hospital, Taipei, Taiwan.

Aims: RNF43 is a tumour suppressor gene that suppresses the Wnt-β-catenin signalling pathway. We investigated the role of RNF43 in intraductal papillary neoplasm of the bile duct (IPNB).

Methods And Results: We conducted mutation analysis of RNF43 in 50 IPNBs, and identified six (12%) RNF43 mutations. RNF43 mutation was more frequent in the intestinal subtype of IPNB (17%) than in the gastric/pancreatobiliary subtype (5%). There was a strong association of RNF43 mutation with GNAS (P = 0.007) mutation, and a borderline correlation with KRAS (P = 0.074) mutation. The presence of macroscopic mucin hypersecretion was closely related to RNF43 (P = 0.024) and GNAS (P < 0.001) mutations. A two-step clustering analysis algorithm successfully categorized IPNBs into two subgroups by using the clinicopathological and molecular features of IPNBs. One subgroup of IPNB represented the 'biliary counterpart of intraductal papillary mucinous neoplasm of the pancreas' (biliary-IPMN), and showed unique features reminiscent of IPMN, such as macroscopic and microscopic mucin hypersecretion, an intestinal cell lineage, GNAS mutation, and RNF43 mutation. Biliary-IPMNs were significantly associated with high expression of cytokeratin (CK) 20, mucin 2 (MUC2), and CDX2, as shown by immunostaining (P = 0.032, P = 0.001, and P = 0.026, respectively), and had a borderline association with low expression of CK7 (P = 0.063). With the use of this splitting algorithm, RNF43 mutations were identified in 36% of the biliary-IPMNs.

Conclusions: The identification of RNF43 mutations in a distinct subset of IPNBs revealed a new molecular role in the pathogenesis of IPNB, and provided a potential application for cancer therapeutics by the use of Wnt pathway inhibitors.
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http://dx.doi.org/10.1111/his.13125DOI Listing
April 2017

Frequent PIK3CA activating mutations in nipple adenomas.

Histopathology 2017 Jan 29;70(2):195-202. Epub 2016 Sep 29.

Department of Dermatology, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan.

Aims: Nipple adenoma (NA) is a rare benign epithelial tumour occurring in the nipple. Histologically, it exhibits variable and often mixed adenosis-like and usual ductal hyperplasia-like growth patterns. Morphologically, it is similar to other benign proliferative breast lesions occurring in the breast parenchyma, which have been shown to harbour activating mutations in PIK3CA, AKT1 or, less frequently, in RAS in more than 50% of cases. In this study, we aimed to analyse the mutation status of PIK3CA, AKT1, RAS and BRAF in NAs and correlated the mutation status with the histological features.

Methods And Results: Mutation analysis of PIK3CA, AKT1, RAS and BRAF was performed in 24 NAs by Sanger sequencing. Our results showed that activating PIK3CA mutations were identified in eight of the 15 NAs (53%) with a predominantly adenosis-like pattern and four of the nine NAs (44%) with a predominantly usual ductal hyperplasia-like pattern. One tumour with a PIK3CA H1047R mutation also had a KRAS Q61H mutation. Two tumours with an adenosis-like pattern had BRAF V600E mutations. Overall, half of the NAs (12 of 24, 50%) in our series had PIK3CA mutations and 58% (14 of 24) had PIK3CA, RAS or BRAF mutations.

Conclusions: Our data indicate that, similar to other benign proliferative lesions occurring in the breast parenchyma, activating PIK3CA mutations are very common in NAs, and KRAS mutation may occur concurrently with PIK3CA mutation. In addition, as BRAF mutation has not been identified in benign proliferative lesions in previous studies, BRAF-mutated NAs appear to have distinct pathogenesis.
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http://dx.doi.org/10.1111/his.13043DOI Listing
January 2017

RNF43 Is an Early and Specific Mutated Gene in the Serrated Pathway, With Increased Frequency in Traditional Serrated Adenoma and Its Associated Malignancy.

Am J Surg Pathol 2016 10;40(10):1352-9

Departments of *Pathology ‡Oncology ∥Medical Genetics, National Taiwan University Hospital †Graduate Institute of Pathology §Graduate Institute of Clinical Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan.

RNF43 is an E3 ligase that suppresses the Wnt/β-catenin signaling pathway and is frequently mutated in microsatellite-unstable colorectal carcinoma. To investigate the pathogenetic role of RNF43 in the serrated pathway, we conducted mutation analysis of RNF43 in several types of colorectal neoplasms. RNF43 mutation was found in 2 of 20 (10%) sessile serrated adenomas, 10 of 36 (28%) traditional serrated adenomas, 7 of 37 (19%) traditional serrated adenomas with cytologic dysplasia, and 9 of 31 (29%) BRAF-mutated/microsatellite-stable colorectal carcinomas; however, no mutation was found in 30 tubulovillous/villous adenomas. All mutations were located upstream of the ring finger domain of RNF43 without clustering, which is distinct from the pattern described for microsatellite-unstable colorectal carcinoma. RNF43 mutation was closely associated with BRAF mutation but inversely associated with KRAS mutation in traditional serrated adenoma with or without cytologic dysplasia (P=0.018 and 0.045, respectively). The finding of RNF43 mutation in sessile serrated adenoma and traditional serrated adenoma, but not in tubulovillous/villous adenoma, indicated that RNF43 mutation is an early and specific molecular aberration in the serrated pathway. The frequency of RNF43 mutation was significantly higher in traditional serrated adenoma with or without cytologic dysplasia and BRAF-mutated/microsatellite-stable colorectal carcinoma than sessile serrated adenoma. The unique molecular spectrum of these tumors suggests a stepwise neoplastic progression from sessile serrated adenoma to traditional serrated adenoma and BRAF-mutated/microsatellite-stable colorectal carcinoma, which should be recognized as the traditional serrated pathway to distinguish from the sessile serrated pathway.
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http://dx.doi.org/10.1097/PAS.0000000000000664DOI Listing
October 2016

Frequent PIK3CA-activating mutations in hidradenoma papilliferums.

Hum Pathol 2016 09 13;55:57-62. Epub 2016 May 13.

Department of Pathology, Wan Fang Hospital, Taipei Medical University, Taipei 11696, Taiwan. Electronic address:

Hidradenoma papilliferum (HP) is a benign epithelial tumor most commonly seen in the vulva. It is proposed to be derived from the anogenital mammary-like glands and is histologically very similar to the mammary intraductal papilloma (IP). Approximately 60% of mammary IPs have activating mutations in either PIK3CA or AKT1, with each gene accounting for 30% of cases. In this study, we screened the mutation statuses of PIK3CA, AKT1, RAS, and BRAF in 30 HPs. The results showed that activating mutations in either PIK3CA or AKT1 were identified in 20 tumors (67%); 19 tumors had PIK3CA mutations (63%; 13 in exon 20 and 6 in exon 9), and 1 had an AKT1 E17K mutation (3%). BRAF V600E mutation was found in an HP that also had a PIK3CA H1047R mutation. No RAS mutation was found. The mutation status was not correlated with the degree of epithelial cell hyperplasia. We conclude that although there might be site-related variations in the mutation frequencies of PIK3CA and AKT1 genes, HP is histologically and also genetically very similar to the mammary IP, suggesting that HP can be viewed as the extramammary counterpart of mammary IP.
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http://dx.doi.org/10.1016/j.humpath.2016.04.014DOI Listing
September 2016

BRAF mutation may have different prognostic implications in early- and late-stage colorectal cancer.

Med Oncol 2016 May 31;33(5):39. Epub 2016 Mar 31.

Department of Oncology, National Taiwan University Hospital, No 7, Chung-Shan South Rd, Taipei, 10002, Taiwan.

The prognostic implication of BRAF mutant colorectal cancer remains paradoxical. Records of BRAF mutant and wild-type colorectal cancer patients at all stages were reviewed. Clinicopathologic features, including microsatellite instability, CpG islands methylator phenotype, and overall survival, of these patients were analyzed. Between 2005 and 2013, 428 colorectal cancer patients were enrolled in this study. The overall survival between BRAF mutant and wild-type patients with early-stage (stages I and II) colorectal cancer differed nonsignificantly (P = 0.99). By contrast, in late-stage (stages III and IV) patients, the median overall survival of BRAF mutant patients (N = 25) was significantly poorer than that of BRAF wild-type (N = 207) patients (BRAF mutant: 21.3 months (95% confidence interval [CI] 7.1-35.5); BRAF wild-type: 53.5 months (95% CI 37.5-69.5), P < 0.0001). In early-stage patients, we found that BRAF mutation was significantly associated with CpG island methylator phenotype-positive (P < 0.001), and microsatellite instability-high status (P = 0.0013). Conversely, in late-stage patients, BRAF mutation was significantly associated with CpG island methylator phenotype-positive (P = 0.0015) and the right-side colon (P = 0.014). BRAF mutation may have different prognostic implications in early- and late-stage colorectal cancer.
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http://dx.doi.org/10.1007/s12032-016-0756-6DOI Listing
May 2016

Targeted next-generation sequencing of cancer genes identified frequent TP53 and ATRX mutations in leiomyosarcoma.

Am J Transl Res 2015 15;7(10):2072-81. Epub 2015 Oct 15.

Department of Pathology, National Taiwan University Hospital, and Graduate Institute of Pathology, National Taiwan University College of Medicine, National Taiwan University Taipei, Taiwan.

Leiomyosarcoma is an aggressive soft tissue sarcoma with poor patient survival. The genetic changes of leiomyosarcoma remain to be discovered. In this study, we analyzed the genetic changes of 44 cancer-related genes by using next-generation sequencing in 54 leiomyosarcomas. We identified TP53 mutations in 19 of the 54 tumors (35%) and ATRX mutations in 9 of the 54 tumors (17%). The TP53-mutated leiomyosarcomas were limited to female patients (P = 0.006). All but 2 of the TP53-mutated leiomyosarcomas were located in the uterus (n = 11) or retroperitoneum (n = 6). The ATRX mutations were associated with poorly differentiated leiomyosarcomas (P = 0.028) and the presence of tumor necrosis (P = 0.015). Kaplan-Meier survival analysis showed that patients with ATRX-mutated leiomyosarcomas had worse overall survival than did patients with ATRX-wild-type leiomyosarcomas. All of the ATRX-mutated leiomyosarcomas showed the alternative lengthening of telomere phenotype. The ATRX mutations did not correlate with ATRX protein expression, as detected using immunohistochemistry. In conclusion, we identified loss of function of the p53 and ATRX pathways being the main mechanisms for leiomyosarcomas. The molecular mechanisms may provide new opportunities to treat these aggressive neoplasms.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4656784PMC
December 2015

Frequent BRAF mutation in early-onset colorectal cancer in Taiwan: association with distinct clinicopathological and molecular features and poor clinical outcome.

J Clin Pathol 2016 Apr 23;69(4):319-25. Epub 2015 Oct 23.

Department of Pathology, National Taiwan University Hospital, Taipei, Taiwan Graduate Institute of Pathology, College of Medicine, National Taiwan University, Taipei, Taiwan.

Background: Occurrence of early-onset colorectal cancer (EOCRC) under the age of 30 is very rare and the molecular characteristics are poorly understood. A low BRAF mutation rate has been noted in several studies of EOCRC from Western countries.

Aims: To determine the clinicopathological and molecular features of EOCRCs in Taiwan.

Methods: KRAS/BRAF gene mutation, mismatch repair protein immunohistochemistry, microsatellite instability and CpG island methylation phenotype analyses were examined to determine the molecular characteristics of EOCRC.

Results: Sixty-six patients with EOCRC at our hospital between 2000 and 2012 were studied. BRAF mutation was detected in 11 of the 59 tumours analysed (19%) and the rate was significantly higher than the overall BRAF mutation rate of colorectal cancer in patients older than 30 years (p<0.001). Clinically, 9 of 11 patients with BRAF-mutated tumours presented with advanced-stage diseases and they presented significantly more frequently with stage IV disease than those with BRAF wild-type tumours (p=0.042). Histologically, BRAF mutation was associated with a poorly differentiated histology, a serrated precursor polyp and focal signet ring cell differentiation (p=0.042, 0.008 and 0.008, respectively). None of the BRAF-mutated tumours was mismatch repair protein-deficient and/or microsatellite instability-high. Overall survival of patients with BRAF-mutated tumours was significantly worse than that of patients with BRAF wild-type tumours, despite adjustment for the disease stages and tumour differentiation.

Conclusions: BRAF mutation was frequent in EOCRCs in Taiwan and was associated with distinct clinicopathological and molecular features.
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http://dx.doi.org/10.1136/jclinpath-2015-203335DOI Listing
April 2016

Traditional serrated adenoma with BRAF mutation is associated with synchronous/metachronous BRAF-mutated serrated lesions.

Histopathology 2016 May 25;68(6):810-8. Epub 2015 Oct 25.

Department of Pathology, National Taiwan University, Taipei, Taiwan.

Aims: To determine whether traditional serrated adenoma (TSA) results in an increased risk of developing subsequent serrated polyps or colorectal cancer (CRC).

Methods And Results: We recruited 111 patients with an index TSA, and analysed the pathological and molecular features of their synchronous/metachronous serrated lesions. Fifty hyperplastic polyps, 14 sessile serrated adenomas, an additional 27 TSAs and 17 CRCs were identified from 46 patients. Twenty-seven percent of TSAs showed a precursor serrated polyp in the periphery and were strongly correlated with BRAF mutation (P < 0.001). Serrated polyps occurred more commonly in patients with BRAF-mutated index TSAs than in patients with KRAS-mutated index TSAs. BRAF-mutated index TSAs were strongly associated with a right-sided location and BRAF mutation of synchronous/metachronous serrated polyps (P = 0.013 and P = 0.005, respectively). The 17 CRCs occurred more frequently in women, and were characterized by a high BRAF mutation rate (59%), a positive CpG island methylator phenotype (59%), and stable or low levels of microsatellite instability (77%).

Conclusions: BRAF-mutated TSA is distinct from KRAS-mutated TSA in predisposing to the acquisition of subsequent serrated neoplasia. This indicates the presence of an intestinal field defect in the tumour microenvironment that results in tumour initiation and malignant progression.
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http://dx.doi.org/10.1111/his.12814DOI Listing
May 2016

TERT promoter mutations in periocular carcinomas: implications of ultraviolet light in pathogenesis.

Br J Ophthalmol 2016 Feb 15;100(2):274-7. Epub 2015 Oct 15.

Department of Pathology, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan Graduate Institute of Pathology, National Taiwan University College of Medicine, Taipei, Taiwan.

Background/aims: Ultraviolet light-signature mutations in the telomerase reverse transcriptase (TERT) gene promoter have been identified in cutaneous melanomas, basal cell carcinomas (BCCs), and squamous cell carcinomas (SCCs). Whether these mutations also occur in periocular tumours, including periocular sebaceous carcinomas (PSCs) and in situ tumours, has not been studied.

Methods: DNA extraction, PCR and Sanger sequencing were used to determine the frequency of TERT promoter mutations in periocular tumours. The presence of mutations was correlated with histological evidence of solar elastosis.

Results: Sixty-three tumours were analysed. TERT promoter mutations were identified in 18 of 22 BCCs (82%), 6 of 10 SCCs (60%), 1 of 2 in situ SCCs (50%), 4 of 9 grade III conjunctival intraepithelial neoplasia (CIN III) (44%) and 0 of 20 PSCs (0%). For BCCs, TERT promoter mutations were not associated with the histological risk categories of the tumours. For CIN III cases, all of the three lesions with solar elastosis had TERT promoter mutations, whereas the mutation was found in only one of the six CIN III cases without solar elastosis.

Conclusions: We demonstrate that ultraviolet light-signature TERT promoter mutations are very common in periocular BCCs, SCCs and CIN III lesions, indicating important roles of ultraviolet light in the pathogenesis of these tumours. In addition, the mutations are present in in situ stage. By contrast, no TERT promoter mutation is found in PSCs.
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http://dx.doi.org/10.1136/bjophthalmol-2015-307503DOI Listing
February 2016

Comprehensive screening of alternative lengthening of telomeres phenotype and loss of ATRX expression in sarcomas.

Mod Pathol 2015 Dec 2;28(12):1545-54. Epub 2015 Oct 2.

Department of Pathology, National Taiwan University Hospital, College of Medicine, National Taiwan University, Taipei, Taiwan.

According to cytogenetic aberrations, sarcomas can be categorized as complex or simple karyotype tumors. Alternative lengthening of telomeres is a telomere-maintenance mechanism common in sarcomas. Recently, this mechanism was found to be associated with loss of either α-thalassemia/mental retardation syndrome X-linked (ATRX) or death domain-associated (DAXX) protein. We previously reported that alternative lengthening of telomeres and loss of ATRX expression were common in leiomyosarcoma, angiosarcoma, pleomorphic liposarcoma, and dedifferentiated liposarcoma. In the present study, we screened an additional 245 sarcomas of other types to determine the prevalence of alternative lengthening of telomeres, loss of ATRX/DAXX expression, and their relationship. Undifferentiated pleomorphic sarcomas were frequently alternative lengthening of telomeres positive (65%) and loss of ATRX was seen in approximately half of the alternative lengthening of telomeres-positive tumors. Nineteen of 25 myxofibrosarcomas were alternative lengthening of telomeres-positive, but only one was ATRX deficient. Three of 15 radiation-associated sarcomas were alternative lengthening of telomeres positive, but none of them was ATRX deficient. Alternative lengthening of telomeres and/or loss of ATRX were uncommon in malignant peripheral nerve sheath tumors, gastrointestinal stromal tumors, and embryonal rhabdomyosarcomas. By contrast, none of the 71 gene fusion-associated sarcomas was ATRX deficient or alternative lengthening of telomeres positive. All tumors exhibited preserved DAXX expression. Combining our previous studies and this study, a total of 384 sarcomas with complex karyotypes were examined, 83 of which were ATRX deficient (22%). By telomere-specific fluorescence in situ hybridization, 45% (138/308) were alternative lengthening of telomeres positive, 55% (76/138) of which were ATRX deficient. Loss of ATRX was highly associated with alternative lengthening of telomeres (P<0.001). We conclude that alternative lengthening of telomeres is a frequent telomere-maintenance mechanism in cytogenetically complex sarcomas. Loss of ATRX is highly associated with this feature.
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http://dx.doi.org/10.1038/modpathol.2015.114DOI Listing
December 2015