Publications by authors named "Xuchen Zhang"

112 Publications

Aberrant von Willebrand factor expression of sinusoidal endothelial cells and quiescence of hepatic stellate cells in nodular regenerative hyperplasia and obliterative portal venopathy.

Histopathology 2020 Jun 7;76(7):959-967. Epub 2020 May 7.

Department of Pathology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.

Aims: Nodular regenerative hyperplasia (NRH) and obliterative portal venopathy (OPV), entities that comprise idiopathic non-cirrhotic portal hypertension (INCPH), are under-recognised diseases of uncertain aetiology and the diagnosis can be easily missed on liver biopsy. The expression of CD34 and von Willebrand factor (vWF) in liver sinusoidal endothelial cells (LSEC) and alpha-smooth muscle actin (ASMA) in hepatic stellate cells (HSCs) is unknown in NRH and OPV. We sought to investigate the pathogenesis and potential immunomarkers that might aid in making the diagnosis of NRH and OPV.

Methods And Results: Immunohistochemical (IHC) staining for CD34, vWF and ASMA was performed in clinically and histologically well-characterised NRH (n = 15) and OPV (n = 47) liver specimens. Among the 47 OPV cases, 37 (78.7%) had concurrent features of NRH. CD34 positive staining was mainly confined to small vessels in the portal tracts and LSECs in periportal areas, a finding similar to that in non-NRH/OPV livers. However, expression of vWF in LSECs was positive in the compressed sinusoids of NRH and in a patchy or geographic pattern, particularly prominent in the perivenular areas and dilated sinusoids of OPV cases. HSCs were negative for ASMA in all NRH and OPV cases.

Conclusion: Our findings indicate that NRH may be a subtle but common concurrent morphological feature in OPV. The aberrant expression of vWF in LSECs suggests that endothelial injury may play a role in the pathogenesis, which may thus aid in the recognition and diagnosis of NRH and OPV, particularly when confronted with otherwise apparent normal liver histology on needle biopsy.
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http://dx.doi.org/10.1111/his.14083DOI Listing
June 2020

Clinicopathologic features of Buschke-Löwenstein tumor: a multi-institutional analysis of 38 cases.

Virchows Arch 2020 Apr 15;476(4):543-550. Epub 2019 Nov 15.

Department of Pathology, Immunology, and Laboratory Medicine, University of Florida College of Medicine, Gainesville, FL, USA.

Buschke-Löwenstein tumor (BLT) is a rare sexually transmitted disease, mostly described in clinical literature as case reports or small series. Here, we investigated the clinicopathologic features of BLT in a total of 38 cases retrieved from multiple academic institutions. The average age was 47.6 ± 12.8 (mean ± SD) years old at diagnosis. The male to female ratio was 4.4:1. Common presenting symptoms were pain/discomfort, bleeding, mass lesion, and discharge. It was frequently linked to smoking and positive human immunodeficiency virus status. The tumor size and thickness were 8.5 ± 6.6 cm and 1.5 ± 1.3 cm, respectively. Histologically, 19 (50%) cases had an invasive squamous cell carcinoma component and were associated with high-risk human papillomavirus infection. There was no lymphovascular or perineural invasion, or nodal metastasis at initial diagnosis. BLTs with invasion had higher frequency of dyskeratosis, neutrophilic microabscesses, and abnormal mitoses, but lower frequency of pushing border compared with BLTs without invasion. All patients underwent wide excision, and some also received chemoradiation therapy. After a median follow-up of 23 months (range 1-207), the recurrence rate was 23.7% and disease-specific mortality was 2.6%. In summary, we presented the largest case series of BLT to date to characterize its unique clinicopathologic features. Our study indicated that certain histologic features such as dyskeratosis, neutrophilic microabscess, and abnormal mitosis in the non-invasive portion may be important clues on lesional biopsy to predict the presence of underlying invasive carcinoma.
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http://dx.doi.org/10.1007/s00428-019-02680-zDOI Listing
April 2020

Neutropenic enterocolitis: A clinico-pathological review.

World J Gastrointest Pathophysiol 2019 Oct;10(3):36-41

Department of Pathology, Yale University School of Medicine, New Haven, CT 06520, United States.

Neutropenic enterocolitis (NE) is a predominantly cecum-based disease with high mortality seen in patients post chemotherapy. The pathogenesis of NE is poorly understood and probably multifactorial involving mucosal injury, neutropenia, and impaired host defense to intestinal organisms. The clinical presentation is characterized as ileocolonic inflammation and bowel wall thickening in patients with neutropenia, fever, and abdominal pain. The pathological features of NE include patchy necrosis, hemorrhage, ulcer, edema, perforation, infiltrating organisms, and characteristically, depletion of inflammatory cells (neutrophils). NE should always be considered as a possible diagnosis in immunosuppressed patients, especially those receiving chemotherapy. High clinical and histological diagnostic discordance rate exists. High index of clinical suspicion and prompt appropriate personalized management are essential to achieve a lower mortality rate.
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http://dx.doi.org/10.4291/wjgp.v10.i3.36DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6829094PMC
October 2019

Morphological spectrum of immune check-point inhibitor therapy-associated gastritis.

Histopathology 2020 Mar 18;76(4):531-539. Epub 2020 Feb 18.

Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.

Aims: Immune check-point inhibitors are frequently used in the treatment of a variety of solid tumours. The mechanism of action of these drugs involves up-regulation of cytotoxic T cells, which can lead to a lack of self-tolerance and immune-related adverse events, including those involving the gastrointestinal tract. This study was performed to characterise the histological features of immune check-point inhibitor therapy-associated gastritis.

Methods And Results: Gastric biopsies from patients on immune check-point inhibitor therapy with clinical suspicion of drug-associated gastrointestinal injury were identified. The predominant histological pattern of injury, distribution of injury, degree of tissue eosinophilia and prominence of apoptosis were recorded. Presenting symptoms, treatment and follow-up data were obtained by medical chart review. The 12 patients included in the study group were treated with ipilimumab, nivolumab or pembrolizumab for a variety of tumours. Symptoms at presentation included nausea, vomiting and diarrhoea. Chronic active gastritis with intra-epithelial lymphocytosis and prominent apoptosis was seen in eight of 12 patients, and was the most useful combination for the diagnosis of drug-induced gastritis in these patients. Four patients showed focal enhancing gastritis with a lymphohistiocytic cuff around inflamed glands reminiscent of Crohn's disease. One of those four patients was homozygous for the ATG16L1 Crohn's disease-associated gene variant, but had no history of inflammatory bowel disease. Ten patients responded to medication withdrawal and steroid therapy, while two required treatment with infliximab.

Conclusions: Awareness of the morphological spectrum of immune check-point inhibitor therapy-associated gastritis is important for the accurate diagnosis and prompt management of these patients.
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http://dx.doi.org/10.1111/his.14029DOI Listing
March 2020

Long-term memory is formed immediately without the need for protein synthesis-dependent consolidation in Drosophila.

Nat Commun 2019 10 7;10(1):4550. Epub 2019 Oct 7.

Tsinghua-Peking Center for Life Sciences, IDG/McGovern Institute for Brain Research and School of Life Sciences, Tsinghua University, 100084, Beijing, China.

It is believed that long-term memory (LTM) cannot be formed immediately because it must go through a protein synthesis-dependent consolidation process. However, the current study uses Drosophila aversive olfactory conditioning to show that such processes are dispensable for context-dependent LTM (cLTM). Single-trial conditioning yields cLTM that is formed immediately in a protein-synthesis independent manner and is sustained over 14 days without decay. Unlike retrieval of traditional LTM, which requires only the conditioned odour and is mediated by mushroom-body neurons, cLTM recall requires both the conditioned odour and reinstatement of the training-environmental context. It is mediated through lateral-horn neurons that connect to multiple sensory brain regions. The cLTM cannot be retrieved if synaptic transmission from any one of these centres is blocked, with effects similar to those of altered encoding context during retrieval. The present study provides strong evidence that long-term memory can be formed easily without the need for consolidation.
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http://dx.doi.org/10.1038/s41467-019-12436-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6779902PMC
October 2019

Differences in Pathology, Staging, and Treatment between HIV and Uninfected Patients with Microscopically Confirmed Hepatocellular Carcinoma.

Cancer Epidemiol Biomarkers Prev 2020 01 1;29(1):71-78. Epub 2019 Oct 1.

Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.

Background: The incidence of hepatocellular carcinoma (HCC) is substantially higher among HIV-infected (HIV) than uninfected persons. It remains unclear if HCC in the setting of HIV infection is morphologically distinct or more aggressive.

Methods: We evaluated differences in tumor pathology in a cohort of HIV and uninfected patients with microscopically confirmed HCC in the Veterans Aging Cohort Study from 2000 to 2015. We reviewed pathology reports and medical records to determine Barcelona Clinic Liver Cancer stage (BCLC), HCC treatment, and survival by HIV status. Multivariable Cox regression was used to determine the hazard ratio [HR; 95% confidence interval (CI)] of death associated with HIV infection after microscopic confirmation.

Results: Among 873 patients with HCC (399 HIV), 140 HIV and 178 uninfected persons underwent liver tissue sampling and had microscopically confirmed HCC. There were no differences in histologic features of the tumor between HIV and uninfected patients, including tumor differentiation (well differentiated, 19% vs. 28%, = 0.16) and lymphovascular invasion (6% vs. 7%, = 0.17) or presence of advanced hepatic fibrosis (40% vs. 39%, = 0.90). There were no differences in BCLC stage ( = 0.06) or treatment ( = 0.29) by HIV status. After adjustment for risk factors, risk of death was higher among HIV-infected than uninfected patients (HR = 1.37; 95% CI, 1.02-1.85).

Conclusions: We found no differences in HCC tumor characteristics or background hepatic parenchyma by HIV status, yet HIV was associated with poorer survival. Of note, pathology reports often omitted these characteristics.

Impact: Systematic evaluation of HCC pathology by HIV status is needed to understand tumor characteristics associated with improved survival.
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http://dx.doi.org/10.1158/1055-9965.EPI-19-0503DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6980754PMC
January 2020

Pancreatic Intraductal Papillary Mucinous Neoplasm With Elevated Pre-Operative Cystic Carcinoembryonic Antigen Level: A Histopathologic Correlation.

Gastroenterology Res 2019 Aug 25;12(4):185-190. Epub 2019 Aug 25.

Department of Pathology, Yale University School of Medicine, New Haven, CT, USA.

Background: To study the relationship between carcinoembryonic antigen (CEA) level, intraductal papillary mucinous neoplasm (IPMN) subtype, and the presence of invasive carcinoma.

Methods: Cystic CEA level and the following pathologic variables: subtypes of IPMN, size of cystic lesion, presence of dysplasia or carcinoma, and main or branch duct involvement from 45 IPMN cases were analyzed.

Results: There was a significant correlation between pre-operative cystic fluid CEA level and the intensity of luminal CEA staining. However, there was no correlation between CEA level and cystic mucinous secretions or mucinous epithelial cytoplasm CEA staining, mucin glycoprotein expression, size of lesion, grade of dysplasia or presence of invasive carcinoma. CEA level was neither sensitive nor specific for the presence of invasive carcinoma.

Conclusions: Cystic CEA level may not be a reliable determinant of the presence or absence of invasive carcinoma in IPMNs, and its use to assess risk of malignancy may be limited.
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http://dx.doi.org/10.14740/gr1201DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6731045PMC
August 2019

Adverse Histologic Features in Colorectal Nonpedunculated Malignant Polyps With Nodal Metastasis.

Am J Surg Pathol 2020 02;44(2):241-246

Department of Pathology, Yale School of Medicine, New Haven, CT.

Tumor differentiation, lymphovascular invasion, margin status, polyp shape, and size are important parameters of malignant polyps (pT1) indicating possible node metastasis, which justifies a surgery. However, the size, margin, and lymphovascular invasion are often unknown or difficult to assess in a piecemeal polypectomy from a nonpedunculated malignant polyp. The aim of the study was to identify adverse histologic features in nonpedunculated malignant polyps associated with an increased risk of nodal metastasis, which may warrant a colectomy procedure. A total of 24 node-positive and 18 node-negative nonpedunculated malignant polyps and their corresponding subsequent resection specimens from 2005 to 2018 were reviewed. Cases with node metastasis were more often positive for high-grade tumor budding (70.8% vs. 16.7%; P=0.0005), poorly differentiated clusters (54.2% vs. 22.2%; P=0.0369), and both high-grade tumor budding and poorly differentiated clusters (45.8% vs. 11.1%; P=0.0160) compared with controls without nodal metastasis. High-grade tumor budding, poorly differentiated clusters, and combined high-grade tumor budding and poorly differentiated clusters increased the risk of nodal metastasis, with odds ratio of 12.1, 4.1, and 14.3, respectively. Furthermore, nodal metastasis could be seen in subsequent colectomy specimen even in completely excised malignant polyps with adverse histologic features. Our findings indicate that high-grade tumor budding and poorly differentiated clusters are important adverse histologic risk features in predicting lymph node metastatic potential. These histologic features should be reported and it may warrant a colectomy when they are present.
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http://dx.doi.org/10.1097/PAS.0000000000001369DOI Listing
February 2020

Genetic dissection of active forgetting in labile and consolidated memories in .

Proc Natl Acad Sci U S A 2019 10 5;116(42):21191-21197. Epub 2019 Sep 5.

Tsinghua-Peking Center for Life Sciences, McGovern Institute for Brain Research, Ministry of Education Key Laboratory of Protein Sciences, School of Life Sciences, Tsinghua University, 100084 Beijing, China;

Different memory components are forgotten through distinct molecular mechanisms. In , the activation of 2 Rho GTPases (Rac1 and Cdc42), respectively, underlies the forgetting of an early labile memory (anesthesia-sensitive memory, ASM) and a form of consolidated memory (anesthesia-resistant memory, ARM). Here, we dissected the molecular mechanisms that tie Rac1 and Cdc42 to the different types of memory forgetting. We found that 2 WASP family proteins, SCAR/WAVE and WASp, act downstream of Rac1 and Cdc42 separately to regulate ASM and ARM forgetting in mushroom body neurons. Arp2/3 complex, which organizes branched actin polymerization, is a canonical downstream effector of WASP family proteins. However, we found that Arp2/3 complex is required in Cdc42/WASp-mediated ARM forgetting but not in Rac1/SCAR-mediated ASM forgetting. Instead, we identified that Rac1/SCAR may function with formin Diaphanous (Dia), a nucleator that facilitates linear actin polymerization, in ASM forgetting. The present study, complementing the previously identified Rac1/cofilin pathway that regulates actin depolymerization, suggests that Rho GTPases regulate forgetting by recruiting both actin polymerization and depolymerization pathways. Moreover, Rac1 and Cdc42 may regulate different types of memory forgetting by tapping into different actin polymerization mechanisms.
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http://dx.doi.org/10.1073/pnas.1903763116DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6800343PMC
October 2019

Grading Pancreatic Neuroendocrine Tumors by Ki-67 Index Evaluated on Fine-Needle Aspiration Cell Block Material.

Am J Clin Pathol 2020 01;153(1):74-81

Department of Pathology, Yale University School of Medicine, New Haven, CT.

Objectives: This study aimed to determine whether Ki-67 index evaluated on cytologic material could reliably grade pancreatic neuroendocrine tumors (PanNETs).

Methods: Cases with adequate cell block and available surgical specimens were included. Ki-67 index was calculated using "eyeballing," "hot spot," and "complete" counting methods.

Results: The overall concordance rates between cytology and surgical specimens were 71%, 73%, and 59%, respectively, by using eyeballing, hot spot, and complete counting approaches. All grade 1 tumors were correctly graded on cytology, but in grade 2 tumors concordance rates were only 36%, 41%, and 9%, respectively. All grade 2 tumors were undergraded when cell blocks contained fewer than 1,000 cells, while concordance rate increased to 57%, 64%, and 14%, respectively, in cases with 1,000 cells or more.

Conclusions: Grade 2 PanNETs can be significantly undergraded when Ki-67 index is evaluated on cell block material. In cases with 1,000 or more cells, the hot spot counting method has better correlation with surgical specimens.
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http://dx.doi.org/10.1093/ajcp/aqz110DOI Listing
January 2020

Theranostic application of lipiodol for transarterial chemoembolization in a VX2 rabbit liver tumor model.

Theranostics 2019 27;9(13):3674-3686. Epub 2019 May 27.

Department of Radiology and Biomedical Imaging, Yale School of Medicine, New Haven, Connecticut, USA.

The goal of this study was to investigate the role of Lipiodol as a tumor-specific imaging biomarker to determine therapeutic efficacy of cTACE and investigate its inter-dependency with tumor perfusion using radiological-pathological correlation in an animal model of liver cancer.

Methods: A total of N=36 rabbits were implanted in the left lobe of the liver with VX2 tumors, treated with cTACE using doxorubicin suspended in Lipiodol, and randomly sacrificed at 24 h, 7 days, or 20 days post-TACE. Unenhanced and contrast-enhanced CT scans including a perfusion protocol were obtained before cTACE and immediately before sacrifice. Tumor vascularity and Lipiodol deposition within tumors and hepatic tissue (non-target deposits) were quantified using 3D quantitative assessment tools and measurements of arterial flow, portal flow, and perfusion index (PI). After sacrifice histologic staining, including hematoxylin and eosin (H&E), CD31, and Oil Red O (ORO) were performed on tumor and liver samples to evaluate necrosis, microvascular density (MVD), and Lipiodol retention over time. Transmission electron microscopy (TEM) was performed to assess Lipiodol deposition and clearance over time.

Results: All cTACE procedures were carried out successfully except for one, which was excluded from further analysis. Twenty-four hours post-TACE, tumor PI (p=0.04) was significantly decreased, which was maintained at 7 days (p=0.003), but not at 20 days (p=0.4). A strong correlation (R = 0.894) was found between the volume of enhancing tumor tissue at baseline and Lipiodol-positive tumor volume post-TACE. Both ORO and TEM showed deposition of Lipiodol across all imaging time points within the VX2 tumors. However, gradual and ultimately near-complete Lipiodol washout was observed over time in the non-tumoral liver. MVD decreased between 24 h and 7 days post-TACE, and then increased 20 days post-TACE (both p<0.01).

Conclusions: Our data provide radiology-pathology evidence for the function of Lipiodol as a theranostic, tumor-specific drug delivery agent because it is both imageable and tumor-seeking, whereby it is preferentially taken up and retained by tumor cells. Those tumor-specific functions also enable Lipiodol to act as an imaging biomarker for the therapeutic efficacy of cTACE. Together with volumetric quantification of tumor vascularization on CT, Lipiodol could be used as a predictor of a patient's response to cTACE and contribute to the therapeutic management of patients with liver cancer.
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http://dx.doi.org/10.7150/thno.32943DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6587357PMC
July 2020

Glucose Metabolic Reprogramming and Cell Proliferation Arrest in Colorectal Micropapillary Carcinoma.

Gastroenterology Res 2019 Jun 7;12(3):128-134. Epub 2019 Jun 7.

Department of Pathology, Yale University School of Medicine, New Haven, CT, USA.

Background: Micropapillary carcinoma (MPC) has been reported as an aggressive variant of colorectal carcinoma (CRC) associated with frequent lymphovascular invasion and poor outcome. Altered glycogen metabolism by metabolic reprogramming plays a critical role for cancer cell growth and survival. We aimed to investigate glucose metabolic reprogramming in colorectal MPC.

Methods: Immmunostains for Ki-67 and glucose transporter 1 (GLUT1) were performed on 10 colorectal MPCs. Real-time PCR analysis of expressions of GLUT1 and glycogen metabolizing enzymes: glycogen synthase (GYS1) and glycogen phosphorylase (PYGL) was performed on cultured monolayer and three-dimensional (3D) spheroid HCT116 colon cancer cells.

Results: GLUT1 was strongly expressed in MPC as compared to adjacent conventional glandular component, and was also significantly increased expression in 3D spheroids. Upregulation of GYS1 and PYGL was markedly increased in 3D spheroids. The proliferation rate (Ki-67) of MPC was significantly lower compared to conventional glandular component. The 3D spheroids showed increased cell cycle arrest. Our results demonstrate altered glycogen metabolism in colorectal MPC.

Conclusion: The reprogramming of glycogen metabolism in MPC provides a source of energy contributing to tumor cell survival in a low proliferation state. Targeting glucose-regulated metabolism may warrant consideration as possible MPC therapies.
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http://dx.doi.org/10.14740/gr1145DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6575135PMC
June 2019

Immunohistochemical and molecular features of cholangiolocellular carcinoma are similar to well-differentiated intrahepatic cholangiocarcinoma.

Mod Pathol 2019 10 11;32(10):1486-1494. Epub 2019 Jun 11.

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

Cholangiolocellular carcinoma is characterized by low grade cytologic atypia, and anastomosing cords and glands resembling cholangioles or canals of Hering. Cholangiolocellular carcinoma has been variously regarded as a subtype of intrahepatic cholangiocarcinoma (World Health Organization 2000), combined hepatocellular-cholangiocarcinoma of stem cell subtype (World Health Organization 2010) and a distinct type of primary liver carcinoma. Capture-based next generation sequencing targeting the coding regions of 479 cancer genes and select introns was performed on 17 cases (5 cholangiolocellular carcinomas, 7 intrahepatic cholangiocarcinomas, 5 mixed cholangiolocellular-intrahepatic cholangiocarcinomas) along with immunohistochemistry for CK19, SALL4, CD56, CD117, and EMA. For 5 mixed cholangiolocellular-intrahepatic cholangiocarcinoma, the individual areas were micro-dissected prior to sequencing. CK19 and EMA were positive in all cases; both luminal and cytoplasmic EMA was seen in 3/5 cholangiolocellular carcinoma and 3/6 intrahepatic cholangiocarcinomas. CD117 and SALL4 were negative in all cases. CD56 was positive in 2/5 cholangiolocellular carcinoma, 4/6 intrahepatic cholangiocarcinoma and 2/5 mixed cases. Mutations typical of intrahepatic cholangiocarcinoma (IDH1/2, PBRM1, FGFR2) were present in 90% of cases with cholangiolocellular carcinoma component. The genomic profile (IDH1/2 mutations, FGFR2 fusions, chromatin-remodeling gene mutations such as ARID1A, PBRM1) and copy number alterations were similar in cholangiolocellular carcinoma, intrahepatic cholangiocarcinoma and mixed cholangiolocellular-intrahepatic cholangiocarcinoma. In all mixed cases, the immunohistochemistry results, mutational profile and copy number alterations in both components were similar. Cholangiolocellular carcinoma should be categorized as a histologic subtype of well-differentiated intrahepatic cholangiocarcinoma, and should not be considered a distinct entity, or combined hepatocellular-cholangiocarcinoma unless a distinct hepatocellular component is also present.
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http://dx.doi.org/10.1038/s41379-019-0290-0DOI Listing
October 2019

Macrotrabecular Hepatocellular Carcinoma: An Aggressive Subtype of Hepatocellular Carcinoma.

Am J Surg Pathol 2019 07;43(7):943-948

Department of Pathology, Yale University School of Medicine, New Haven, CT.

The macrotrabecular (MT) pattern of hepatocellular carcinoma (HCC) has been suggested to represent a distinct HCC subtype. We retrospectively reviewed 231 HCC cases. Detailed pathologic evaluation for histologic patterns, including MT-pattern, was performed for each case and recorded as percentage involved at 10% intervals. MT-pattern was defined as having trabeculae >6 cells thick. After excluding all recognized HCC subtypes, remaining cases were deemed conventional HCC (CV-HCC) and served as controls. HCCs with a component of ≥10%, ≥30% and ≥50% MT-pattern were identified in 41 (17.7%), 24 (10.4%) and 4 (1.7%) cases, respectively. The clinicopathologic features of HCCs with 10% to 29% MT-pattern (n=17, 7.4%) were largely similar to CV-HCC. No significant difference was observed between the 30% and 49% (n=20) and ≥50% (n=4) MT groups, hence these were combined for further analysis as MT-HCC. MT-HCCs (≥30% MT-pattern) were larger tumors (5.5 vs. 3.1 cm), were less likely to be associated with cirrhosis (54% vs. 79%), were more likely to have hepatitis B (21% vs. 5%) and less likely hepatitis C infection (33% vs. 58%) compared with CV-HCC. MT-HCC was associated with the presence of anaplastic tumor cells (42% vs. 14%), higher alpha-fetoprotein level, higher AJCC stage, and higher histologic grade. Compared with patients with CV-HCC, patients with MT-HCC had poorer overall survival. Patients with MT-HCC who underwent primary resection or transplantation had a higher recurrence rate and worse recurrence-free survival. Our findings suggest that ≥30% MT-pattern could be used as the more appropriate cut-off for defining MT-HCC, which represents a unique and aggressive HCC histologic subtype.
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http://dx.doi.org/10.1097/PAS.0000000000001289DOI Listing
July 2019

Clinical utility of genomic analysis in adults with idiopathic liver disease.

J Hepatol 2019 06 15;70(6):1214-1221. Epub 2019 Apr 15.

Department of Internal Medicine, Section of Digestive Diseases, Yale School of Medicine, New Haven, CT, USA; Department of Pathology, Yale School of Medicine, New Haven, CT, USA. Electronic address:

Background & Aims: Adult patients suffering from liver disease of unknown cause represent an understudied and underserved population. The use of whole-exome sequencing (WES) for the assessment of a broader spectrum of non-oncological diseases, among adults, remains poorly studied. We assessed the utility of WES in the diagnosis and management of adults with unexplained liver disease despite comprehensive evaluation by a hepatologist and with no history of alcohol overuse.

Methods: We performed WES and deep phenotyping of 19 unrelated adult patients with idiopathic liver disease recruited at a tertiary academic health care center in the US.

Results: Analysis of the exome in 19 cases identified 4 monogenic disorders in 5 unrelated adults. Patient 1 suffered for 18 years from devastating complications of undiagnosed type 3 familial partial lipodystrophy due to a deleterious heterozygous variant in PPARG. Molecular diagnosis enabled initiation of leptin replacement therapy with subsequent normalization of liver aminotransferases, amelioration of dyslipidemia, and decreases in daily insulin requirements. Patients 2 and 3 were diagnosed with MDR3 deficiency due to recessive mutations in ABCB4. Patient 4 with a prior diagnosis of non-alcoholic steatohepatitis was found to harbor a mitochondrial disorder due to a homozygous pathogenic variant in NDUFB3; this finding enabled initiation of disease preventive measures including supplementation with antioxidants. Patient 5 is a lean patient with hepatic steatosis of unknown etiology who was found to have a damaging heterozygous variant in APOB.

Conclusions: Genomic analysis yielded an actionable diagnosis in a substantial number (∼25%) of selected adult patients with chronic liver disease of unknown etiology. This study supports the use of WES in the evaluation and management of adults with idiopathic liver disease in clinical practice.

Lay Summary: We performed whole-exome sequencing in 19 adult patients with unexplained liver disease after an unrevealing conventional work-up performed by a hepatologist. In 5 cases, genomic analysis led to a diagnosis and informed treatment and management of the disease. Therefore, we suggest using whole-exome sequencing in the evaluation and management of adults with unexplained liver disease.
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http://dx.doi.org/10.1016/j.jhep.2019.01.036DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6526061PMC
June 2019

Endothelial toll-like receptor 4 maintains lung integrity via epigenetic suppression of p16.

Aging Cell 2019 06 20;18(3):e12914. Epub 2019 Feb 20.

Pulmonary, Critical Care and Sleep Medicine, Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut.

We previously reported that the canonical innate immune receptor toll-like receptor 4 (TLR4) is critical in maintaining lung integrity. However, the molecular mechanisms via which TLR4 mediates its effect remained unclear. In the present study, we identified distinct contributions of lung endothelial cells (Ec) and epithelial cells TLR4 to pulmonary homeostasis using genetic-specific, lung- and cell-targeted in vivo methods. Emphysema was significantly prevented via the reconstituting of human TLR4 expression in the lung Ec of TLR4-/- mice. Lung Ec-silencing of TLR4 in wild-type mice induced emphysema, highlighting the specific and distinct role of Ec-expressed TLR4 in maintaining lung integrity. We also identified a previously unrecognized role of TLR4 in preventing expression of p16 , a senescence-associated gene. Lung Ec-p16 -silencing prevented TLR4-/- induced emphysema, revealing a new functional role for p16 in lungs. TLR4 suppressed endogenous p16 expression via HDAC2-mediated deacetylation of histone H4. These findings suggest a novel role for TLR4 in maintaining of lung homeostasis via epigenetic regulation of senescence-related gene expression.
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http://dx.doi.org/10.1111/acel.12914DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6516428PMC
June 2019

Safety and Feasibility of a Lower-Cost Stapler in Bariatric Surgery.

Obes Surg 2019 02;29(2):401-405

Department of Surgery, Gastrointestinal Section, Yale University, 40 Temple Street, Suite 7B, New Haven, CT, 06510, USA.

Background: Laparoscopic staplers are integral to bariatric surgery. Their pricing significantly impacts the overall cost of procedures. An independent device company has designed a stapler handle and single-use reloads for cross-compatibility and equivalency with existing manufacturers, at a lower cost.

Objectives: We aim to demonstrate non-inferior function and cross-compatibility of a newly introduced stapler handle and reloads compared to our institution's current stapling system in a large animal survival study.

Setting: University-affiliated animal research facility, USA.

Methods: Matched small bowel anastomoses were created in four pigs, one with each stapler (a total of two per animal). After 14 days, investigators blinded to stapler type evaluated the anastomoses grossly and microscopically. Each anastomosis was scored on multiple measures of healing. Individual parameters were added for a global "healing score."

Results: Clinical stapler function and gross quality of anastomoses were similar between stapler groups. Individual scores for anastomotic ulceration, reepithelialization, granulation tissue, mural healing, eosinophilic infiltration, serosal inflammation, and microscopic adherences were also statistically similar. The mean "healing scores" were equal. While this study was underpowered for subtle differences, safe and reliable performance in large animals still supports the feasibility of introducing new devices into human use.

Conclusions: The new stapler system delivers a similar technical performance and is cross-compatible with currently marketed stapling devices. An equivalent quality device at a lower price point should enable case cost reduction, helping to maintain hospital case margin and procedure value in the face of potentially declining reimbursement. This device may provide a safe and functional alternative to currently used laparoscopic surgical staplers.
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http://dx.doi.org/10.1007/s11695-018-3580-6DOI Listing
February 2019

Calcifying Nested Stromal-Epithelial Tumor of the Liver: An Update and Literature Review.

Arch Pathol Lab Med 2019 02 24;143(2):264-268. Epub 2018 Oct 24.

From the Department of Pathology, Yale University School of Medicine, New Haven, Connecticut.

Calcifying nested stromal-epithelial tumor is a rare entity that has gone by a variety of names in the literature: ossifying malignant mixed epithelial and stromal tumor, ossifying stromal-epithelial tumor, and desmoplastic nested spindle cell tumor of the liver. To our knowledge, approximately 38 cases have been reported in the literature. The histogenesis is still largely unknown but histopathologically is characterized by nests of spindle and epithelioid cells in an organoid arrangement surrounded by a prominent dense myofibroblastic stroma with occasional psammomatous calcification and focal heterotopic ossification. Vascular invasion is rare and tumoral recurrence is uncommon with only a single reported case of metastasis leading to death. Treatment is mainly by surgical intervention with the role of chemotherapy seeming limited, but lack of data hinders a true recommendation. It is important to rule out other processes such as hepatoblastoma, calcified hemangioma, synovial sarcoma, metastatic gastrointestinal stromal tumor, desmoplastic small round cell tumor, among others, which appear similar radiographically and histopathologically.
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http://dx.doi.org/10.5858/arpa.2017-0346-RSDOI Listing
February 2019

The DNA repair transcriptome in severe COPD.

Eur Respir J 2018 10 4;52(4). Epub 2018 Oct 4.

Dept of Medicine, Yale School of Medicine, New Haven, CT, USA.

Inadequate DNA repair is implicated in the pathogenesis of chronic obstructive pulmonary disease (COPD). However, the mechanisms that underlie inadequate DNA repair in COPD are poorly understood. We applied an integrative genomic approach to identify DNA repair genes and pathways associated with COPD severity.We measured the transcriptomic changes of 419 genes involved in DNA repair and DNA damage tolerance that occur with severe COPD in three independent cohorts (n=1129). Differentially expressed genes were confirmed with RNA sequencing and used for patient clustering. Clinical and genome-wide transcriptomic differences were assessed following cluster identification. We complemented this analysis by performing gene set enrichment analysis, Z-score and weighted gene correlation network analysis to identify transcriptomic patterns of DNA repair pathways associated with clinical measurements of COPD severity.We found 15 genes involved in DNA repair and DNA damage tolerance to be differentially expressed in severe COPD. K-means clustering of COPD cases based on this 15-gene signature identified three patient clusters with significant differences in clinical characteristics and global transcriptomic profiles. Increasing COPD severity was associated with downregulation of the nucleotide excision repair pathway.Systematic analysis of the lung tissue transcriptome of individuals with severe COPD identified DNA repair responses associated with disease severity that may underlie COPD pathogenesis.
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http://dx.doi.org/10.1183/13993003.01994-2017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6422831PMC
October 2018

Fan-Shaped Body Neurons in the Drosophila Brain Regulate Both Innate and Conditioned Nociceptive Avoidance.

Cell Rep 2018 08;24(6):1573-1584

Tsinghua-Peking Center for Life Sciences, IDG/McGovern Institute for Brain Research, MOE Key Laboratory of Protein Sciences, School of Life Sciences, Tsinghua University, Beijing 100084, China. Electronic address:

Multiple brain regions respond to harmful nociceptive stimuli. However, it remains unclear as to whether behavioral avoidance of such stimuli can be modulated within the same or distinct brain networks. Here, we found subgroups of neurons localized within a well-defined brain region capable of mediating both innate and conditioned nociceptive avoidance in Drosophila. Neurons in the ventral, but not the dorsal, of the multiple-layer organized fan-shaped body (FB) are responsive to electric shock (ES). Silencing ES-responsive neurons, but not non-responsive neurons, leads to reduced avoidance of harmful stimuli, including ES and heat shock. Activating these neurons consistently triggers avoidance and can serve as an unconditional stimulus in an aversive classical conditioning task. Among the three groups of responsive neurons identified, two also have reduced activity in ES-conditioned odor avoidance. These results demonstrate that both innate and conditioned nociceptive avoidance might be represented within neurons confined to a single brain region.
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http://dx.doi.org/10.1016/j.celrep.2018.07.028DOI Listing
August 2018

Primary Esophageal Mixed Sarcomatoid and Small Cell Neuroendocrine Carcinoma With Brain Metastasis: A Challenging Diagnosis on Biopsy.

Int J Surg Pathol 2019 Feb 16;27(1):84-88. Epub 2018 Jul 16.

1 New York University Medical Center, New York, NY, USA.

Mixed carcinomas in the esophagus are highly uncommon neoplasms that represent a diagnostic challenge on small tissue biopsies. We present a case of a primary mixed sarcomatoid-small cell carcinoma of the esophagus that was diagnosed after repeat sampling of the lesion. The components were morphologically distinct and could be further classified by immunohistochemistry. Next-generation sequencing identified mutations in PIK3CA and CDKN2A. The small cell component morphology was also identified in brain metastasis.
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http://dx.doi.org/10.1177/1066896918782426DOI Listing
February 2019

Anti-PD-1 Therapy-Associated Perforating Colitis.

Case Rep Gastrointest Med 2018 31;2018:3406437. Epub 2018 May 31.

Department of Pathology, Section of Medical Oncology, Yale University School of Medicine, New Haven, CT, USA.

Inhibition of immune checkpoint T cell regulatory molecules by using programmed cell death protein 1 (PD-1), or its ligand (PDL-1), and cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) has been increasingly used to treat advanced malignancies. The immune-related adverse effects associated with these treatments such as diarrhea, colitis, and CTLA-4 treatment-associated perforating colitis have been reported. However, anti-PD-1/PD-L1-associated perforating colitis has rarely been reported. We report a case of colonic perforation in a patient recently treated with pembrolizumab, a PD-1 inhibitor for metastatic melanoma. Awareness of anti-PD-1/PD-L1-associated colitis and perforation will facilitate a timely diagnosis and management as they are increasingly used in oncology.
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http://dx.doi.org/10.1155/2018/3406437DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6000840PMC
May 2018

Epithelioid Angiosarcoma: An Unusual Cause of Gastrointestinal Bleeding.

Int J Surg Pathol 2019 May 26;27(3):277-279. Epub 2018 Jun 26.

1 Yale University, New Haven, CT, USA.

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http://dx.doi.org/10.1177/1066896918784180DOI Listing
May 2019

Giant Duodenal Lipoma: a Rare Cause of Vomiting, Anorexia, Unintentional Weight Loss, and Duodenal Intussusception.

J Gastrointest Cancer 2019 09;50(3):693-694

Department of Pathology, Yale University School of Medicine, 310 Cedar Street, PO Box 208023, New Haven, CT, 06510, USA.

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http://dx.doi.org/10.1007/s12029-018-0105-4DOI Listing
September 2019

The microscopic anatomy of the esophagus including the individual layers, specialized tissues, and unique components and their responses to injury.

Ann N Y Acad Sci 2018 12 15;1434(1):304-318. Epub 2018 May 15.

Department of Pathology, University of Michigan, Ann Arbor, Michigan.

The esophagus, a straight tube that connects the pharynx to the stomach, has the complex architecture common to the rest of the gastrointestinal tract with special differences that relate to its function as a conduit of ingested substances. For instance, it has submucosal glands that are unique and have a specific protective function. It has a squamous lining that exists nowhere else in the gut except the anus and it has a different submucosal nerve plexus when compared to the stomach and intestines. All of the layers of the esophageal wall and the specialized structures including blood and lymphatic vessels and nerves have specific responses to injury. The esophagus also has unique features such as patches of gastric mucosa called inlet patches at the very proximal part and it has a special sphincter mechanism at the most distal aspect. This review covers the normal microscopic anatomy of the esophagus and the patterns of reaction to stress and injury of each layer and each special structure.
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http://dx.doi.org/10.1111/nyas.13705DOI Listing
December 2018

Morphologic and Immunohistochemical Characteristics of Anorectal Melanoma.

Int J Surg Pathol 2018 Dec 14;26(8):725-729. Epub 2018 May 14.

1 Department of Pathology, Yale University School of Medicine, New Haven, CT, USA.

Anorectal melanoma is a rare aggressive disease. Due to its rarity and considerable histologic and immunohistochemical variabilities, misdiagnosis as lymphoma, carcinoma, sarcoma, and/or gastrointestinal stromal tumor is not uncommon, particularly in amelanotic cases. We reviewed histologic features and immunohistochemical stains of 19 anorectal melanoma cases. Histopathologic features were evaluated including junctional activity, melanin pigment, and morphologic features. Immunohistochemical stains were performed using Sox10, S100 protein, HMB-45, melan-A, CD56, and cytokeratins. Epithelioid histopathologic morphology was observed in 63.2% of the cases followed by 47.4% of the cases with spindle-cell, 26.3% with lymphoma-like, and 26.3% with pleomorphic morphologies. Junctional melanocytic activity was seen in almost half of the cases. Melanin pigment was absent (amelanotic) in nearly 40% of the cases. Immunohistochemically, diffuse positive expression of Sox10, S100 protein, melan-A, and HMB-45 was seen in 100%, 40%, 53.3%, and 38.5% of the cases, respectively. Cytokeratins were negative and CD56 was positive in 2 cases. These findings indicate that anorectal melanomas often show one or combined histolopathologic features without presence of melanin pigment and absence of junctional melanocytic activity. Anorectal melanoma should be kept in mind in the differential diagnosis of malignant neoplasms of anorectal region with epithelioid, spindle-cell, lymphoma-like, and pleomorphic morphologies. Sox10 immunohistochemistry stain can be used as a first-line screening tool to avoid extensive or unnecessary workups and/or potential misdiagnosis.
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http://dx.doi.org/10.1177/1066896918773177DOI Listing
December 2018

Active Protection: Learning-Activated Raf/MAPK Activity Protects Labile Memory from Rac1-Independent Forgetting.

Neuron 2018 04 15;98(1):142-155.e4. Epub 2018 Mar 15.

Tsinghua-Peking Center for Life Sciences, IDG/McGovern Institute for Brain Research, MOE Key Laboratory of Protein Sciences, School of Life Sciences, Tsinghua University, Beijing 100084, China. Electronic address:

Active forgetting explains the intrinsic instability of a labile memory lasting for hours. However, how such memory maintains stability against unwanted disruption is not completely understood. Here, we report a learning-activated active protection mechanism that enables labile memory to resist disruptive sensory experiences in Drosophila. Aversive olfactory conditioning activates mitogen-activated protein kinase (MAPK) transiently in the mushroom-body γ lobe, where labile-aversive memory is stored. This increased MAPK activity significantly prolongs labile memory retention and enhances its resistance to disruption induced by heat shock, electric shock, or odor reactivation. Such experience-induced forgetting cannot be prevented by inhibition of Rac1 activity. Instead, protection of Rac1-independent forgetting correlates with non-muscle myosin II activity and persistence of learning-induced presynaptic structural changes. Increased Raf/MAPK activity, together with suppressed Rac1 activity, completely blocks labile memory decay. Thus, learning not only leads to memory formation, but also activates active protection and active forgetting to regulate the formed memory.
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http://dx.doi.org/10.1016/j.neuron.2018.02.025DOI Listing
April 2018

Metastatic Renal Cell Carcinoma as Solitary Subcentimeter Polypoid Gastric Mucosal Lesions: Clinicopathologic Analysis of Five Cases.

Gastroenterology Res 2018 Feb 23;11(1):25-30. Epub 2018 Feb 23.

Department of Pathology, Duke University Medical Center, Durham, NC, USA.

Background: The stomach is an uncommon site for metastatic carcinoma. Approximately 6% of renal cell carcinomas (RCCs) may metastasize to the stomach. The majority of the reported metastatic RCCs in the stomach presented as large masses or ulcers greater than a centimeter in size. It is very rare to encounter metastatic RCC as a solitary small polypoid gastric mucosal lesion.

Methods: In this study, we collected surgical pathology cases of gastric metastasis from RCC that measured 1.0 cm or less at the time of endoscopy. The clinicopathological characteristics were analyzed.

Results: Five patients with subcentimeter metastatic RCC involving the gastric mucosa were identified. The clinical presentation for upper endoscopic examination was non-specific. Two of the five patients did not have a known history of RCC. In the three patients with a previous history of RCC, the interval from primary RCC diagnosis to the detection of gastric mucosal metastasis was 5, 6, and 10 years, respectively. Endoscopically, all the lesions were solitary, ranging in size from 0.4 to 1 cm. Histologically, all five cases were of the clear cell type consisting of a bland clear cell proliferation within the lamina propria. Although the tumor cells were relatively bland, the presence of clear cytoplasm, nuclear membrane irregularity, occasional enlarged hyperchromatic atypical nuclei, and destructive growth in the center of the lesion should promote immunohistochemical workup. Immunohistochemically, the RCC cells exhibited at least patchy immunoreactivity for cytokeratin and RCC markers. In two cases, there were many CD68 positive foamy histiocytes intermingled with the tumor cells.

Conclusion: Metastatic RCC can rarely present as subcentimeter polypoid gastric mucosal lesions. The remote or unknown history of RCC, the non-specific endoscopic appearance, and the bland histological features may lead to a potential diagnostic pitfall. It is of importance to raise the awareness of such an unusual presentation of metastatic RCC in the stomach and to include metastatic RCC in the differential diagnosis for gastric mucosal polyps with clear cell morphology.
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http://dx.doi.org/10.14740/gr952wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5827898PMC
February 2018

Clinical and epidemiological characterization of histoplasmosis cases in a nonendemic area, Connecticut, United States.

Med Mycol 2018 Oct;56(7):896-899

Yale School of Medicine, Department of Internal Medicine, Section of Infectious Diseases, New Haven, Connecticut, USA.

We performed a retrospective analysis of histoplasmosis cases diagnosed at our institution in New Haven, Connecticut, from 2005 to 2015. Among 12 cases of active histoplasmosis, seven were immunosuppressed and five had human immunodeficiency virus (HIV). Eleven patients reported travel to potentially endemic areas at a median of 105 days prior to presentation; travel to the Caribbean was most common (n = 6). Median time to diagnosis from symptom onset and first Histoplasma antigen testing were 41 and 28 days, respectively. Consistent with reports from other non-endemic areas, our findings suggest that the epidemiology of histoplasmosis may differ in Connecticut, potentially contributing to delayed diagnoses.
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http://dx.doi.org/10.1093/mmy/myx120DOI Listing
October 2018
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