Xuchen Zhang’s research while affiliated with Yale-New Haven Hospital and other places

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Publications (125)


Hepatic Arterial Flow-Induced Portal Tract Fibrosis in Portal Hypertension: The Role of VCAM-1 and Osteopontin-Expressing Macrophages
  • Preprint

February 2025

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1 Read

Ruixue Ma

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Li Gong

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Choa Dong

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Background The liver undergoes significant hemodynamic changes during surgery, transplantation, or cirrhosis with portal hypertension(PH). The hepatic artery buffer response(HABR), which compensates for reduced portal venous flow by increasing hepatic artery(HA) flow, is hypothesized to induce pathological portal tract remodeling. This study investigates the molecular mechanisms underlying this process. Methods PH was induced in Sprague-Dawley rats via partial portal vein ligation(PPVL). Structural evaluation(microCT), immune cell profiling, hemodynamic measurements, and transcriptomic analysis in macrophages(Mϕ) from sham or PPVL rats were conducted. Results MicroCT revealed decreased portal vein flow and increased HA flow correlated with portal pressure(r=0.799, p<0.01). A 2-fold increase in portal tract fibrosis(p<0.001) was observed with increased α-SMA+ myofibroblasts in PPVL rats. CD68+ Mϕ peaked at 10 days post-PPVL, and their depletion significantly reduced fibrosis(p<0.001), indicating critical roles of Mϕ in portal tract remodeling. VCAM-1 was elevated in HA endothelium and portal fibroblasts (PFs); VCAM-1 neutralization reduced collagen accumulation(p<0.05), CD68+ Mϕ(46.3%, p<0.01), and CD3+ T cells(18%, p<0.05). Mϕ-conditioned medium increased VCAM-1 in PFs(8-fold, p<0.001) and enhanced PF migration, while VCAM-1 knockdown reduced this effect (p<0.01). Single-cell RNA sequencing data(GSE171904) and RNA-FISH revealed increased interactions between osteopontin (Spp1)+ Mϕ and PFs, with Spp1+ Mϕ driving fibrosis. Spp1 knockdown in Mϕ co-culture reduced PF fibrogenic markers, while recombinant Spp1 upregulated Col1a1, Fn1, and Acta2 expression in PFs. Conclusion Increased VCAM-1 in arterial endothelial cells and PFs facilitates the recruitment of Spp1+ Mϕ, which drive HA flow-mediated vascular remodeling and portal tract fibrosis. These findings highlight arterial flow-induced fibrosis as a key mechanism in PH, potentially contributing to disease progression and decompensation. Synopsis Liver hemodynamic changes in portal hypertension drive extracellular matrix accumulation and portal tract remodeling via Spp1+ macrophages. This study highlights how altered blood flow induces fibrosis, and its potential role in decompensation, and identifies therapeutic targets for advanced liver disease.


Colorectal adenosquamous carcinoma: clinicopathologic analysis of two large cohorts and literature review confirm poor prognosis and reveal prognostic aspects

January 2025

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10 Reads

Histopathology

Aims: We compiled two cohorts of colorectal adenosquamous carcinoma (ASC) to describe its histologic and molecular aspects using modern parameters to compare them with literature reports using meta-analysis of cohorts and individual case series. Methods and results: We identified 53 colorectal ASC from 19 North American academic medical centres, in addition to national database reports on 94 Dutch cases. We analysed available clinical, histologic, and immunohistochemical features and patient outcome. ASC comprised 0.02% of colorectal cancers in the Dutch database. The median cohort patient ages at resection were 65 and 69 years (North American and Dutch cohorts, respectively), with a roughly equal male:female ratio. The squamous component represented between 5% and 95% of each tumour, with a median of 50%. Tumour-infiltrating lymphocytes (TILs) were generally low (66%), and tumour budding was often Bd1 (64%). Most cases were pT3 (55%) or pT4 (40%), with nodal metastases in more than half (58%). Twenty-three cases (43%) metastasized distantly, most commonly to the liver. Mismatch repair (MMR) deficiency was identified in 34% of the cases. Follow-up was available for 48 patients; 13 (27%) had recurrent disease and 29 (60%) died. A total of 31 patients progressed, with median time to progression of 18 months. Available data for the Dutch cohort revealed largely similar findings, as did review of cases in the literature. Conclusion: Colorectal ASC usually presents at an advanced stage. Despite high rates of MMR deficiency and low tumour budding, TILs were generally low, and there is a high recurrence rate and poor prognosis.


Steatotic Liver Disease: Navigating Pathologic Features, Diagnostic Challenges, and Emerging Insights

January 2025

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9 Reads

Advances in Anatomic Pathology

Steatotic liver disease (SLD) is now used as an overarching category encompassing five subcategories: metabolic dysfunction-associated steatotic liver disease (MASLD), metabolic and alcohol related/associated liver disease (MetALD), alcohol-related/associated liver disease (ALD), SLD with specific etiology, and cryptogenic SLD. This review summarizes foundational and recent advances in the histologic evaluation of SLD, including common pathologic features across all subcategories, distinctions associated with different etiologies, scoring and grading systems, and the evolution of digital pathology techniques for SLD assessment.


Liver Lymphatic Dysfunction as a Driver of Fibrosis and Cirrhosis Progression
  • Preprint
  • File available

January 2025

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10 Reads

The liver lymphatic system plays a critical role in maintaining interstitial fluid balance and immune regulation. Efficient lymphatic drainage is essential for liver homeostasis, but its role in liver disease progression remains poorly understood. In cirrhosis, lymphangiogenesis initially compensates for increased lymph production, but impaired lymphatic drainage in advanced stages may lead to complications such as ascites and portal hypertension. This study aimed to evaluate how liver lymphatic dysfunction affects disease progression and to assess therapeutic strategies. Using a surgical model to block liver lymphatic outflow, we found that impaired drainage accelerates liver injury, fibrosis, and immune cell infiltration, even in healthy livers. Mechanistically, enhanced TGF-β signaling in liver lymphatic endothelial cells (LyECs) contributed to reduced lymphatic vessel (LV) density and function in late-stage decompensated cirrhosis. This dysfunction was linked to the progression from compensated to decompensated cirrhosis, particularly in patients with primary sclerosing cholangitis (PSC). Conversely, liver-specific overexpression of VEGF-C via AAV8 improved lymphatic drainage, restored LV density, reduced fibrosis, mitigated liver injury, and alleviated portal hypertension in cirrhotic rats. These findings establish impaired liver lymphatic function as a pivotal driver of cirrhosis progression and identify VEGF-C as a promising therapeutic target to prevent decompensation.

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The evolving role of liver biopsy: Current applications and future prospects

Hepatology Communications

Histopathologic evaluation of liver biopsy has played a longstanding role in the diagnosis and management of liver disease. However, the utility of liver biopsy has been questioned by some, given the improved imaging modalities, increased availability of noninvasive serologic tests, and development of artificial intelligence over the past several years. In this review, we discuss the current and future role of liver biopsy in both non-neoplastic and neoplastic liver diseases in the era of improved noninvasive laboratory, radiologic, and digital technologies.


A rare case of biliary adenofibroma showing proliferation of individual biliary tubules and microcystic structures within a fibrous stroma (a). The tumor shows an extremely low Ki67 proliferation index in both the epithelium and stroma (b)
Magnification: a: 40×; b: 200×.
Entities that mimic biliary adenofibroma
(a) Von Meyenburg complex, a small, incidental biliary lesion featuring dilated, irregular, and anastomosing bile ducts lined by bland cuboidal epithelium within a collagenous stroma. (b) Bile duct adenoma consists of small, evenly spaced bile duct structures with mild cytologic atypia and scant fibrous stroma. (c) A multilocular biliary cyst shows features of an intraductal papillary neoplasm of the bile duct lined by mucinous epithelium (left) and smaller cysts lined by non-mucinous epithelium (right), similar to biliary adenofibroma. (d) A large duct-type intrahepatic cholangiocarcinoma contains individual glands within a fibrous stroma resembling biliary adenofibroma but with marked cytologic atypia and perineural invasion. Magnification: a-c: 40×; d: 100×.
An intrahepatic cholangiocarcinoma showing mixed histologic patterns, characterized by low-grade tubulocystic morphology that may be misinterpreted as a biliary adenofibroma at the bottom, a classic cholangiolocellular carcinoma pattern on the right, and a ductal plate malformation-like pattern on the left (a). Higher power shows the transition of the lower-grade microcystic component to the higher-grade solid component of this tumor (b), both components sharing similar nuclear features
Magnification: a: 20×; b: 200×.
Hepatic Biliary Adenofibroma: Histological Characteristics, Diagnostic Challenges, and Its Role as a Precursor to Intrahepatic Cholangiocarcinoma

December 2024

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8 Reads

Hepatic biliary adenofibroma is an exceedingly rare biliary neoplasm that primarily affects adults. It typically presents as a solitary mass composed of low-grade microcystic and tubuloglandular bile duct structures, which are lined by low columnar to cuboidal non-mucin-producing biliary epithelium and supported by abundant fibrous stroma. Histologically, it resembles the Von Meyenburg complex but is much larger in size and often shows cytologic atypia. Although considered benign, emerging case studies and analyses suggest that biliary adenofibroma may serve as a precursor lesion to intrahepatic cholangiocarcinoma. However, its extreme rarity, coupled with an incompletely understood histogenesis, perpetuates diagnostic uncertainty and may lead to misclassification with other similar entities. This review consolidates the current understanding of the histopathological and molecular characteristics of biliary adenofibroma, highlights its differential diagnosis, explores its potential progression to cholangiocarcinoma, and discusses unresolved questions while proposing future research directions.


Clinicopathologic features and prognosis of steatohepatitic hepatocellular carcinoma based on varying cutoffs of tumoral steatohepatitic changes

October 2024

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7 Reads

American Journal of Clinical Pathology

Objectives Steatohepatitic hepatocellular carcinoma (SH-HCC) is currently recognized as a distinct histologic subtype of HCC. The prognosis and specific criteria for determining the amount of steatohepatitis required to define SH-HCC are still unclear. Methods After excluding all recognized HCC subtypes from 505 HCC cases (2010-2019), the remaining cases were categorized as conventional HCC (CV-HCC) (n = 223). The cases classified as SH-HCC (n = 171) were further divided into groups based on the percentage of steatohepatitis: 5% or more, 30% or more, and 50% or more. Results Hepatitis C virus infection was the predominant underlying liver disease in both the CV-HCC and SH-HCC groups. Metabolic dysfunction-associated steatotic liver disease (formerly nonalcoholic fatty liver disease) was more prevalent in all cases of SH-HCC with different steatohepatitic cutoffs than in cases of CV-HCC. There were no differences in the stage of fibrosis of the background liver between the CV-HCC and SH-HCC groups. SH-HCC with different cutoffs exhibited a notable increase in the presence of glycogenated nuclei, Mallory-Denk bodies, and hyaline globules in tumor cells. Survival analysis did not reveal substantial differences in overall survival between the CV-HCC and SH-HCC groups and among patients with SH-HCC with different steatohepatitis cutoffs. Conclusions The degree of intratumoral steatohepatitis in patients with SH-HCC does not appear to be a notable prognostic factor. The presence of steatohepatitis in the tumor is better recognized as 1 of the histopathologic patterns of HCC.



The WSI IMS user interface. In the WSI IMS, the pathologist has access to the cases (each case consisting of an H&E and Masson's trichrome) where they can review the slides, move around the slide, zoom in and out, and finally enter their scores.
Study design. The study design is noninferior overall percent agreement (OPA) of individual pathologist's steatohepatitis evaluation (defined as MAS > 4 with a score of >1 for each feature and absence of atypical features suggestive of other liver disease) on the WSI with glass GT as compared to the OPA of their glass reads with glass GT with a 0.05 noninferiority margin.
Comparison of easy, medium, and hard cases for glass and WSI reads. All cases in the study were divided into hard, medium, and easy based on pathologist agreement. Easy cases were defined as cases where all study pathologists agreed on the component score, medium cases as cases where two of three pathologists agreed on a score, and hard cases where all study pathologists disagreed on the component score. (A–D) Contingency tables of easy, medium, and hard cases for each of the categories (steatosis, inflammation, ballooning, and fibrosis). (E) An example of an easy H&E slide (all three study pathologists agreed on a score for each component). (F) An example of a medium/hard H&E slide (all 2/3 or 3/3 study pathologists disagreed on a score). (G) An example of an easy Masson's trichrome slide (all three study pathologists agreed on a score for each component). (H) An example of a medium/hard Masson's trichrome slide (all 2/3 or 3/3 study pathologists disagreed on a score).
Validation of a whole slide image management system for metabolic‐associated steatohepatitis for clinical trials

September 2024

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34 Reads

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1 Citation

The gold standard for enrollment and endpoint assessment in metabolic dysfunction‐associated steatosis clinical trials is histologic assessment of a liver biopsy performed on glass slides. However, obtaining the evaluations from several expert pathologists on glass is challenging, as shipping the slides around the country or around the world is time‐consuming and comes with the hazards of slide breakage. This study demonstrated that pathologic assessment of disease activity in steatohepatitis, performed using digital images on the AISight whole slide image management system, yields results that are comparable to those obtained using glass slides. The accuracy of scoring for steatohepatitis (nonalcoholic fatty liver disease activity score ≥4 with ≥1 for each feature and absence of atypical features suggestive of other liver disease) performed on the system was evaluated against scoring conducted on glass slides. Both methods were assessed for overall percent agreement with a consensus “ground truth” score (defined as the median score of a panel of three pathologists’ glass slides). Each case was also read by three different pathologists, once on glass and once digitally with a minimum 2‐week washout period between the modalities. It was demonstrated that the average agreement across three pathologists of digital scoring with ground truth was noninferior to the average agreement of glass scoring with ground truth [noninferiority margin: −0.05; difference: −0.001; 95% CI: (−0.027, 0.026); and p < 0.0001]. For each pathologist, there was a similar average agreement of digital and glass reads with glass ground truth (pathologist A, 0.843 and 0.849; pathologist B, 0.633 and 0.605; and pathologist C, 0.755 and 0.780). Here, we demonstrate that the accuracy of digital reads for steatohepatitis using digital images is equivalent to glass reads in the context of a clinical trial for scoring using the Clinical Research Network scoring system.


of Clinical and Pathologic Information of 11 Patients.
Clinical and Pathologic Information of Each Individual Patient.
Histology Shift in Esophageal Cancer Between Biopsies and Resections After Neoadjuvant Therapy: A Pilot Study

August 2024

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3 Reads

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1 Citation

Preoperative neoadjuvant therapy followed by resection is the mainstay treatment for locally advanced esophageal adenocarcinoma. We recently observed the histology shift from predominant esophageal adenocarcinoma in the biopsy to neuroendocrine neoplasm with or without adenocarcinoma in the post-treatment resection. The underlying mechanism of this finding is uncertain, and there is limited information in the literature. A total of 11 patients were identified: 10 patients received presurgical chemoradiation and 1 with chemotherapy. All biopsies were diagnosed with adenocarcinoma. When neuroendocrine immunomarkers were retrospectively performed on 5 biopsies, 2 showed focal positivity, although the classic neuroendocrine morphology was not readily appreciated. All resections contained neuroendocrine neoplasm, including 8 of well-differentiated type and 3 of neuroendocrine carcinomas. Two post-treatment esophagectomies consisted of neuroendocrine neoplasm only without residual adenocarcinoma. Upon follow-up, 8 patients died of the disease (median survival = 26 months), and 3 patients were alive after a median follow-up of 14 months. The overall median survival time was better than the reported esophageal neuroendocrine carcinoma (15 months). The 5-year observed survival rate was 11.3%, which was lower than the Surveillance, Epidemiology, and End Results 5-year survival rate of adenocarcinoma (21.8%). We reported a small series of esophageal adenocarcinoma that showed histology shift between biopsy and esophagectomy after neoadjuvant therapy. Our limited data suggest that prognosis of this group is different than the conventional adenocarcinoma. Awareness of this morphological change reminds pathologists to examine the biopsy specimens thoroughly, because recognition of neuroendocrine neoplasm, especially high-grade neuroendocrine component, might potentially affect pre- and post-surgical regimens.


Citations (67)


... AI-based tools have the potential to solve many issues around standardized, accurate and reproducible scoring, within and across trials. Multiple pathologists can assess biopsies on validated WSI viewers 23 for sample adequacy and evaluability and for overall diagnosis and additional findings, while using AI tools to efficiently provide the accurate, standardized and consistent scores needed. The AIM-MASH outputs have been validated according to their proposed use with representative trial datasets, including a sample of screen failures and a majority of enrolled patients at risk for MASH (defined as nonalcoholic fatty liver disease (NAFLD) activity score (NAS) ≥ 4 with fibrosis score ≥2), both baseline and follow-up time points variable in disease activity, stain, scanning site and drug candidate intervention. ...

Reference:

Clinical validation of an AI-based pathology tool for scoring of metabolic dysfunction-associated steatohepatitis
Validation of a whole slide image management system for metabolic‐associated steatohepatitis for clinical trials

... involvement is extremely rare and is associated with a poor prognosis. 2 It can occur at any age but predominantly affects girls under the age of 2. Endoscopic and pathological examinations are essential for diagnosis; however, related endoscopic manifestations are few documented, especially the dynamic endoscopic findings. Herein, we report a pediatric case of GIT-LCH who underwent three digestive endoscopies and was successfully treated with dabrafenib. ...

Clinicopathologic Features of Gastrointestinal Tract Langerhans Cell Histiocytosis
  • Citing Article
  • June 2024

Modern Pathology

... 2,3,9,10 Additionally, pagetoid squamous cell carcinoma in situ and pagetoid ESCC have also been reported. [11][12][13][14][15] Small cell carcinoma of the esophagus (SCCE), a rare tumor with aggressive behavior and poor prognosis, can occur alongside ESCC, adenocarcinoma, or precursor lesions, such as high-grade squamous dysplasia (HGSD) or Barrett's esophagus with dysplasia. 16 However, SCCE coexisting with Paget's disease has never been reported. ...

Esophageal squamous cell carcinoma with pagetoid spread: a clinicopathologic study

Virchows Archiv

... In addition, it is necessary to perform immunohistochemistry to confirm the presence of epithelial components or sarcomatoid tissue surrounded by epithelial tissue that has a heavy heterogeneous proliferation of carcinoma in situ. Otherwise, it should be differentiated from sarcoma, to avoid misdiagnosis when the proportion of sarcoma components in SC tissue is too large [26]. ...

Colorectal Carcinoma With Sarcomatoid Components Report of 15 Cases and Literature Review of an Exceedingly Rare Carcinoma Subtype
  • Citing Article
  • December 2023

The American Journal of Surgical Pathology

... In other fields, particularly oncology, scientific evidence links H&E images to AI-generated heatmaps and gene expression patterns derived from spatial transcriptomics [107]. An important objective of this initiative is to generate spatial transcriptomics data for a subset of patients to better understand the biological pathways in areas identified by AI as relevant for diagnosis and prognosis. ...

Deep learning-based phenotyping reclassifies combined hepatocellular-cholangiocarcinoma

... In addition to the already well-known therapy-related cytologic changes (nuclear pyknosis, cytoplasmic eosinophilia), stromal fibrosis, and mucin pools, 12,13 recent studies have demonstrated that neuroendocrine differentiation may be induced by neoadjuvant therapy within the tumor, which was shown to be associated with a relatively worse prognosis. 13,14 In our study, we identified PCD in 8 of 64 (12.5%) cases, which tended to have a worse prognosis than their negative counterparts (P = .07 by log-rank test). ...

Histology Shift in Esophageal Cancer Between Biopsies and Resections After Neoadjuvant Therapy: A Pilot Study

... Let-7 targets collagen genes and transforming growth factor-beta (TGF-β) signaling, which is central to ECM homeostasis. Dysregulated TGF-β signaling is a hallmark of BAV-associated aortopathies [61]. ...

Let-7 suppresses liver fibrosis by inhibiting hepatocyte apoptosis and TGF-β production
  • Citing Article
  • October 2023

Molecular Metabolism

... We then explored the role of immune cells in the development of portal tract fibrosis. In line with our previous publication (26), immunohistochemistry (IHC) showed a significant increase in CD68+ macrophages in the portal tract at 10 days post-PPVL, followed by a decrease at 30 days ( Figure 1F). This pattern closely mirrors the changes observed in portal tract fibrosis ( Figures 1D&E). ...

The Sympathetic Nervous System Promotes Hepatic Lymphangiogenesis, which Is Protective Against Liver Fibrosis
  • Citing Article
  • September 2023

American Journal Of Pathology

... While these cells are vital for healthy hepatic function, approaches utilized by researchers to characterize cholangiocytes and biliary tree architecture during development and disease progression are not standardized to quantify cell number and biliary tract structure in an unbiased researcher-independent way. Current methods for the analysis of cholangiocytes include time-consuming and error-prone observer-driven manual or automated-cell counting (5,6), nonquantitative retrograde imaging of the biliary tract using India ink injection (7,8), resin cast (9,10), or various tissue-clearing methods (11,12). The latter three approaches provide visualization of disease-associated perturbations in branch architecture within the biliary tree yet lack the ability to quantify biliary cells or structures. ...

An optimized visualization and quantitative protocol for in-depth evaluation of lymphatic vessel architecture in the liver
  • Citing Article
  • August 2023

AJP Gastrointestinal and Liver Physiology

... Liver biopsy also plays a significant role in the diagnosis and molecular characterization of iCCA. [72] The current World Health Organization classification of digestive tumors divides iCCA into 2 main categories, which include small duct type ( Figure 1L) and large duct type. [73] Recent genomic profiling studies of iCCA have identified genomic alterations that allow for prognostic information in small duct iCCA where fibroblast growth factor receptor 2 fusions are associated with better prognosis, while iCCA with isocitrate dehydrogenase 1 and isocitrate dehydrogenase 2 mutations have a worse prognosis. ...

Cholangiocarcinoma: Pathologic and Molecular Classification in the Era of Precision Medicine
  • Citing Article
  • June 2023

Archives of Pathology & Laboratory Medicine