Neoadjuvant PD-(L)1 blockade plus platinum-based chemotherapy for potentially resectable oncogene-positive non-small cell lung cancer.

BACKGROUND: Whether programmed cell death-1/ligand-1 (PD-1/PD-L1) blockade-based neoadjuvant treatment may benefit locally advanced oncogene-mutant non-small cell lung cancer (NSCLC) patients remains controversial. This retrospective study was designed to observe the efficacy and safety of neoadjuvant PD-1/PD-L1 blockade plus chemotherapy versus chemotherapy and corresponding tyrosine kinase inhibitors (TKIs) in patients with resectable oncogene-positive NSCLC. METHODS: Patients with potential resectable NSCLC harbouring oncogene alterations who had received neoadjuvant treatment were retrospectively recruited, and an oncogene-negative cohort of patients who received neoadjuvant PD-(L)1 blockade-based neoadjuvant treatment was reviewed for comparison during the same period. The primary aim was to observe the treatment efficacy and event-free survival (EFS) of these agents. Safety profile, molecular target, and immunologic factor data, including PD-L1 expression and tumour mutational burden (TMB), were also obtained. RESULTS: A total of 46 patients were recruited. Thirty-one of them harboured oncogene alterations, including EGFR, KRAS, ERBB2, ROS1, MET, RET, ALK, and FGFR3 alterations. Among the oncogene-positive patients, 18 patients received neoadjuvant PD-(L)1 blockade immunotherapy plus chemotherapy (oncogene-positive IO group), 13 patients were treated with neoadjuvant chemotherapy and/or corresponding TKIs or TKIs alone (oncogene-positive chemo/TKIs group), and the other 15 patients were oncogene negative and received neoadjuvant PD-(L)1 blockade plus chemotherapy (oncogene-negative IO group). The pathological complete response (pCR) and major pathological response (MPR) rates were 22.2% (4 of 18) and 44.4% (8 of 18) in the oncogene-positive IO group, 0% (P = 0.120) and 23.1% (3 of 13) (P = 0.276) in the oncogene-positive chemo/TKIs group, and 46.7% (7 of 15) (P = 0.163) and 80.0% (12 of 15) (P = 0.072) in the oncogene-negative IO group, respectively. By the last follow-up, the median EFS time had not reached in the oncogene-positive IO group, and was 29.5 months in the oncogene-positive chemo/TKIs group and 38.4 months in the oncogene-negative IO group. CONCLUSION: Compared with chemotherapy/TKIs treatment, neoadjuvant treatment with PD-(L)1 blockade plus platinum-based chemotherapy was associated with higher pCR/MPR rates in patients with partially resectable oncogene-mutant NSCLC, while the pCR/MPR rates were lower than their oncogene-negative counterparts treated with PD-(L)1 blockade-based treatment. Specifically, oncogene alteration types and other predictors of response to immunotherapy should be taken into account in clinical practice.

Clinicopathologic Features of Gastrointestinal Tract Langerhans Cell Histiocytosis.

Gastrointestinal (GI) tract involvement by Langerhans cell histiocytosis (LCH) is rare and its clinicopathologic characteristics have only been described in case reports and small series. We reviewed hematoxylin and eosin- and CD1a, S100, and Langerin immunohistochemical-stained slides from 47 patients with well-documented demographic and clinical findings. Our cases included 8 children and 39 adults, with a mean follow-up of 63 months. All pediatric patients had concurrent multisystem LCH, presented with GI symptoms, and showed non-polypoid lesions. Seven (88%) showed multifocal GI disease, including five with multiple GI organ involvement. All sampled lesions from children exhibited infiltrative growth. More than half had died of the disease or manifested persistent LCH at last follow-up. Twenty-five of 39 (64%) adults had LCH involving only the GI tract (single-system), with the remaining 14 (36%) exhibiting multi-system disease. Adult single-system GI LCH was typically encountered incidentally on screening/surveillance endoscopy (72%). Most exhibited isolated colorectal involvement (88%) as a solitary polyp (92%), with a well-demarcated/noninfiltrative growth pattern (70%), and excellent prognosis (100%). In comparison, adult patients with multi-system LCH more frequently presented with GI symptoms (92%, P<0.001), non-colorectal GI site involvement (50%, P=0.02), multifocal GI lesions (43%, P=0.005), non-polypoid lesions (71%, P<0.001), infiltrative histologic growth pattern (78%, P=0.04), and persistent disease (57%, P<0.001). Adult multi-system LCH patients appear to exhibit similar clinicopathologic features to those of pediatric patients. These results demonstrate that adults with single-system LCH involving the GI tract have an excellent prognosis, while multi-system LCH occurring at any age carries an unfavorable prognosis. High-risk features of GI LCH include pediatric age, GI symptomatology, non-colorectal GI involvement, multifocal GI disease, non-polypoid lesions, and infiltrative growth pattern.

Histologic Features of Mycobacterial Spindle Cell Pseudotumors: A Multi-institutional Clinicopathologic Analysis of 14 Cases.

Mycobacterial spindle cell pseudotumors (MSPs) are a rare and diagnostically challenging manifestation of non-tuberculous mycobacterial (NTM) infections. Proper recognition of these pseudotumors is important because they are treatable and benign. In this study, we evaluated the morphologic patterns of MSPs to improve their pathologic identification. Clinical and morphologic features of 14 MSPs were analyzed. Histologic factors evaluated included the architectural growth pattern of spindled or epithelioid macrophages, granulomas and their location within the lesion, neutrophilic microabscesses, multinucleated giant cells, necrosis, and effacement of background tissue. The composition of inflammatory infiltrates, organism density by acid-fast staining, and stromal changes were also assessed. In addition, 8 of 14 cases underwent molecular microbiology identification by a clinical amplicon-sequencing assay for non-tuberculous mycobacteria. MSP sites included 2 bowel, 10 lymph nodes, 1 liver, and 1 extremity. Cases with available clinical history (n=10) all occurred in immunocompromised patients. All demonstrated effacement of normal structures with spindled cells arranged in a storiform or fascicular architectural pattern. In addition, all cases showed lymphocytic inflammation, with prominent concurrent neutrophilic inflammation in 50% (7/14) of cases. Other morphologic findings included foamy histiocytes (64%, 9/14), peripherally situated granulomas (21%, 3/14), and neutrophilic microabscesses (21%, 3/14). All tested cases were positive for NTM by PCR methods. Mycobacterium avium was the most commonly isolated pathogen (6/8). Mycobacterial spindle cell pseudotumors show predominantly spindled morphology that may be mistaken as a neoplasm. Surgical pathologists who evaluate lymph nodes, soft tissue, and gastrointestinal tissues should be aware of this spindled tumefactive phenomenon in the setting of immunocompromised patients. Recognition of key morphologic features of neutrophilic inflammation, peripheral granulomas, or foamy histiocytes within a spindled lesion can help guide the pathologist to a correct diagnosis of an inflammatory process secondary to infection rather than a spindle cell neoplasm. Accurate diagnosis to facilitate appropriate antimicrobial and/or surgical therapy requires a comprehensive evaluation combining clinical, histopathologic, and microbiological findings.

Artificial intelligence-aided steatosis assessment in donor livers according to the Banff consensus recommendations.

OBJECTIVES: Severe macrovesicular steatosis in donor livers is associated with primary graft dysfunction. The Banff Working Group on Liver Allograft Pathology has proposed recommendations for steatosis assessment of donor liver biopsy specimens with a consensus for defining "large droplet fat" (LDF) and a 3-step algorithmic approach. METHODS: We retrieved slides and initial pathology reports from potential liver donor biopsy specimens from 2010 to 2021. Following the Banff approach, we reevaluated LDF steatosis and employed a computer-assisted manual quantification protocol and artificial intelligence (AI) model for analysis. RESULTS: In a total of 113 slides from 88 donors, no to mild (<33%) macrovesicular steatosis was reported in 88.5% (100/113) of slides; 8.8% (10/113) was reported as at least moderate steatosis (≥33%) initially. Subsequent pathology evaluation, following the Banff recommendation, revealed that all slides had LDF below 33%, a finding confirmed through computer-assisted manual quantification and an AI model. Correlation coefficients between pathologist and computer-assisted manual quantification, between computer-assisted manual quantification and the AI model, and between the AI model and pathologist were 0.94, 0.88, and 0.81, respectively (P < .0001 for all). CONCLUSIONS: The 3-step approach proposed by the Banff Working Group on Liver Allograft Pathology may be followed when evaluating steatosis in donor livers. The AI model can provide a rapid and objective assessment of liver steatosis.

Histopathology and its clinical correlation of liver biopsy in patients with treated autoimmune hepatitis.

The diagnosis of autoimmune hepatitis (AIH) relies on well-established criteria encompassing histological, serological, and clinical features. Diagnosing AIH may become challenging when encountering patients who have undergone steroid therapy for other co-existing diseases. Thirty-nine liver biopsies from 25 patients with treated and untreated AIH were classified into three groups: 1) Newly diagnosed untreated biopsies (n = 16); 2) Newly diagnosed partially treated biopsies from patients already on steroid treatment for other co-existing diseases (n = 9); 3) Previously diagnosed biopsies from patients who had undergone complete treatment (n = 14). In the untreated AIH group, at least 50 % of the cases exhibited the following features: at least moderate portal inflammation (81 %), at least moderate lobular inflammation (56 %), ductular reaction (94 %), inflammation gradient from bile duct to interface (88 %), unequivocal interface hepatitis (100 %), emperipolesis (56 %), plasma cell cluster (88 %), apoptosis or necrosis (63 %), pericentral inflammation (63 %), and periportal fibrosis (88 %). Although all these diagnostically sensitive histologic features were present in significantly fewer cases after treatment (p < 0.05), the features of ductular reaction, inflammation gradient from bile duct to interface, pericentral inflammation, and periportal fibrosis were likely to persist after treatment, especially in partially treated cases; these features did not show a significant association with higher transaminase levels (P > 0.05) and were considered as indirect features of hepatocytic injury. Our data suggest categorizing AIH histological features into direct and indirect hepatocytic injuries. Direct hepatocytic injury features significantly correlate with transaminase levels and respond well to treatment, while indirect ones show weaker transaminase correlation and relative treatment resistance.

Esophageal squamous cell carcinoma with pagetoid spread: a clinicopathologic study.

Pagetoid spread in esophageal squamous epithelium associated with underlying esophageal adenocarcinoma (EAC) has been well studied. Case reports describing pagetoid spread of esophageal squamous cell carcinomas (ESCC) also exist in the literature. The latter, however, has not been systematically studied. In this study, we report seven cases of pagetoid spread associated with ESCC. The clinical, morphologic, and immunophenotypic profiles of pagetoid spread in the context of ESCC and EAC are compared. Cases of pagetoid spread of ESCC were identified through computerized search of pathology archives at five institutions. Additional cases were identified through manual review of surgical resection cases of treatment naive ESCC in Mass General Brigham (MGB) pathology archive. Clinical history was collected via chart review. Immunohistochemistry for CK7, CK20, CDX2, p53, p63, and p40 was performed on selected cases. A computerized search of pathology archives of five institutions revealed only two cases. A manual review of 76 resected untreated ESCC revealed five additional cases with unequivocal pagetoid spread of ESCC, indicating the condition was not uncommon but rarely reported. Patient age ranged from 54 to 78 years (median, 65). There were six women and one man. One case had in situ disease, five had pT1 (1 pT1a and 4 pT1b), and one had pT3 disease. One of the patients with pT1 tumor had a positive lymph node, while the remaining six patients were all N0. Four tumors were in the proximal to mid esophagus, and three in the distal esophagus. Patient survival ranged from 25 months to more than 288 months. The pagetoid tumor cells demonstrated enlarged, hyperchromatic nuclei with variable amounts of eosinophilic cytoplasm. The cytoplasm was often condensed to the perinuclear area, creating peripheral clearing. By immunohistochemistry, the pagetoid cells were positive for p40 (6/6) and p63 (7/7) and negative for CDX2 (7/7). The tumor cells showed mutant-type staining for p53 in five of seven cases. One of the patients had pagetoid tumor cells at the resection margin and subsequently had recurrent disease 2 years later. All other patients had negative resection margins and did not have local recurrence. Four cases of pagetoid spread in the context of EAC were used as a comparison group. Previously published studies were also analyzed. These tumors were all located in the distal esophagus or gastroesophageal junction. All cases were associated with underlying invasive EAC. Pagetoid spread associated with EAC often had cytoplasmic vacuoles or mucin. They were more frequently positive for CK7 than pagetoid ESCC (p = 0.01). Both ESCC and EAC may give rise to pagetoid spread of tumor cells within surface squamous epithelium. Pagetoid spread from ESCC and EAC have overlapping morphologic features. P40 and p63 immunostains can facilitate the distinction between ESCC and EAC. P53 immunostain can aid in confirmation of malignancy. Understanding their overlapping pathologic features will help pathologists avoid pitfalls and diagnose these lesions correctly on biopsy specimens.

Improving diagnostic yield of pancreatic serous cystadenoma with cyst fluid ancillary testing, adjunct immunohistochemistry, and additional fine-needle biopsy sampling.

BACKGROUND: Fine-needle aspiration (FNA) diagnosis of pancreatic serous cystadenoma (SCA) remains challenging. This retrospective study aimed to evaluate the roles of cyst fluid ancillary testing and combined fine-needle biopsy (FNB) in improving the diagnostic yield. METHODS: The authors retrospectively reviewed cytology cases that were histologically confirmed SCAs. Clinical features and FNA cyst fluid biochemical and molecular analysis results along FNB findings were reviewed. RESULTS: The study cohort included 31 cases from 13 male and 18 female patients with a mean age of 65. The original cytologic diagnoses were nondiagnostic (n = 6, 19%), negative for malignant cells/cyst contents (n = 7, 23%), atypical cells (n = 3, 10%), nonmucinous cyst (n = 11, 35%), and serous cystadenoma (n = 4, 13%). Cyst fluid carcinoembryonic antigen (CEA) analysis was performed in 17 cases, all of which showed a low CEA level (<192 ng/mL). All 14 cases with molecular testing showed a wild-type KRAS. Inhibin immunohistochemistry was retrospectively performed on the FNA cell blocks, inhibin was positive in six of seven cases tested. In 15 cases with concurrent FNA and FNB biopsies, the diagnosis of SCA was seen in only one FNA case (7%) but 13 FNB cases (87%). CONCLUSIONS: This study suggests that FNA diagnosis of SCA remains challenging even with ancillary testing including cyst fluid CEA level and KRAS mutation analysis. Adjunct inhibin immunostaining may help improve the cytologic diagnosis of selective SCA cases. FNB appears superior to FNA for a definite diagnosis of SCA.

Cholangiocarcinoma: Pathologic and Molecular Classification in the Era of Precision Medicine.

CONTEXT.­: Cholangiocarcinoma (CCA) is a heterogeneous cancer of the bile duct, and its diagnosis is often challenging. OBJECTIVE.­: To provide insights into state-of-the-art approaches for the diagnosis of CCA. DATA SOURCES.­: Literature review via PubMed search and authors' experiences. CONCLUSIONS.­: CCA can be categorized as intrahepatic or extrahepatic. Intrahepatic CCA is further classified into small-duct-type and large-duct-type, whereas extrahepatic CCA is classified into distal and perihilar according to site of origin within the extrahepatic biliary tree. Tumor growth patterns include mass forming, periductal infiltrating, and intraductal tumors. The clinical diagnosis of CCA is challenging and usually occurs at an advanced tumor stage. Pathologic diagnosis is made difficult by tumor inaccessibility and challenges in distinguishing CCA from metastatic adenocarcinoma to the liver. Immunohistochemical stains can assist in differentiating CCA from other malignancies, such as hepatocellular carcinoma, but no distinctive CCA-specific immunohistochemical profile has been identified. Recent advances in next-generation sequencing-based high-throughput assays have identified distinct genomic profiles of CCA subtypes, including genomic alterations that are susceptible to targeted therapies or immune checkpoint inhibitors. Detailed histopathologic and molecular evaluations of CCA by pathologists are critical for correct diagnosis, subclassification, therapeutic decision-making, and prognostication. The first step toward achieving these goals is to acquire a detailed understanding of the histologic and genetic subtypes of this heterogeneous tumor group. Here, we review state-of-the-art approaches that should be applied to establish a diagnosis of CCA, including clinical presentation, histopathology, staging, and the practical use of genetic testing methodologies.

Detection of Large-Droplet Macrovesicular Steatosis in Donor Livers Based on Segment-Anything Model.

Liver transplantation is an effective treatment for end-stage liver disease, acute liver failure, and primary hepatic malignancy. However, the limited availability of donor organs remains a challenge. Severe large-droplet fat (LDF) macrovesicular steatosis, characterized by cytoplasmic replacement with large fat vacuoles, can lead to liver transplant complications. Artificial intelligence models, such as segmentation and detection models, are being developed to detect LDF hepatocytes. The Segment-Anything Model, utilizing the DEtection TRansformer architecture, has the ability to segment objects without prior knowledge of size or shape. We investigated the Segment-Anything Model's potential to detect LDF hepatocytes in liver biopsies. Pathologist-annotated specimens were used to evaluate model performance. The model showed high sensitivity but compromised specificity due to similarities with other structures. Filtering algorithms were developed to improve specificity. Integration of the Segment-Anything Model with rule-based algorithms accurately detected LDF hepatocytes. Improved diagnosis and treatment of liver diseases can be achieved through advancements in artificial intelligence algorithms for liver histology analysis.

Colorectal Carcinoma With Sarcomatoid Components: Report of 15 Cases and Literature Review of an Exceedingly Rare Carcinoma Subtype.

Colorectal carcinoma with sarcomatoid components (which includes so-called carcinosarcomas and sarcomatoid carcinomas) is a rare subtype with 50 reported cases in the literature and overlapping criteria with undifferentiated carcinoma. We collected and described 15 cases from 10 men and 5 women, with a mean age of 66 years. Symptoms included abdominal pain and gastrointestinal bleeding. Most tumors presented in the rectosigmoid region, with a mean size of 8.2 cm. The sarcomatoid component, on average, represented 58% of the tumors and took many forms, including spindled (10 cases), anaplastic (9 cases), and rhabdoid (3 cases); one case showed osteoid matrix. Tumor budding was usually high, and tumor-infiltrating lymphocytes were usually low. The sarcomatoid component was keratin-positive in 10 cases. One case showed loss of mismatch repair protein expression, and 2 cases showed SMARCA4 loss (1 also with SMARCA2 loss). Molecular testing identified mutations in KRAS (n=1), NRAS (n=2), BRAF (n=2), APC (n=1), and TP53 (n=1) in a few cases. Tumors often presented at advanced stage, with 11 cases pT4, 9 cases with nodal metastases, and 7 cases with distant metastases. Follow-up was available for 10 cases (median: 2 months), with 2 alive without disease, 3 alive with disease, and 5 dead. Our findings roughly corresponded with those in previously reported cases. Colorectal carcinoma with sarcomatoid components is rare and aggressive, with a poor prognosis for many patients. We suggest that spindled cells, anaplasia, heterologous elements, and/or a component with definable sarcomatous lineage be used to distinguish colorectal carcinoma with sarcomatoid components from undifferentiated carcinoma.

Let-7 suppresses liver fibrosis by inhibiting hepatocyte apoptosis and TGF-ß production.

OBJECTIVE: FAS-mediated apoptosis of hepatocytes and aberrant TGF-ß signaling are major drivers of liver fibrosis. Decreased miRNA let-7 expression in the livers of patients and animals with fibrosis suggests a mechanistic link of let-7 to hepatic fibrogenesis. METHODS: Using transient transfection we tested the effects of let-7 overexpression and TET3 siRNA knockdown on FAS and TGF-ß1 expression and FAS-mediated apoptosis in human and mouse primary hepatocytes. We assessed the therapeutic activity of let-7 miRNA delivered via adeno-associated viral vectors in mouse models of carbon tetrachloride (CCl4)-induced and bile duct ligation (BDL)-induced liver fibrosis. RESULTS: Let-7 decreased TGF-ß1 production from hepatocytes through a negative feedback loop involving TET3. On the other hand, let-7 post-transcriptionally inhibits FAS expression, thereby suppressing hepatocyte apoptosis. Hepatic-specific delivery of let-7 miRNA mitigated liver fibrosis in both CCl4 and BDL mouse models. CONCLUSIONS: Let-7 is a crucial node in the signaling networks that govern liver fibrosis progression. Let-7 and/or its derivatives may be used as therapeutic agents for liver fibrosis.

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

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.

Postinfantile Giant Cell Hepatitis in Native and Allograft Livers: A Multi-Institutional Clinicopathologic Study of 70 Cases.

Postinfantile giant cell hepatitis (PIGCH) is a rare hepatitis pattern in adults with variable etiologies and clinical outcomes. We conducted a multi-institutional retrospective study to define the clinicopathologic characteristics of patients with PIGCH. A total of 70 PIGCH cases were identified and reviewed for pathological features, including fibrosis, cholestasis, inflammation, steatosis, necrosis, and apoptosis, as well as the distribution of giant cells and the maximum number of giant cells per high-power field. Demographic and clinical data, including age, sex, laboratory results, etiologies, and follow-up results, were recorded. Among the 70 cases, 40% (28/70) were associated with autoimmune liver diseases, followed by 9 (13%) with unknown etiology, 8 (11%) with viral infection, 5 (7%) with medications, 5 with combined etiologies, and 4 (6%) with malignancies (mostly chronic lymphocytic leukemia). Notably, another 16% were de novo PIGCH in liver allografts, most of which occurred after a rejection event. During follow-up, 26 (37%) patients died of the disease and 44 (63%) were alive. Deceased patients were characterized by older age (mean age, 54.9 vs 45.5 years; P = .02), higher alkaline phosphatase level (mean value, 253.3U/L vs 166.3 U/L; P = .03), higher fibrosis stage (stage 3-4 vs stage 0-2, 57.7% vs 29.6%; P = .03), being more likely to have de novo PIGCH after transplantation (23.1% vs 11.4%; P = .04), and being less likely to have primary autoimmune liver disease etiology (26.9% vs 47.7%; P = .04). These results indicate that PIGCH is a rare pattern of liver injury associated with different etiologies and variable clinical outcomes. Autoimmune liver disease with PIGCH is associated with better survival, whereas de novo PIGCH in allografts is associated with poorer survival. Older age, higher alkaline phosphatase level, and advanced fibrosis are adverse prognostic factors.

Solid-Tubulocystic carcinoma: A new variant of intrahepatic cholangiocarcinoma.

A new variant of intrahepatic cholangiocarcinoma (iCCA) has been recognized in recent years presenting predominantly as a large hepatic mass in young woman with the characteristic expression of inhibin by immunohistochemistry. This variant iCCA was originally termed as cholangioblastic variant of iCCA, and subsequently proposed to be renamed as inhibin-positive hepatic carcinoma or solid-tubulocystic variant of iCCA to better reflect its immunohistochemical profile or morphologic spectrum. The tumor histologically is composed of small to medium sized cells with scant to moderate amount of eosinophilic cytoplasm heterogeneously organized in solid, tubular, and cystic growth patterns. The tumor cells are positive for biliary markers, inhibin and albumin, and have a novel recurrent gene fusion, NIPBL::NACC1. Awareness of this new iCCA variant and its clinicopathologic features will aid in the diagnostic work-up and avoid confusion with other primary and metastatic hepatic neoplasms.

Histology and clinical correlations in autoimmune hepatitis, primary biliary cholangitis, and autoimmune hepatitis-primary biliary cholangitis overlap syndrome.

OBJECTIVES: The diagnosis of autoimmune hepatitis (AIH), primary biliary cholangitis (PBC), and AIH-PBC overlap syndrome (OS) relies on their histologic features and clinical findings. In this study, we aimed to identify specific morphologic features of these diseases and evaluate their clinical correlation. METHODS: We included initial biopsies from untreated patients with AIH (n = 14), PBC (n = 10), and OS (n = 7). Histologic features of the portal tract, portal-lobular interface, and hepatic lobule, fibrosis, as well as clinical data including serology, autoantibodies, treatment, and prognosis were reviewed and analyzed. RESULTS: Our results showed that several histologic features differed significantly between AIH and PBC (p < 0.05). Among these features, OS cases were more likely to present with bile duct-centered processes (presence of bile duct damage while absence of inflammation gradient from bile duct to interface, plasma cell cluster and pericentral inflammation) unlike those seen in AIH (p < 0.05), and interface-centered processes (unequivocal interface hepatitis, ductular reaction, and periportal fibrosis) which were not seen in PBC (p < 0.05). We observed a significant correlation between transaminase levels and lobular inflammation, including numbers of lymphocyte, plasma cell and eosinophil. Our study also found that anti-smooth muscle antibody positivity was associated with interface hepatitis (p < 0.01), while antimitochondrial antibody positivity was associated with duct damage (including ductopenia) and granulomas (p < 0.05). CONCLUSION: Our results highlight distinctive morphological features between AIH and PBC. The possibility of overlap syndrome should be considered when encountering AIH with bile duct-centered processes or PBC with interface-centered processes in morphology and correlation with autoantibodies.

Pathology of Acute and Acute-on-Chronic Liver Failure.

Liver failure can develop as either acute liver failure in the absence of preexisting liver disease, or as acute-on-chronic liver failure in a patient with underlying chronic liver disease or cirrhosis. A timely liver biopsy is helpful to distinguish acute and chronic liver disease, identify precipitating factors, provide prognostic information based on pathologic changes, and aid in making appropriate decisions for patient management. This article will discuss the pathologic features of acute and acute-on-chronic liver failure. Developing an appreciation for the histopathologic patterns of injury observed in these entities is essential for a practical understanding of the diagnostic process.

Clinicopathologic characterization of hepatocellular adenomas in men: a multicenter experience.

Hepatocellular adenomas (HCAs) are benign liver neoplasms which most commonly present in women in their reproductive age. In men, they are rare and have a higher risk of malignant transformation to hepatocellular carcinoma (HCC). Here we present our multicenter experience with HCA in men in the United States. A total of 27 HCA cases were included, with a mean age of presentation of 37 years (range, 9-69 years) and a mean size of 6.8 cm (range, 0.9-18.5 cm). Based on the 2019 World Health Organization classification, the most common subtype identified was inflammatory HCA (IHCA; 10 cases, 37.0%) followed by unclassified HCA (UHCA; 7 cases, 25.9%), HNF1A-inactivated HCA (H-HCA; 6 cases, 22.2%), ß-catenin-activated IHCA (b-IHCA; 3 cases, 11.1%), and ß-catenin-activated HCA (b-HCA; 1 case, 3.7%). Six additional cases diagnosed as hepatocellular neoplasm of uncertain malignant potential (HUMP) were also included in the study. These cases presented in a mean age of 46 years (range, 17-64 years) and a size of 10.8 cm (range, 4.2-16.5 cm). We evaluated the significance of androgen receptor (AR) expression by immunohistochemistry (IHC); of the 16 cases with materials available, 8 were considered positive using the Allred score system (2 IHCA, 2 H-HCA, 1 UHCA, and 3 HUMP). Of the total cases, 12 were diagnosed on biopsies, for which follow-up information is available for 7, and none of them show evidence of malignant transformation. Of the 21 resection cases, a concomitant well-differentiated HCC within the same lesion was identified in 5 cases (23.8%), which were diagnosed as HCA (n = 4) or HUMP (n = 1). Overall, 15% of cases in our entire cohort of HCA and HUMP showed concomitant HCC, while none of the 7 biopsy cases showed any malignant transformation on follow-up (range, 22-160 months; mean, 61.8 months).

Focal Nodular Hyperplasia in the Pediatric Population: A Multicenter Experience.

BACKGROUND: Focal nodular hyperplasia (FNH) is a benign liver lesion classically presenting in young females. In children, FNH is rare and its detailed clinicopathologic characteristics remain largely unknown. Furthermore, there are no studies comparing pediatric FNH features to those presenting in adults. METHODS: In this study, we analyzed a total of 47 FNH cases in pediatric patients (age range: 23 days to 18 years) from 3 centers and compared them to a cohort of 31 FNH cases in adult patients (age range: 20-64 years). RESULTS: Of the pediatric cases, 13 cases (28%) had a history of a prior malignancy of which 4 were treated with chemoradiation and stem cell transplantation (SCT), 5 with chemoradiation alone and 3 with chemotherapy and SCT. In the pediatric cases 41 (87%) had a central scar and 46 (98%) had fibrous septa. Both pediatric and adult FNH were more common in female patients. Cases in pediatric patients were also significantly associated with larger size (P = .047), absence of dystrophic vessels (P = .001), absence of sinusoidal dilatation (P = .029), pseudoacini formation (P = .013), and steatosis (P = .029). CONCLUSION: In our experience although most cases of pediatric FNH show the classic histologic features seen in adults, some significant differences exist, and awareness of these findings could aid in the evaluation of these rare cases.

Multi-Institutional Study of Pathologist Reading of the Programmed Cell Death Ligand-1 Combined Positive Score Immunohistochemistry Assay for Gastric or Gastroesophageal Junction Cancer.

The assessment of the expression of programmed cell death ligand-1 (PD-L1) using immunohistochemistry (IHC) has been controversial since its introduction. The methods of assessment and the range of assays and platforms contribute to confusion. Perhaps the most challenging aspect of PD-L1 IHC is the combined positive score (CPS) method of interpretation of IHC results. Although the CPS method is prescribed for more indications than any other PD-L1 scoring system, its reproducibility has never been rigorously assessed. In this study, we collected a series of 108 gastric or gastroesophageal junction cancer cases, stained them using the Food and Drug Administration-approved 22C3 assay, scanned them, and then circulated them to 14 pathologists at 13 institutions for the assessment of interpretative concordance for the CPS system. We found that higher cut points (10 or 20) performed better than a CPS of <1 or >1. We used the Observers Needed to Evaluate Subjective Tests algorithm to assess how the CPS system might perform in the real-world setting and found that the cut points of <1 or >1 showed an overall percent agreement of only 30% among the pathologist raters, with a plateau occurring at 8 raters. The raters performed better at higher cut points. However, the best cut point of <20 versus that of >20 was still disappointing, with a plateau at an overall percent agreement of 70% (at 7 raters). Although there is no ground truth for CPS, we compared the score with quantitative messenger RNA measurement and showed no relationship between the score (at any cut point) and messenger RNA amount. In summary, we showed that CPS shows high subjective variability among pathologist readers and is likely to perform poorly in the real-world setting. This system may be the root cause of the poor specificity and relatively low predictive value of IHC companion diagnostic tests for PD-1 axis therapies that use the CPS system.

Neoadjuvant PD-1 blockade plus chemotherapy versus chemotherapy alone in locally advanced stage II-III gastric cancer: A single-centre retrospective study.

BACKGROUND: PD-1 blockade has been shown to have promising efficacy and acceptable safety profiles in advanced and metastatic gastric cancer; however, the efficacy and safety of neoadjuvant PD-1 blockade-based immunotherapy plus chemotherapy in locally advanced gastric cancer (LAGC) remain uncertain. METHODS: We performed a retrospective review of patients with LAGC who received neoadjuvant treatment followed by D2 radical resection at the Affiliated Hospital of Qingdao University from 2019 to 2021. The primary aim was to investigate the difference in pathological response rates between neoadjuvant PD-1 immunotherapy plus chemotherapy and neoadjuvant chemotherapy alone. Multivariable models for pathological complete response (pCR) were constructed to investigate the factors that facilitate pCR. TRIAL REGISTRATION: QYFYWZLL27406. RESULTS: A total of 77 patients were included in the analysis, among whom 34 (44.2%) received neoadjuvant PD-1 blockade immunotherapy plus chemotherapy. A higher pCR rate was observed in the neoadjuvant PD-1 blockade immunotherapy plus chemotherapy group (8 of 34, 23.5% vs. 2 of 43, 4.7%, P=0.019). Multivariate logistic regression analysis of pCR revealed neoadjuvant PD-1 blockade plus chemotherapy regimen promoted pCR (OR 12.95, P=0.016). Regarding safety, 76.5% (26 of 34) of patients in the PD-1 blockade plus chemotherapy group and 76.7% (33 of 43) of patients in the chemotherapy group experienced treatment-related adverse events (TRAEs), and grade 3 or worse adverse events were 29.4% (10 of 34) and 34.9% (15 of 43), respectively. CONCLUSION: Neoadjuvant PD-1 blockade plus chemotherapy induced a higher pCR rate than neoadjuvant chemotherapy, and the combined therapy was tolerable in LAGC patients.