HPHS Journal Watch: July/August 2022

Advances in Anatomic Pathology

Gastrointestinal and Hepatobiliary Immune-related Adverse Events: A Histopathologic Review

Alruwaii ZI, Montgomery EA. Adv Anat Pathol. 2022 Jul 1;29(4):183-193.


This review includes a summary of histopathologic changes in gastrointestinal and hepatic toxicities related to immune checkpoint inhibitors (anti-CTLA-4 and anti-PD-1 drugs and inhibitors). Histologic patterns of injury (including lobular and cholangitic patterns as well as more unusual patterns of injury such as steatosis/steatohepatitis and granulomatous hepatitis) are summarized with representative images and a discussion of the pathologic differential diagnoses.

American Journal of Clinical Pathology

Tumor Size, Not Small Vessel Invasion, Predicts Survival in Patients With Hepatocellular Carcinoma

Zhang D, Love T, Hao Y, et al. Am J Clin Pathol. 2022 July 1;158(1):70-80.


In this study, the authors studied 3 independent cohorts of patients with hepatocellular carcinoma (HCC) to reassess and modify the tumor staging criteria for HCC. The first/initial cohort consisted of 103 patients at a single institution (University of Rochester Medical Center (URMC)); the 2 validation cohorts consisted of 250 patients at a single institution (Mount Sinai Hospital (MSH)) and 9685 patients from the Surveillance, Epidemiology, and End Results (SEER) data set. Clinicopathologic and histomorphological evaluations were performed. Based on univariate and multivariate analysis, the largest tumor size (irrespective of number of tumor foci) and large vessel invasion involving the portal vein branch (but not microscopic small vessel invasion) were prognostic. Kaplan-Meier survival analysis showed that the AJCC 7th edition staging failed to separate T1 from T2 on overall survival (OS) and disease-specific survival (DSS) while 8th edition staging failed to separate T1b from T2. The authors propose a modified staging system that defines T2 as solitary, >2 cm up to 5 cm or multiple, none >5 cm, and T3 as solitary, >5 cm or multiple, at least one >5 cm. This modified staging system results in better stratification of risk with separation of OS and DSS in the initial as well as validation cohorts and should be considered in future revisions of the AJCC staging system.

Recurrent Liver Allograft Injury in Patients With Donor-Derived Malignancy Treated With Immunosuppression Cessation and Retransplantation

Lee BT, Ganjoo N, Fiel MI, et al. Am J Clin Pathol. 2022 Aug 4;158(2):199-205.


The authors present 2 cases of patients with donor-derived malignancy of the liver allograft who were treated with complete immunosuppression cessation and subsequent rapidly progressive liver allograft rejection and failure and retransplantation. The initial explants of the allografts showed severe rejection (chronic ductopenic rejection, foam cell arteriopathy), also with sinusoidal obstruction syndrome (SOS) and C4d positivity. The tumors in the allografts were necrotic (complete in one, partial in the other). On follow-up, both patients were cancer-free, but both had recurrent allograft failure with persistent C4d positivity, requiring a third transplant.

Clinical, Laboratory, and Histologic Correlates of Serum Antinuclear Antibody in Hispanic Pediatric Patients With Nonalcoholic Fatty Liver Disease

Wu H, Zhu L, Kinnear D, et al. Am J Clin Pathol. 2022 Aug 4;158(2):221-227.


Nonalcoholic fatty liver disease (NAFLD) is the most common liver abnormality in children aged 2-19 years in the United States. Anti-nuclear antibodies (ANAs) are non-organ-specific autoantibodies that can be detected in 31.7% of healthy individuals and 3.0% of healthy children but are also reported to be positive in 16.3-51% of patients with NAFLD. Previous pediatric studies involving patients of multiple ethnicities were inconclusive regarding any association between ANA status and degree of steatosis. This study was an investigation of the clinical, laboratory, and histologic features in 38 Hispanic patients with a focus on ANA status (positive ANA is defined as titer of 1:40 or greater). All were first diagnostic liver biopsies. 20 patients (53%) were ANA positive, with range of titers 1:40 (n=3) to 1:1280 (n=4). F-active antibody was also positive in 15% of ANA-positive patients (n=3), all at low titers; LKM antibody was negative in all patients tested. ANA positive patients had overall higher serum fasting insulin levels and higher insulin resistance whereas ANA negative patients had higher levels of serum HDL cholesterol; triglyceride levels were comparable in ANA positive and negative patients. There was no significant difference in gender, age, obesity, random glucose levels, obstructive sleep apnea, hypergammaglobulinemia, peripheral blood eosinophilia, the presence of F-active antibody, or serum AST, ALT, GGT, or alkaline phosphatase levels. Histologically, of note, no patient had cirrhosis, but bridging fibrosis was seen in 9 patients. There was no difference in histologic parameters overall between ANA positive and negative patients (including moderate to severe steatosis, more than minimal portal inflammation, presence/degree of interface inflammation, plasma cells, ballooning, bridging fibrosis, grade 2 lobular inflammation, or NAS score).

The Quantification and Significance of Extramedullary Hematopoiesis Seen on Liver Biopsy Specimens

Tremblay D, Saberi S, Mascarenhas J, et al. Am J Clin Pathol. 2022 Aug 4;158(2):277-282.


In adults, extramedullary hematopoiesis (EMH) is considered pathologic, occurring in response to insufficient marrow function or ineffective hematopoiesis. Hematologic diseases can be associated with EMH, including myeloproliferative neoplasms (MPNs), but also non-hematologic diseases may lead to EMH such as HIV infection, cirrhosis, and hepatic angiomyolipomas. At present, there is no system to predict whether EMH is secondary to a primary hematologic disorder and no formal grading system exists. In this study, the authors identified 42 patients with EMH on liver biopsy and developed an EMH grading system where an EMH focus was defined as a distinct area within the microscopic field that has a tight group/cluster of at least 5 hematopoietic cells, with grading based on the number of EMH foci in 10 random high-power fields (HPF) at x40 magnification (0.238 mm2 field area) in the hepatic lobule. Grade 0 = no EMH foci; grade 1 = 2 or fewer EMH foci; grade 2 = 3-5 EMH foci; grade 3 = 6 or more EMH foci. Seventeen (40.5%) patients had a known hematologic disorder, with MPNs being most common; 25 (59.5%) patients had nonhematologic disorders (cirrhosis most common, others including inflammatory bowel disease, solid tumors, and congestive heart failure). Of patients without a hematologic disorder (n=25), 76% had grade 1 EMH, 24% had grade 2, and none had grade 3. Patients with an underlying hematologic disorder (n=17) had a significantly higher EMH grade, with only 3 patients with grade 1 EMH; all patients with grade 3 EMH had an underlying hematologic disorder. Thus, grade 3 EMH in the absence of a known hematologic condition should prompt a hematologic evaluation.

Archives of Pathology & Laboratory Medicine

Histologic Changes in Core-Needle Liver Biopsies From Patients With Acute-on-Chronic Liver Failure and Independent Histologic Predictors of 28-Day Mortality

Valoda B, Anand A, Yadav R, et al. Arch Pathol Lab Med. 2022;146:846-854.


Acute on chronic liver failure (ACLF) is a clinical syndrome where patients who have underlying chronic liver disease rapidly decompensate and have high 28-day mortality. The authors reviewed liver core needle biopsies from 152 patients with a clinical diagnosis of ACLF in order to examine the histologic features that may aid in prognostication for these very ill patients. The clinical cause of decompensation was varied, although alcohol use was the most common etiology (31%). On histologic review, over half of the ACLF liver biopsies had “high” apoptotic hepatocytes, significant cholestasis, diffuse periportal inflammation, prominent ductular reaction, ballooned hepatocytes, and advanced fibrosis. Although only 15% of ACLF biopsies showed dense lobular inflammation, it was this histologic feature that was found to be associated with increased risk for short-term mortality once after adjusting for clinical cause of decompensation.

Clinical Gastroenterology and Hepatology

Aminotransferases During Treatment Predict Long-Term Survival in Patients With Autoimmune Hepatitis Type 1: A Landmark Analysis

Biewenga M, Verhelst X, Baven-Pronk M, et al. Clin Gastroenterol Hepatol. 2022 Aug;20(8):1776-1783.e4.


This paper evaluated the prognostic value of aminotransferases and immunoglobulin G (IgG) in patients with probable or definite AIH type 1 (n=301 patients) according to the revised pretreatment International AIH Group criteria. All patients with AIH type 2 (defined by the presence of anti-LKM-1 antibodies) and patients with primary biliary cirrhosis or primary sclerosing cholangitis overlap syndromes were excluded. The authors found that higher aminotransferases during treatment were significantly associated with long-term transplant-free survival, independent of age, aminotransferases at diagnosis, and cirrhosis. Elevated IgG was not predictive of long-term transplant-free survival in the first year of treatment, although in univariate analysis at 24- and 36-months, elevated IgG was associated with a worse long-term transplant-free survival in a limited number of patients.


β-Catenin Sustains and Is Required for YES-associated Protein Oncogenic Activity in Cholangiocarcinoma

Zhang Y, Xu H, Cui G, et al. Gastroenterology. 2022 Aug;163(2):481-494.


Intrahepatic cholangiocarcinoma (iCCA) accounts for approximately 15% of primary liver tumors and has a poor prognosis. There has been very limited benefit in targeting driver mutations such as FGFR2 and IDH1/2 in CCA therapeutics. The authors of this study use mouse models of CCA to explore a potential role for targeting nonmutated proteins involved in transcription in iCCA. The authors focus on two signaling cascades and the interplay with β-Catenin, whose role in CCA has not yet been established. Aberrant activation of YES-associated protein (YAP) has previously been implicated in intrahepatic cholangiocarcinoma (iCCA) and the transcriptional enhanced associate domain (TEAD)-mediated transcriptional regulation is the primary signaling event downstream of YAP. The authors found that TEAD factors are required for YAP-dependent iCCA development, and that β-Catenin physically interacts with YAP in human and mouse iCCA. The ablation of Ctnnb1 strongly suppressed human iCCA cell growth and Yap-dependent cholangiocarcinogenesis. Interestingly, activated/nonphosphorylated β-Catenin was detected in more than 80% of human iCCAs. In conclusion, YAP induces the development of cholangiocarcinoma via TEAD-dependent transcriptional activation and the transcriptional activity of YAP depends upon the binding of β-Catenin. Thus, the study reveals significant and potentially targetable crosstalk between YAP and β-Catenin pathways in cholangiocarcinogenesis.


MicroRNA-206 promotes the recruitment of CD8+ T cells by driving M1 polarisation of Kupffer cells

Liu N, Wang X, Steer CJ, Song G. Gut. 2022 Aug;71(8):1642-1655.


The pathogenesis of hepatocellular carcinoma (HCC) involves a strong immune-mediated phenomenon, but there is also considerable immunosuppression in HCC, which is a significant barrier of resistance to immunotherapy. There is a need to understand the mechanism of immunosuppression in HCC to develop novel therapeutic agents without unwanted immune response. Kupffer cells (KCs), which constitute 15% of liver cells, can initiate an antigen-specific immune response because they express histocompatibility complex (MHC) class I and class II as well as costimulatory molecules. In HCC, KCs undergo an M1 to M2 phenotypic shift, which promotes cancer growth by suppressing the adaptive immune system. It is now well established that polarization of KCs is involved in CD8-positive T cell recruitment and their inability to reach tumor cells, which is an important mechanism of resistance to immunotherapy. On the other hand, AKT activation is required for M2 activation. Coordinated activation of the AKT/mTOR and RAS/ MAPK cascades is also associated with biological aggressiveness and poor prognosis of HCC. This group of investigators recapitulated this phenomenon in vivo by hydrodynamically transfecting activated forms of AKT (myr-AKT) and NRas (NRas-V12) oncogenes (AKT/Ras) into the mouse liver. The preliminary data from this group showed that, in addition to hepatocytes, hydrodynamic delivery also activated AKT signaling in KCs, which led to dysregulation of microRNA (miRNAs). This characteristic of miRNAs allows them to speculate that they could precisely regulate the immune response and avoid excessive or inadequate immune response. The authors used AKT/Ras mice to investigate the contribution of KCs to immune homeostasis and HCC and determined how miRNA modulated immunological pathways and HCC development. In summary, activation of AKT/Ras signaling triggered M2 polarisation of KCs, which subsequently impaired cytotoxic T cell infiltration to the cancer site. MiR-206 drove M1 polarisation of KCs and CCL2 production. Activation of CCL2/CCR2 signal- prevented HCC. Based on the unique nature of miR-206 to enhance immune surveillance, it represents a potentially novel immunotherapeutic agent against HCC.

Clinical relevance of biomarkers in cholangiocarcinoma: critical revision and future directions

Macias RIR, Cardinale V, Kendall TJ, et al. Gut. 2022 Aug;71(8):1669-1683.


The identification of tissue biomarkers is extremely important in Cholangiocarcinoma (CCA) as this sporadic cancer is often diagnosed at advanced stages with a dismissal prognosis and no identifiable risk factors in this malignancy. A multi-specialty group within the European network for the study of Cholangiocarcinoma discussed the clinical role of biomarkers at tissue and molecular levels extensively and outlined their potential applications. This group also identified biomarkers with a role in diagnosis, predicting prognosis, and response to therapy. In addition to limitations of current biomarkers, they also focussed on some promising areas like Artificial intelligence, patient-derived cell organoids, and targeted therapy for future research. The article first focused on the diagnostic hallmarks and pitfalls in routine histology and then concentrated on the role of molecular tissue biomarkers in the diagnosis of cholangiocarcinoma. In addition, the authors discussed research needs and perspectives under four headings: 1) Liquid biopsy: from tissue analysis to serum biomarkers 2) AI tools: hidden information in H&E stain 3) Organoids: ‘minitumors’ for drug selection and 4) Radiomics and radiogenomics.

Hepatology Communications

Setting up criteria for drug-induced autoimmune-like hepatitis through a systematic analysis of published reports

Björnsson ES, Medina-Caliz I, Andrade RJ, Lucena MI. Hepatol Commun. 2022 Aug;6(8):1895-1909.


This study reviewed 186 published case reports of drug-induced autoimmune-like hepatitis (DI-AILH) in order to establish criteria to define suspected DI-AILH and distinguish the phenotype from idiopathic AIH. Criteria in this study included positive autoimmune markers with histology compatible with AIH, incomplete recovery or worsening of liver tests after stopping the implicated agent, need for corticosteroids to improve the liver injury, and lack of relapse after stopping corticosteroids. This study supports well-known causes of DI-AILH including nitrofurantoin, methyldopa, hydralazine, minocycline, and infliximab. Additionally, this study recognizes a trend in immune modulators or other drugs that affect the immune system (such as interferon) as causes of DI-AILH. Khat and Tinospora cordifolia were the only herbal and dietary supplements found to be able to induce DI-AILH. Primarily statins were the only type of drug that fulfilled all criteria of being suspected of inducing classic AIH.

Nonalcoholic steatohepatitis is the most common indication for liver transplantation among the elderly: Data from the United States Scientific Registry of Transplant Recipients

Stepanova M, Kabbara K, Mohess D, et al. Hepatol Commun. 2022 Jul;6(7):1506-1515.


This large retrospective study included all wait-listed candidates and liver transplant recipients ≥65 years in the United States (1,209 elderly liver transplant candidates in a nationwide registry) and compared clinical characteristics compared to adult patients 18-64 years of age. The study found a nearly 2.5-fold increase in the proportion of patients 65 years of age or older who were listed for liver transplantation with the most common etiology for the cohort being NASH (31% vs. 13% in patients 18–64 years). The rate of HCC was also 2 times higher in older patients (30% in ≥65 vs. 15% in 18–64-year-olds across all study years).

Abnormal liver tests are not sufficient for diagnosis of hepatic graft-versus-host disease in critically ill patients

Yang AH, Han MAT, Samala N, et al. Hepatol Commun. 2022 Aug;6(8):2210-2220.


This retrospective study reviewed the clinical features including liver biomarkers, clinical and/or biopsy confirmed graft-versus-host disease (GVHD) of various organs, and autopsy findings of 51 patients at the NIH Clinical Center who underwent hematopoietic cell transplantation (HCT) and expired of various causes. The autopsy specimens (37 of which had adequate liver tissue) were evaluated for the presence of hepatic GVHD based on NIH histopathologic consensus criteria (characterized by duct injury with absence of significant inflammation after exclusion of other potential etiologies). The authors found a significant discordance between clinical suspicion of GVHD and autopsy findings, with thirteen patients who had clinical findings consistent with HGVHD based on Keystone Criteria or the NCC but did not show signs of HGVHD at autopsy. Of the 15 patients who satisfied the clinical criteria for HGVHD, almost all (n = 12, 80%) died of infection-related causes. The authors conclude that liver biopsy should be considered in cases where the liver injury progresses despite appropriate treatment particularly given the risk of opportunistic infections and organ toxicity immunosuppressive agents.


Novel histological scoring for predicting disease outcome in primary sclerosing cholangitis

Sjöblom N, Boyd S, Kautiainen H, et al. Histopathology. 2022 Aug;81(2):192-204.


The authors analyzed 300 PSC patients and developed a tailored classification system for PSC (PSC histoscore system) based on histological features associated with disease progression. A compound endpoint consisting of liver transplantation, development of cholangiocarcinoma, or death was used as outcome measurement. The results indicated that stage (fibrosis, bile duct loss, ductular reaction, and chronic cholestasis) and grade (portal inflammation, portal edema, hepatitis activity, and cholangitis activity) parameters were independent predictive risk factors for the compound endpoint (P < 0.001). High disease grade (2-6) and stage (2-4) better correlated with clinical endpoints when evaluated with the PSC histoscore system compared to the adapted Nakanuma classification. The risk for disease progression in sequential endoscopic retrograde cholangiography (ERC) examinations was increased with elevated total PSC histoscores.

Liver Transplantation

Sinusoidal obstruction syndrome after liver transplantation: A multicenter observational study

Caballero-Marcos A, Peligros I, Pérez-Rojaset J, et al. Liver Transpl. 2022 Jul;28(7):1257-1261.


This multicenter study included forty-one cases of sinusoidal obstruction syndrome (SOS) in patients with liver transplantation (LT). The median time between LT and SOS onset was 2.43 months (IQR 1.64–11.01). Clinical features are nonspecific. No patient showed the classical triad of hepatomegaly, ascites, and jaundice. Ascites was very frequent at the time of diagnosis (80.5%), whereas jaundice was present in only 39.0% of cases. HVPG was elevated in 96.2% of the patients who had HVPG measurements. Most biopsies showed histologic features of SOS, including sinusoidal dilatation (97.6%), perisinusoidal hemorrhage/congestion (75.6%), and centrilobular vein fibrosis (75.6%). Since clinical features were nonspecific, histological evidence is essential to establish the diagnosis of SOS in patients with LT.

Acute cellular rejection in liver transplantation recipients following vaccination against coronavirus disease 2019: A case series

Sarwar R, Adeyi OA, Lake J, et al. Liver Transpl. 2022 Aug;28(8):1388-1392.


The authors reported 5 liver transplant recipients who developed biopsy-proven acute cellular rejection (ACR) following vaccination against COVID-19. The median time from vaccination to elevations in liver enzymes was 11 days (range 7–19 days, three patients after the first dose and two patients after the second dose). All episodes of ACR were easily treated without any serious complications. The findings highlight the need for comprehensive post-vaccination surveillance programs in liver transplant recipients.

Prepared by:
Lindsey Westbrook, MD (Editor); University of Colorado
Dana Balitzer, MD; University of California San Francisco
Soo-Jin Cho, MD, PhD; University of California San Francisco
Ashim Das, MD; Post Graduate Institute of Medical Education and Research, India
Gillian Hale, MD, MPH; University of Utah
Meredith Pittman, MD; Maimonides Medical Center
Daniel Roberts, MD; Cleveland Clinic
Nafis Shafizadeh, MD; Southern California Permanente Medical Group
Xuefeng Zhang, MD; Cleveland Clinic

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