Clinicopathologic comparison between sporadic and syndromic Peutz-Jeghers polyps.

Peutz-Jeghers polyps (PJPs) are hamartomatous polyps that may define patients with Peutz-Jeghers syndrome (PJS), a rare inherited polyposis syndrome with high cancer risk. However, the clinical significance of 1-2 sporadic PJPs (without other PJS stigmata) regarding malignant potential and identification of new PJS probands is still unclear. We identified 112 patients with 524 histologically confirmed PJPs and categorized them based on polyp number into syndromic (n = 38) if ≥3 PJPs or diagnosed PJS, solitary (1 PJP, n = 61), and intermediate (2 PJPs, n = 13). Clinicopathologic features, including presence of dysplasia in the polyp and development of neoplasia in the patient, were compared on a per-patient and per-polyp basis. Whereas patients with solitary and intermediate PJPs were not different from each other, patients with syndromic PJPs were, in multivariate analysis, younger (P = .001) and more likely to develop neoplasia (P = .02) over a 62.6-months median follow-up than patients with sporadic PJPs. On an individual polyp basis, syndromic PJPs were more likely, in multivariate analysis, to occur in the small intestine (P < .001), but less likely to harbor metaplasia (P = .03) or dysplasia (P = .001), than sporadic PJPs. Dysplasia and metaplasia were more likely in larger PJPs, by multivariate analysis (P = .007 and P < .001, respectively). These data suggest that strict criteria for PJS (including ≥3 PJPs), as currently used, stratify patients into distinct groups with significant differences in clinicopathologic parameters, particularly regarding risk of neoplasia. However, sporadic PJPs exhibit characteristics such as dysplasia and are thus important to recognize and diagnose but perhaps as heralding only a forme fruste PJS.

Intratumoral dendritic cell-CD4+ T helper cell niches enable CD8+ T cell differentiation following PD-1 blockade in hepatocellular carcinoma.

Despite no apparent defects in T cell priming and recruitment to tumors, a large subset of T cell rich tumors fail to respond to immune checkpoint blockade (ICB). We leveraged a neoadjuvant anti-PD-1 trial in patients with hepatocellular carcinoma (HCC), as well as additional samples collected from patients treated off-label, to explore correlates of response to ICB within T cell-rich tumors. We show that ICB response correlated with the clonal expansion of intratumoral CXCL13+CH25H+IL-21+PD-1+CD4+ T helper cells ("CXCL13+ TH") and Granzyme K+ PD-1+ effector-like CD8+ T cells, whereas terminally exhausted CD39hiTOXhiPD-1hiCD8+ T cells dominated in nonresponders. CD4+ and CD8+ T cell clones that expanded post-treatment were found in pretreatment biopsies. Notably, PD-1+TCF-1+ (Progenitor-exhausted) CD8+ T cells shared clones mainly with effector-like cells in responders or terminally exhausted cells in nonresponders, suggesting that local CD8+ T cell differentiation occurs upon ICB. We found that these Progenitor CD8+ T cells interact with CXCL13+ TH within cellular triads around dendritic cells enriched in maturation and regulatory molecules, or "mregDC". These results suggest that discrete intratumoral niches that include mregDC and CXCL13+ TH control the differentiation of tumor-specific Progenitor exhasuted CD8+ T cells following ICB.

Human Immunodeficiency Virus-associated Immune Complex Kidney Disease Progressing to End-stage Kidney Disease.

A 58-year-old man with human immunodeficiency virus (HIV) infection presented with a week-long history of gross hematuria, nephrotic proteinuria, and acute kidney injury. The patient was non-adherent with combination antiretroviral therapy. A kidney biopsy showed cellular crescents with disruption of Bowman's capsule, C3-dominant immune complex deposition, consistent with HIV-associated immune complex kidney disease (HIVICK). During the course, his worsening kidney function warranted initiation of hemodialysis. This case highlights the fact that HIV patients are at an increased risk of developing HIVICK, especially in the setting of non-adherence. A greater understanding of HIVICK among HIV patients should promote additional investigation into its etiology and viable treatments.

Radiological and pathological assessment with EOB-MRI after Y90 radiation lobectomy prior to liver resection for hepatocellular carcinoma.

BACKGROUND: Radiation lobectomy (RL) utilizes Yttrium-90 (Y90) radioembolization for achieving tumor control and inducing contralateral lobe hypertrophy. Our objective was to evaluate the chronological changes occurring radiologically and histopathologically after Y90 RL. METHODS: We retrospectively reviewed 22 patients with chronic liver disease who underwent Y90 RL prior to planned liver resection for hepatocellular carcinoma. Gadolinium ethoxybenzyl diethylenetriamine penta-acetic acid (Gd-EOB-DTPA) enhanced magnetic resonance imaging (EOB-MRI) was performed every 3 months. RESULTS: Future liver remnant volume (FLRV) significantly increased up to 9 months after Y90 RL. Gd-EOB-DTPA uptake in the treated lobe experienced a 40% reduction in enhancement ratio (ER) during ensuing first 3 months, and never recovered. The reduced ER in the non-tumoral parenchyma was significantly correlated with increased FLRV and FLR (r = 0.41 and r = 0.35, respectively; both p < 0.01). Histopathological evaluation of non-tumor liver tissue found features of sinusoidal obstruction syndrome as an early change after Y90 RL (median 5.7 months) and parenchymal collapse as a late change (mean 11 months). DISCUSSION: The reduced uptake of Gd-EOB-DTPA at 3 months post Y90 RL correlates with a significant increase in FLRV prior to liver resection. EOB-MRI evaluation at 3 months can guide future plan of action after Y90 RL.

Characterization and Prediction of Signal Intensity Changes in Normal Liver Parenchyma on Gadoxetic Acid-enhanced MRI Scans after Liver-directed Radiation Therapy.

Purpose To better characterize and understand the significance of focal liver reaction (FLR) development in a large cohort of patients who underwent gadoxetic acid-enhanced MRI after being treated with radiation therapy (RT) for hepatobiliary tumors. Materials and Methods This retrospective study evaluated 100 patients (median age, 65 years [first and third quartiles, 60-69 years]; 80 men) who underwent RT for hepatocellular carcinoma, bile duct tumors, or liver metastases at Mount Sinai Hospital between March 1, 2018, and February 29, 2020. CT simulation scans were fused to MRI scans obtained 1-6 months and 6-12 months after RT, using the hepatobiliary phase of the MRI. To define FLR volume, two radiation oncologists independently delineated the borders of the hypointensity observed on MRI scans in the liver region where RT was delivered. Biologically effective dose (BED) thresholds for the formation of FLRs were calculated, along with albumin-bilirubin (ALBI) scores and grades, and overall survival. Results Most patients developed FLRs, which decreased in volume over time. Median BED threshold values for FLR development were 63.6 Gy at 1-6 months and 88.7 Gy at 6-12 months. While higher baseline ALBI scores were associated with a lower rate of FLRs, there was a significant association between FLR volume and increase in ALBI score at 1-6 months (P = .048). Twelve- and 24-month survival estimates for the cohort were 81% and 48%, respectively. Histopathologic analysis of seven explanted liver specimens demonstrated findings consistent with radiation-induced liver disease. Conclusion FLRs were a clear measure of liver damage after RT and were associated with the development of liver dysfunction and focal radiation-induced liver disease. Keywords: MRI, Radiation Therapy Supplemental material is available for this article. © RSNA, 2022.

Gallbladder Cancer: A Single-Institution 10-Year Experience-Analysis of Adenocarcinoma Subtypes and Tumors Arising from Intracholecystic Papillary Neoplasms.

BACKGROUND: Gallbladder cancer accounts for 1.2% of global cancer diagnoses. Literature on biliary-type adenocarcinoma (BTA), and specifically carcinoma arising from intracholecystic papillary-tubular neoplasms (ICPNs), is limited. This study describes a retrospective, single-institution experience with gallbladder cancer, focusing on histological subtypes and prognosis. METHODS: A retrospective review was performed of patients who underwent cholecystectomy for a malignant neoplasm of the gallbladder between 2007 and 2017. Demographic, clinicopathologic, and operative variables, as well as survival outcomes, were analyzed. RESULTS: From a total of 145 patients, BTAs were most common (93, 64%). Compared with non-BTAs, BTAs were diagnosed at a lower American Joint Committee on Cancer stage (p = 0.045) and demonstrated longer median recurrence-free survival (38 vs. 16 months, p = 0.014; median follow-up 36 months). Tumors arising from ICPNs (18, 12%) were more commonly associated with BTA (14 cases). Compared with BTAs not associated with ICPNs (29 patients), associated cases demonstrated lower pathologic stage (p = 0.006) and lower rates of liver and perineural invasion (0% vs. 49% and 14% vs. 48%, respectively; p < 0.05). Cumulative 5-year survival probability was higher for patients with gallbladder neoplasm of any subtype associated with ICPNs compared with those that were not associated with ICPNs (54% vs. 41%, p = 0.019; median follow-up 23 months). This difference was also significant when comparing BTAs associated with ICPNs and non-associated cases (63% vs. 52%, p = 0.005). CONCLUSIONS: This study demonstrated unique pathological and prognostic features of BTAs and of carcinomas arising from ICPNs. Histopathological variance may implicate prognosis and may be used to better guide clinical decision making in the treatment of these patients.

Neoadjuvant cemiplimab for resectable hepatocellular carcinoma: a single-arm, open-label, phase 2 trial.

BACKGROUND: Surgical resection of early stage hepatocellular carcinoma is standard clinical practice; however, most tumours recur despite surgery, and no perioperative intervention has shown a survival benefit. Neoadjuvant immunotherapy has induced pathological responses in multiple tumour types and might decrease the risk of postoperative recurrence in hepatocellular carcinoma. We aimed to evaluate the clinical activity of neoadjuvant cemiplimab (an anti-PD-1) in patients with resectable hepatocellular carcinoma. METHODS: For this single-arm, open-label, phase 2 trial, patients with resectable hepatocellular carcinoma (stage Ib, II, and IIIb) were enrolled and received two cycles of neoadjuvant cemiplimab 350 mg intravenously every 3 weeks followed by surgical resection. Eligible patients were aged 18 years or older, had confirmed resectable hepatocellular carcinoma, an Eastern Cooperative Oncology Group performance status of 0 or 1, and adequate liver function. Patients were excluded if they had metastatic disease, if the surgery was not expected to be curative, if they had a known additional malignancy requiring active treatment, or if they required systemic steroid treatment or any other immunosuppressive therapy. After resection, patients received an additional eight cycles of cemiplimab 350 mg intravenously every 3 weeks in the adjuvant setting. The primary endpoint was significant tumour necrosis on pathological examination (defined as >70% necrosis of the resected tumour). Secondary endpoints included delay of surgery, the proportion of patients with an overall response, change in CD8+ T-cell density, and adverse events. Tumour necrosis and response were analysed in all patients who received at least one dose of cemiplimab and completed surgical resection; safety and other endpoints were analysed in the intention-to-treat population. Patients underwent pre-treatment biopsies and blood collection throughout treatment. This trial is registered with ClinicalTrials.gov (NCT03916627, Cohort B) and is ongoing. FINDINGS: Between Aug 5, 2019, and Nov 25, 2020, 21 patients were enrolled. All patients received neoadjuvant cemiplimab, and 20 patients underwent successful resection. Of the 20 patients with resected tumours, four (20%) had significant tumour necrosis. Three (15%) of 20 patients had a partial response, and all other patients maintained stable disease. 20 (95%) patients had a treatment-emergent adverse event of any grade during the neoadjuvant treatment period. The most common adverse events of any grade were increased aspartate aminotransferase (in four patients), increased blood creatine phosphokinase (in three), constipation (in three), and fatigue (in three). Seven patients had grade 3 adverse events, including increased blood creatine phosphokinase (in two patients) and hypoalbuminaemia (in one). No grade 4 or 5 events were observed. One patient developed pneumonitis, which led to a delay in surgery by 2 weeks. INTERPRETATION: This report is, to our knowledge, the largest clinical trial of a neoadjuvant anti-PD-1 monotherapy reported to date in hepatocellular carcinoma. The observed pathological responses to cemiplimab in this cohort support the design of larger trials to identify the optimal treatment duration and definitively establish the clinical benefit of preoperative PD-1 blockade in patients with hepatocellular carcinoma. FUNDING: Regeneron Pharmaceuticals.

Solitary Peutz-Jeghers Type Polyp of Jejunum with Gastric Fundic and Antral Gland Lining Mucosa: A Case Report and Review of Literature.

Solitary Peutz-Jeghers type polyps are characterized by a hamartomatous polyp of the gastrointestinal (GI) tract in a patient without mucocutaneous pigmentation, family history of Peutz-Jeghers syndrome, or STK11/LKB1 mutations. Histologically identical to the polyps in Peutz-Jeghers syndrome, these sporadic polyps can arise anywhere along the GI tract, with typical arborizing smooth muscles extending from the muscularis mucosa. While the lining mucosa is generally the same as the organ in which it arises, gastric pyloric and osseous metaplasia have been reported in intestinal polyps in Peutz-Jeghers syndrome. Herein, the authors report the first case of a small intestinal solitary Peutz-Jeghers type polyp with gastric antral and fundic gland lining mucosa. A 43-year-old male was admitted for small bowel obstruction. Diagnostic laparoscopy revealed jejuno-jejunal intussusception with an associated polyp measuring 7.2 cm. Histological examination showed a hamartomatous polyp with arborizing smooth muscle bundles extending from the muscularis mucosae. The polyp was lined by non-dysplastic gastric antral and fundic gland mucosa, and was sharply demarcated from the adjacent non-polypoid intestinal mucosa. Colonoscopy, esophagogastroduodenoscopy and small bowel enteroscopy revealed no additional polyps or masses. Thorough investigation of the patient's family history was negative for Peutz-Jeghers syndrome or mucocutaneous pigmentation. Molecular analysis of the lesion was negative for STK11/LKB1 mutations. A diagnosis of solitary Peutz-Jeghers type polyp of the small bowel with gastric antral and fundic gland mucosal lining was rendered.

Hydralazine-Induced Antineutrophil Cytoplasmic Antibody-Associated Vasculitis: Asymptomatic and Renal-Restricted Presentation.

BACKGROUND Hydralazine, a potent vasodilator widely used to treat hypertension, has been implicated in an increasing number of cases of drug-induced autoimmune diseases in recent years. However, antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis secondary to hydralazine use has rarely been described and most reported cases involved multi-organ-related vasculitis, including skin and lung-kidney manifestations. ANCA-associated vasculitis is an immune-inflammatory condition characterized by necrotizing vasculitis with few or no immune deposits, predominantly affecting small vessels. The fact that the vasculitis is associated with hydralazine use and improves with discontinuation of hydralazine supports the diagnosis of hydralazine-induced disease. The case we report is a hydralazine-induced, ANCA-associated, pauci-immune crescentic glomerulonephritis with a presentation limited to the kidneys. CASE REPORT A 66-year-old woman was admitted to the hospital for worsening renal function over a month with no symptoms. Serology work-up was significantly positive for antinuclear, perinuclear ANCA, anti-histone, anti-double-stranded DNA, anti-cardiolipin, and anti-myeloperoxidase antibodies. The patient ultimately underwent a kidney biopsy, which revealed pauci-immune crescentic glomerulonephritis. Her kidney function improved with cessation of hydralazine as well as therapy with pulse steroids. CONCLUSIONS Hydralazine is commonly prescribed to treat hypertension. Healthcare providers should be aware of potentially severe hydralazine-induced ANCA-associated vasculitis, which can present with various clinical manifestations. Serologic studies have indicated that it has features that overlap with lupus. Biopsy is helpful for making a definitive diagnosis and developing individual treatment plans. Early diagnosis, cessation of the offending drug, and initiation of immunosuppressive therapy are key for favorable prognosis.

Crohn's-like Enteritis in X-Linked Agammaglobulinemia: A Case Series and Systematic Review.

BACKGROUND: X-linked agammaglobulinemia (XLA) is an inherited primary immunodeficiency that usually manifests clinically with recurrent sinopulmonary infections. Gastrointestinal manifestations are mostly driven by acute infections and disturbed mucosal immunity, but there is a notable prevalence of inflammatory bowel disease (IBD). Differentiating between XLA-associated enteritis, which can originate from recurrent infections, and IBD can be diagnostically and therapeutically challenging. OBJECTIVE: This study presents a critical appraisal of the clinical, radiological, endoscopic, and histological features associated with XLA-associated Crohn disease (CD)-like enteritis. METHODS: We report 3 cases and performed a systematic review of the literature describing the diagnoses and outcomes. RESULTS: An XLA-related enteropathy presented in adolescence with an ileocolonic CD-like phenotype without perianal disease. Abdominal pain, noninfectious diarrhea, and weight loss were the most common symptoms. Imaging and endoscopic findings closely resemble CD. However, histologically, it presents without nodular lymphoid hyperplasia and only 2 studies reported the presence of granulomas. In addition, in XLA-associated enteritis, immunohistochemistry showed the absence or marked reduction in B cells and plasma cells. CONCLUSIONS: An XLA-associated enteritis is a distinct pathological process that presents clinically in a manner similar to ileocolonic CD. It is important to evaluate for infectious diarrhea, which is common in XLA and can mimic IBD clinically. Complete multidisciplinary evaluation is, therefore, recommended for XLA patients with persistent gastrointestinal symptoms. Although more research is needed, therapeutic selection for XLA-associated enteritis is like that of IBD, and the possible risk of drug interactions and complications from increasing immunosuppression should be considered.

EpCam is required for maintaining the integrity of the biliary epithelium.

BACKGROUND & AIMS: Tufting enteropathy (TE) is a rare congenital disorder often caused by mutations in the gene encoding epithelial cell adhesion molecule (EpCam). The disease leads to diarrhoea, intestinal failure and dependence on total parenteral nutrition (TPN). These patients often have liver impairments, but the pathology and mechanism of the damage are not well understood. We evaluated liver biopsies from TE patients to understand the pathophysiology. METHODS: We identified three patients with TE who underwent liver biopsy. Two normal controls and 45 patients on TPN secondary to short gut syndrome were selected for comparison (five were age- and TPN duration matched to the TE patients). RESULTS: We found that all TE patients showed a complete loss of EpCam expression in enterocytes and biliary epithelial cells, while the normal and TPN groups show basolateral expression. Histologically TE patients showed ductopenia, which was not seen in control groups. E-cadherin and ß-catenin are normally located along the lateral membrane of biliary epithelial cells. However, they were relocated to the apical membrane in TE patients, indicating a defect in the apical-basal polarity of cholangiocytes. We examined hepatic reparative cells and found near absence of hepatic progenitor cells and intermediate hepatobiliary cells with mild reactive ductular cells in TE patients. CONCLUSION: Our findings show that TE is associated with disrupted polarity of cholangiocyte and ductopenia. We demonstrate for the first time a role of EpCam in the maintenance of integrity of biliary epithelium. We also provided evidence for a disrupted development of hepatic reparative cells.

Morphology of tumor and nontumor tissue in liver resection specimens for hepatocellular carcinoma following nivolumab therapy.

Nivolumab is an immune checkpoint inhibitor (ICI) approved for treatment of many cancers, including hepatocellular carcinoma (HCC). Liver injury is a known complication in patients treated with nivolumab for nonliver tumors. To date, the morphologic changes to tumor and nontumor liver have not been well-characterized in HCC patients. We identified 20 patients who underwent partial hepatectomy or liver transplantation after receiving nivolumab for HCC. Demographics, laboratory values, and imaging results were obtained from medical records. All available slides from resection specimens were evaluated for tumor necrosis, tumor-infiltrating lymphocytes (TILs), and features of liver injury. Patients in the study included 16 males and 4 females with median age of 56 years. The underlying liver disease was HBV in 10, HCV in 6, and unknown/other in 4. Twelve patients were treated with nivolumab in the neoadjuvant setting, whereas eight were treated with nivolumab, usually along with other therapies, before undergoing liver transplantation. On review of resection specimens, three patients (all from the neoadjuvant group) demonstrated marked treatment response attributable to nivolumab. TILs were present in 17/20 cases. One case that showed treatment response in the neoadjuvant group demonstrated non-necrotizing granulomas and prominent bile duct intraepithelial lymphocytes (IELs) in the nontumor liver. One case from the transplant group showed bile duct damage and prominent ductular reaction after long-term nivolumab therapy (32 doses). Our findings indicate that nivolumab is effective in a subset of patients, including in the neoadjuvant setting. Granulomas and bile duct IELs are rare findings in cases treated with nivolumab but, when seen, may indicate potential response to therapy. Bile duct damage and ductular reaction may be manifestations of long-term nivolumab therapy. Future prospective and longitudinal studies with pretreatment tumor biopsies may help identify patients apt to respond to ICI therapy and further characterize patterns of ICI-related liver injury.

Steatohepatitic Variant of Hepatocellular Carcinoma Is Associated With Both Alcoholic Steatohepatitis and Nonalcoholic Steatohepatitis: A Study of 2 Cohorts With Molecular Insights.

Steatohepatitic hepatocellular carcinoma (SH-HCC) is a variant of hepatocellular carcinoma (HCC) with established association with nonalcoholic steatohepatitis (NASH), while its association with alcoholic steatohepatitis (ASH) is unclear. We studied 2 cohorts of patients who underwent resection for HCC in the setting of steatohepatitis. In our Mount Sinai (New York) cohort, we found SH-HCC in 17/24 (71%) patients with NASH and in 14/19 (74%) patients with ASH, while SH-HCC was the predominant tumor morphology in 12/24 (50%) in the NASH group and 9/19 (47%) in the ASH group. Upon review, 12/19 patients diagnosed with ASH also had diabetes and/or a body mass index >30. When these patients were removed, we still found similar rates of SH-HCC (6/7 [86%] showed SH-HCC, while SH-HCC was predominant in 3/7 [43%]. Interestingly, glycogenated hepatocyte nuclei were seen in the nontumor liver in 4/7 (57%) of these cases. In our Japan cohort, we also found similar rates of SH-HCC in NASH and ASH patients with HCC, 15/58 (26%), and 16/45 (36%), respectively. We determined molecular subclassification of tumors from the Japan cohort and found no difference in the distribution of S1, S2 and S3 subclasses among the ASH and NASH groups, though, among cases of SH-HCC, there was a trend toward an association of ASH with S1 (P=0.054) and NASH with S3 (P=0.052). Our study shows that SH-HCC is common in both ASH and NASH and that both underlying liver diseases produce tumors with similar molecular profiles, though different pathways may underlie the development of SH-HCC in ASH versus NASH.

Human Papillomavirus (HPV69/HPV73) Coinfection associated with Simultaneous Squamous Cell Carcinoma of the Anus and Presumed Lung Metastasis.

BACKGROUND: Human papillomaviruses (HPVs) have been linked to a variety of human cancers. As the landscape of HPV-related neoplasia continues to expand, uncommon and rare HPV genotypes have also started to emerge. Host-virus interplay is recognized as a key driver in HPV carcinogenesis, with host immune status, virus genetic variants and coinfection highly influencing the dynamics of malignant transformation. Immunosuppression and tissue tropism are also known to influence HPV pathogenesis. METHODS: Herein, we present a case of a patient who, in the setting of HIV positivity, developed anal squamous cell carcinoma associated with HPV69 and later developed squamous cell carcinoma in the lungs, clinically presumed to be metastatic disease, associated with HPV73. Consensus PCR screening for HPV was performed by real-time PCR amplification of the L1 gene region, amplification of the E6 regions with High-Resolution Melting Curve Analysis followed by Sanger sequencing confirmation and phylogenetic analysis. RESULTS: Sanger sequencing of the consensus PCR amplification product determined that the anal tissue sample was positive for HPV 69, and the lung tissue sample was positive for HPV 73. CONCLUSIONS: This case underscores the importance of recognizing the emerging role of these rare "possibly carcinogenic" HPV types in human carcinogenesis.

Predictors of Recurrence and Survival in Patients With Surgically Resected Pancreatic Neuroendocrine Tumors.

OBJECTIVE: Given the lack of consensus on surveillance guidelines after pancreatic neuroendocrine tumor (PanNET) resection, we assessed outcomes in a large cohort of patients with nonmetastatic, surgically resected PanNETs. METHODS: Data of patients with PanNETs resected between 1990 and 2017 were retrospectively collected using databases at 3 academic institutions. The National Death Index was queried to determine vital status. Kaplan-Meier analysis was used to estimate recurrence-free survival (RFS) and disease-specific survival (DSS) rates. Variables associated with recurrence and disease-related death were identified through Cox multivariate analyses. RESULTS: Of 307 patients with PanNET who underwent resection, recurrence occurred in 79 (26%) of patients. For stage I and II disease, 5-year RFS rates were 90% and 43%, whereas 5-year DSS rates were 98% and 86% (P < 0.0001 and P = 0.0038, respectively). For grades 1, 2, and 3 disease, 5-year RFS rates were 87%, 49%, and 18%, and 5-year DSS rates were 98%, 89%, and 51% (P < 0.0001 for both). Stage II, grade 2, and grade 3 disease were each associated with increased recurrence and disease-specific death. CONCLUSIONS: Stage and grade are important prognostic factors that should be utilized to tailor postsurgical surveillance after curative resection of PanNET.

Intratumoral heterogeneity and clonal evolution in liver cancer.

Clonal evolution of a tumor ecosystem depends on different selection pressures that are principally immune and treatment mediated. We integrate RNA-seq, DNA sequencing, TCR-seq and SNP array data across multiple regions of liver cancer specimens to map spatio-temporal interactions between cancer and immune cells. We investigate how these interactions reflect intra-tumor heterogeneity (ITH) by correlating regional neo-epitope and viral antigen burden with the regional adaptive immune response. Regional expression of passenger mutations dominantly recruits adaptive responses as opposed to hepatitis B virus and cancer-testis antigens. We detect different clonal expansion of the adaptive immune system in distant regions of the same tumor. An ITH-based gene signature improves single-biopsy patient survival predictions and an expression survey of 38,553 single cells across 7 regions of 2 patients further reveals heterogeneity in liver cancer. These data quantify transcriptomic ITH and how the different components of the HCC ecosystem interact during cancer evolution.

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

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.