Mimickers of immunoglobulin G4-related hepatobiliary disease on biopsy.

With the growing recognition of IgG4-related hepatobiliary disease, establishing a definitive diagnosis relies mainly on a combination of clinical findings, serological markers, and imaging modalities. However, the role of histopathological evaluation remains indispensable, particularly in cases necessitating differential diagnosis or malignancy exclusion. While diagnosing IgG4-related hepatobiliary disease through surgical resection specimens is often straightforward, pathologists encounter substantial challenges when evaluating biopsies. The increasing rarity of surgical interventions exacerbates this due to improved disease recognition and suspicion. Numerous confounding factors, including the absence of the characteristic histologic features, limited tissue sample size, biopsy artifacts, and the limited value of IgG4 counts, further complicate the diagnostic process. Additionally, many other disorders exhibit clinical and histological features that overlap with IgG4-related disease, intensifying the complexity of interpreting biopsy specimens. This article explores the clinical and histomorphologic features of IgG4-related hepatobiliary disease and its potential mimickers. It offers valuable insights for pathologists and clinicians when confronted with biopsy specimens from hepatobiliary organs.

Interleukin 21 Drives a Hypermetabolic State and CD4+ T-Cell-Associated Pathogenicity in Chronic Intestinal Inflammation.

BACKGROUND & AIMS: Incapacitated regulatory T cells (Tregs) contribute to immune-mediated diseases. Inflammatory Tregs are evident during human inflammatory bowel disease; however, mechanisms driving the development of these cells and their function are not well understood. Therefore, we investigated the role of cellular metabolism in Tregs relevant to gut homeostasis. METHODS: Using human Tregs, we performed mitochondrial ultrastructural studies via electron microscopy and confocal imaging, biochemical and protein analyses using proximity ligation assay, immunoblotting, mass cytometry and fluorescence-activated cell sorting, metabolomics, gene expression analysis, and real-time metabolic profiling utilizing the Seahorse XF analyzer. We used a Crohn's disease single-cell RNA sequencing dataset to infer the therapeutic relevance of targeting metabolic pathways in inflammatory Tregs. We examined the superior functionality of genetically modified Tregs in CD4+ T-cell-induced murine colitis models. RESULTS: Mitochondria-endoplasmic reticulum appositions, known to mediate pyruvate entry into mitochondria via voltage-dependent anion channel 1 (VDAC1), are abundant in Tregs. VDAC1 inhibition perturbed pyruvate metabolism, eliciting sensitization to other inflammatory signals reversible by membrane-permeable methyl pyruvate supplementation. Notably, interleukin (IL) 21 diminished mitochondria-endoplasmic reticulum appositions, resulting in enhanced enzymatic function of glycogen synthase kinase 3 ß, a putative negative regulator of VDAC1, and a hypermetabolic state that amplified Treg inflammatory response. Methyl pyruvate and glycogen synthase kinase 3 ß pharmacologic inhibitor (LY2090314) reversed IL21-induced metabolic rewiring and inflammatory state. Moreover, IL21-induced metabolic genes in Tregs in vitro were enriched in human Crohn's disease intestinal Tregs. Adoptively transferred Il21r-/- Tregs efficiently rescued murine colitis in contrast to wild-type Tregs. CONCLUSIONS: IL21 triggers metabolic dysfunction associated with Treg inflammatory response. Inhibiting IL21-induced metabolism in Tregs may mitigate CD4+ T-cell-driven chronic intestinal inflammation.

Clinical Outcomes After Endoscopic Management of Low-Risk and High-Risk T1a Esophageal Adenocarcinoma: A Multicenter Study.

INTRODUCTION: Endoscopic eradication therapy (EET) is standard of care for T1a esophageal adenocarcinoma (EAC). However, data on outcomes in high-risk T1a EAC are limited. We assessed and compared outcomes after EET of low-risk and high-risk T1a EAC, including intraluminal EAC recurrence, extraesophageal metastases, and overall survival. METHODS: Patients who underwent EET for T1a EAC at 3 referral Barrett's esophagus endotherapy units between 1996 and 2022 were included. Patients with submucosal invasion, positive deep margins, or metastases at initial diagnosis were excluded. High-risk T1a EAC was defined as T1a EAC with poor differentiation and/or lymphovascular invasion, with low-risk disease being defined without these features. All pathology was systematically assessed by expert gastrointestinal pathologists. Baseline and follow-up endoscopy and pathology data were abstracted. Time-to-event analyses were performed to compare outcomes between groups. RESULTS: One hundred eighty-eight patients with T1a EAC were included (high risk, n = 45; low risk, n = 143) with a median age of 70 years, and 84% were men. Groups were comparable for age, sex, Barrett's esophagus length, lesion size, and EET technique. Rates of delayed extraesophageal metastases (11.1% vs 1.4%) were significantly higher in the high-risk group ( P = 0.02). There was no significant difference in the rates of intraluminal EAC recurrence ( P = 0.79) and overall survival ( P = 0.73) between the 2 groups. DISCUSSION: Patients with high-risk T1a EAC undergoing successful EET had a substantially higher rate of extraesophageal metastases compared with those with low-risk T1a EAC on long-term follow-up. These data should be factored into discussions with patients while selecting treatment approaches. Additional prospective data in this area are critical.

Reversibility and developmental neuropathology of linear nevus sebaceous syndrome caused by dysregulation of the RAS pathway.

Linear nevus sebaceous syndrome (LNSS) is a neurocutaneous disorder caused by somatic gain-of-function mutations in KRAS or HRAS. LNSS brains have neurodevelopmental defects, including cerebral defects and epilepsy; however, its pathological mechanism and potentials for treatment are largely unclear. We show that introduction of KRASG12V in the developing mouse cortex results in subcortical nodular heterotopia and enhanced excitability, recapitulating major pathological manifestations of LNSS. Moreover, we show that decreased firing frequency of inhibitory neurons without KRASG12V expression leads to disrupted excitation and inhibition balance. Transcriptional profiling after destabilization domain-mediated clearance of KRASG12V in human neural progenitors and differentiating neurons identifies reversible functional networks underlying LNSS. Neurons expressing KRASG12V show molecular changes associated with delayed neuronal maturation, most of which are restored by KRASG12V clearance. These findings provide insights into the molecular networks underlying the reversibility of some of the neuropathologies observed in LNSS caused by dysregulation of the RAS pathway.

Histologic evaluation in the diagnosis and management of celiac disease: practical challenges, current best practice recommendations and beyond.

Celiac disease (CD) is an immunoallergic enteropathy affecting genetically susceptible individuals upon dietary exposure to gluten. In current clinical practice, the diagnosis of CD is based on a combination of clinical, serologic, and histologic factors with the possible exception of pediatric patients. Histopathologic evaluation of small intestinal tissue plays a critical role in the disease diagnosis and management, despite many practical challenges. Recently published best practice guidelines help to standardize biopsy sample procurement, tissue preparation, histology interpretation, and reporting, to optimize patient care. In addition, an increasing demand for monitoring the disease course, particularly demonstrating the efficacy of dietary and nondietary interventions for disease management, calls for the use of quantitative histology. With the advent of a gradual transition toward digital pathology in routine diagnostic practice, quantitative histopathologic evaluation in CD shows a promising future.

Large B-cell lymphoma with IRF4 gene rearrangements: Differences in clinicopathologic, immunophenotypic and cytogenetic features between pediatric and adult patients.

Large B-cell lymphoma (LBL) with interferon regulatory factor 4 (IRF4) rearrangement (LBL-IRF4), a provisional entity in the 2017 WHO classification, primarily arises in children and young adults and has a favorable prognosis. However, few studies have addressed the clinicopathologic and cytogenetic features of older adults with IRF4-rearranged B-cell lymphomas. From a database of all internal and external cases (08/01/2015 to 12/01/2020) on which interphase fluorescence in situ hybridization was performed at the Mayo Clinic, we identified 43 patients with B-cell lymphoma and IRF4 rearrangements. Consistent features included large cell morphology, expression of CD20, BCL6, and MUM1, and absence of MYC-R. All pediatric cases (n = 12) arose in Waldeyer's ring (WR), cervical lymph node (CLN), or bowel, and lacked BCL6-R and BCL2-R, and all but one showed classic morphology. Adults with WR, CLN, or bowel involvement (n = 22) were younger (median 32 years). Their lymphomas resembled pediatric cases morphologically and lacked BCL2-R, although 30% harbored BCL6-R (P = 0.043). Lymphomas that involved other anatomic sites (n = 9) arose in older adults (median 68 years; P = 0.002) and often showed atypical morphology (P < 0.001). All lacked BCL6-R and 2 of 4 harbored BCL2-R (P < 0.001). LBL-IRF4 - arising in WR, CLN, or bowel may represent a distinct clinicopathologic entity characterized by pediatric/younger adult age, classic morphology, and lack of BCL2-R. In contrast, B-cell lymphomas with IRF4-R that arise in other sites usually involve older adults, are often morphologically atypical and/or harbor BCL2-R, and may be more akin to diffuse LBL, not otherwise specified.

Solitary Involvement of the Liver: A Rare Manifestation of Langerhans Cell Histiocytosis.

BACKGROUND Langerhans cell histiocytosis (LCH) is a rare condition caused by a neoplastic proliferation of myeloid cells. It can present as a single-system or multi-system disorder. Worse prognosis is associated with the hematopoietic system (spleen, liver, bone marrow), which is routinely observed in multi-system disease. Because of the varied presentation of this disorder, diagnosis can be difficult, and therefore suitable treatment can be delayed. CASE REPORT We report a case of hepatic LCH in a 51-year-old man who presented with epigastric abdominal pain, with imaging demonstrating a hepatic nodule. A low ejection fraction on hepatobiliary iminodiacetic acid scan suggested chronic cholecystitis. Therefore, the patient underwent a cholecystectomy for biliary dyskinesia, in which liver nodules were noted, and biopsies were taken. The biopsies demonstrated characteristic findings of LCH along with positive immunohistochemical markers and negative BRAF V600E mutation. Radiologic and pathologic findings were consistent with LCH within the liver, associated with bile duct injury and mild biliary obstruction. The patient was placed on a cladribine regimen. His abdominal pain improved. CONCLUSIONS LCH limited to the liver is uncommon and can appear as chronic biliary disease, as was suspected in this case. Despite the poor prognosis of hematopoietic LCH, early recognition can lead to better outcome and chemotherapy susceptibility. This patient was most likely in the first stage of liver LCH, given his presentation, which could have aided his response to chemotherapy. The lack of BRAF V600E mutation could have contributed to a positive prognosis and more possibilities for treatment.

MRI-detected extramural venous invasion of rectal cancer: Multimodality performance and implications at baseline imaging and after neoadjuvant therapy.

MRI is routinely used for rectal cancer staging to evaluate tumor extent and to inform decision-making regarding surgical planning and the need for neoadjuvant and adjuvant therapy. Extramural venous invasion (EMVI), which is intravenous tumor extension beyond the rectal wall on histopathology, is a predictor for worse prognosis. T2-weighted images (T2WI) demonstrate EMVI as a nodular-, bead-, or worm-shaped structure of intermediate T2 signal with irregular margins that arises from the primary tumor. Correlative diffusion-weighted images demonstrate intermediate to high signal corresponding to EMVI, and contrast enhanced T1-weighted images demonstrate tumor signal intensity in or around vessels. Diffusion-weighted and post contrast images may increase diagnostic performance but decrease inter-observer agreement. CT may also demonstrate obvious EMVI and is potentially useful in patients with a contraindication for MRI. This article aims to review the spectrum of imaging findings of EMVI of rectal cancer on MRI and CT, to summarize the diagnostic accuracy and inter-observer agreement of imaging modalities for its presence, to review other rectal neoplasms that may cause EMVI, and to discuss the clinical significance and role of MRI-detected EMVI in staging and restaging clinical scenarios.

Mesenteric and Retroperitoneal Mucinous Cystic Neoplasms: A Case Series.

Aims. Mucinous cystic neoplasms (MCNs) are cystic neoplasms with mucinous epithelium surrounded by ovarian-like stroma. Extraovarian MCN occurring in the liver and pancreas have been well characterized. However, only rare case reports of MCN arising outside of these locations have been reported. MCNs arising in unusual locations should enter the differential diagnosis of mucinous intra-abdominal tumors and must be distinguished from more common mimics. Therefore, we aimed to examine a series of MCNs of the retroperitoneum and mesentery to characterize the clinicopathologic features of this entity. Methods and results. Seven MCNs arising in the abdominal mesentery or retroperitoneum were retrospectively identified. A clinicopathologic, histologic, and immunohistochemical (keratin 7, keratin 19, keratin 20, calretinin, inhibin-α, steroidogenic factor-1 (SF-1), estrogen receptor (ER), progesterone receptor (PR), PAX8, CDX2, and CD10) analysis was performed. All 7 MCNs were from females with a median age of 41 years old and a median size of 8 cm. All cases demonstrated mucinous with or without concomitant non-mucinous epithelium overlying spindle cell ovarian-like stroma. Luteinized cells were noted. The epithelium was positive for keratin 7 and keratin 19 in all 7 cases, while the stroma expressed ER, PR, and SF-1 in all cases stained. Calretinin was focally positive in the stroma of 3 of 7 cases, while inhibin-α was focally expressed in 5 of 6 cases. Conclusions. These results highlight the clinicopathologic, histologic, and immunophenotypic similarities between MCNs of the mesentery, retroperitoneum, pancreas, and liver. Overlapping features suggest a common histogenesis for all MCNs, which could include periductal fetal mesenchyme, aberrant migration of primordial germ cells, or abnormal differentiation or metaplasia of the embryonic coelomic epithelium.

The enhancer activity of long interspersed nuclear element derived microRNA 625 induced by NF-κB.

Transposable elements (TEs) are DNA sequences that cut or introduced into the genome, and they represent a massive portion of the human genome. TEs generate a considerable number of microRNAs (miRNAs) are derived from TEs (MDTEs). Numerous miRNAs are related to cancer, and hsa-miRNA-625 is a well-known oncomiR derived from long interspersed nuclear elements (LINEs). The relative expression of hsa-miRNA-625-5p differs in humans, chimpanzees, crab-eating monkeys, and mice, and four primers were designed against the 3'UTR of GATAD2B to analyze the different quantities of canonical binding sites and the location of miRNA binding sites. Luciferase assay was performed to score for the interaction between hsa-miRNA-625 and the 3'UTR of GATAD2B, while blocking NF-κB. In summary, the different numbers of canonical binding sites and the locations of miRNA binding sites affect gene expression, and NF-κB induces the enhancer activity of hsa-miRNA-625-5p by sharing the binding sites.

Liver manifestations in a cohort of 39 patients with congenital disorders of glycosylation: pin-pointing the characteristics of liver injury and proposing recommendations for follow-up.

BACKGROUND: The congenital disorders of glycosylation (CDG) are a heterogeneous group of rare metabolic diseases with multi-system involvement. The liver phenotype of CDG varies not only according to the specific disorder, but also from patient to patient. In this study, we sought to identify common patterns of liver injury among patients with a broad spectrum of CDG, and to provide recommendations for follow-up in clinical practice. METHODS: Patients were enrolled in the Frontiers in Congenital Disorders of Glycosylation natural history study. We analyzed clinical history, molecular genetics, serum markers of liver injury, liver ultrasonography and transient elastography, liver histopathology (when available), and clinical scores of 39 patients with 16 different CDG types (PMM2-CDG, n = 19), with a median age of 7 years (range: 10 months to 65 years). For patients with disorders which are treatable by specific interventions, we have added a description of liver parameters on treatment. RESULTS: Our principal findings are (1) there is a clear pattern in the evolution of the hepatocellular injury markers alanine aminotransferase and aspartate aminotransferase according to age, especially in PMM2-CDG patients but also in other CDG-I, and that the cholangiocellular injury marker gamma-glutamyltransferase is not elevated in most patients, pointing to an exclusive hepatocellular origin of injury; (2) there is a dissociation between liver ultrasound and transient elastography regarding signs of liver fibrosis; (3) histopathological findings in liver tissue of PMM2-CDG patients include cytoplasmic glycogen deposits; and (4) most CDG types show more than one type of liver injury. CONCLUSIONS: Based on these findings, we recommend that all CDG patients have regular systematic, comprehensive screening for liver disease, including physical examination (for hepatomegaly and signs of liver failure), laboratory tests (serum alanine aminotransferase and aspartate aminotransferase), liver ultrasound (for steatosis and liver tumors), and liver elastography (for fibrosis).

Molecular Genetic Landscape of Sclerosing Pneumocytomas.

OBJECTIVES: Sclerosing pneumocytomas are rare pulmonary neoplasms that are typically benign. However, rare patients experience progressive disease, and therapy targeting specific genetic underpinnings could be an attractive therapeutic option. Recent studies have found recurrent AKT 1 mutations in sclerosing pneumocytoma, but little is known about whether oncogenic fusion genes may also be present. METHODS: To better understand the genetic background, 10 sclerosing pneumocytomas were subjected to next-generation sequencing cancer mutation panel testing (n = 9) and/or RNA sequencing (n = 3). The patients were all women (average age, 47 years; range, 17-74 years). RESULTS: Eight patients had solitary sclerosing pneumocytomas, while one had two tumors, and one had many bilateral tumors. Recurrent mutations were noted in genes involved in the mTOR pathway, including AKT1, PIK3R1, and PTEN. AKT1 alterations were particularly common, present in 78%. No recurrent genetic fusions were identified. The patient in our study with multiple bilateral lesions was treated with the mammalian target of rapamycin (mTOR) inhibitor everolimus, with no objective radiographic evidence of treatment response after 4 months. CONCLUSIONS: Our data further support that abnormal activation of the mTOR pathway is a consistent genetic event in sclerosing pneumocytoma. This warrants further exploration to determine if mTOR pathway inhibitors may be effective in patients with metastatic or recurrent disease.

Acute Liver Rejection in a Multiple Myeloma Patient Treated with Lenalidomide.

Herein we present a patient that underwent a liver transplant due to primary biliary cholangitis (PBC) and after 9 years developed multiple myeloma. Following the cessation of mycophenolate mofetil and 2 weeks after lenalidomide treatment was started, the patient experienced acute cellular rejection. The patient recovered after treatment with corticosteroids, resumption of mycophenolate mofetil, and cessation of lenalidomide. Lenalidomide-associated allograft rejection has been reported in other organs. However, this is the first case report of liver rejection induced by lenalidomide.

Aberrant keratin expression is common in primary hepatic malignant vascular tumors: A potential diagnostic pitfall.

Malignant vascular neoplasms such as epithelioid hemangioendothelioma (EHE) and angiosarcoma (AS) can arise within the liver. The aim of this study was to study the expression of keratins CK7, AE1/AE3 and OSCAR in primary hepatic EHE and AS. 9 cases of hepatic EHE and 13 cases of hepatic AS were stained with ERG, CK7, keratin AE1/AE3 and keratin OSCAR. Their expression was graded as 1+ (1-25% of tumor cells positive), 2+ (26-50%), 3+ (51-75%) or 4+ (>75%). ERG was positive in all 9 (100%) EHEs and all 13 (100%) ASs. CK7 was positive in 5/9 (56%) EHEs (2, 1+; 1, 2+; 1, 3+; 1, 4+) and 1/13 (8%) AS (2+). Keratin OSCAR was positive in 6/9 (67%) EHEs (5, 1+; 1, 2+) and 4/13 (31%) ASs (2, 1+; 1, 2+; 1, 4+). Keratin AE1/AE3 was positive in 6/9 (67%) EHEs (3, 1+; 3; 2+) and 4/13 (31%) ASs (2, 1+; 1, 2+; 1, 4+). Overall, 6/ 9 (67%) EHEs were positive for at least one keratin marker, of which 5 were positive for all 3 keratins (AE1/AE3, OSCAR and CK7) while 1 was positive only for 2 keratins (OSCAR and AE1/AE3). 4/13 (31%) of ASs were positive for both keratins OSCAR and AE1/AE3, of which 1 case was also positive for CK7. Aberrant keratin expression is common in primary hepatic EHEs (67%) and ASs (31%). Awareness of this diagnostic pitfall is important for avoiding misdiagnosis of these primary hepatic malignant vascular tumors as carcinomas.

Carboxypeptidase A1 and regenerating islet-derived 1α as new markers for pancreatic acinar cell carcinoma.

Acinar cell carcinoma (ACC) is a rare tumor that differentiates toward pancreatic acinar cells and shows evidence of pancreatic enzyme production. Mixed acinar-neuroendocrine carcinoma (MANC) is defined as having more than 30% of both acinar and neuroendocrine cell types as per immunohistochemistry analysis. Trypsin is currently the most commonly used stain for acinar differentiation. In this study, we investigate the utility of two novel markers, carboxypeptidase A1 (CPA1) and regenerating islet-derived 1α (REG1a), in diagnosing ACC/MANC. Immunohistochemical staining for CPA1 and REG1a was performed on 14 cases of ACC and 5 cases of MANC as well as on 80 other pancreatic tumors including 20 cases each of ductal adenocarcinoma, well-differentiated neuroendocrine tumor, mucinous cystic neoplasm, and solid pseudopapillary tumor. All ACCs and MANCs were positive for CPA1 (all diffuse) and REG1a (12 diffuse, 4 patchy, and 3 focal). A diffuse or patchy staining pattern was significantly more common in ACC/MANC cases (100% diffuse/patchy for CPA1 and 84% for REG1a) than in other pancreatic tumors (5% diffuse/patchy for CPA1 and 7.5% for REG1a), with a P-value of <0.0001 for both CPA1 and REG1a. The sensitivity and specificity of diffuse/patchy staining for CPA1 and REG1a in diagnosing pancreatic ACC/MANC were 100% and 95% for CPA1 and 84% and 93% for REG1a, respectively. In conclusion, CPA1 and REG1a are sensitive markers for ACC that can be used as additional acinar cell differentiation markers to help in the diagnosis of pancreatic ACC and MANC. A negative result for CPA1 virtually excludes ACC/MANC.

Enhancer Function of MicroRNA-3681 Derived from Long Terminal Repeats Represses the Activity of Variable Number Tandem Repeats in the 3' UTR of SHISA7.

microRNAs (miRNAs) are non-coding RNA molecules involved in the regulation of gene expression. miRNAs inhibit gene expression by binding to the 3' untranslated region (UTR) of their target gene. miRNAs can originate from transposable elements (TEs), which comprise approximately half of the eukaryotic genome and one type of TE, called the long terminal repeat (LTR) is found in class of retrotransposons. Amongst the miRNAs derived from LTR, hsa-miR-3681 was chosen and analyzed using bioinformatics tools and experimental analysis. Studies on hsa-miR-3681 have been scarce and this study provides the relative expression analysis of hsa-miR-3681-5p from humans, chimpanzees, crab-eating monkeys, and mice. Luciferase assay for hsa-miR-3681-5p and its target gene SHISA7 supports our hypothesis that the number of miRNA binding sites affects target gene expression. Especially, the variable number tandem repeat (VNTR) and hsa-miR-3681-5p share the binding sites in the 3' UTR of SHISA7, which leads the enhancer function of hsa-miR-3681-5p to inhibit the activity of VNTR. In conclusion, hsa-miR-3681-5p acts as a super-enhancer and the enhancer function of hsa-miR-3681-5p acts as a repressor of VNTR activity in the 3' UTR of SHISA7.

Neuroendocrine Cells Are Commonly Absent in the Intestinal Crypts in Autoimmune Enteropathy.

The absence of neuroendocrine (NE) cells in the intestinal mucosa in autoimmune enteropathy (AIE) has been occasionally reported. However, the status of NE cells has not been studied in detail in AIE. Small bowel and colonic biopsies were retrospectively retrieved from 18 AIE patients (26 baseline [18 small bowel and 8 colon]; and 15 follow-up [11 duodenum and 4 colon] biopsies in 11 patients). Thirty-three common variable immunodeficiency (CVID) patients (30 small bowel and 16 colon), 15 inflammatory bowel disease patients (5 duodenum and 10 colon), 13 immunoglobulinA deficiency patients (13 duodenum and 5 colon), and 10 normal controls (5 colon and 5 duodenum) were selected as control groups. Histologic features (villous atrophy, intraepithelial lymphocytosis, acute inflammation, crypt apoptosis, and absence or presence of goblet cells, Paneth cells and plasma cells) were recorded. Chromogranin immunostain was performed and chromogranin-positive NE cells were counted per 10 consecutive, well-oriented crypts. On the basis of the number of chromogranin-positive NE cells, cases were graded as being absent (≤3 NE cells), markedly decreased (≤15), and intact (>15). The NE cell status correlated with histologic features. The median age of 18 AIE patients was 38.5 years (range: 11 to 74 y) and 14 patients were male. Fourteen of 18 (78%) patients showed loss (absent or markedly decreased) of NE cells in the small bowel and/or colon in the baseline biopsies including 12 (of 18) small bowel and 6 (of 8) colon biopsies. Follow-up biopsy was available in 11 patients. Six of 7 (85%) patients who showed loss of NE cells in the baseline biopsies regained NE cells in the follow-up biopsies, and 1 patient continued to show loss of NE cells. Four patients who showed intact NE cells in the baseline remained unchanged in the follow-up. Among the control groups, 3 of 33 (9%) CVID patients showed loss of NE cells. NE cells were not lost in the biopsies of all 15 and 13 patients with inflammatory bowel disease and immunoglobulinA deficiency, respectively, or the 10 normal controls. In all 41 biopsies (26 baseline plus 15 follow-up) with AIE, NE cell loss was significantly associated with increased crypt apoptosis and loss of goblet cells (P=0.001, both) but not with other histologic findings. In conclusion, our study suggests that NE cells may also be the target cells in AIE and commonly lost in the intestinal crypts in AIE, and consequently loss of NE cells can be used as an adjunct histologic feature for diagnosis of AIE.

Increased Plasma Cells and Decreased B-cells in Tumor Infiltrating Lymphocytes are Associated with Worse Survival in Lung Adenocarcinomas.

INTRODUCTION: Clinical significance of tumor-infiltrating plasma cells and B-cells in lung adenocarcinoma is not well known. METHODS: CD3, CD20 and MUM1 immunostains were performed on representative tumor blocks selected from 120 consecutive lung adenocarcinoma cases treated by surgical resection at Mayo Clinic Rochester. CD3+ T-cells, CD20+ B-cells, and MUM1+ plasma cells were enumerated separately in the intraepithelial (IE) compartment and the stroma (ST) by digital image analyses using whole sections. Measured tumor-infiltrating plasma cells and B-cells were correlated with patient's overall survival (OS) using Cox proportional hazards analysis. RESULTS: Median age of patients was 69 years (range, 46-91 years) and 52 were male. Median numbers (interquartile range) of CD20+ B-cells per 1mm2 of tumor area (IE plus ST) and IE compartment within tumor area were 590 (224-1276) and 101 (38-109), respectively; the corresponding numbers of MUM1+ plasma cells were 298 (180-605), and 67 (22-145), respectively. The proportion of MUM1+ plasma cell among all TILs (MUM1+ cells/[CD3+ cells +CD20+ cells+MUM1+ cells] × 100) ranged 1%-59% (median13%) in the tumor area and showed a significant association with OS by univariate Cox analysis (negative correlation with hazard ratio (HR)=12.50 [95% confidence interval (CI), 1.75-89.27]). There was a significant association between IE CD20+ B-cells and the patient's OS in univariate analysis (positive correlation with HR=0.81 [95% CI, 0.68-0.96]). Both parameters remained significant by multivariate analysis. CONCLUSION: High plasma cell % among TILs in the tumor area and low IE B-cell count were associated with worse prognosis in lung adenocarcinoma patients.

Regenerative hepatic pseudotumor: a new pseudotumor of the liver.

Cases of new pseudotumors of the liver were collected from multiple medical centers. Four resection and 4 biopsy specimens were collected, including 4 women and 4 men at an average age of 48 ± 15 years (range: 28-73 years). The lesions were visible on imaging but were either ill-defined or had indeterminate features for characterization. They ranged in size from 2 to 9 cm and were multiple in five cases. The resection specimens showed lesions that had vague borders but were visible in juxtaposition to the normal liver on gross examination. Histologically, the lesions also had ill-defined borders and were composed of benign reactive liver parenchyma. Central vein thrombi were seen in 5 cases, and portal vein thrombi, in 2 cases. These vascular changes were associated reactive parenchymal changes including sinusoidal dilation, patchy bile ductular proliferation, and portal vein abnormalities. All lesions lacked the histological findings of hepatic adenomas, focal nodular hyperplasia, or other known tumors and pseudotumors of the liver. In summary, this study provides a detailed description of a new pseudotumor of the liver: a reactive, hyperplastic mass-like lesion that forms in association with localized vascular thrombi, for which we propose the term regenerative hepatic pseudotumor. This lesion can closely mimic other benign or malignant hepatic tumors on imaging and histology.

Tumor immune response and immunotherapy in gastric cancer.

Remarkable developments in immuno-oncology have changed the landscape of gastric cancer (GC) treatment. Because immunotherapy intervenes with tumor immune response rather than directly targeting tumor cells, it is important to develop a greater understanding of tumor immunity. This review paper summarizes the tumor immune reaction and immune escape mechanisms while focusing on the role of T cells and their co-inhibitory signals, such as the immune checkpoint molecules programmed death-1 and programmed deathligand 1 (PD-L1). This paper also describes past clinical trials of immunotherapy for patients with GC and details their clinical implications. Strong predictive markers are essential to improve response to immunotherapy. Microsatellite instability, Epstein-Barr virus, PD-L1 expression, and tumor mutational burden are now regarded as potent predictive markers for immunotherapy in patients with GC. Novel immunotherapy and combination therapy targeting new immune checkpoint molecules such as lymphocyte-activation gene 3, T cell immunoglobulin, and mucin domain containing-3, and indoleamine 2,3-dioxygenase have been suggested, and trials are ongoing to evaluate their safety and efficacy. Immunotherapy is an important treatment option for patients with GC and has great potential for improving patient outcome, and further research in immuno-oncology should be carried out.