Neutrophilic inflammation in gallbladder carcinoma correlates with patient survival: A case-control study.

Gallbladder carcinoma is an uncommon malignancy with an overall 5-year survival of less than 5%. Gallbladder carcinoma has been strongly linked with cholelithiasis and chronic inflammation. Case reports and series have described cholecystitis with acute (neutrophilic) inflammation in association with gallbladder carcinoma, although a clear relationship to patient outcome has not been established. Our series included 8 cases of gallbladder carcinoma with high tumor-associated neutrophils (>25 per high power field) that were associated with shorter patient survival (Cox regression coefficient 6.2, p = 0.004) than age- and stage-matched controls. High tumor-associated neutrophils were not associated with gallbladder rupture/perforation or increased bacterial load measured by 16S PCR. Neutrophilic inflammation with gallbladder carcinoma correlates to shorter survival, independent of patient age and stage of carcinoma. The findings suggest that the degree of neutrophilic inflammation may have prognostic significance in specimens from patients with gallbladder carcinoma after cholecystectomy. Further studies with larger case numbers are needed to confirm and generalize these findings.

Establishment of Chronic Typhoid Infection in a Mouse Carriage Model Involves a Type 2 Immune Shift and T and B Cell Recruitment to the Gallbladder.

Typhoid fever, caused primarily by Salmonella enterica serovar Typhi (S Typhi), is a life-threatening systemic disease responsible for significant morbidity and mortality worldwide. Three to 5% of individuals infected with S Typhi become chronic carriers due to bacterial persistence in the gallbladder. We have demonstrated that Salmonella forms biofilms on gallstones to establish gallbladder carriage. However, an in-depth molecular understanding of chronic carriage in the gallbladder, from the perspective of both the pathogen and host, is poorly defined. To examine the dynamics of the gallbladder in response to Salmonella infection, we performed transcriptional profiling in the mouse gallbladder at early (7 days) and chronic (21 days) time points. Transcriptome sequencing (RNA-Seq) revealed a shift from a Th1 proinflammatory response at 7 days postinfection (dpi) toward an anti-inflammatory Th2 response by 21 dpi, characterized by increased levels of immunoglobulins and the Th2 master transcriptional regulator, GATA3. Additionally, bioinformatic analysis predicted the upstream regulation of characteristic Th2 markers, including interleukin-4 (IL-4) and Stat6. Immunohistochemistry and fluorescence-activated cell sorter (FACS) analysis confirmed a significant increase in lymphocytes, including T and B cells, at 21 dpi in mice with gallstones. Interestingly, the levels of Salmonella-specific CD4 T cells were 10-fold higher in the gallbladder of mice with gallstones at 21 dpi. We speculate that the biofilm state allows Salmonella to resist the initial onslaught of the Th1 inflammatory response, while yet undefined events influence a switch in the host immunity toward a more permissive type 2 response, enabling the establishment of chronic infection.IMPORTANCE The existence of chronic typhoid carriers has been in the public eye for over 100 years in part because of the publicity around Typhoid Mary. Additionally, it has been known for decades that the gallbladder is the main site of persistence and recently that gallstones play a key role. Despite this, very little is known about the physiological conditions that allow Salmonella enterica serovar Typhi to persist in the gallbladder. In this study, we analyze the transcriptional profile of the gallbladder in a mouse model of chronic carriage. We found a shift from an early proinflammatory immune response toward a later anti-inflammatory response, which could explain the stalemate that allows Salmonella persistence. Interestingly, we found a 10-fold increase in the number of Salmonella-specific T cells in mice with gallstones. This work moves us closer to understanding the mechanistic basis of chronic carriage, with a goal toward eradication of the disease.

Case series of cancer patients who developed cholecystitis related to immune checkpoint inhibitor treatment.

BACKGROUND: Immune checkpoint inhibitors (ICIs) represent a promising novel class of cancer therapy, but immune-mediated adverse events can complicate ICI treatment. Acute cholecystitis in patients receiving ICI therapy has not been characterized. We aimed to describe the clinical features of patients who developed ICI-related cholecystitis. METHODS: We evaluated a case series of patients at a tertiary cancer center who received ICI therapy and developed cholecystitis, diagnosed by clinical presentation and diagnostic imaging, during 2010-2018. Patients with a history of chronic cholecystitis or other etiologies of acute cholecystitis, such as cholelithiasis, were excluded. A chi-square test was used to compare the frequency of cholecystitis between ICI regimens. Kaplan-Meier and log rank analyses were used to compare survival between subgroups. RESULTS: Of the 4253 patients who received ICIs in the study period, 25 (0.6%) patients developed suspected ICI-related cholecystitis. Alternatively, of the 31,426 cancer-matched patients who received non-ICI therapy, 72 (0.2%) developed acalculous cholecystitis (P < 0.001). Among the 25 included patients, the median time from ICI initiation to cholecystitis was 6 months (range, 0.1-31 months). Fifteen (60%) patients received an inhibitor of programmed death protein 1 (anti-PD-1) or of its ligand (anti-PD-L1) as a single agent, and 10 (40%) patients received an inhibitor of cytotoxic T-lymphocyte associated protein 4 (anti-CTLA-4) therapy alone or combined with anti-PD-1/L1. Anti-CTLA-4 monotherapy was associated with a higher risk of cholecystitis (P = 0.006). ICI therapy was discontinued in 20 patients, in three (12%) as a result of acute cholecystitis. Two (8%) patients developed sepsis, and four (16%) had perforation of the gallbladder wall. Five (20%) patients underwent surgical cholecystectomy, and eight (32%) underwent percutaneous drainage. Five (20%) patients were treated with steroids; two of them required surgery. Ten (40%) patients were able to restart ICI therapy. Patients who received a combination of anti-CTLA-4 and anti-PD-1/L1 had more complications of cholecystitis than did patients who received either agent alone (P = 0.03). CONCLUSIONS: ICI treatment can result in a clinical condition similar to typical acute cholecystitis in a minority of patients. ICI-related cholecystitis should be managed in a similar fashion to typical cholecystitis. The efficacy of steroids for the treatment of ICI-related cholecystitis is unclear.

Biliary Tract Cancer: Implicated Immune-Mediated Pathways and Their Associated Potential Targets.

There is a well-established link between biliary tract cancers (BTC) and chronic inflammatory conditions such as primary sclerosing cholangitis, chronic cholecystitis, chronic cholelithiasis, liver fluke-associated infestations, and chronic viral hepatic infections. These associated risk factors highlight the potential for development of immune-modulatory agents in this poor-prognostic disease group with limited treatment options. Clinical trials have evaluated the role of immune cells, inflammatory biomarkers, vaccines, cytokines, adoptive cell therapy, and immune checkpoint inhibitors in patients with BTC. Although these have demonstrated the importance of the immune environment in BTC, currently none of the immune-based therapies have been approved for use in this disease group. The role of immunomodulatory agents is a developing field and has yet to find its way 'from bench to bedside' in BTC.

The Effect of HLA-DRB1 on Cholecystitis.

BACKGROUND: Cholecystitis is one of the major digestive diseases. Its prevalence is particularly high in some populations. Significant risk factors associated with cholecystitis include age, sex, obesity, diet, parity and type 2 diabetes. OBJECTIVE: To determine the association between HLA-DRB1 and cholecystitis. METHODS: This case-control study included forty Iraqi Arab patients who had cholecystitis with multiple calculi treated by cholecystectomy admitted in the surgical ward at Al-Kindy Teaching Hospital Baghdad between September -2013 to June -2014. The control group consisted of forty healthy volunteers among the staff of Al-Kindy College of Medicine. Control and cholecystitis patients groups were typed for identifying the DRB1* alleles using DNA-based methodology (PCR-SSOP). RESULTS: There was an increased frequency of HLA-DRB1*0301 in patients with cholecystitis compared with healthy controls (p=0.0442, odd ratio=4.1111, 95% CI: 1.0372-16.2949). CONCLUSION: HLA-DRB1*0301, as a genetic factor, seems to have an association with cholecystitis.

Chronic cholecystitis with Cystoisospora belli in an immunocompetent patient.

A 47-year-old woman presented with a history of vague abdominal pain for several years, which worsened over the past 2 months, with pain more prominent in the right upper quadrant. She also had a history of peptic ulcer disease. The ultrasound scan of right upper quadrant revealed normal gallbladder and oesophagogastroduodenoscopy was unremarkable. A (99m)technetium labelled hepato iminodiacetic acid (HIDA) scan with cholecystokinin provocation demonstrated a decreased gallbladder ejection fraction (EF) of 32%. On this basis, the patient was diagnosed with biliary dyskinesia and underwent an elective laparoscopic cholecystectomy. Histopathological analysis revealed chronic cholecystitis with Cystoisospora belli identified in the gallbladder wall. Cystoisospora has been identified to cause an opportunistic acalculous cholecystitis among immunocompromised hosts, especially those with AIDS. This is the first case report of chronic cholecystitis due to C. belli in an immunocompetent patient.

Hyalinizing cholecystitis with features of immunoglobulin G4-related disease-coincidence or an unrecognized association? A case report.

Hyalinizing cholecystitis (HC) is a recently described rare subtype of chronic cholecystitis characterized by dense, paucicellular collagenous transmural fibrosis, which usually replaces the mucosa and muscularis propria. Immunoglobulin (Ig)G4-associated cholecystitis is also a newly described cholecystitis variant characterized by transmural or extramural lymphoplasmacytic inflammation, lymphoid follicles, storiform fibrosis, phlebitis, and increased tissue IgG4-positive plasma cells. We describe a case of cholecystitis in an elderly white man who harbored features of both HC and IgG4-associated cholecystitis. In retrospect, the patient also had a significantly elevated serum IgG4 level. To the best of our knowledge, an association between HC and IgG4-related disease has not been previously described in the literature. Although not entirely conclusive, our observations raise the possibility that some cases of HC represent the end stage of IgG4-related disease.

[Influence of ursodeoxycholic acid on the immune status of patients with cholesterosis of gall-bladder depending on cholesterol index in blood].

Application of ursodeoxycholic acid in a standard dosage for 3 months provided a positive effect in relation to the indexes of the immune system for patients with the cholesterosis of gall-bladder. It is shown that medicine assists renewal of T-cell immunity, renders positive influence on B-link and renewal of index of immunoregulation can be seen. Reliable increase of specific receptors to CD25, HLA-DR and high level of CD95 testifies about including of the scray reaction of organism under influence of ursodeoxycholic acid on the remaining high indexes of B-cell of immunity. At the initial indexes of lipid spectrum, corresponding to the norm, the efficiency of normalization of immunological changes is more considerable than at the higher level of general cholesterol of serum of blood.

Recent advances in the concept and pathogenesis of IgG4-related disease in the hepato-bilio-pancreatic system.

Recent studies have proposed nomenclatures of type 1 autoimmune pancreatitis (AIP) (IgG4-related pancreatitis), IgG4-related sclerosing cholangitis (IgG4-SC), IgG4-related cholecystitis, and IgG4-related hepatopathy as IgG4-related disease (IgG4-RD) in the hepato-bilio-pancreatic system. In IgG4-related hepatopathy, a novel concept of IgG4-related autoimmune hepatitis (AIH) with the same histopathological features as AIH has been proposed. Among organs involved in IgG4-RD, associations with pancreatic and biliary lesions are most frequently observed, supporting the novel concept of "biliary diseases with pancreatic counterparts." Targets of type 1 AIP and IgG4-SC may be periductal glands around the bile and pancreatic ducts. Based on genetic backgrounds, innate and acquired immunity, Th2-dominant immune status, regulatory T (Treg) or B cells, and complement activation via a classical pathway may be involved in the development of IgG4-RD. Although the role of IgG4 remains unclear in IgG4-RD, IgG4-production is upregulated by interleukin 10 from Treg cells and by B cell activating factor from monocytes/basophils with stimulation of toll-like receptors/nucleotide-binding oligomerization domain-like receptors. Based on these findings, we have proposed a hypothesis for the development of IgG4-RD in the hepato-bilio-pancreatic system. Further studies are necessary to clarify the pathogenic mechanism of IgG4-RD.

IgG4-related cholecystitis presenting as biliary malignancy: report of three cases.

An increased awareness of IgG4-related diseases has led to an escalation in the number of sites known to be involved by this fibroinflammatory disease. We report three cases of IgG4-related cholecystitis which were thought to represent biliary malignancies both clinically and radiographically. All three cases underwent surgery tailored towards presumed malignant neoplasms. Only following pathologic examination was the true nature of the disease identified. Recognition of the clinical, radiographic, and pathologic presentation of IgG4-related cholecystitis is essential for the consideration of this disease process prior to surgical management for suspected gallbladder malignancies. However, the pre-operative diagnosis remains challenging and extensive surgical intervention is often necessary given the distressing presentation of IgG4-related cholecystitis.

Recent Advances in the Concept and Pathogenesis of IgG4-Related Disease in the Hepato-Bilio-Pancreatic System

Recent studies have proposed nomenclatures of type 1 autoimmune pancreatitis (AIP) (IgG4-related pancreatitis), IgG4-related sclerosing cholangitis (IgG4-SC), IgG4-related cholecystitis, and IgG4-related hepatopathy as IgG4-related disease (IgG4-RD) in the hepato-bilio-pancreatic system. In IgG4-related hepatopathy, a novel concept of IgG4-related autoimmune hepatitis (AIH) with the same histopathological features as AIH has been proposed. Among organs involved in IgG4-RD, associations with pancreatic and biliary lesions are most frequently observed, supporting the novel concept of "biliary diseases with pancreatic counterparts." Targets of type 1 AIP and IgG4-SC may be periductal glands around the bile and pancreatic ducts. Based on genetic backgrounds, innate and acquired immunity, Th2-dominant immune status, regulatory T (Treg) or B cells, and complement activation via a classical pathway may be involved in the development of IgG4-RD. Although the role of IgG4 remains unclear in IgG4-RD, IgG4-production is upregulated by interleukin 10 from Treg cells and by B cell activating factor from monocytes/basophils with stimulation of toll-like receptors/nucleotide-binding oligomerization domain-like receptors. Based on these findings, we have proposed a hypothesis for the development of IgG4-RD in the hepato-bilio-pancreatic system. Further studies are necessary to clarify the pathogenic mechanism of IgG4-RD.

Occurrence of anaplastic large cell lymphoma following IgG4-related autoimmune pancreatitis and cholecystitis and diffuse large B-cell lymphoma.

IgG4-related sclerosing disease is an established disease entity with characteristic clinicopathological features. Recently, the association between IgG4-related sclerosing disease and the risk of malignancies has been suggested. IgG4-related autoimmune pancreatitis with pancreatic cancer has been reported. Further, a few cases of extraocular malignant lymphoma in patients with IgG4-related sclerosing disease have also been documented. Herein, we describe the first documented case of anaplastic large cell lymphoma (ALCL) following IgG4-related autoimmune pancreatitis and cholecystitis and diffuse large B-cell lymphoma (DLBCL). A 61-year-old Japanese male, with a past history of DLBCL, was detected with swelling of the pancreas and tumorous lesions in the gallbladder. Histopathological study of the resected gallbladder specimen revealed diffuse lymphoplasmacytic infiltration with fibrosclerosis in the entire gallbladder wall. Eosinophilic infiltration and obliterative phlebitis were also noted. Immunohistochemically, many IgG4-positive plasma cells had infiltrated into the lesion, and the ratio of IgG4/IgG-positive plasma cells was 71.6%. Accordingly, a diagnosis of IgG4-related cholecystitis was made. Seven months later, he presented with a painful tumor in his left parotid gland. Histopathological study demonstrated diffuse or cohesive sheet-like proliferation of large-sized lymphoid cells with rich slightly eosinophilic cytoplasm and irregular-shaped large nuclei. These lymphoid cells were positive for CD30, CD4, and cytotoxic markers, but negative for CD3 and ALK. Therefore, a diagnosis of ALK-negative ALCL was made. It has been suggested that the incidence of malignant lymphoma may be high in patients with IgG4-related sclerosing disease, therefore, intense medical follow-up is important in patients with this disorder.

ATP-binding cassette sterol transporters are differentially expressed in normal and diseased human gallbladder.

BACKGROUND AND AIMS: Gallbladder epithelial cells (GBEC) are exposed to high cholesterol concentrations in bile, and export cholesterol via an ATP-binding cassette (ABC) transporter-mediated pathway in vitro. These findings suggest that aberrant expression and/or function of ABC sterol transporters may be associated with cholesterol-related gallbladder diseases (CAGD). In this study, we investigated the relative levels of the sterol transporters ABCA1, ABCG5, and ABCG8 in human gallbladders in CAGD, and the relationship between ABCA1 and inflammation. METHODS: Expression of ABCA1, ABCG5, and ABCG8 was evaluated in 31 gallbladders with CAGD and 6 normal gallbladders by western blotting and immunohistochemistry. RT-PCR was used to measure ABCA1 mRNA expression. To investigate the relationship between ABCA1 and inflammation, wWestern blots were performed on cultured dog GBEC treated with lipopolysaccharide (LPS) using an anti-ABCA1 antibody. RESULTS: Immunohistochemistry showed ABCA1 to be localized predominantly to the basolateral membrane, while ABCG8 formed a diffuse intracellular pattern at the apical pole of human GBEC. ABCA1 and ABCG8 expression was more prominent in GBEC that were surrounded by cholesterol-laden macrophages. ABCA1 and ABCG8 expression was increased in gallbladders with CAGD. Western blots showed increased ABCA1, ABCG5, and ABCG8 expression in CAGD. ABCA1 mRNA levels were increased in all gallbladders with CAGD. LPS treatment of cultured dog GBEC enhanced ABCA1 expression. CONCLUSIONS: The sterol transporters ABCA1, ABCG5, and ABCG8 may play a role in the pathogenesis of human CAGD. Inflammation appears to be a key factor that increases ABCA1 expression and activity in the human gallbladder.

TLR4 expression in normal gallbladder, chronic cholecystitis and gallbladder carcinoma.

BACKGROUND/AIMS: Chronic inflammation is a risk factor for gallbladder carcinoma. The molecular mechanisms linking inflammation and gallbladder carcinogenesis are incompletely understood. Toll-like receptors are involved in inflammatory response and play an important role in the innate immune system by initiating and directing immune response to pathogens. We tested the hypothesis that TLR4 participated in the development of gallbladder carcinoma through investigating the expression of TLR4 in chronic cholecystitis, gallbladder carcinoma and normal gallbladder. METHODOLOGY: The expression of TLR4 in 30 specimens of chronic calculous cholecystitis, 13 specimens of gallbladder adenocarcinoma and 10 specimens of normal gallbladder tissue was determined by immunohistochemistry, western blotting analysis and quantitative RT-PCR. RESULTS: We showed that TLR4 was mostly localized to the glandular and luminal epithelium of gallbladder. TLR4 expression was lower in gallbladder carcinoma tissue than in chronic cholecystitis and normal gallbladder tissue, whereas the difference between chronic cholecystitis tissue and normal gallbladder tissue was not statistically significant. CONCLUSIONS: The expression of TLR4 may be closely associated with the course of gallbladder carcinoma.

IgG4-associated cholecystitis: another clue in the diagnosis of autoimmune pancreatitis.

PURPOSE: Autoimmune pancreatitis (AIP) is the pancreatic manifestation of IgG4-associated systemic disease (ISD). Criteria for diagnosis of AIP include recognition of extra-pancreatic organ involvement. Because the diagnosis of AIP can be challenging, even for experts, it is important for clinicians to recognize other target organ damage in this disease. Typical gallbladder findings in AIP have been increasingly recognized. Because cholecystectomy is common in the community, the availability of previous tissue from the gallbladder can provide an important supportive clue in the diagnosis of AIP. The objective of this review is to examine the literature on common gallbladder pathology findings in AIP, and discuss their clinical utility. RESULTS: Gallbladder involvement in AIP seems to be common. Transmural lymphoplasmacytic inflammatory infiltrates, extramural inflammatory nodules, the presence of tissue eosinophilia, phlebitis, and increased tissue IgG4 are all seen more frequently in the gallbladders of patients with AIP. These findings are not 100% specific, because some can be seen in primary sclerosing cholangitis and pancreatic adenocarcinoma. CONCLUSION: Cholecystectomy for the purpose of diagnosing AIP is not recommended. However, if gallbladder specimens from a previous cholecystectomy are available, an expert review of gallbladder slides with IgG4 immunostaining may help to provide additional criteria for diagnosis of autoimmune pancreatitis.

Pathological features of IgG4-related sclerosing disease.

PURPOSE OF REVIEW: The spectrum of IgG4-related systemic disease (IgG4-RSD) continues to widen. At most of the sites involved by this condition, the clinical presentation can mimic neoplasm. Pathologic assessment of small biopsies can be critical to proper management. This review summarizes the histologic features of IgG4-RSD and the role of immunohistochemistry of IgG4 in the diagnosis. RECENT FINDINGS: The review period saw further expansion of the list of sites putatively involved by IgG4-RSD, with new, or more detailed, entries related to lung, lymph nodes, stomach, and thyroid. A tentative consensus was reached on the issue of subtypes of autoimmune pancreatitis. The role of immunohistochemistry for IgG4 as an adjunct to the diagnosis of IgG4-RSD was further clarified. SUMMARY: Sclerosing lymphoplasmacytic inflammation at almost any site can represent a manifestation of IgG4-RSD. There are several histologic features that can suggest the diagnosis. Immunohistochemistry for IgG4 is a useful diagnostic test to further support the diagnosis.