Amphipathic Liponecrosis Impairs Bacterial Clearance and Causes Infection During Sterile Inflammation.

BACKGROUND & AIMS: Although transient bacteremia is common during dental and endoscopic procedures, infections developing during sterile diseases like acute pancreatitis (AP) can have grave consequences. We examined how impaired bacterial clearance may cause this transition. METHODS: Blood samples from patients with AP, normal controls, and rodents with pancreatitis or those administered different nonesterified fatty acids (NEFAs) were analyzed for albumin-unbound NEFAs, microbiome, and inflammatory cell injury. Macrophage uptake of unbound NEFAs using a novel coumarin tracer were done and the downstream effects-NEFA-membrane phospholipid (phosphatidylcholine) interactions-were studied on isothermal titration calorimetry. RESULTS: Patients with infected AP had higher circulating unsaturated NEFAs; unbound NEFAs, including linoleic acid (LA) and oleic acid (OA); higher bacterial 16S DNA; mitochondrial DNA; altered ß-diversity; enrichment in Pseudomonadales; and increased annexin V-positive myeloid (CD14) and CD3-positive T cells on admission. These, and increased circulating dead inflammatory cells, were also noted in rodents with unbound, unsaturated NEFAs. Isothermal titration calorimetry showed progressively stronger unbound LA interactions with aqueous media, phosphatidylcholine, cardiolipin, and albumin. Unbound NEFAs were taken into protein-free membranes, cells, and mitochondria, inducing voltage-dependent anion channel oligomerization, reducing ATP, and impairing phagocytosis. These were reversed by albumin. In vivo, unbound LA and OA increased bacterial loads and impaired phagocytosis, causing infection. LA and OA were more potent for these amphipathic interactions than the hydrophobic palmitic acid. CONCLUSIONS: Release of stored LA and OA can increase their circulating unbound levels and cause amphipathic liponecrosis of immune cells via uptake by membrane phospholipids. This impairs bacterial clearance and causes infection during sterile inflammation.

Performance of Endoscopic Ultrasound-Guided Versus Percutaneous Liver Biopsy in Diagnosing Stage 3-4 Fibrosis.

BACKGROUND: Percutaneous liver biopsy (P-bx) is the gold standard for diagnosing advanced fibrosis. Despite the proven technical feasibility of EUS-guided liver bx (EUS-bx) as a novel alternative way of liver biopsy, the clinical applicability remains to be determined. AIMS: The primary aim of this study is to evaluate if EUS-bx, compared to P-bx, can effectively and safely obtain adequate specimen and accurately predict hepatic fibrosis. METHODS: This is a single center, retrospective chart review among patients with liver diseases at a tertiary endoscopy center from February 2011 to March 2020. We assessed the EUS-bx versus P-bx outcomes by success rate, performance, and safety profile. The primary outcome was the association between EUS-bx clinical variables and the presence of histologic liver fibrosis stage ≥ 3. The secondary outcomes were the associations between EUS-bx and variables indicative of fibrosis. RESULTS: Fifty-nine patients underwent EUS-bx; and 59, P-bx. All EUS-bx procedures were successfully completed. All 56/56 (100%) of EUS-bx vs. 50/52 (96.2%) P-bx were considered adequate samples. Tissue lengths were significantly longer in the EUS-bx cohort (p < 0.0001) with a trend towards a greater number of portal tracts. 46/56 (82.1%) cases of EUS-bx vs. 32/52 (61.5%) of P-bx had > 10 portal tracts; 21/56 (37.5%) cases of EUS-bx vs. 14/52 (26.9%) of P-bx had > 15 portal tracts. There were 6 (10.2%) EUS-bx vs. 1 (1.7%) P-bx related complication leading to a phone call (p = 0.061). CONCLUSIONS: EUS-bx can safely performed and accurately predict liver fibrosis stage as the standard P-bx without being influenced by procedure-related factors.

Endoscopic Ultrasound-Guided Porto-systemic Pressure Gradient Measurement Correlates with Histological Hepatic Fibrosis.

BACKGROUND AND AIMS: Endoscopic ultrasound is a novel diagnostic approach to chronic liver diseases (CLDs), and EUS-guided porto-systemic pressure gradient measurement (EUS-PPG) is an important expansion with a well-developed technique. However, the clinical value and applicability of EUS-PPG measurement in predicting histologically advanced hepatic fibrosis remain unknown. METHODS: This was a single-center retrospective study on patients with various CLDs undergoing EUS-PPG and EUS-guided liver biopsy (EUS-bx) to assess if EUS-PPG measurements correlate with histological fibrosis stage and various surrogate markers for severity of CLDs and its safety. Cases with EUS-PPG were identified at the University of California Irvine, a tertiary endoscopy center, between January 2014 and March 2020. RESULTS: In 64 patients, the mean age was 57.5; 40 (62.5%), males; mean Child-Turcotte-Pugh (CTP) and Model for End-Stage Liver Disease (MELD) scores, 5.9 and 10.4, respectively. The procedure success rate was 100%. Twenty-nine (45.3%) had EUS-PPG ≥ 5 mmHg that was associated with clinical cirrhosis (p < 0.0001), clinical portal hypertension (p = 0.002), hepatic decompensation (p = 0.013), MELD-Na > 10 (p = 0.036), PLTs ≤ 120 × 109/L (p = 0.001), INR ≥ 1.05 (p = 0.007), presence of EV, GV, or PHG (p < 0.0001), biopsy-proven fibrosis stage ≥ 3 (p = 0.002), APRI > 2 (p = 0.001), and FIB-4 > 3.25 (p = 0.001). Multivariable analysis confirmed that EUS-PPG ≥ 5 mmHg was significantly associated with liver biopsy-proven fibrosis stage ≥ 3 (LR 27.0, 95% CI = 1.653-360.597, p = 0.004), independent of C-cirrhosis, C-PHTN, thrombocytopenia, splenomegaly, and APRI score > 2, and FIB-4 score > 3.25. There were no serious complications related to EUS-PPG procedures. CONCLUSIONS: EUS-PPG measurements provide excellent correlation with histological hepatic fibrosis stage and various clinical, laboratory, endoscopic and imaging variables indicative of advanced liver disease without serious adverse events.

Comparison of Two Specialized Histology Needles for Endoscopic Ultrasound (EUS)-Guided Liver Biopsy: A Pilot Study.

BACKGROUND: EUS-guided liver biopsy (EUS-LB) has been shown to be a safe and effective alternative to percutaneous liver biopsy. The optimal needle device and technique for EUS-LB is still evolving. The aim of this study was to compare the efficacy of two second-generation 19G fine-needle biopsy (FNB) (Franseen- and Fork-tip) devices for EUS-LB. METHODS: This is a repeated-measure crossover study with a prospectively maintained cohort of patients. We performed EUS-LB with a one-pass and single-actuation method using two 19G FNB needles in 22 consecutive patients between 10/2018 and 9/2019. Patients were randomized to left vs right liver lobes to be biopsied as well as the needle sequence. The specimens obtained were evaluated for adequacy for histologic diagnosis. The primary outcome was number of complete portal tracts (CPTs), post-fix aggregate, and longest specimen length. Secondary outcomes were prefix aggregate specimen length and the specimen adequacy judged by two expert pathologists. RESULTS: A total of 44 liver biopsies were performed in 22 patients. The CPTs were higher in the Franseen-tip needle group compared to the Fork-tip needle group (14.4 vs 9.5, p = 0.043). Post-fix aggregate specimen length (44.9 mm vs 34.6 mm, p = 0.097), the post-fix longest specimen length (19.9 mm vs 13.7 mm, p = 0.175), and prefix aggregate specimen length (51.7 mm vs 45 mm, p = 0.265) were not significantly different. Both needles showed similarly high histologic adequacy (100% vs 95.5%, p = 0.312). Interestingly, the right of the liver showed higher yield of CPTs with both needles (Franseen, 16.2 vs. 12.8, p = 0.003, the Fork-tip, 12.8 vs. 7.0, p < 0.0001). CONCLUSION: EUS-guided liver biopsy using the 19G Franseen-tip needle may provide more CPTs than 19G Fork-tip needle on a single-pass, single-actuation comparison.

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.

Leukocyte cell-derived chemotaxin 2 (LECT2)-associated amyloidosis is a frequent cause of hepatic amyloidosis in the United States.

Using laser microdissection and mass spectrometry (MS)-based proteomics, we subtyped amyloid deposits from 130 cases of hepatic amyloidosis. Although we confirmed that immunoglobulin light chain amyloidosis was the most frequent cause of hepatic amyloidosis, leukocyte cell-derived chemotaxin 2 (LECT2) amyloidosis (ALect2) accounted for 25% of cases. This novel finding was associated with Hispanic ancestry, incidental discovery of amyloid in liver specimens sampled for other unrelated conditions, and a characteristic pattern of hepatic amyloid deposition. Although ALect2 patients had a common LECT2 polymorphism, pathogenic mutations were not discovered, suggesting that constitutive or compensatory LECT2 overexpression led to ALect2 deposition. These findings indicate that ALect2 is a common cause of hepatic amyloidosis in the population of the United States, and subtyping hepatic amyloid deposits by an accurate analytic method such as MS is required for optimal clinical management of hepatic amyloidosis patients and to avoid incorrect and unnecessarily toxic therapies.

Biphenotypic hepatic tumors: imaging findings and review of literature.

PURPOSE: To describe imaging findings in biphenotypic hepatic tumors (BPT) and a proposal for new imaging classification based on contrast-enhanced imaging. METHODS: Retrospective review of CT, MRI, PET/CT, and ultrasound findings in 39 patients with histologically confirmed BPT was performed. Tumor markers including AFP, L3 fraction, CA 19.9, CA 125, and CEA were recorded. Based on the dynamic enhancement features, BPT were categorized into 4 enhancement patterns (Types 1-4). Enhancement patterns were correlated with other imaging findings and tumor markers. Imaging features and tumor markers that were not consistent with diagnosis of hepatocellular carcinoma or intrahepatic cholangiocarcinoma based on enhancement pattern were considered discordant findings. RESULTS: Enhancement patterns in 29 patients (CT/MR) included 23 Type 2 (continuous peripheral rim of late arterial hyperenhancement with washout or fade in portal venous and/or delayed phases, ±delayed central enhancement) and 2 of each Types 1, 2, and 3. Discordant imaging findings were present in two patients with Type 2 pattern and in one patient with Type 1 pattern. Both AFP and CA 19.9 were elevated in 15 of 33 of patients. Tumor markers AFP and CA 19.9 were discordant in 17 of 21 patients with Type 2 pattern, two of two patients with Type 3 pattern. Most BPTs were markedly PET avid with average SUV max of 8.2. Most frequent ultrasound appearance is peripheral hypoechogenicity and central hyperechogenicity. CONCLUSIONS: BPT most commonly present with imaging features similar to cholangiocarcinoma or metastases. BPT can be suggested when imaging findings or tumor markers are discordant with the most likely diagnosis based on enhancement pattern.

Liver masses: a clinical, radiologic, and pathologic perspective.

Liver masses present a relatively common clinical dilemma, particularly with the increasing use of various imaging modalities in the diagnosis of abdominal and other symptoms. The accurate and reliable determination of the nature of the liver mass is critical, not only to reassure individuals with benign lesions but also, and perhaps more importantly, to ensure that malignant lesions are diagnosed correctly. This avoids the devastating consequences of missed diagnosis and the delayed treatment of malignancy or the unnecessary treatment of benign lesions. With appropriate interpretation of the clinical history and physical examination, and the judicious use of laboratory and imaging studies, the majority of liver masses can be characterized noninvasively. Accurate characterization of liver masses by cross-sectional imaging is particularly dependent on an understanding of the unique phasic vascular perfusion of the liver and the characteristic behaviors of different lesions during multiphasic contrast imaging. When noninvasive characterization is indeterminate, a liver biopsy may be necessary for definitive diagnosis. Standard histologic examination usually is complemented by immunohistochemical analysis of protein biomarkers. Accurate diagnosis allows the appropriate selection of optimal management, which is frequently reassurance or intermittent follow-up evaluations for benign masses. For malignant lesions or those at risk of malignant transformation, management depends on the tumor staging, the functional status of the uninvolved liver, and technical surgical considerations. Unresectable metastatic masses require oncologic consultation and therapy. The efficient characterization and management of liver masses therefore requires a multidisciplinary collaboration between the gastroenterologist/hepatologist, radiologist, pathologist, hepatobiliary or transplant surgeon, and medical oncologist.

Gallbladder carcinomas: review and updates on morphology, immunohistochemistry, and staging.

Gallbladder is a common surgical pathology specimen. However, carcinomas of the gallbladder are relatively rare in most western countries. Hence, general surgical pathologists may not be that familiar and comfortable diagnosing these tumors. In this review, we discuss the morphological and immunohistochemical characteristics of gallbladder carcinomas, provide updates on tumor classification and staging of these tumors as per the most recent WHO classification, and focus on practical considerations that would be most relevant to diagnosis and clinical management of these tumors.

Cost benefit analysis and pathology review of ileostomy and colostomy specimens processed over a 20-year period.

Rising healthcare costs have been linked to overtreatment and overuse of available resources. Identifying and eliminating low-value services is vital for reducing such costs. At many institutions, including ours, all ileostomy and colostomy specimens are sent for pathological evaluation. It is estimated that approximately 120,000 ileostomy/colostomy procedures are done every year, and at least 1 million patients have stomas at any given time in North America. Hence, we decided to analyze the pathological findings and cost-benefit of undertaking the pathological evaluation of these colostomy and ileostomy specimens. The pathology database of our department was searched for all ileostomy and colostomy specimens received between 2000 and 2020, resulting in a total of 2762 cases (1944 ileostomy and 818 colostomy). We performed a cost-benefit analysis and pathologic review of these cases. The results of our study show that 99.38% of these specimens did not show any significant pathological abnormality, and non-neoplastic pathologic findings accounted for 99.63% of cases. Less than 1% of our cases showed any clinically significant pathological findings. All 10 cases that showed a neoplastic or malignant diagnosis showed some abnormal finding that was appreciated at the time of gross examination. We conclude that microscopic evaluation of ileostomy and colostomy specimens incurs significant costs and provides no clear value or relevant information for patient care. The results of our study provide support for ileostomy and colostomy specimens to be triaged by gross-only pathological examination in the first instance for the vast majority of cases.

A Journey From Appendicitis to a Rare Appendiceal Mucinous Neoplasm.

We present here a 66-year-old Caucasian male whose persistent abdominal pain thought to be due to appendicitis and associated acute splanchnic thrombosis. He was initially managed with antibiotics and anticoagulation. But further work up revealed a low-grade appendiceal mucinous neoplasm causing the splanchnic vein thrombosis. Additionally, diagnosis and management of this rare tumor and appropriate work up for splanchnic thrombosis will be briefly reviewed here.

Atypical Presentations of Collagenous Gastritis Mimicking Celiac Sprue.

Collagenous gastritis has been reported as a rare cause of nausea, diarrhea, weight changes, and early satiety in female patients. Here, we describe two women aged 43 and 71 years who presented with similar symptoms. Gastric biopsies from both individuals showed thickened, irregular subepithelial collagen bands (>10 µm). The pathogenesis of collagenous gastritis is poorly understood, but it may be the presenting symptom for many underlying autoimmune conditions. In particular, there is a well-established connection between collagenous disorders of the gastrointestinal tract and celiac sprue, Sjögren syndrome, and lymphocytic colitis; however, none of these conditions had been diagnosed in our patients. The older woman had incidentally discovered hypogammaglobinemia and IgA deficiency, whereas the younger woman suffered from fibromyalgia. Although a gluten-free diet and budesonide have been effective in some cases, there is no standardized therapy for collagenous gastritis. Our patients trialed diet modification and have required no additional medical interventions.

Establishment and Characterization of a New Human Intrahepatic Cholangiocarcinoma Cell Line LIV27.

Cholangiocarcinoma (CCA) is a highly lethal cancer arising from the biliary tract epithelium. The cancer biology of this neoplasm is not well understood. To date, only a few CCA cell lines have been reported, which were mostly developed from Asian patients. In this study, we report and characterize a new intrahepatic CCA cell line, LIV27, derived from a surgically resected tumor in a 67-year-old Caucasian woman with primary sclerosing cholangitis (PSC). LIV27 cells grow well in collagen-coated flasks or plates with a doubling time of 57.8 h at passage 14. LIV27 cells have high tumorigenicity in nude mice and stain positive for CK7 and CK19, markers that differentiate CCA from hepatocellular carcinoma. Karyotype analysis showed that LIV27 is aneuploid. We established a single-locus short tandem repeat profile for the LIV27 cell line. This newly established cell line will be a useful model for studying the molecular pathogenesis of, and developing novel therapies for, cholangiocarcinoma.

Atypical Cells in Peritoneal Cleft: A Pitfall in Diagnosis of Colorectal Adenocarcinoma.

Atypical cells in peritoneal clefts are usually either reactive mesothelial cells or pT4 colonic adenocarcinoma in colon specimen removed for primary colon cancer. However, rarely if ever are these atypical cells metastasis from other primary visceral malignancy due to "sac-like" anatomic structure of this area. We present a case where these atypical cells were determined to be metastasis of gynecological origin by judicious use of immunohistochemical stains. A final diagnosis of serous tubal intraepithelial carcinoma of right fallopian tube was diagnosed only after total abdominal hysterectomy bilateral salpingo-oophorectomy. To our knowledge, this is the first report of a serous tubal intraepithelial carcinoma presenting as stage 4 colonic adenocarcinoma. The importance of this interesting case is 2-fold. It highlights the peritoneal cleft as an anatomic region not often recognized or discussed as well as tumor presentation in this region. In addition, this example stresses the need for additional mesothelial markers in addition to WT-1 workup of atypical mesothelial proliferation.

A limited panel of INSM1 and LEF1 immunostains accurately distinguishes between pancreatic neuroendocrine tumor and solid pseudopapillary neoplasm.

Solid pseudopapillary neoplasm (SPN) and well differentiated pancreatic neuroendocrine tumor (PNET) can show significant cytomorphological overlap. In this study, we evaluated the role of INSM1 and LEF1 immunohistochemical stains in distinguishing between these two tumors. 22 SPN and 25 PNET surgically resected cases were stained for both INSM1 and LEF1. All the 22 cases of SPN showed strong and diffuse nuclear staining for LEF1 (in >95 % of tumor cells), while all 25 PNET were negative for LEF1. All 25 PNET cases were positive for INSM1 (moderate to strong intensity nuclear staining in >50 % of the tumor cells), while all 22 cases of SPN were negative for INSM1. The results of our study show that a limited panel comprising of INSM1 and LEF1 immunostains accurately distinguishes between SPN and PNET.

Increased PD-L1 and p16 expression are common in oropharyngeal squamous cell carcinoma.

Overexpression of p16 is closely related to human papillomavirus (HPV)-associated oropharyngeal squamous cell carcinoma (SCC) and pertains a prognostic relevance. Programmed cell death 1-ligand 1 (PD-L1) is another important marker, as anti-PD-L1 immunotherapy is available. Retrospective analysis of 57 cases of the SCC involving oropharynx (27 cases), hypopharynx (5 cases), larynx (11 cases), and oral cavity (14 cases) was performed. Each case was scrutinized for the basaloid morphology, p16, and PD-L1 expression. Basaloid morphology was identified in 47% of total cases. The majority of basaloid SCC variants were located in the oropharynx (89%). High expression of p16 was mostly observed in the oropharynx. High PD-L1 expression was seen predominantly in oropharyngeal and hypopharyngeal locations. Further studies in a larger cohort are necessary to correlate PD-L1 and p16 expression with survival.

Hepatocellular carcinomas can be Special AT-rich sequence-binding protein 2 positive: an important diagnostic pitfall.

Special AT-rich sequence-binding protein 2 (SATB2) is a sensitive and specific marker for tumors originating with the colon and appendix. It is now commonly used in surgical pathology, while working up carcinomas of unknown primary. We had anecdotally encountered occasional hepatocellular carcinomas (HCCs) that were SATB2 positive. Immunohistochemical expression of SATB2 in HCC has not yet been examined in detail. In this study, we evaluated SATB2 expression in 46 HCCs. Nineteen (41%) of 46 HCCs were positive for SATB2. SATB2 expression in HCCs was more commonly seen in poorly differentiated tumors (11 of 13 cases, 85%) than well and moderately differentiated tumors (8 of 33 cases, 24%), p value = 0.0001. No other statistically significant correlations were observed (p > 0.05). There were no other statistically significant correlations between SATB2 expression and age, gender, background liver disease, and cirrhosis (p > 0.05). Results of our study show that a significant subset (41%) of HCCs can be SATB2 positive. Awareness of this phenomenon is important as SATB2 expression in a liver tumor does not completely exclude a diagnosis of HCC.

Clinicopathological significance of lymphocytic colitis/collagenous colitis in inflammatory bowel disease.

Patients with inflammatory bowel disease (IBD) may occasionally present with lymphocytic colitis/collagenous colitis (LC/CC) either before or after the onset of IBD. Although a few reports have described a small number of such cases, the relationship between these 2 disorders is still unclear. We evaluated 27 patients with diagnosis of either ulcerative colitis (UC) or Crohn disease (CD) and LC/CC. Clinical, endoscopic, and pathological features were reviewed. Ten patients with initial diagnoses of LC (n = 2)/CC (n = 8) evolved into UC (n = 7) or CD (n = 3) after a median interval of 14 months (range, 2-44 months). Among these, 4 patients with LC/CC evolving into IBD also had recurrent CC in a quiescent phase of IBD. Seventeen patients with initial diagnosis of UC (n = 11) or CD (n = 6) developed LC (n = 6)/CC (n = 11) after a median interval of 108 months (range, 15-548 months). IBD patients with initial presentation of LC/CC were significantly older than those who developed LC/CC after onset of IBD (66.5 versus 34.0 years old, P = .001). The interval time between LC/CC to IBD was significantly shorter than that of IBD to LC/CC (14 versus 108 months, P = .007). Quiescent UC with superimposed CC was the most common pattern (n = 8). Patients with CD had shorter interval time to develop LC/CC than UC patients, although it was not statistically significant (60.5 versus 139 months, P = .14). Endoscopically, most patients that started with LC/CC had unremarkable findings, but 11 of 17 patients who developed LC/CC after IBD showed quiescent chronic colitis. Histologically, LC/CC patients with diagnosis of IBD, either before or after, more frequently show active inflammation. Chronicity was more commonly seen in biopsy of LC/CC patients with a history of IBD. Our study found that IBD patients with initial presentation of LC/CC tend to occur in older age, with shorter interval time and frequent active inflammation in initial LC/CC. These findings suggest that LC/CC may be a spectrum of IBD as the initial presentation in a subset of older IBD patients. On the other hand, IBD patients can develop LC/CC associated with chronic mucosal injury many years after the onset of IBD (typically with >10 years interval time while patients are in remission phase), for which these 2 processes seem unrelated to each other.

Incidence and significance of GATA3 positivity in gallbladder adenocarcinoma.

GATA3 immunostaining is a sensitive marker for mammary and urothelial carcinomas. It is routinely used in surgical pathology during workup of carcinomas of unknown origin. To the best of our knowledge, this is the first focused study of GATA3 expression in gallbladder adenocarcinomas. In this study, we evaluated GATA3 expression in 38 gallbladder adenocarcinomas. Eight of 38 (21%) gallbladder adenocarcinomas were positive for GATA3. The expression of GATA3 tended to be moderate to strong when present. It was patchy (<50% positivity) in 4 cases, characterized by discrete clusters or groups of malignant cells with areas of intervening negative tumor cells, whereas it was diffuse (>50% positivity) in the other 4 cases. GATA3 expression did not show any significant correlation with clinicopathologic features such as sex, histologic grade, perineural invasion, vascular invasion, pathologic stage, or distance metastasis. The results of our study show that a subset of gallbladder adenocarcinomas (21%) can be GATA3 positive. Awareness of this phenomenon is important while working up GATA3-positive carcinomas immunohistochemically.