Faculty Bibliography

Although coronavirus disease 2019 (COVID-19) is transmitted via respiratory droplets, there are multiple gastrointestinal and hepatic manifestations of the disease, including abnormal liver-associated enzymes. However, there are not many published articles on the pathological findings in the liver of patients with COVID-19. We collected the clinical data from 17 autopsy cases of patients with COVID-19 including age, sex, Body mass index (BMI), liver function test (alanine aminotransaminase (ALT), aspartate aminotransaminase (AST), alkaline phosphatase (ALP), direct bilirubin, and total bilirubin), D-dimer, and anticoagulation treatment. We examined histopathologic findings in postmortem hepatic tissue, immunohistochemical (IHC) staining with antibody against COVID-19 spike protein, CD68 and CD61, and electron microscopy. We counted the number of megakaryocytes in liver sections from these COVID-19-positive cases. Abnormal liver-associated enzymes were observed in 12 of 17 cases of COVID-19 infection. With the exception of three cases that had not been tested for D-dimer, all 14 patients' D-dimer levels were increased, including the cases that received varied doses of anticoagulation treatment. Microscopically, the major findings were widespread platelet-fibrin microthrombi, steatosis, histiocytic hyperplasia in the portal tract, mild lobular inflammation, ischemic-type hepatic necrosis, and zone 3 hemorrhage. Rare megakaryocytes were found in sinusoids. COVID-19 IHC demonstrates positive staining of the histiocytes in the portal tract. Under electron microscopy, histiocyte proliferation is present in the portal tract containing lipid droplets, lysosomes, dilated ribosomal endoplasmic reticulum, microvesicular bodies, and coronavirus. The characteristic findings in the liver of patients with COVID-19 include numerous amounts of platelet-fibrin microthrombi, as well as various degrees of steatosis and histiocytic hyperplasia in the portal tract. Possible mechanisms are also discussed.

BACKGROUND AND AIMS/OBJECTIVE:Collagenous colitis (CC) is an inflammatory bowel disorder with unknown etiopatogenesis involving human leukocyte antigen (HLA)-related immune-mediated responses, environmental and genetic risk factors. We carried out an array-based genetic association study in a cohort of CC patients and investigated the common genetic basis between CC and Crohn's disease (CD), ulcerative colitis (UC) and celiac disease. METHODS:DNA from 804 CC formalin-fixed, paraffin-embedded tissue samples was genotyped with Illumina Immunochip. Matching genotype data on controls and CD, UC and celiac disease cases were provided by the respective Consortia. A discovery association study followed by meta-analysis with an independent cohort, polygenic risk score (PRS) calculation, and cross-phenotype analyses were performed. Enrichment of regulatory expression quantitative trait loci (eQTLs) among the CC variants was assessed in hemopoietic and intestinal cells. RESULTS:Three HLA alleles (HLA-B*08:01, HLA-DRB1*03:01, and HLA-DQB1*02:01), related to the ancestral haplotype 8.1, were significantly associated with increased CC risk. We also identified an independent protective effect of HLA-DRB1*04:01 on CC risk. PRS quantifying the risk across multiple susceptibility loci was strongly associated with CC risk. An enrichment of eQTLs was detected among the CC susceptibility variants in various cell types. The cross-phenotype analysis identified a complex pattern of polygenic pleiotropy between CC and other immune-mediated diseases. CONCLUSION/CONCLUSIONS:In this largest genetic study of CC to date with histologically confirmed diagnosis, we strongly implicated the HLA locus and proposed potential non-HLA mechanisms in disease pathogenesis. We also detected a shared genetic risk between CC, celiac disease, CD and UC, which supports clinical observations of comorbidity.

Background: Cytomegalovirus (CMV) infection of gastrointestinal organs (GI) is the most common manifestation of tissue-invasive disease, especially in immunocompromised individuals. It is often seen in patients with IBD, post transplantation, HIV and cancer. The histopathologic diagnosis of CMV infection relies on histologic evaluation of viral inclusions and immunohistochemistry (IHC) confirmation. To avoid missing CMV infection in patients, numerous CMV IHC test requests are submitted by physicians or pathologists each year. However, more than 90% percent of cases are reported negative. The high volume of test requests not only negatively impact the efficiency of CMV test resource, but also increase the cost burden for hospital and patients. We analyzed the CMV IHC test data and related clinical information in order to improve the practices by eliminating the unnecessary use of resources.
Design(s): CMV IHC test orders from 2017 to 2018 were retrieved from surgical pathology computerized database to find CMV IHC results, physician or pathologist requests, tissue inflammatory status, blocks tested, and other related clinical information. After excluding the cases from non-gastrointestinal sources, cytology, autopsy and resection specimens, 1025 individual orders of CMV IHC on GI biopsy specimens were included. Analysis was performed to find out the significant factors contributory to positive test results.
Result(s): The overall CMV IHC positive rate is 4.1% (43/1025) in our institution. The positive rate from physician request and pathologist order was not significantly different (5.5% vs 3.7%).Cases with multiple tissue blocks generated a higher positive rate as compared to single block (6.8% vs 2.6%, p=0.0019).Cases with severe inflammation showed significant higher positive CMV staining than that with moderate or less inflammation (5.3% vs 2%).CMV positivity in biopsies from post-transplant patients, IBD, cancer or others was 13.6%, 3.5%, 4.4% or 3.9%, respectively. Positive rate in post-transplantation patients was higher than other populations.
Conclusion(s): Significant number of negative CMV stains could be cut down through optimizing the test orders. While ordering CMV IHC on GI biopsy specimens, clinical history and severity of tissue inflammation should be considered. For high risk cases such as post transplantation, multiple blocks may need to be submitted. IBD patients did not have higher CMV positive rate than other patient population, perhaps due to recently improving therapeutic approach

Background: Pancreatic neuroendocrine tumors (pNETs), originating from diffuse neuroendocrine cells, are a clinically rare and heterogeneous disease of the pancreas which have increased significantly in incidence over the past few decades. As the therapeutic options continue to expand, it is necessary to define robust prognostic markers to guide clinical decision making and improve patient outcome. Although several biomarkers for NETs exist, sensitive and specific markers that diagnose tissue-specific NETs and predict tumor growth and behavior are generally lacking. CD47 is a transmembrane ligand which inhibits phagocytosis. Overexpression of CD47 has been associated with increased tumor growth and metastasis in a variety of malignancies. In this study, we examine the prognostic implications of CD47 expression in pNETs.
Design(s): 44 well differentiated pNET resection specimens (17 G1, 23 G2, and 4 G3) were selected and analyzed using CD47 immunohistochemistry. Staining intensity and percentage of positive tumor cells was quantified using the H-score method. Statistical analysis was utilized to correlate H-score with various clinicopathologic parameters.
Result(s): Membranous and cytoplasmic staining of CD47 was seen in pNETs and normal endocrine cells. High expression of CD47 was seen in all samples of pNETs compared to the surrounding noncancerous pancreatic tissues. H-score of CD47 in pNETs with lymph node metastasis was significantly lower than in pNETs without lymph node metastasis (128.2+/-9.0 and 161.7+/-11.0, P=0.038). CD47 expression inversely correlate with perineural invasion (127.4+/-7.7 vs 170.0+/-11.6, P=0.004), and lymphovascular invasion (128.8+/-7.6 vs 178.8+/-13.6, P=0.002). Further analysis revealed that CD47 expression in pNETs was also inversely related to mitotic count (P=0.045). CD47 expression did not correlate with patient's age, gender, tumor size, stage, grade, or Ki-67 proliferation index.
Conclusion(s): CD47 was overexpressed in all pNETs. CD47 expression significantly correlated with lymph node metastasis, perineural invasion, lymphovascular invasion, and mitosis. The data indicated that CD47 may be a promising marker for predicting pNET prognosis

Familial adenomatous polyposis (FAP) is an autosomal dominant syndrome associated with mutation in the adenomatous polyposis coli (APC) gene, a tumour suppressor located on chromosome 5q21. Attenuated familial adenomatous polyposis (AFAP) is a variant associated with fewer and later onset of colon polyps. AFAP-associated APC mutations have largely been found before codon 157, in exon 9 or after codon 1595. We present the case of a 44-year-old man incidentally found to have numerous gastric polyps during bariatric surgery, with innumerable polyps in the remaining part of the stomach and the entire colon, with rectal sparing, consistent with AFAP phenotype. Genetic testing demonstrated the c.7682dup (p.Ser2562Lysfs*21) variant in exon 15 of APC. This represents a previously undescribed APC mutation. This mutation likely yields end-binding protein 1 and human disc large binding protein inactivation, causing cell cycle microtubule dysregulation and tumour suppressor inactivation. Through loss of these regulatory mechanisms, this mutation is associated with AFAP phenotype. The patient was treated surgically and is doing well.

OBJECTIVES/OBJECTIVE:To investigate the diagnostic potential of AEG-1 and GPC-3 in hepatocellular carcinoma (HCC). METHODS:AEG-1 and GPC-3 immunohistochemistry were performed on HCC, adjacent nontumor tissue (ANT), and dysplastic nodules (DN). RESULTS:H score of AEG-1 or GPC-3 in HCC was significantly higher than in ANT or DN. In HCC, 92% and 54% showed AEG-1 and GPC-3 positivity, respectively. In ANT, 16.2% were AEG-1 and 7.6% GPC-3 positive. AEG-1 staining was mostly diffuse, whereas GPC-3 frequently showed focal staining. AEG-1 alone showed high sensitivity but low specificity and accuracy. GPC-3, on the other hand, showed high specificity but low sensitivity and accuracy. Combination of both stains boosted the sensitivity, specificity, and accuracy to 94.6%, 89.5%, and 90.5%, respectively, when only diffuse staining was considered as positive. CONCLUSIONS:AEG-1 or GPC-3 alone seemed not an ideal marker for HCC. The combination of AEG-1 and GPC-3 might improve early diagnosis of HCC.